CHARACTERIZING A NOVEL GENETIC LOCUS ASSOCIATED WITH FAMILIAL CO-OCCURRENCE OF THORACIC AORTIC ANEURYSMS AND INTRACRANIAL ANEURYSMS

The Mendelian inheritance of genetic mutations can lead to adult-onset cardiovascular disease. Several genetic loci have been mapped for the familial form of Thoracic Aortic Aneurysms (TAA), and many causal mutations have been identified for this disease. Intracranial Aneurysms (ICA) also show linkage heterogeneity, but no mutations have been identified causing familial ICA alone. Here, we characterized a large family (TAA288) with an autosomal dominant pattern of inherited aneurysms. It is intriguing that female patients predominantly present with ICA and male patients predominantly with TAA in this family. To identify a causal mutation in this family, a genome-wide linkage analysis was previously performed on nine members of this family using the 50k GenChips Hind array from Affymetrix. This analysis eventually identified a single disease-segregating locus, on chromosome 5p15. We build upon this previous analysis in this study, hypothesizing that a genetic mutation inherited in this locus leads to the sex-specific phenotype of TAA and ICA in this family First we refined the boundaries of the 5p15 disease linked locus down to the genomic coordinates 5p15: 3,424,465- 6,312,925 (GRCh37/hg19 Assembly). This locus was named the TAA288 critical interval. Next, we sequenced candidate genes within the TAA288 critical interval. The selection of genes was simplified by the relatively small number of well-characterized genetic elements within the region. Seeking novel or rare disease-segregating variants, we initially observed a single point alteration in the metalloproteinase gene ADAMTS16 fulfilling this criteria. This variant was later classified as a low-frequency population polymorphism (rs72647757), but we continued to explore the potential role of the ADAMTS16 as the cause of disease in TAA288. We observed that fibroblasts cultured from TAA288 patients consistently upregulated the expression of this gene more strongly compared to matched control fibroblasts when treated with the cytokine TGF-β1, though there was some variation in the exact nature of this expression. We also observed evidence that this protein is expressed at elevated levels in aortic aneurysm tissue from patients with mutations in the gene TGFBR2 and Marfan syndrome, shown by immunohistochemical detection of this protein.

Genetic alterations associated with prostate cancer progression

Prostate cancer is the second most commonly diagnosed cancer among men in the United States. In this study, evidence is presented to support the hypothesis that specific chromosomal aberrations (involving one or more chromosomal regions) are associated with prostate cancer progression from organ-confined to locally advanced tumors and that some aberrations seen in high frequency in metastatic tumors may also be present in a subset of primary tumors. To determine the appropriate approach to address this hypothesis, I have established a modified CGH protocol by microdissection and DOP-PCR for use in detecting chromosomal changes in clinical prostate tumor specimens that is more sensitive and accurate than conventional CGH methods. I have successfully performed the improved CGH protocol to screen for genetic changes of 24 organ confined (pT2) and 21 locally advanced (pT3b) clinical prostate cancer specimens without metastases (N0M0). Comparisons of tumors by stage or Gleason scores following contingency table analysis showed that seven regions of the genome differed significantly between pT2 and pT3b tumors or between low and high Gleason tumors suggesting that these regions may be important in local prostate cancer progression. These included losses on 6p21–25, 6q24–27, 8p, 10q25–26, 15q22–26, and 18cen–q12 as well as gain of 3p13–q13. Multivariate analyses showed that loss of 8p (step1) and loss of 6q25–26 (or 6p21–25 or 10q25–26) (step 2) were predictive of pathologic stage or Gleason groups with 80% accuracy. Additional 5–7 steps in the multivariate model increased the predictive value to 91–95%. Comparison of the CGH data from the primary prostate tumors of this study with those obtained from published literature on metastases and recurrent tumors showed that the clinically more aggressive stage pT3b tumors shared more abnormalities in high frequency with metastases and recurrent tumors than less aggressive stage pT2 tumors. Furthermore, loss of 11cen–q22 was shared only between the primary tumors and metastases while gain of Xcen–q13 and loss of 18cen–q12 were in common between primary and recurrent tumors. These analyses suggest that the multistage model of prostate cancer progression is not linear and that some early primary tumors may be predisposed to metastasize or evolve into recurrent tumors due to the presence of specific genetic alterations. ^

