The widespread use of antibiotics has led to dramatic increases in the incidence and severity of Clostridium difficile infection (CDI). No group of patients suffers more from CDI than the elderly. Nursing homes (NH) represent the perfect storm of a vulnerable group of frail elders living in confined communities. Nursing home residents suffer from increased morbidity and mortality from CDI and corresponding high rates of C. difficile colonization. Upwards of 40 to 50% of CDI current cases originate from NHs and the prevalence of colonization rates remain high within these facilities, with as many as half of the residents being colonized with C. difficile at any given time. One factor that has become of increasing interest and a target of preventive strategies is the human intestinal microbiome. A healthy, diverse microbiome interacts with the host immune system and contributes to pathogen resistance. In this investigation, we first examine elder specific variables to determine if the associated risks of CDI differ by home living environment (nursing home versus community-dwelling). We then go on explore the relationships of NH environment, frailty, nutritional status, and residents’ age with microbiome composition and potential metabolic function. Finally, we describe the C. difficile colonization patterns among elderly NH residents and the associated risk of colonization based on clinical variables and microbiome determinants. A better understanding of the microbiome’s contribution to C. difficile colonization will provide the basis for informing rational interventions and public health policies to better combat CDI in the nursing home.

Artificial urinary sphincters have been used for decades for treatment of urinary incontinence. A commonly used device, the AMS 800 consists of a urethral cuff, pump and an abdominal reservoir. Notable complications of this system include scrotal or labial hematomas, infection or erosion of the cuff and rarely migration of its components. Although there are few reported cases related to effects from pump migration, those documenting reservoir related complications are even rarer. We present a case of reservoir migration adjacent to the ascending colon causing ischemic changes mimicking colonic neoplasm. Our patient, a 66-year old male with medical history of adenocarcinoma of prostate status post radical prostatectomy, had been having abdominal pain for a month. A CT scan showed cecal and proximal ascending colonic irregular nodular thickening suggestive of colonic mass. It also revealed a low-density structure next to the ascending colon abutting into area of the mass. A follow up colonoscopy showed a fungating, ulcerated mass extending from cecum to ascending colon concerning for a malignancy of which biopsy was also done. The patient then underwent right open hemicolectomy. During surgery, a balloon reservoir was seen in the abdominal cavity with its adherence to the right colon but not eroding into it. The surgeon dissected the balloon, repositioned and re-peritonealized it before closing the abdomen. The colonoscopic and surgical pathology instead demonstrated findings of ischemic colitis with mucosal ulceration in cecum and ascending colon limited to the mucosa but no evidence of cancer. Retrospective chart review revealed history of artificial urinary sphincter implantation for urinary incontinence related to radical prostatectomy for adenocarcinoma eight years prior. With manufacturer suggested implant location of the reservoir in prevesical space, the possibility of migration needs to be accounted for. Although there are not many reports of artificial sphincter reservoir related complications, there are cases documenting inflatable penile prosthesis reservoir erosion into abdominal and pelvic structures. As the CT scan demonstrated reservoir indentation into the ascending colon, it likely led to chronic irritation of the adjacent colonic wall due to mass effect. It is hypothesized that constant pressure on colonic wall likely led to localized ischemia. This resulted in localized inflammation including submucosal edema, which can create a mass-like appearance when severe. This case emphasizes that, while preliminary radiographic imaging and even gross colonoscopy findings may be suggestive of a malignancy, it is imperative to await biopsy results to confirm the diagnosis of a malignant neoplasm. Our case report emphasizes the consideration of diagnoses other than colon cancer when faced with a colonic mass especially in the setting of implanted intra-abdominal foreign body to avoid unnecessary surgery and related complications.

