Nonsteroidal Anti-Inflammatory Drugs Impact on the Outcomes of Hospitalized Patients with Clostridium difficile Infection.

PURPOSE: Mouse model experiments have demonstrated an increased Clostridium difficile infection (CDI) severity with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) use. We aim to evaluate the impact of NSAIDs in humans after a diagnosis of CDI on primary outcomes defined as I) all-cause mortality and II) toxic mega-colon attributable to CDI. PATIENTS AND METHODS: All hospitalized patients with a diagnosis of CDI were divided into two groups; those with NSAIDs administered up to 10 days after onset of CDI versus no NSAIDs use. The primary outcomes were analyzed between the groups, while controlling for severity of CDI. A logistic regression analysis was performed to identify the predictors of worse outcomes. RESULTS: NSAIDs were administered in 14% (n=80) of the 568 hospitalized visits for an average of 2.5 days after the CDI diagnosis. All-cause mortality was high in patients who did not receive NSAIDs as compared to those who did receive NSAIDs (16.6% vs 12.5%, p 0.354). Patients who were prescribed NSAIDs were more likely to have toxic mega-colon as compared to those who were not prescribed NSAIDs (2.5% vs 0.6%, p 0.094). Results were not statistically significant, even after controlling for CDI severity. Logistic regression analysis did not identify NSAIDs administration as a significant factor for all-cause mortality in CDI patients. CONCLUSION: This retrospective study results, contrary to mouse model, did not show association between NSAID use and CDI related mortality and toxic mega-colon. Shorter duration of NSAIDs use, younger people in study group, and timely CDI treatment may have resulted in contrasting results.

Clinical relevance of endoscopically identified extrinsic compression of the oesophagus and stomach.

BACKGROUND: Various degree of extrinsic compression of the oesophagus and stomach are experienced during upper endoscopy. However, its utility in clinical practice has not been studied. METHODS: Electronic chart review of all upper gastrointestinal endoscopies done at our hospital between 2005 and 2016 was performed. A total of 79 patients with documented extrinsic compression on upper gastrointestinal procedure report who had a preceding or subsequent abdomen/chest CT imaging performed within 6 months were included. RESULTS: 30 (38%) out of 79 patients had abnormal finding on CT scan. 14 (47%) out of 30 patients had an associated malignant lesion, whereas remaining had a benign lesion. Overall, patients with associated gastrointestinal symptoms (60% vs 22%, p=0.001) or history of weight loss (50% vs 16%, p=0.001) had increased odds of having an abnormal finding on CT scan compared with the patients who lacked such symptoms. Pancreatic cancer was the most commonly diagnosed malignancy. On subgroup analysis of patients with extrinsic compression and malignant lesion on imaging study, the likelihood of a malignancy was higher in blacks as compared with Hispanics (71%:29% vs 39%:61%, p=0.031), and with presence of gastrointestinal symptoms (64% vs 22%, p=0.003), presence of weight loss (64% vs 16%, p=0.0001) and hypoalbuminaemia (p=0.001). CONCLUSION: Finding an extrinsic compression of the oesophagus and stomach on an upper endoscopy may suggest malignancy, and hence should prompt further work-up. Posterior wall gastric body compression may signal the presence of pancreatic cancer.

Symptomatic Gallstones in the Young: Changing Trends of the Gallstone Disease-Related Hospitalization in the State of New York: 1996 - 2010.

BACKGROUND: The aim of the study was to evaluate if the gallstone-related hospitalizations in the young (< 20 years of age) have increased over time in both the Bronx County and New York State as a whole. METHODS: We retrospectively reviewed 15 years (1996 - 2010) of Statewide Planning and Research Cooperative System (SPARCS) data of New York State Department of Health. Patients with ICD-9 code diagnosis of 574 (cholelithiasis) among the first three discharge diagnoses were reviewed. RESULTS: Total number of all cause admissions to hospitals had increased from 2.44 million to 2.77 million (1996 - 2010). However, gallstone-related hospitalizations had decreased from 1.7% to 1.2%. It was noted that there was a 30% increment in the proportion of those below 20 years of age with gallstone disease requiring hospitalization over the same period. This young patient population contributed only 2.04% to all gallstone-related hospitalizations in 1996, whereas it had increased to 2.96% in 2010. This trend was more pronounced in women, Hispanics and in those who were residing in the Bronx County as compared to all other New York counties combined. CONCLUSION: The gallstone-related hospitalizations in the young (< 20 years of age) have increased over time in both the Bronx County and New York State as a whole. This could be due to increasing prevalence of risk factors such as obesity, physical inactivity, diabetes and early pregnancy.