Genetic variants associated with metastatic prostate cancer

Introduction. Distant metastasis remains the leading cause of death among prostate cancer patients. Several genetic susceptibility loci associated with Prostate cancer have been identified by the Genome Wide Association Studies (GWAS). To date, few studies have explored the ability of these SNPs to identify metastatic prostate cancer. Based on the identification of genetic variants as predictors of aggressive disease, a case comparison study of prostate cancer patients was designed to explore the association of 96 GWAS single nucleotide polymorphisms (SNPs) with metastatic disease. ^ Method. 1242 histologically confirmed prostate cancer patients, with and without metastatic disease, were enrolled into the study. Data were collected from personal interviews, hospital database and abstraction of medical records. Ninety six SNPs identified from GWAS studies based on their associations with prostate cancer risk were genotyped in the study population. Univariate and multivariate logistic regression analyses were used to explore the relationships of the variants with metastatic prostate cancer in Whites and African American men. ^ Results. Four SNPs showed independent associations with metastatic prostate cancer (rs721048 in EHBP1 (2p15), rs3025039 in VEGF (6p12), rs11228565 in Intergenic(11q13.2) and rs2735839 in KLK3(19q13.33)) in the White population. For SNP rs2735839 in KLK3, genotype GA was 1.71 times as likely to be associated with metastatic prostate cancer diagnosis as genotype AA after adjusting for other significant SNPs and covariates (95% CI, 1.12-2.60; p=0.012). In men of African descent, three SNPs: rs1512268 in NKX3-1(8p21.2), rs12155172 in intergenic (7p15.3) & rs10486567 in JAZF1 (7p15.2) were positively associated with metastatic disease in the multivariate analysis. The strongest SNP was rs1512268 heterozygous genotype AG in NKX3-1(8p21.2) which was associated with 3.97-fold increased risk of metastatic prostate cancer diagnosis (95% CI, 1.69-9.34; p =0.002). ^ Conclusion. Genetic variants associated with metastatic prostate cancer were different in Whites and African American men. Given the high mortality rate recorded in men diagnosed with metastatic prostate tumor, further studies are needed to validate associations and establish their clinical application.^

Influence of Anchoring on Miscarriage Risk Perception Associated with Amniocentesis

INFLUENCE OF ANCHORING ON MISCARRIAGE RISK PERCEPTION ASSOCIATED WITH AMNIOCENTESIS Publication No. ___________ Regina Nuccio, BS Supervisory Professor: Claire N. Singletary, MS, CGC Amniocentesis is the most common invasive procedure performed during pregnancy (Eddleman, et al., 2006). One important factor that women consider when making a decision about amniocentesis is the risk of miscarriage associated with the procedure. People use heuristics such as anchoring, the action of using a prior belief regarding the magnitude of risk as a frame of reference for new information to be synthesized, to better understand risks that they encounter in their lives. This study aimed to determine a woman’s perception of miscarriage risk associated with amniocentesis before and after a genetic counseling session and to determine what factors are most likely to anchor a woman’s perception of miscarriage risk associated with amniocentesis. Most women perceived the risk as low or average pre-counseling and were likely to indicate the numeric risk of amniocentesis as <1% risk. A higher percentage of patients correctly identified the numeric risk as <1% post-counseling when compared to pre-counseling. However, the majority of patients’ feeling about the risk perception did not change after the genetic counseling session (60%), regardless of how they perceived the risk before discussing amniocentesis with a genetic counselor. Those whose risk perception did change after discussing amniocentesis with a genetic counselor showed a decreased risk perception (p<0.0001). Of the multitude of factors studied, only two showed significance: having a friend or relative with a personal or family history of a genetic disorder was associated with a lower risk perception (p=0.001) and having a child already was associated with a lower risk perception (p=0.038). The lack of significant factors may reflect the uniqueness of each patient’s heuristic framework and reinforces the importance of genetic counseling to elucidate individual concerns.

A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus.

A gain-of-function R620W polymorphism in the PTPN22 gene, encoding the lymphoid tyrosine phosphatase LYP, has recently emerged as an important risk factor for human autoimmunity. Here we report that another missense substitution (R263Q) within the catalytic domain of LYP leads to reduced phosphatase activity. High-resolution structural analysis revealed the molecular basis for this loss of function. Furthermore, the Q263 variant conferred protection against human systemic lupus erythematosus, reinforcing the proposal that inhibition of LYP activity could be beneficial in human autoimmunity.

Severe aortic and arterial aneurysms associated with a TGFBR2 mutation.