Objective: Access to care is key to effective rectal cancer treatment. We hypothesized that ethnic/racial minorities living in high population density areas would have the greatest delays in cancer care compared to whites living in medium population density areas. Methods: Using 2004-2016 National Cancer DataBase data, we identified stage I-III patients with invasive rectal adenocarcinoma who underwent surgery. The data were analyzed by race/ethnicity (whites, blacks, or Hispanics) and population density (metropolitan or urban/rural). Multivariable ANCOVA was performed to evaluate the duration of time from diagnosis to surgery. Results: The study population consisted of 76,131 patients: 65,172 Non-Hispanic whites (NHW; 85.6%), 6,167 Non-Hispanic blacks (NHB; 8.1%), and 4,792 Hispanics (6.3%). Of these, 61,363 patients (80.6%) lived in metropolitan areas. Among direct-to-surgery patients, the greatest difference in mean time from diagnosis to surgery was 20.3 days (urban/rural NHW, 53.3 days, vs. metropolitan Hispanics, 73.6 days). Among patients receiving neoadjuvant therapy, the greatest difference in mean time from diagnosis to surgery was 18.8 days (urban/rural NHW, 136.9 days, vs. metropolitan NHB, 155.7 days). After multivariable adjustment for several socioeconomic and clinical factors, among direct-to-surgery patients, metropolitan Hispanics had a 16.5-day delay (95% CI 12.9-20.0) compared with urban/rural NHW. In patients receiving neoadjuvant therapy, metropolitan NHB had an 18.1-day delay (95% CI 16.1-20.0) compared to urban/rural NHW. Conclusion: The combination of high population density and racial/ethnic minority status was associated with delays in rectal cancer care that persisted after adjusting for other important factors. Understanding which populations are at risk and perceived obstacles to timely care will help inform interventions to minimize treatment access disparities.

Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent issue in the modern world, predisposing patients to serious pathology such as cirrhosis and hepatocellular carcinoma. Mitochondrial dysfunction, and in particular, diminished hepatic oxidative phosphorylation (OXPHOS) capacity, have been observed in NAFLD livers, which may participate in NAFLD pathogenesis. To examine the role of OXPHOS in NAFLD, we generated a model of enhanced hepatic OXPHOS using mice with liver-specific transgenic expression of LRPPRC, a protein which activates mitochondrial transcription and augments OXPHOS capacity. When challenged with high-fat feeding, mice with enhanced hepatic OXPHOS were protected from the development of liver steatosis and inflammation, critical components in the pathogenesis of NAFLD. This protection corresponded to increased liver and whole-body insulin sensitivity. Moreover, mice with enhanced hepatic OXPHOS have increased availability of oxidized NAD+, which promotes complete fatty acid oxidation in hepatocytes. Interestingly, mice with enhanced hepatic OXPHOS were also protected from obesogenic effects of long-term high-fat feeding. Consistent with this, enhanced hepatic OXPHOS increased energy expenditure and adipose tissue oxidative gene expression, suggesting a communication between the liver and adipose tissue to promote thermogenesis. Examination of pro-thermogenic molecules revealed altered bile acid composition in livers and serum of LRPPRC transgenic mice. These mice had increased expression of bile acid synthetic enzymes, genes which are induced by NAD+ dependent deacetylase SIRT1 activation of the transcriptional co-regulator PGC-1a. These findings suggest that enhanced hepatic OXPHOS transcriptionally regulates bile acid synthesis and dictates whole-body energy expenditure, culminating in protection from obesity.

Hepatitis C is the most common chronic bloodbourne infection in the United States, with an estimated prevalence of 2.7 million. The total cost of care for this patient population was estimated to be $6.5 billion in 2013. Since 1998, the Centers for Disease Control (CDC) have recommended hepatitis C screening for specific high risk populations, but until recently there was no recommendation for age-based screening. The recent advent of new, more efficacious therapies for hepatitis C have made early identification significantly more important. Consequently, the CDC updated its recommendations in 2012 based on recent evidence to include one-time screening for all individuals born between 1945 and 1965. In 2013, the US Preventive Services Task Force (USPSTF) also incorporated this recommendation into their hepatitis C screening guidelines. In spite of this, there is some debate in the medical community regarding cohort screening for hepatitis C, and some data indicates widespread misunderstanding of current screening recommendations among primary care providers. The purpose of this project was to evaluate current knowledge and understanding of hepatitis C screening guidelines among a group of family medicine residents at East Tennessee State University, and to improve their knowledge in order to promote more appropriate screening practices in their patient population. To accomplish this, 13 question surveys were administered to residents to assess their current knowledge. Following these surveys, residents attended an education session covering current recommendations from the CDC and USPSTF. The 13 question survey was administered again in the post-intervention period. A t-test revealed that post-intervention survey scores increased significantly on 8 out of 13 questions. The intervention was successful at improving knowledge of current hepatitis C screening recommendations in the target population. Future research should be directed at broadening the intervention to include a variety of other providers, and at assessing the impact on execution of screening in the patient population, particularly regarding application to people born in the specified birth cohort.

