ALLERGEN SENSITIZATION AND IMMUNOMODULATION BY SYNTHETIC LIGANDS, PUL-042, IN AN ALLERGEN-INDUCED ASTHMA MURINE MODEL

Allergen-induced asthma is the leading form of asthma and a chronic condition worldwide. Common allergens are known to contribute to the pathogenesis of this disease. Murine models of allergic asthma have mostly used an intraperitoneal route of sensitization (not airway) to study this disease. Allergic asthma pathophysiology involves the activation of TH2-specific cells, which triggers production of IgE antibodies, the up-regulation of TH2-specific cytokines (i.e. IL-4, IL-5, IL-9 and IL-13), increased airway eosinophilia, and mucin hypersecretion. Although there are several therapeutics currently treating asthmatic patients, some of these treatments can result in drug tolerance and may be linked to increased mortality. CpG oligodeoxynucleotides (ODNs) is a synthetic ligand that targets Toll-like Receptor (TLR) 9. It has been evaluated as a therapeutic agent for the treatment of cancer, infectious diseases, and for treating allergy and asthma. PUL-042 is also a synthetic TLR ligand and is composed of two agonists against TLR2/6 heterodimer and TLR9. Previous studies have evaluated PUL-042 for its ability to confer resistance against bacterial and viral lung infection. These findings, combined with studies performed using CpG ODNs, led to speculation that PUL-042 dampens the immune response in allergen-induced asthma. My thesis research investigated airway route sensitization and airway delivery of PUL-042 to evaluate its effects in reducing an allergen-induced asthma phenotype in a murine model. The results of this study contribute to the foundation for future investigations to evaluate the efficacy of PUL-042 as a novel therapy in allergic-asthma disease.

Effectiveness of an early postoperative feeding protocol

Background. The increasing emphasis on medical outcomes and cost containment has made it imperative to identify patient populations in which aggressive nutritional care can improve quality of care. The aim of this prospective study was to implement a standardized early jejunal feeding protocol for patients undergoing small and large bowel resection, and to evaluate its effect on patient outcome and cost.^ Methods. Treatment patients (n = 81) who met protocol inclusion criteria had a jejunal feeding tube inserted at the time of surgery. Feeding was initiated at 10 cc/hour within 12 hours after bowel resection and progressed if hemodynamically stable. The control group (n = 159) received usual care. Outcome measures included postoperative length of stay, total direct cost, nosocomial infection rate and health status (SF-36) scores.^ Results. By postoperative day 4, the use of total parenteral nutrition (TPN) was significantly greater in the control group compared to the treatment group; however, total nutritional intake was significantly less. Multiple regression analysis indicated an increased likelihood of infection with the use of TPN. A reduction of 3.5 postoperative days (p =.013) with 4.3 fewer TPN days per patient (p =.001) and a 9.6% reduction in infection rate (p =.042) was demonstrated in the treatment group. There was no difference in health status scores between groups at discharge and 3 months post-discharge.^ Conclusion. These positive outcomes and an average total cost savings of $4,145 per treatment patient indicate that the treatment protocol was effective. ^

Effect of continuous gastric enteral feeding on tonometric measurement of gastric intramucosal carbon dioxide levels in healthy volunteers

