UTMB Health SHARED (Univ. of Texas Medical Branch at Galveston)
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Vision Impairment and Health Outcomes among Older Mexican Americans: Findings from the Hispanic Established Population for the Epidemiologic Study of the Elderly
No full textBackground: Vision impairment (VI) is one of the most common conditions in older adults. It is associated with negative health outcomes leading to disability and decreased quality of life. Objectives: To examine 1) predictor factors of VI; 2) the effect of VI on physical and cognitive function, frailty, disability, and falls; and 3) VI as predictor of eye and health care utilization among older Mexican Americans over time. Design: Longitudinal study. Participants: Mexican Americans aged 70 years and older (N=1,979) from the Hispanic Established Population for the Epidemiologic Study of the Elderly (1998-2016). Measures: Included self-reported VI as the independent variable; physical and cognitive function, modified frailty phenotype, disability, falls, and health care utilization as outcome variables; and socio-demographics, social isolation, smoking status, body mass index, comorbidities, depressive symptoms, and hearing impairment as covariates. Analysis: Generalized estimating equation models were performed to estimate the odds ratio of health outcomes and health care utilization. Results: Percent of VI ranged from 3.7% to 4.3% for near vision impairment (NVI), 12.9% to 27.8% for distant vision impairment (DVI), and 13.7% to 27.6% for VI (NVI or DVI). Predictors of NVI, DVI, and VI were time (years), lower Mini Mental State Exam score, depressive symptoms, and hearing impairment. Spanish interview was a predictor of NVI only. Over time, participants with cognitive impairment and frailty had greater odds of reporting DVI and VI (NVI or DVI) than those without VI; those with limitations in instrumental activities of daily living had greater odds of reporting NVI, DVI, and VI (NVI or DVI) than those without VI; those with limitations in activities of daily living had greater odds of reporting VI than those without VI; and those who reported falls had greater odds of reporting NVI and VI (NVI or DVI) than those without VI. Those with VI had greater odds of having medical doctor visits and been hospitalized than those without VI.
Conclusions: VI among older Mexican Americans was high and is a strong independent predictor of cognitive impairment, frailty, disability, and falls. These findings suggest that current vision health disparities exist among older Mexican Americans.
Pulmonary vascular malfunction and inflammation during Orientia tsutsugamushi infection
No full textScrub typhus is a potentially lethal illness caused by infection with the bacterium, Orientia tsutsugamushi. Scrub typhus remains a neglected tropical disease, despite being a tremendous burden in endemic areas. Lung injury is one of the most common pathologies that arise from severe cases of scrub typhus, but the underlying mechanisms are unclear. Development of relevant animal models allow for investigation into the cellular populations that are contributing to the observed lung pathology during O. tsutsugamushi infection.
The first objective of this work was to characterize the activation of the pulmonary endothelium during infection. Although O. tsutsugamushi is considered an endotheliotropic bacterium, no research has been conducted to evaluate changes in the endothelium in vivo during infection. Prolonged activation and loss of barrier integrity in pulmonary endothelium are initial steps to the development of lung injury during infection. To this end, we analyzed the increase of expression of the activation markers and decrease of barrier proteins on pulmonary endothelial cells. Activation of endothelial cells results in the recruitment of circulating immune cells, especially neutrophils; however, excessive neutrophil recruitment can exacerbate lung injury and endothelial damage. Neutrophils were recruited in significant numbers by late infection and developed an activated phenotype. Further, depletion of neutrophils at various points of infection attenuated either weight loss or mortality of infected mice and modulated the macrophage and T cell populations in the lungs. These data suggest a pathogenic and regulatory role of neutrophils during scrub typhus.
