Aims: To assess the diagnostic accuracy of four undiagnosed Type 2 diabetes mellitus risk scores accounting for erectile dysfunction status. Methods: This was a population-based cross-sectional study. Type 2 diabetes was defined according to a oral glucose tolerance test and self-reported physician diagnosis. Erectile dysfunction was defined according to the answer to the question, ‘Have you had difficulties obtaining an erection in the last 6 months?’ (yes/no). The risk scores used were the FINDRISC, LA-FINDRISC, American Diabetes Association score and the Peruvian Risk Score. A Poisson regression model was fitted to assess the association between Type 2 diabetes and erectile dysfunction. The area under the receiver-operating characteristic curve was estimated overall and by erectile dysfunction status. Results: A total of 799 men with a mean (sd) age of 48.6 (10.7) years were included in the study. The overall prevalence of Type 2 diabetes was 9.3%. Compared with healthy men, men with Type 2 diabetes had 2.71 (95% CI 1.57–4.66) higher chances of having erectile dysfunction. Having excluded men aware of Type 2 diabetes status (N=38), the area under the receiver-operating characteristic curve of three of the risk scores (not the American Diabetes Association score) improved among those who had erectile dysfunction in comparison with those who did not; for example, the area under the receiver-operating characteristic curve of the LA-FINDRISC score was 89.6 (95% CI 78.7–99.9) in men with erectile dysfunction and 76.5 (95% CI 68.5–84.4) overall. Conclusions: In a population-based study, erectile dysfunction was more common in men with Type 2 diabetes than in the otherwise healthy men. Screening for erectile dysfunction before screening for Type 2 diabetes seems to improve the accuracy of well-known risk scores for undiagnosed Type 2 diabetes. / Antonio Bernabe-Ortiz is a Research Training Fellow in Public Health and Tropical Medicine (103994/Z/14/Z), funded by the Wellcome Trust. / Revisión por pares

Because the child with minimal brain dysfunction has problems perceiving the world around him, and as a result, is hindered in the learning process; the purpose of this study was to determine the effect of two different methods of instruction in and practice of two series of similar locomotor skills upon the ability of children with minimal brain dysfunction to switch from one activity to another within each series.

Norepinephrine (NE) is one of three catecholamine neurotransmitters in the brain and has been studied extensively in relation to the biology of suicide as well as psychiatric disorders that significantly increase the risk of suicide. NE became a candidate for the pathology of depression in the 1950s, but not because of a discovery of altered concentrations of NE in depressed patients or suicide victims. Instead, NE was one of the neurotransmitters along with dopamine and serotonin that was directly affected by newly discovered antidepressant drugs. Since that time, NE has been one of the most studied neurotransmitters with regard to depression biology and suicide, second only to serotonin. However, interest in the role of NE in suicide and depression has dwindled considerably over the past 10 years. In fact, interest in monoamines appears to be waning overall, possibly driven by a push by the National Institutes of Health for paradigm shifts in understanding psychiatric disease biology. The move away from interest in the monoamines is also being driven by high-throughput technologies such as microarrays, which divert investigators from traditional disease candidates to novel proteins and pathways. Despite the current trends, evidence that points to dysfunction in the central noradrenergic system in depression and suicide is very strong and it remains quite possible that deficits in NE signaling may lie at the very root of psychiatric disorders that contribute to suicide. This chapter reviews the neurobiology and functional output of the brain noradrenergic system in relation to the potential involvement of NE in depression and suicide.

Endothelial dysfunction and/or injury is pivotal to the development of cardiovascular and inflammatory pathology. Endothelial dysfunction and/or injury has been described in Human Immunodeficiency Virus (HIV) infection. Elaboration of circulating markers of endothelial activation, such as soluble adhesion molecules and procoagulant proteins, occurs in HIV infection. Certain endothelial cells, such as those lining liver sinusoids, human umbilical vein endothelial cells, bone marrow stromal endothelial cells or brain microvascular endothelial cells, have been shown to be variably permissive for HIV infection. Entry of virus into endothelial cells may occur via CD4 antigen or galactosyl-ceramide receptors. Other mechanisms of entry including chemokine receptors have been proposed. Nevertheless, endothelial activation may also occur in HIV infection either by cytokines secreted in response to mononuclear or adventitial cell activation by virus or else by the effects of the secreted HIV-associated proteins, gp 120 (envelope glycoprotein) and Tat (transactivator of viral replication) on endothelium. Enhanced adhesiveness of endothelial cells, endothelial cell proliferation and apoptosis as well as activation of cytokine secretion have all been demonstrated. Synergy between select inflammatory cytokines and viral proteins in inducing endothelial injury has been shown. In HIV infection, dysfunctional or injured endothelial cells potentiate tissue injury, inflammation and remodeling, and accelerate the development of cardiovascular disease.