Purpose. The aim of this research was to evaluate the effect of enteral feeding on tonometric measurement of gastric regional carbon dioxide levels (PrCO2) in normal healthy volunteers. Design and methods. The sample included 12 healthy volunteers recruited by the University Clinical Research Center (UCRC). An air tonometry system monitored PrCO2 levels using a tonometer placed in the lumen of the stomach via orogastric intubation. PrCO2 was automatically measured and recorded every 10 minutes throughout the five hour study period. An oral dose of famotidine 40 mg was self-administered the evening prior to and the morning of the study. Instillation of Isocal® High Nitrogen (HN) was used for enteral feeding in hourly escalating doses of 0, 40, 60, and 80 ml/hr with no feeding during the fifth hour. Results . PrCO2 measurements at time 0 and 10 minutes (41.4 ± 6.5 and 41.8 ± 5.7, respectively) demonstrated biologic precision (Levene's Test statistic = 0.085, p-value 0.774). Biologic precision was lost between T130 and T140 40 when compared to baseline TO (Levene's Test statistic = 1.70, p-value 0.205; and 3.205, p-value 0.042, respectively) and returned to non-significant levels between T270 and T280 (Levene's Test statistic = 3.083, p-value 0.043; and 2.307, p-value 0.143, respectively). Isocal® HN significantly affected the biologic accuracy of PrCO2 measurements (repeated measures ANOVA F 4.91, p-value <0.001). After 20 minutes of enteral feeding at 40 ml/hr, PrCO2 significantly increased (41.4 ± 6.5 to 46.6 ± 4.25, F = 5.4, p-value 0.029). Maximum variance from baseline (41.4 ± 6.5 to 61.3 ± 15.2, F = 17.22, p-value <0.001) was noted after 30 minutes of Isocal® HN at 80 ml/hr or 210 minutes from baseline. The significant elevations in PrCO2 continued throughout the study. Sixty minutes after discontinuation of enteral feeding, PrCO2 remained significantly elevated from baseline (41.4 ± 6.5 to 51.8 ± 9.2, F = 10.15, p-value 0.004). Conclusion. Enteral feeding with Isocal® HN significantly affects the precision and accuracy of PrCO2 measurements in healthy volunteers. ^

Linkage and association of candidate obesity genes in Mexican-Americans from Starr County, Texas

Obesity and related chronic diseases represent a tremendous public health burden among Mexican Americans, a young and rapidly-expanding population. This study investigated the impact of variation within eight candidate obesity genes, which include leptin (LEP), leptin receptor (LEPR), neuropeptide Y (NPY), NPYY1 receptor (NPYY1), glucagon-like peptide-1 (GLP-1), GLP-1 receptor (GLP1R), beta-3 adrenergic receptor (β3AR), and uncoupling protein (UCP1), on variation in human obesity status and/or quantitative traits related to obesity in Mexican Americans from Starr County, Texas. The Trp64Arg polymorphism within β3AR was typed in 820 random individuals and 240 pedigrees (N = 2,044). The Arg allele frequency was significantly greater in obese versus non-obese individuals (0.20 versus 0. 15, respectively). In addition, within the random sample, the Arg allele was associated with significantly greater body weight (p = 0.031) and body mass index (BMI, p = 0.008) than the Trp allele. In the family sample, the Trp64Arg locus was also linked to percent fat (p = 0.045) but not to body weight or BMI. No linkage between obesity, diabetes, hypertension, or gallbladder disease and the Trp64Arg mutation was observed in families using affected sib pair linkage analysis or the transmission disequilibrium test. Microsatellite markers proximate to the remaining seven genes were typed in 302 individuals from 59 families. Sib pair linkage analysis provided evidence for linkage between obesity and NPY within affected sibling pairs (p = 0.042; n = 170 pairs). NPY was also linked to weight (p = 0.020), abdominal circumference (p = 0.031), hip circumference (p = 0.012), DBP (p ≤ 0.005), and a composite measure of body mass/fat (p ≤ 0.048) in all sibling pairs (n = 545 pairs). Additionally, LEP was linked to waist/hip ratio (p ≤ 0.009), total cholesterol (p ≤ 0.030), and HDL cholesterol (p ≤ 0.026), and LEPR was linked to fasting blood glucose (p ≤ 0.018) and DBP (p ≤ 0.003). Subsequent to the linkage analyses, the NPY gene was sequenced and eight variant sites identified. Two variant sites (-880I/D and 69I/D) were typed in a random sample of 914 individuals. The 880I/D variant was significantly associated with waist/hip ratio (p = 0.035) in the entire sample (N = 914) and with BMI (p = 0. 031), abdominal circumference (p = 0.044), and waist/hip ratio (p = 0.041) in a non-obese subsample (BW < 30 kg/m2, n = 594). The 69I/D variant was a rare mutation observed in only one pedigree and was not associated with obesity or body size/mass within this pedigree. Results of this study indicate that variation at or near β3AR, LEP, LEPR, and NPY may exert effects which increase obesity susceptibility and influence obesity-related measures in this population. ^