In addition to endothelial cells, O. tsutsugamushi has been shown to replicate in macrophages in vitro and in vivo. The second objective of this study was to determine the state of macrophage polarization in the lungs of mice lethally infected with O. tsutsugamushi and determine how this polarization affects bacterial growth. Macrophages were recruited in high numbers to the lung at both day 6 and day 9 of infection, and they were almost entirely polarized to an inflammatory, “M1”, phenotype. The M1 polarization was also shown to be capable of slowing bacterial growth in vitro in comparison to macrophages polarized to an “M2” phenotype. Mechanisms of macrophage activation and restriction of O. tsutsugamushi growth are unknown
Investigating the role of non-structural genes in the genotype and phenotype of yellow fever vaccine strain 17D
No full textThe first yellow fever outbreak was recorded in 1648 in the Yucatan Peninsula. Almost 300 years later, a live-attenuated vaccine against yellow fever virus, the causative agent of yellow fever, was successfully derived by serial passage of Asibi virus 176 times in chick and mouse embryo tissue. The resulting vaccine strain, 17D, gave rise to all substrains in use today. Strain 17D and the resulting substrains, 17DD and 17D-204, were found to differ from Asibi virus by 20 amino acid substitutions with nine substitutions in the structural proteins of the virus and the remaining eleven in the non-structural proteins. Despite the long-term use and success of the 17D vaccine, it remains unknown which of the 20 residues contribute to its stably attenuated phenotype. By utilizing previously established genotypic and phenotypic differences between 17D and Asibi viruses, this dissertation aims to determine which NS proteins contribute to these differences. Using an infectious clone system, non-structural substitutions from 17D-204 virus were introduced into an Asibi infectious clone while Asibi virus residues were introduced into a 17D-204 infectious clone. The impact of the introduced substitutions on genetic diversity, multiplication kinetics, sensitivity to the antiviral Ribavirin, and attenuation in an AG129 mouse model were evaluated. 17D-204 virus is known to have reduced genetic diversity, increased multiplication kinetics in A549 cells, increased resistance to Ribavirin, and is attenuated in AG129 mice when compared to Asibi virus. These studies identified substitutions in several non-structural proteins that significantly impact genetic diversity (NS2B, NS4B, and NS5) and multiplication kinetics (NS5), providing evidence for the involvement of the NS proteins in 17D-204 viral attenuation. Substitutions within these proteins warrant further study. It was also found that the lack of genetic diversity exhibited by vaccine strains of yellow fever virus is not universal to attenuated strains of the virus. The attenuated FVV HeLa p5 strain was found to have similar genetic diversity and sensitivity to Ribavirin when compared with the original unpassaged strain, FVV. These findings highlight the importance of 17D-204 virus’s genetic stability and the contribution of that stability to the strain’s continued use as a live attenuated vaccine
HIV-Associated Neurocognitive Disorders: Role of Viral Reservoirs and Lipid Dysregulation
No full textHIV infection has become a chronic and manageable disease due to the effective use of combined anti-retroviral therapies (cART). However, several chronic aging-related comorbidities, including HIV-associated neurocognitive disorders (HAND), persist in the HIV-infected population; but the mechanisms are unknown. We hypothesized that neurocognitive decline in the HIV-infected population is dependent on CNS viral reservoirs by mechanisms of damage amplification mediated by host lipids. HIV CNS damage, in the current cART era, is mediated by a low number of HIV DNA positive macrophages/microglia and astrocytes that support a residual viral mRNA and protein synthesis. Some HIV proteins are secreted and taken into the neighboring uninfected cells, generating bystander damage in the CNS. Viral reservoirs are associated with local myelin structure compromise resulting in the release of several myelin components, including the lipid sulfatide. Soluble sulfatide compromises gap junctional communication and calcium waves, which contribute to the amplification of CNS damage and cognitive impairment that distress the HIV-infected population.
Our pending experiments aim to categorize Cx43 interacting proteins after sulfatide treatment by proteomics, to identify specific astrocyte populations that become susceptible to HIV infection or bystander damage by single-cell RNA sequencing, and detect lipid dysregulation in primary human cultures of HIV-infected astrocytes using MALDI-MSI or MALDI-2 MSI.
