GENETICA Y SEXOLOGIA INTEGRAL

EPIGENOMA E INTERACTOMA

2012-02-01T11:06:00.000-08:00

Review

Heredity (2010) 105, 105–112;

published online 24 February 2010

Invironmental epigenetics

V Bollati1 and A Baccarelli1,2

1Department of Environmental and Occupational Health, Center of Molecular and Genetic Epidemiology, Università degli Studi di Milano and Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy

2Department of Environmental Health, Exposure, Epidemiology and Risk Program, Harvard School of Public Health, Boston, MA, USA

Correspondence: Dr A Baccarelli, Department of Environmental and Occupational Health, Center of Molecular and Genetic Epidemiology, Università degli Studi di Milano and Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Via San Barnaba 8, 20122 Milan, Italy. E-mail andrea.baccarelli@unimi.it

Abstract

Epigenetics investigates heritable changes in gene expression that occur without changes in DNA sequence. Several epigenetic mechanisms, including DNA methylation and histone modifications, can change genome function under exogenous influence. We review current evidence indicating that epigenetic alterations mediate effects caused by exposure to environmental toxicants. Results obtained from animal models indicate that in utero or early-life environmental exposures produce effects that can be inherited transgenerationally and are accompanied by epigenetic alterations. The search for human equivalents of the epigenetic mechanisms identified in animal models is under way. Recent investigations have identified a number of environmental toxicants that cause altered methylation of human repetitive elements or genes. Some exposures can alter epigenetic states and the same and/or similar epigenetic alterations can be found in patients with the disease of concern. On the basis of current evidence, we propose possible models for the interplay between environmental exposures and the human epigenome. Several investigations have examined the relationship between exposure to environmental chemicals and epigenetics, and have identified toxicants that modify epigenetic states. Whether environmental exposures have transgenerational epigenetic effects in humans remains to be elucidated. In spite of the current limitations, available evidence supports the concept that epigenetics holds substantial potential for furthering our understanding of the molecular mechanisms of environmental toxicants, as well as for predicting health-related risks due to conditions of environmental exposure and individual susceptibility.

Keywords: epigenetics; DNA methylation; histone modifications; environmental exposures; transgenerational effects

Epigenetic mechanisms

Epigenetics is the study of heritable changes in gene expression that occur without changes in DNA sequence (Wolffe and Guschin, 2000). Epigenetic mechanisms are flexible genomic parameters that can change genome function under exogenous influence, and also provide a mechanism that allows for the stable propagation of gene activity states from one generation of cells to the next. There are at least two kinds of epigenetic information that can be inherited with chromosomes. The first is DNA methylation, and the second involves changes in chromatin proteins, usually due to modifications in histone tails.

DNA methylation

DNA methylation is a covalent modification, heritable by somatic cells after cell division. 5-Methyl-cytosine represents 2–5% of all cytosines in mammalian genomes and is found primarily on CpG dinucleotides (Millar et al., 2003; Lister et al., 2009; Rossella et al., 2009).

Cytosine methylation of CpG dinucleotides is found in close proximity to critically important cis elements within promoters and is often associated with a repressed chromatin state and inhibition of transcription (Orphanides and Reinberg, 2002). DNA methylation also has an important role in the maintenance of genome integrity by transcriptional silencing of repetitive DNA sequences and endogenous transposons (Bestor, 1998; Hedges and Deininger, 2007).

Histone modifications

Histones can be modified by acetylation, methylation, phosphorylation, glycosylation, sumoylation and ADP ribosylation (Suganuma and Workman, 2008). The most common modifications are acetylation and methylation of lysine residues in the amino terminal of histone 3 (H3) and histone 4 (H4). Increased acetylation induces transcription activation, whereas decreased acetylation usually induces transcription repression. Methylation of histones is associated with either repression or activation of transcription, depending on the lysine residue position (Yan and Boyd, 2006).

Environmental health and genes: beyond gene–environment interactions

According to the WHO (World Health Organization), more than 13 million deaths annually are due to environmental causes and as much as 24% of disease is caused by exposures that can be averted (Prüss-Üstün and Corvalán, 2006). The list of environmental threats to human health includes a large number of environmental pollutants. For instance, in the third National Report on Human Exposure to Environmental Chemicals by the Center for Disease Control and Prevention, 148 different environmental chemicals that can be detected in the blood and urine were found in a sample of the US population. The list of pollutants evaluated included metals, phytoestrogens, polycyclic aromatic hydrocarbons, dioxin-like chemicals, polychlorinated biphenyls, phthalates and several classes of pesticides (Department of Health and Human Services Centers for Disease Control and Prevention, 2005).

In Figure 1, we propose a categorization of how environmental exposures, with particular interest in environmental toxic chemicals, may interact with genetic and epigenetic mechanisms. In particular, we are interested in contrasting genetic vs epigenetic mechanisms in their possible interplays with environmental exposures.

Gene–environment interactions

The interplay between the environment and human genome has been traditionally presented under the framework of gene–environment interactions (Figure 1, path A; also indicated as genotype–environment or G × E interaction) (Ishibe and Kelsey, 1997; Kraft and Hunter, 2005; Dempfle et al., 2008; Baccarelli, 2009; London and Romieu, 2009). Under this model, diseases result from interactions between the individual genetic make-up and environmental factors. Geneticists have always held true that the expression of a genetic trait in the phenotype is highly variable, largely depending on the environment to which the individual carrying the trait of concern is subjected. For instance, in patients with phenylketonuria, which is caused by mutations to a gene coding the liver enzyme phenylalanine hydroxylase, the amino acid phenylalanine does not get converted into tyrosine and reaches high levels in the blood and other tissues (Scriver, 2007). The elevated phenylalanine levels affect brain development leading to mental retardation. However, a low-phenylalanine diet can keep the blood phenylalanine levels low and avoid the severe effects of phenylketonuria.

The same concept can be approached from the realm of environmental health: some individuals have low risk of developing a disease as a result of an environmental exposure, whereas others are much more susceptible. For example, individuals who carry genetic polymorphisms that make their cells less capable of responding to oxidative stress have been found in several investigations to be more susceptible to the cardiovascular and respiratory effects of air pollution, which produces health effects in humans, at least in part, through oxidative stress generation (Park et al., 2006; Chahine et al., 2007; Baccarelli et al., 2008a).

A purely DNA sequence-based approach (naked DNA snapshot) is not sufficient to fully explain the risks of common diseases, which are modulated by other nongenetic or extragenetic mechanisms. In fact, growing evidence shows that the molecular influences of the environment extend well beyond the interaction with the DNA sequence. Several investigations, as we will discuss in the following sections, have shown that environmental toxicants modify epigenetic states.

Gene–environment vs epigene–environment

In gene–environment interactions (Figure 1, path A), the genetic polymorphisms that modify the effects of environmental exposures are transmitted transgenerationally according to Mendelian genetics, and the trait determining effect modifications is generally assumed to follow the same genetic model (dominant, codominant, recessive) as that of the levels of expression or function of the protein coded by the locus of concern. A second well-established area of interplay (Figure 1, path B) includes the direct effects of environmental exposures on the genome, for example, DNA damage and/or mutations induced by environmental exposures. In environmental health, the recognition that exposures could produce DNA mutations represented a major landmark for risk assessment and prevention. Consequently, genotoxic agents have been categorized according to their capability to alter DNA sequence and thus increase disease risk (Siemiatycki et al., 2004). Such information has been fundamental to determine environmental risks and shape current regulatory efforts for exposure reduction. In particular, potential carcinogenic agents have been carefully tested in in vitro and in vivo models of mutagenicity. In human subjects, some of these molecular events may represent early events along the pathways linking carcinogen exposure to cancer. For example, in our own study on the population exposed after the Seveso, Italy accident to high doses of dioxin (Pesatori et al., 2008; Baccarelli et al., 2008b), a powerful promoting carcinogen in animals, we showed an increased number of t(14;18) translocations detectable in phenotypically normal blood lymphocytes collected from healthy subjects (Baccarelli et al., 2006). This effect may represent an early expansion of lymphocyte clones potentially related to the increased risk of non-Hodgkin's lymphoma among subjects exposed to high doses of dioxin (Steenland et al., 2004). Environmentally induced DNA mutations can have a transgenerational effect only if occurring in the germ line. For instance, parental exposure to ionizing radiation has been shown to increase the frequency of germline mutations detectable in the next generation (Charles, 2001), and confer a predisposition to cancer (Dubrova et al., 2000).

In principle, the effect-modification model should apply to epigene–environment interactions and to gene–environment interactions. Similar to the effect modifications shown or postulated for genetic polymorphisms (Figure 1, path A), epigenetic differences determining disease risk could make individuals less or more vulnerable to environmental insults (Figure 1, path C). However, to the best of our knowledge, a formal concept of epigene–environment interaction has not yet been developed and we are not aware of examples of epigene–environment interactions in environmental health or toxicology studies. In environmental studies, the flexibility of epigenetic states has generated a growing interest in evaluating the direct alterations that environmental exposures may produce on epigenetic states (Figure 1, path D), including changes in DNA methylation and histone modifications. Investigations that evaluated alterations in DNA methylation and histone modifications in response to environmental chemical exposures were reviewed by us in a recent article (Baccarelli and Bollati, 2009). In this review, we will discuss the biological basis for potential interplays with epigenetic states that might be activated in the presence of environmental exposures and determine health-related effects. We will also discuss whether available evidence suggests that epigenetics provides biological mechanisms for transgenerational environmental effects.

Epigenetic reprogramming in mammalian development

In mammals, DNA methylation is essential for embryogenesis, during which methylation patterns change dynamically to adapt embryos to be fit for further differentiation (Reik et al., 2001). Two main waves of genome-wide epigenetic reprogramming characterize mammalian development that occurs at the zygote stage and during primordial germ-cell formation (Shi and Wu, 2009).

The genome becomes demethylated during preimplantation to give rise to a totipotent zygote able to generate any cell type. Active DNA demethylation occurring in the paternal genome shortly after fertilization is independent of DNA replication. In contrast, the maternal genome remains highly methylated and undergoes passive DNA demethylation after embryo development (Mayer et al., 2000; Santos et al., 2002). After the first cell cycle, the maternal allele passively loses methylation through cell divisions up to the blastocyst stage (Shi and Wu, 2009). When implantation occurs, DNA methylation levels are then restored by de novo methylation that triggers cell lineage differentiation (Sassone-Corsi, 2002).

The second reprogramming event also occurs during embryogenesis, but only in the primordial germ cells in which DNA methylation patterns are erased at all single copy genes and some repetitive elements (Lees-Murdock and Walsh, 2008).

Similar to the pattern of asymmetric DNA methylation in parental genomes, histone H3K9 trimethylation and dimethylation exhibit asymmetric modifications in the parental pronuclei (Kurdistani et al., 2004; Santos et al., 2005; Valls et al., 2005; Wang et al., 2007; Yoshida et al., 2007).

The dilemma of epigenetic inheritance: can epigenetic marks survive reprogramming?

The cycles of erasure/reprogramming that occur during embryogenesis raise the question about how and how frequently epigenetic marks are inherited transgenerationally, and whether epigenetic inheritance occurs in humans and in animal models (Whitelaw and Whitelaw, 2008). Animal experiments provide us with a few examples suggesting that epigenetic marks that are established during the life of an organism can be passed on to the following generations (Probst et al., 2009). These include epigenetic states of murine genes associated with distinctive phenotypes, such as the agouti locus in the viable yellow (Avy/a) mice (determining fur color variation between yellow and dark brown), the Axin-fused (Axinfu) allele (associated with a kinked tail) (Morgan et al., 1999; Rakyan and Whitelaw, 2003) and the CabpIAP gene, which was identified using a bioinformatic approach and shows sequence homology to the rat CDK5 activator-binding protein (Druker et al., 2004).

All these models derive their properties from metastable epialleles, which are alleles that are variably expressed because of epigenetic modifications that are established very early during development (Rakyan et al., 2002). In metastable epialleles, the epigenetic state can be altered and the alteration shows transgenerational inheritance. Metastable alleles are most often determined by the presence of a retrotransposable element (or retrotransposon). In particular, the murine metastable epialleles Avy, AxinFu and CabpIAP are all associated with contraoriented insertions of a retrotransposable intracisternal A particle (IAP) sequence, a family of retrovirus-like genetic elements coding for virus-like particles (Duhl et al., 1994; Vasicek et al., 1997; Druker et al., 2004).

Epigenetic inheritance and metastable alleles in animal experiments: the viable yellow agouti Avy mouse

The viable yellow agouti Avy allele is the most extensively studied murine metastable epiallele. In viable yellow (Avy/a) mice, transcription originating in an IAP retrotransposon inserted upstream of the agouti gene (A) causes ectopic expression of agouti protein, resulting in yellow fur, obesity, diabetes and increased susceptibility to tumors (Morgan et al., 1999). Avy mice show variable expressivity because they are epigenetic mosaics for activity of the retrotransposon: isogenic Avy mice have coats that vary in a continuous spectrum from full yellow, through variegated yellow/agouti, to full agouti (pseudoagouti). The distribution of phenotypes among offspring is related to the phenotype of the dam; when an Avy dam has the agouti phenotype, her offspring is more likely to be agouti. It has been shown that the offspring color is not the result of a maternally contributed environment, but rather genuinely inherited, and is associated with transmission of a silenced Avy allele through the female germ line (Morgan et al., 1999).

Is there enough evidence for epigenetic inheritance in humans?

Determining whether equivalents of metastable epialleles exist and are frequent in humans poses substantial challenges. There are just a few reports that have been used to suggest inheritance of epigenetic states in humans. For example, in several cases of familial colorectal cancer, the mismatch repair genes MLH1 and MSH2, which usually exhibit low or no methylation, have been found to be silenced because of promoter methylation, and this has been occasionally detected in successive generations (Suter et al., 2004; Chan et al., 2006; Hitchins et al., 2007). However, these were reports of single families and it is has been argued that the promoter methylation identified, even if detected in multiple family members, could be explained by somatic events that occurred after fertilization (Horsthemke, 2007). Whitelaw and Whitelaw (2008) have recently remarked that, in the light of current evidence, the notion that epigenetic marks can be directly inherited across generations in humans remains contentious.

Environmental influences on epigenetic states during early development in animal models

Modifications to the environment during early development can lead to permanent changes in the pattern of epigenetic modifications (Fauque et al., 2007). Pregnant female rats exposed during time of sex determination to the endocrine disruptor vinclozolin have been shown to exhibit in their male offspring transgenerational disease state leading to spermatogenic defects, prostate disease, kidney disease, immune system abnormalities, hypercholesterolemia and an increased rate of tumor development in the F1–F4 generation offspring (Anway et al., 2005, 2006a, 2006b; Anway and Skinner, 2006; Chang et al., 2006). Both the F1 generation embryo and F2 generation germ line are directly exposed when an F0 generation pregnant mother is exposed. Therefore, only the F3 generation can provide the first unequivocal signs of transgenerational inheritance. The transgenerational disease states in the vinclozolin F1–F4 generation animals were found to be associated with a transgenerational alteration in the epigenetic programming of the male germ line (Anway et al., 2005).

A second example of an epigenetic toxicant is represented by bisphenol A (BPA), a high-production-volume chemical used in the manufacture of polycarbonate plastic. In utero or neonatal exposure to BPA is associated with higher body weight, increased breast and prostate cancer, as well as altered reproductive function. Dolinoy et al. (2007a) showed that maternal BPA exposure shifted the coat color distribution of viable yellow agouti (Avy) mouse offspring toward yellow by decreasing CpG (cytosine-guanine dinucleotide) methylation in the IAP sequence upstream of the Agouti gene (Waterland, 2009). In addition, CpG methylation was also decreased at the CabpIAP metastable locus. DNA methylation at the Avy locus was similar in tissues from the three germ layers, suggesting that BPA affected epigenetic patterning during early stem-cell development. Moreover, maternal dietary supplementation with either methyl donors folic acid or the phytoestrogen genistein blunted the DNA-hypomethylating effect of BPA (Dolinoy et al., 2007a). However, as this investigation was conducted only up to the F2 generation, it did not directly show inheritance of the epigenetic modifications induced by BPA exposure.

Translating environmental epigenetic effects from animal models to humans

Translating results obtained in mouse models to humans is not straightforward. The agouti model cannot be directly applied to humans, and neither is there a human equivalent of kinked tails. One common characteristic of the mouse models described above is that their metastable alleles all include an IAP retrotransposon. IAP sequences are endogenous retrovirus-like mobile elements, present at 1000 copies in the mouse genome. These elements transpose in a replicative manner through an RNA intermediate and its reverse transcription, and their transposition should therefore be tightly controlled by their transcription level (Dupressoir and Heidmann, 1997). In humans, more than one-third of DNA methylation occurs in retrotransposons (Kochanek et al., 1993; Schmid, 1998), which represent a large portion of the human genome (Bernstein et al., 2006). Among these sequences, Alu and LINE-1 retrotransposons are the most plentiful families representing ~30% of the human genome (Kazazian and Goodier, 2002; Grover et al., 2004; Babushok and Kazazian, 2007) and are heavily methylated (Yang et al., 2004). Owing to their high representation throughout the genome, Alu and LINE-1 have been proposed as surrogate markers for estimating the global DNA methylation level (Yang et al., 2004; Weisenberger et al., 2005), but growing evidence indicates that they could have specific and distinct cellular roles (Wallace et al., 2008). Hypomethylation of repetitive elements favors their activity as retrotransposable sequences and has been suggested to have deleterious effects on cells, initially through insertional mutations (Kazazian, 2004), and later by introducing genome instability through deletions and genomic rearrangements (Ostertag and Kazazian, 2001; Gilbert et al., 2002; Wallace et al., 2008).

In healthy populations, inter-individual methylation variations at Alu or LINE-1 elements from blood DNA have also been associated with risk factors for cancer, neurological and cardiovascular diseases (Bollati et al., 2007; Rusiecki et al., 2008; Baccarelli and Bollati, 2009; Baccarelli et al., 2009). In addition, the finding of an age-associated decline in repetitive-element methylation in normal tissues of aging individuals suggests a possible role in various common human age-related diseases (Bollati et al., 2009).

Epigenetics and environmental toxicants in humans

Exposure to air pollution, particularly to particulate matter (PM), has been associated with increased morbidity and mortality from cardiorespiratory disease, as well as with lung cancer risk (Samet et al., 2000; Brook et al., 2004; Peters, 2005; Vineis and Husgafvel-Pursiainen, 2005; Baccarelli et al., 2008c). In a human study, we recently showed that promoter methylation of the iNOS (inducible Nitric Oxide Synthase) gene was lower in blood samples obtained from foundry workers with well-characterized exposure to PM with aerodynamic diameter <10 μm (PM10) (Tarantini et al., 2008). iNOS demethylation is expected to increase the expression and activity of the iNOS protein, which could in turn contribute to inflammation and oxidative stress generation, which are primary mechanisms linking inhalation of air pollutants to their acute health effects (Baccarelli et al., 2007; Chahine et al., 2007; Alexeeff et al., 2008). In the same study, long-term exposure to PM10 was negatively associated with methylation in both Alu and LINE-1 (Tarantini et al., 2008). In a recent investigation, we showed that exposure to black carbon, a marker of particles from vehicular traffic, was also associated with decreased DNA methylation in LINE-1, measured in 1097 blood DNA samples obtained from the NAS (Normative Aging Study), an investigation of elderly men in the Boston area. As repetitive-element hypomethylation is believed to occur in patients with cancer (Ehrlich, 2002) and cardiovascular disease (Castro et al., 2003); such changes may reproduce epigenetic processes related to disease development and represent mechanisms by which particulate air pollution affects human health (Baccarelli et al., 2008c). Several in vitro studies have established an association between DNA methylation and environmental metals, which are components of PM, including nickel, cadmium, lead and particularly arsenic (McVeigh et al., 2001; Bleich et al., 2006; Wright and Baccarelli, 2007; Dolinoy et al., 2007b).

In addition, in an animal study, Yauk et al. (2008) showed that sperm DNA of mice exposed to steel plant air was hypermethylated compared with control animals and this change persisted even after removal from environmental exposure. This finding calls for further research to determine whether air pollutants produce DNA methylation changes that are transmitted transgenerationally.

In our laboratory, we also investigated whether DNA methylation changes are induced by low-benzene exposure in peripheral blood DNA of gasoline station attendants and traffic police officers. High-level exposure to benzene has been associated with increased risk of acute myelogenous leukemia (Snyder, 2002). In our study, airborne benzene exposure was associated with a significant reduction in LINE-1 and Alu methylation. Airborne benzene was also associated with hypermethylation in p15 and hypomethylation of the MAGE-1 cancer-antigen gene (Bollati et al., 2007). These findings show that low-level benzene exposure may induce altered DNA methylation reproducing the aberrant epigenetic patterns found in malignant cells, which in most reports have been found to exhibit repetitive-element hypomethylation as well as either hypermethylation or hypomethylation of specific genes, depending on the gene function. In addition, benzene-associated demethylation of repetitive elements may help explain the epidemiological data linking benzene exposure to increased risk of multiple myeloma (Costantini et al., 2008; Kirkeleit et al., 2008), which also exhibits reduced methylation in Alu and LINE-1 repetitive elements (Bollati et al., 2007).

Other exposures that are associated with increased risk of hematopoietic malignancies, such as persistent organic pollutants, have been associated with changes in repetitive-element DNA methylation. Rusiecki et al. (2008) evaluated the relationship between plasma persistent organic pollutant concentrations and blood global DNA methylation, estimated in Alu repeated elements, and in 70 Greenlandic Inuit, a population presenting some of the highest reported levels of persistent organic pollutants worldwide. In this study, a significant inverse linear relationship was found for DDT, DDE, β-BHC, oxychlordane, α-chlordane, mirex, several PCBs and the sum of all persistent organic pollutants (Rusiecki et al., 2008). As most of the exposures investigated increase oxidative stress in human tissues, it is possible that the production of reactive oxygen species represents a unifying process to account for most of these findings across different chemicals (Wright and Baccarelli, 2007; Baccarelli and Bollati, 2009). Oxidative DNA damage can interfere with the ability of methyltransferases to interact with DNA (Valinluck et al., 2004), thus resulting in a generalized altered methylation of cytosine residues at CpG sites (Turker and Bestor, 1997).

Final remarks

In the last few years, several investigations have examined the relationship between exposure to environmental chemicals and epigenetics, and identified several toxicants that modify epigenetic marks. Most of the studies conducted so far have been focused on DNA methylation, whereas only a few recent investigations have studied the effects of environmental chemicals on histone modifications (Baccarelli and Bollati, 2009). In animal models, environmental effects that might involve epigenetic mechanisms have been shown to be transmitted transgenerationally. Whether the transgenerational epigenetic effects of environmental exposures are present in humans, or whether epigenetic inheritance exists at all in humans, remains to be elucidated.

Nonetheless, growing evidence indicates that epigenetics holds substantial potential for developing biological markers to predict which exposures would put exposed subjects at risk and which individuals will be more susceptible to develop disease. In human studies, this will require the use of laboratory methods with enhanced precision, sensitivity and coverage, so that epigenetic changes can be detected as early as possible and well ahead of disease diagnosis. For several exposures, it has been proven that chemicals can alter epigenetic marks and that the same or similar epigenetic alterations can be found in patients with the disease of concern and/or in diseased tissues. Future prospective investigations are required to determine whether exposed subjects develop epigenetic alterations over time and, in turn, whether such alterations increase the risk of disease.

REFERENCES

1.Alexeeff SE, Litonjua AA, Wright RO, Baccarelli A, Suh H, Sparrow D et al. (2008). Ozone exposure, antioxidant genes, and lung function in an elderly cohort: VA normative aging study. Occup Environ Med 65: 736–742.

2.Anway MD, Cupp AS, Uzumcu M, Skinner MK (2005). Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308: 1466–1469.

3.Anway MD, Leathers C, Skinner MK (2006a). Endocrine disruptor vinclozolin induced epigenetic transgenerational adult-onset disease. Endocrinology 147: 5515–5523.

4.Anway MD, Memon MA, Uzumcu M, Skinner MK (2006b). Transgenerational effect of the endocrine disruptor vinclozolin on male spermatogenesis. J Androl 27: 868–879.

5.Anway MD, Skinner MK (2006). Epigenetic transgenerational actions of endocrine disruptors. Endocrinology 147(6 Suppl): S43–S49.

6.Babushok DV, Kazazian Jr HH (2007). Progress in understanding the biology of the human mutagen LINE-1. Hum Mutat 28: 527–539.

7.Baccarelli A (2009). Breathe deeply into your genes!—Genetic variants and air pollution effects (Editorial). Am J Respir Crit Care Med 179: 431–432.

LA EXPERIENCIA TRANSEXUAL

2012-02-01T09:22:00.000-08:00

A Piece of My Mind

JAMA. 2012;307(4):371-372.

Of What Am I Afraid?Anne Dohrenwend, PhD, ABPP

Author Affiliation: Department of Internal Medicine Residency Program, McLaren Regional Medical Center, Flint, Michigan (anned@mclaren.org).

KEYWORDS: BRCA1 GENES, BRCA2 GENES, BREAST NEOPLASMS, CHEMOTHERAPY, ADJUVANT, DISEASE PROGRESSION, DRUG THERAPY, GENETIC PREDISPOSITION TO DISEASE, METHYLATION, DNA, MUTATION, OUTCOME ASSESSMENT (HEALTH CARE), OVARIAN NEOPLASMS, PHENOTYPE, SURVIVAL, WOMEN'S HEALTH.

When a physician has a question about a transgender patient, he or she often looks to me. They seek me out, not only because I teach behavioral medicine, but because I belong to the clan, GLBT.1 They expect me, as part of that family, to understand the transgender experience. Certainly, gay, lesbian, bisexual, and transgender individuals are united, in many ways, by the bond of shared oppression. As a bisexual woman married to a woman, I know what it's like to be different, to be misunderstood, to shoulder the burden of legal inequities, but there is much about the transgender life that I don't understand.

Transgender individuals experience an enduring conflict between internalized gender and biological sex. Cross-dressing can serve as both a statement of gender identity and an attempt to correct for this biological error. Sometimes, medical and surgical interventions are pursued—hormone treatment and gender reassignment. Health risks are associated with these interventions, but then again, being transgender is a health risk in and of itself. As many as half of all transgender people report being physically assaulted because of their gender identity,2 and as many as one-third attempt suicide at some point in their lives.

transgender individuals could use more advocates in the medical community. You might assume, because I am gay, that I have done my share to train residents in the optimal care of transgender patients, but that would be an incorrect assumption. In fact, I know little about the health care needs of transgender people. While I have been an eager advocate for the rights of gays, lesbians, and bisexuals, I’ve been pitifully silent on transgender rights. When I write about GLBT health, I all but leave the transgender population out, usually with a caveat that their different needs require a different forum. Why does my solidarity with GLBTs crumble at the “T”? The answer (the one we’d all like to avoid) is transference.

Strictly speaking, transference is the projection, or transfer, of feelings about a parent (or parental figure) onto someone else, but people often use the term transference more loosely to describe projections from any source, not just those with parental origins. Gestalt therapists have a word for this broader understanding of transference. “Unfinished business” occurs when unmet needs or conflicts from a past context reassert themselves in the present context. Unfinished business is identified by its irrationality—it causes misinterpretations, overreactions, and underreactions. Unfinished business is stubborn stuff. It will continue to reassert itself into thoughts, feelings, and actions until the business is attended to and brought to a close. This is accomplished by identifying distorted thoughts and feelings and following them back to their origins.

Most physicians are familiar with countertransference—when the patient's transference provokes an emotional reaction in the clinician. Awareness of countertransference is critical in order to avoid unhelpful emotional entanglements with patients, but it is equally critical that physicians take stock of their own transference reactions. Problem dynamics between physician and patient don't always start with the patient.

About a year ago, I wrote a letter in support of a transgender patient's breast reduction. Doing so was not easy for me. Why? Women get breast augmentations to boost their femininity, and they don't need a letter from a psychologist to have it done. Why then should a person need a letter to have a breast reduction for the opposite effect, and why should I feel conflicted about providing that letter? At the time, I tried to make sense of my emotions by writing and got nowhere. I typed a few sentences, deleted them, and then left the empty document on my desktop with the name “F to M.”3 Ever since then, that file has been staring out at me, daring me to think. What is this really about? What am I feeling, and from where does that feeling(s) originate?

First thoughts: I am afraid that I don't know what it's like to be transgender because I cannot imagine feeling cut off from my body. No, worse than that—to feel disgusted with certain aspects of my body. I like the skin I inhabit. I look in the mirror and what I see fits. When I don't like what I see, it is because I’ve done my body wrong—I should’ve eaten better, slept more, exercised. I have never felt as if I was sentenced to life in a cage; my soul moves freely in its home. Nor do I feel that being female puts me at odds with myself as a sexual being. I’ve never yearned for different sexual hardware or felt unable to express myself, sexually, due to a lack of it. In essence, my body serves as an extension of me. It is the soluble membrane through which my spirit mingles with the world. Not so for the transgender individual. His body is a prison. Her body is a barrier to authenticity, a wall that separates self from the world.

All that may be true, but it does not explain my hesitancy to treat transgender patients. I don't know what it's like to struggle for every breath or to fight a lethal enemy, but I don't hesitate to treat patients with COPD or cancer.

Of what am I afraid?

I am afraid, very afraid, of glibly supporting gender reassignment in someone who will one day regret the choice. What if—after all the hormones, the operations, the painful disclosures, the losses due to estrangement and oppression—my patient decides that gender change was not the answer or that the gain was not worth the cost? Gender change is a massive decision. I can think of few decisions that have more at stake for which patients seek assistance. Marriage, divorce, coming out—none of these things are as life altering as gender change. No wonder I feel so insecure, so afraid, of proving an inadequate guide.

There is more. I am tired of people confusing sexual orientation with gender identity. Sexual orientation is about the gender to whom one is attracted—men, women, or both. Gender identity has nothing to do with attraction. It's the internal voice that speaks in male or female. Some conceive of gender as neither male nor female but instead as a range of gender-based sensations. A person may feel very female in some circumstances but retain a reservoir of maleness for other situations. Gender is confusing because culture confounds attempts to define it. What is it to be feminine or to be masculine? In one culture, clothing may define what is feminine and, in another, the ability to hunt. I’ve never thought of myself as particularly feminine, and yet I have always felt very female.

So why do I care if people confuse gender identity with sexual orientation? Maybe because this collapsing of sexual orientation with gender identity leads to stereotypes that feel limiting to me, eg, the “bull dyke” and the “lipstick lesbian.” I don't like being put in a box, especially when that box is made to fit someone else. The tendency to think of gays and lesbians as assuming either a masculine or feminine role is derivative of heterosexual intercourse. It reflects an inability to imagine same-sex relations without imposing a heterosexual framework. There has to be a nut and a bolt, a top and a bottom—a man and a woman.