No trato digestório a colite ulcerativa apresenta necrose no intestino como processos patofisiológicos. Este projeto visou estudar neurônios com códigos químicos do sistema nervoso entérico (SNE) e a morfologia estrutural do intestino grosso de animais com colite ulcerativa. Grupos: a) Colite: injetados com TNBS, b) PBS: injetados com PBS e c) controle. Os tecidos foram preparados por métodos imunohistoquímicos de duplas marcações do receptor P2X7 com NOS, ChAT, Calb, Calr, anti-HuC/D (pan-neuronal) e S100 (células glias). No grupo Colite, no plexo mioentérico, o receptor P2X7 estava diminuído. No tecido lesado apresentou aumento de neutrófilos e da lâmina própria, alteração de colágeno e destruição do epitélio e células caliciformes. Reduziram colocalizações de neurônios com receptor no plexo mioentérico e aumento no plexo submucoso. Houve reduções nas densidades e áreas dos neurônios no SNE. Conclui-se que a colite afetou os neurônios entéricos e células gliais, causou alterações morfológicas, sendo assim, pode afetar motilidade intestinal. / In the digestive tract ulcerative colitis have a bowel necrosis as pathophysiological processes. This project aimed to study neurons with their respective chemicals codes the enteric nervous system (ENS) as well as structural morphology of the distal colon of animals with ulcerative colitis. Groups: a) colitis: TNBS injected, b) PBS: PBS injected and c) control. The tissues were prepared by immunohistochemical methods for double marking with P2X7 receptor, ChAT, Calb, Calr, anti-HUC / D (pan-neuronal) and S100 (glial cells). In the colitis group, the myenteric plexus, the P2X7 receptor decreased. In the injured tissue showed increased neutrophils, alteration and destruction of collagen and epithelial goblet cells. There were reduced colocalizations of neurons with receptor in myenteric plexus and increase in submucosal plexus. There were reductions in the densities and areas neurons of ENS. Concluded that colitis affected enteric neurons and glial cells, causing morphological changes and could be affect intestinal motility.

Patients with liver disease have an increased risk for malnutrition because of side effects of the disease. The Nutrition Focused Physical Exam (NFPE) was developed for nutrition professionals to aid physicians in a nutrition-based diagnosis of malnutrition. The purpose of this study was to examine the NFPE for its validity in liver disease patients being evaluated for transplant. In addition, the NFPE was used to assess incidence and severity of malnutrition in end stage liver disease patients and compare these results to already developed malnutrition tools such as the Patient Generated-Subjective Global Assessment (PG-SGA), Triceps Skinfolds (TSF), Mid-Arm Circumference (MAC), Lumbar Index, and Total Psoas Muscle Area (TPA). The NFPE was found to be highly correlated with PG-SGA results. There was a weak correlation between the NFPE and the TSF, MAC, and Lumbar Index/TPA, except when comparing the bottom 25% quartile of the Lumbar Index to severe malnutrition using the NFPE. This resulted in a moderate correlation. The odds-ratio for hospital admission based on malnutrition and severe malnutrition were both extremely high (14.571, 18.857 respectively). These preliminary results reinforce the significance of the NFPE and the need for additional studies using this tool.

Crohn’s disease (CD) affects about 780,000 people in the United States alone, and it is estimated that 6-15 per 100,000 persons will receive a diagnosis of this disease each year. There currently is no cure for Crohn’s disease, and available medical therapies simply serve to alleviate the inflammation. This does not help treat fibrostenosis that Crohn’s disease patients may develop, which can only be treated surgically. Finding alternatives to treat CD requires an understanding of mechanisms at the biochemical level. In this thesis, we attempted to gain a better understanding of certain pathways found to be active in Crohn’s disease-affected ileal smooth muscle cells. We found an upregulation of the ER stress pathway via expression of its surrogate, the GRP78 protein. We also showed evidence that the phosphoinositide 3-kinase (PI3K) pathway, a key proliferative pathway, is linked to ER stress in these cells, and is an upstream driving force of the ER stress response. Further research on the link between the PI3K and ER stress pathways needs to be conducted, and can potentially serve as a target for therapeutics to help reduce proliferation in fibrostenotic Crohn’s disease-affected ileal smooth muscle cells.

