Prediction, Prevention and Treatment of Virally Induced Type 1 Diabetes: A Dissertation

Several viral infections have been associated with human type 1 diabetes (T1D), although it has proven difficult to unequivocally establish them as causative agents. In rodent models, however, viruses have definitely been established to cause T1D. The treatment of weanling BBDR rats with the combination of a TLR3 ligand, pIC, and an ssDNA parvovirus, KRV, precipitates T1D in nearly 100% of rats within a short, predictable timeframe. In this dissertation, we utilized the BBDR rat model to (1) identify early serum biomarkers that could predict T1D precipitated by viral induction and (2) test the efficacy of leptin, a therapeutic agent, which may have the ability to prevent diabetes onset, reverse new onset diabetes and prevent autoimmune recurrence of diabetes in rats transplanted with syngeneic islet grafts. Identification of biomarkers has long served as an invaluable tool for disease prediction. In BBDR rats, we identified an acute phase response protein, haptoglobin, as a potential biomarker for pIC + KRV induced T1D using the global proteomic profiling techniques, 2D gel analysis and iTRAQ. Upon validating this biomarker, we determined that haptoglobin was sensitive in predicting T1D in the pIC + KRV model, in which nearly 100% of the rats become diabetic, but not in models where diabetes expression was variable (KRV only or RCMV only models). However, analysis of the serum kinetics of haptoglobin and its functional capacity in the blood has given us insights into the potential role of early phase reactants in modulating virally mediated T1D. An alternative means of regulating T1D pathogenesis is through leptin. Leptin is a hormone with pleotropic roles in the body, particularly affecting energy metabolism and immune regulation. These characteristics make leptin an intriguing candidate for therapeutic testing in T1D models. Our studies have determined that high doses of leptin delivered via an adenovirus (AdLeptin) or alzet pump delivery system can prevent diabetes in \u3e 90% of rats treated with pIC + KRV. We further showed that serum hyperleptinemia was associated with decreased body weight, decreased non-fasting serum insulin levels and lack of islet insulitis in pIC + KRV treated rats pretreated with AdLeptin compared with those pretreated with PBS. We discovered that hyperleptinemia induced a profound decrease in splenic weight and splenic cellularity, including reductions in CD4+ and CD8+ T cells, DC/MACs and B cells. These findings indicate a potential mechanism whereby hyperleptinemia protects rats from virally induced T1D through the promotion of peripheral immunosuppression. Among pIC + KRV treated rats, we have also found that leptin therapy can reverse hyperglycemia in a subset of new onset diabetics for up to 20 days. In the absence of exogenous insulin, leptin treatment of new onset diabetics prevented the rapid weight loss associated with osmotic diuresis, as well as the ketosis observed in vehicle treated diabetic rats. Overall, these findings point to the therapeutic value of leptin in maintaining glycemic control and preventing ketosis in an insulin deficient state, in the absence of exogenous insulin therapy. Additionally, we have also determined that AdLeptin treatment can prolong the survival of syngeneic islets transplanted into diabetic BBDR rats for up to 50 days post transplant. Although hyperleptinemia generated by AdLeptin was unable to prevent insulitis into islet grafts, this insulitis did not appear to be destructive as islet grafts continued to stain positively for insulin when compared with control rats whose grafts succumbed to recurrent autoimmunity. In the various therapeutic settings in which we have tested leptin treatment, we have found this hormone to have significant beneficial effects. These findings merit further evaluation of leptin as a therapeutic agent in human T1D

Blockade of the Programmed Death-1 (PD1) Pathway Undermines Potent Genetic Protection from Type 1 Diabetes