BACKGROUND: A 24-year-old man presented with previously diagnosed Marfan's syndrome. Since the age of 9 years, he had undergone eight cardiovascular procedures to treat rapidly progressive aneurysms, dissection and tortuous vascular disease involving the aortic root and arch, the thoracoabdominal aorta, and brachiocephalic, vertebral, internal thoracic and superior mesenteric arteries. Throughout this extensive series of cardiovascular surgical repairs, he recovered without stroke, paraplegia or renal impairment. INVESTIGATIONS: CT scans, arteriogram, genetic mutation screening of transforming growth factor beta receptors 1 and 2. DIAGNOSIS: Diffuse and rapidly progressing vascular disease in a patient who met the diagnostic criteria for Marfan's syndrome, but was later rediagnosed with Loeys-Dietz syndrome. Genetic testing also revealed a de novo mutation in transforming growth factor beta receptor 2. MANAGEMENT: Regular cardiovascular surveillance for aneurysms and dissections, and aggressive surgical treatment of vascular disease.

ROLE OF PROSTAGLANDIN E2 IN THE REGULATION OF PANCREATIC STELLATE CELLS HYPER ACTIVITY ASSOCIATED WITH PANCREATIC CANCER

Pancreatic cancer is one of the most lethal type of cancer due to its high metastasis rate and resistance to chemotherapy. Pancreatic fibrosis is a constant pathological feature of chronic pancreatitis and the hyperactive stroma associated with pancreatic cancer. Strong evidence supports an important role of cyclooxygenase-2 (COX-2) and COX-2 generated prostaglandin E2 (PGE2) during pancreatic fibrosis. Pancreatic stellate cells (PSC) are the predominant source of extracellular matrix production (ECM), thus being the key players in both diseases. Given this background, the primary objective is to delineate the role of PGE2 on human pancreatic stellate cells (PSC) hyper activation associated with pancreatic cancer. This study showed that human PSC cells express COX-2 and synthesize high levels of PGE2. PGE2 stimulated PSC migration and invasion; expression of extra cellular matrix (ECM) genes and tissue degrading matrix metallo proteinases (MMP) genes. I further identified the PGE2 EP receptor responsible for mediating these effects on PSC. Using genetic and pharmacological approaches I identified the receptor required for PGE2 mediates PSC hyper activation. Treating PSC with Specific antagonists against EP1, EP2 and EP4, demonstrated that blocking EP4 receptor only, resulted in a complete reduction of PGE2 mediated PSC activation. Furthermore, siRNA mediated silencing of EP4, but not other EP receptors, blocked the effects of PGE2 on PSC fibrogenic activity. Further examination of the downstream pathway modulators revealed that PGE2 stimulation of PSC involved CREB and not AKT pathway. The regulation of PSC by PGE2 was further investigated at the molecular level, with a focus on COL1A1. Collagen I deposition by PSC is one of the most important events in pancreatic cancer. I found that PGE2 regulates PSC through activation of COL1A1 expression and transcriptional activity. Downstream of PGE2, silencing of EP4 receptor caused a complete reduction of COL1A1 expression and activity supporting the role of EP4 mediated stimulation of PSC. Taken together, this data indicate that PGE2 regulates PSC via EP4 and suggest that EP4 can be a better therapeutic target for pancreatic cancer to reduce the extensive stromal reaction, possibly in combination with chemotherapeutic drugs can further kill pancreatic cancer cells.

Risk factors associated with first symptomatic infection of {\it Cryptosporidium parvum\/} in an infant population in Bilbeis, Egypt

Diarrhea disease is a leading cause of morbidity and mortality, especially in children in developing countries. An estimate of the global mortality caused by diarrhea among children under five years of age was 3.3 million deaths per year. Cryptosporidium parvum was first identified in 1907, but it was not until 1970 that this organism was recognized as a cause of diarrhea in calves. Then it was as late as 1976 that the first reported case of human Cryptosporidiosis occurred. This study was conducted to ascertain the risk factors of first symptomatic infection with Cryptosporidium parvum in a cohort of infants in a rural area of Egypt. The cohort was followed from birth through the first year of life. Univariate and multivariate analyses of data demonstrated that infants greater than six months of age had a two-fold risk of infection compared with infants less than six months of age (RR = 2.17; 95% C.I. = 1.01-4.82). When stratified, male infants greater than six months of age were four times more likely to become infected than male infants less than six months of age. Among female infants, there was no difference in risk between infants greater than six months of age and infants less than six months of age. Female infants less than six months of age were twice more likely to become infected than male infants less than six months of age. The reverse occurred for infants greater than six months of age, i.e., male infants greater than six months of age had twice the risk of infection compared to females of the same age group. Further analysis of the data revealed an increased risk of Cryptosporidiosis infection in infants who were attended in childbirth by traditional childbirth attendants compared to infants who were attended by modern childbirth attendants (nurses, trained midwives, physicians) (RR = 4. 18; 95% C.I. = 1.05-36.06). The final risk factor of significance was the number of people residing in the household. Infants in households which housed more than seven persons had an almost two-fold risk of infection compared with infants in homes with fewer than seven persons. Other risk factors which suggested increased risk were lack of education among the mothers, absence of latrines and faucets in the homes, and mud used as building material for walls and floors in the homes. ^