That's not all. I am afraid that affiliation with the transgender community may discourage social support for GLB rights. (Now I’m getting somewhere.) The GLB community has come so far. We have, in many states, won equality in hiring, hospital visitation, and adoption. In a handful of states, we have won the right to marry. Polls show a solid movement in the direction of tolerance toward same-sex unions. Not so for the transgender community. They suffer more discrimination, more assaults, more unfair treatment than any other minority community in the United States. Transgender people not only battle with an internal conflict more painful than any I can imagine, but have to fight every day for a modicum of social acceptance that will allow them to make a survival wage. My fear of being associated with transgender patients, at the bottom of it all, is really a terror of losing ground gained in the fight for equality. I’m afraid to be associated with them because I never want to be treated like them.

There you have it. I am ashamed of this fear, which makes it perfect detritus for transference. Will knowing this about myself make a difference? Will I be the teacher and psychologist I hope to be when someone asks me about transgender patients? I suspect that my anger, fear, sadness, about the oppression of gays will always be a source of transference in need of checking on any number of subjects, but, as of this writing, I commit to adding transgender patients to my lecture list. I commit to facing my fears. Transgender patients deserve my attention. They deserve the attention of the medical community.

Health care professionals (whether physician, psychiatrist, or psychologist) are constantly confronted with a tremendous array of emotional triggers. Some of those triggers reside in the patient's personality, some in their disease, and others in their social, ethnic, or economic composition. In order to provide the best possible care, we need to be aware of what sets off our transference and be ready to do whatever is required to free ourselves of it. I don't know if you feel it, that stuckness with regard to transgender patients. Given the lack of scholarly attention paid to this population, I suspect I’m not the only one out there with unclaimed baggage on the subject. Then again, that may be my transference, poking up its head, attempting to minimize my slipup or normalize my irrationality. Transference, once detected, often requires ongoing supervision.

The exploration of transference is, I believe, quintessential to ethical and professional practice. If we don't remove our junk from the patient-physician relationship, we are bound to provide subpar treatment. If the transference is of a particularly toxic nature, we run the risk of doing significant harm. No one is immune to transference. It is as natural as silt collecting around a drain. The stuff, our stuff, has to settle somewhere, and so I leave you with a challenge. What do you avoid? Who do you resist?

Of what are you afraid?

Next SectionAuthor InformationAuthor Affiliation:

Department of Internal Medicine Residency Program, McLaren Regional Medical Center, Flint, Michigan (anned@mclaren.org).

Haas AP, Eliason M, Mays VM, et al. Suicide and suicide risk in lesbian, gay, bisexual, and transgender populations: review and recommendations. J Homosex. 2011;58(1):10-51.

Kitts RL. Barriers to optimal care between physicians and lesbian, gay, bisexual, transgender, and questioning adolescent patients. J Homosex. 2010;57(6): 730-747.

Obedin-Maliver J, Goldsmith ES, Stewart L, et al. Lesbian, gay, bisexual, and transgender–related content in undergraduate medical education. JAMA. 2011;306(9):971-977.

References

1.GLBT. sometimes written LGBT, is an initialism for gay, lesbian, bisexual, and transgender. The frequent conflating of these populations communicates the sense of comradeship felt by many sexual minorities.

2.In 2009, the Matthew Shepard and James Byrd, Jr. Hate Crimes Prevention Act was signed into law. This federal legislation defines bias-motivated violence toward certain populations, including transgender individuals, as hate crimes, and thus subject to harsher penalties than similar crimes that are not bias motivated. Most state hate crime legislation still does not include the transgender population as a targeted group; this raises the question as to whether hate crimes against transgender citizens will be rigorously enforced at the state level.

3.F to M is a commonly used abbreviation for female to male.

CELULAS TRONCALES EN NEUROPATIAS

2012-01-30T10:27:00.000-08:00

Review

Gene Therapy (2011) 18, 1–6;

published online 30 September 2010

Progress and prospects: stem cells and neurological diseases

S Gögel1, M Gubernator1 and S L Minger1

1Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London, UK

Correspondence: Dr S Gögel, Current address: Medical and Molecular Genetics, King’s College London, 8th Floor Tower Wing, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK. E-mail: stefanie.gogel@kcl.ac.uk

Abstract

The central nervous system has limited capacity of regenerating lost tissue in slowly progressive, degenerative neurological conditions such as Parkinson's disease (PD), Alzheimer's disease or Huntington's disease (HD), or in acute injuries resulting in rapid cell loss for example, in cerebrovascular damage (for example, stroke) or spinal cord injury. Although the adult brain contains small numbers of stem cells in restricted areas, they do not contribute significantly to functional recovery. Transplantation of stem cells or stem cell-derived progenitors has long been seen as a therapeutic solution to repair the damaged brain. With the advent of the induced pluripotent stem cells technique a new and potentially better source for transplantable cells may be available in future. This review aims to highlight current strategies to replace lost cellular populations in neurodegenerative diseases with the focus on HD and PD and traumatic brain injuries such as stroke, discussing many of the technical and biological issues associated with central nervous system cell transplantation.

Keywords: cell replacement therapy; stem cells; Parkinson's disease; ischaemic stroke; Huntington's disease

In brief

Progress

•Different cell types might be useful in transplantation studies for different neurodegenerative diseases.

•Transplantation studies in neurodegenerative diseases provide data on safety and feasibility of this procedure.

•Cell transplantation provides an improvement of symptoms for a limited period of time for Huntington's disease patients.

•Enhancement of endogenous repair mechanisms are being targeted for further amelioration of symptoms in stroke patients.

•Early clinical trials for cell transplantation with different cell types in ischaemic stroke show no adverse effects in the patients and the functional outcome is highly variable.

•Cell transplantation in Parkinson's disease is feasible and leads to amelioration of motor functions with room for further improvement.

•Improvement of differentiation protocols for human embryonic stem cells (hESCs) into transplantable dopaminergic progenitors is one focus of recent research.

Prospects

•The necessity for cell replacement therapy is stimulated by the rising incidence of degenerative diseases based on demographic changes in an ageing society.

•Different neurodegenerative diseases might require different cell sources that have yet to be determined. In addition, the optimal time point of implantation relative to disease onset will have to be a focus of future research.

•Improvement of differentiation protocols will lead to more pure populations of transplantable cells derived from either hESCs or even induced pluripotent stem cells.

•Logistical, ethical, societal and economical hurdles have to be overcome in order to make cell replacement therapy available for the broad public.

Different cell types might be useful in transplantation studies for different neurodegenerative diseases

Cell replacement therapy could in the future aid in alleviating symptoms or even reversing disease progression of neurological disorders where pharmacological interventions and other treatment modalities are no longer sufficient or are not available. Over the last decade, convincing evidence has emerged of the capability of various stem cell populations to induce regeneration in animal models of Parkinson's disease (PD), Huntington's disease and Alzheimer's disease (AD) along with multiple sclerosis and cerebral ischaemia.

Cell populations derived from embryonic stem cells (ESCs) have tremendous potential to fulfil the requirements to be a cell source for neural cell replacement therapy.1, 2 ESCs are highly expandable pluripotent cells capable of differentiating into all cell types of the human body, including nervous system tissues. They are derived from the inner cell mass of preimplantation blastocysts to yield a homogenous, self-renewing cell population. As the transplantation of undifferentiated human ESCs (hESCs) is associated with high risk of unwanted proliferation leading to cancerous structures, it is no longer seen as a potential therapeutic approach. Rather the directed differentiation of hESCs into specific neural progenitor subtypes is therefore required. Other potential cell sources for central nervous system (CNS) transplantation include foetal or adult neural stem cells (NSCs), mesenchymal stem cells (MSCs) or bone marrow-derived cell populations amongst others. MSCs for example, are easy to obtain and their use is not incriminated with contentious ethical issues.

NSCs can be expanded over a long period of time and as they are already neuralized (for example, committed to a CNS cell fate) there is no need for recapitulating early developmental signals that lead to neuroectodermal commitment. However, the transplantation of foetal NSCs into the adult brain is accompanied by numerous ethical, scientific and legislative hurdles.3, 4 In addition, the prolonged culturing of NSCs leads to an ever increasing glial differentiation pattern at the expense of neuronal differentiation, which significantly reduces the therapeutic potential of foetal NSCs.5 MSCs may prove to be superior to NSCs as they can be derived from a variety of adult tissues such as bone marrow and cord blood, as well as foetal liver and lung and the developing tooth bud. Bone marrow MSCs are, to date, the most commonly used stem cell source with regard to the treatment of haematopoietic diseases and thus their isolation and application is well established. As these cells seem to be able to pass the blood–brain barrier, no invasive intracerebral surgery is required and instead peripheral systemic application can be envisaged. However, the extent to which MSCs can be directed to a neural cellular fate either ex vivo or in vivo following implantation remains a point of contention among researchers.

Recently, a new cell type has emerged in the stem cell field that might be useful in cell transplantation. Takahashi and Yamanaka,6 succeeded in reprogramming mouse fibroblast cells into cells that are highly similar to ESCs, commonly referred to as ‘induced pluripotent stem cells’. Only one year later, this new technique that reverses developmental processes of cells was applied to human somatic cells.7, 8 This exciting technique allows the derivation of induced pluripotent stem cells from patient's own skin and their subsequent differentiation into cell types lost by neurodegenerative diseases or sporadic injury. Ultimately it is envisaged that these tailor-made patient stem cells are used for cellular transplantation in a variety of degenerative processes in the ageing human body. All the different cell types discussed here might be useful in transplantation studies for the different neurological diseases (see Figure 1).

Figure 1.

Schematic drawing illustrating the different cell types and their origin that can be used in cell therapy in brain diseases. Human embryonic stem cell lines are derived from the inner cell mass of the blastocyst; foetal brain cells can be obtained from aborted foetuses; induced pluripotent stem cells are derived by reprogramming of differentiated cells such as human fibroblasts; mesenchymal stem cells are harvested from cord blood or bone marrow. These different cell types can be differentiated into neuronal precursors that are transplanted into the diseased brain.

Transplantation studies in neurodegenerative diseases provide data on safety and feasibility of this procedure

For cell replacement therapies to move towards clinical application, lasting functional and clinical improvement and absence of deleterious side effects in experimental animal models need to be established. Proof-of-principle studies are necessary to show posttransplant cellular survival, host brain integration, synaptic innervation of target brain regions and correct morphological differentiation in vivo functionally to replace cells lost as a result of the underlying lesion. Differentiation protocols, which will yield a highly efficient cell fate commitment to produce high quality transplantable cells, are required. Behavioural and underlying functional improvement should clearly be demonstrated. The understanding of functional recovery on a cellular level is crucial to optimise circuit reconstruction and progenitor cell guidance. Lastly, the clinical stratification of patients needs to be implemented as variable clinical efficacy of cell therapy in early versus late disease progression is assumed. As the pathologies of the CNS are characterized by different underlying mechanisms, it is therefore likely that specific stem cells and derivates need to be transplanted for each condition in order to affect disease-specific repair processes. This review focuses on transplantation studies for neurodegenerative diseases such as PD, HD and stroke, which have, to date, provided data on safety and feasibility of the procedure.

Cell transplantation provides an improvement of symptoms for a limited period of time for HD patients

HD is an autosomal dominant genetic disorder caused by a mutation in the huntingtin locus resulting in a progressive degeneration of predominantly medium-spiny GABAergic neurons in the striatum (see Figure 2). Later in the disease progression more widespread neuronal degeneration can be observed, such as in the neocortex and hippocampus. Patients subsequently develop severe movement and cognitive problems. Currently there are no disease-modifying treatments available and death occurs 10–20 years after disease onset.

Figure 2.

Schematic coronal section of the human brain illustrating the different areas that are affected in diseases such as PD, HD or stroke and in which different cell replacement therapies should be directed. HD affects initially the GABAergic neurons in the striatum, but during the course of the disease extends to other brain areas. PD is caused by the degeneration of dopaminergic neurons in the caudate nucleus and putamen of the neostriatum. Neuronal and glial degeneration following cerebrovascular damage (stroke) can occur in any area of the brain.

As the early form of HD is characterized by the relatively specific loss of one particular cell type, the medium spiny neurons, Huntington's would seem to represent a good example of a ‘simple’ cell-replacement strategy to replace lost tissue with transplantation of specific replacement cell types thus, hopefully inducing successful long-lasting recovery of the lost striato-cortical circuitry. Indeed, in animal models of HD, transplantation of non-human foetal striatal tissue has provided proof-of-principle that such transplants elicit anatomical and behavioural improvements.9

Since 1990, several clinical trials have been conducted using transplanted foetal neural tissue into the striatum of patients with HD.9 The number of patients that have received foetal transplants is rather small and the efficacy of the procedure measured in terms of clinical improvement of the patients is variable (see Table 1). In one pilot study, initiated in Créteil, France, by Marc Peschanski and Anne-Catherine Bachoud-Lévi, three out of five patients showed a plateau of motor and cognitive improvements already 2 years after transplantation of foetal neural grafts into the left and right striatum, which faded over the following four years for motor disabilities, whereas cognitive function remained stable. In a phase II trial following this pilot study, the researchers successfully involved additional immunosuppressive therapy as antibodies against foetal donor antigens were detected in patient's blood samples.10

Similar results have been obtained in a separate study initiated by Kopyov and colleagues in Los Angeles. Post-mortem examination, 6 years after transplantation, of foetal lateral ganglionic eminence from 5–8 donors into bilateral caudate nucleus and putamen in two patients showed viability of grafts. However, they exhibited limited graft–host connectivity and did not induce clinical improvement.11 In one patient the graft led to cyst formation and overgrowth 10 years posttransplantation and the patient died because of advanced HD.12

In an exceptional case, Reuter et al.13 reported improvement in motor function and striatal PET scans over a period of 5 years in one of two patients who received bilateral foetal striatal tissue, and Capetian et al.14 reported in a post-mortem analysis of a single patient 6 months after transplantation, differentiation and integration of the transplanted tissue into the host tissue without improvement of movement or psychiatric symptoms.

The most recent study that analysed the brains of three patients who received a graft a decade before their death suggests that although the grafted cells differentiate and integrate into the host tissue, they degenerate even more rapidly than the patient's own tissue.15 Cellular implants given to patients who were at a more advanced stage of disease with significant atrophy of relevant brain tissues might be the reason for their high incidence of surgical side effects such as haematomas and the poor survival of the grafts implanted into the heavily atrophied caudate. Transplantation therefore seems to provide an improvement of symptoms for a limited period of time, but does not represent a significant disease-modifying strategy for HD. The fact that striatal grafts without abnormal gene expression degenerate over time suggests that the local environment including microglial activation against the graft and excitotoxic glutamatergic inputs from the cortex is not supportive for long-term graft survival. These latest results can be interpreted as a huge drawback to clinical application of cell transplantation for HD, particularly as early results were promising.

Enhancement of endogenous repair mechanisms are being targeted for further amelioration of symptoms in stroke patients

Neuronal and glial degeneration can occur following cerebrovascular damage resulting from the blockage of blood flow in selected brain areas, resulting in motor, sensory and cognitive disturbances. Over time, atrophy leads to further long-term damage and therapeutic approaches are currently limited to thrombolytic treatment, which has a narrow time window and cannot be applied to all patients. Despite the predominantly focal nature of ischaemia, many different cell types can be affected, which in theory makes this neurological disorder not an ideal candidate for cell replacement therapy. However, it is hypothesized that the reconstruction of only a small fraction of lost circuitry could be sufficient in promoting functional improvement for patients.

It has been shown that stroke-induced stimulation of neurogenesis and migration of neural stem or progenitor cells into regions of ischaemic damage occurs in humans, but the extent to which neurogenesis is able to replace lost neurons or contributes to functional improvement in stroke patients is still unclear.16, 17 If neurogenic neuronal cell replacement is compromised because of the local ischaemic environment, these cells could be supported by intracerebral infusion of cytokines or transplantation of cells overexpressing neurotrophic factors such as brain-derived neurotrophic factor, nerve growth factor, vascular endothelial growth factor and glial cell-derived neurotrophic factor.18, 19

Early clinical trials for cell transplantation with different cell types in ischaemic stroke show no adverse effects in the patients and the functional outcome is highly variable

The idea of recovering lost function by replacing damaged tissue with transplants in stroke patients remains relatively unexplored. Very few data are available and early clinical trials have provided data on the safety and feasibility of cell transplantation. Only a small number of patients have been transplanted. For example, neural progenitors from a human immortalized teratocarcinoma cell line (NT2/N) were transplanted into 12 patients from 6 months to 4.5 years after basal ganglia strokes. No adverse events were observed up to 5 years after transplantation and patients displayed some improvement as based on the European Stroke Scale. In a randomized phase II follow-up trial, a total of 18 patients received either 5 or 10 million human neuronal cells 1–6 years after stroke. Again no cell-related adverse effects were observed, but side effects of the transplantation procedure including a seizure and a subdural haematoma were noted in two patients. In all, 6 out of 14 patients showed an improvement in European Stroke Scale scores at 6 months, but there was no improvement in European Stroke Scale motor scores; however, the everyday memory test score improved significantly. In a separate study, Savitz et al.20 transplanted porcine cells pretreated with anti-MHC1 antibody to avoid immune reaction into 5 patients 1.5–10 years after experiencing basal ganglia stroke. Two patients showed worsening of motor deficits or developed seizures briefly after transplantation. This study was, therefore, terminated by the Food and Drug Administration.

Bang et al.21 transplanted autologous MSCs from bone marrow (5 patients) in a phase I/II clinical trial including 30 patients with cerebral infarcts within the middle cerebral arterial territory. No adverse cell-related effects were observed, and a 1-year follow-up assessment showed no significant improvement in function.

Altogether these human trials imply that stem cell therapy in ischaemic brain is feasible, the limited clinical trial data obtained thus, far provide little consistent evidence of clinical benefit.22, 23, 24 Further research to determine the optimal cell population and method of administration is needed to improve the outcome of cell therapy for stroke. In addition, the optimal time point of post-ischaemic transplantation has yet to be determined, as activated microglia might limit survival of transplanted cells.

Basic research on the common animal models, mouse and rat, will help further understand the mechanisms underlying the beneficial effects of stem-cell therapy. For example, the systematic administration of bone marrow mononuclear cells in mice after cortical infarction increased cell proliferation of endothelial cells and neural progenitor cells (NPCs) within the infarct region.25 Nakagomi et al.26 could show that co-transplantation of endothelial cells and NPCs increased survival of ischaemia-induced NPCs even more than transplantation of NPCs alone. It is speculated that endothelial precursor cells increase angiogenesis and consequently promote neurovascular repair.27 A possible role for glial cell-derived neurotrophic factor in cell survival has been demonstrated by administration of this cytokine after middle cerebral artery occlusion in rats and by genetically modifying NPCs with glial cell-derived neurotrophic factor before transplantation in rats after middle cerebral artery occlusion.28, 29 These results suggest that trophic factor mechanism rather than cell replacement per se, contribute predominantly to the behavioural improvement in animal models. Therefore, the combination of stimulating endogenous neurogenesis with cytokines and stem cell technology will likely have a huge impact in the future treatment of stroke patients.

Cell transplantation in PD is feasible and leads to amelioration of motor functions with room for further improvement

Foetal tissue transplantation for PD has spearheaded cell replacement therapy for neurodegenerative diseases. PD is mainly caused by the degeneration of mesencephalic substantia nigral dopaminergic (DA) neurons and a progressive loss of DA neurotransmission in the caudate and putamen of the neostriatum (see Figure 2). Patients experience motor dysfunction such as tremor, rigidity and bradykinesia, as well as disturbances in sleep and cognition. To date, L-DOPA and other dopamine agonists provide motor symptoms relief but are only effective early in the course of the disease. Deep brain stimulation is an additional therapeutic option for PD patients. Given the relatively specific loss of a single neuronal cell type, researchers hypothesized that cellular replacement of DA neurons might be feasible. Beginning in the 1970s, transplantation of post-mitotic foetal ventral mesencephalic cell suspension demonstrated significant behavioural improvement when transplanted into animal models of PD with clinical translation of these procedures into human patients in the mid-1980s.

In total, 300–400 patients worldwide have now been treated with foetal cell transplantation.30 Open-label trials showed functional benefit for motor symptoms; however, the double-blind trials failed to show significant benefit compared with placebo.31 Overall, highly variable clinical results and in some cases the development of dyskinesias, low graft survival together with the large number of early human embryos required for optimal clinical benefits (1–8 per putamen) suggest that alternative and more reliable cell sources are required.32 Recently, strict patient selection and surgical parameters, such as implantation sites, number of needle tracks and cellular deposits have also been highlighted as factors that impact on maximum therapeutic benefit.33

Isolation of tissue from the developing brain to produce expandable populations of NSCs was the logical progression from clinical studies. Several groups developed protocols for the derivation of multipotent NSCs from the developing mesencephalon.34 Although human NSCs are highly expandable ex vivo and protocols improved to enrich DA neuron progenitor, the number of DA neurons produced is at most 15% of the total cellular population.35, 36 Thus, this approach appears to be non favourable for the development of PD therapies, instead future therapies might aim towards the use of embryonic stem cell or even induced pluripotent stem cell-derived dopamine neurons.

Improvement of differentiation protocols for hESCs into transplantable DA progenitors is one focus of recent research

The current major strategy now for CNS transplantation for PD is the generation of transplantable DA progenitor cells from ESCs. Key to success of using ES cells in PD cell replacement therapy is the efficient and stable generation of midbrain A9 DA neurons. A large variety of differentiation protocols have been reported using exposure to soluble growth and neurotrophic factors to drive DA neuronal differentiation.

Roy et al.37 demonstrated that formation of embryoid bodies from hESCs followed by exposure to sonic hedgehog and fibroblast growth factor-8 enhanced the generation of mesencephalic neurons (up to 67% of neurons were TH+) and such cells were able significantly to reverse lesion-induced behavioural deficits in a rodent model of PD. However, the transplants also contained large numbers of residual mitotically active neuroepithelial cells that continued to proliferate following implantation. Alternatively, a number of groups have shown that co-culture of hESCs with a second cellular ‘feeder’ layer can improve lineage specification towards a mesencephalic cell fate. The co-culture of ES cells with the DA-inducing PA6 mouse stromal cell line promoted the differentiation of mouse, primate and human ES cells into functional DA neurons.38 PD-lesioned animals transplanted with PA6-cultured cells displayed significant behavioural recovery, although transplantation still led to teratoma formation in some of the grafted animals.39 A further strategy for the generation of A9 DA neurons involves the gene transfer and overexpression of genetic determinants important for early midbrain development. ESCs transfected with cDNAs encoding transcription factors, important in early mesencephalic lineage specification, have shown enhanced DA differentiation. The proportion of cells differentiating into DA neurons has been shown to increase significantly (50–65% of all neurons are TH+) following transduction with either Lmx1a or Nurr1+Pitx3.40, 41 When these cells were transplanted into the striatum of PD-lesioned mice, significant recovery of drug-induced rotational behaviour was visible 6 weeks following implantation. Collectively these findings suggest that it is possible to generate large number of DA neurons from ES cells, but the presence of contaminating non-DA cells and continued proliferation of transplanted cells suggests that further refinement of these differentiation protocols is required before these cells could be used in a clinical setting. Further research is also required to explore the potential safety risks of genetic manipulation of stem cells for clinical application.

Conclusions

Proof-of-principle studies in experimental animals have shown that the cell replacement of degenerated neural tissue using stem cells of various sources is feasible and can lead to improvement of lost function. In humans, the early transplantation trials show a huge variety of outcomes ranging from significant clinical benefit to worsening of symptoms with severe side effects. As the pathophysiology differs in PD, HD and stroke, different cell sources for transplantation might be required for optimal clinical improvement. Continued basic research is therefore necessary before cell replacement therapy can become a realistic clinical strategy.

Prospects

The use of stem cells in the therapeutic field and in drug development has been of considerable interest in contemporary bioscience. In recent years our knowledge and understanding of stem cell biology and regenerative medicine has increased substantially. ESCs not only continuously divide, they are also able to differentiate into approximately 220 different cell types of the human body. The isolation of tissue stem cells could offer a less ethically contentious and more practical source of replacement tissue for organs that are susceptible to age-related diseases or traumatic injury. These diseases include Alzheimer's and Parkinson's disease, but also stroke, myocardial infarction and diabetes to mention a few. They have become a serious health problem in our societies as people now live longer. A large part of stem cell research aims to identify the ideal cell type and time point of cell transplantation. Future research will also lead to improved protocols that generate more pure populations of transplantable cells. With the continuous progress in stem cell research, modern clinical medicine is at the threshold of transformation.

References

1.Zietlow R, Lane EL, Dunnett SB, Rosser AE. Human stem cells for CNS repair. Cell Tissue Res 2008; 331: 301–322.

2.Kim SU, de Vellis J. Stem Cell-Based Cell Therapy in Neurological Diseases: A Review. J Neurosci Res 2009; 87: 2183–2200.

3.Lovell-Badge R. The regulation of human embryo and stem-cell research in the United Kingdom. Nat Rev Mol Cell Biol 2008; 9: 998–1003.

4.Mathews DJ, Sugarman J, Bok H, Blass DM, Coyle JT, Duggan P et al. Cell-based interventions for neurologic conditions: ethical challenges for early human trials. Neurology 2008; 71: 288–293.

5.Anderson L, Burnstein RM, He X, Luce R, Furlong R, Foltynie T et al. Gene expression changes in long term expanded human neural progenitor cells passaged by chopping lead to loss of neurogenic potential in vivo. Exp Neurol 2007; 204: 512–524.

6.Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126: 663–676.

7.Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131: 861–872.

EROS Y AFRODITA

2012-01-29T17:19:00.000-08:00

Eros, Afrodita y el sentimiento amoroso

Xabier F. Coronado

LA JORNADA SEMANAL,29 DE ENERO,2012

AFRODITA

¿Qué entendemos por amor? Quizá haya pocas palabras con tal cantidad de posibles interpretaciones. El concepto de amor es tan contradictorio que se puede referir a algo inmaterial, puro y casto, como el amor espiritual; o a algo físico, apasionado y lúbrico, como el amor motivado por el erotismo. Cuando alguien nombra el amor, a veces no sabemos con certeza a qué se está refiriendo. Es normal, pues a menudo no tenemos una idea clara de lo que significa el amor para nosotros mismos.

El amor no es algo único, hay muchos tipos de amor y muchas maneras de amar. Entonces, ¿ese sentimiento que nos invade en situaciones tan diferentes no es siempre el mismo? Quizá no…, o tal vez el amor sí, es el mismo, pero se mezcla con emociones, deseos y pasiones que lo hacen diferente en cada ocasión. Posiblemente existe el Amor con mayúscula, puro, sin contaminar, pero lo que determina el tipo de amor es el sujeto-objeto hacia el que enfocamos ese sentimiento. Por eso, para entendernos, casi siempre tenemos que ponerle un apellido: amor filial o paterno, amor propio, amor carnal, amor al dinero, a la naturaleza, a Dios, a nuestros semejantes, etcétera.

En el diccionario oficial de la academia de la lengua, nos encontramos que la palabra amor (del latín, amor, –oris) tiene doce definiciones directas y no menos de veinte acepciones de uso. La primera definición dice que es un sentimiento que mueve a desear el bien a “la realidad amada”; la segunda se refiere a la atracción sexual; la tercera al “apetito sexual de los animales”; y el resto contempla otras posibilidades diferentes. En el diccionario de María Moliner la definición es más precisa, trata sobre el uso de la palabra amor en diferentes sentidos: concreto o abstracto, corriente o cuando se refiere a conceptos elevados. También indica que se sustituye familiarmente por “querer” o “cariño”.

Las fuentes: mitología, filosofía y literatura

El amor tiene, en la tradición grecolatina, su propia diosa: Afrodita/Venus. Según la mitología griega, Afrodita, diosa del amor y la belleza, es hija de Zeus –rey de todos los dioses concebido por Cronos y Rea–, y de Dione –nacida de Océano y Gea. Según otra versión, Afrodita surgió del mar. La narración mítica cuenta que Cronos, dios del tiempo, para destronar a su padre Urano –personificación del cielo como elemento masculino primigenio–, lo castra con una hoz gigantesca y después arroja sus genitales al mar que, al ser fecundado, engendra a Afrodita; por eso también se la conoce como “la diosa nacida de las olas”.

En la mitología Afrodita se presenta como esposa de Hefesto, dios del fuego, pero siempre aparece cortejada por numerosos amantes divinos y humanos. Se dice que de la unión de Afrodita con Ares, dios de la guerra, nació Eros, el dios del amor. También existen diferentes versiones sobre el origen de Eros. Parménides dice que es el primer dios concebido y, según nos relata Hesíodo en su Teogonía, Eros emergió del Caos primordial a la vez que Gea (la Tierra) y Tártaro (el Inframundo). En cambio, el poeta Aristófanes, en su obra Las aves, relata que Eros nació de un huevo incubado por Nix (la Noche), que había fecundado Érebo (la Oscuridad).

Eros representa la atracción sexual de los seres vivos y también la fertilidad. Se le conoce como un ser ambivalente, voluble y caprichoso que siempre consigue el objeto de su deseo. Eros es el ayudante de su madre Afrodita y encauza la fuerza esencial del amor hacia los seres humanos. Según la tradición griega, madre e hijo se reparten el trabajo, mientras Afrodita rige el amor entre mujeres y hombres, Eros sería el mentor del amor entre hombres. En la tradición romana (Cupido), se representa alado y ciego, portando un arco, y se dice que las heridas causadas por sus flechas inspiran amor.

Platón, uno de los principales teóricos del sentimiento amoroso, dedica dos de sus célebres diálogos a tratar este tema: “Fedro o del amor” y “Symposio (Banquete) o de la erótica.” En contra de lo que entendemos por “amor platónico”, el carácter del amor que expresa Platón en sus obras no es la renuncia al ser amado sino su relación con los ideales de la vida; el amor es un estímulo para crear la “vida ascendente”.

En el “Banquete”, Platón reflexiona, a través del discurso de sus personajes, sobre la naturaleza de Eros y el papel que juega en la vida humana. Fedro, el primero en tomar la palabra, entiende por Eros la pasión sexual y apoya la teoría del dios primigenio: “De entre los dioses, Eros es el más antiguo, el más venerable y el más eficaz para asistir a los hombres en la adquisición de virtud y felicidad.” Pausanias, dice que no todo amor es hermoso ni digno de ser alabado y sostiene que “no hay Afrodita sin Eros”, y que como hay dos Afroditas, “una más antigua y sin madre, es hija de Urano y la llamamos Urania; la otra, más joven, es hija de Zeus y Dione y se llama Pandemo”, también hay dos Eros. El de Urania infunde un amor elevado y “obliga al amante y al amado a dedicar mucha atención a sí mismos con respecto a la virtud”; en cambio, el Eros de Pandemo atrae el amor con el que aman los hombres vulgares, que desean más los cuerpos que sus almas. El siguiente comensal, el médico Erixímaco, opina sobre este doble Eros y dice: “Uno es el amor que reside en lo que está sano y el otro reside en lo que está enfermo, son el amor bello y el amor vergonzoso.” Es decir, un Eros hermoso, celeste, y otro vulgar, terrenal, “que debe aplicarse con cautela para cosechar el placer sin que provoque ningún exceso”. Con cada nuevo discurso las alabanzas a Eros se incrementan; Aristófanes piensa que los hombres no se han percatado del poder de Eros porque no han erigido en su honor grandes templos, y Agatón ve en el dios del amor la personificación de todo lo bello.

