Associations between hypothalamic-pituitary-adrenal axis system gene variants and cortisol reactivity in preschoolers: Main effects and gene-environment interactions

Exposure to stressful events during early development has consistently been shown to produce long lasting effects on the hypothalamic-pituitary-adrenal (HPA) axis, which may increase vulnerability to mood and anxiety disorders. Recently reported genetic association studies indicate that these disorders may be influenced, in part, by gene-environment interactions (GxE) involving polymorphisms within the corticotrophin-releasing hormone and monoaminergic system genes. However, little is known about how genetic variants and life stress work to shape children’s neuroendocrine reactivity and emerging symptoms. Therefore, the aim of this thesis is to examine main effects of candidate genes and GxE on the neuroendocrine stress response and internalizing symptoms in a community sample of 409 preschoolers. In Chapter 2 analyses show associations between variants of the CRHR1 and CRHBP genes and children’s cortisol responses to a standardized laboratory stress task. I also found evidence for GxE, where variants of the CRH system genes moderated the impact of childhood stress on early-emerging symptoms of depression and anxiety. A functional polymorphism of the catechol-O-methyltransferase (COMT) gene, the val158met, has been implicated in the etiology of stress-related mood disorders. Therefore, in Chapter 3, I examined links between the val158met polymorphism, cortisol reactivity to stress, and internalizing symptoms. I found evidence for association between the val158met genotype and cortisol reactivity to stress. Additionally, the val158met genotype moderated the link between childhood stress and emerging symptoms of anxiety. Due to the proposed role of dopamine and serotonin gene polymorphisms in research on GxE in internalizing disorders, in Chapters 4 and 5, I examined whether associations between dopaminergic and serotonin candidate gene polymorphisms and childhood cortisol reactivity and internalizing symptoms were moderated by childhood life stress. Analyses showed evidence for GxE predicting children’s symptoms. Specifically, polymorphisms of DRD2 and DAT1 genes moderated the effect of childhood stress on emerging symptoms of anxiety. With regard to serotonin pathway polymorphisms, I found associations between the serotonin transporter promoter polymorphism (5-HTTLPR) and children’s anxious symptoms. Additionally, consistent with previously reported findings, the interaction between MAOA 30bp VNTR and childhood stress predicted child anxiety symptoms. Limitations of this work include a relatively small sample size for genetic analyses, as well as the examination of a limited number of markers at each gene. Additionally, I did not correct for multiple statistical tests in some analyses due to the hypothesis-driven nature of the work. Taken together, the analyses show the complex underpinnings of individual differences in stress regulation, and highlight specific genetic vulnerabilities that influence early psychophysiological reactivity, that may in turn contribute to the development of stress-related disorders later in development

Restaurant Hope: Engineering a Choice-Based Service Initiative to Address Hunger

The objective of this service-learning project was to humanize the face of hunger for volunteers by empowering patrons attending a soup kitchen with the choice of selecting their meal for dinner. This experience helped foster an emotional connection between patrons and volunteers. A traditional soup kitchen utilizes a single-option, inexpensive meal approach that is cooked and delivered by volunteers. However, this service project, entitled Restaurant Hope, addressed these issues by providing patrons with a diverse menu. In addition, patrons were given the opportunity to request more food (to try other options on the menu) and take home leftover food depending on availability. Choices patrons made in terms of menu preferences were tracked. Volunteers, soup kitchen administrators, and patrons were interviewed to obtain feedback on this service initiative and how it impacted their perceptions on the issue of hunger in their local community

Association of Epstein Barr Virus (EBV) with nasopharyngeal carcinoma (NPC)

Aim: To observe the frequency of nasopharyngeal carcinoma (NPC) and its association with Epstein Barr Virus (EBV) infection. Setting: This study included consecutive cases of nasopharyngeal carcinoma, which were diagnosed in the Department of Pathology at the Aga Khan University Hospital, Karachi in the period of two years (1996-97). Methods: These tumors were initially evaluated on H&E stained sections. The tumors showing evidence of keratinization were excluded from the study. The Epstein Barr Virus was detected with the help of Polymerase chain reaction in formalin fixed, paraffin embedded tissue sections. Results: During the study period, seventeen cases of nasopharyngeal carcinoma were diagnosed which comprised 0.3% of all malignant tumors. The age ranged from 5 years to 70 years with male to female ratio of 2.4:1. The NPC was more prevalent in adults (71%) as compared to children (29%) under 15 years. Six cases (35%) exhibited positive signal for Epstein Barr Virus. Conclusion: Nasopharyngeal carcinoma is an infrequent tumor. The prevalence of Epstein Barr virus infection in nasopharyngeal carcinoma is quite low as compared to other regions of the world

Girls\u27 internalizing symptoms and white matter tracts in Cortico-Limbic circuitry

© 2019 The Authors Dysfunction in cortico-limbic circuitry is implicated in internalizing disorders (i.e., depressive and anxious disorders), but less is known about whether structural variations precede frank disorder and thus potentially mark risk. We therefore examined associations between white matter (WM) tract microstructure in cortico-limbic circuitry at age 7 and concurrent and longitudinal patterns of internalizing symptoms in 42 typically developing girls using Diffusion Tensor Imaging (DTI). Girls\u27 internalizing symptoms were concurrently associated with reduced fractional anisotropy (FA) in segments of the cingulum bundle (CB) and the uncinate fasciculus (UF), bilaterally. Moreover, latent profile analysis showed that girls with increasing internalizing symptoms, based on assessments at ages 3, 6, 7, and 8, had reduced FA in these segments compared to girls with stably low symptoms. These results point to a putative neural mechanism underlying the course of childhood internalizing symptoms