Non B-DNA structures and genomic instability associated with myotonic dystrophy type 2 (CCTG).(CAGG) repeats

There are many diseases associated with the expansion of DNA repeats in humans. Myotonic dystrophy type 2 is one of such diseases, characterized by expansions of a (CCTG)•(CAGG) repeat tract in intron 1 of zinc finger protein 9 (ZNF9) in chromosome 3q21.3. The DM2 repeat tract contains a flanking region 5' to the tract that consists of a polymorphic repetitive sequence (TG)14-25(TCTG)4-11(CCTG) n. The (CCTG)•(CAGG) repeat is typically 11-26 repeats in persons without the disease, but can expand up to 11,000 repeats in affected individuals, which is the largest expansion seen in DNA repeat diseases to date. This DNA tract remains one of the least characterized disease-associated DNA repeats, and mechanisms causing the repeat expansion in humans have yet to be elucidated. Alternative, non B-DNA structures formed by the expanded repeats are typical in DNA repeat expansion diseases. These sequences may promote instability of the repeat tracts. I determined that slipped strand structure formation occurs for (CCTG)•(CAGG) repeats at a length of 42 or more. In addition, Z-DNA structure forms in the flanking human sequence adjacent to the (CCTG)•(CAGG) repeat tract. I have also performed genetic assays in E. coli cells and results indicate that the (CCTG)•(CAGG) repeats are more similar to the highly unstable (CTG)•(CAG) repeat tracts seen in Huntington's disease and myotonic dystrophy type 1, than to those of the more stable (ATTCT)•(AGAAT) repeat tracts of spinocerebellar ataxia type 10. This instability, however, is RecA-independent in the (CCTG)•(CAGG) and (ATTCT)•(AGAAT) repeats, whereas the instability is RecA-dependent in the (CTG)•(CAG) repeats. Structural studies of the (CCTG)•(CAGG) repeat tract and the flanking sequence, as well as genetic selection assays may reveal the mechanisms responsible for the repeat instability in E. coli, and this may lead to a better understanding of the mechanisms contributing to the human disease state. ^

Psychosocial variables associated with sexual risk behavior among an urban seventh grade population

This dissertation examines the psychosocial factors associated with sexual risk behavior among low socio-economic, minority middle school students in a large urban school district in Houston, Texas and is presented in the form of three articles. Article One examines the association between knowledge, perceived risk of HIV/STD, and self-reported lifetime engagement in vaginal sex among seventh grade students. The purpose of Article Two is to examine the association between knowledge about condoms, condom use attitudes, perceived peer norms about condom use, condom use negotiation self-efficacy, condom use self-efficacy, condom use intentions and actual condom use among seventh grade middle school adolescents. Finally, Article Three examines the association between attitudes, perceived peer norms, refusal self-efficacy about sex, sexual and abstinence intentions among seventh grade adolescents. By providing a better understanding of factors influencing sexual intentions and sexual behaviors among this population, these articles will enable practitioners to develop effective evidence-based interventions to delay sexual initiation and prevent youth from engaging in risky sexual behaviors, including risk of HIV/STDs and unintended pregnancy.^

Critical indicators associated with negative performance in a selectively manned unit