Por fin, llegamos al discurso de Sócrates, quien revela que Eros es un gran demon–genio o espíritu intermedio entre los dioses y los hombres–, que interpreta y comunica a los dioses las cosas de los hombres y a éstos lo relativo a las divinidades, “al estar en medio de unos y otros llena el espacio entre ambos, de suerte que el todo queda unido consigo mismo como un continuo”. Sócrates sostiene una nueva teoría sobre el origen de Eros y afirma que el dios del amor fue engendrado por Poros (la abundancia) y Penia (la pobreza), durante la celebración del nacimiento de Afrodita. Como consecuencia de ser concebido ese día, Eros siempre será ayudante de Afrodita y, por naturaleza, amante de lo bello. Según Sócrates, sus progenitores marcaron las características de Eros: “Es siempre pobre y, lejos de ser delicado y bello, como cree la mayoría, es flaco, desaseado, sin calzado y sin domicilio, sin más lecho que la tierra se acuesta a la intemperie, en las puertas y al borde de los caminos, lo mismo que su madre está siempre peleando con la miseria. Pero, por otra parte, de acuerdo a la naturaleza de su padre, está al acecho de lo bello y de lo bueno; es valiente y activo, perseverante y hábil cazador, siempre urdiendo alguna trama, ávido de sabiduría y rico en recursos, amante del conocimiento, un formidable mago, hechicero y sofista. No es por naturaleza ni inmortal ni mortal. Todo lo que adquiere lo disipa, de suerte que Eros nunca es rico ni pobre, y está, además, en medio de la sabiduría y la ignorancia.” Con estas palabras de Sócrates, Platón describe las cualidades del amor humano y sus contrastes.

Siguiendo el hilo de las fuentes filosóficas llegamos a Aristóteles, discípulo de Platón, que abarcó en sus escritos todo el conocimiento de la época. Cuando trata sobre el amor, el pensador macedonio considera que el hombre no ha de amar cualquier cosa, “sino aquella que es digna de amor”. En su libro La gran moralnos dice que el verdadero objeto del amor debe ser el bien, e insiste en que lo que se ama, a pesar de que nos parece bueno, a veces no lo es: “La mayor parte del amor procede de afecto y deleite, y por esto aman, y fácilmente desisten.” También trata sobre el placer y, al considerar que no siempre es un bien, concluye que no debe ser, en sí mismo, el objetivo del amor.

Una visión más hedonista y apasionada del amor la encontramos en el poeta romano Ovidio. En su época, el autor de El arte de amarfue considerado el maestro del amor erótico: “Si alguien en la ciudad de Roma ignora el arte de amar, lea mis páginas, y ame instruido por sus versos.” Ovidio fue un enamorado totalmente convencido y entregado (“yo me someteré al amor, aunque me destroce el pecho con sus saetas y sacuda sobre mí sus antorchas encendidas”) que no dudaba que el placer era algo inherente al amor. Ovidio trató sin rubor las pasiones que se mueven en los diferentes tipos de relaciones amorosas. Su obra magna, Metamorfosis, compendia en quince volúmenes la mitología grecorromana y es una crónica de los amores entre dioses y héroes. A pesar de ser un escritor famoso y reconocido en Roma, el emperador César Augusto lo desterró por razones imprecisas ‒los motivos fueron, según el propio Ovidio, “un poema y un error”, y pasó sus últimos años de vida en el exilio, desde donde compuso Las Tristes, una obra doliente y resentida que buscaba el perdón del César.

Sin noticias de Afrodita

Gradualmente se produce la masculinización del tema amoroso y el tándem divino que manejaba los asuntos del amor (Eros y Afrodita) se va disgregando. Durante el imperio romano, Eros, en su molde de Cupido, dispara las flechas que trasmiten el amor a los mortales mientras que Venus/Afrodita, se desvanece en un plano más etéreo. Posteriormente, con el nacimiento e institucionalización de las religiones monoteístas ‒de dios único y masculino‒, comienza un largo período de fanatismo religioso que rechaza el carácter erótico del amor hasta sumirlo en la condena y el olvido. El sentimiento amoroso pasa a estar dominado por el amor sublime hacia un dios paternal. Los grandes místicos, como santa Teresa de Jesús o san Juan de la Cruz, experimentan en sus obras profundos éxtasis amorosos enfocados en lo divino y Dios aparece como el único ente digno de ser amado.

Para volver a encontrar alguna referencia a Eros, aquel dios primigenio, tuvieron que pasar cientos de años. En los albores del siglo xx, Eros reaparece en la obra del pensador austríaco Sigmund Freud. En su libro Metapsicología(1905), el creador del psicoanálisis resucita al olvidado dios helénico y lo utiliza de manera renovada, convierte a Eros en “el principio del ser” y lo identifica como el instinto de la vida. Para Freud, la existencia es la fusión de este Eros con Tánatos, el instinto de la muerte. Así, Eros retoma el lugar principal que la mitología y los antiguos filósofos le habían dado. Pero, ¿qué fue del amor? No hay noticias de Afrodita.

Con el último cambio de siglo, la tendencia parece enfocada hacia otro tipo de sentimiento amoroso: el amor por uno mismo. En la actualidad, época de individualismo feroz y culto al ego, todo parece tender a que permanezcamos mirándonos en la computadora, enamorados de la imagen virtual que proyectamos de nosotros mismos. Mientras tanto, el mundo real se desmorona.

Las nuevas tecnologías, la comunicación extrema y la red digital que envuelve al planeta, contribuyen a extender ese narcisismo virtual, regido por un dios personal, benévolo y consentidor con uno mismo, pero estricto e implacable para condenar a los demás. Esta tendencia se integra en la sociedad y se filtra en la cultura. Ese yoísmo de masas se hace presente en blogs y redes sociales que aspiran a convertirse en sectas globales, en ellas cualquiera puede tener diariamente su “minuto filosófico” como aporte circunstancial dirigido al mundo añadido.

Para intervenir en ese juego, aquí queda esta reflexión de Aristóteles (Moral a Eudemo, capítulo VI: “Del Amor Propio”): “Sobre el amor propio se ha discutido mucho si el hombre puede o no amarse a sí mismo. Hay personas que creen que lo primero de todo es amarse a sí mismo, y que, convirtiendo en regla el amor propio miden por él todas sus amistades para juzgarlas.”

SEXUALIDAD DE LAS PLANTAS

2012-01-28T16:30:00.000-08:00

Research Article

Heredity (2002) 88, 94–101.

Plant sex determination and sex chromosomes

D Charlesworth1

1Institute of Cell, Animal and Population Biology, University of Edinburgh, Scotland, UK

Correspondence: D Charlesworth, Institute of Cell, Animal and Population Biology, University of Edinburgh, Ashworth Laboratory King's Buildings, West Mains Road., Edinburgh EH9 3JT, UK. E-mail: Deborah.Charlesworth@ed.ac.uk

Abstract

Sex determination systems in plants have evolved many times from hermaphroditic ancestors (including monoecious plants with separate male and female flowers on the same individual), and sex chromosome systems have arisen several times in flowering plant evolution. Consistent with theoretical models for the evolutionary transition from hermaphroditism to monoecy, multiple sex determining genes are involved, including male-sterility and female-sterility factors. The requirement that recombination should be rare between these different loci is probably the chief reason for the genetic degeneration of Y chromosomes. Theories for Y chromosome degeneration are reviewed in the light of recent results from genes on plant sex chromosomes.

Keywords: dioecy, sex linkage, Y chromosomes, Silene latifolia

Introduction: why are plant sex chromosomes of particular interest?

The genetic control of sex determination is becoming well understood in several animal systems, particularly Drosophila melanogaster, Caenorhabditis elegans and mammals. In plants, understanding the sex determination system is closely connected with understanding how separate sexes evolved, and current theoretical ideas about this also illuminate the evolution of sex chromosomes. Angiosperms are also of particular interest for empirical studies of sex chromosome evolution, because they probably evolved separate sexes repeatedly and relatively recently. Other plants, particularly Bryophytes (see Okada et al, 2001), also have interesting independently evolved sex chromosomes.

In many sexually reproducing plant species (and some animals) all individuals are essentially alike in their gender condition. Many such 'sexually monomorphic' species are hermaphroditic. The term 'cosexual' (Lloyd, 1984) is used when individual plants have both sex functions, whether present within each flower (hermaphrodite), or in separate male and female flowers (monoecious). A minority of plant species are 'sexually polymorphic', including dioecious species, with separate males and females (Table 1). Many dioecious species with hermaphrodite relatives have evident rudiments of opposite sex structures in flowers of plants of each sex, suggesting recent evolution of unisexual flowers (Darwin, 1877). The low frequency and scattered taxonomic distribution of dioecy and sex chromosomes suggest that cosexuality is the ancestral angiosperm state (Figure 1) (Charlesworth, 1985; Renner and Ricklefs, 1995. Sex chromosomes therefore probably evolved repeatedly and quite recently.

Figure 1.

The wide taxomic distribution of dioecy and sex chromosomes in angiosperms, based on the phylogenetic analysis of Soltis et al, (1999). Presence of dioecy is indicated by X inside a square. Filled symbols indicate taxa in which sex chromosomes have been studied. Black indicates the presence of species in which heteromorphic sex chromosomes have been found, either cytologically or by genetic mapping, and grey indicates that sex chromosomes are believed to be absent.

In some plant taxa, it is possible to estimate how many times dioecy has evolved, and how long ago. Dioecy probably evolved twice in the Hawaiian genus Schiedia (Weller et al, 1995). The best studied case at present is the large genus Silene, in the same family (Caryophyllaceae). Many Silene species are gynodioecious and others are hermaphroditic. A phylogeny constructed from internal transcribed spacer (ITS) sequences of nuclear ribosomal RNA genes of Silene species suggests two origins of dioecy in this genus also (Desfeux et al, 1996). Using a molecular clock, these data suggest an age of probably less than 20 million years for the heteromorphic sex chromosomes of the close relatives Silene latifolia and S. dioica. Comparative analysis suggests that dioecious lineages often have short evolutionary lives (Heilbuth, 2000). Thus separate sexes may have evolved more than 100 times in the flowering plants, given that 160 families have dioecious members.

The genetics of sex determination in plants, and plant sex chromosomes

Sex inheritance and sex chromosomes in plants are strikingly similar to those in animals. The majority of plants studied have heterozygous males, or, when the chromosomes are visibly different (perhaps half of plants that have separate sexes, see Westergaard, 1958), male heterogamety (XY males, XX females). In many dioecious plants, males are 'inconstant', ie produce occasional fruits (Lloyd, 1975b; Lloyd and Bawa, 1984). Self fertilisation of such plants in several species has provided genetic evidence that males are heterozygous. As will be explained below, the male genotype must include a dominant suppressor of femaleness (SuF). On selfing, a 3:1 ratio of males to females is expected if SuF/SuF is viable, or 2:1 if the Y chromosome is genetically degenerated and this genotype is inviable. Each of these ratios has been found (Westergaard, 1958; Testolin et al, 1995). Some plant Y chromosomes are therefore at least partially genetically degenerate.

Several kinds of evidence suggest the involvement of two loci in sex determination. Some data come from crosses between dioecious plants and related monoecious or hermaphrodite species (Westergaard, 1958). In Silene dioica and latifolia, there is direct evidence from cytological studies of Y chromosome deletions. There are three functionally different Y chromosome regions (see Figure 2), the SuF region, and two regions containing factors controlling early and late anther development (Westergaard, 1958; Grant et al, 1994; Farbos et al, 1999; Lardon et al, 1999). In these species, X and Y pairing in male meiosis is confined to the tips (Westergaard, 1958; Parker, 1990; Lardon et al, 1999), and recombination is absent for most of the Y chromosome.

Figure 2.

The Silene latifolia Y chromosome, showing genes and anonymous markers that have been identified. The deletions causing hermaphroditism (bsx mutations), and those causing complete sterility (ie early-stage anther abortion) of Y-bearing plants (asx mutations), as well as the X-43 subtelomeric sequence, are described in Farbos et al (1999) and Lardon et al (1999), and the Bgl markers are described in Donnison et al (1996). The locations of the S1X4 and S1X1 loci are inferred from the finding of a male-sterile plant (with anthers aborted late in stamen development) which has no copy of S1X4 detectable by PCR, but which appears to carry a Y chromosome, since S1X1 is present (DA Filatov, unpublished data). The estimate of a recombination fraction of 30–40% between S1X1 and S1X4 is based on unpublished data of V Laporte and V Hykelova.

Why are sex determining loci linked?

The evidence for multiple sex determining genes suggests that non-recombination between the X and Y chromosomes evolved to prevent recombination between these loci, since recombination would produce maladaptive phenotypes, particularly neuter individuals (Figure 3b; Lewis, 1942). It is widely assumed that the linkage evolved after establishment of unlinked male and female sterility genes, ie that these loci have been brought into proximity by inversions and/or translocations (Lewis, 1942). A genetic model of the evolutionary transition from cosexuality to dioecy suggests, however, that linkage may often be necessary from the outset (Charlesworth and Charlesworth, 1978a). Starting from cosexuality, the evolution of two sexes must generally require at least two genetic changes, one (male-sterility) creating females and the other (female-sterility) producing males (Figure 3a, Charlesworth and Charlesworth, 1978a). The process may sometimes have been more gradual, with partial sterility mutations (Lloyd, 1975a; Charlesworth and Charlesworth, 1978b). Plants and animals with a single sex-determining determining locus are probably often derived from systems with male-determining chromosomes (Bull, 1983; Traut and Willhoeft, 1990), as separate sexes cannot evolve in a single mutational step from an initial hermaphroditic or monoecious state (except under the extremely improbable assumption that a mutation arises in a cosex whose heterozygotes have one sex, and homozygotes the other sex, eg Aa male and aa female).

Figure 3.

(a) The possible genetic changes that could occur in the transition from cosexual to separate sexed populations. (b) Effects of a female-sterility 'modifier' allele on hermaphrodites and females, in the absence of sex-limitation of its phenotypic effects. A trade-off between male and female functions is assumed, so that a gene increasing male fertility will often have the effect of reducing female fertility.

The existence of inconstant males (but not females) in many dioecious species (eg Galli et al, 1993; Testolin et al, 1995) supports this scenario of a major recessive mutation leading to females, followed by selection for modifiers making the cosexes more male, as in Figure 3. Once females have been established in a population, the availability of their ovules favours higher investment in pollen output, so there is a selective pressure on the cosexual morph to evolve a greater male bias (Charlesworth and Charlesworth, 1978a). Modifier genes that make cosexes more male-like should, however, also reduce female fertility (Figure 3b), unless they are sex-limited in their expression. This counter-selects against such factors, so partial female-sterility factors are generally most likely to spread in a gynodioecious population if they are linked to the male-sterility gene (Charlesworth and Charlesworth, 1978a; Nordborg, 1994). The spread of alleles beneficial in one sex but not in the other (antagonistic pleiotropy) similarly depends on linkage (Charlesworth and Charlesworth, 1980; Rice, 1997). There will also be selection for tighter linkage between the male-sterility locus and modifier loci (Charlesworth and Charlesworth, 1978a). Thus a cluster of linked loci in a particular chromosomal region, with suppressed recombination, and containing the sex determining loci and loci affecting male functions, will probably evolve.

Sex-linked markers should permit tests of whether the region involved in sex determination in dioecious species is also a single chromosomal location in cosexual relatives, or whether the sex determining genes were initially on different chromosomes, and only later came into proximity. All diploid Silene species have the same chromosome number (n = 12), suggesting that translocations of whole chromosomes have not contributed to the enlarged X and Y, though movements of lesser genome regions are possible.

Evolution of sex chromosomes

The theory outlined here explains the evolution of a rarely recombining chromosome region containing the sex determining genes, an incipient sex chromosome system. The female haplotype carries a recessive male-sterility allele, while the dominant male-determining chromosome would carry female-sterility alleles (and the wild-type allele at the male-sterility locus; Figure 3). Sex chromosome evolution is intimately connected with Y chromosome degeneration. Most current understanding of how the distinctive properties of Y chromosomes evolved comes from theoretical work on the evolution of genomic regions with low recombination. Such regions are subject to several processes, given a sufficiently high rate of deleterious mutations (Charlesworth and Charlesworth, 2000).

One process is mutation accumulation by Muller's ratchet (Muller, 1964; Haigh, 1978), leading to an increasing number of mutations, which become fixed as the process continues (Charlesworth and Charlesworth, 2000). Drosophila population sizes may be too high for this stochastic process to explain neo-Y chromosome degeneration (Charlesworth, 1996), and most plants have more chromosomes, and therefore fewer genes on a proto-Y chromosome than on a Drosophila chromosome, so in plants the mutation rate to deleterious alleles may be too low. Another possibility is hitch-hiking: favourable mutant alleles arise on the proto-Y and rise in frequency to fixation, concomitantly fixing deleterious alleles on the same chromosome (Rice, 1987). A third suggestion relies on accelerated fixation of deleterious mutations on a non-recombining chromosome (because selection against deleterious alleles leads to reduced effective population size; Charlesworth, 1996). All these processes involve reduced effective population size, and should therefore lead to low Y-chromosomal genetic diversity (Charlesworth and Charlesworth, 2000).

The relatively recent origin of plant Y chromosomes, compared with those of most animals, make dioecious plants particularly suitable for studying the early stages of the degeneration process. The availability of closely related species, probably with chromosomes having gene content similar to that of the ancestral sex chromosomes, should show how genes have evolved since becoming sex-linked, offering a system to test between the different hypotheses. Most animal Y chromosomes degenerated long ago, making the processes responsible inaccessible to study, except in species with translocations between the sex chromosomes and autosomes. In species with X-autosome translocations, the neo-Y is not physically attached to the pre-existing Y chromosome, so its degeneration may result largely from the same kind of processes as in the initial evolution of Y chromosomes, but this is not certain. In plants, however, a there is de novo evolution of Y chromosomes. If plant, as well as animal Y chromosomes have degenerated, this would be evidence that the process is very general.

Have plant Y chromosomes degenerated?

Before using plants to study genetic degeneration, we need to know if their Y chromosomes are indeed degenerating. The evidence from the best studied species suggests some degeneration. Rumex acetosa Y chromosomes are heterochromatic (Clark et al, 1993; Réjon et al, 1994; Lengerova and Vyskot, 2001). On the other hand, DNAse digestion experiments suggest transcriptional activity of this Y chromosome (Clark et al, 1993), though this could be due to the presence of dispersed repetitive sequences that are transcribed, such as transposable elements. The high frequency of chromosome rearrangements in this species (Wilby and Parker, 1988), and variability of its Y chromosome morphology (Wilby and Parker, 1986), are consistent with such a possibility, but it has not yet been tested. Some X-linked mutations are not masked by the Rumex Y chromosome (Smith, 1963), ie males are hemizygous for this region, like classical sex-linked loci in many animals.

In Silence latifolia, the two X chromosomes differ in the time of replication, as might be expected if one of them is transcriptionally silenced, and they appear to be differentially methylated, possibly indicating that dosage compensation is occurring by X inactivation in females (Vyskot et al, 1999). Gene expression from Y chromosomes is suggested by estimates of methylation levels (Vyskot et al, 1993), which may imply that many Y-linked genes have not degenerated greatly, if at all (though again the possibility of transposons cannot be excluded). The large size of the Y chromosomes in S. latifolia and dioica (Costich et al, 1991) and many other dioecious plants (Parker, 1990), also suggests that plant Y chromosomes have accumulated repetitive sequences, which have been found on Y chromosomes of S. latifolia (Donnison et al, 1996; Zhang et al, 1998; Lardon et al, 1999) and R. acetosa (Réjon et al, 1994). So far, however, abundances are mostly similar on the X and autosomes (Clark et al, 1993; Donnison et al, 1996; Scutt and Gilmartin, 1997). Thus the evidence is inconclusive, and the nature and range of kinds of such sequences is currently almost totally unknown.

In most studied species with heteromorphic sex chromosomes YY genotypes are inviable (see above), as are androgenic haploid plants of S. latifolia, with only a Y chromosome (Ye et al, 1990), while X-haploid plants are viable. However, the viability and fertility of occasional YY dihaploids (Vagera et al, 1994) argues against complete loss or inactivation of genes, presumably because increased gene dosage permits survival. Finally, female biased sex ratios in both S. latifolia (see Correns, 1928, but also Carroll, 1990) and Rumex acetosa (Smith, 1963; Wilby and Parker, 1988) as well as other dioecious species suggest that pollen grains with Y chromosomes grow more slowly than X-bearing pollen. This suggests that plant Y chromosomes have reduced gene functions (Smith, 1963; Lloyd, 1974), though segregation distortion has not been ruled out (Taylor, 1994).

Molecular genetics of plant Y chromosomes

Our understanding of the evolution of plant sex chromosomes and sex determination should be advanced by the use of molecular markers, so several groups are searching for these. The region containing the sex determining loci must initially have been fully homologous between the two alternative chromosomes. One goal of studies of plant sex chromosomes is therefore to test for homology. Both X- and Y-linked markers are now being discovered in plants with and without heteromorphic sex chromosomes (eg Testolin et al, 1995; Harvey et al, 1997; Polley et al, 1997; Zhang et al, 1998; Mandolino et al, 1999). Most markers are, however, anonymous, and cannot tell us which X-linked loci have homologues on the Y chromosomes and which do not.

Isolation of male-specific cDNAs from developing flower buds or reproductive organs has not yet led to discovery of sex determining genes (Matsunaga et al, 1996; Barbacar et al, 1997), probably because sex-determination happens very early in flower development (Grant et al, 1994), so the genes identified are controlled in response to sex, rather than the controlling loci. Genes known to be important in floral development, including the homoeotic MADS-box genes also appear not to have direct roles in sex determination (Hardenack et al, 1994; Ainsworth et al, 1995). This is not surprising, as these mutations change floral organ identities, whereas in unisexual flowers apparently normal reproductive organs merely stop developing, as predicted by the genetic model above.

Both X- and Y-linked expressed loci have now been identified in S. latifolia. One approach is to directly search for sex-linked genes (Guttman and Charlesworth, 1998). This has identified the X-linked MROS-X (male reproductive organ specific) gene and its Y-linked homologue, MROS3-Y, which appears to have degenerated. MROS3-Y contains only a short region of homology to the MROS3-X sequence. This region has been evolving in a neutral manner, with a ratio of silent to replacement substitutions, Ka/Ks, of 0.974, close to unity, as expected for a sequence evolving without selective constraints (Nei, 1987).

Another approach has isolated Y-linked genes present in mRNA populations from S. latifolia male flower buds. Two gene pairs have so far been characterised. Based on sequence similarity to other genes, the SlX/Y1 pair appears to encode a WD-repeats protein (Delichère et al, 1999) and SlX/Y4 a fructose-2, 6-bisphosphatase (Atanassov et al, 2001), and neither is likely to be involved in sex determination. The recombination fraction between SlX1 and SlX4 (Figure 2) suggests that they are far apart on the X, and potentially also on the Y chromosome, unless this has been rearranged. Comparisons of the coding sequences of these X-and Y-linked genes, including outgroup sequences in non-dioecious Silene species, yield Ka/Ks < 0.2 (Atanassov et al, 2001). The protein sequences of both the Y- and X-linked genes have therefore been maintained for at least most of their evolutionary history since the X and Y ceased recombining, ie these Y-linked genes have not degenerated. Silent site divergence between SlX4 and SlY4 is similar to that between the X- and Y-chromosome copies of MROS3, and both suggest an age estimate of the sex chromosome system similar to that based on the ITS sequences (Desfeux et al, 1996). The SlX1 and SlY1 genes are considerably less diverged. It will be very interesting to study more X/Y-linked gene pairs to test whether the Y chromosome seems to have been built up in a stepwise manner, as seems to be true of the human Y (Lahn and Page, 1999; Waters et al, 2001).

If the Y chromosomes of dioecious Silenes are actively degenerating, Y-linked genes are predicted to have reduced diversity, and we can use patterns of diversity at non-degenerated loci (such as those just described) to test for selective sweeps. In samples from several S. latifolia and S. dioica populations, SlY1 diversity is indeed lower than that of SlX1, after correcting for the smaller number of Y than X chromosomes in populations (Caballero, 1995). Analysis using outgroup sequences shows that this is not due to a higher mutation rate of the Y-linked genes (Filatov et al, 2001). Tests such as Tajima's test do not suggest selective sweeps (Filatov et al, 2000, 2001). However, these tests are affected by subdivision (Schierup et al, 2000), for which there is evidence in these species (McCauley, 1994; Giles et al, 1998; Ingvarsson and Giles, 1999; Richards et al, 1999), which probably affects the Y chromosome more than other chromosomes, because of its smaller effective size (Wang, 1999). Larger samples from within single populations are therefore needed. It is also difficult to test for diversity differences in the presence of introgression between the two Silene species. Y-chromosome variants differ between the two species, whereas some X-linked variants are shared between them (Filatov et al, 2001). A final difficulty is that autosomal loci are also needed in order to know whether Y-chromosomal variation is reduced, or X-linked diversity elevated. The one autosomal locus so far studied has low diversity, but this does not point to increased X-linked diversity, because this gene appears to have experienced a selective sweep (Filatov et al, 2001), so more autosomal genes are needed. Comparisons are also needed with species whose Y-chromosome is fully degenerated. If low diversity is also found in these, it would point to causes such as mutation rate differences, rather than effects of the selective processes during genetic degeneration.

Discussion

With the availability of molecular techniques, we may now hope to understand more about how sex chromosomes evolve. Mapping data, even with anonymous markers, should give estimates of the fraction of X-linked loci that are located in the pairing and differential regions. In the absence of useful chromosome banding patterns that identify regions, single-copy anonymous markers can also be useful for mapping in combination with Y-chromosome deletions (Donnison et al, 1996). Deletion mapping of the Y chromosome does not precisely pinpoint the sex-determination loci, but it should be possible to define the regions in which these genes are located Figure 2 summarises current information about the S. latifolia Y.

Once genes have been identified and sequenced, we will be able to estimate how long sex chromosome evolution takes. This should help us evaluate the plausibility of the proposed mechanisms for the process. The results of such studies may, in turn, contribute to our knowledge of mutation rates to deleterious mutations, and to a growing body of understanding of evolution in the absence of recombination. Studies of the early stages of sex chromosome degeneration offer the potential to have a eukaryote version of the interesting results on genome degradation in asexual prokaryotes (Wernergreen and Moran, 1999). If, as appears likely, plant sex chromosomes are found to be only partially genetically degenerated, they may offer opportunities to help understand the relationship between the evolution of genetic degeneration and of dosage compensation.

References

1.Ainsworth, CC, Crossley, S, Buchanan-Wollaston, V, Thangavelu, M, Parker, J (1995). Male and female flowers of the dioecious plant sorrel show different patterns of MADS box gene expression. Pl Cell, 7: 1583–1598.

2.Atanassov, I, Delichère, C, Filatov, DA, Charlesworth, D, Negrutiu, I, Monéger, F (2001). A putative monofunctional fructose-2,6-bisphosphatase gene has functional copies located on the X and Y sex chromosomes in white campion (Silene latifolia). Mol Biol Evol, 18: 2162–2168.

PubMed

3.Barbacar, N, Hinnisdaels, S, Farbos, I, Moneger, F, Lardon, A, Delichère, Cet al (1997). Isolation of early genes expressed in reproductive organs of the dioecious white campion (Silene latifolia) by subtraction cloning using an asexual mutant. Plant J, 12: 805–817.

4.Bull, JJ (1983). Evolution of Sex Determining Mechanisms. Benjamin/Cummings: Menlo Park, CA.

5.Caballero, A (1995). On the effective size of populations with separate sexes, with particular reference to sex-linked genes. Genetics, 139: 1007–1011.

PubMed

6.Carroll, SB, Mulcahy, DL (1990). Progeny sex ratios in dioecious Silene latifolia. Am J Bot, 80: 551–556.

7.Charlesworth, D (1984). Androdioecy and the evolution of dioecy. Biol J Linn Soc, 23: 333–348.

VARIACIONES DE ADN EN LA SALUD Y ENFERMEDAD

2012-01-26T14:31:00.000-08:00

Review

Journal of Human Genetics (2012) 57, 6–13; published online 29 September 2011

Implications of gene copy-number variation in health and diseases

Suhani H Almal1 and Harish Padh1

1Department of Cellular and Molecular Medicine, BV Patel Pharmaceutical Education and Research Development (PERD) Centre, Thaltej-Gandhinagar Highway, Ahmedabad, India

Correspondence: Dr H Padh, Department of Cellular and Molecular Medicine, BV Patel Pharmaceutical Education and Research Development (PERD) Centre, Thaltej-Gandhinagar Highway, Thaltej, Ahmedabad 380 054, Gujarat, India. E-mail: hpadh@yahoo.com

Abstract

Inter-individual genomic variations have recently become evident with advances in sequencing techniques and genome-wide array comparative genomic hybridization. Among such variations single nucleotide polymorphisms (SNPs) are widely studied and better defined because of availability of large-scale detection platforms. However, insertion–deletions, inversions, copy-number variations (CNVs) also populate our genomes. The large structural variations (>3 Mb) have been known for past 20 years, however, their link to health and disease remain ill-defined. CNVs are defined as the segment of DNA >1 kb in size, and compared with reference genome vary in its copy number. All these types of genomic variations are bound to have vital role in disease susceptibility and drug response. In this review, the discussion is confined to CNVs and their link to health, diseases and drug response. There are several CNVs reported till date, which have important roles in an individual's susceptibility to several complex and common disorders. This review compiles some of these CNVs and analyzes their involvement in diseases in different populations, analyses available evidence and rationalizes their involvement in the development of disease phenotype. Combined with SNP, additional genomic variations including CNV, will provide better correlations between individual genomic variations and health.

Keywords: CNV; diseases; gene copy number; genetic variants; health; neurodisorders; pharmacogenetics; SNP

Introduction

Variations in one's genomic DNA make one unique in terms of disease susceptibility and response to drugs. Single nucleotide polymorphisms (SNPs) are the most widely studied form of genetic variations and few of the SNPs have been linked to susceptibility to diseases and serves as a marker for certain disorders. Beside SNPs, submicroscopic copy-number variations (CNVs) are now considered important form of genetic variations. Findings in past few years have indicated a strong association of CNVs with several complex and common disorders that have a profound effect on our health.

CNVs are a segment of DNA that is 1 kb or larger and present at a variable copy number in comparison with a reference genome.1, 2 CNVs in general are stable and can be inherited. At times they can also develop spontaneously during meiosis. The exact mechanism of the development of new CNV is not clearly understood.3 Deletions, duplications, segmental duplications, insertions, inversions and translocations represent some of the processes resulting in CNV (Figure 1). Variations in the gene copy number can be detected using a variety of platforms, which have evolved rapidly in recent past.4, 5

Figure 1.

Types of genomic variants. Genomic variants in form of CNVs can be classified primarily as deletion, duplication, segmental duplication and inversion. These variations can encompass the entire gene or a segment of a particular gene represented in the figure.