To further examine lipid dysregulation, we also developed a MALDI-2 MSI method to detect lipid classes and species that are not detected with regular MALDI-MSI, using the brain tissue sections of the AD 3xTg mouse model. We proved that this assessment is compatible with subsequent immunofluorescence and histological analyses in the same tissue section. This approach is innovative and helpful in performing a multi-omics characterization for several pathologies, including HAND
Synaptic Excitatory to Inhibitory imbalance in Alzheimer’s Disease
No full textAlzheimer’s disease is the most common cause of dementia worldwide, and it is characterized by progressive impairment of cognitive performance, brain atrophy, neuronal and synaptic loss, and abnormal aggregation of amyloid beta and tau proteins. Notably, prodromal Alzheimer’s disease is characterized by mild cognitive impairment, increments in the occurrence of seizures and abnormal electroencephalographic activity. Clinical and animal model studies suggest that hyperexcitability and cognitive impairment may be mechanistically linked, through synaptic abnormalities that disturb the excitatory/inhibitory balance (E/I ratio) in circuits vulnerable to Alzheimer’s disease pathology. We measured electrophysiological, anatomical, transcriptional, and cellular E/I ratios in human brain. Our findings establish a strong correlational link between E/I imbalance and loss of cognition; and showed a pro-excitatory shift of this balance in brain regions known to be hyperactive in Alzheimer’s disease subjects
The Role of Short-Chain Fatty Acids on Intestinal Epithelial Cell Migration
No full textInflammatory Bowel Disease (IBD) is a chronic remitting and relapsing autoimmune disorder of the gastrointestinal tract that affects millions of people worldwide with incidence and prevalence on the rise. Increases in the rates of IBD have been partly attributed to shifts toward a western diet, which emphasizes calorie dense, nutrient poor foods high in saturated fats, sugars, and artificial sweeteners. Importantly, dietary fiber intake is low in the United States and abroad. Dietary fiber is fermented into short-chain fatty acids (SCFAs) by the gut microbiota and is vital to proper gut function. Previous studies have found that diets lacking fiber, SCFAs, or receptors for SCFAs predispose both animals and humans to IBD and colorectal cancer. However, in order to utilize SCFAs for clinical management of IBD, we must further understand their functions and mechanisms of action. This work describes the effects of SCFAs, specifically propionate, on intestinal epithelial cell migration and wound healing. Intestinal epithelial cell migration is critical for epithelial restitution, the first phase in wound healing in the intestine. The studies in this dissertation demonstrated the effectiveness of SCFAs to trigger epithelial cell migration independent of proliferation up the crypt-villus axis and reduce ulceration in mice in a model of colitis. Notably, the effects of SCFAs on epithelial migration in a histone deacetylase inhibition (HDACi) and GPR43 dependent manner allows for further targeting of these pathways to circumvent some of the current pitfalls of SCFAs, mainly their ability to inhibit epithelial proliferation, which could be detrimental to ulcer healing
Illness Perception and Cardiovascular Risk Awareness in Adults with Type 2 Diabetes Mellitus
No full textTwo out of 3 people with T2DM, over the age of 64, will die of cardiovascular disease (CVD). Currently, there is a global push to broaden the awareness of the risk for CVD in the DM population and this study is no exception. Illness perception (IP) has been shown to affect positive healthcare behaviors in people with T2DM however the relationship between IP and CVD risk awareness (CVD-RA) has never been evaluated. The purpose of this study was to determine if there is a relationship between IP and CVD-RA in people with T2DM. This descriptive, cross-sectional study recruited a purposive sample of 200 men and women, between the ages of 45 and 75 from a local health clinic. Data was collected by survey method using a demographic questionnaire, and 2 verified instruments, one to measure IP and the other to measure 4 sub-groups of CVD-RA. Data was analyzed by descriptive statistics, Pearson Correlation, multiple regression and Cronbach’s Alpha. Inversely, 71% of participants were aware of their CVD-RA however, they reported a low susceptibility to developing CVD and only a moderate level of intention to change behavior. While the study did find a correlation between IP and Perceived Risk for CVD, there were no significant associations between IP and Knowledge of CVD Risk, Perceived Benefits and Health Eating. The findings of this study can be used to develop interventions for both HCPs and people with T2DM to help improve health behaviors
Assessing the Effect of “Time of Birth” on Nasopharyngeal Microbial Load in Infants
No full textAcute otitis media (AOM) is one of the most common childhood infections and its pathogenesis involves complex interactions between bacteria and viruses. Bacteria and viruses contributing to the AOM are collectively known as otopathogens. The objective of the capstone is to assess the effect of “month of birth” (MOB) on the microbial load of the most abundant otopathogen, Moraxella Catarrhalis. This is a retrospective analysis of data collected between 2009 – 2014 as part of a longitudinal study to determine risk factors for AOM. Subjects were recruited near birth and followed up to 1 year of age. For measurement of nasopharyngeal microbial abundance, approximately seven specimens were taken per subject. The total number of patients and specimens in the dataset are 139 and 948 respectively. The outcome variable was the log-transformed relative abundance of Moraxella genera. Its relationship with MOB was modeled using generalized additive mixed effects models (GAMM) controlling for age, month of specimen collection and other covariates while blocking on subject to control for repeated measures. Model selection was based on Bayesian Information Criterion (BIC). MOB showed a statistically significant non-linear relationship with Moraxella microbial abundance (p < 0.001). Increasing age and birth order were positively associated with the outcome (p < 0.001 and p = 0.03 respectively). The effect of MOB displayed a cyclic seasonal nature. This finding suggests that the timing of birth affects the average Moraxella microbial abundance in the first year of life. Our data demonstrate that MOB can be used to identify high risk populations for AOM. Further investigation on the underlying mechanisms mediating this complex relationship may aid in broadening the clinical understanding of AOM disease process