Introduction. Selectively manned units have a long, international history, both military and civilian. Some examples include SWAT teams, firefighters, the FBI, the DEA, the CIA, and military Special Operations. These special duty operators are individuals who perform a highly skilled and dangerous job in a unique environment. A significant amount of money is spent by the Department of Defense (DoD) and other federal agencies to recruit, select, train, equip and support these operators. When a critical incident or significant life event occurs, that jeopardizes an operator's performance; there can be heavy losses in terms of training, time, money, and potentially, lives. In order to limit the number of critical incidents, selection processes have been developed over time to “select out” those individuals most likely to perform below desired performance standards under pressure or stress and to "select in" those with the "right stuff". This study is part of a larger program evaluation to assess markers that identify whether a person will fail under the stresses in a selectively manned unit. The primary question of the study is whether there are indicators in the selection process that signify potential negative performance at a later date. ^ Methods. The population being studied included applicants to a selectively manned DoD organization between 1993 and 2001 as part of a unit assessment and selection process (A&S). Approximately 1900 A&S records were included in the analysis. Over this nine year period, seventy-two individuals were determined to have had a critical incident. A critical incident can come in the form of problems with the law, personal, behavioral or family problems, integrity issues, and skills deficit. Of the seventy-two individuals, fifty-four of these had full assessment data and subsequent supervisor performance ratings which assessed how an individual performed while on the job. This group was compared across a variety of variables including demographics and psychometric testing with a group of 178 individuals who did not have a critical incident and had been determined to be good performers with positive ratings by their supervisors.^ Results. In approximately 2004, an online pre-screen survey was developed in the hopes of preselecting out those individuals with items that would potentially make them ineligible for selection to this organization. This survey has aided the organization to increase its selection rates and save resources in the process. (Patterson, Howard Smith, & Fisher, Unit Assessment and Selection Project, 2008) When the same prescreen was used on the critical incident individuals, it was found that over 60% of the individuals would have been flagged as unacceptable. This would have saved the organization valuable resources and heartache.^ There were some subtle demographic differences between the two groups (i.e. those with critical incidents were almost twice as likely to be divorced compared with the positive performers). Upon comparison of Psychometric testing several items were noted to be different. The two groups were similar when their IQ levels were compared using the Multidimensional Aptitude Battery (MAB). When looking at the Minnesota Multiphasic Personality Inventory (MMPI), there appeared to be a difference on the MMPI Social Introversion; the Critical Incidence group scored somewhat higher. When analysis was done, the number of MMPI Critical Items between the two groups was similar as well. When scores on the NEO Personality Inventory (NEO) were compared, the critical incident individuals tended to score higher on Openness and on its subscales (Ideas, Actions, and Feelings). There was a positive correlation between Total Neuroticism T Score and number of MMPI critical items.^ Conclusions. This study shows that the current pre-screening process is working and would have saved the organization significant resources. ^ If one was to develop a profile of a candidate who potentially could suffer a critical incident and subsequently jeopardize the unit, mission and the safety of the public they would look like the following: either divorced or never married, score high on the MMPI in Social Introversion, score low on MMPI with an "excessive" amount of MMPI critical items; and finally scores high on the NEO Openness and subscales Ideas, Feelings, and Actions.^ Based on the results gleaned from the analysis in this study there seems to be several factors, within psychometric testing, that when taken together, will aid the evaluators in selecting only the highest quality operators in order to save resources and to help protect the public from unfortunate critical incidents which may adversely affect our health and safety.^

Single nucleotide polymorphisms (SNPs) associated with TGF-beta pathway and their significance in systemic sclerosis - A multilevel analysis

Systemic sclerosis (SSc) or Scleroderma is a complex disease and its etiopathogenesis remains unelucidated. Fibrosis in multiple organs is a key feature of SSc and studies have shown that transforming growth factor-β (TGF-β) pathway has a crucial role in fibrotic responses. For a complex disease such as SSc, expression quantitative trait loci (eQTL) analysis is a powerful tool for identifying genetic variations that affect expression of genes involved in this disease. In this study, a multilevel model is described to perform a multivariate eQTL for identifying genetic variation (SNPs) specifically associated with the expression of three members of TGF-β pathway, CTGF, SPARC and COL3A1. The uniqueness of this model is that all three genes were included in one model, rather than one gene being examined at a time. A protein might contribute to multiple pathways and this approach allows the identification of important genetic variations linked to multiple genes belonging to the same pathway. In this study, 29 SNPs were identified and 16 of them located in known genes. Exploring the roles of these genes in TGF-β regulation will help elucidate the etiology of SSc, which will in turn help to better manage this complex disease. ^

Is H. pylori infection associated with diarrhea in a cohort of 3- to 8-year-old Colombian children?