Any of the processes mentioned earlier may result into disruption of genes in the region and therefore may result in the development of diseases. The phenotypic effect on the disease process will, however, depend on how CNVs affect dosage-sensitive genes or their regulatory elements. It is also conceivable that the development of the phenotypic disease may not depend upon a single CNV but a combination of various CNVs and other genetic variations such as SNPs (Figure 2). Therefore, identification of the all the susceptibility factors affecting the diseases development is a better predictive diagnosis rather than correlating the diseases with fewer susceptibility factors.

Figure 2.

Genetic variations and susceptibility to polygenic diseases. A schematic representation involving several genetic variants (SNP, CNV, INDELs, and so on) and possible involvement of environmental factors in defining susceptibility to multifactorial diseases. A stronger correlation to disease susceptibility can be explained by taking in account the various factors affecting susceptibility to diseases such as environment factor, different type of genomic variants (SNP, CNVs, indels, and so on) as depicted in the figure.

The challenge was to identify meaningful differences in the genomic information between individuals. When the database for SNP variations in the human genome became available, it was soon realized that the available technologies were inadequate to detect other forms of variations such as CNVs, insertion–deletions (INDELs) and inversions. It was also realized that the other variations such as CNVs, INDELs and inversions are present in the human genome with frequencies much higher than expected. At the same time these variants were too small to be detected by the microscopic techniques and therefore a new set of convenient and cheaper technology platforms evolved enabling us to map the human genome for CNVs.5 In 2006, Redon et al.6 constructed a first-generation CNV map of the human genome with the use of SNP genotyping arrays and Whole-Genome TilePath BAC arrays and among the 270 individuals studied, 12% of the human genome was found to be covered by CNVs whereas the total number of CNVs included in the Database of Genomic Variants (DGV) was reported to account for 29.7% of the human genome, which is often over estimated. Some examples of CNVs include single or multiple genes, which contribute to clinical phenotype whereas smaller CNVs affecting single exons may also account for a proportion of human diseases.7 Recently, the 1000 genome project came up with a map of human genome variation based on the population-scale genome sequencing. In this approach, they screened individuals under three categories namely: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother–father–child trios and exon-targeted sequencing of 697 individuals from seven populations at the pilot scale. They analyzed ~15 million SNPs, 1 million short INDELs and 20 000 structural variants describing the location, allele frequency and local haplotype structure of the variants. They also found that on an average each person carried 250–300 loss of function variants in annotated genes and 50–100 variants previously implicated in inherited disorders.8

There are several database where the CNVs are cataloged (DGV; http://projects.tcag.ca/variation/), public database such as Toronto DGV and European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations (ECARUCA, http://www.ecaruca.net). Another database, which archives the clinically relevant CNVs is DECIPHER (DatabasE of Chromosomal Imbalance and Phenotype in Human using Ensembl Resources; http://www.sanger.ac.uk/PostGenomics/decipher/).9 Till (May 2009), over 2200 cases of >50 diseases have been included in DECIPHER.7 The structural variation in the human genome and its implication in human health has been recently reviewed by Stankiewicz and Lupski.10

Furthermore, it is likely that these numbers are underestimated and advances in the technologies will help us in discovering more CNVs in the human genome.4 The major limitation in studying CNVs, despite of the recent technical advances, is the size or the breakpoint position, the total number and its gene content. It's conceivable that with the availability of various accessible technologies we might have a high-resolution CNV map of the human genome in the near future. However, the implication of CNV on health will have to wait several large-scale correlation studies not only with one CNV but also with permutations and combinations of various likely variations.

Techniques to detect CNVs

With the discovery of CNVs as the new form of genetic variations contributing to the disease susceptibility and progression, the task is how to detect these structural variations. The method to detect CNV should be convenient and inexpensive so that it can be applied to a large number of samples from a given population. Only when the data are available from various different populations the real impact of CNVs on health can be assessed. The major hurdle in detection is that a larger fraction of these CNVs do not have defined breakpoint. Demarcated breakpoints usually permit development of simple detection methods around the breakpoints. Beside conventional PCR several other modified PCR-based techniques have evolved, which are considered to be robust assays for screening the targeted region of the genome. Among these quantitative methods are multiplex ligation-dependent probe amplification, multiplex amplification and probe hybridization, quantitative multiplex PCR of short fluorescent fragments, semiquantitative fluorescence in situ hybridization, dynamic allele-specific hybridization and paralogue ratio test. The methodologies to detect CNV have been recently reviewed by Dhawan and Padh (2009).4

Genome-wide association studies have been widely used techniques to identify gene(s) and its variants associated in disease process. Genome-wide association studies are generally carried out in cases versus control populations.1, 11 Evaluating the technicality of each method, and its advantages and drawbacks, weighed against the objectives of the study can help us select the appropriate techniques.

CNV and pathophysiology

Recently, many CNVs have been reported to affect disease susceptibility. Among them are various complex neurological disorders, cardiovascular diseases, infectious and autoimmune diseases, metabolic diseases, cancer and several other common disorders (Table 1).

CNV and neurological disorders

Parkinson's disease

Parkinson's disease (PD) is a progressive nervous disease associated with the symptoms such as muscular rigidity, resting tremors, bradykinesia (slowing of movements) and posture instability. It is found to affect 1% of the population over 50 years of age.12 A novel triplication in SNCA gene, located on 4q21 is found to be linked to autosomal dominant PD and showed the dosage effect. Further, the gene expression profiling reflected an approximately twofold increase of SNCA protein in blood, mRNA in the brain tissue and also the deposition of large aggregates of this protein in the brain tissue.13

CNV in terms of gain of the copies of SNCA gene showed a profound effect on PD. The SNCA triplication was reported in a family of Swedish American descent with autosomal dominant early-onset PD.13 SNCA duplication was also reported in a Swedish family, suggesting a dosage effect of SNCA in selected cases of PD.13

Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurological disorder characterized by dementia among elderly people, which is mainly due to the intracellular tangles and extracellular plaques of amyloid getting deposited in the vulnerable regions of the brain.

Copy number gain of the APP gene (the amyloid precursor protein) is hypothesized to be one of the causes of AD.15 In the Dutch population, duplication of the APP gene has been reported and was found to be associated with autosomal dominant early-onset AD and cerebral amyloid angiopathy.14, 15, 16

It is interesting to note the association of the Alzheimer's with Down's syndrome that is due to trisomy 21. APP gene maps on the same chromosome so those with Down's syndrome have three copies of the gene and are more prone to Alzheimer's. Genetic variations in the form of point mutations, in at least 15 genomic loci17 and genetic variations in the promoter region of APP gene are found to be associated with AD.18

Mental retardation and developmental disorders

Mental retardation (MR) that is a nonprogressive cognitive impairment is also affected by the CNV seen in the genomic loci of several genes. Studies of large cohorts may help in detecting and confirming the roles of rare de novo CNVs in MR. MR occurs in 2–3% of newborns in the general population, however, its cause has remained elusive.19 X-linked MR showed six overlapping duplications at the Xp11.22 in six unrelated males. Further, it was noted that this duplication covered a 320-kb region involving four genes (SMC1A, RIBC1, HSD17B10 and HUWE1), three candidates of which may convey the phenotype of MR.19 Apart from duplication, many other forms of genetic variations such as point mutation in SMC1A and HUWE1 genes and a silent mutation in HSD17B10 gene conveyed the phenotypes of MR along with other distinguished characteristic.20 The conclusion drawn from the above findings showed that it is a dosage-sensitive gene, which confers the MR phenotype in the patients with duplicated genes. MECP2, X-linked methyl-CpG-binding protein 2 gene at Xq28 is also found to be associated with the developmental delay, MR and fatal infantile encephalopathy in males, and recently it has been reported that low copy number of MECP2 gene confers a clinical phenotype, resulting in MR or developmental delay and altered neurological symptoms (particularly seizures) phenotypes in males.21, 22, 23, 24 Needless to say, this is perhaps one of the most complex phenotype and the clear picture will emerge when all possible loci and their interactions are well defined.

Apart from this several other submicroscopic duplications and deletions in 17q13.3 involving LIS1 and/or the 14-3-3ε genes are shown to confer a risk to MR and several other characteristics features.25

The deletion in exonic regions of NRXN1 gene, located on chromosome 2p16.3, is found to predispose one to a wide spectrum of developmental disorders. These neurexins are a group of highly polymorphic cell surface proteins involved in synapse formation and signaling. Variants comprising a variety of mutations such as missense mutation, translocation, whole-gene deletion and intra-genic copy number changes result into a significant association with a variety of phenotypic changes such as autism, schizophrenia (SZ) and nicotine dependence.26

Autism

Autism is a pervasive neurodegenerative disorder characterized by impaired communication or linguistic skills, social interaction, cognition, some form of repetitive and restricted stereotyped interest, ritual or other behavior. The symptoms vary from person-to-person and no two persons have identical symptoms and hence called Autism spectrum disorder.27 A case–control study using the representational oligonucleotide microarray analysis technology was applied to identify the CNVs involved in Autism. Representational oligonucleotide microarray analysis was first explored for the detection of the genomic aberrations in cancer and healthy humans. In this technique by arraying oligonucleotide probes designed from the human genome sequence, and hybridizing with representations from cancer helped in detecting regions with altered copy number.28 Subsequently with the help of this technique revealed more spontaneous development of CNVs in Autism spectrum disorder patients than in unaffected controls.29

Both duplication and deletion were observed for Autism spectrum disorder. There are several loci associated with autism susceptibility such as duplication of 15q11-13 (AUTS4; MIM 608636) and deletion of 16p11.2 (AUTS14; MIM611913). A reciprocal microduplication and recurrent microdeletion at 16p11.2 have been shown to be associated with autism and may account for 1% of the cases.30 Applying the homozygosity mapping analysis in pedigrees several large inherited, homozygous deletions were observed. On analysis, it was found that this deletion spans 886 kb on chromosome 3q24 affecting DIA1 gene, whose expression level changes in relation to neuronal activity.31

Schizophrenia

Schizophrenia (SZ) is a chronic, debilitating illness with extensive neurological and psychiatric features. Its prevalence is ~1% of the population. Several CNVs are found to be associated with SZ.32, 33

Various deletions located on positions such as 1q21.1, 15q11.2 and 15q13.3 were found to be associated with SZ and psychosis, when studied in case–control samples analyzed by the International Schizophrenia Consortium and subsequently confirmed by other studies.34, 35 Furthermore, the previously reported deletion at 22q11.2 associated with SZ phenotype in DGV/velocardiofacial syndrome was also confirmed by these groups.36 Another group of researchers identified 90 CNVs in 54 patients, of which 13 were rare CNVs disrupting genes associated with SZ such as MYT1L, CTNND2 and ASTN2.37 To confirm the association of these rare CNVs a large cohort of samples is needed.

Bipolar disorder

Bipolar disorder is a psychiatric disorder characterized with profound and prolong mood swings and depression. It has been found that submicroscopic variation in GSK3β gene, which codes for glycogen synthetase kinase, a key component of Wnt signaling pathway and a target of lithium salt is involved in the susceptibility to bipolar disorder. The duplication or the increase in the copy number of GSK3β gene disrupts the 3′-coding element as well as affects the neighboring genes. Findings from the study suggested that there was a significant increase in the GSK3β copy number in the bipolar disorder patients as compared with control.38

CNV and susceptibility to other common disorders

HIV/AIDS susceptibility

Chemokines are secreted proteins involved in the immunoregulatory and inflammatory processes. The CCL3L1 gene copy number influences the susceptibility to HIV/AIDS. CCL3L1 gene, which encodes on 17q12, is the major coreceptor for CCR5 and is a dominant suppressive chemokine. Therefore, an increase in the copy number of this gene leads to reduction in susceptibility to HIV, as reported for the Caucasian population. The copy number of the CCL3L1 gene varies from 0 to 10 copies in the Caucasian population.39

The recruitment of lymphocytes by β-chemokines is a feature of autoimmunity conditions such as rheumatoid arthritis. The finding of the association of CCR5Δ32 variant with protection against rheumatoid arthritis led to hypothesis that gene copy number of CCL3L1 gene influences susceptibility to rheumatoid arthritis and type 1 diabetes. When studied in two independent Caucasian cohorts (New Zealand and UK population) it was found that high copy number (higher than two copies) of CCL3L1 gene was a risk factor for rheumatoid arthritis.40

Crohn disease and psoriasis

Crohn disease (CD) is a chronic inflammatory bowel disease, causing inflammation of the digestive tract. It has been shown that deficient expression of defensins, which are endogenous antimicrobial peptides protecting intestinal mucosa against bacterial invasion, can lead to chronic CD. Therefore, it was hypothesized that the low copy number of the β-defensin gene cluster may also be associated with chronic CD. Various other reported deletions and SNPs in genes have shown a strong correlation with CD. HBD-2 (human beta-defensin 2) gene is found to be associated with CD. When studied, it was found that patients with ulcerative colitis and healthy individuals have a median of 4 copies per diploid genome (range 2–10 copies), whereas patients with CD had lower copy number as compared with controls (P=0.002). Further, it was found that individuals with less than three copies of HBD-2 gene have a significantly higher risk of developing colonic CD as compared with individuals having four or more copies (odds ratio of 3.06).41

In contrast, the increased copy number of β-defensin genes was shown to be associated with psoriasis, which is a chronic autoimmune skin disease with a prevalence of 2–3% in individuals of the European ancestry.42, 43 Apart from β-defensin genes, individuals with deletion in LCE3B and LCE3C genes of late cornified envelope (LCE) gene cluster are found to be susceptible to psoriasis. The absence of the well characterized 32199 bp region was significantly associated (P=1.38E−08) with risk of psoriasis when studied in family-based samples from Spain, The Netherlands, Italy and the United States (P=5.4E−04).43

Immunity-related GTPase family, M was found to be associated with CD through earlier SNP studies. Recently, a 20-kb deletion has been found to attribute susceptibility to CD. The deleted portion is located upstream of the gene and is found to be in perfect linkage disequilibrium. It has been hypothesized that as immunity-related GTPase family M expression can affect the autophagy of internalized bacteria, the deletion might alter the expression level of immunity-related GTPase family M, thus, contributing to phenotype associated with CD.44

Pancreatitis

Pancreatitis is a multigene-associated disorder, including the cationic trypsinogen gene PRSS1. In the earlier studies, the R122H missense mutation was found to increase the activity of trypsin in vitro, which led to the suggestion that PRSS1 might be a dosage-sensitive gene. Upon further analysis, a novel 605 kb triplication was observed in a cohort of 34 French families with hereditary pancreatitis encompassing the PRSS1 gene resulting into CNV of PRSS1 gene.45

Systemic lupus erythematosus and glomerulonephritis

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of connective tissues and affects the skin, joints, kidney and serosal membranes, due to failure in regulation of the immune system. A strong correlation was found between the CNV of FCGR3B gene and SLE where an increased risk of development of SLE in individuals with fewer than the two copies of FCGR3B gene reported in the UK cohorts and the same correlation was confirmed in an another Caucasian population.46 FcγR3B is a glycosylphosphatidylinositol-linked, low-affinity receptor for immunoglobulin G found predominantly on human neutrophils. The low copy number of FCGR3B gene is associated with impaired clearance of the immune complex, which is a characteristic feature of SLE.47 Complement component 4 (C4, including C4A and C4B) gene mutations were also found to be associated with SLE. On examining the Americans of European descent, the copy number of C4 gene varied from 2 to 6 (C4A, 0–5; C4B 0–4). The risk of SLE was found to be increased in subjects with low C4 copies but decreased in those with high C4 copies.48

Asthma

Asthma is a chronic inflammatory genetic disorder characterized by a condition marked by recurrent attacks of dyspnea and constriction of the bronchii, also termed as bronchial asthma whereas the bronchial asthma due to allergy is called atopic asthma.

Genetic polymorphism of the glutathione S-transferase (GST) gene, which is mainly involved in the antioxidant defense is well known as a risk factor for several environmental diseases and was thus hypothesized that CNV in the GST genes might be associated with the asthma susceptibility.49, 50 CNVs of the GST genes were examined in patients with atopic asthma and it was found that the null genotypes of GSTT1 and GSTM1 together with GSTP1 Val/Val polymorphism have a significant role in the asthma pathogenesis.51

CNV and cardiovascular disease

Structural variations are also found to be affecting the susceptibility to many cardiovascular diseases. A common CNV in LPA gene on chromosome 6, which encodes for atherogenic apolipoprotein (a), which is the primary determinant of the plasma lipoprotein is a risk factor for atherosclerosis.52, 53 Apart from this CNVs were also found to be associated with the lipoprotein disorders. It was found that the low-density lipoprotein receptor gene (LDLR) is found to be affected in the patients with familial hypercholesterolemia.53, 54

CNV and metabolic diseases

Type 2 diabetes

Type 2 diabetes is a chronic metabolic disorder characterized by high glucose level or insulin resistance. Various SNPs have been linked to the high risk for diabetes but other genetic variations such as CNV were not explored. Recently, it has been discovered that CNV at leptin receptor, which is mainly involved in satiety and energy expenditure is found to be significantly associated with risk to type 2 diabetes. The role of leptin and leptin receptor in obesity is well established and common genetic variation such as SNPs at the LEPR gene locus are found to be associated with obesity, hyperinsulinemia, type 2 diabetes mellitus and variation in the levels of leptin in different populations. The expansion of the map of genetic variation has revealed many new loci associated with the disease. In a recent study, the association of the LEPR gene locus encompassing ~200 kb on chromosome 1 was studied in the Korean population using the genome-wide SNP array data and it was found that CNV at the LEPR gene locus is significantly associated with metabolic traits and the risk to type 2 diabetes mellitus.55

Overweight and obesity

People with body mass index of 25 kg m−2 are considered overweight and those with body mass index of 30 kg m−2 are considered obese. As per one estimate 66% of the US population is overweight and among them about 30% are obese.56 Obesity represents complex metabolic disorder affecting multiple systems and the cause of obesity is complex and unclear. It still remains a multigenic and multifactorial condition influenced by ‘‘environment’’. It is conceivable that beside environmental factors, several types of genetic variants such as SNP, CNV and others might be involved in precipitating obesity. In one instant, an early onset severe obesity in the Caucasian population was linked to deletion of 16p11.2 segment resulting in severe hyperphagia and insulin resistance. Examination of the deleted region revealed genes such as SH2B1, known to be involved in signaling pathways involving leptin and insulin. In another case, CNV at 10q11.22 was found associated with body mass index. The region in question has PPYR1 gene, regulating energy balance.57, 58

Amylase gene

CNVs is found not only contributing to the disease in general but also is found to be involved with diet, such as salivary amylase gene (AMY1 gene), which is associated with the starchy food consumption in a population. It has been reported that higher copy number of AMY1 gene is correlated positively with salivary amylase protein levels and a population with high-starch food consumption has higher copy number of AMY1 gene and improves the digestion of starchy foods and may reduce the burden of intestinal diseases.59

CNV and drug metabolism

Cytochrome P450 (CYP450) is a superfamily of hemoproteins involved in metabolism of xenobiotics such as clinically used drugs, procarcinogens and environmental pollutants.

Among superfamily of CYPs, CYP2A6 is an important human hepatic P450 enzyme, which is involved in drug metabolism including nicotine. CNVs such as duplication and deletion are found to be associated with the smoking behavior and susceptibility toward lung cancer and tobacco-related diseases. The association of the deletion variant was studied in the Chinese population. Frequency of the deletion variant (CYP2A6del) when studied in 96 Chinese subjects, was found to be 15.1%, but only 1% in Finns (n=100) and 0.5% in Spaniards (n=100).60

Apart from deletion, a novel duplication was reported in the African-American population and was found to increase nicotine metabolism and may affect smoking behavior in contrast to the European-American, Korean or Japanese populations.61

Another gene studied in the Caucasian-American and in the African-American population is SULT1A1 gene, which catalyzes the sulfate conjugation of a wide variety of drugs and is found to be genetically polymorphic. Apart from established SNPs at the 5′-flanking region, it also shows CNV. The range of copies of SULT1A1 gene varies from one to approximately five copies in both the populations. When the enzyme activity in the human liver and platelet samples was checked it showed a positive correlation with the number of copies of SULT1A1 gene.62

Further, CNV mainly in the form of deletion has been reported in GSTs conferring the susceptibility to cancers in various populations hypothesizing that the lack of these enzymes may impair metabolic elimination of various carcinogenic compound thereby increasing risk toward cancers. These phase II GSTs GSTT1, GSTM1 and GSTP1 catalyse glutathione-mediated reduction of exogenous and endogenous electrophiles. These GSTs have broad and overlapping substrate specificities and it has been hypothesized that allelic variants associated with less effective detoxification of potential carcinogens may confer an increased susceptibility to cancer.63 Lack of GSTM1 enzyme may impair metabolic elimination of carcinogenic compounds from the body thereby increasing cancer risk.64, 65

CNV and cancer

Understanding cancer genetics and identifying all possible variant alleles that might predispose one to a variety of cancer is the prime objective. To this end, several biomarkers through SNP studies have revealed an association with cancer and many other complex traits.66

In search for the common CNVs, which are associated with malignancy, a map was created that cataloged all the known CNVs whose loci coincide with that of the already known cancer-related genes. Upon analysis it was found that 49 cancer genes directly encompassed or overlapped by CNV in more than one person in a large reference population. Further, validating the initial observation it was found that many of the genes were reported in the DGV and 40% of the cancer-related genes are disrupted by a CNV as analyzed by DGV. Thus, it can be proposed that structural variations are found to be associated with risk for cancer. Deletions and duplication in the cancer-related genes are found to be polymorphic in different population.67

One of the examples of CNV as a risk to cancer with conferred phenotypic effect is MTUS1 gene, which maps on chromosome 8p spanning a deletion of 1128 bp covering the entire exon 4 of the gene. When studied in the German population, the deletion of exon 4 of MTUS1 was found to be associated with the slower progression of disease in both familial and high-risk breast cancer patients.68

There are many large structural variations, which might predispose to cancer but it has been less appreciated as the deletions and duplication breakpoints are not well characterized in many cases and the PCR method to detect these large structural variation is not reliable. Therefore, to characterize these structural variations involved in cancer syndromes newer methods such as multiplex ligation-dependent probe amplification and others needs to be used, which allow the detection of copy number changes in a single gene or exon.

Recently, apart from the constitutional mutations predisposing to cancer there are several acquired (somatic) copy number alterations present in the tumor genome, which need to be analyzed with the help of high-throughput technology.67

Conclusion

The human genome variations comprise of SNPs, as well as other variants such as CNVs, INDELs, inversions and larger structural alterations. SNPs have been widely studied in various populations primarily because of the ease of detection in large number of samples. However, recent technological advances have opened up investigations into other types of variations mentioned above. In past few years, we have learned a lot about the CNVs and their implication on our health and diseases. Observation from the comprehensive maps generated by Redon et al.6 and Jakobsson et al.69 have established CNVs as one of the prominent genetic variation having an important role in inter-individual and inter-ethnic differences in susceptibility to common and complex diseases.70

Still more technical advances are awaited for large-scale survey of CNVs, INDELs and other variants in many racial and ethnic populations. CNVs are also thought to have a key role in the evolution by gene duplication and exon reshuffling contributing to major phenotypic consequences. Our attempts to establish such variations and their link to health and disease will remain limited until reliable data of all such genetic variations in several different populations is generated. Only then the reliable genetic basis of disease development and drug response will be understood. It is also conceivable that a combination of several genetic variants will dictate the development of complex diseases. With this limitation in this review an attempt is made to evaluate link between the known CNVs to the development of complex diseases. It is heartening that in several cases an association is established between diseases and CNVs, however, the observations need to be independently replicated in other populations.

Future perspective

Until recently SNP was the basis of studying human genome variability and its contribution to phenotypic variations and disease susceptibility. However, with the discovery of other structural variations (deletions, duplications and inversions) a better understanding of the genetic variability or diseases susceptibility is emerging. It has been seen that CNVs contribute to phenotypic change or disease by various molecular mechanisms mentioned elsewhere. Based on such mechanism, the structural variations predispose to susceptibility to various complex diseases. The mechanism of disease development may not be very apparent in several cases. For any new CNV locus, it has to be studied in different populations to catalog its extent of diversity. The observation then has to be validated with a large sample size using the high-resolution simple method yielding distribution map of such CNV.

Another important aspect with the discovery of structural variation is to study its evolutionary perspective. For example, it has been reported in a study that segmental duplication events are found to be affecting the genome variability greater than single base-pair change in chimpanzee and human genomes.71, 72, 73 CNV distribution among various populations should pave the way to understand evolution and mechanism of development of newer CNV. Finally, it is very important to take in account all structural variations to fully understand the mechanism underlying the phenotype, disease development and human diversity. The available variants then can be studied in all possible permutations and combinations to identify a right combination leading to phenotypic changes. In future, when this becomes possible, we may have most phenotypes linked to a combination of few variants. That will be the ultimate outcome of the human genome initiative started in 1980s.

References

1.Feuk, L., Carson, A. R. & Scherer, S. W. Structural variation in the human genome. Nat. Rev. Genet. 7, 85–97 (2006).

2.Lupski, J. R. Structural variation in the human genome. N. Engl. J. Med. 356, 1169–1171 (2007).

3.Lupski, J. R. & Stankiewicz, P. Molecular mechanisms for rearrangements and their conveyed phenotypes in genomic disorders. PLoS Genet. 1, 627–633 (2005).

4.Dhawan, D. & Padh, H. Pharmacogenetics: technologies to detect copy number variations. Curr. Opin. Mol. Ther. 11, 670–680 (2009).

5.Boone, P. M., Bacino, C. A., Shaw, C., Eng, P. A., Hixson, P. M., Pursley, A. N. et al. Detection of clinically relevant exonic copy-number changes by array CGH. Hum. Mutat. 31, 1326–1342 (2010).

6.Redon, R., Ishikawa, S., Fitch, K. R., Feuk, L., Perry, G. H., Andrews, T. D. et al. Global variation in copy number in the human genome. Nature 444, 444–454 (2006).

7.Zhang, F., Gu, W., Hurles, M. E. & Lupski, J. R. Copy number variation in human health, disease, and evolution. Annu. Rev. Genom. Hum. Genet. 10, 45–481 (2009).

Article

YERGUETE,DESAPENATE

2012-01-22T12:26:00.000-08:00

Grupo escolar

Félix Grande

Fila dos, desde abajo.

El sexto, de derecha a izquierda.

En tus ojos dos clavos de silencio,

garrapatas de sino. ¡Cuánto miedo,

cuánto dos ojos, hijo mío, pariente

absoluto y menesteroso!

Yérguete. Desapénate:

disfruta ya del desagravio:

esta cazuela de sosiego

que ambos nos hemos merecido:

yo aquí en tu infancia y tú allá en mi posguerra...

Atiende, hijopaterno de mí:

no van a fusilar a papá:

el maestro don Ramón es buena gente y no va a denunciarlo.

Merienda en paz: mamá no va a tirarse al pozo,

ni se va a ahorcar en el árbol del patio,

oh llanto seco en su jaula de susto,

pobre mamá, pobre mujer tu madre mía,

perdónala en mis canas, hijo.

Perdónate en su sofocación.

Traigo buenas noticias para ti:

tu hermana Luisi, la gran caries

en tu dentadura de amor,

la que tanto se fue en su féretro blanco

vendrá mucho desde la muerte

riendo alborotando a iluminar los corredores

y a besar en nuestras mejillas

lágrimas de resurrección: respira, pues,

hasta el acuífero de tus dos pulmoncillos,

y mírame, ¡victoria!, tan viejo y tan alegre:

Desapénate, hijo. Levántate y merienda

leche espumosa, pan de trigo, rebanada

de mundo; sáciate: desayuna

la vitamina hercúlea de la vida estupenda:

tu duración y mi serenidad.

...Y, por favor, desclávate de allí, sonríe

siquiera un poco para mí: yo, tu padre, tu hijo.

No creas todo lo que deambula

por tu cabeza hereditaria. Te lo digo

en secreto: hoy es siempre todavía. Ssss...

¿No ves cómo se abren

ventanas, puertas, manos ...cómo

el día y la noche se besan en la boca universal?

Desde el eslabón tuyo de la fotografía

haz un esfuerzo: otea

esa liberación en el pañuelo incógnito

que agita para ti el destino:

ahí verás el amor con la A majestuosa

de medio siglo de hondonada junta.

Verás a Guadalupe encaramada al mundo:

conócela: ¡es tu hija, chaval!

¡Pon a sus pies tu pleitesía!

Verás a tus hermanos con su mujer, sus hijos y sus nietos:

todos cenados y almorzados, todos

hambrones de salud y con zapatos, todos risueños

en la ventisca de vivir.

Traigo buenas noticias para ti:

verás España, Europa, América inclusive:

¡viajero tú, como las almas y los pudientes!

...Y verás mi cabeza blanca,

como la de papá, semilla y duración y resistencia

de lo que un día será tu partita de canas.

¿No te das cuenta, desapénate?

Cálmate. Cálmame. Danos por fin la paz que necesitas

para envejecer despacito y morir sonriendo,

hijo mío, mi infancia, fila dos desde abajo

allá en el fondo, acá en el fondo.

LA JORNADA SEMANAL,22 DE ENERO 2012

De Libro de familia, Visor, 2011.

RicardoVenegas

ricardovenegas_2000@yahoo.com

Buscando el rostro de la poesía

En los años preparatorianos fundé con algunos amigos un círculo literario. Pegábamos poemas en un muro los lunes (como los “San Lunes” de Guillermo Prieto); nos interesaba la reacción de los que se detenían para leer. ¿Qué encontrarían en un poema o en la reseña de un libro? Nos agradaba la idea de Octavio Paz: “la poesía y el toreo son artes de exponer”. Por esos años alguien me prestó libros de poemas de Efraín Huerta (Estampida de poemínimos) y de Marco a. Montes de Oca (Pedir el fuego). Más adelante conocí a los Contemporáneos; me sedujo el lenguaje, la prestidigitación que rebasaba lo elemental, el objeto no era real, su sustento estaba –está– en el lenguaje. Luego vinieron las definiciones: “El don de apoderarse de las cosas mediante inesperados bautismos”, “el alma inaugurando una forma”, “un caracol nocturno en un rectángulo de agua”, “el sonido de la pluma cuando cae hasta el fondo del cañón del Colorado”, “una fiesta del intelecto”, “pan de los elegidos, alimento maldito”, también era el “golpe de dados” al que Vicente Quirarte se refiere cuando afirma que “la poesía es una apuesta en favor de la vida. Quien se atreve a servirla acepta existir al filo del tiempo, a verse expuesto a caídas y elevaciones, a tempestades y sequías”.