Stellar Image Interpretation System Using Artificial Neural Networks:

A supervised Artificial Neural Network (ANN) based system is being developed employing the Bi-polar function for identifying stellar images in CCD frames. It is based on feed-forward artificial neural networks with error back-propagation learning. It has been coded in C language. The learning process was performed on a 341 input pattern set, while a similar set was used for testing. The present approach has been applied on a CCD frame of the open star cluster M67. The results obtained have been discussed and compared with those derived in our previous work employing the Uni-polar function and by a package known in the astronomical community (DAOPHOT-II). Full agreement was found between the present approach, that of Elnagahy et al, and the standard astronomical data for the cluster. It has been shown that the developed technique resembles that of the Uni-Polar function, possessing a simple, much faster yet reliable approach. Moreover, neither prior knowledge on, nor initial data from, the frame to be analysed is required, as it is for DAOPHOT-II.

Intraoperative ICG-NIR Fluorescence Angiography Visualization of Testicular Perfusion in Operations for Testicular Torsion

Purpose: Indocyanine Green (ICG) near-infrared (NIR) fluorescence angiography is used in assessing testicular perfusion after reduction of testicular torsion to assess tissue viability. Introduction: Determination of viability of a testicle after reduction of a testicular torsion has been performed by numerous methods including visual assessment, Doppler ultrasound, and cutting the testicular capsule. Each of these has limitations, are not always reproducible, and may involve damage to the testicle and confusion of capsular blood flow for internal perfusion. A possible alternative to these methods is the use of ICG-NIR fluorescence angiography. ICG was FDA-approved in 1959 and has been in use for over 60 years across various fields including colorectal and breast surgery, with few reported adverse events related to the injectable dye. Intraoperative use of an NIR camera causes the dye to fluoresce. ICG -NIR is used in this report to demonstrate the perfusion or lack thereof during reduction of testicular torsion. Method: Thirty patients in a single center presented with testicular torsion from November 2015 – August 2019, and were evaluated by a combination of 3 Pediatric Surgeons and 2 Pediatric Urologists using ICG-NIR during torsion reduction procedures. An anesthesiologist injected 1.25 mg (/kg) ICG dye intravenously and the surgeon used the NIR camera to visualize the testicle In-situ to assess the local perfusion before and after testicle reduction. After investigation of testicle viability, the surgeon determined whether to proceed with an orchiopexy or orchiectomy based on tissue perfusion. Results: Thirty patients in a single center presented with testicular torsion from November 2015 – August 2019, and were evaluated by a combination of 3 Pediatric Surgeons and 2 Pediatric Urologists using ICG-NIR during torsion reduction procedures. This process identified the extent of perfusion and differentiated capsular from internal testicular perfusion. It provided assurance of blood flow or definitively confirmed lack of tissue viability, allowing surgeons to proceed with orchiopexies or orchiectomies, respectively. ICG-NIR findings were correlated with standard methods of assessing testicular perfusion, and all patients received contralateral orchiopexy. Conclusion: In patients presenting with testicular torsion, the determination of testicular viability after reduction is very subjective, and complication risk from the surgery can vary based numerous factors including surgeon level of experience, method utilized to assess perfusion, and hemodynamic status of the patient. Use of technologies that image vascular irrigation prior to decision to resect or leave the testicle in place may help to reduce these complications. This study was limited by small sample size in a single center. Future studies with higher volume should compare postoperative complications using this technology compared to other accepted methods of assessing testicle perfusion. This will help elucidate benefits to current surgical outcomes, as well as to gauge success of future novel techniques used in testicular salvage during torsion reductions

The serotonin transporter promoter polymorphism moderates the continuity of behavioral inhibition in early childhood.

Persistently elevated behavioral inhibition (BI) in children is a marker of vulnerability to psychopathology. However, little research has considered the joint influences of caregiver and child factors that may moderate the continuity of BI in early childhood, particularly genetic variants that may serve as markers of biological plasticity, such as the serotonin transporter linked polymorphic region (5-HTTLPR). We explored this issue in 371 preschoolers and their caregivers, examining whether parent characteristics (i.e., overinvolvement or anxiety disorder) and child 5-HTTLPR influenced the continuity of BI between ages 3 and 5. Measures were observational ratings of child BI, observational and questionnaire measures of parenting, and parent interviews for anxiety disorder history, and children were genotyped for the 5-HTTLPR. Parent factors did not moderate the association between age 3 and age 5 BI; however, child BI at age 3 interacted with children\u27s 5-HTTLPR variants to predict age 5 BI, such that children with at least one copy of the short allele exhibited less continuity of BI over time relative to children without this putative plasticity variant. Findings are consistent with previous work indicating the 5-HTTLPR short variant increases plasticity to contextual influences, thereby serving to decrease the continuity of BI in early childhood