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Using sex differences in psychopathology to study causal mechanisms: unifying issues and research strategies.

BACKGROUND: Although there is an extensive literature, both speculative and empirical, on postulated differences between males and females in their rates of particular types of disorder, very little is known about the mechanisms that underlie these sex differences. The study of mechanisms is important because it may provide clues on aetiological processes. The review seeks to outline what is known, what are the methodological hazards that must be dealt with, and the research strategies that may be employed. METHODS: We note the need for representative general samples, and for adequate measurement and significance testing if valid conclusions are to be drawn. We put forward three levels of causes that have to be considered: a genetically determined distal basic starting point; the varied consequences of being male or female; and the proximal risk or protective factors that are more directly implicated in the causal mechanisms that predispose to psychopathology. In delineating these, we argue that three key sets of evidential criteria have to be met: a) that the risk factors differ between males and females; b) that they provide for risk or protection within each sex; and c) that when introduced into a causal model, they eliminate or reduce the sex differences in the disorders being studied. RESULTS: A male excess mainly applies to early onset disorders that involve some kind of neurodevelopmental impairment. A female excess mainly applies to adolescent-onset emotional disorders. No variables have yet met all the necessary criteria but some good leads are available. The possible research strategies that may be employed are reviewed. CONCLUSIONS: The systematic investigation of sex differences constitutes an invaluable tool for the study of the causal processes concerned with psychopathology.

Adolescent↗

Sir Archibald Garrod and alkaptonuria -'story of metabolic genetics'.

Clinical disorders have intrigued the human mind for thousands of years. Many are enshrined in history as 'medical curiosities'. This report is a tribute to one of the greatest minds of modern genetics and medicine, Sir Archibald Edward Garrod (1857--1936), who brought forward the scientific study of inborn errors of metabolism. Garrod's concept of 'chemical individuality' with no awareness of 'genes' more than 100 years ago is an amazing example of futuristic thinking. His own words reflect this, 'Owing, as I believe, to their chemical individuality different human beings differ widely in their liability to individual maladies, and to some extent in the signs and symptoms which they exhibit'. The concept of chemical individuality is here to stay. Garrod has also provided insight into a number of scientific concepts and modern thinking.

Alkaptonuria↗

Innate immune responses to environmental allergens.

Aero-allergens, including plant pollens, house dust mite particles, fungal spores, and mycelium fragments, are continuously inhaled and deposited on the airway mucosa. These particles and their soluble components actively interact with innate recognition systems present in the mucosal layer (e.g., surfactant proteins) and with various receptors present on a diversity of cells in the airways. Deposited particles are first removed by active transportation, the rate of which is either enhanced or inhibited by components present in the inhaled substances. Cleaning further depends on innate recognition, beginning with (a) soluble factors released into the mucosal surface layer that bind different bio-organic components; (b) innate receptors on phagocytic cells, alveolar macrophages, and dendritic monocytes; and (c) innate receptors on airway epithelial cells. Different innate receptor families (Toll-like receptors [TLRs], nucleotide-binding oligomerization domain receptors, and protein-activated receptors [PARs]) have been demonstrated on airway cells, including alveolar macrophages, monocytes, dendritic cells, and airway tissue cells (e.g., epithelial cells and mast cells). However, although the functional role of these receptors has been studied for infectious diseases, the functional role for reaction of airways to inhaled bio-organic substances, including allergens, is largely unexplored. Indirect evidence for functional interactions has come from in vivo animal studies, as well as in vitro studies with monocytes, macrophages, and epithelial cells, which have demonstrated release of cytokines and chemokines after contact with allergens such as house dust mite, cat, pollen, and fungi. Most allergens show direct activation of airway epithelial cells, suggesting a role for the innate receptors. However, the role of TLRs, PARs, and other receptors was studied for only a limited number of allergens. Current studies indicate synergistic interactions between members of the same receptor family (TLRs) as well as synergistic interactions between members of different families (TLRs, PARs, and nucleotide-binding oligomerization domain receptors), modulating responses into feed-forward or inhibitory actions. Study of these synergistic interactions and their genetic variations will provide insight regarding how the innate immune system determines the inflammatory reactions of the airways and the outcome of the T-helper-1- and T-helper-2-type responses to inhaled allergens.