Aims/Hypothesis Inhibition of PD1-PDL1 signaling in NOD mice accelerates onset of type 1 diabetes implicating this pathway in suppressing the emergence of pancreatic beta cell reactive T-cells. However, the molecular mechanism by which PD1 signaling protects from type 1 diabetes is not clear. We hypothesized that differential susceptibility of Idd mouse strains to type 1 diabetes when challenged with anti PDL1 will identify genomic loci that collaborate with PD1 signaling in suppressing type 1 diabetes. Methods: Anti PDL1 was administered to NOD and various Idd mouse strains at 10 weeks of age and onset of disease was monitored by measuring blood glucose levels. Additionally, histological evaluation of the pancreas was performed to determine degree of insulitis. Statistical analysis of the data was performed using Log-Rank and Student's t-test. Results: Blockade of PDL1 rapidly precipitated type 1 diabetes in nearly all NOD Idd congenic strains tested, despite the fact that all are moderately (Idd5, Idd3 and Idd10/18) or highly (Idd3/10/18 and Idd9) protected from spontaneous type 1 diabetes by virtue of their protective Idd genes. Only the Idd3/5 strain, which is nearly 100% protected from spontaneous disease, remained normoglycemic following PDL1 blockade. Conclusions: These results indicate that multiple Idd loci collaborate with PD1 signaling. Anti PDL1 treatment undermines a large portion of the genetic protection mediated by Idd genes in the NOD model of type 1 diabetes. Basal insulitis correlated with higher susceptibility to type 1 diabetes. These findings have important implications since the PD1 pathway is a target for immunotherapy

A comparison between the cardio-stress indices of an active and a sedentary population

Die moderne leefwyse bring dikwels mee dat ons die belangrikheid van liggaamlike oefening uit die oog verloor. Ons toenemend passiewe leefwyse het gelei tot ’n aansienlike toename in die voorkoms van lewenstylsiektes soos hipertensie en verskeie vorme van vaskulêre patologie. In hierdie studie word die kardiostres-indekse (KSI’e) van aktiewe en sedentêre individue met mekaar vergelyk ten einde insig te verkry in die uitwerking van die aansienlike veranderinge wat in die gemoderniseerde samelewing plaasgevind het. Die aktiewe populasie het bestaan uit 217 weermagrekrute wat reeds 20 weke van hul basiese weermagopleiding voltooi het. Die (n = 126) lede van die sedentêre populasie is gewerf uit ’n tradisionele tersiêre onderwysinstansie. Die deelnemers uit beide populasies moes drie toetssessies bywoon wat gedurende week 1, week 12 en week 20 gehou is. Hulle het ’n nie-ingrypende ViportTMtoets ondergaan om hul KSI, harttempo en QRS-duur te bepaal. Die resultate het getoon dat alhoewel die basislyn vir KSI, bloeddruk en harttempo aanvanklik hoër was onder die aktiewe populasie, die aanvang van die liggaamsoefeningprogram ten opsigte van hierdie drie faktore ’n geleidelike afname en dus ’n verandering in die rigting, en uiteindelik gesonder marges tot gevolg gehad het. Die KSI het egter nie die normale reikwydte ten opsigte van een van die twee groepe bereik nie, wat daarop gedui het dat alhoewel liggaamlike aktiwiteit fisiologiese stresvlakke verminder, ander sleutelfaktore, te wete leefwyse en stresvlakke, ook in ag geneem moet word. Die studie onderskryf die idee dat ’n toename in liggaamlike aktiwiteit die potensiaal het om ’n individu se vatbaarheid vir kardiovaskulêre siektes te verminder. Die studie ondersoek ook die uitwerking van oefening op die hart deur die gebruik van KSI as ’n meetinstrument.A comparison between the cardio-stress indices of an active and a sedentary population. Our modern lifestyle often results in the importance of physical exercise being overlooked. The increasingly passive way of life has resulted in a notable increase in the prevalence of lifestyle disorders, such as hypertension and some forms of vascular pathology. This study compares the cardio-stress indices (CSIs) of active and sedentary individuals to provide insight into the impact of the significant changes that have taken place in the modernised society. The active population consisted of 217 military recruits who had completed 20 weeks of basic military training. The sedentary population (n = 126) was sourced from a traditional tertiary institution where the focus is on attending lectures. Participants from both populations were required to attend three testing sessions, which were held during Week 1, Week 12 and Week 20. Subjects underwent a non-invasive ViportTM test to measure their CSI, heart rate and QRS duration. The results showed that although baseline readings for CSI, blood pressure (BP) and heart rate (HR) were initially higher among the active population, the commencement of the physical training programme resulted in a steady decline in respect of these three factors to approach healthier margins. However, the CSI for neither population reached the normal range, indicating that although physical activity reduces physiological stress levels, other key factors, namely lifestyle stress levels, must also be taken into account.The study supports the notion that increased physical activity has the potential to reduce the predisposition of an individual to cardiovascular disorders and contributes towards establishing the effect of training on heart health by using CSI as a means of measurementhttp://www.satnt.ac.zaay201