In Western countries the incidence of amyotrophic lateral sclerosis (ALS) is 1.89 per 100,000 per year and the prevalence is 5.2 per 100,000. The incidence of ALS is lower among African, Asian, and Hispanic ethnicities when compared to Caucasians. The mean age of onset for sporadic ALS is about 60 years and there is a slight male predominance (male to female ratio of 1.5 to 1). Approximately two thirds of patients with ALS have the spinal form of the disease with symptoms presenting in the extremities. Patients typically have evidence of both lower motor neuron degeneration (atrophy, weakness, and fasciculations) and upper motor neuron degeneration (spasticity, weakness, and hyperreflexia). Patients with limb onset ALS typically complain of focal muscle weakness and wasting. The symptoms may start either distally or proximally in the upper and/or lower limbs. Gradually spasticity develops in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset ALS typically present with dysarthria and dysphagia for solid or liquids. Limb symptoms can develop simultaneously with bulbar onset. In the vast majority of patients, limb weakness will occur within 1-2 years of bulbar onset ALS symptoms. A case of bulbar and sporadic limb ALS in a 70-year-old veteran, presenting with right diaphragmatic paralysis and respiratory failure, is presented.

The mechanisms responsible for myocardial dysfunction in the setting of sepsis remain undefined. Fas ligation with its cognate ligand (FasL) induces apoptosis and activates cellular inflammatory responses associated with tissue injury. We determined whether interruption of Fas/FasL interaction by cardiac-specific expression of soluble Fas (sFas), a competitive inhibitor of FasL, would improve myocardial dysfunction and inflammation in a lipopolysacharide (LPS)-induced mouse model of sepsis. Wild-type (WT) and sFas transgenic mice were injected intraperitoneally with 10 mg/kg LPS or with an equivalent volume of saline. At 18 h after LPS administration, echocardiographic evaluation revealed a significant decrease in left ventricular fractional shortening in the WT mice, whereas the fractional shortening was preserved in the sFas mice. Activation of nuclear factor-kappa B (NF-κB) and the increase in the transcript levels of proinflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 resulting from LPS treatment were attenuated in the myocardium of sFas mice. sFas expression also inhibited LPS-induced upregulation of Toll-like receptor 4 (TLR-4) and inducible nitric oxide synthase (iNOS), and formation of peroxynitrite in the myocardium. LPS-induced increase in caspase-3/7 activity and apoptotic cell death were suppressed in sFas mice compared with WT mice. LPS-induced lung injury and increase in lung water content were also significantly reduced in sFas mice. These data indicate that neutralization of FasL by expression of sFas significantly preserves cardiac function and reduces inflammatory responses in the heart, suggesting that Fas/FasL signaling pathway is important in mediating the deleterious effects of LPS on myocardial function.

Indiana University-Purdue University Indianapolis (IUPUI) / Depressed adults are at increased risk of developing atherosclerotic cardiovascular disease (CVD). However, heterogeneity in the depressed population engenders a key question: Are there subgroups of depressed adults at greater risk of developing CVD? Because other affective traits – i.e., anxiety, hostility/anger, and low trait positive affect – have also been associated with increased CVD risk, depressed adults with higher levels of these co-occurring affective traits may have an elevated risk of developing CVD. Consequently, the present study’s first aim was to examine, in depressed adults, which affective traits (depression, anxiety, hostility/anger, or low positive affect) are associated with endothelial function, a marker of cumulative CVD risk. In addition, because the other affective traits overlap with depressive symptom severity, this study’s second aim was to investigate which components of pairs of affective traits (shared versus unique) are related to endothelial function. Finally, given that the mechanisms underlying affective trait-endothelial function relationships in depressed adults are unknown, this study’s third aim was to explore traditional CVD risk status as a candidate mediator of observed relationships. To achieve these aims, I combined pre-treatment, cross-sectional data from three randomized controlled trials involving 138 depressed primary care patients with no history of clinical CVD. Assessments included validated self-report questionnaires for affective traits, brachial artery flow-mediated dilation (FMD) for endothelial function, and 10-year Framingham risk score for traditional CVD risk status. I conducted structural equation modeling (SEM) with confirmatory factor analysis to examine the relationships of interest after adjusting for age, sex, race/ethnicity, education, and baseline arterial diameter. Although the shared variance between each affective trait pair could not be modeled due to poor fit, adequate fitting models revealed that hostility/anger and the unique components of hostility/anger were associated with poorer endothelial function (standardized coefficients = -.18 and -.22, respectively). All of the other affective traits and their components (depression, anxiety, positive affect, unique depression, unique anxiety, and unique positive affect) were not related to endothelial function (all ps > .08). Traditional CVD risk status did not partially explain the relationship between the unique components of hostility/anger and endothelial function (standardized coefficient for the indirect effect = .00; p = .89). If my results are supported by future findings, it would suggest that depressed adults with hostility/anger (a) may be a subgroup of the depressed population at greater risk of developing CVD and (b) may be in need of earlier, more intense, and/or different CVD primary prevention efforts. Future studies are needed to confirm this relationship and identify underlying mechanisms.