Air Pollutants↗

[Disorders in the formation of the hematologic status of mice following rat lymph node transplantation during the early postnatal period].

The cell composition of peripheral blood, bone marrow and spleen of CBA mice after the transplantation ca. 20.10(6) lymph node cells of a Wistar rat, sensitized against mouse liver antigens 10--15 days prior to the transplantation, during first 24 hrs after birth was studied. The runt disease developed in 100% recipients and was characterized by sharp disturbances of the formation of immuno- and hemopoietic systems. All runting animals suffered from aplastic anemia, leukopenia with predominance of hyperlobular neutrophils and histio-monocytes in the peripheral blood. The total number of cells in bone marrow decreased almost 15 times. The elimination of erythroid line was coupled with relative augmentation of undifferentiated myeloid and monocytoid cells. The cellular pool of spleen increased twice and more. The intensive proliferation of histio-monocytes and macrophages was accompanied by the destruction and depletion of lymphatic structures. A suggestion is put forward to the effect that the incorporation of "not-self" genetic information, such as non-syngeneic lymphocytes, during the early postnatal period may not only induced some genuine immunological effects, but inhibit the normal way of differentiation in proliferating cell systems due to the lack of their mutual adaptation as well.

Anemia, Aplastic↗

The pathogenesis of chronic alcoholic pancreatitis.

The pathogenesis of chronic alcoholic pancreatitis has not been elucidated yet. There are many theories about this topic. The first regards the initial injuries in the ductal pancreatic system. The second considers that the primary lesion is located in the acinar cells. Three hypotheses are elaborated in this respect: the intervention of toxic metabolites, oxidative stress or neuroimmmune system. The third theory sustains that a severe initial attack of acute pancreatitis may induce lesions typical of chronic pancreatitis. Recently the intervention of genetic factors, responsible for the susceptibility chronic pancreatitis has been put forward.

Fibrosis↗

A genetic algorithm to select variables in logistic regression: example in the domain of myocardial infarction.

Actual use of regression models in clinical practice depends on model simplicity. Reducing the number of variables in a model contributes to this goal. The quality of a particular selection of variables for a logistic regression model can be defined in terms of the number of variables selected and the model's discriminatory performance, as measured by the area under the ROC curve. A genetic algorithm was applied to search for the best variable combinations for modeling presence of myocardial infarction in a data set of patients with chest pain. Using an external validation set, the resulting model was compared with models constructed with standard backward, forward and stepwise methods of variable selection. The improvement in discriminatory ability yielded by the genetic algorithm variable selection method was statistically significant (p < 0.02).

Algorithms↗

Studies of the Vi (gamma-2c) subgroup of gamma-globulin. A relationship between concentration and genetic type among normal individuals.

Further delineation of the antigens characteristic of the Vi or gamma(2c) subgroup of gamma-globulin was carried out utilizing a number of rabbit and primate antisera. Two genetic antigens characteristic of this subgroup, Gm(b) and Gm(g), were also detected by precipitation techniques with certain of the antisera. These were clearly differentiated from antigens common to all proteins of this subgroup. The concentration, of Vi protein in normal and pathological sera from several population groups was measured quantitatively utilizing a variety of immunological procedures. All sera studied showed measurable levels. The mean value for Caucasian sera was 1.06 mg/ml, representing approximately 8% of gammaG-globulin. This agreed closely with a figure of 8.4% for the incidence of myeloma proteins of the Vi subgroup among all gammaG-myeloma proteins in Caucasians. A relationship was found between the Vi subgroup concentration and the specific genetic type of a given individual. Measurements of the Gm(b) genetic determinants, which are found solely in Vi-type proteins, brought forward this relationship. Gm(b+) individuals showed higher concentrations of Vi-type gamma-globulin than those who were Gm(b-), and this difference was statistically significant for both the homozygous and heterozygous states. It appeared that the structural genes for Gm(b+) polypeptide chains showed a greater synthetic capacity than those for Gm(b-) types. The possible significance of such effects in governing the relative composition of the antibody population in a given individual is discussed.

Black or African American↗

Rates of spontaneous mutation in an archaeon from geothermal environments.