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Risk factors for Coronavirus disease 2019 (Covid-19) death in a population cohort study from the Western Cape province, South Africa

Risk factors for coronavirus disease 2019 (COVID-19) death in sub-Saharan Africa and the effects of human immunodeficiency virus (HIV) and tuberculosis on COVID-19 outcomes are unknown. We conducted a population cohort study using linked data from adults attending public-sector health facilities in the Western Cape, South Africa. We used Cox proportional hazards models, adjusted for age, sex, location, and comorbidities, to examine the associations between HIV, tuberculosis, and COVID-19 death from 1 March to 9 June 2020 among (1) public-sector “active patients” (≥1 visit in the 3 years before March 2020); (2) laboratory-diagnosed COVID-19 cases; and (3) hospitalized COVID-19 cases. We calculated the standardized mortality ratio (SMR) for COVID-19, comparing adults living with and without HIV using modeled population estimates.Among 3 460 932 patients (16% living with HIV), 22 308 were diagnosed with COVID-19, of whom 625 died. COVID19 death was associated with male sex, increasing age, diabetes, hypertension, and chronic kidney disease. HIV was associated with COVID-19 mortality (adjusted hazard ratio [aHR], 2.14; 95% confidence interval [CI], 1.70–2.70), with similar risks across strata of viral loads and immunosuppression. Current and previous diagnoses of tuberculosis were associated with COVID-19 death (aHR, 2.70 [95% CI, 1.81–4.04] and 1.51 [95% CI, 1.18–1.93], respectively). The SMR for COVID-19 death associated with HIV was 2.39 (95% CI, 1.96–2.86); population attributable fraction 8.5% (95% CI, 6.1–11.1)

The role of innate immune pathways in type 1 diabetes pathogenesis.

PURPOSE OF REVIEW: Type 1 diabetes (T1D) is an autoimmune disease typically believed to result from malfunctions in adaptive immune response signaling which result in activation of self-reactive T cells. However, recent research has indicated components of the innate immune response as having a key role in the initiation of the autoimmune process of T1D. This review will highlight recent studies which examined the role of innate immune response signaling and the connections to T1D pathogenesis. RECENT FINDINGS: Investigations indicate that components of innate immunity, including inflammation and Toll-like receptor signaling, are involved in pancreatic islet infiltration and insulitis. Recent studies examining the role of viral infections in T1D development also implicate innate immune response signaling in disease pathogenesis. SUMMARY: Current research indicates that components of innate immune response signaling are involved in the initiation of the autoimmune process which results in the eventual destruction of beta cells during T1D pathogenesis. Continuing efforts by researchers to uncover the molecular pathways of innate immunity linked to T1D development could potentially lead to therapeutics capable of preventing and curing the autoimmune disease

Effects of exercise on the visual performance of female rugby players

Visual performance is an important factor in sport excellence. Over the past few years, aspects like hand-eye co-ordination, visual reaction time and their relation to eye exercises have been addressed frequently. Theories maintain that visual involvement varies according to the environmental demands, and that athlete's visual characteristics therefore vary according to the sports in which they specialise, have also been covered. It is well known that environmental demands are matched by task-specific motor response. The extension of this theory shows that visual ability can affect both motor learning and performance, and that the nature of the visual involvement will vary according to environmental demands. The purpose of this study was to determine if exercise will improve the visual performance of female rugby players, in order to achieve maximal results on the sports field. Twenty female rugby players aged 19 to 24 were chosen as subjects. In order to evaluate the effect of sport vision specific exercises on hand-eye co-ordination, a pretest - post-test experimental groups design was adopted for the study. The pre-exercise and post-exercise values of the subjects in the control and experimental groups were pooled to determine the averages and differences. From the results, it can be seen that there was an improvement in the performance of the subjects who were exposed to the specific exercises. This study could assist in advocating a theoretical framework and providing an empirical data base to guide and evaluate future research