Prevalence of undiagnosed hyperglycaemia in patients presenting to the Department of Emergency Medicine with no known history of diabetes.

BACKGROUND: Diabetes is considered a major epidemic of the 21st century. Usually, diabetes begins asymptomatically and the diagnosis takes place an average of 8-12 years after the onset of dysglycaemia. Blood check for glucose is taken at different medical setting, whether at the fasting condition or randomly. Previous studies had shown that abnormal blood glucose predicts future diabetes. Hence, medical staff should consider taking reasonable actions in patients with abnormal blood glucose. OBJECTIVE: To assess the prevalence of hyperglycaemia in patients presenting to the Department of Emergency Medicine (DEM) with no known history of diabetes, and to evaluate how often were they recommended following this up as an outpatient by the medical staff. DESIGN: A cross-sectional study examined the medical records of adult patients referred to the DEM during 1 November 2011-31 January 2012. PARTICIPANTS: Patients with random blood glucose ≥140 mg/dL and no known history of diabetes were included in the study. The discharge letter was examined for the presence of instructions to conduct further follow up. KEY RESULTS: A total of 16 784 patients presented to the DEM. Of these, 402 patients (2.4%) without known diabetes were hyperglycaemic, 346 patients had blood glucose levels ≥140 mg/dL and 56 patients had blood glucose levels above 200 mg/dL. Only 35 of the 402 included patient files (8.7%) contained instructions for further investigation. There was no statistically significant difference between those who received a letter for further follow up compared with those who did not receive it with respect to age, sex or blood glucose levels. CONCLUSION: Over 2% of patients who presented to the DEM were hyperglycaemic, without a prior diagnosis of diabetes. A small per cent was recommended to have outpatient follow-up. This represents a missed opportunity for earlier diagnosis of diabetes and emphasised the need for raising medical staff awareness concerning abnormal blood glucose and its implication.

When Intensive Insulin Therapy (MDI) Fails in Patients With Type 2 Diabetes: Switching to GLP-1 Receptor Agonist Versus Insulin Pump.

Treatment with insulin, alone or with oral or injectable hypoglycemic agents, is becoming increasingly common in patients with type 2 diabetes. However, approximately 40% of patients fail to reach their glycemic targets with the initially prescribed regimen and require intensification of insulin therapy, which increases the risks of weight gain and hypoglycemia. Many of these patients eventually reach a state in which further increases in the insulin dosage fail to improve glycemic control while increasing the risks of weight gain and hypoglycemia. The recently completed OpT2mise clinical trial showed that continuous subcutaneous insulin infusion (CSII) is more effective in reducing glycated hemoglobin (HbA1c) than intensification of multiple daily injection (MDI) insulin therapy in patients with type 2 diabetes who do not respond to intensive insulin therapy. CSII therapy may also be useful in patients who do not reach glycemic targets despite multidrug therapy with basal-bolus insulin and other agents, including glucagon-like peptide (GLP)-1 receptor agonists; current guidelines offer no recommendations for the treatment of such patients. Importantly, insulin and GLP-1 receptor agonists have complementary effects on glycemia and, hence, can be used either sequentially or in combination in the initial management of diabetes. Patients who have not previously failed GLP-1 receptor agonist therapy may show reduction in weight and insulin dose, in addition to moderate improvement in HbA1c, when GLP-1 receptor agonist therapy is added to MDI regimens. In subjects with long-standing type 2 diabetes who do not respond to intensive insulin therapies, switching from MDI to CSII and/or the addition of GLP-1 receptor agonists to MDI have the potential to improve glycemic control without increasing the risk of adverse events.

Non-Alcoholic Fatty Pancreatic Disease: A Review of Literature.

There is an epidemic of obesity worldwide. The prevalence of obesity has doubled over the last three decades. Obesity, especially abdominal obesity is associated with insulin resistance that can lead to pancreatic steatosis and non-alcoholic fatty pancreatic disease (NAFPD). NAFPD describes a phenotype entity ranging from deposition of fat in the pancreas to pancreatic inflammation, and resultant fibrosis, which is similar to that of non-alcoholic fatty liver disease (NAFLD). NAFPD may represent a meaningful manifestation of metabolic syndrome. Pancreatic steatosis can be diagnosed on ultrasound, computed tomography (CT) scan or magnetic resonance imaging (MRI). In addition to a correlation between pancreatic steatosis and metabolic syndrome, pancreatic steatosis may lead to a worse outcome in pancreatitis and may be an etiological factor in pancreatic cancer, but we need further research to examine the associations, pathophysiology, and the impact of pancreatic steatosis and NAFPD on the human health.