To estimate the efficacy of mechanisms which may prevent or repair thermal damage to DNA in thermophilic archaea, a quantitative assay of forward mutation at extremely high temperature was developed for Sulfolobus acidocaldarius, based on the selection of pyrimidine-requiring mutants resistant to 5-fluoro-orotic acid. Maximum-likelihood analysis of spontaneous mutant distributions in wild-type cultures yielded maximal estimates of (2.8 +/- 0.7) x 10(-7) and (1.5 +/- 0.6) x 10(-7) mutational events per cell per division cycle for the pyrE and pyrF loci, respectively. To our knowledge, these results provide the first accurate measurement of the genetic fidelity maintained by archaea that populate geothermal environments. The measured rates of forward mutation at the pyrE and pyrF loci in S. acidocaldarius are close to corresponding rates reported for protein-encoding genes of Escherichia coli. The normal rate of spontaneous mutation in E. coli at 37 degrees C is known to require the functioning of several enzyme systems that repair spontaneous damage in DNA. Our results provide indirect evidence that S. acidocaldarius has cellular mechanisms, as yet unidentified, which effectively compensate for the higher chemical instability of DNA at the temperatures and pHs that prevail within growing Sulfolobus cells.

DNA Damage↗

[Hereditary neoplastic diseases (genetic predisposition and cancer syndromes)].

After one decade of molecular genetic studies, little doubt remains that cancer is a genetic disease. While mutations in somatic cells may cause cancer, they don't carry forward to the next generation. In fact, most cancers arise in this way. In some individuals mutations in cancer related genes may be present at the constitutional level, inherited from one of the parents. An individual who carries a mutant allele of an inherited cancer gene has a variable risk of cancer that is influenced by other genetic and non-genetic factors (such as other cellular genes, dietary, lifestyle, and environmental factors). Collectively, the syndromes affect about 1% of cancer patients. During the past decade about 25 different cancer susceptibility genes have been reported to be linked to the known hereditary cancer syndromes. Over the period of the last three to five years, studies of the specific mutations responsible for these syndromes and the cellular signaling pathways disrupted by the mutant proteins have begun to provide unprecedented insights into the molecular origin and pathogenesis of inherited and sporadic forms of cancer. This article reviews the cancer susceptibility genes and cancer syndromes, particularly those associated with common malignancies (breast, prostate and colorectal carcinomas). Results of the mutation analysis in BRCA1 and BRCA2 genes of Hungarian breast/ovarian cancer families will be briefly discussed. These data indicate a strong founder effect for some mutations of BRCA1 gene in Hungary. As a results of recent publicity of discoveries of molecular genetics--particularly those related to common malignancies--due to publicity in the scientific and the lay press awareness and demand for predictive DNA tests have dramatically increased worldwide over the past 3 years. The author, as a member of the Breast Cancer Linkage Consortium, shares the consensus view that genetic testing and genetic counseling for cancer risk together with surveillance and management should for the present be offered only through specialist clinical genetic departments as part of a research evaluation.

DNA, Neoplasm↗

The use of live attenuated Salmonella for oral vaccination.

Studies of the pathogenesis of Salmonella at the molecular level have led to the identification of several classes of genes that are involved in survival in the host. This has led to the availability of a panel of attenuating lesions which are now being used to develop several rationally attenuated strains which are being evaluated as oral vaccines against human and animal salmonellosis. Much effort has been directed towards the development of a more efficacious single dose oral typhoid vaccine and there are now several candidates in Phase 1 studies. The successful development of a genetically defined oral typhoid vaccine will not only be a major step forward in the control of typhoid but will pave the way for development of practical human vaccines based on using the strain to deliver heterologous antigens to the human immune system. We have concentrated on developing a single dose oral tetanus vaccine based on constructing strains expressing fragment C (a non-toxic immunogenic protein derived from tetanus toxin). Several different promotors have been used for controlling the expression of fragment C and these have been introduced into double aro mutants of S. typhimurium and compared for their ability to elicit protective immune responses in mice. This work has demonstrated that it is possible to protect mice against tetanus toxin challenge after a single oral dose of one of these recombinant Salmonella strains. Analogous hybrid S. typhi double aro mutants have now been constructed for potential use in humans.

Administration, Oral↗

DNA profiling of Tilapia guinasana, a species endemic to a single sinkhole, to determine the genetic divergence between color forms.