The Estudio Comunitario sobre la Salud del Niño cohort study followed 326 3- to 8-year-old Colombian children for 4 years to observe the natural history of Helicobacter pylori infection and identify risk factors for acquisition, recurrence and persistence. Acute H. pylori infection during childhood may predispose to other enteric infections and therefore increase the risk of diarrheal disease. This dissertation aimed to estimate the effect of H. pylori infection on the occurrence of diarrhea and parasitic co-infections. The analysis used Generalized Estimating Equations to obtain odds ratios to estimate relative risks for diarrhea and the Zhang-Yu algorithm to estimate relative risks for on parasitic infections. Andersen-Gill models were used to estimate rate ratios for the effect of H. pylori status on the recurrence of parasitic infections. H. pylori status was classified for the entire follow-up duration in 1 of 3 categories: persistently positive, intermittently positive, and persistently negative. Multivariable models included child’s sex, age, symptoms, medication use, and socio-environmental factors. H. pylori infection was weakly and imprecisely associated with diarrheal disease, which occurred at an unexpectedly low frequency in this study. Persistently H. pylori-positive children had a somewhat higher incidence of reported diarrhea than intermittently positive or persistently negative children. Stratified analysis revealed that the presence of specific helminthes modified the effect of persistent H. pylori infection on diarrhea. The incidence of any parasitic infections was higher in children with persistent H. pylori infection relative to those with intermittent or persistently negative status, but this association did not hold when adjusted for the full set of selected covariates. The effects of H. pylori persistent status were similar for the occurrence or recurrence of Giardia duodenalis, Entamoeba histolytica, and Ascaris lumbricoides. These results show that H. pylori frequently co-exists with other parasites in Andean children and suggest that intermittently H. pylori–positive children might be at a lower risk of parasitic infections than persistently positive children. The relationship of H. pylori infection, helminthic infection and diarrheal disease should be further explored in studies that devote more intensive resources to accurate ascertainment of diarrhea.^

Risk and protective factors associated with depression among racial and ethnic mothers of adolescents

The central paradigm linking disadvantaged social status and mental health has been the social stress model (Horwitz, 1999), the assumption being that individuals residing in lower social status groups are subjected to greater levels of stress not experienced by individuals from higher status groups. A further assumption is that such individuals have fewer resources to cope with stress, in turn leading to higher levels of psychological disorder, including depression (Pearlin, 1989). Despite these key assumptions, there is a dearth of literature comparing the social patterning of stress exposure (Hatch & Dohrenwend, 2007; Meyer, Schwartz, & Frost, 2008; Kessler, Mickelson, & Williams, 1999; Turner & Avison, 2003; Turner & Lloyd, 1999; Turner, Wheaton, & Lloyd, 1995), and the distribution and contribution of protective factors, posited to play a role in the low rates of depression found among African- and Latino-Americans (Alegria et al., 2007; Breslau, Aguilar-Gaxiola, Kendler, Su, Williams, & Kessler, 2006; Breslau, Borges, Hagar, Tancredi, Gilman, 2009; Gavin, Walton, Chae, Alegria, Jackson, & Takeuchi, 2010; Williams, & Neighbors, 2006). Thus, this study sought to describe both the distribution and contribution of risk and protective factors in relation to depression among a sample of African-, European-, and Latina-American mothers of adolescents, including testing a hypothesized mechanism through which social support, an important protective factor specific to women and depression, operates. ^ Despite the finding that the levels of depression were not statistically different across all three groups of women, surprising results were found in describing the distribution of both risk and protective factors, in that results reported among all women who were mothers when analyzed masked differences within each ethnic group when SES was assessed, a point made explicit by Williams (2002) regarding racial and ethnic variations in women's health. In the final analysis, while perceived social support was found to partially mediate the effect of social isolation on depression, among African-Americans, the direct effect of social isolation and depression was lower among this group of women, as was the indirect effect of social isolation and perceived social support when compared to European- and Latina-American mothers. Or, put differently, higher levels of social isolation were not found to be as associated with more depression or lower social support among African-American mothers when compared to their European- and Latina-American counterparts. ^ Women in American society occupy a number of roles, i.e., that of being female, married or single, mother, homemaker or employee. In addition, to these roles, ethnicity and SES also come into play, such that the intersection of all these roles and the social contexts that they occupy are equally important and must be taken into consideration when making predictions drawn from the social stress model. Based on these findings, it appears that the assumptions of the social stress model need to be revisited to include the variety of roles that intersect among individuals from differing social groups. More specifically, among women who are mothers and occupy a myriad of other roles, i.e., that of being female, married or single, African- or Latina-American, mother, homemaker or employee, the intersection of all the roles and the social contexts that women occupy are equally important and must be taken into consideration when looking at both the types and distribution of stressors across women. Predictions based on simple, mutually exclusive categories of social groups may lead to erroneous assumptions and misleading results.^