Withdrawal time in excellent or very poor bowel preparation qualities.

AIM: To evaluate association(s) between withdrawal time and polyp detection in various bowel preparation qualities. METHODS: Retrospective cohort analysis of screening colonoscopies performed between January 2005 and June 2011 for patients with average risk of colorectal cancer. Exclusion criteria included patients with a personal history of adenomatous polyps or colon cancer, prior colonic resection, significant family history of colorectal cancer, screening colonoscopy after other abnormal screening tests such as flexible sigmoidoscopy or barium enema, and screening colonoscopies during in-patient care. All procedures were performed or directly supervised by gastroenterologists. Main measurements were number of colonic segments with polyps and total number of colonic polyps. RESULTS: Multivariate analysis of 8331 colonoscopies showed longer withdrawal time was associated with more colonic segments with polyps in good (adjusted OR = 1.16; 95%CI: 1.13-1.19), fair (OR = 1.13; 95%CI: 1.10-1.17), and poor (OR = 1.18; 95%CI: 1.11-1.26) bowel preparation qualities. A higher number of total polyps was associated with longer withdrawal time in good (OR = 1.15; 95%CI: 1.13-1.18), fair (OR = 1.13; 95%CI: 1.10-1.16), and poor (OR = 1.20; 95%CI: 1.13-1.29) bowel preparation qualities. Longer withdrawal time was not associated with more colonic segments with polyps or greater number of colonic polyps in bowel preparations with excellent (OR = 1.07, 95%CI: 0.99-1.26; OR = 1.11, 95%CI: 0.99-1.24, respectively) and very poor (OR = 1.02, 95%CI: 0.99-1.12; OR = 1.05, 95%CI: 0.99-1.10, respectively) qualities. CONCLUSION: Longer withdrawal time is not associated with higher polyp number detected in colonoscopies with excellent or very poor bowel preparation quality.

Analysis: accuracy performance of the Medtronic NexSensor for 6 days in an inpatient setting using abdomen and buttocks insertion sites.

In an article in this issue of Journal of Diabetes Science and Technology, Peoples and colleagues address the issue that, while continuous glucose sensors have been shown to improve hemoglobin A1c, they are still fraught with concerns regarding accuracy and flexibility in sensor placement. Their study aimed to evaluate whether NexSensor, an improved version of the already commercially available Sof-Sensor, can be used for 6 days instead of the 3 days approved for Sof-Sensor in the United States. Also, the article aims to compare the accuracy of wearing the sensor in the abdomen versus the buttocks, given that this offers more flexibility than the approved labeling for Sof-Sensor, which is only in the abdomen. The study demonstrated that NexSensor is both safe and accurate for 6 days at both insertion sites. There was no statistically significant difference between the sites. As far as improved accuracy, the authors find evidence in favor of NexSensor as compared to Sof-Sensor, although this evidence is preliminary and is not backed by statistical significance measures.

Hypertension in diabetes: treatment considerations.

Treatment of blood pressure in the patient with diabetes remains a challenge. While data extrapolated from many trials seemed to imply that lower blood pressures leads to more favorable cardiovascular outcomes, this paper reviews newer trials designed to treat to blood pressure targets below 130/80 mmHg in patients with long term established diabetes, which showed that this goal may prove more harmful than helpful. In clinical practice this may be less relevant due to the fact that less than half of patients are even at the goal of 130/80. The interaction between glucose control and blood pressure control are also discussed, emphasizing the importance of multifactorial treatment.

Present and future: pharmacologic treatment of obesity.

Obesity now presents one of the biggest health problems of our times. Diet and exercise are best for both prevention and treatment; unfortunately, both require much discipline and are difficult to maintain. Medications offer a possible adjunct, but their effect is modest, they are limited by side effects, and the weight loss lasts only as long as the drug is being taken, since as soon as treatment is stopped, the weight is regained. Sibutramine, a sympathomimetic medication which was available for long-term treatment, is the most recent of the drugs to be withdrawn from the market due to side effects; in this case it was an increased risk of cardiovascular events. This paper reviews those medications which are available for treatment of obesity, including many of those recently taken off the market. It also discusses some of the newer treatments that are currently being investigated.

Outcomes of Patients With Cocaine Induced Chest Pain in An Inner City Hospital.