The immunological mechanisms involved in virus-induced hepatitis were examined by measuring the cytotoxic capabilities and the morphological and antigenic phenotypes of leukocytes isolated from the livers of virus-infected mice. Large granular lymphocytes (LGL) of both natural killer (NK) cell and cytotoxic T lymphocyte (CTL) phenoytpes [phenotypes] accumulated in livers of mice infected with lymphocytic choriomeningitis virus (LCMV) of either the nonhepatotropic Armstrong strain (LCMV-ARM) or the hepatotropic WE strain (LCMV-WE). NK cell activity and LGL number increased 3- to 4-fold between days 1 and 5 postinfection (p.i.). These LGL were characterized as NK cells on the basis of cell surface antigens, kinetics of appearance, target cell range, and morphology. By day 7 p.i., virus-specific, H-2-restricted, Thy-1+, Lyt-2+CTL activity was present in the liver, and its appearance correlated with a second wave of LGL accumulation. Total CTL activity, leukocyte numbers, and CTL/LGL numbers were at least 5-fold higher in the livers of LCMV-WE-infected mice than in the livers of LCMV-ARM-infected mice. Mice infected with the cytopathic viruses, mouse hepatitis virus and murine cytomegalovirus, experienced greater increases in NK/LGL by day 3 p.i. than did mice either infected with LCMV or injected with poly I:C. The early and late accumulations of LGL in the virus-infected liver were associated with the appearance of two waves of LGL with blast cell morphology expressing the phenotypes of NK cells and CTL, respectively. Thus, the organ-associated accumulation, blastogenesis, and in situ proliferation of cytotoxic LGL provide a means for the localization and site-specific augmentation of a host's cell-mediated antiviral defenses. The mechanism of inhibition of virus synthesis in vivo by immune splenocytes containing virus-specific CTL was examined in mice dually infected with two different viruses and then adoptively immunized with spleen cells immune to one of the two viruses. Only the titer of the virus to which the splenocytes were immune was reduced in titer, and no nonspecific antiviral effect was seen on the titer of the 'bystander' heterologous virus. These data are consistent with an in vivo mechanism of CTL-mediated antiviral resistance involving direct cytotoxicity rather than release and dissemination of antigen-nonspecific antiviral factors, such as interferon, following recognition of appropriate viral antigen.

No trato digestório a colite ulcerativa apresenta necrose no intestino como processos patofisiológicos. Este projeto visou estudar neurônios com códigos químicos do sistema nervoso entérico (SNE) e a morfologia estrutural do intestino grosso de animais com colite ulcerativa. Grupos: a) Colite: injetados com TNBS, b) PBS: injetados com PBS e c) controle. Os tecidos foram preparados por métodos imunohistoquímicos de duplas marcações do receptor P2X7 com NOS, ChAT, Calb, Calr, anti-HuC/D (pan-neuronal) e S100 (células glias). No grupo Colite, no plexo mioentérico, o receptor P2X7 estava diminuído. No tecido lesado apresentou aumento de neutrófilos e da lâmina própria, alteração de colágeno e destruição do epitélio e células caliciformes. Reduziram colocalizações de neurônios com receptor no plexo mioentérico e aumento no plexo submucoso. Houve reduções nas densidades e áreas dos neurônios no SNE. Conclui-se que a colite afetou os neurônios entéricos e células gliais, causou alterações morfológicas, sendo assim, pode afetar motilidade intestinal. / In the digestive tract ulcerative colitis have a bowel necrosis as pathophysiological processes. This project aimed to study neurons with their respective chemicals codes the enteric nervous system (ENS) as well as structural morphology of the distal colon of animals with ulcerative colitis. Groups: a) colitis: TNBS injected, b) PBS: PBS injected and c) control. The tissues were prepared by immunohistochemical methods for double marking with P2X7 receptor, ChAT, Calb, Calr, anti-HUC / D (pan-neuronal) and S100 (glial cells). In the colitis group, the myenteric plexus, the P2X7 receptor decreased. In the injured tissue showed increased neutrophils, alteration and destruction of collagen and epithelial goblet cells. There were reduced colocalizations of neurons with receptor in myenteric plexus and increase in submucosal plexus. There were reductions in the densities and areas neurons of ENS. Concluded that colitis affected enteric neurons and glial cells, causing morphological changes and could be affect intestinal motility.