Prevalence of Premature Ovarian Failure in Women with Tuberous Sclerosis

Tuberous Sclerosis Complex (TSC) is an autosomal dominant tumor suppressor disorder characterized by hamartomas, or benign growths, in various organ systems. Inactivating mutations in either the TSC1 or the TSC2 gene cause most cases of TSC. Recently, the use of ovarian specific conditional knock-out mouse models has demonstrated a crucial role of the TSC genes in ovarian function. Mice with complete deletion of Tsc1 or Tsc2 showed accelerated ovarian follicle activation and subsequent premature follicular depletion, consistent with the human condition premature ovarian failure (POF). POF is defined in women as the cessation of menses before the age of 40 and elevated levels of follicle stimulating hormone (FSH). The prevalence of POF is estimated to be 1%, affecting a substantial number of women in the general population. Nonetheless, the etiology of most cases of POF remains unknown. Based on the mouse model results, we hypothesized that the human TSC1 and TSC2 genes are likely to be crucial for ovarian development and function. Moreover, since women with TSC already have one inactivated TSC gene, we further hypothesized that they may show a higher prevalence of POF. To test this hypothesis, we surveyed 1000 women with TSC belonging to the Tuberous Sclerosis Alliance, a national support organization. 182 questionnaires were analyzed for information on menstrual and reproductive function, as well as TSC. This self-reported data revealed 8 women (4.4%) with possible POF, as determined by menstrual history report and additional supportive data. This prevalence is much higher than 1% in the general population. Data from all women suggested other reproductive pathology associated with TSC such as a high rate of miscarriage (41.2%) and menstrual irregularity of any kind (31.2%). These results establish a previously unappreciated effect of TSC on women’s reproductive health. Moreover, these data suggest that perturbations in the cellular pathways regulated by the TSC genes may play an important role in reproductive function.

Dysregulation of alternative splicing of coagulation factor V results in bleeding disorder, east Texas type and other disorders of hemostasis

The studies completed herein explore different phenotypes related to the genetic defects that predispose individuals to a disruption of normal hemostasis. In the first study, a novel autosomal dominant bleeding disorder, which is characterized by excessive bleeding with trauma or surgery and menorrhagia in affected women, was studied in a large family (16 affected individuals) from east Texas. Affected members had a prolongation of their PT and/or aPTT, but normal clinical coagulation studies. Previous linkage analysis by Kuang et. al. (2001) mapped the defective gene to 1g23-24 (LODmax 7.22), which contains the gene for coagulation factor V (FV). I identified an alteration (A2440G) in the FV gene in exon 13 that segregated with the disease and was not present in 62 controls. Interestingly, this alteration resulted in a 22-fold up-regulation of a novel alternative splicing variant in patients' RNA versus controls. This translated into a similar fold increase in a 250-kDa isoform of FV seen in patients' plasma versus controls. A recombinant of this splicing event exhibited an increased sensitivity to cleavage by activated protein C (APC) that was more striking in the presence of PS. In addition, this novel isoform had increased APC cofactor activity, thus increasing the degradation of FVIIIa. These data indicated that A2440G up-regulates an alternatively spliced transcript of FV, and increases a FV isoform that hinders coagulation as opposed to promoting it like its wild-type counterpart. ^ The second study reports the largest screening to date of African Americans in two independent cohorts for a rare prothrombin variant, C20209T, which is suspected to be associated with thrombotic disease. The Texas Medical Center Genetics Resource (TexGen) Stroke DNA repository revealed 1.67% (Fisher p=0.27) of African American stroke patients were heterozygous for the 20209*T allele. Screening of the Atherosclerosis Risk in Communities Study (ARIC) cohort (n=3470) for the 20209*T allele revealed a population prevalence of 0.58% in individuals of African American descent; however, all associations with thrombotic disease were negative. Analysis of these two independent cohorts revealed that, unlike its neighbor G20210A, the C20209T variant does not increase the risk of thrombotic events in the African American population. ^

Posttraumatic stress disorder among veterans of the Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) wars: Psychological comorbidities, postdeployment social support and unit support