Northwestern South Africa and Namibia contain a number of sinkholes in the dolomitic rock formations found in this area. These contain isolated populations of Tilapia. Most contain Tilapia sparmanii, but the one in Namibia, Guinas, is of particular interest as it contains the endemic species, Tilapia guinasana, which exhibits none sex-limited polychromatisms, which is unique for Tilapia. This sinkhole is under environmental threat, particularly as a result of being a recreational diving site. This study, using randomly amplified polymorphic DNA sequences (RAPDs), when analyzed using analysis of variance (ANOVA), shows that the colour forms of Tilapia guinasana are genetically distinct. This confirms previous evidence that assortative mating between color forms takes place. The various possible hypotheses for the occurrence and genetic stability of the color polymorphism are discussed. Further, a new hypothesis is put forward based on a need to maximize outbreeding in fully isolated population with no possibility of increase in size above the maximum and limited carrying capacity of the sinkhole.

Animals↗

Prevention of disability on grounds of suffering.

This paper examines one particular justification for the screening and termination of embryos/fetuses which possess genetic features known to cause disability. The particular case is that put forward in several places by John Harris. He argues that the obligation to prevent needless suffering justifies the prevention of the births of disabled neonates. The paper begins by rehearsing Harris's case. Then, drawing upon claims advanced in a recent paper in the Journal of Medical Ethics, it is subjected to critical scrutiny, focusing on Harris's "suffering claim" (the claim that a life with disability inevitably involves suffering on a significant scale).(1) It is argued that the suffering claim must be false if understood as an empirical claim. And, even if understood as a conceptual truth, it mistakenly assimilates the concepts of harm and suffering. Finally, again focusing on Harris's recent work in this area, his characterisation of disability as a "harmed condition" is shown not to apply in the case of at least some moderate forms of intellectual disability.

Abortion, Induced↗

Genetic aspects of inflammatory bowel disease: how far have we come, and where are we heading?

Crohn"s disease and ulcerative colitis are related complex genetic disorders, with gene-gene and gene-environment interactions that are critical to their pathogenesis. Multiple genetic loci have been implicated through genome-wide searches. Of these, a locus on Crohn"s disease has been definitively established in the pericentromeric region of chromosome 16. Multiple candidate gene studies have been forwarded, and functionally significant variants in immune-associated genes will provide additional insight. Characterization of the genetic variation responsible for causing inflammatory bowel disease will result in development of novel therapeutic approaches as well as in tailoring of specific therapies to individual patients based on their specific molecular pathogenesis.

Genetic Linkage↗

The coming of age of our understanding of the enterohepatic circulation of bile salts.

Recent advances in molecular biology have greatly accelerated knowledge relating to the significance of the enterohepatic circulation of bile salts. This review highlights the role that both oxysterols and bile salts play as ligands which, when bound to nuclear hormone receptors, activate transcription factors that set into play feed-forward catabolism of cholesterol to bile salts and feedback control of bile acid synthesis. The nuclear hormone receptors, liver X receptor (LXR) and farnesoid X receptor (FXR) both combined as heterodimers with retinoid X receptor and with oxysterols and bile salts, respectively as their ligands, initiate powerful genetic controls over cholesterol and bile acid homeostatic mechanisms. LXR/RXR signals molecular control of feed-forward catabolism of cholesterol to bile acids while FXR/RXR initiates feedback control of bile acid synthesis. An additional nuclear hormone receptor, small heterodimer partner (SHP), is required to inhibit the competence factor, liver receptor homolog-1 to achieve repression of bile acid synthesis in the liver and in so doing SHP autoregulates its own function. Additionally, while bile acid synthesis is repressed, pool size is preserved by the action of FXR/RXR at both hepatic and intestinal levels, which genetically signals enhanced hepatocyte bile salt transport by the bile salt export pump (BSEP) and the ileal bile acid binding protein (IBABP) for ileal reabsorption. During activation of cholesterol catabolism, LXR/RXR enhances reverse cholesterol transport by increasing cholesterol efflux via the ABC-1 transporter from extrahepatic cells. This cholesterol is then taken up by high-density lipoprotein (HDL) and transported back to the liver for further cholesterol catabolism and elimination in bile. The genetic coordination of nuclear hormone receptor function within the territory of the enterohepatic of bile salts allows for normal cholesterol and bile acid homeostasis thereby preventing atherosclerosis.