La gran poeta y maestra Elsa Cross nos preguntó un día en un taller literario si los ahí presentes sabíamos una definición, propia, de la poesía, o si sabíamos qué era. Algunos, dando tumbos, lograron entretejer sus palabras. Yo aún no lo sé, pero, modestamente, creo que es más efectivo preguntar “¿cómo la intuyes?”, y creo que no saberlo es un primer paso hacia la naturaleza de la escritura poética. Algunos maceran el poema, lo rumian, lo mastican largamente hasta que un día tropiezan con la pluma o el teclado y lo concretan. Otros escuchan el “dictado imprevisto” y son poseídos por una fuerza de sentido…

Hasta hoy no hay noción permanente sobre lo que es la poesía, sólo recipientes de fondo y forma llamados poemas. He visto a la poesía, la he escuchado en la música, en el cine, incluso la he tocado… La escuchará, la engullirá, la tocará, la olfateará o la verá quien pueda descifrarla, o más sencillamente, quien la entienda sin que necesariamente la entienda: desde que nacemos todos somos lectores de poesía.

En India se sabe que la poesía, para escribirla, “sólo se entrega a quien ella quiere”, y es creíble desde el ángulo de las preferencias. Algunos serán apolíneos, otros dionisiacos; las enormes distancias que hay entre un poeta como Paz y otro como Neruda, lo ejemplifican (Víctor Toledo dixit). Ambos poetas recorren caminos distintos pero llegan al mismo punto: consuman el poema (el Nobel es coincidencia).

Poesía no eres tú, indica el título del Poemario de Rosario Castellanos. Paco Ignacio Taibo i le contestó a Castellanos con Pit, “el gato culto” que aparecía en la sección cultural de El Universal, cuando dijo: “Poesía no eres tú, es la otra.”

EL DISCURSO MISANTROPICO

2012-01-22T12:18:00.000-08:00

El inconveniente de ser Cioran

Augusto Isla

LA JORNADA SEMANAL,22 DE ENERO 2012

Bajo la luz del Renacimiento, el genial Pico della Mirándola (1463-1494) publicó, a sus escasos veintitrés años, su Oratio de Hominis Dignitatae que le sirvió de prólogo a las novecientas tesis que tituló Conclusiones philosophicae cabalisticae et teologicae. Su célebre discurso fue y sigue siendo un paradigma del humanismo, entendido como exaltación del hombre cuyo libre albedrío lo puede conducir ya a las alturas de un ángel, ya a los abismos de la bestialidad. Como todo humanista, creyó que su pensamiento ayudaría al bienestar del hombre, centro del universo; como todo cristiano optimista y tolerante, si los hay, abrió su corazón a los vientos del sincretismo y de la diversidad. Lleno de amor al género humano, consideró que éste era capaz de vincularse con Dios sin mediaciones, sin rituales, sin dogmas. Pero aquel joven que tempranamente dominó el griego, el árabe, el hebreo... pagó caro su atrevimiento: fue juzgado, condenado por herejía y padeció la cárcel. Sometido y humillado, el brillante discípulo de Marsilio Ficino, ofendió a musulmanes y judíos. Sin embargo, esta flaqueza no logra eclipsar los destellos de su gran Oratio, ejemplo vivo de un humanismo que supo apreciar la grandeza humana.

cada sociedad genera sus humanismos: estudios, ideales, para mejorar la condición humana. La Antigüedad clásica, el Renacimiento, la Ilustración, el romanticismo... Unos miran hacia adelante, otros hacia el pasado. Todos son emanaciones de una inconformidad con lo vivido; unos permanecen como testimonios individuales; otros se convierten en ideologías orgánicas y trascienden como conciencia colectiva. Innovar o revivir; crear o imitar modelos, no importa. El Renacimiento imita a los antiguos, pero quiere superarlos. Todo vale si de lo que se trata es que la humanidad, tan elástica como perfectible, prosiga por un camino ascendente.

En contraste con el humanismo de Pico, en el crepúsculo de una civilización ensoberbecida por su progreso, cabe la sensación de vejez, el agotamiento, el tedio, el vacío. Émile Michel Cioran (1911-1995) expresa con suma inteligencia esa atmósfera decadente. Aunque nace y crece lejos de los grandes centros urbanos, en una Rumania rural, a los veintiún años parece haber leído todo, por así decirlo. El escenario ya no es Rasinari, donde vio la luz primera, ya no es ese universo pastoril, donde ha sido feliz como un “animal salvaje”, ni Sibiu donde, sustraído del paraíso bucólico, el adolescente alimenta su timidez, sino Bucarest donde, insomne, pasea por sus calles, disfruta sus burdeles; ahí donde dice “adiós a la filosofía” y sus sistemas, señales todos de “una vida personal pobre e insulsa”, ahí donde, harto de cultura e historia, escribe En las cimas de la desesperación. En las primeras páginas de este libro, en el capítulo “yo y el mundo”, apunta, entre paréntesis, “escrito el 8 de abril de 1933, el día en que cumplo veintidós años, experimento una extraña sensación al pensar que soy, a mi edad, un especialista de la muerte”.

Todo Cioran está aquí: el sin sentido de la vida, la tanática avidez de sí mismo, la persistente autodenigración: “Soy una fiera de sonrisa grotesca que se contrae y se dilata infinitamente, que muere y crece al mismo tiempo, exaltada entre la esperanza de la nada y la desesperación del todo”; y más adelante: “Soy un fósil de los comienzos del mundo […] soy la contradicción absoluta, el paroxismo de las antinomias y el límite de las tensiones; en mí todo es posible, pues soy el hombre que se reirá en el momento supremo, en la agonía final, en la hora de la última tristeza.” Nunca deja de ver hacia adentro. Ya en París, adonde viaja como becario del Instituo Francés de Bucarest, escribe en una “Carta a un amigo lejano” (1957): “Me veo, en medio de los civilizados, como un intruso, un troglodita enamorado de caducidad, sumergido en plegarias subversivas, presa de un pánico que no emana de una visión del mundo, sino de las crispaciones de la carne y de las tinieblas de la sangre [...] Sí, en mis crisis de fatuidad, me inclino a creerme el epígono de una horda ilustre por sus depredaciones, un turanio de corazón, heredero legítimo de las estepas, el último mongol.”

Si aquel joven no se suicida, es porque le repugna “lo mismo la vida que la muerte”. Cioran vivirá ochenta y cuatro años. En el transcurso de su larga vida, continuará observándose, y desde esa experiencia interior centrará su atención en el hombre. No cambiará su actitud hacia el mundo. Se odiará a sí mismo y odiará al género humano. He aquí un humanismo al revés, una misantropía. Y escribirá y escribirá. No por gusto ni por capricho, sino como una catarsis.

Desde la perspectiva individual –soledad, desesperación, sufrimiento– la misantropía de Cioran dibuja un conflicto con el mundo; pero vista desde la dimensión cultural, ¿el narciso negro que lo recorre no es reflejo de su tiempo? ¿No están ya el aburrimiento, el tedio y el vacío, en Baudelaire, en Mallarmé? Pero Cioran es algo más que un simple crítico de la modernidad; es un desencantado de la civilización, innecesaria para él; su desaliento se remonta a los orígenes: el nacimiento del hombre está marcado por la insignificancia; es poca cosa. El hecho de que se considere el centro del universo es una cosa; que lo sea, otra. En el fondo, es una criatura megalómana; “un mamífero que debería haber tenido un destino mediocre, está comprometido con un destino que le queda demasiado grande”. El hombre está maldito desde sus comienzos. Por eso, lo que inventa se vuelve contra él, y cuanto más se agita, más se acerca a su final. La historia es la negación de todos los valores, la prueba de su fracaso: “Todos sus sueños se estrellan contra lo grotesco del desarrollo histórico.” El devenir humano es también un antídoto contra las utopías, esos “monstruosos cuentos de hadas”. Y sin embargo, las necesita; son su fuerza, pues las ilusiones contenidas en ellas, como la libertad, por ejemplo, son imprescindibles para soportar la vida, para evadir la atroz condición humana. El progreso mismo, salvo en su aspecto tecnológico, es una ilusión, la “utopía por excelencia”, mas, por grande que sea, no lo salvará. Pienso en todos esos bobos que idolatran a Steve Jobs.

El discurso misantrópico de Cioran es un grito, un estallido, una bofetada; “una sucesión de exclamaciones”; sus deslumbrantes verdades no emergen de una lógica serena, sino de una inspiración furiosa. En vano discutir con él. De ahí que en sus “Reflexiones sobre Cioran” Susan Sontag desatine debatiendo con las “argumentaciones” del rumano: Cioran no argumenta; clava su ponzoña con rencorosa precisión. Por eso el aforismo es su arma más afilada; en él encuentra la palabra más justa, la más hiriente injuria contra sí mismo, contra la vida, contra Dios. A Cioran se le toma o se le deja en sus claridades y en sus sombras. Hay quienes devoran todo lo que escribe, por coincidir con su cansancio, con su rabia o por mero esnobismo; pero también hay quienes pronto lo abandonan, como un amigo a quien le di a leer Breviario de podredumbre, por considerarlo monótono, hiperbólico y acaso insincero.

Cioran escribe sus primeros cinco libros en rumano. Pero en 1947 decide redactar en francés; era, para él, un idioma odioso “con todas sus palabras pensadas y repensadas, afinadas y sutiles hasta la inexistencia, volcadas hacia la exacción del matiz, inexpresivas a fuerza de haber expresado tanto, de terrible precisión, cargadas de fatiga y de pudor, discretas hasta en la vulgaridad [...] Una sintaxis de una rigidez, de una dignidad cadavérica las estruja y les asigna un lugar de donde ni el mismo Dios podría desplazarlas”; detesta sus rigores, empero asume el reto y lo conquista. Él, tan indiferente a toda gloria –aspiración ridícula– anhela secretamente ser leído. Breviario de podredumbre fue un martirio: lo rehace cuatro veces para no ser considerado un “meteco”. Este libro, extraído según él, de sus “bajos fondos” para injuriarse e injuriar la vida, le abre el camino de la consagración como uno de los grandes escritores en lengua francesa. Escritos en rumano o en francés, los títulos mismos de sus libros llevan la impronta de su morbidez: Silogismos de amargura, La tentación de existir, Desgarradura, El inconveniente de haber nacido. . . Todos parecen ser variaciones del primero, a cada vez más concisos, más fragmentarios, en ascenso sonoro como el Bolero, de Ravel.

entre el creer y el no creer, en la imposibilidad de la fe –invención cristiana–, así vive su alma atormentada, llena de amor a los místicos, deseosa de eterna calma, de un éxtasis que por momentos experimentó en su estancia alemana allá por los años treinta. Como todo blasfemo es un pensador profundamente religioso. ¿Cristiano a su pesar? Como Nietzsche, aborrecía el cristianismo ¿Pero acaso no lo llevaba en la sangre, como una tara? Su padre era sacerdote ortodoxo; mas a diferencia del germano que creía en el hombre y en su capacidad de superarse a sí mismo, Cioran pensaba que creer en el hombre es una necedad, una locura. En La tentación de existir, la retórica anticristiana se concentra en el odio a san Pablo, “un judío no judío, un judío pervertido, un traidor [...] Cuando ya no sé a quién detestar, abro las Epístolas y en seguida me tranquilizo. Tengo a mi hombre [...] Una civilización podrida pacta con su mal, ama el virus que la roe, no se respeta a sí misma, deja a un san Pablo ir y venir. . . Por esto mismo, se confiesa vencida, carcomida, acabada. El olor de la carroña atrae y excita a los apóstoles, sepultureros ávidos y locuaces [...] El paganismo les trató con ironía, arma inofensiva, demasiado noble para doblegar a una horda insensible a los matices.” Y sin embargo, ¿no se asemeja Cioran al de Tarso, no desprecia, como éste, el mundo, la carne; no mira con malos ojos toda sensualidad, no incluso percibe en el comer “un acto de envilecimiento cotidiano”, aunque a diferencia del apóstol, Cioran nada espera de su renuncia?

fernando Savater, en un hermoso libro, Ensayo sobre Cioran, por el que luchó durante muchos meses para que fuese aceptado como tesis doctoral en la Universidad Complutense de Madrid, dio en el clavo en su apreciación: “La única tarea [de Cioran], si se la puede llamar así, es el desengaño.” Es comprensible que las demoliciones del pensador rumano fueran rechazadas como habitantes de la academia filosófica, que alguien proveniente de la periferia del mundo y aspirase a “sensibilizarse a la oscuridad que la policromía ilusoria pretende enmascarar” fuese indigno de ser considerado como filósofo a despecho de que sus reflexiones sobre la existencia, el tiempo, la vida, Dios, la historia, la libertad... se abordaran de otra manera, evitando toda pedagogía, gozando la negación de la felicidad, de la vanidad de todo esfuerzo, del orden mismo del mundo. Difícil resulta la aceptación de alguien al que se le revela la inanidad del ser, ese despertar de la conciencia que riñe con “las personas decentes y de provecho”, esa violencia que admite la eternidad de la miseria, ya la interior, ya la de la vida social. Pues que el hombre ensucia y degrada todo lo que lo rodea. En lo personal mucho agradezco a Savater que haya despertado mi curiosidad y que de su mano muchos lectores de habla hispana nos hayamos adentrado en el atrayente infierno cioraniano.

en política, ¿qué es Cioran, de izquierda o de derecha? Ninguna calificación podría atraparlo. Para él, todas las sociedades son malas, pero hay peores. Así, rechaza lo mismo la sociedad burguesa, ilusión libertaria y “quintaesencia de la injusticia “, que la tiranía comunista. Rechazar o aceptar el orden establecido, da igual; nada cambiará. En su ensayo “El pensamiento reaccionario” –a propósito de Joseph de Maistre–, leemos: “Lo trágico del universo político reside en esa fuerza oculta que conduce a todo movimiento a negarse a sí mismo, a traicionar su inspiración original y corromperse a medida que se afirma y avanza. Porque en política, como en todo, nadie se realiza sino a través de su propia ruina.” Cioran no pertenece a nadie; el juvenil pasaje de su adhesión a La Guardia de Hierro –movimiento fascista, ultranacionalista, antisemita– le produce a la postre, “vergüenza intelectual”. Y aquí, de nuevo, Sontag se equivoca atribuyéndole “una sensibilidad católica de derechas”. Cioran es un proclamador de la pasividad, de la negación, incluso de ese no hacer nada en la vida. Un escéptico desesperado.

Escéptico, el rumano duda incluso del valor del intelecto. Cioran prefiere la compañía de la gente humilde –pescadores, campesinos–, de aquellos que nada saben o cuya sabiduría es no convencional: “un barrendero sabe más de la vida que un filósofo”; y por eso mismo logran el acceso a la felicidad. Un escéptico que, sin embargo, no cesa de admirar. Ejercicios de admiración lo ponen contra la pared de sus dubitaciones; admira a Jorge Luis Borges, a Mircea Eliade... a María Zambrano, a quien dedica palabras conmovedoras como éstas: “Quisiéramos consultarla en los momentos cruciales de una vida, en el umbral de una conversión, de una ruptura, de una traición, en la hora de las últimas confidencias, graves y comprometedoras, para que nos revele y explique a nosotros mismos, para que nos dispense, por así decirlo, una absolución especulativa, y nos reconcilie tanto con nuestras impurezas como con nuestros callejones sin salida y nuestros estupores.”

cioran, el pensador, camina por una senda, la del asco a la gente y a sí mismo; Cioran, el hombre inmerso en su cotidianeidad, ¿por otra? Responde a las cartas de personas desconocidas, acepta entrevistas, se muestra compasivo; ofrece refugio a víctimas de la persecución durante la guerra; se ocupa de la suerte de sus sobrinos; derrocha gentileza, simpatía y humor cuando recibe visitas en su departamento de París, “ese cementerio bullicioso” que será su cárcel a partir de 1937; disfruta ya las caminatas en el parque de Luxemburgo, ya las veladas con sus amigos. Piénsese lo que se quiera; él es así: si por un lado, nos dice que “los sentimientos entre amigos son falsos”; y por otro, confiesa su cariño hacia los suyos, como Samuel Beckett. Es contradictorio, pero nunca pierde la lucidez, ni siquiera en el enunciado de sus paradojas: “Que la vida no tenga sentido es una razón para vivir, la única, su realidad.” Si como pensador arroja sus flechas envenenadas, después, en su diario vivir, las recoge y las guarda. Así, no obstante que nos diga que “inclinarse hacia el bien es una aberración, una violencia con el ser”, si alguien lo consuma es por una especie de distracción del orden; pues bien, él acaba siendo un distraído, un hombre pleno de bondad, un hombre de luz, como suele decirse.

ya viejo, Cioran se deja retratar. Sus profundas arrugas deletrean un inmenso sentimiento de duelo. Viéndose tal vez en el espejo de Diógenes, en El ocaso del pensamiento (1940) se pregunta: “¿Qué habrá impulsado a Diógenes hacia la catastrófica ruptura del hechizo ingenuo, delicado y envolvente de la existencia? [...] ¿Qué consuelo le habrá faltado, qué caricias le truncaron, para separarle de la felicidad a la que debió ser sensible incluso si nació con vocación de réprobo?” Algo perdió también Cioran en el camino, como el entrañable cínico, como ¿las fresas salvajes del personaje de Bergman, el sombrero que guarda el patriarca de La gata sobre el tejado caliente? ¿El trineo de El ciudadano Kane, de Orson Wells? Sí, algo que nada compensa. Ni los amores, ni la gloria, ni las cosas acumuladas en el desván de la memoria; algo que lo obliga a mirar hacia la nada, hacia las cenizas que son “el desenlace de todo”, y en lo que sustenta su humanismo al revés, su misantropía.

Tal vez la clave esté en las últimas páginas de Ejercicios de admiración cuando nos dice: “Yo nací cerca de los Cárpatos y adoré el pueblo donde pasé mi infancia. A los diez años tuve que abandonarlo para ir al liceo de la ciudad. Fue una experiencia terrible que nunca olvidaré: el espectáculo de un animal llevado al matadero. Los condenados a muerte deben conocer sensaciones semejantes antes del suplicio final. Yo sabía que lo perdía todo, que era expulsado de mi propio edén y que no merecía ese castigo. Cuando pienso en ello tras una vida entera, me doy cuenta de que tenía razón de haber reaccionado así, que en el fondo la civilización es un error y que el hombre debería haber vivido en la intimidad con los animales, apenas diferente a ellos. En ningún caso debería haber ido más allá del estatuto del pastor. La conclusión de una vida se reduce a la constatación de un fracaso.” Pero ese fracasado, ese hombre que se consideraba un holgazán, alguien que no servía para nada ni quería servir para nada, nos ha dejado un testimonio tan cruel como grandioso, que perdurará con su lucidez mientras se prolongue la aventura del hombre.

El caballo de Turín:

más allá del bien y el mal

Antonio Valle

A Luis Tovar

LA JORNADA SEMANAL , 29 DE ENERO 2012
Hay casos en que los psicólogos somos como los caballos:
nos sentimos inquietos cuando vemos moverse
ante nosotros nuestra propia sombra.
El ocaso de los ídolos,
Friedrich Nietzsche
Como debe ser –antes de publicar sus notas sobre películas que se encuentran en exhibición–, algunos críticos y especialistas tuvieron cuidado de no revelar demasiadas claves de El caballo de Turín. Aunque varias de sus reflexiones privilegiaban el valor “indiscutible” que tiene la imagen sobre el resto de los elementos, me pareció que aunque este filme no hace concesiones a las tendencias discursivas más burdas, tampoco es una obra que apunte hacia el cine mudo. Es cierto, en esta historia se dicen pocas palabras pero, justamente por eso, son imprescindibles. Otros ensayistas celebraban la fotografía de Fred Kelemen pero decían que en ella había algo de somnífero. En efecto, algunos plano-secuencias pueden provocar reacciones tipo “ensoñaciones diurnas”, ya que el tiempo en este filme es parecido a la sensación del paso del tiempo que tienen algunos sueños; aunque desde las primeras tomas cerradas del caballo, y especialmente los retratos inspirados en el poderoso cine expresionista alemán, es evidente su fuerza extraordinaria.
En cuanto a la música de Mihály Vig, seguramente inspirado por Nietzsche –que en El origen de la tragedia abordó uno de los ensayos más lúcidos en torno al espíritu de la música–, ésta es una corriente subterránea que no deja de latir durante todo el filme. Por supuesto, la clave argumental se encuentra en la mítica escena del caballo de Turín, anécdota del nervous break down irreversible que sufrió el filósofo alemán en 1889. En esta cinta, más que al concepto del eterno retorno, Béla Tarr hace el recorrido de un viaje para el que ya no habrá regreso. Una “inocente” transgresión irá revelando la intensidad dramática, cuando el protagonista “venza” la última resistencia con la que oculta su aviesa intención. Invalidado de la mano derecha, tan clásico como siniestro, el personaje codicia, con el ojo cíclope de las fuerzas pasionales desatadas, el alimento crudo que terminará engullendo. Así quebrantará la frontera que separa, como dice Lévi-Strauss, a lo crudo de lo cocido, es decir a la naturaleza de la civilización.
No puedo evitar decir que no hay nada más desalentador para los espectadores potenciales que avisarles: “en este filme no hay una historia”, ya que esta cinta ha sido confeccionada mediante una trama de zurcido –fino e invisible– extraordinariamente consistente, que recuerda las milenarios enredos entre Tiestes y Pelopia; pero también al caso más reciente de la austríaca Elizabeth Frtzl, quien permaneció retenida por su padre en un sótano durante veinticuatro años. Es asombroso descubrir lo que se propone Béla Tarr cuando presenta a un grupo de gitanos, paganos y felices, atravesando el páramo mortal en el que permanecen azogados los protagonistas. O que un monólogo, por demás contemporáneo, rebose de referentes nihilistas y apocalípticos. En El caballo de Turín –al cual, por cierto, algunos identifican como yegua; ¿acaso estarían pensando en The nightmare, la pesadilla de Borges?–, el animal se niega a beber agua de un pozo que fatalmente está a punto de secarse, lo cual, simbólicamente, significa que se han roto los vasos que comunicaban las aguas del inconsciente con la tierra yerma. No en balde los aforismos cáusticos escritos en Más allá del bien y el mal, cuyo subtítulo es: Preludio para una filosofía del futuro, son considerados como precursores de otro de los llamados maestros de la sospecha, el creador austríaco de El malestar en la cultura. He aquí dos ejemplos de ello. “En último término lo que amamos es nuestro deseo, no aquello que deseamos.” O: “–Esto no me gusta.– – ¿Por qué? –Porque no estoy a su altura.” Más allá de lo evidente, y para estar a tono con El caballo de Turín, donde no sólo no se impone lo “visual” sobre los demás recursos cinematográficos, sino que justamente gran parte de lo que no se ve en pantalla –pero que acaso alcancemos a vislumbrar en el “teatro de luz y sombras” personal–, es lo verdaderamente significativo. Como dice el mismo Nietzsche, “cuando estamos ante la presencia de las cosas más raras, es difícil –por mucho que nos esforcemos– observar el proceso si no es con ayuda de nuestra invención”. Precisamente “eso” –que no vemos– es el “ingrediente” invisible con el que Béla Tarr desafía a nuestra inteligencia. Siendo consecuente con el rigor del guión, al final, el maestro húngaro de plano nos deja ya sin las mínimas palabras, sin imágenes ni aliento, y nos abandona en “la nada”; en medio de esa breve eternidad que es la bóveda de un cine a oscuras; eso sí, rodando hasta el fondo de cada uno en la compañía de un chelo abismal. Es conveniente recordar la presunción de Lévi-Strauss, que consideraba a la música como la mejor vía para aprehender el mythos. Esta excelente pieza cinematográfica hace un homenaje a un hombre de letras que “respiraba” música, porque gracias a ella “las pasiones pueden gozar de sí mismas”. Nietzsche estaba seguro de que “ver las cosas de una manera profunda y radical es ya una violación, un deseo de hacer daño a la voluntad básica del espíritu que tiende siempre a la apariencia y a lo que se encuentra en la superficie”.
Este filme confirma cuán ridículo es asegurar que una imagen vale más que mil palabras. El filósofo que amaba a Dionisos (el que sabía mezclar la música) estaba seguro de que la humanidad eternizaba (fijaba) sólo aquello que ya no podía “vivir ni volar”. Cuando se abrazó a un caballo escarnecido en una calle de Turín, después de pedirle perdón a la bestia, el vibrante filósofo enmudeció para siempre. No es imposible que, antes de morir, Nietzsche escuchara en alguna armonía sus últimos “viejos y queridos… malos pensamientos...” Finalmente, lo obvio (o casi): la cinta del húngaro Béla Tarr está construida con imágenes y palabras inolvidables, con riadas luminiscentes y sonoras que tienen el poder de provocar emociones terribles y extraordinarias.

EL ESTADO DE BIENESTAR

2012-01-20T15:04:00.000-08:00

Economía Moral

La necesidad de refundar la política social /VI

Objetivo para transformar el Estado MEXICANO en un auténtico Estado de bienestar: EB

Julio Boltvinik

LA JORNADA,20 DE ENERO 2012

Se debe definir como objetivo central del proyecto de nación la riqueza humana o florecimiento humano, esto es: desarrollo y satisfacción de las necesidades humanas y desarrollo y aplicación de las capacidades humanas de todos y todas. Lo que se busca es no sólo bienestar sino desarrollo, florecimiento, enriquecimiento humano. No sólo la vida buena, también la vida plena. Debe promoverse aquello que propicie el cumplimiento del objetivo y rechazarse lo que lo frene. Requisito para alcanzarlo es la articulación virtuosa de las políticas sociales, culturales y económicas, lo cual a su vez supone superar la separación tajante (hoy vigente) entre las dos primeras y la tercera. Objetivos derivados centrales son la regulación democrática de los mercados y la desmercantilización de los bienes y servicios básicos y de la vida. El capitalismo, por la desigualdad y enajenación que le caracterizan genera inevitablemente pobreza económica (PE) y pobreza humana (PH). Los más avanzados EB han aminorado la desigualdad generadora de PE y así han logrado reducir ésta sustancialmente (Véase gráfica que muestra este logro). En cambio, al no haberse fijado el objetivo de eliminar o reducir la enajenación, han avanzado menos en la reducción de la PH.

¿Cómo reconocemos un EB? Una respuesta es que un EB auténtico es aquel en el cual la mayor parte de sus actividades rutinarias están dirigidas a atender las necesidades del bienestar humano. De acuerdo con este criterio, muchos estados autoproclamados como EB no son tales. Otra respuesta deriva de la distinción entre EB residuales e institucionales. Mientras los primeros sólo asumen la responsabilidad cuando familia o mercado fallan (principio de subsidiariedad) y restringen sus compromisos a grupos sociales marginales y ‘merecedores’ (niños, mujeres, ancianos), los segundos atienden a todos, son universalistas y prevalece un compromiso institucionalizado con el bienestar. Un EB residual no es un auténtico EB, como tampoco lo es aquel que restringe su compromiso a grupos sociales marginales y merecedores (niños, mujeres, ancianos). Cuando los beneficios son universales, pero magros, sí estamos ante un EB que, sin embargo, logra avanzar muy poco en la desmercantilización, puesto que el sostenimiento de la vida sigue dependiendo centralmente del mercado. Tanto el universalismo de beneficios uniformes y bajos como el asistencialismo focalizado a la pobreza extrema (que prevalece en México) generan un dualismo social en el cual los estratos altos se atienden vía el mercado y los magros beneficios públicos quedan para los de a pie. Cuando ello ocurre, los estratos altos dejan de apoyar el EB y resisten el pago de los impuestos requeridos.

Para construir en México un EB auténtico deben extenderse los derechos sociales, que tienden a disminuir el estatus de mercancía de las personas y, en el límite (cuando se incluye el derecho a un ingreso ciudadano universal), permiten que el nivel de vida se independice del mercado, que el sostenimiento de la vida no dependa de la venta de la fuerza de trabajo. Algunos criterios y medidas iniciales para construir tal EB son: a) El EB debe conformarse por la administración pública en su conjunto (no sólo por los sectores sociales). Se requiere reformar la Constitución para que el Banco de México se ocupe también del crecimiento económico y no sólo del control de la inflación. El proceso de interacción para definir los ingresos y gastos públicos debe modificarse: la Ley de Ingresos no debe aprobarse (como ahora) al margen de las necesidades de gasto. Debe instaurarse una mecánica de iteraciones múltiples entre gasto requerido y posibilidades de ingresos (incluyendo reformas legislativas). b) Para financiar el EB no basta con la austeridad en el gasto corriente ni el rigor fiscalizador; se requiere un sistema impositivo más progresivo y que recaude más. c) La auténtica lucha contra la pobreza supone la disminución sustancial de la desigualdad del ingreso que importa: reducirlo en la cúspide y aumentarlo en el abismo. Como muestra la historia, la pobreza se puede erradicar sólo cuando la curación es mero complemento de la prevención y no, como ahora, la receta única: se espera a que los hogares se empobrezcan y lo demuestren para curarlos con transferencias minimalistas y condicionadas. No hay mejor prevención de la pobreza que el universalismo desmercantilizador. d) Debe ponerse en marcha un programa de recuperación del salario mínimo (SM) diseñado para duplicar cada diez años su poder adquisitivo real. e) Sobre las transferencias monetarias: i) deben pasar de condicionadas y focalizadas (a hogares individuales) a incondicionales y universales (o, transitoriamente, a focalizadas territorialmente) y deben fundarse en un derecho específico; ii) la beca educativa del Oportunidades debe universalizarse a todos los estudiantes de escuelas públicas desde preescolar hasta preparatoria; iv) se debe instituir una nueva transferencia monetaria universal e incondicionada para todos los hogares con menores que aún no asistan a la escuela; e) Crear el Servicio Nacional de Salud (SNS) Gratuito y Universal (financiado con impuestos generales) que comprenda los tres niveles de atención y la rehabilitación, y que no excluya ningún padecimiento, ninguna persona, ningún medicamento, consolidando en una única institución pública las diversas instituciones de salud hoy existentes; f) universalizar la seguridad social por tres vías: i) transformar las transferencias para adultos mayores del DF y del gobierno federal en la pensión de la rama no contributiva de la seguridad social cubriendo a todos los mayores de 65 y más (o menores de esa edad que no puedan trabajar por razones de salud o discapacidad) del país e ir reescalando su monto hasta llegar a un salario mínimo; ii) afiliar a todos los que trabajan en el sector informal y otorgarles durante los días que cubran las constancias de incapacidad (por enfermedad o accidente o cualquier otra causa) emitidas por el SNS, al menos un salario mínimo diario; iii) reformar el sistema de pensiones del IMSS y del Issste por sistemas solidarios que garanticen a todos una pensión digna; g) Tareas educativas prioritarias: elevar la calidad de la educación; ampliar los horarios de preescolar y primaria conformando la escuela de tiempo completo; activar la educación para adultos con la meta de que todos los de 15 años y más tengan un nivel educativo al menos de secundaria; ampliar sustancialmente la oferta de espacios en educación media superior y superior, y la oferta de estancias infantiles (guarderías) gratuitas para todas las familias que necesiten o quieran el servicio de cuidado diario de menores. h) Prohibir toda publicidad de alimentos chatarra y su venta en cualquier establecimiento educativo o público; incluir, en todas las escuelas públicas de tiempo completo una comida caliente además de revisar el contenido de los desayunos escolares (ambos gratuitos); subsidiar los alimentos básicos.

http://julioboltvinik.org/ - julio.boltvinik@gmail.com

Añadir un comentario

Dialectica

YEO

Así debe ser esta columna siempre. sin propaganda PRDista

Responder a este comentario

Gusto

Olgalina Franco Jarquín

Me da gusto volverte a encontrar y leer lo escribes, saludos.Responder a este comentario

Una luz en el camino

Jose Ramos

Gracias a Dios que todavía existen personas con buenas ideas para tener un país mejor. Estoy completamente seguro que se puede lograr, vamos por ello. Aprendan señores políticos, no solo llenen sus bolsillos, también pueden mejorar su país y su gente.Responder a este comentario

LA DIGNIDAD

2012-01-18T16:19:00.000-08:00

Dignidad

Claudio Lomnitz*

LA JORNADA, 11 DE ENERO 2012

Hoy, con tanto indignado, vale la pena esbozar una genealogía del concepto de dignidad. El asunto abre una ventana al trabajo que tienen las izquierdas por delante, si quieren conseguir una fórmula de unidad que vaya más allá de una breve coyuntura, o de arreglos de cúpula.