Much attention has been given to treating Operation Iraqi Freedom/Operation Enduring (OIF/OEF) Veterans with posttraumatic stress disorder (PTSD). However, little attention is given to those Veterans who do not meet diagnostic criteria for PTSD but who may still benefit from intervention. Research is needed to investigate the impact of how different racial/ethnic backgrounds, different levels of social support and comorbid mental health disorders impact OIF/OEF Veterans with varying levels of PTSD. The purpose of this dissertation is to examine the association of comorbid Axis I disorders, race/ethnicity, different levels of postdeployment social support and unit support on OIF/OEF Veterans with varying levels of PTSD. Data for this dissertation were from postdeployment screenings of OIF/OEF Veterans from a large Veterans Affairs hospital in southeast Texas. To examine the study hypotheses, we conducted multinomial logistic regressions of the clinician reported data. ^ The first article examined the prevalence of subthreshold and full levels of PTSD and compared Axis I and alcohol use comorbidity rates among 1,362 OIF/OEF Veterans with varying levels of PTSD. Results suggest that OIF/OEF Veterans with subthreshold PTSD experience similar levels of psychological distress as those with full PTSD and highlight the need to provide timely and appropriate mental health services to individuals who may not meet the diagnostic criteria for full PTSD. ^ These results suggest that OIF/OEF Veterans of all race/ethnicities can benefit from strong social support systems. Postdeployment social support was found to be a protective factor against the development of PTSD among White, Black and Hispanic veterans while deployment unit support was a protective factor only among Black Veterans. The second article investigated the association between postdeployment social support and unit support with varying levels of PTSD by race/ethnicity among 1,115 OIF/OEF Veterans. ^ The results of this study can help to formulate treatment and interventions for OIF/OEF Veterans with varying levels of PTSD and social support systems.^

Treatment modalities of female Operation Iraqi Freedom/Operation Enduring Freedom Veterans with posttraumatic stress disorder: A systematic review of the literature

Objective. To review professional literature regarding treatment modalities of post-traumatic stress disorder (PTSD) amongst female Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) veterans, to assess the efficacy of these treatment options, and to summarize implications of the findings from this literature. Design. Systematic review of published literature. Data sources. Medline, Pubmed, Psycinfo. Review Methods. Articles selected for the literature review pertain to the treatment options of female OIF or OEF veterans who have a diagnosis of PTSD. In addition, other relevant articles, such as articles that discuss the prevalence of the problem, access to care, and similar treatment modalities for PTSD in other war settings, were selected for background information for the review. Results. The search strategy identified 1,305 potential journal articles, taken from thorough searches in Medline, Pubmed, and Psycinfo. These articles were then imported into Refworks. Following final screening, there were 18 articles included in the systematic review and 28 articles used as background information. The remaining articles were excluded following screening of abstract and/or full text of articles. Treatment modalities presented in these trials include: Exposure Therapy (average of 68% reduction in PTSD symptoms), Imagery Rehearsal Therapy (23% reduction), Body-Oriented Therapy (57% reduction), Electroconvulsive Therapy (35% reduction), Holographic Reprocessing (47% reduction), a self-defense training program (13% reduction), Cognitive Behavioral Therapy (65% reduction) and a variety of pharmacotherapies (antipsychotics at 81% reduction, sympatholytic drug at 100% reduction). Outcomes of the studies included in this systematic review were measured by using personal assessment of whether there was a reduction in symptoms of PTSD, based on the results in each study. Conclusion. Overall, all of the treatment modalities investigated in the systematic review proved to be somewhat effective in relieving the burden of symptoms of PTSD amongst female veterans of OIF/OEF. In addition to pharmacotherapy, which had the highest reduction in PTSD symptoms, both the Exposure Therapy and the Cognitive Behavioral Therapy techniques proved to have the most positive results. As all of the therapies had a positive effect on this population, to some degree, a study needs to be done in the future to compare and contrast the efficacy of each therapy intervention when applied to a standardized population.^