BACKGROUND: Cocaine induced chest pain is a major reason for admission in Safety Net Hospitals in the United States. The majority of patients admitted undergo extensive work-up leading to enormous economic burden. We hypothesize that in individuals with low risk, cocaine does not further increase adverse cardiovascular outcomes. METHODS: We conducted a retrospective chart review of all patients admitted with chest pain to our hospital between 07/01/09 and 06/30/10. We excluded patients with modifiable risk factors for coronary artery disease (CAD). The study population was divided into cocaine and non-cocaine group based on urine drug screen. We analyzed data including demographic, laboratory, cardiac testing, detection of CAD, length of stay and mortality rates. RESULTS: A total of 426 individuals matched our inclusion and exclusion criteria and were considered to have no known modifiable cardiac risk factors; 54 in cocaine group and 372 in non-cocaine group. Based on physician discretion, 41(76%) in the cocaine group and 239(64%) in the non-cocaine group underwent various modalities of cardiac testing. Cardiac testing was positive in 6(2.5%) patients in non-cocaine group and none in the cocaine group (p=0.597). There was no significant difference between length of stay and in-hospital mortality between the two groups. CONCLUSIONS: In individuals at low risk for CAD, cocaine use resulted in higher rate of cardiac testing. However, there is no difference in prevalence of CAD and in-hospital mortality between the two groups. We conclude that cocaine does not increase adverse outcomes in patients with low risk for CAD.

Significance of bowel wall thickening on computed tomography scan: higher risk of pathology among African Americans compared to Hispanics.

PURPOSE: The aims of our study were to examine the role of colonoscopy as further workup for bowel wall thickening reported on computed tomography (CT) scans and to investigate whether there were significant differences in pathology found among the racial groups in our study population. METHODS: This is a retrospective study from March 2005 and January 2007 of all patients who have undergone colonoscopy for bowel wall thickening found on CT scans of the abdomen. RESULTS: Of 94 patients with bowel wall thickening on CT scans, 7 (8%) had adenocarcinoma, 5 (5%) had large adenomas, 3 (3%) had infectious colitis, 2 (2%) ischemic colitis, 1 (1%) had inflammatory bowel disease, and 1 (1%) had a benign stricture. Bowel wall thickening on CT scan predicted clinical pathology in 34% of African Americans, as compared to 14% of Hispanics. Patients with significant pathology were more likely to have anemia and lower albumin levels. CONCLUSION: Patients with bowel wall thickening found on CT scans should be referred for colonoscopy, given that significant pathology is found in 20% of the cases. African Americans were 2.5 times more likely to have clinically significant pathology as compared to Hispanics.

Exendin-4 improves reversal of diabetes in NOD mice treated with anti-CD3 monoclonal antibody by enhancing recovery of beta-cells.

Immune modulators can arrest loss of insulin secretion in type 1 diabetes mellitus (T1DM), but they have not caused permanent disease remission or restored normal insulin secretion. We tested whether exendin-4, a glucagon-like peptide-1 receptor agonist, would enhance remission of T1DM in NOD mice treated with anti-CD3 monoclonal antibody (mAb) and studied the effects of exendin-4 treatment on cellular and metabolic responses of beta-cells. Diabetic NOD mice treated with anti-CD3 mAb and exendin-4 had a higher rate of remission (44%) than mice treated with anti-CD3 mAb alone (37%) or exendin-4 (0%) or insulin or IgG alone (0%) (P < 0.01). The effect of exendin-4 on reversal of diabetes after anti-CD3 mAb was greatest in mice with a glucose level of less than 350 mg/dl at diagnosis (63 vs. 39%, P < 0.05). Exendin-4 did not affect beta-cell area, replication, or apoptosis or reduce the frequency of diabetogenic or regulatory T cells or modulate the antigenicity of islet cells. Reversal of T1DM with anti-CD3 mAb was associated with recovery of insulin in glucose transporter-2(+)/insulin(-) islet cells that were identified at diagnosis. Glucose tolerance and insulin responses improved in mice treated with combination therapy, and exendin-4 increased insulin content and insulin release from beta-cells. We conclude that treatment with glucagon-like peptide-1 receptor agonist enhances remission of T1DM in NOD mice treated with anti-CD3 mAb by enhancing the recovery of the residual islets. This combinatorial approach may be useful in treatment of patients with new-onset T1DM.