Arteriosclerosis↗

A statistical framework for genetic association studies of power curves in bird flight.

How the power required for bird flight varies as a function of forward speed can be used to predict the flight style and behavioral strategy of a bird for feeding and migration. A U-shaped curve was observed between the power and flight velocity in many birds, which is consistent to the theoretical prediction by aerodynamic models. In this article, we present a general genetic model for fine mapping of quantitative trait loci (QTL) responsible for power curves in a sample of birds drawn from a natural population. This model is developed within the maximum likelihood context, implemented with the EM algorithm for estimating the population genetic parameters of QTL and the simplex algorithm for estimating the QTL genotype-specific parameters of power curves. Using Monte Carlo simulation derived from empirical observations of power curves in the European starling (Sturnus vulgaris), we demonstrate how the underlying QTL for power curves can be detected from molecular markers and how the QTL detected affect the most appropriate flight speeds used to design an optimal migration strategy. The results from our model can be directly integrated into a conceptual framework for understanding flight origin and evolution.

Journal Article↗

Identification of novel mutations causing familial primary congenital glaucoma in Indian pedigrees.

PURPOSE: To determine the possible molecular genetic defect underlying primary congenital glaucoma (PCG) in India and to identify the pathogenic mutations causing this childhood blindness. METHODS: Twenty-two members of five clinically well-characterized consanguineous families were studied. The primary candidate gene CYP1B1 was amplified from genomic DNA, sequenced, and analyzed in control subjects and patients to identify the disease-causing mutations. RESULTS: Five distinct mutations were identified in the coding region of CYP1B1 in eight patients of five PCG-affected families, of which three mutations are novel. These include a novel homozygous frameshift, compound heterozygous missense, and other known mutations. One family showed pseudodominance, whereas others were autosomal recessive with full penetrance. In contrast to all known CYP1B1 mutations, the newly identified frameshift is of special significance, because all functional motifs are missing. This, therefore, represents a rare example of a natural functional CYP1B1 knockout, resulting in a null allele (both patients are blind). CONCLUSIONS: The molecular mechanism leading to the development of PCG is unknown. Because CYP1B1 knockout mice did not show a glaucoma phenotype, the functional knockout identified in this study has important implications in elucidating the pathogenesis of PCG. Further understanding of how this molecular defect leads to PCG could influence the development of specific therapies. This is the first study to describe the molecular basis of PCG from the Indian subcontinent and has profound and multiple clinical implications in diagnosis, genetic counseling, genotype-phenotype correlations and prognosis. Hence, it is a step forward in preventing this devastating childhood blindness.

Adult↗

A Markov process of gene frequency change in a geographically structured population.

A Markov process (chain) of gene frequency change is derived for a geographically-structured model of a population. The population consists of colonies which are connected by migration. Selection operates in each colony independently. It is shown that there exists a stochastic clock that transforms the originally complicated process of gene frequency change to a random walk which is independent of the geographical structure of the population. The time parameter is a local random time that is dependent on the sample path. In fact, if the alleles are selectively neutral, the time parameter is exactly equal to the sum of the average local genetic variation appearing in the population, and otherwise they are approximately equal. The Kolmogorov forward and backward equations of the process are obtained. As a limit of large population size, a diffusion process is derived. The transition probabilities of the Markov chain and of the diffusion process are obtained explicitly. Certain quantities of biological interest are shown to be independent of the population structure. The quantities are the fixation probability of a mutant, the sum of the average local genetic variation and the variation summed over the generations in which the gene frequency in the whole population assumes a specified value.

Alleles↗

Plant genetic assays and their use in studies on environmental mutagenesis in developing countries.

The detection of point mutation at specific loci in Zea mays for use in research in environmental mutagenesis is described. The frequency of forward or reverse mutation at the waxy locus may be determined in gametophytes (pollen grains) and this provides the measurement of large numbers of individuals and thus a high genetic resolution. The analysis of mutation induction in pollen grains is well suited for in situ studies. Methods to identify forward mutation at the yellow-green-2 locus in leaf primordial cells and the use of this assay to identify mutagenic agents after acute exposure are presented. These rapid, relatively simple point mutation assays can be used to evaluate the genotoxic hazards of environmental agents and complex environmental mixtures in developing countries.

Developing Countries↗