Circulating Soluble CD163 is Associated with Steatohepatitis and Advanced Fibrosis in Nonalcoholic Fatty Liver Disease

OBJECTIVES: Soluble CD163 (sCD163), a marker of Kupffer cell activation detectable in serum, correlates with inflammation and fibrosis in chronic viral hepatitis, but its role in nonalcoholic fatty liver disease is unknown. We hypothesized that sCD163 would correlate with nonalcoholic fatty liver disease activity and fibrosis. METHODS: Liver biopsies and serum were obtained from 145 obese subjects undergoing gastric bypass surgery. Subjects were divided into four groups based on fibrosis stage and nonalcoholic fatty liver disease activity score (NAS); Group 1: F0, NAS=0; Group 2: F<2, 0<NAS<5; Group 3: NAS≥5, F<3; or Group 4: F≥3, any NAS. Serum sCD163 and the monocyte/macrophage marker sCD14 were measured by enzyme-linked immunosorbent assay. Relationships between sCD163, sCD14, fibrosis stage, and NAS were examined. Area under the receiver operating charateristic for the diagnosis of nonalcoholic steatohepatitis based on the Clinical Research Network definition was calculated. RESULTS: sCD163 increased with progressive liver histology, with lowest values in normal histology and highest levels in those with nonalcoholic steatohepatitis and advanced fibrosis (Group 1: 552 ng/ml, Group 2: 721 ng/ml, Group 3: 803 ng/ml, and Group 4:1,031; P=0.001). sCD14 also differed significantly across groups (Group 1: 1,877 ng/ml, Group 2: 1632 ng/ml, Group 3: 1,706 ng/ml, and Group 4: 2111; P=0.008, respectively). sCD163 correlated with steatosis grade (P<0.001), lobular inflammation (P=0.033), and hepatocyte ballooning (P<0.001). In a multivariable ordered logistic regression model, there was a significant association between every 100 ng/ml increase in sCD163 and higher fibrosis stage, with an odds ratio of 1.16 (95% confidence interval 1.02–1.31), P=0.020. The odds ratios of the association between every 100 ng/ml increase in sCD163 and higher NAS was 1.17 (95% confidence interval 1.04–1.32), P=0.010. A sCD163-based predictive score demonstrated an area under the receiver operating charateristic of 0.70 (95% confidence interval: 0.58–0.82) for the diagnosis of nonalcoholic steatohepatitis. Soluble CD14 did not correlate with fibrosis stage or NAS. CONCLUSIONS: In obese subjects, serum sCD163, but not sCD14, correlated with fibrosis stage and NAS. These data support a role for activated Kupffer cells in the pathogenesis of nonalcoholic steatohepatitis and fibrosis, and suggest potential clinical utility for assessment of sCD163 levels

TLR agonists prevent the establishment of allogeneic hematopoietic chimerism in mice treated with costimulation blockade

Activation of TLR4 by administration of LPS shortens the survival of skin allografts in mice treated with costimulation blockade through a CD8 T cell-dependent, MyD88-dependent, and type I IFN receptor-dependent pathway. The effect of TLR activation on the establishment of allogeneic hematopoietic chimerism in mice treated with costimulation blockade is not known. Using a costimulation blockade protocol based on a donor-specific transfusion (DST) and a short course of anti-CD154 mAb, we show that LPS administration at the time of DST matures host alloantigen-presenting dendritic cells, prevents the establishment of mixed allogeneic hematopoietic chimerism, and shortens survival of donor-specific skin allografts. LPS mediates its effects via a mechanism that involves both CD4(+) and CD8(+) T cells and results from signaling through either the MyD88 or the type I IFN receptor pathways. We also document that timing of LPS administration is critical, as injection of LPS 24 h before treatment with DST and anti-CD154 mAb does not prevent hematopoietic engraftment but administration the day after bone marrow transplantation does. We conclude that TLR4 activation prevents the induction of mixed allogeneic hematopoietic chimerism through type I IFN receptor and MyD88-dependent signaling, which leads to the up-regulation of costimulatory molecules on host APCs and the generation of alloreactive T cells. These data suggest that distinct but overlapping cellular and molecular mechanisms control the ability of TLR agonists to block tolerance induction to hematopoietic and skin allografts in mice treated with costimulation blockade