Student Number : 9809910J - MA research report - School of Human and Community Development - Faculty of Humanities / This study explores the perceptions of women suffering from vaginismus regarding their condition, themselves and their significant relationships. The subjective world of women suffering from vaginismus was therefore focused upon, within the context of a qualitative paradigm. Four volunteers who were diagnosed with the condition by a sexologist at the DISA health clinic, and were at the time seeking treatment for the condition, participated in the research. The research was conducted in the form of a semi-structured interview. Various psychological, emotional and social themes were explored. The participants’ responses were recorded and then analysed utilising content analysis. Within the analysis, a lack of constancy was noted amongst the participants. Differences with regard to etiological themes, personality profiles, emotions as well as relationships with intimate partners and parents were found. This is coherent with findings in the literature, which are also inconsistent. However, it should be noted that that whilst few aspects were found to be universal, most shared some commonality. Thus, various trends were established. The experience of vaginismus appears to be stressful, impacting on one’s emotions, selfesteem and intimate relationships. Trends were identified with regard to choice of partner. However, different relationship dynamics were found suggesting that couples react differently to the experience of vaginismus. All of the participants gave vague descriptions of their parental figures and relationships. Thus, it is difficult to make assertions regarding these relationships. Patterns of interaction and behaviour were experienced during the interviews. Avoidance of emotion was prevalent. The tendency to idealise relationships was found with all of the participants. The participants also appeared to make contradictory statements throughout the interviews.

The broad goals of this dissertation were to explore possible causes of erectile dysfunction (ED), and examine outcomes associated with the condition. To address these objectives, data from the Vietnam Era Twin Study of Aging (VETSA), a longitudinal study of cognitive aging, were utilized. Previous research demonstrated moderate heritability of ED in middle-aged men, but questions remain about the replicability of these findings given that only one study exists on the topic and it utilized an unvalidated ED measure. Additionally, it is unknown to what extent genetic factors account for stability and change of ED symptomatology over time. In the first study, we conducted a longitudinal assessment of ED using the Sexual Health Inventory for Men (SHIM) administered to 668 male twins. Results revealed that the heritability (proportion of variance explained by genetic factors) of ED at both time points is moderate (0.3 –0.6). Over the past two decades ED has been recognized as primarily a disorder of vascular dysfunction. Inflammation is an important correlate of vascular dysfunction. Chapter 2 examined the association of ED with four inflammatory serum protein indices [albumin, globulin, albumin/globulin ratio (AGR), and the albumin*globulin interaction (AGI)] in 388 men free from cardiovascular disease (CVD). Results indicated that the AGR, albumin, and globulin protein levels are significantly associated with ED, even after accounting for other risk factors. Intriguingly, AGR and globulin levels were found to be more strongly associated with ED than conventional vascular risk factors, such as hypertension, high cholesterol, obesity, and smoking. As such, globulin and AGR may be useful biomarkers when diagnosing and managing ED. The simplicity and affordability of these assays make these markers particularly valuable. Given the negative impact that vascular disease has on cognition, Chapter 3 explored whether men with ED are at greater risk for experiencing cognitive decline compared to healthy peers. In total, 485 men free from CVD were administered cognitive tests across 13 domains. Tests were readministered 5 years later. Results revealed that men with ED were more likely to show significant decline on tasks of set-shifting, tool/mechanical knowledge, vocabulary, and verbal fluency.

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