La palabra dignidad deriva del latín dignus, que significa merecedor. Tener dignidad es ser merecedor de algún reconocimiento. Por eso, en el medievo, la dignidad se refería por igual a una cualidad noble que a los atributos que representaban un cargo. Todavía hoy, la palabra “dignatario” se refiere a una persona que ocupa un cargo y que cuida de su dignidad. Así, la dignidad no es tan sólo un sentimiento privado, sino también un atributo visible y público de los cargos honrosos. Si se profana ese aspecto externo de la dignidad, el sujeto ofendido puede exigir su restitución. Es el origen del duelo de honor, que combina la competencia de los juegos grecorromanos con la lucha por la reintegración de la dignidad mancillada.

En casos donde quedaba ofendida la dignidad de una persona débil –una mujer, por ejemplo, o un viejo– o ausente, la parte ofendida podía ser representada por un sustituto o campeón, que podía igualmente restituir la dignidad de la parte ofendida. Más adelante, la ley se erigiría en la campeona de la dignidad del débil.

Importa entender a todas éstas, que antes de la modernidad la dignidad no era un atributo general, sino sólo de algunos, de los merecedores, de los nobles. Por eso el vocablo “villano” pasa de referirse a los plebeyos a representar a todo el que carece, justamente, de dignidad y, por tanto, de empatía, sutileza y bondad. (“El buey suelto, bien se lame, contestó el villano vil / tengo el ganado en la sierra, y a mi ganadico quiero ir”.)

El honor femenino, preservado en la virginidad de la doncella, también tenía sus dignidades que lo hacían público: el velo era tan parte de la dignidad de la doncella como la casulla lo era de la misa y del cura que la oficiaba. El desarrollo de una cultura del honor, y su popularización a punta de espada, fomentó que la dignidad pudiera quedar plasmada en cosas igual de frágiles que un velo, como la pluma blanca del sombrero de Cyrano de Bergerac, o el “¿qué me ves?” de un villista beodo.

No es hasta la Revolución Francesa cuando se extiende la dignidad al género humano todo. “Los derechos del hombre y del ciudadano” fue una fórmula que significaba que todo humano era digno de reconocimientos simple y llanamente por serlo. Y desde entonces se abrió un horizonte de lucha por ampliar derechos, prerrogativas y dignidades. En el siglo XIX, la lucha contra la esclavitud y por los derechos de la mujer fue la punta de lanza de este gran esfuerzo por ampliar la dignidad.

En el XX, se sumaron la lucha contra del racismo, contra la discriminación sexual y contra la discriminación al migrante, entre otras.

Pero aquí vale la pena reflexionar en dos cosas. Primero, importa distinguir entre el reclamo de dignidad de quienes no la han tenido y el reclamo del indignado. La revuelta zapatista en Chiapas, por ejemplo, fue un reclamo de dignidad para indígenas y campesinos, o sea un reclamo de ampliación radical del reconocimiento ciudadano. Fue un reclamo de extensión de derechos, de autonomía y de autogobierno.

La indignación de los indignados de hoy es otra cosa: una expresión herida de gente que tenía ya sus dignidades, ante expectativas violadas e incumplidas. Por eso la indignación no tiene en sí misma signo político, mientras la demanda de dignidad de quienes no la han tenido sí que lo tiene. La exigencia de dignidad para las mujeres, los indios, los negros, las minorías religiosas o los migrantes indocumentados será siempre una demanda progresista, mientras la demanda de restitución de una dignidad ofendida puede ser cualquier cosa. Igual de indignados están los anarquistas de la Plaza del Sol que los miembros de Tea Party en Iowa. De hecho, la restitución de la dignidad es un reclamo políticamente delicado, que igual aprovecha un gobierno autoritario que se erige en “gran dignificador”, que una democracia social, que busca la verdadera ampliación de derechos.

Finalmente, esta breve arqueología también recuerda que la dignidad no es sólo un atributo del individuo, sino, y muy principalmente, de ley y de los cargos de quienes la sustentan. Desde el cargo público se defiende la dignidad del débil. Mientras no haya dignidad para el cargo, es difícil que la haya para los débiles. Por eso nuestros diputados, gobernadores y síndicos deben cuidarse de no hablar como verduleras.

* Antropólogo, profesor de la Universidad Columbia. Autor de Idea de la muerte. Publicó junto a Friedrich Katz El Porfiriato y la Revolución en la historia de México; una conversación. Colaborará catorcenalmente.

Añadir un comentar

agradecimiento

casimiro buenavista

gracias!

Felicitación

Rafael Gutiérrez

¡Bienvenidas las colaboraciones de Claudio Lomnitz!

SENECTUD Y POSTMODERNIDAD

2012-01-17T16:06:00.000-08:00

Senilidad y Postmodernidad

Ilustraciones de Marga Peña

Fabrizio Andreella

fabrizio108@yahoo.com

LA JORNADA SEMANAL 15 DE NERO 2012

“Ponte de pie ante las canas y honra el rostro del anciano.” Con el lenguaje tajante de quien no admite derogaciones, así prescribe Dios a su pueblo a través de Moisés, según se lee en el Levítico (19,32). Hoy, en los países más ricos del planeta, una conducta social conforme o cercana a esa ley parecería una forma vacía y fastidiosa de tradicionalismo.

Frente al espejo, despertando en la mañana con el cuerpo adolorido, el anciano ve su rostro como una delación. Cada arruga lo acusa de no profesar la religión de la modernidad –la juventud– y sus valores sagrados de belleza y performance. Un culto que los regímenes totalitarios del siglo XXsiempre han alimentado con la exaltación de cuerpos fuertes y disciplinados, aptos para exhibir la sumisión de la voluntad individual a la gloria colectiva.

Para sobrevivir a su senescencia, el mundo occidental hiperdesarrollado, que concibe la libertad como derecho de acceso a la visibilidad en el escaparate mediático, ha enmendado ligeramente ese culto de manera astuta: todo mundo, a cualquier edad, puede considerarse joven y actuar como tal.

Con este juvenilismo, la tijera entre natura y cultura, entre realidad e imaginación, entre deseo y goce, se abre implacablemente. Aquí es donde la experiencia concreta de la vejez sufre, púdicamente escondida a los demás, las heridas psicológicas de la ineptitud y de la insuficiencia. Porque la vejez, en un mundo senil que sueña y simula la juventud, puede llegar a ser un dolor ocultado.

Antes de fallecer, Alicia Montoya dijo: “Quiero que la muerte me agarre viva.” Creo que bien habría aprobado y aplaudido a Amélie Van Elsbeen, que hace dos años, en Bélgica, luchó para conquistar el derecho a morir con la eutanasia. No tenía ningún problema de salud, ninguna discapacidad o dolor físico. ¿Cuál era entonces el motivo de su súplica? El problema era su edad: tenía noventa y tres años y se sentía cansada de vivir. Su vejez era para ella incurable e insoportable.

Fácil sería “clinicalizar” la experiencia de Amélie tachándola de demencia depresiva senil. Pero su muerte (sí, su triste victoria llegó) revela mucho más si damos un paso atrás y nos preguntamos cuál es el contexto social en el cual puede nacer la aspiración a acabar con la vida por añeja.

Abraham o cualquier campesino de antaño moría “viejo y saciado de la vida” porque estaba dentro del ciclo natural de la vida; porque ya había recibido de su vida, al final de sus días, todo lo que la existencia le podía ofrecer; porque no le quedaba ningún enigma que resolver y podía así sentirse “satisfecho”. Por el contrario, un hombre civilizado, inmerso en un mundo que se enriquece continuamente con saberes, diferentes ideas y nuevos problemas, puede llegar a estar “cansado de la vida”, pero no “saciado”.

Son palabras de Max Weber, que ya en 1919, en La ciencia como vocación, nos indicaba los peligros psicológicos de una sociedad que cultiva el “progreso sin límites”, los peligros que llevaron Amélie, cansada y no saciada de vivir, a preferir la muerte.

En la relación entre progreso y soledad se encuentra una de las claves de la condición psicológica senil en el así llamado Primer Mundo. La tecnología ofrece muchas prótesis para vigorizar los sentidos y los órganos ablandados por la edad. Pero esta aséptica compasión material no puede narcotizar la soledad y el confort médico, técnico y mediático no puede neutralizar la necesidad afectiva de intercambio. Ser atendido no es lo mismo que ser amado. Ser confortado no es lo mismo que ser apreciado. Ser respetado no es lo mismo que ser importante para los demás.

III

La brecha digital, ese concepto que ilustra la desigualdad geográfica y socioeconómica en el acceso a las tecnologías, es una realidad también generacional. Claro, hay muchos ancianos que usan con placer celulares e internet, pero no es lo nuevo el problema, sino lo rápido de la evolución tecnológica que nunca permite la sensación de “saciedad”. En la historia del hombre, la incesante y apresurada innovación de los instrumentos que nos ayudan a vivir es algo peculiar de los últimos treinta años. Esa especie de “síndrome de las piernas inquietas” de la tecnología siempre es declamada como una de sus mayores virtudes, y una reflexión sobre el desequilibrio psicológico provocado por un ambiente que nunca se detiene es indudablemente marginal. Pero ese trastorno bien lo conocen los ancianos, que no se entusiasman con una vida ritmada por el tambor obsesivo de la última novedad.

En efecto, la vejez se apoya en el bastón de actos, palabras y pensamientos semejantes entre sí. Un hábito que es al mismo tiempo timón y brújula para alojarse en el mundo. La etimología nos sugiere que “hábito” es palabra que tiene que ver con la protección ofrecida por la habitación y el vestido. ¿Y qué tiene de malo lo habitual? Dicen que la costumbre es enemiga de la inteligencia, pero ¿por qué lo que en la juventud se valora como obsesión apasionada en la vejez se desdeña como boba rutina? ¿Y por qué uno no puede escoger por sí mismo los aspectos de la vida que quiere lanzar en el viento del cambio y aquellos que prefiere abandonar a las aguas tibias de los hábitos ya adquiridos?

La vejez ya no es, como en el pasado, el reino de la sabiduría conquistada gracias a la cantidad de experiencias y conocimientos adquiridos. Victor Hugo veía la vejez como “la adolescencia del infinito”. Pero el anciano hoy no ama el futuro. Descansa mirando hacia donde sus ojos pueden llegar más lejos, o sea en el pasado. Allá es donde no sufre marginación y su autoestima no se desmorona. Allá es donde no hay lifting, botox o cosméticos que oculten la obscenidad social de su figura moldeada por los años.

El cuerpo es hoy un figurante en el showde la modernidad, el instrumento para mantener el poder de la visibilidad; por eso es un cuerpo ensamblado con los instrumentos de la medicina, la cirugía, el maquillaje y la moda. La verdad exhibida y declarada por el cuerpo viejo es escondida por la falsificación estética socialmente aceptada.

Hoy la vejez es el territorio desolado donde una mente que preferiría las certidumbres de una rutina y de los recuerdos sufre el cansancio psicológico de los cambios continuos; donde un corazón que quisiera sentir su función familiar y social vislumbra en los rituales del amor calendarizado toda su inutilidad; donde un cuerpo que demandaría discreción, pudor y dignidad, se enfrenta con el reto grotesco del performance.

Entonces, ¿qué cuerpo vive el anciano en un mundo juvenilista que cultiva fantasías vendidas como partes de una actitud moderna, valiente, al paso de los tiempos? ¿Qué instrumentos tiene para enfrentar el desesperado afán colectivo de enmendar los cuerpos de los signos del tiempo?

El sildenafilo, que todos conocemos con su nombre de batalla, Viagra, es un fármaco que tiene una historia emblemática. Originariamente diseñado para disfunciones del miocardio como la angina de pecho, acabó con no resultar tan efectivo con el tejido muscular del corazón, pero sí con el tejido eréctil de otro órgano muy hinchado, y por eso castigado por la naturaleza con un declive que antecede la caída del deseo que lo fomenta.

Hoy la pastilla azul ofrece a la tercera edad el privilegio de un cuerpo que alcanza las metas sugeridas o impuestas por los impulsos sexuales. Es un cuerpo que rechaza la inteligencia biológica, esa sabiduría de la especie que pretende que las pasiones se aflojen para preparar el organismo al último tránsito. De hecho, un cuerpo desapasionado es filosófica y fisiológicamente más apto para despedirse. Y entonces, ¿qué antropología promueve ese remedio que ha revolucionado, no sólo la vida sexual, sino también la categoría de lo posible a nivel psíquico y el concepto de límite a nivel corporal?

Patentado hace quince años, el Viagra es el símbolo de una sociedad que envejece viviendo en una cultura donde reinan todos los mitos, deseos, conductas y formas de pensar del mundo juvenil. Su utilización es consecuente con una visión economicista del anciano como persona que debe ser autónomo, sin estorbar el ritmo industrial que la vida impone a sus familiares. Por eso se le otorgan instrumentos como el Viagra, para aparentar públicamente que el curso del tiempo es reformable por la ciencia, y para vivir la acedia y la pesadumbre del crepúsculo solamente en la vergüenza privada.

Con esta emulación obligada de la juventud, el anciano no tiene ninguna característica propia, nada de admirable y original que pueda ofrecer a los demás. Es un joven de segunda categoría, una chabacana imitación made inChina de la juventud. Esto es posible porque la biología ya no es un río donde navegar serenamente en espera del piélago final; más bien es el campo de batalla de la voluntad, que va contra el flujo del agua y confía en un placer pírrico, como el salmón que se consigna a las fauces del oso.

La juventud artificial prometida por la ciencia médica no alimenta solamente los apetitos sexuales, porque favorece también la dependencia mental de una cultura que oculta y rehúsa la muerte y que sustenta el consumo como condición esencial de una existencia digna. Aquí se puede entender por qué el deseo, en sus infinitas variantes, es constantemente venerado, promovido y servido por la publicidad: es la gasolina del consumo.

Consumir es la contribución del ciudadano al crecimiento económico de su país, así nos dicen los sacerdotes del capitalismo. Desde un punto de vista ideológico, los consumos de productos, dinero, ideas, artes, creencias, instintos o afectos, todos tienen la misma importancia y el mismo efecto: someter el sujeto a la cadena del deseo. Y la vejez, que en su desarrollo natural llega a eximir el individuo del deseo, no es culturalmente “orgánica”, diría Antonio Gramsci, a la sociedad consumista del capitalismo moderno.

VII

Impotencia del cuerpo, incontinencia del deseo: esta es la fractura entre natura y cultura que genera la laceración psicológica de la vejez postmoderna. Un viejo que a nivel pulsional no envejece, sufre la excesiva abundancia de pasiones como un viejo que, atrapado por la depresión senil, sufre el desierto emocional de su aislamiento.

A esta huida del presente a través de las alas del deseo artificial es reservado el mismo destino del vuelo de Ícaro: al acercarse al sol ardiente del placer, la cera de esas alas se derriten.

Al contrario, un cuerpo que relaja los músculos, que cede los cabellos y los dientes, que se despide de las pasiones, que desnuda el alma de su decoración corporal, ¿no es acaso una maravillosa confesión de haber vivido intensamente, sin esconderse a los ojos de los hombres y a la mano del destino?

Hoy, en aquellas partes del mundo donde los estándares de vida son más altos, a menudo el acercamiento a la muerte con las prácticas de la dignidad laica o de la fe religiosa es desplazado por el alejamiento de la muerte con el hipnotizado recital consumista de una identidad “último modelo”. Mucho más viril y sabia a la vez es la melancólica visión barroca de Góngora, con la cual quiero homenajear la blancura del pelo, la cartografía de las arrugas, los archivos en los ojos de todos aquellos rostros viejos escarbados por los versos del tiempo: “Si quiero por las estrellas/ saber, tiempo, donde estás,/ miro que con ellas vas,/ pero no vuelves con ellas./ ¿Adónde imprimes tus huellas/ que con tu curso no doy?/ Mas, ay, qué engañado estoy,/ que vuelas, corres y ruedas;/ tú eres, tiempo, el que te quedas,/ y yo soy el que me voy.”

ANGIOCARDIOPATIA : 200 ANIVERSARIO

2012-01-17T15:52:00.000-08:00

Review Article

200th Anniversary Article

A Tale of Coronary Artery Disease and Myocardial Infarction

Elizabeth G. Nabel, M.D., and Eugene Braunwald, M.D.

N Engl J Med 2012; 366:54-63

January 5, 2012

Comments open through December 31, 2012

The remarkable facts, that the paroxysm, or indeed the disease itself, is excited more especially upon walking up hill, and after a meal; that thus excited, it is accompanied with a sensation, which threatens instant death if the motion is persisted in; and, that on stopping, the distress immediately abates, or altogether subsides; have . . . formed a constituent part of the character of Angina Pectoris.1

“Remarks on Angina Pectoris” by John Warren, M.D., appeared in 1812 as the first article in the first issue of The New England Journal of Medicine and Surgery.1 Warren's description of angina pectoris (derived from the Latin angina, “infection of the throat”; from the Greek α̋γχόνη, “strangling”; and from the Latin pectus, “chest”) is equally apt for physicians and medical students today. At the time, the pathogenesis was unknown, and treatment consisted of bloodletting, a tincture of opium, bed rest, or a combination thereof. In 1799, Caleb H. Parry speculated that Syncope Anginosa was related to coronary-artery ossification (i.e., calcification), occurring predominantly in men at about 50 years of age and rarely in women or children.2

Medical knowledge in the 18th and 19th centuries was grounded in clinical observation and anatomical dissection. Cardiovascular science emerged in the physiological era of the late 19th and early 20th centuries, first in Europe and subsequently in North America. To celebrate the 200th anniversary of the New England Journal of Medicine, our essay focuses on the themes of coronary artery disease and myocardial infarction to highlight the interplay between science and medicine, emphasizing how the remarkable advances in our understanding of the pathogenesis of heart disease have produced life-saving and life-extending therapies.

The Emergence of Coronary Artery Disease

After Heberden's clinical description of angina3 in 1772, it took almost a century for pathologists to focus their attention on the coronary arteries and describe thrombotic occlusions in addition to “ossification.” However, for decades thereafter, these observations were not related to the symptoms of myocardial ischemia, which had become well known to physicians. Near the end of the 19th century, cardiovascular physiologists noted that occlusion of a coronary artery in the dog caused “quivering” of the ventricles and was rapidly fatal.4,5 These three great branches of medical knowledge — clinical medicine, pathology, and physiology — advanced in separate yet parallel universes. In 1879, the pathologist Ludvig Hektoen concluded that myocardial infarction is caused by coronary thrombosis “secondary to sclerotic changes in the coronaries.”6 In 1910, two Russian clinicians who were trained in pathology described five patients with the clinical picture of acute myocardial infarction, which was confirmed at postmortem examination.7 Two years later, James B. Herrick emphasized total bed rest as the treatment for this condition8 and by 1919 had used electrocardiography to diagnose it.9 These approaches were the standard of care for patients with myocardial infarction until the mid-20th century.

Coronary Risk Factors

Two seminal developments in the 1960s radically changed our understanding and management of acute myocardial infarction, which struck down and killed or greatly impaired apparently healthy men in their 40s or 50s, during their most productive years. One of the first acts of the National Heart Institute, later renamed the National Heart, Lung, and Blood Institute (NHLBI), was to establish the Framingham Heart Study in 1948, which involved the close collaboration of professionals from three disciplines: clinical cardiology, biostatistics, and epidemiology. Their goal was to understand how heart disease developed by studying the lifestyles of the residents of Framingham, Massachusetts. The first description of their findings, “Factors of Risk in the Development of Coronary Heart Disease,”10 indicated that elevations in blood pressure and cholesterol levels were associated with an increased incidence of ischemic heart disease and acute myocardial infarction. The study also showed a high frequency of myocardial infarction among women, which often occurred later in life than it did in men. The identification of elevated blood pressure and cholesterol levels as risk factors and the institution by the NHLBI of national programs to educate clinicians and the public about the importance of controlling these risk factors have contributed to dramatic improvements in age-adjusted cardiac death rates (Figure 1Figure 1

Decline in Deaths from Cardiovascular Disease in Relation to Scientific Advances.).11 (See the timeline in the Supplementary Appendix, available with the full text of this article at NEJM.org.) With the identification of these coronary risk factors and others that followed, the veil that masked the underlying mechanisms in angina and myocardial infarction was lifted, and the concept that coronary heart disease and its complications could be prevented was introduced. Increasingly large multicenter clinical trials subsequently showed that both primary and secondary prevention was possible when steps were taken to lower blood pressure and serum total cholesterol. Fortunately, drugs to reduce these risk factors safely became available as a result of a series of productive collaborations between industry and academic medicine.

Coronary Care Units

Until 1961, patients with acute myocardial infarction — if fortunate enough to survive until they reached a hospital — were placed in beds located throughout the hospital and far enough away from nurses' stations that their rest would not be disturbed. Patients were commonly found dead in their beds, presumably from a fatal tachyarrhythmia. Indeed, the risk of death occurring in the hospital was approximately 30%. The development of the coronary care unit,12 which provided continuous monitoring of the electrocardiogram, closed-chest cardiac resuscitation, and external defibrillation, reduced in-hospital mortality by half among patients admitted with acute myocardial infarction.

Physiology, Cardiac Catheterization, Angioplasty, and Surgery

The publication of De Motu Cordis in 1628, William Harvey's seminal description of the circulation and the function of the heart,13 set the stage for the physiological era several centuries later. The 19th-century French physiologist Claude Bernard catheterized animals and measured the pressures in the great vessels and cardiac chambers.14 This experiment led to the first human cardiac catheterization, performed by Werner Forssman — on himself — in 1929,15 which in turn led to the exploration of cardiac hemodynamics by André Frédéric Cournand and Dickinson W. Richards.16 All three of these investigators were awarded the Nobel Prize in Physiology or Medicine in 1956.

Cardiac catheterization paved the way for the development of coronary arteriography in 1958.17 When combined with left ventriculography, the use of this imaging technique allowed clinicians to elucidate the natural history of coronary artery disease. Coronary arteriography and left ventriculography became the standard diagnostic tool for defining pump function and vessel anatomy and provided the foundation for surgical treatment by means of coronary revascularization. The development and refinement of the technique of open-heart surgery required close collaborations among surgeons, engineers, cardiologists, anesthesiologists, and hematologists.18 The field of invasive cardiology soon emerged, built on the pioneering work of Dotter and Judkins, although Andreas Grüntzig is considered the father of percutaneous interventional cardiology (Figure 2Figure 2

Percutaneous Coronary Angiography and Intervention in the Treatment of Arterial Stenosis.).19 The initial technique of balloon angioplasty was followed by the insertion of bare-metal stents, and today, drug-eluting stents are used to prevent coronary restenosis.20 Once again, cross-disciplinary collaborations, this time among engineers, cardiologists, radiologists, and pathologists, forged remarkable advances in terms of improved vascular devices and techniques. Obstructions in the heart and circulation can now be successfully opened, and abnormal openings successfully closed, in the catheterization laboratory.

Modern Therapy

By the 1970s, in-hospital mortality from acute myocardial infarction was approximately 15%, and in the first year after hospital discharge, roughly 10% of patients died from left ventricular failure associated with large infarctions. Studies in laboratory animals suggested that infarct size could be reduced by rectifying the imbalance between myocardial oxygen supply and demand.21 In 1976, cardiologists were able to open acutely occluded coronary arteries by intracoronary infusion of the fibrinolytic agent streptokinase.22 The Italian Group for the Study of Streptokinase in Myocardial Infarction (Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico) (GISSI) trial, one of the first cardiac “mega-trials” (involving more than 10,000 patients), showed that intravenous streptokinase reduced early mortality in patients with acute myocardial infarction.23 The Second International Study of Infarct Survival (ISIS-2) showed that the addition of aspirin (an antiplatelet drug) led to further reductions in mortality.24 Coronary angioplasty and stenting,25 together with newer, more potent platelet inhibitors (e.g., P2Y12 and glycoprotein IIb/IIIa platelet–receptor blockers), further reduced in-hospital mortality to about 7%. The efficacy of these treatments, including ventricular defibrillation, depends on a short interval between the onset of symptoms and the patient's arrival at the hospital. Considerable progress has been achieved since the 1970s through massive public and professional education programs led by partnerships among the NHLBI, the American Heart Association, and the American College of Cardiology. It was also in this era that randomized, controlled clinical trials became the paradigm for the advancement of clinical cardiovascular therapeutics.

Based on studies in animals showing the benefits of angiotensin-converting–enzyme inhibitors in experimentally induced myocardial infarction, the Survival and Ventricular Enlargement (SAVE) trial showed that long-term administration of these inhibitors reduced mortality among patients with left ventricular dysfunction after infarction.26 The use of beta-adrenergic blockers and aldosterone blockers in these patients further reduced mortality. Despite these notable advances, however, life-threatening heart failure still occurs late in patients with extensive ventricular scarring as a consequence of large infarcts. Implantable defibrillators,27 cardiac resynchronization therapy with pacemakers,28 and left ventricular assist devices29 have improved the prognosis for such patients. Cardiomyocytes from patients with severe heart failure have been found to be deficient in sarcoplasmic reticulum Ca2+ ATPase (SERCA2a). In a pilot study, an adeno-associated virus has been used to deliver the gene for SERCA2a by intracoronary infusion, with seemingly beneficial results.30

Unstable Angina and Non–ST-Segment Elevation Myocardial Infarction

In the late 1930s, alert clinicians called attention to what we now refer to as unstable angina and non–ST-segment elevation acute coronary syndrome. Patients with this disorder have severe anginal pain, usually at rest, often with biochemical evidence of some myonecrosis and severe, multivessel, obstructive coronary artery disease. These patients now outnumber those with ST-segment elevation myocardial infarction by about 3 to 1 and account for about 1 million hospital admissions yearly in the United States. Patients with non–ST-segment elevation acute coronary syndrome have improvement with prompt coronary revascularization and require inhibition of the two clotting-system pathways with aspirin and a platelet P2Y12-receptor antagonist (e.g., clopidogrel), together with an anticoagulant (low-molecular-weight heparin). Their course after hospital discharge is improved by an intensive reduction in low-density lipoprotein (LDL) cholesterol levels31 and administration of an anticoagulant.32 The latter advance is reported in this issue of the New England Journal of Medicine, 32 highlighting that after 200 years, the clinical problems of coronary artery disease and myocardial infarction are still being actively investigated and reported in the Journal.

Coronary Atherosclerosis

The ability to access vascular and cardiac tissue rapidly led to the development of animal models of vascular disease, as well as clinical studies in humans. Two lines of investigation in the 1970s and 1980s forged the field of vascular biology: the observations that thrombotic occlusion of a ruptured or eroded atherosclerotic plaque led to acute myocardial infarction33 and that nitric oxide was a physiological dilator of blood vessels, a discovery for which Furchgott, Ignarro, and Murad received the 1998 Nobel Prize in Physiology or Medicine (Figure 3AFigure 3

Discoveries in Vascular Biology Pertaining to Atherosclerosis.).34,36-38 This pioneering work transformed our understanding of the cellular interactions in both normal and diseased blood vessels and influenced the direction of subsequent research. Investigators shifted their attention from animal preparations of intact vessels to molecular and cellular regulation and, ultimately, to the genes that encode the growth factors, enzymes, other proteins, and RNAs responsible for the development of normal or diseased vessels.

On the basis of these and other studies, we now understand that atherosclerosis is a chronic inflammation of arteries, which develops over decades in response to the biologic effects of risk factors (Figure 3B).34,39,40 Atherogenesis begins as a qualitative change to intact endothelial cells; when subjected to oxidative, hemodynamic, or biochemical stimuli (from smoking, hypertension, or dyslipidemia) and inflammatory factors, they change their permeability to promote the entry and retention of blood-borne monocytes and cholesterol-containing LDL particles. Inflammation and biochemical modifications ensue, causing endothelial and smooth-muscle cells to proliferate, produce extracellular matrix molecules, and form a fibrous cap over the developing atheromatous plaque. Plaques lead to clinical symptoms by producing flow-limiting stenoses (causing stable angina) or by provoking thrombi that interrupt blood flow on either a temporary basis (causing unstable angina) or a permanent one (causing myocardial infarction). Physical disruption (rupture) of the plaque exposes procoagulant material within the core of the plaque to coagulation proteins and platelets, triggering thrombosis.41

Evidence of the causative role of LDL cholesterol in atherosclerosis is threefold: first, genetic mutations that impair receptor-mediated removal of LDL cholesterol from plasma cause fulminant atherosclerosis; second, animals with low LDL-cholesterol levels have no atherosclerosis, whereas increasing these levels experimentally leads to disease; and third, human populations with low LDL-cholesterol levels have minimal atherosclerosis, and the process increases in proportion to the level of LDL cholesterol in the blood.42,43 A remarkable victory for patients with coronary artery disease came when the LDL-cholesterol pathway was delineated43,44 (Figure 4AFigure 4

The LDL-Receptor Pathway and Treatment with LDL Cholesterol–Lowering Drugs, which Improves Cardiovascular Outcomes.) and the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), discovered by Akira Endo,46 was developed to lower LDL-cholesterol levels. Brown and Goldstein's discovery of the LDL-receptor pathway,44 for which they were awarded the 1985 Nobel Prize in Physiology or Medicine, provided a genetic cause for myocardial infarction in persons with familial hypercholesterolemia and introduced three general concepts to cell biology: receptor-mediated endocytosis, receptor recycling, and feedback regulation of receptors. This last concept is the mechanism by which statins selectively lower LDL-cholesterol levels in plasma, reducing the risk of myocardial infarction and prolonging life, as shown in multiple, definitive clinical trials (Figure 4B).45,47

However, statin therapy does not eliminate cardiovascular risk.48,49 Levels of high-density lipoprotein (HDL) cholesterol correlate inversely with cardiovascular risk, but despite considerable improvements in our understanding of HDL cholesterol and its metabolism, none of the pharmacologic agents that raise HDL cholesterol that have been tested so far have had a significant effect on cardiovascular morbidity and mortality. Ongoing clinical trials of agents that raise HDL-cholesterol levels and that have other antiinflammatory and antiatherosclerotic effects are currently under way.50

Genomics, Cell-Based Therapies, and Molecular Targeting — The Next Frontiers

Several active areas of investigation hold promise for future advances in cardiovascular science and medicine, including genetics and genomics, molecular targeting, pharmacogenomics, and stem-cell biology and regenerative medicine.