Role of viral vectors in candidate HIV vaccine-induced immune responses
No full textOver 30 years since the discovery of HIV, the development of a vaccine for the prevention of HIV/AIDS remains a global research priority. Several candidate vaccines have reached clinical efficacy trials in recent years; of these, only the RV144 trial, which utilized the recombinant canarypox vector ALVAC, demonstrated moderate, short-term efficacy, while multiple trials utilizing the recombinant human adenovirus vector Ad5 either demonstrated no efficacy or transiently increased the risk of HIV infection in vaccine recipients with pre-existing immunity to the Ad5 vector. The aim of this dissertation is to help fill the gap in our knowledge of host responses to vaccine vectors in HIV vaccination. Using PBMC collected from participants in the RV144 and HVTN204 clinical trials who received an ALVAC- or Ad5-vectored vaccine, respectively, we show that ALVAC-specific CD4 T cells are significantly less susceptible to HIV infection than Ad5-specific CD4 T cells, which could potentially contribute to the efficacy or non-efficacy of the vaccine regimens employing these two vectors. We also show that, compared to Ad5-specific CD4 T cells, ALVAC-specific CD4 T cells have lower surface expression of CCR5 and CXCR4, higher β-chemokine production, and a more Th1-slanted phenotype, all of which are associated with resistance to HIV infection. Unexpectedly, we also found that ALVAC, but not Ad5, induced a robust vector-specific CD8 T cell response which limited the proliferation of autologous vector-specific CD4 T cells and contributed to their reduced HIV susceptibility. We show that ALVAC-primed APCs are sufficient to induce reduced HIV susceptibility and CCR5 expression in autologous CD4 T cells. We also show that ALVAC- but not Ad5-primed APCs significantly upregulate the Th1-promoting cytokine IL-12, which has been previously reported to induce β-chemokine production and reduce surface expression of CCR5 on CD4 T cells. Finally, we show that ALVAC-primed APCs are themselves less susceptible to HIV infection than Ad5-primed APCs, as well as expressing higher levels of HIV restriction genes, particularly TRIM5 and tetherin. Taken together, our findings reveal a previously unappreciated role for vector-induced immune responses in HIV vaccination and provide new insights for rationale design of candidate HIV vaccines
The Effects of Diabetic Foot Care Education on Assessments and Behaviors among Adults with Diabetes Mellitus Experiencing Homelessness
No full textAdults with diabetes mellitus experiencing homelessness are at risk for preventable diabetic foot complications, including diabetic foot ulcers and non-traumatic lower extremity amputation. Several risk factors such as the lack of routine healthcare, insurance, nutritious meals, and access to diabetic foot self-care education, impact the individual’s risk for developing diabetic foot ulcers which may lead to non-traumatic lower extremity amputations. The purpose of the study was to measure the effects of RN-led diabetic foot self-care education on the participants’ perceived risks for diabetic foot ulcer or amputation, diabetic foot self-care behaviors, and clinical diabetic foot assessments. The aims of the study were to increase the participant’s knowledge and ability to recognize their individual risk factors for developing diabetic foot ulcer (DFU) and amputation and to decrease the participant’s risk for diabetic foot ulcer and increase the participant’s knowledge of diabetic foot self-care behaviors. A quasi-experimental single group repeated measures design was instituted to meet the aims of the study. The Diabetes Foot: Risk Assessment Education Program was utilized and presented over a period of four-weeks. The educational intervention focused on DFU and/or amputation risk identification and reduction and promoted five daily diabetic foot self-care behaviors to reduce risk for diabetic foot complications. Thirty individuals meeting inclusion criteria enrolled in the study, and twenty completed the four-week study. The dependent variables consisted of perceived DFU or amputation risk, diabetic foot self-care behaviors, and diabetic foot assessments. Based upon the findings, the participants accurately identified their individual risk factors for DFU or amputation. The risk factors consisted of loss of protective sensation, foot deformity and/or a previous DFU and/or amputation and no difference was noted between the pretest and posttest measures. The educational intervention was effective to increase two diabetic foot self-care behaviors from baseline to the remaining weeks of the intervention. Behavioral change was statistically significant for check feet and look in shoes, as assessed by the diabetic foot self-care behaviors on the Summary of Diabetic Self-Care Activities. The behaviors of wash feet, soak feet, and dry between the toes did not change. The Inlow’s 60-Second Diabetic Foot Screen was used for the foot assessments. The educational intervention was not effective to change diabetic foot assessment total scores. The diabetic foot self-care education had a small to moderate effect on two diabetic foot self-care behaviors. Additional studies are needed which focus on the reduction of diabetic foot complications among adults with diabetes mellitus experiencing homelessness.