DNA nucleotide excision repair gene single nucleotide polymorphisms and hereditary nonpolyposis colorectal cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease caused by germline mutations in DNA mismatch repair(MMR) genes. The nucleotide excision repair(NER) pathway plays a very important role in cancer development. We systematically studied interactions between NER and MMR genes to identify NER gene single nucleotide polymorphism (SNP) risk factors that modify the effect of MMR mutations on risk for cancer in HNPCC. We analyzed data from polymorphisms in 10 NER genes that had been genotyped in HNPCC patients that carry MSH2 and MLH1 gene mutations. The influence of the NER gene SNPs on time to onset of colorectal cancer (CRC) was assessed using survival analysis and a semiparametric proportional hazard model. We found the median age of onset for CRC among MMR mutation carriers with the ERCC1 mutation was 3.9 years earlier than patients with wildtype ERCC1(median 47.7 vs 51.6, log-rank test p=0.035). The influence of Rad23B A249V SNP on age of onset of HNPCC is age dependent (likelihood ratio test p=0.0056). Interestingly, using the likelihood ratio test, we also found evidence of genetic interactions between the MMR gene mutations and SNPs in ERCC1 gene(C8092A) and XPG/ERCC5 gene(D1104H) with p-values of 0.004 and 0.042, respectively. An assessment using tree structured survival analysis (TSSA) showed distinct gene interactions in MLH1 mutation carriers and MSH2 mutation carriers. ERCC1 SNP genotypes greatly modified the age onset of HNPCC in MSH2 mutation carriers, while no effect was detected in MLH1 mutation carriers. Given the NER genes in this study play different roles in NER pathway, they may have distinct influences on the development of HNPCC. The findings of this study are very important for elucidation of the molecular mechanism of colon cancer development and for understanding why some mutation carriers of the MSH2 and MLH1 gene develop CRC early and others never develop CRC. Overall, the findings also have important implications for the development of early detection strategies and prevention as well as understanding the mechanism of colorectal carcinogenesis in HNPCC. ^

Factor H variant Y402H and the prevalence of hypertension and proteinuria: The Atherosclerosis Risk in Communities study

Hypertension is a significant risk factor for cardiovascular disease, which in turn is a major cause of morbidity and mortality worldwide. While the pathogenesis of vascular injury and subsequent end organ damage is complex, there is emerging data to support a role for the complement system in endovascular diseases. The complement Factor H Y402H polymorphism has been associated with a number of vasculopathies, including age-related macular degeneration (AMD), ischemic stroke and myocardial infarction. The current study evaluated the relationship of the Y402H polymorphism with hypertension and microalbuminuria in large the bi-racial Atherosclerosis Risk in Communities (ARIC) study. The Y402H polymorphism was found to be associated with a 48% (p-value 0.042) increase in the risk of developing incident hypertension in African American participants. No significant association was found with the Y402H polymorphism and microalbuminuria. The results from this investigation reveal the first association of the Factor H Y402H polymorphism and an increased risk of incident hypertension in African Americans. ^

Attention-Deficit/Hyperactivity Disorder and antidepressants and prescription medications: A pilot study

Background. Attention Deficit-Hyperactivity Disorder (AD/HD) diagnosis in children and adolescents has been on the rise over the last couple of decades and a multitude of studies have been conducted in an aim to better understand the disease. Literature has explored the role of several factors suspected of contributing to development of the disease, including: prenatal smoking exposures, environmental exposures, and low-birth weight. However, there is very limited reporting of fetal/infant exposure to antidepressants and prescription medications and the long-term behavioral outcomes, namely development of AD/HD. The purpose of this study was to evaluate the relationship between mother's exposure to prescription medications and/or antidepressants around the time of conception, during pregnancy, or while breastfeeding and the development of Attention-Deficit/Hyperactivity Disorder in offspring. Methods. Secondary analysis of data from a case-control study was performed. Exposure histories were collected for the mother and offspring. Data were collected using a secure, confidential, self-report, online survey to evaluate the relationship between antidepressant and/or prescription medication exposure and the development of AD/HD. The period of exposure to these drugs was defined as: around the time of conception, during pregnancy, or while breastfeeding. Cases were defined as a child who had been diagnosed with AD/HD. Controls were defined as a child who had not been diagnosed with AD/HD. Results. Prescription medication and antidepressant medication exposures around the time of conception, during pregnancy, or while breastfeeding were not associated with development of AD/HD. However, traumatic brain injury (OR=2.77 (1.61–4.77)) and preterm birth (OR=1.48 (1.04–2.12)) were identified as potential risk factors. These results support existing literature on AD/HD, but future work must be undertaken to better evaluate fetal/infant medication exposures and long-term behavioral outcomes.^