Genetic investigations have led to discoveries of the heritable components of cardiovascular risk factors and coronary artery disease, including studies of families with inherited genetic mutations51 and genomewide association studies across populations.52 Multiple chromosomal loci associated with coronary artery disease harbor protein-coding genes known to be important in variations in lipid levels. In addition, associations of single-nucleotide polymorphisms with chemokines suggest that an inflammation pathway may regulate the process of coronary atherosclerosis.52 To date, the major contribution of these genomewide association studies has been new insights into biologic pathways that were often unsuspected and that underlie the development of cardiovascular disease. These insights have in turn led to hypothesis-driven research in which molecular, genetic, biochemical, and cellular techniques are used to investigate pathways. Knowledge of molecular pathways is essential to the development of therapeutics, defined conceptually as “molecular targeting.”

Pharmacogenomics applies our understanding of genetic variability in patients' responsiveness to a drug in order to inform clinical decisions about dosing and selection. The anticoagulant warfarin is a case in point. Genetic variation in CYP2C9 and VKORC1, the two genes that encode the liver proteins required for warfarin metabolism, explains up to 40% of the differences observed among patients in their responses to the same dose of warfarin. The Food and Drug Administration has used this information to revise warfarin labeling in order to allow for genotype-specific dose ranges.53 In patients with gene variants in the cytochrome P-450 enzyme, CYP2C19, the antiplatelet drug clopidogrel is less efficacious and the risk of coronary artery disease is increased.54 Deep sequencing of the genes related to drug absorption, distribution, metabolism, and excretion may identify specific variants that contribute to the heterogeneity of patients' responsiveness to cardiovascular drugs.

Cell-based therapies ranging from autologous noncardiac cells (e.g., bone marrow, skeletal muscle, fat, and endothelial progenitors) to allogeneic mesenchymal cells and putative resident cardiac progenitors have been studied in preclinical animal models and in early trials in humans, with mixed, yet promising, results.55-57 A subset of progenitors is mobilized in vivo by paracrine signals in cases of cardiac injury, suggesting that the delivery of such signals to the heart or vasculature may stimulate regenerative tissue.58

Global Cardiovascular Disease

Cardiovascular disease, including heart disease and stroke, is the leading cause of death worldwide, including low-income and middle-income countries.59 Several factors account for the increasing burden of cardiovascular diseases, including a longer average life span, tobacco use, decreased physical activity, and increased consumption of unhealthful foods.60 New collaborations are under way to address cardiovascular and other noncommunicable diseases by building capacity in health care delivery, research, and training and developing low-cost interventions.61,62

Conclusions

From John Warren's description of angina pectoris in 1812 as a strangling of the chest vaguely related to ossification of the coronary arteries to our current understanding of the genetic and molecular basis of coronary artery disease, the pathways of discovery, innovation, and therapeutic advancement in cardiovascular science and medicine over the past two centuries have been truly remarkable. We are now poised to take advantage of scientific opportunities, fueled by the results of rich epidemiologic studies of populations and large, randomized clinical trials evaluating science-based therapeutics, and thus further refine the cardiovascular care of patients around the globe.

Source Information

From Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Address reprint requests to Dr. Nabel at Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115, or at enabel@partners.org.

LA DIETA E INMUNIDAD INTESTINAL

2012-01-17T12:44:00.000-08:00

Clinical Implications of Basic Research

Diet and Intestinal Immunity

Herbert Tilg, M.D.

N Engl J Med 2012; 366:181-183

January 12, 2012

“You are what you eat.” A couple of recent studies underscore the relevance of this adage to the immune system. New studies by Kiss et al.1 and Li et al.2 show how certain dietary components derived from vegetables interact with intestinal immune receptors and thereby regulate the organogenesis of lymphoid follicles, intestinal immunity, and the microbiota.

Western diets are considered to be risk factors for certain diseases, particularly inflammatory bowel disease (IBD).3 High vegetable intake is thought to protect against ulcerative colitis, whereas a diet rich in certain fats, polyunsaturated fatty acids, and meat is considered to increase the risk of both Crohn's disease and ulcerative colitis. Accordingly, it is possible that dietary components prevent or induce inflammation in the gastrointestinal tract.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is ubiquitously expressed in vertebrate cells. AhR ligands are mainly environmentally derived and include dioxin and natural chemicals, such as derivatives of tryptophan, bacterial metabolites, and phytochemicals (e.g., polyphenols and glucosinolates). Activation of AhR occurs after engagement with certain AhR ligands and results in its translocation into the nucleus, where it binds to its dimerization partner, AhR nuclear translocator (Arnt) (Figure 1Figure 1

Dissecting Diet and Intestinal Immunity.). The heterodimer then binds to and activates many genes with functions in immunity and inflammation. Both studies1,2 showed that specific components of cruciferous vegetables of the Brassicaceae family (e.g., broccoli, cabbage, and brussels sprouts) are physiologic ligands of AhR and thereby manipulate the host's immune system. Kiss et al. went on to show that activation of AhR by these ligands is critical to postnatal expansion of certain innate lymphoid cells and the formation of intestinal lymphoid follicles. Mice that are deficient in AhR have a diminished immune response and are highly susceptible to infection with Citrobacter rodentium.1 Li et al. observed that AhR is critical to the maintenance of intraepithelial lymphocytes, cells that mediate local immunity and defense. They also observed that AhR deficiency resulted in increased epithelial vulnerability, immune activation, and altered composition of the microbiota.

The interaction of certain bacterial products with intestinal epithelial cells through so-called pattern-recognition receptors such as toll-like receptors has evolved as a major pathway for bacteria and viruses interacting with the host. These two studies raise the possibility of dietary pattern-recognition receptors that link diet and intestinal immunity. They also suggest that AhR ligands may exert health benefits both in disease prevention (e.g., in persons at risk for IBD) and treatment (e.g., for IBD, the metabolic syndrome, and other disorders). AhR is down-regulated in the intestinal tissue of persons with IBD, and activation of AhR signaling by specific agonists inhibits inflammation and colitis in the gastrointestinal tract of mice.4 The treatment of mice with an AhR antagonist made disease more severe in a mouse model of colitis.4 Beneficial effects of AhR ligands are known to be associated with an increase in levels of interleukin-22, a cytokine that supports intestinal integrity, and the production of mucus and defensins (a class of antimicrobial peptides).4 This observation is consistent with a finding by Kiss et al. that retinoid-related orphan receptor–gamma t (RORγt+) intestinal lymphoid cells, which produce interleukin-22, are required to maintain epithelial expression of certain antimicrobial genes. It therefore seems that dietary factors engaging with AhR affect not only cytokine expression but also the synthesis of defensins and other antimicrobial peptides, thereby influencing microbial composition.

Several questions are raised by these studies. Are AhR-mediated signals needed for the postnatal maintenance or expansion of RORγt+ intestinal lymphoid cells? If so, what happens in case of starvation, in which engagement with physiologic dietary AhR ligands is lacking over a long period? May this affect epithelial integrity and promote intestinal inflammation and susceptibility to infection? How might certain diets affect AhR expression and local immunity? Which other dietary pattern-recognition receptors exist? Is there such a thing as an “inflammatory diet” and, if so, how might such a diet interfere with the immune system? Another twist is the suggestion that engagement with AhR is harmful in the context of cancer progression. The tryptophan metabolite kynurenine, an endogenous AhR ligand, is produced by cancer cells and is able to suppress antitumor immune responses.5

That all being said, Kiss et al. and Li et al., by providing a compelling link between diet and protective immune functions, have opened up a new line of inquiry. The search for foods containing similar immunomodulatory compounds has begun.

Source Information

From the Christian Doppler Research Laboratory for Gut Inflammation, Medical University Innsbruck, Innsbruck, and Academic Teaching Hospital, Hall in Tirol — both in Austria.

SIN TETAS NO HAY PARAISO

2012-01-10T10:50:00.000-08:00

En 20 años aumentaron 80%; rinoplastias, lipoescultura e implante mamario, los más solicitados

México, quinto lugar mundial en cirugías estéticas: expertos

Muchas madres llevan a sus hijas adolescentes a las clínicas porque las ven como “inversión”

Ariane Díaz

Periódico La Jornada

Sábado 7 de enero de 2012, p. 33

Procedimientos para aumentar el busto, cirugías de nariz (rinoplastías), liposucciones y otros tratamientos cosméticos son cada vez más socorridos por mujeres de todas las edades que sueñan con ver en el espejo una imagen diferente de sí mismas que les permita incluso acceder a un mejor nivel de vida.

Las cirugías plásticas, antes un “artículo de lujo” o mero capricho de la vanidad, aumentaron 80 por ciento en los recientes 20 años, en razón de 20 a 25 por ciento por cada lustro, según estimaciones de la Asociación Mexicana de Cirugía Plástica, Estética y Reconstructiva (Amcper).

A su vez, la Sociedad Internacional de Cirugía Plástica y Estética (Isaps, por sus siglas en inglés) señala que México ocupa el quinto lugar a escala mundial por el número de intervenciones cosméticas, detrás de Estados Unidos, China, Brasil e India.

Elsa Muñiz, antropóloga y experta en el estudio del cuerpo y la belleza, asegura que este boom de intervenciones se debe sobre todo a la comercialización de la figura.

Para conseguir empleo y hasta marido

En el competido mundo de hoy –dice, “hombres y mujeres ya no tenemos poder sobre algo más que nuestro cuerpo. Es el único espacio que nos queda para decidir; y esto, aunado a la falta de oportunidades en todos los sentidos, hace que el físico se convierta en mercancía para conseguir empleo y hasta marido”.

También investigadora de la Universidad Autónoma Metropolitana (UAM) en el posgrado de Estudios de la Mujer, afirma que incluso son las propias madres de muchas jóvenes quienes las llevan al cirujano o a las clínicas de belleza porque llegan a considerar a sus hijas como una “inversión”.

“Van a que les inyecten las piernas o les hagan cualquier otro procedimiento estético con la idea de que su belleza sea una forma de obtener cosas, desde un buen empleo hasta matrimonio.”

Judith Muñoz, cirujana con especialidad en mesoterapia y responsable de una clínica de belleza, asegura que ha recibido señoras que “llevan a niñas de 14 años para que les modele la cintura, reciban terapia celular para que les crezca la pompa, les aplique la vacuna contra el acné –aunque tengan sólo un barrito– o les haga peeling (exfoliación química para rejuvenecer la piel) a esa edad. Lo dicen abiertamente: ‘es una inversión para que te cases bien’”.

Sin embargo, cirujanos plásticos de la Secretaría de Salud (Ssa) y la Amcper afirman que la recurrencia a estos métodos de embellecimiento aún no constituye un problema de salud pública ni se presenta en un porcentaje “alarmante”, si bien reconocen que hay en México una creciente demanda.

De acuerdo con Giovanni Betti, vocero de la Amcper, del universo de pacientes que acude a la cirugía estética, 80 por ciento son mujeres, y de ellas, entre 12 y 15 por ciento aún son adolescentes.

Otros cálculos de esa agrupación médica apuntan a la realización de más de 400 mil procedimientos cada año, tanto de cirugía plástica como reconstructiva, en tanto que la Ssa lleva a cabo sólo entre 2 mil y 2 mil 500.

El aumento de busto, la rinoplastía (cirugía de nariz), la lipoescultura o liposucción y la cirugía de orejas son los procedimientos con mayor demanda, coinciden cirujanos consultados.

Ni la Ssa ni la Amcper permiten una cirugía estética en menores de edad sin el consentimiento de los padres, y se llevan a cabo sólo cuando la salud o la autoestima del paciente se está viendo afectadas debido a alguna deformación o crecimiento anormal.

Silvia Espinosa, jefa del servicio de Cirugía Plástica y Reconstructiva del Hospital General de México, dice que para practicarse una cirugía estética el paciente “debe tener un carácter formado, una personalidad y ser dueño de sus opiniones”.

Explica que aunque una adolescente de 15 años demande una intervención cosmética, “hay que esperar a que termine su desarrollo físico y que madure mentalmente para saber qué quiere. Lo importante es que no se vea forzada por la mamá”.

Señala que los requisitos médicos incluyen la maduración física completa, que se alcanza después de los 20 años, pero sobre todo que la o el paciente tenga madurez sicológica para decidir sobre su cuerpo.

Incluso –advierte–, los cirujanos plásticos deben estar alertas y mantener principios éticos sólidos para detectar el trastorno corporal dismórfico –gran preocupación por un defecto imaginario de la apariencia o ansiedad exagerada ante la presencia de un defecto ligero–, el cual puede llevar a una persona al quirófano en reiteradas ocasiones, porque nunca se muestra conforme con su apariencia.

¿Pacto con el diablo o redención?

Elsa Muñiz afirma que, en muchos casos, más que elevar la autoestima, la cirugía plástica produce el efecto contrario: “la gente termina fijándose más en sus defectos y cada vez se encuentra más. Se vuelve un pacto con el diablo”.

Silvia, quien ya cumplió 50 años, ha entrado al quirófano 17 veces: lifting facial (para rejuvenecimiento), blefaroplastia (extracción de grasa y exceso de piel en párpados), cirugía de nariz, aumento de busto, abdominoplastia (quitar grasa y piel del abdomen y dejarlo plano), liposucciones, implante de gemelo (aumento de pantorrillas) y lifting de brazos, procedimientos que ha repetido en dos o más ocasiones.

Alejandra Buggs, directora del Centro de Salud Mental y Género de México, señala que las cirugías estéticas pueden llevar a una persona a entrar y salir de los quirófanos por el resto de su vida.

“En el caso de los implantes (silicones o de solución salina), hay que cambiarlos cada ocho o 10 años, lo que significa que si una chica se opera a los 16 años, deberá pasar de nuevo por ese proceso a los 24 años, luego a los 32 y después a los 40”.

Con las rinoplastias, la región nasal se vuelve mucho más frágil y hasta una gripa mal cuidada puede degradar el cartílago, lo que requeriría volver a operar.

La terapeuta apunta que una constante en las consultas sicológicas y talleres que llevan a cabo en ese centro es la angustia de las mujeres por el rechazo a su cuerpo. “Las mujeres estamos expuestas a trampas corporales, es decir, a buscar el modelo de belleza creado por una visión patriarcal y occidental, y al tratar de alcanzarlo nos exponemos a un sinfín de situaciones riesgosas, como esos procedimientos quirúrgicos”.

La doctora Espinosa considera que los efectos de una cirugía estética son generalmente positivos. Estrene figura a meses sin intereses

Los especialistas consultados afirman que México se ha convertido en destino del llamado “turismo médico”, e incluso podría hablarse de un “turismo plástico”, junto a países como Colombia, Venezuela y Brasil.

“En Guadalajara y Tijuana ya hay paquetes que incluyen boleto de avión (viaje redondo), cirugía y enfermera para cuidados posoperatorios en el hospital o el hotel durante tres días”, dice Judith Muñoz.

La boyante industria de la cirugía plástica está al alcance de casi todos los bolsillos, pues hoy las clínicas cuentan con la posibilidad de pagar con tarjeta de crédito a seis o 12 meses.

Éstas también ofrecen créditos para cirugía plástica con una baja tasa de interés mensual.

En contraste, la extracción de un quiste en hospitales privados puede oscilar entre 35 mil y 75 mil pesos, y un trasplante de riñón podría alcanzar el medio millón. En la Ssa los costos dependen del resultado del estudio socioeconómico que se realiza al paciente.

Añadir un comentario

la educaciòn medica en Mexico

Juan Antonio Preza Martinez

Desde hace unos años la educación Medica en el mundo se ha centrado en la formación de médicos empresarios pasando a segundo plano los valores humanos, el bien a la sociedad, ayudar a los que menos tienen los estudiantes de medicina adquieren ademas de las competencias para la practica medica la forma de incrementar sus ganancias económicas a costa de olvidar la ética medica que sobre todo en nuestro país debe ser sagrada y lo peor de todo la enseñanza la reciben en ocasiones de sus propios maestros

Pues resulta ......

Alvaro Cortes

Aquella tentativa de hacer una crítica contra las cirujias esteticas en colombia con la novela sin tetas no hay paraiso, se ha revertido y ha mostrado precisamente lo contrario, con tetas si hay paraiso. Queremos ser otros y modificando nuetro cuerpo en ocaciones llegamos a serlo.

modelos

oscar

Es mas atractiva una mujer activa, saludable, culta. Cosa que no se logra con visturí, liposucciones, anfetaminas, cremas, productos milagro y ropa costosa.

De todo un poco

Rodrigo Arias

Estoy de acuerdo con usted. Pero es innegable que en ocasiones, la belleza física es un determinante, querámoslo o no. No es lo mismo una indígena totonaca regordeta que una delgada mujer indígena nordica.

mar

La verdadera fealdad es la interna. El que tenga un buen corazon, lleno de Alegria, siempre estara y sera bello!!

mar

Los tranzas existen desde la era de Matusalem! lo que hacen es heredarlas a sus hijos y asi sucecivamente. Debemos tomar conciencia para no imitarlos y sobre todo no ser complices!No inviertan el dinero en los bancos, util;icemos el dinero en nosotros mismos con obras colectivas en donde todos seamos beneficiados.

ESCLEROSIS LATERAL DE STEPHEN HAWKING

2012-01-09T10:49:00.000-08:00

El célebre astrofísico padece una forma atípica de esclerosis lateral amiotrófica

Desafiando toda adversidad, Stephen Hawking cumplirá mañana 70 años

Hawking ha realizado grandes aportaciones al mundo de la ciencia puraFoto Ap

Periódico La Jornada

Sábado 7 de enero de 2012, p. 4

Londres, 6 de enero. Cuando le diagnosticaron su enfermedad neurodegenerativa hace casi medio siglo le dieron pocos años de vida, pero Stephen Hawking, uno de los científicos más famosos del mundo, se dispone a celebrar este domingo su cumpleaños número 70, desafiando toda adversidad.

Paralizado, obligado a utilizar una silla de ruedas y a comunicarse mediante un ordenador, Hawking continúa trabajando incansablemente para develar los misterios del universo y hacer accesibles a un público lo más amplio posible los complicados conceptos de la física.

¿Existe o no existe Dios? Cientos de lectores confían en él a la hora de responder a esa pregunta. El astrofísico británico sigue practicando y despertando una increíble fascinación.

Cuando dice algo, el mundo escucha con atención. Todo lo que Hawking opina respecto de cuestiones como ¿por qué está el hombre en el mundo?, ¿existe otra vida en el amplio universo y, de ser así, debemos contactar con ellos? se observa, se debate e influye la opinión vital de miles de personas.

“Soy de la opinión de que todos y no sólo los físicos teóricos, quieren saber de dónde vienen”, comentó en 1988 a propósito del éxito de su bestseller Una breve historia del tiempo. El libro, que analiza las teorías físicas sobre el desarrollo del universo, le dio a conocer a escala internacional.

Según los pronósticos médicos, el británico debería haber muerto hace muchos años debido a esclerosis lateral amiotrófica. “Las personas a las que se le detecta esta enfermedad mueren al cabo de unos 14 meses del diagnóstico. Obviamente, Stephen Hawking es excepcional por la cantidad de tiempo que ha vivido con ella”, explicó Elaine Gallagher, de la Asociación de Enfermedades Neurodegenerativas.

El astrofísico atribuye su celebridad a la dolencia que padece desde los 21 años y que ha mermado progresivamente sus funciones motoras.

“La gente está fascinada por el contraste entre mis poderes físicos sumamente limitados y la inmensidad del universo con el que trato”, explica con modestia y humor en su página web (www.hawking.org.uk/) el autor de la La gran ilusión: las grandes obras de Albert Einstein.

Su fama es tal que ha hecho apariciones estelares en series de televisión como Star Trek o Los Simpson, donde en una discusión en un bar amenaza al torpe padre protagonista, Homero, con “robarle” su curiosa “teoría sobre el universo en forma de dona”.

Para el astrónomo real Martin Rees, quien lo conoció cuando ambos cursaban doctorados en la Universidad de Cambridge, Hawking “se ha convertido posiblemente en el científico más famoso del mundo, aclamado por sus investigaciones brillantes, por sus libros que registran superventas y, por encima de todo, por su asombroso triunfo sobre la adversidad”.

Considera, sin embargo, que su éxito entre el gran público “no debe eclipsar” las grandes aportaciones de Hawking al mundo de la ciencia pura, en particular en los campos de los agujeros negros, la teoría de la relatividad y la ley de la gravedad.

Ocupó durante 30 años la famosa Cátedra Lucasiana de Matemáticas en la Universidad de Cambridge, lo que lo convierte en sucesor de Isaac Newton.

Entre sus mayores éxitos se encuentra su predicción, a comienzos de los años 70, de que los agujeros negros, concentraciones enormes de masa que generan un campo gravitatorio al que ninguna partícula puede escapar, podían perder energía bajo ciertas circunstancias.

Al igual que Albert Einstein, lleva años buscando una fórmula para conciliar las teorías contradictorias sobre la relatividad y la física cuántica.

“Indudablemente ha hecho más que cualquiera desde Einstein para mejorar nuestro conocimiento de la gravedad”, afirmó el ex presidente de la Real Sociedad, una de las instituciones científicas más antiguas y prestigiosas del mundo en la que Hawking fue admitido en 1974, con sólo 32 años.

Mañana domingo, el Centro de Cosmología Teórica de la Universidad de Cambridge, dirigido por Hawking, realizará un acto público para el cual las entradas están agotadas desde hace semanas.

Este simposio sobre El estado del universo estará precedido por una conferencia en la que científicos de prestigio mundial examinarán la situación actual en materia de agujeros negros, cosmología y física fundamental, ámbitos que han centrado los trabajos de Hawking.

El Museo de la Ciencia de Londres ha encargado también para la ocasión una serie de fotografías que celebran la vida y la obra del astrofísico, que el público podrá visitar a partir del 20 de enero.

Nacido en la localidad inglesa de Oxford el 8 de enero de 1942, justamente en el tricentenario de la muerte de Galileo, Hawking siempre creyó que la ciencia era su destino y, aconsejado por los médicos, concentró todas sus energías en el estudio de la cosmología.

“Cuando Stephen ya no pudo hacer uso de sus manos y manipular ecuaciones en papel, lo compensó entrenándose en manipular formas y topologías complejas en su mente a gran velocidad. Esa capacidad le permitió encontrar soluciones a difíciles problemas físicos que nadie más podía resolver, y probablemente él mismo no hubiera sido capaz de hacerlo sin esa nueva habilidad”, dijo el físico teórico estadunidense Kip Thorne, unos de sus colaboradores habituales.

En su vida privada, Hawking ha estado casado dos veces y tiene tres hijos. Su ex mujer Jane Hawking publicó un libro a finales de los años 90 en el que le describía como un tirano en casa y un egoísta al que había que recordar con frecuencia que no era Dios.

Más allá de sus trabajos científicos, ha confesado que el enigma que no ha logrado desentrañar todavía son las mujeres, a las que considera “un misterio total”, dijo hace unos días a la revista New Scientist.

Hawking no cuenta con la vida después de la muerte, dijo al diario The Guardian. Sin embargo, no oculta su miedo a morir: “Veo el cerebro como una computadora que deja de trabajar cuando sus componentes dejan de funcionar. No hay vida después de la muerte para las computadoras estropeadas; es un cuento para la gente que tiene miedo a la oscuridad y, ¿cómo se traduce e interpreta eso para la gente cuyo hardware aún funciona? Debemos sacar el máximo valor de nuestros actos”.

Añadir un comentario

Científico o vulgar pragmático

Ecléctico

S. Hawking, bien que explota su situación física para dárselas de "científico público #1". Asustar a la gente con "el coco", como en su momento S.Freud, misógno como A. Eistein. Milagrero con el éxtito de su salud. Sabe todo, pero no sabe comportarse como científico honesto. Como que había que recomendarle leer a Karl Popper, para que no siga de "mamila", con aseveraciones filosóficas que quiere nos traguemos sin chistar. ahora sale con su "jalada", por demás "mamila", de que las mujeres "un misterio total"... ji-jí, rían y adórenme. Zapatero a tus zapatos.

Felicidades

Clarisa

Muchas felicidades al gran científico Stephen Hawking. Que bueno que ya llegó a los 70 años.

How Has Stephen Hawking Lived to 70 with ALS?

An expert on Lou Gehrig's disease explains what we know about this debilitating condition and how Hawking has beaten the odds

By Katherine Harmon

January 7, 2012

A mind untouched:

An ALS expert explains how the disease affects various patients differently--and leaves some mentally debilitated by dementia.

Stephen Hawking turns 70 on Sunday, beating the odds of a daunting diagnosis by nearly half a century.

The famous theoretical physicist has helped to bring his ideas about black holes and quantum gravity to a broad public audience. For much of his time in the public eye, though, he has been confined to a wheelchair by a form of the motor-neuron disease amyotrophic lateral sclerosis (ALS). And since 1985 he has had to speak through his trademark computer system—which he operates with his cheek—and have around-the-clock care.

But his disease seems hardly to have slowed him down. Hawking spent 30 years as a full professor of mathematics at the University of Cambridge. And he is currently the director of research at the school's Center for Theoretical Cosmology.

But like his mind, Hawking's illness seems to be singular. Most patients with ALS—also known as Lou Gehrig's disease, for the famous baseball player who succumbed to the disease—are diagnosed after the age of 50 and die within five years of their diagnosis. Hawking's condition was first diagnosed when he was 21, and he was not expected to see his 25th birthday.

Why has Hawking lived so long with this malady when so many other people die so soon after diagnosis? We spoke with Leo McCluskey, an associate professor of neurology and medical director of the ALS Center at the University of Pennsylvania, to find out more about the disease and why it has spared Hawking and his amazing brain.

What is ALS—and is there more than one form of it?

ALS, which is also known as a motor-neuron disease—and colloquially as Lou Gehrig's disease in the U.S.—is a neurodegenerative disease. Each muscle is controlled by motor neurons that reside in the brain in the frontal lobe. These are controlled electrically and are synaptically connected to motor neurons that reside lower down in the brain—as well as motor neurons that reside in the spinal cord. The guys in the brain are called the upper motor neurons, and the guys in the spine are called the lower motor neurons. The disease causes weakness of either upper motor neurons or lower motor neurons or both.

It's been known for quite some time that there are variants of ALS. One is referred to as progressive muscular atrophy, or PMA. It appears to be an isolated illness of the lower motor neurons. However, pathologically, if you do an autopsy of a patient, they will have evidence of deterioration of upper motor neurons.

There is also primary lateral sclerosis—PLS—and clinically it looks like an isolated upper motor-neuron disorder. However, pathologically they also have lower motor-neuron disorder.

The other classic syndrome is called progressive baldor palsy—or progressive supranuclear palsy—which is weakening of cranial muscles, like the tongue, face and swallowing muscles. But it pretty much always spreads to limb muscles.

Those are the four classic motor-neuron disorders that have been described. And it was thought for quite some time that these disorders were limited to motor neurons. It's now clear that that's not true. It's now well recognized that 10 percent of these patients can develop degeneration in another part of the brain, such as other parts of the frontal lobe that don't contain the motor neurons or the temporal lobe. So some of these patients can actually develop dementia, called frontal-temporal lobe dementia.

One of the misconceptions about ALS is that it's only a motor-neuron disease, and that's not true.

What has Stephen Hawking's case shown about the disease?

One thing that is highlighted by this man's course is that this is an incredibly variable disorder in many ways. On average people live two to three years after diagnosis. But that means that half the people live longer, and there are people who live for a long, long time.

Life expectancy turns on two things: the motor neurons running the diaphragm—the breathing muscles. So the common way people die is of respiratory failure. And the other thing is the deterioration of swallowing muscles, and that can lead to malnutrition and dehydration. If you don't have these two things, you could potentially live for a long time—even though you're getting worse. What's happened to him is just astounding. He's certainly an outlier.

Has he lived so long because he got the disease when he was young and had the juvenile-onset type?

Juvenile-onset is diagnosed in the teenage years, and I don't know enough about his course to say. But it's probably something similar to juvenile-onset disorder, which is something that progresses very, very, very slowly. I have patients in my clinic who were diagnosed in their teens and are still alive in their 40s, 50s or 60s. But not having ever examined him or taken a history, it's a little hard for me to say.

He's a very good example of the sparing of the non-motor parts of the brain that can occur.

How frequent are these cases of very slow-progressing forms of ALS?

I would say probably less than a few percent.

How much do you think Stephen Hawking's longevity has been due to the excellent care that he has received versus the biology of his particular form of ALS?

It's probably a little bit of both. I just know him from television, so I don't know what kind of interventions he's had. If he really isn't on a ventilator, then it's his biology—it's the biology of his form of the neurodegenerative disease that determines how long he will live. For trouble swallowing you can elect to have a feeding tube placed, which basically takes malnutrition and dehydration off the table. But mostly it's about the biology of the disease.

Hawking obviously has quite the active mind, and previous statements that he has made seem to indicate he has a pretty positive mental outlook, despite his condition. Is there any evidence that lifestyle and psychological well-being do much to help with patients' outcomes? Or is the disease usually too quick for that to make a difference?

I don't believe that adds to longevity.

ALS still doesn't have a cure. What have we learned about the disease recently that might help us find one—or at least better treatments?

Beginning in 2006 it became clear that like a lot of other neurodegenerative diseases, ALS was determined by the accumulation of abnormal proteins in the brain. Ten percent of ALS is genetic and based on a gene mutation. I'm sure there are also at-risk genes for ALS, but there are now multiple genes that have been identified as potentially causing the disease. Each one of them are interesting in that they lead to the accumulation of different proteins in the brain. Knowing specific genes gives us particular mechanisms in the brain, and would potentially give us targets for therapies. But none of this has given us any robust therapies yet.

What does Stephen Hawking's case mean for people who have the disease?

It's just an incredible, incredible example of the variability of the disease—and the hope for patients who have it that they could also live a long life. Unfortunately, it's a small percentage of people for whom that actually happens.

SCIENTIFIC AMERICAN

MICROTUBULOS EN NEROPATIAS

2012-01-08T11:17:00.000-08:00

Clinical Implications of Basic Research

Microtubules, Axonal Transport, and Neuropathy

Erika L.F. Holzbaur, Ph.D., and Steven S. Scherer, M.D., Ph.D.

N Engl J Med 2011; 365:2330-2332

December 15, 2011

A physical dimension of a cell is seldom its Achilles' heel. Yet for the neurons that are affected in most kinds of peripheral neuropathy, it is the length of their axons that best accounts for their selective vulnerability. As shown in Figure 1Figure 1

Axonal Integrity and the Microtubule., the axon is contiguous with its cell soma. The soma synthesizes the components of the axon and its terminals, which may be as far as a meter away. Axonal transport is driven by molecular motors that run on a polarized “highway” formed by microtubules. Kinesins drive transport outward, delivering new building blocks for axons (e.g., neurofilaments) and terminals and shuttling organelles such as mitochondria to areas of high energy demand. Transport from the terminals back to the cell soma is driven by cytoplasmic dynein and its activator, dynactin; they carry degradative organelles (lysosomes and autophagosomes) and endosomes that contain signaling platforms from the terminals.

Microtubules are formed from the association of dimers of α-tubulin and β-tubulin into protofilaments, which associate laterally to form a tubule. The addition of tubulin subunits to the plus end of the filament leads to growth of the polymer, whereas subunit loss leads to shortening. In dividing cells, this dynamic remodeling is a constant process, but in neurons, microtubule-associated proteins (e.g., tau) dampen microtubule dynamics. The importance of microtubules and the motors that move along them has long been appreciated but has been underscored by recent discoveries of mutations in the genes that encode microtubules and their motor proteins. These cause neurodevelopmental and neurodegenerative diseases of diverse phenotypes, such as asymmetric polymicrogyria, the Perry syndrome, a form of motor neuropathy, a form of hereditary spastic paraplegia, and several forms of Charcot–Marie–Tooth disease, the term for hereditary neuropathy.

Dominant mutations of HSPB1 and HSPB8 also cause a hereditary axonal neuropathy.2 These genes encode members of the family of small heat-shock proteins (sHSPs), all of which bind to unfolded proteins and prevent their aggregation.3 Despite the widespread expression of HSPB1 and HSPB8, a motor-predominant axonal neuropathy is the sole phenotype of these dominant mutations. Building on their prior work, which showed that a subset of dominant HSPB1 mutants have enhanced binding to their client proteins, Almeida-Souza et al.1 recently reported that tubulin is a binding partner of HSPB1. With the use of biochemical and cellular assays, the authors showed that some HSPB1 mutants have increased binding to tubulin, enhancing the stability of microtubules and leading to dampened dynamics. They proposed that the stabilization of microtubules is the mechanism by which dominant HSPB1 mutant proteins cause a length-dependent neuropathy.

Their idea has an interesting parallel with regard to paclitaxel (Taxol), a chemotherapeutic drug that can cause neuropathy. Paclitaxel binds to microtubule polymer with high affinity, leading to stabilization, an effect similar to that apparently caused by some dominant HSPB1 mutants. Because stabilized microtubules remain effective tracks for microtubule motors, it is unclear how the modest stabilization observed leads to axonal degeneration. One possibility is that this stabilization blocks remodeling of the cytoskeleton at synaptic sites, a newly appreciated site of action.4 Alternatively, the binding of mutant HSPB1 along the microtubule might sterically block transport; the mobility of kinesin-1 in particular has been shown to be susceptible to this effect.5

Stabilized microtubules, however, are unlikely to be the complete answer to the question of how HSPB1 mutants cause neuropathy. Not all HSPB1 mutants affect chaperone activity. The sHSPs bind to many substrates, and there are other reported effects of sHSP mutants.3 For example, overexpression of the two different HSPB1 mutants (but not wild-type HSPB1) results in aggregates of HSPB1 together with other proteins, including neurofilament subunits. These aggregates could be taken as evidence that the HSPB1 mutants have decreased chaperone activity, at least toward these substrates. Another issue that makes the elucidation of the mechanism particularly challenging is that if a neuropathy takes years to develop, the mutants that cause such a neuropathy would be expected to have relatively subtle defects. (This has recently been shown to be the case with a specific mutant version of Rab7, which causes Charcot–Marie–Tooth disease.) Only with time are the cumulative effects of the mutation on cellular function likely to become fully apparent.

Source Information

From the Departments of Physiology (E.L.F.H.) and Neurology (S.S.S.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia.

References

1 Almeida-Souza L, Asselbergh B, d'Ydewalle C, et al. Small heat-shock protein HSPB1 mutants stabilize microtubules in Charcot-Marie-Tooth neuropathy. J Neurosci 2011;31:15320-15328

.2 Evgrafov OV, Mersiyanova I, Irobi J, et al. Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat Genet 2004;36:602-606

.3 Haslbeck M, Franzmann T, Weinfurtner D, Buchner J. Some like it hot: the structure and function of small heat-shock proteins. Nat Struct Mol Biol 2005;12:842-846

4 Conde C, Caceres A. Microtubule assembly, organization and dynamics in axons and dendrites. Nat Rev Neurosci 2009;10:319-332

.5 Dixit R, Ross JL, Goldman YE, Holzbaur EL. Differential regulation of dynein and kinesin motor proteins by tau. Science 2008;319:1086-1089

ARTRITIS REUMATOIDE

2012-01-07T11:19:00.000-08:00

Review Article

Mechanisms of Disease

The Pathogenesis of Rheumatoid Arthritis

Iain B. McInnes, F.R.C.P., Ph.D., and Georg Schett, M.D.

N Engl J Med 2011; 365:2205-2219

December 8, 2011

rheumatoid arthritis is a common autoimmune disease that is associated with progressive disability, systemic complications, early death, and socioeconomic costs.1 The cause of rheumatoid arthritis is unknown, and the prognosis is guarded. However, advances in understanding the pathogenesis of the disease have fostered the development of new therapeutics, with improved outcomes. The current treatment strategy, which reflects this progress, is to initiate aggressive therapy soon after diagnosis and to escalate the therapy, guided by an assessment of disease activity, in pursuit of clinical remission.

However, several unmet needs remain. Current conventional and biologic disease-modifying therapies sometimes fail or produce only partial responses. Reliable predictive biomarkers of prognosis, therapeutic response, and toxicity are lacking. Sustained remission is rarely achieved and requires ongoing pharmacologic therapy. The mortality rate is higher among patients with rheumatoid arthritis than among healthy persons, and cardiovascular and other systemic complications remain a major challenge. Molecular remission and the capacity to reestablish immunologic tolerance remain elusive. Elucidation of the pathogenic mechanisms that initiate and perpetuate rheumatoid arthritis offers the promise of progress in each of these domains. Rheumatoid arthritis is predominantly classified on the basis of the clinical phenotype.2 We believe it is important to make the transition to a new molecular taxonomy that defines discrete disease subgroups with distinct prognostic and therapeutic significance.3

Rheumatoid arthritis is characterized by synovial inflammation and hyperplasia (“swelling”), autoantibody production (rheumatoid factor and anti–citrullinated protein antibody [ACPA]), cartilage and bone destruction (“deformity”), and systemic features, including cardiovascular, pulmonary, psychological, and skeletal disorders. These clinical features pose critical mechanistic questions: What genetic–environmental interactions must occur to facilitate autoimmunity a priori, and why does this beget articular localization? Why does synovial inflammation perpetuate? What drives local destruction leading to joint dysfunction? Why does rheumatoid arthritis cause systemic illness? We herein summarize key pathogenetic advances informing these issues.

Genetic and Environmental Factors

Rheumatoid arthritis involves a complex interplay among genotype, environmental triggers, and chance. Twin studies implicate genetic factors in rheumatoid arthritis, with concordance rates of 15 to 30% among monozygotic twins and 5% among dizygotic twins.4 Genomewide analyses make it clear that immune regulatory factors underlie the disease.5 The long-established association with the human leukocyte antigen (HLA)–DRB1 locus has been confirmed in patients who are positive for rheumatoid factor or ACPA; alleles that contain a common amino acid motif (QKRAA) in the HLA-DRB1 region, termed the shared epitope, confer particular susceptibility.6 These findings suggest that some predisposing T-cell repertoire selection, antigen presentation, or alteration in peptide affinity has a role in promoting autoreactive adaptive immune responses. Other possible explanations for the link between rheumatoid arthritis and the shared epitope include molecular mimicry of the shared epitope by microbial proteins, increased T-cell senescence induced by shared epitope–containing HLA molecules, and a potential proinflammatory signaling function that is unrelated to the role of the shared epitope in antigen recognition.7,8

Many other identified risk alleles in ACPA-positive rheumatoid arthritis consistently aggregate functionally with immune regulation (Table 1Table 1

Candidate Genes with Single-Nucleotide Polymorphisms (SNPs) Linked to Rheumatoid Arthritis and Their Potential Function in Pathogenesis.), implicating nuclear factor κB (NF-κB)–dependent signaling (e.g., TRAF1–C5 and c-REL) and T-cell stimulation, activation, and functional differentiation (e.g., PTPN22 and CTLA4).9-12 Moreover, gene–gene interactions that increase disease risk, as described between HLA-DRB1 and PTPN22, exemplify the complexity of the net risk conferred by any given gene.13 Genetic risk factors for ACPA-negative disease appear to be no less important than those for ACPA-positive disease. However, they are less well established and involve different HLA alleles (e.g., HLA-DRB1*03), interferon regulatory factors (e.g., interferon response factor 5), and lectin-binding proteins (e.g., C-type lectin domain family 4 member A).3 This fundamental dichotomy in genetic risk on the basis of ACPA expression provides the first clear evidence that a molecular taxonomy for “the rheumatoid arthritis syndrome” is feasible. Patients with ACPA-positive disease have a less favorable prognosis than those with ACPA-negative disease, which suggests that such molecular subsets are clinically useful.

Findings from studies of gene–environment interactions complement these observations. Smoking and other forms of bronchial stress (e.g., exposure to silica) increase the risk of rheumatoid arthritis among persons with susceptibility HLA–DR4 alleles.14 Moreover, smoking and HLA-DRB1 alleles synergistically increase one's risk of having ACPA.15 Unifying these observations is the finding that environmental stressors of pulmonary and other barrier tissues may promote post-translational modifications, through peptidyl arginine deiminase, type IV (PADI4), that result in quantitative or qualitative alteration in citrullination of mucosal proteins.

Loss of tolerance to such neoepitopes elicits an ACPA response (which can be detected with a diagnostic anti–cyclic citrullinated peptide [CCP] assay) (Figure 1Figure 1

Multistep Progression to the Development of Rheumatoid Arthritis.).16,17 Several citrullinated self-proteins are recognized in anti-CCP assays, including α-enolase, keratin, fibrinogen, fibronectin, collagen, and vimentin. Characterization of subsets of seropositive patients to elicit true disease autoantigens is ongoing. An estimated 43 to 63% of patients with ACPA-positive rheumatoid arthritis are seropositive for citrullinated α-enolase, which is strongly associated with HLA-DRB1*04, PTPN22, and smoking.18 Similar interactions are reported for citrullinated vimentin and fibrinogen epitopes.19

Infectious agents (e.g., Epstein–Barr virus, cytomegalovirus, proteus species, and Escherichia coli) and their products (e.g., heat-shock proteins) have long been linked with rheumatoid arthritis, and although unifying mechanisms remain elusive, some form of molecular mimicry is postulated.20,21 The formation of immune complexes during infection may trigger the induction of rheumatoid factor, a high-affinity autoantibody against the Fc portion of immunoglobulin, which has long served as a diagnostic marker of rheumatoid arthritis and is implicated in its pathogenesis. Furthermore, rheumatoid arthritis appears to be associated with periodontal disease: Porphyromonas gingivalis expresses PADI4, which is capable of promoting citrullination of mammalian proteins.22 Finally, the gastrointestinal microbiome is now recognized to influence the development of autoimmunity in articular models, and specific (and potentially tractable) clinical bacterial signatures that are associated with autoantibody-positive rheumatoid arthritis are emerging.23

The greater risk of rheumatoid arthritis among women than among men has long been recognized. The onset of rheumatoid arthritis is also associated with adverse life events. Molecular explanations for such phenomena are emerging from animal models of inflammation, which show a link between the hypothalamic–pituitary–adrenal axis and cytokine production.24 The central nervous system is normally involved in immune regulation and homeostasis, and neuroimmunologic interactions regulate disease development in rodent models of arthritis. Such effects may operate locally (several neurotransmitters are expressed in synovitis in rheumatoid arthritis) or centrally (cytokines are rapidly up-regulated in the hypothalamus during peripheral inflammation). Translation of these observations to effective treatment of rheumatoid arthritis is challenging.

Critical issues remain unresolved. Autoantibodies, such as rheumatoid factor and ACPA, are often (but not always) detected in patients before the development of arthritis (prearticular phase of rheumatoid arthritis); in some series, autoantibody levels have increased and there has been evidence of epitope spreading as the onset of disease approaches.25 Why the systemic loss of tolerance is linked to a localized onset of inflammation in the joint is still unclear (transitional phase of rheumatoid arthritis). It is possible that biologic features of the targeted autoantigen (e.g., regulation of cellular metabolism in the case of α-enolase and glucose-6-phosphatase) may contribute. Other possible factors include local microvascular, neurologic, biomechanical, and microtrauma-related mechanisms (Figure 1).

Synovial Immunologic Processes and Inflammation

Synovitis occurs when leukocytes infiltrate the synovial compartment. Leukocyte accumulation primarily reflects migration rather than local proliferation. Cell migration is enabled by endothelial activation in synovial microvessels, which increases the expression of adhesion molecules (including integrins, selectins, and members of the immunoglobulin superfamily) and chemokines. Accordingly, neoangiogenesis, which is induced by local hypoxic conditions and cytokines, and insufficient lymphangiogenesis, which limits cellular egress, are characteristic features of early and established synovitis.26,27 These microenvironmental changes, combined with profound synovial architectural reorganization and local fibroblast activation, permit the buildup of synovial inflammatory tissue in rheumatoid arthritis (Figure 2Figure 2

Adaptive and Innate Immune Processes within the Joint in Rheumatoid Arthritis.).

Adaptive Immune Pathways

The genetics of rheumatoid arthritis and the presence of autoantibodies clearly place adaptive immunity at the center of early pathogenesis. However, even though T cells are abundant in the synovial milieu, the functional role of T cells remains insufficiently understood. Direct targeting of T cells by cyclosporine or T-cell–depleting therapeutics has shown limited or no efficacy.28 This finding may reflect “broad spectrum” deletion of regulatory as well as effector T cells and suggests the need to target T-cell subsets. The synovium in rheumatoid arthritis contains abundant myeloid cells and plasmacytoid dendritic cells that express cytokines (interleukin-12, 15, 18, and 23), HLA class II molecules, and costimulatory molecules that are necessary for T-cell activation and antigen presentation.29,30 Moreover, the use of abatacept (a fusion protein containing cytotoxic T-lymphocyte–associated antigen 4 and the FC fragment of IgG1) to disrupt antigen presentation by blocking T-cell costimulation (through the interaction of CD28 with CD80 or CD86) is efficacious in rheumatoid arthritis. Autoreactive T cells against citrullinated self-proteins have been identified. Synovial T-cell oligoclonality, germinal-center reactions, and B-cell hypermutation suggest ongoing local antigen-specific, T-cell–mediated B-cell help.31,32

Although rheumatoid arthritis is conventionally considered to be a disease that is mediated by type 1 helper T cells, attention has increasingly focused on the role of type 17 helper T cells (Th17), a subset that produces interleukin-17A, 17F, 21, and 22 and tumor necrosis factor α (TNF-α)33,34 (Table 2Table 2

Key Molecules and Signal Mediators Implicated in the Pathogenesis of Rheumatoid Arthritis. and the Supplementary Appendix, available with the full text of this article at NEJM.org). Macrophage-derived and dendritic-cell–derived transforming growth factor β and interleukin-1β, 6, 21, and 23 provide a milieu that supports Th17 differentiation and suppresses differentiation of regulatory T cells, thus shifting T-cell homeostasis toward inflammation. Interleukin-17A, which synergizes with TNF-α to promote activation of fibroblasts and chondrocytes, is currently being targeted in clinical trials.35 Regulatory (forkhead box P3 [Foxp3+]) T cells that are detected in tissues from patients with rheumatoid arthritis appear to have limited functional capability.36 This imbalance between Th17 and regulatory T cells may also reflect local TNF-α, which blocks the activity of regulatory T cells.37 An additional pathogenic pathway comprises antigen-nonspecific, T-cell contact–mediated activation of macrophages and fibroblasts, operating through interactions between CD40 and CD40 ligand, CD200 and CD200 ligand, and intracellular adhesion molecule 1 and leukocyte-function–associated antigen 1.38

Humoral adaptive immunity is integral to rheumatoid arthritis. Synovial B cells are mainly localized in T-cell–B-cell aggregates — indeed, some tissues have ectopic lymphoid follicles39 — that are supported by the expression of factors that include a proliferation-inducing ligand (APRIL), B-lymphocyte stimulator (BLyS), and CC and CXC chemokines (e.g., CXC chemokine ligand 14 and CC chemokine ligand 21).40 Plasmablasts and plasma cells are more widely distributed in the synovium and also in juxta-articular bone marrow. A pathogenic role for CD20+ B cells is confirmed by the efficacy of rituximab in rheumatoid arthritis.41 Because plasma cells are not targeted by anti-CD20 antibodies, and autoantibody levels are variably altered after treatment, these clinical observations suggest that the role of B cells and their progeny in the pathogenesis of rheumatoid arthritis goes beyond autoantibody production to include autoantigen presentation and cytokine production (e.g., interleukin-6, TNF-α, and lymphotoxin-β).

Activation of the Innate Immune System

A variety of innate effector cells, including macrophages, mast cells, and natural killer cells, are found in the synovial membrane, whereas neutrophils reside mainly in synovial fluid. Macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and granulocyte–macrophage colony-stimulating factor (GM-CSF) enhance maturation of these cells, their efflux from the bone marrow, and trafficking to the synovium.42 In particular, macrophages are central effectors of synovitis; clinically effective biologic agents consistently reduce macrophage infiltration in the synovium.43 Macrophages act through release of cytokines (e.g., TNF-α and interleukin-1, 6, 12, 15, 18, and 23), reactive oxygen intermediates, nitrogen intermediates, production of prostanoids and matrix-degrading enzymes, phagocytosis, and antigen presentation.

This pattern of expression of proinflammatory cytokines and inducible nitric oxide synthase suggests a predominant M1 macrophage phenotype. Macrophages are activated by toll-like receptors (TLRs) (e.g., TLR 2/6, 3, 4, and 8) and nucleotide-binding oligomerization domain (NOD)–like receptors (NLRs) that recognize a range of pathogen-associated molecular patterns and damage-associated molecular patterns that potentially include bacterial, viral, and putative endogenous ligands.44 Macrophage activation is also driven by cytokines, cognate interactions with T cells, immune complexes, lipoprotein particles and liver X–receptor agonists (e.g., oxysterols, oxidized low-density lipoprotein [LDL], and serum amyloid A–rich high-density lipoprotein [HDL]), and the protease-rich microenvironment through protease-activated receptor 2.45 Moreover, microRNA species (e.g., microRNA-155) have been implicated in the regulation of synovial cytokine expression.46,47

Neutrophils contribute to synovitis by synthesizing prostaglandins, proteases, and reactive oxygen intermediates.48 Mast cells that produce high levels of vasoactive amines, cytokines, chemokines, and proteases, through ligation of TLR, suppression of tumorigenicity 2 (ST2), Fc receptor γ, and Fc receptor ε, also play a role.49,50 A fraction of ACPA belongs to the IgE class, which may elicit mast-cell activation through Fc receptor ε.51 These findings, which provide evidence that activation of the innate immune pathway contributes to synovitis, could lead to the development of treatments that modulate TLR-dependent, NLR-dependent, and inflammasome-dependent pathways.

Cytokines and Intracellular Signaling Pathways

Cytokine production that arises from numerous synovial cell populations is central to the pathogenesis of rheumatoid arthritis. Cytokine patterns may shift over time; early rheumatoid arthritis has an apparently distinct cytokine profile, involving the expression of interleukin-4, 13, and 15,52 that subsequently evolves in chronic disease. TNF-α plays a fundamental role through activation of cytokine and chemokine expression, expression of endothelial-cell adhesion molecules, protection of synovial fibroblasts, promotion of angiogenesis, suppression of regulatory T cells, and induction of pain.53,54 Similarly, interleukin-6 drives local leukocyte activation and autoantibody production but mediates systemic effects that promote acute-phase responses, anemia, cognitive dysfunction, and lipid-metabolism dysregulation. The central role of these two cytokines has been confirmed by successful therapeutic blockade of membrane and soluble TNF-α and the interleukin-6 receptor in patients with rheumatoid arthritis (Table 3Table 3

Approved Immune-Targeted Therapies in Rheumatoid Arthritis.).

Interleukin-1 family cytokines (e.g., interleukin-1α, 1β, 18, and 33) are abundantly expressed in rheumatoid arthritis. They promote activation of leukocytes, endothelial cells, chondrocytes, and osteoclasts.55,56 However, clinical benefits after interleukin-1 inhibition have been modest. Although this paradox is not fully understood, it may reflect functional redundancy in the canonical TLR and interleukin-1–receptor signaling pathways. Other efforts to target cytokines (e.g., interleukin-17 and 17 receptor, BLyS, APRIL, and GM-CSF) with the use of biologic approaches are ongoing.55,56 The range of available therapeutics based on the biologic characteristics of synovial cytokines will probably expand (Table 2).

Elucidation of the complex intracellular signaling molecules (particularly kinases) that regulate cytokine-receptor–mediated functions may facilitate the development of specific small-molecule inhibitors. Although many intracellular signaling pathways are active in the synovium, clues to those with hierarchical importance have been provided by clinical trials. Positive clinical outcomes in phase 2 studies of the Janus kinase (JAK) 1 and 3 inhibitor tofacitinib implicate JAK pathways that mediate the function of several cytokines, interferons, and growth factors in the pathogenesis of rheumatoid arthritis57,58 (Table 2). Moreover, inhibition of spleen tyrosine kinase by fostamatinib, which is effective in some subgroups of patients, is commensurate with its role in the function of B-cell and Fc receptors.59,60 Other intracellular targets, including phosphatidylinositol 3-kinase, Bruton's tyrosine kinase, and other components of the NF-κB pathway, offer intriguing possibilities for therapeutic strategies. In contrast, despite a strong preclinical rationale, the targeting of p38 mitogen-activated protein kinase has been disappointing in clinical settings, which probably indicates that the molecular signaling network in rheumatoid arthritis has functional redundancy.

Mesenchymal Tissue Responses

The normal synovium contains mesenchymal-derived, fibroblast-like synoviocytes (FLSs) and resident macrophages. In rheumatoid arthritis, the membrane lining is expanded, and FLSs assume a semiautonomous phenotype characterized by anchorage independence, loss of contact inhibition, and the expression of high levels of disease-relevant cytokines and chemokines, adhesion molecules, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs).61 FLSs thereby contribute directly to local cartilage destruction and the chronicity of synovial inflammation, and they promote a permissive microenvironment that sustains T-cell and B-cell survival and adaptive immune organization.62

The molecular mechanisms that sustain synovial hyperplasia are incompletely understood. The increased proliferative capacity of FLSs is not explanatory. A more likely possibility is altered resistance to apoptosis, which is mediated by diverse pathways, including mutations of the tumor-suppressor gene p5363; expression of stress proteins (e.g., heat-shock protein 70), which foster the survival of FLSs64; and modulation of the function of the endoplasmatic reticulum by synoviolin, an E3 ubiquitin ligase that regulates the balance of cell proliferation and apoptosis.65 Synoviolin negatively regulates p53 expression and its biologic functions. In addition, cytokine-induced activation of the NF-κB pathway in FLSs favors survival after ligation of TNF-α receptor. Methylation and acetylation of cell-cycle regulatory genes and expression of microRNAs may be critical factors.66

Synovial hyperplasia could also reflect increased influx of mesenchymal cells. In a mouse model of arthritis with severe combined immunodeficiency, FLSs were shown to migrate and thereby promote articular involvement.67 A crucial advance has been the elucidation of the molecular pathways that sustain integral membrane structure in rheumatoid arthritis. Cadherin-11 and β-catenin mediate FLS-homotypic interactions that are essential for membrane formation and for subsequent inflammation.68

Structural Damage

Cartilage Damage

A hyperplastic synovium is the major contributor to cartilage damage in rheumatoid arthritis. Loss of the normally protective effects of synovium (e.g., reduced expression of lubricin)69 alter the protein-binding characteristics of the cartilage surface, promoting FLS adhesion and invasion. FLS synthesis of MMPs (particularly MMP-1, 3, 8, 13, 14, and 16) promotes disassembly of the type II collagen network, a process that alters glycosaminoglycan content and water retention and leads directly to biomechanical dysfunction. MMP-14 appears to be the predominant MMP expressed by FLSs to degrade the collagenous cartilage matrix.70 Other matrix enzymes (e.g., ADAMTS 5) degrade aggrecan and thus further diminish cartilage integrity.

Endogenous enzyme inhibitors, such as TIMPs, fail to reverse this destructive cascade. Moreover, articular cartilage itself has limited regenerative potential. Chondrocytes physiologically regulate matrix formation and cleavage: under the influence of synovial cytokines (particularly interleukin-1 and 17A) and reactive nitrogen intermediates, cartilage is progressively deprived of chondrocytes, which undergo apoptosis. These processes ultimately lead to the destruction of the surface cartilage and the radiographic appearance of joint-space narrowing.

Bone Erosion

Bone erosion occurs rapidly (affecting 80% of patients within 1 year after diagnosis71) and is associated with prolonged, increased inflammation.72 Synovial cytokines, particularly macrophage colony-stimulating factor and receptor activator of NF-κB ligand (RANKL), promote osteoclast differentiation and invasion of the periosteal surface adjacent to articular cartilage.73 TNF-α and interleukin-1, 6, and potentially 17 amplify osteoclast differentiation and activation.74 Moreover, clinical inhibition of TNF-α, interleukin-6, and RANKL retards erosion in rheumatoid arthritis. Notably, blockade of RANKL acts only on bone, with no effect on inflammation or cartilage degradation.75 Osteoclasts have the acidic enzymatic machinery necessary to destroy mineralized tissues, including mineralized cartilage and subchondral bone; destruction of these tissues leads to deep resorption pits, which are filled by inflammatory tissue.

Mechanical factors predispose particular sites to erosion. Thus, “mechanically vulnerable” sites such as the second and third metacarpals are prone to erosive changes.76 Breach of cortical bone permits synovial access to the bone marrow, which causes inflammation of the bone marrow (osteitis as observed on magnetic resonance imaging), in which T-cell and B-cell aggregates gradually replace marrow fat.77 It is unclear whether these lesions occur in conjunction with synovium-induced erosions or whether osteitis necessarily or independently precedes erosion.78 It is conceivable that rheumatoid arthritis starts in the bone marrow and subsequently involves the synovial membrane.

Eroded periarticular bone shows little evidence of repair in rheumatoid arthritis, unlike bone in other inflammatory arthropathies. Cytokine-induced mediators, such as dickkopf-1 and frizzled-related protein 1, potently inhibit the differentiation of mesenchymal precursors into chondroblasts and osteoblasts (CD271+).79 Mesenchymal stem cells, which have the potential to differentiate into adipocytes, chondrocytes, and osteoblasts, can be detected in the synovium.80,81 However, the biologic characteristics of synovial mesenchymal stem cells, their relationship to FLSs and other stromal cells, and the effect of local inflammation on their activities remain unknown, and an understanding of these factors will crucially inform reparative therapeutic strategies.

Systemic Consequences of Rheumatoid Arthritis

Rheumatoid arthritis is associated with increased rates of cardiovascular illness (standardized mortality rate, approximately 1.5), including myocardial infarction, cerebrovascular events, and heart failure (Figure 3Figure 3

Mechanisms That Contribute to Clinically Observed Long-Term Complications in Patients with Rheumatoid Arthritis.).82-84 These increased rates are not explained by traditional risk factors,85,86 use of glucocorticoids or nonsteroidal antiinflammatory drugs, or shared genetic features. Circulating inflammatory pathways that are implicated include cytokines (interleukin-6 and TNF-α), acute-phase reactants, immune complexes, and altered lipid particles (e.g., serum amyloid A–rich HDL) that increase endothelial activation and potentially render atheromatous plaques unstable.87 Increased levels of acute-phase reactants are an independent cardiovascular risk factor in the general population.88 Cytokines also make muscle and adipose tissues insulin-resistant, resulting in an “inflammatory metabolic” syndrome. Moreover, vascular risk is increased early in the course of rheumatoid arthritis, perhaps reflecting subclinical inflammation in the prearticular phase.89,90

Lipid biochemical features are intimately, and reciprocally, linked to inflammation to ensure metabolically efficient host defense. In consequence, active rheumatoid arthritis is associated with reduced serum levels of total, HDL, and LDL cholesterol, which may then be paradoxically elevated by effective therapy.91 Nevertheless, effective therapeutics decrease cardiovascular risk and favorably modify vascular physiology.92-94 Statin drugs also reduce surrogates of vascular risk and inflammatory factors in patients with rheumatoid arthritis, and risk adjustment for statin use in patients with rheumatoid arthritis is now advocated.95

Inflammation in rheumatoid arthritis also affects the brain (fatigue and reduced cognitive function), liver (elevated acute-phase response and anemia of chronic disease), lungs (inflammatory and fibrotic disease), exocrine glands (secondary Sjögren's syndrome), muscles (sarcopenia), and bones (osteoporosis). Osteoporosis affects the axial and appendicular skeleton, with only a modest elevation of the acute-phase response or subclinical inflammation, and probably occurs before the onset of articular disease.96-98 Effective antiinflammatory treatment retards bone loss and suppresses the high rate of systemic bone resorption, as measured with the use of bone-turnover biomarkers.

The risk of lymphoma is increased among patients with rheumatoid arthritis99 and is strongly associated with inflammatory disease activity; sustained disease activity confers the highest risk.100 Clonal selection of B cells, disturbed immune surveillance due to impaired activity of regulatory T cells, and impaired function of natural killer cells are postulated mechanisms.

The higher rates of lung cancer among patients with rheumatoid arthritis than among other persons may be explained in part by the association between smoking and rheumatoid arthritis. However, inflammation increases the risk of lung cancer independently of smoking, perhaps because of the long-known extraarticular effects of rheumatoid arthritis on fibrotic remodeling of interstitial lung tissue.

Conclusions

The pathogenetic advances described herein have paralleled the introduction of new, effective therapies and remarkable improvement in clinical outcomes. Severe disease manifestations, such as vasculitis, nodule formation, scleritis, and amyloidosis, that are associated with persistent, uncontrolled inflammation have become rare. A rich pipeline of biologic and small-molecule agents, and of potential clinical biomarkers, exists that will add to our therapeutic armamentarium. In time, this should render remission achievable in increasing numbers of patients.

However, much remains to be resolved. We need to understand the factors that lead to loss of tolerance and that cause localization of inflammation in the joint. We need to find ways to promote immunologic resolution or homeostasis and repair of damaged joints. We must elucidate the mechanisms driving the various systemic disorders that contribute substantially to reductions in the quality and length of life. Ultimately, we must strive to develop curative and preventive therapeutics that will transform the notion of rheumatoid arthritis as a chronic disease.

Address reprint requests to Dr. McInnes at the College of Medical, Veterinary, and Life Sciences, University of Glasgow, Level 4, Sir Graeme Davis Bldg., 120 University Pl., Glasgow G12 8QQ, United Kingdom, or at iain.mcinnes@glasgow.ac.uk; or to Dr. Schett at the Department of Internal Medicine 3, University of Erlangen–Nuremberg, Krankenhausstr. 12, 91054 Erlangen, Germany, or at georg.schett@uk-erlangen.de.