A systematic review of clostridium difficile infection in patients with iatrogenic immunesuppression

Background: Incidence of C. difficile infection (CDI) has increased dramatically in the past decade and is the most frequent cause of nosocomial infectious diarrhea. The outcome of infection may range from mild diarrhea to life-threatening pseudomembranous colitis depending on the immunological response of the host, which is highly compromised in this special population that includes bone marrow transplant (BMT), solid organ transplant (SOT) and cancer patients on cytotoxic chemotherapy. ^ Objectives: We conducted a meta-analysis to assess the incidence rates of CDI and the time to onset of infection in patients with iatrogenic immune suppression. ^ Methods: Original studies were identified through an extensive search of electronic databases including PubMed, Ovid Medline (R), RefWorks and Biological Abstracts and their references. The overall incidence rate of CDI in the immune suppressed population was calculated using random effects model and their 95% confidence interval was derived. Differences in the incidence of CDI and time to onset of infection were calculated between the groups and within the groups. Publication bias was assessed using a funnel plot. Results: Twenty nine published articles involving 7,424 patients met the eligibility requirements. The overall incidence of CDI in the immune suppressed population is 11.1% (95% Confidence Interval (CI): 9.2–13.4%). The incidence of CDI was higher in SOT patients (14.2%, 95% CI: 6.8–21.5%); (p-value-0.022) and in cancer patients on cytotoxic chemotherapy (11.4%, 95% CI: 8.4–15.4%); (p = 0.042) than in BMT patients (10.5%, 95% CI: 7.9–13.1%). In a subgroup analysis of BMT population, the incidence of CDI is significantly higher in patients who received allogeneic BMT (15.1%, 95% CI: 11.2–20.0%; p value <0.0001). Similarly, in the SOT population, the incidence of CDI was higher in patients who underwent liver transplantation (11.0%, 95% CI: 5.6–20.3%); (p= 0.0672). The median time to onset of infection was shorter in BMT patients (p=0.0025). ^ Conclusions: It is evident from the combined analysis of these 29 published studies that the incidence of CDI in the immune suppressed population is higher. However, early diagnosis and treatment of CDI will help reduce the morbidity and mortality due to CDI in this special population.^

The response of Texas public health agencies and workers to the emergency preparedness initiatives after 9/11

The purpose of this research was to better understand the impact of the terrorist attacks in 2001 on public health, particularly for Texas public health. This study employed mixed methods to examine changes to public health culture within Texas local public health agencies, important attitudes of public health workers toward responding to a disaster, and the funding policies that might ensure our investment in public health emergency preparedness is protected. ^ A qualitative analysis of interviews conducted with a large sample of public health officials in Texas found that all the constituent parts of a peculiar culture for public health preparedness existed that spanned the state's local health departments regardless of size, or funding level. The new preparedness culture in Texas had the hallmarks necessary for a robust public health preparedness and emergency response system. ^ The willingness of public health workers, necessary to make these kinds of changes and mount a disaster response was examined in one of Texas' most experienced disaster response teams—the public health workers for the City of Houston. A hypothesized latent variable model showed that willingness mediated all other factors in the model (self-efficacy, knowledge, barriers, and risk perception) for self-reported likelihood of reporting to work for a disaster. The RMSEA for the final model was 0.042 with a confidence interval of 0.036—0.049 and the chi-squared difference test was P=0.08, indicating a well-fitted model that suggests willingness is an important factor for consideration by preparedness planners and researchers alike. ^ Finally, with disasters on the rise and federal funding for preparedness dwindling, a review of states' policies for the distribution of these funds and their advantages and disadvantages were examined through a review of current literature and public documents, and a survey of state-level public health officials, emergency management professionals and researchers. Although the base plus per-capita method is the most common, it is not necessarily perceived to be the most effective. No clear "optimal" method emerged from the study, but recommendations for a strategic combination of three methods were made that has the potential to maximize the benefits of each method, while minimizing the weaknesses.^