Effects of autoimmunity and immune therapy on beta-cell turnover in type 1 diabetes.

beta-Cell mass can expand in response to demand: during pregnancy, in the setting of insulin resistance, or after pancreatectomy. It is not known whether similar beta-cell hyperplasia occurs following immune therapy of autoimmune diabetes, but the clinical remission soon after diagnosis and the results of recent immune therapy studies suggest that beta-cell recovery is possible. We studied changes in beta-cell replication, mass, and apoptosis in NOD mice during progression to overt diabetes and following immune therapy with anti-CD3 monoclonal antibodies (mAbs) or immune regulatory T-cells (Tregs). beta-Cell replication increases in pre-diabetic mice, after adoptive transfer of diabetes with increasing islet inflammation but before an increase in blood glucose concentration or a significant decrease in beta-cell mass. The pathogenic cells are responsible for increasing beta-cell replication because replication was reduced during diabetes remission induced by anti-CD3 mAb or Tregs. beta-Cell replication stimulated by the initial inflammatory infiltrate results in increased production of new beta-cells after immune therapy and increased beta-cell area, but the majority of this increased beta-cell area represents regranulated beta-cells rather than newly produced cells. We conclude that beta-cell replication is closely linked to the islet inflammatory process. A significant proportion of degranulated beta-cells remain, at the time of diagnosis of diabetes, that can recover after metabolic correction of hyperglycemia. Correction of the beta-cell loss in type 1 diabetes will, therefore, require strategies that target both the immunologic and cellular mechanisms that destroy and maintain beta-cell mass.

Expansion and redifferentiation of adult human pancreatic islet cells.

Beta-cell replacement represents the ultimate cure for type 1 diabetes, however it is limited by availability of organ donors. Adult human islets are difficult to propagate in culture, and efforts to expand them result in dedifferentiation. Here we describe conditions for expansion of adult human islet cells, as well as a way for their redifferentiation. Most cells in islets isolated from human pancreata were induced to replicate within the first week of culture in expansion medium. Cells were propagated for 16 population doublings, without a change in replication rate or noticeable cell mortality, representing an expansion of over 65,000-fold. Replication was accompanied by a decrease in expression of key beta-cell genes. Shift of the cells to differentiation medium containing betacellulin resulted in redifferentiation, as manifested by restoration of beta-cell gene expression and insulin content. These methods may allow transplantation of functional islet cells from single donors into multiple recipients.

Treatment of type 1 diabetes with anti-T-cell agents: from T-cell depletion to T-cell regulation.

Studies in animal models of type 1 diabetes had suggested that the disease was due to an immune-mediated destruction of insulin-producing cells. As this understanding was developed, clinical trials that were directed against T cells were begun, because these lymphocytes were thought to be the primary mediators of disease. Initial studies used broad-spectrum agents and showed general efficacy in either preventing the loss of insulin secretion or reducing the need for exogenous insulin. Although encouraging, the enthusiasm for this approach waned due to the lack of long-term effects and toxicities. These studies were followed by trials with more specific agents, but the issue of toxicity remained. Newer agents, such as anti-CD3 antibody, are also targeted against T cells but the toxicity and efficacy of modified anti-CD3 antibody, for example, appears to be improved over previously tested agents. In addition, our understanding of the immunologic effects of anti-T-cell agents has evolved. Data now suggest that efficacy and duration of the effects of anti-T-cell drugs can be enhanced when the agents provoke immune modulation rather than depletion of effector cells.

Activation of human T cells by FcR nonbinding anti-CD3 mAb, hOKT3gamma1(Ala-Ala).

Dimeric Fc receptor (FcR) nonbinding anti-CD3 antibodies have been developed to minimize toxicities associated with classical anti-CD3 monoclonal antibodies (e.g., OKT3). Studies with murine analogs of non-FcR-binding antibodies have shown reduced mitogenicity compared to OKT3. In a trial of an FcR nonbinding humanized anti-CD3 mAb hOKT3gamma1(Ala-Ala) for treatment of patients with type 1 diabetes, we found significant increases in IL-10 and IL-5 in the serum of 63% and 72% of patients, respectively, and TNF-alpha and IL-6 levels that were lower than those previously reported following OKT3 therapy. The activation signal delivered by hOKT3gamma1(Ala-Ala) was associated with calcium signaling and cytokine production by previously activated human cells in vitro. However, the production of IL-10, compared to IFN-gamma on a molar basis, was greater after culture with hOKT3gamma1(Ala-Ala) than with OKT3. Flow cytometric studies confirmed that OKT3 induced IFN-gamma and IL-10 production, but hOKT3gamma1(Ala-Ala) induced only detectable IL-10 production in CD45RO(+) cells. Moreover, in vivo, we found IL-10(+)CD4(+) T cells after drug treatment. These cells were heterogeneous but generally CD45RO(+), CTLA-4(-), and expressed CCR4. A subgroup of these cells expressed TGF-beta. Thus, the non-FcR binding anti-CD3 mAb, hOKT3gamma1(Ala-Ala) delivers an activation signal to T cells that is quantitatively and qualitatively different from OKT3. It leads to the generation of T cells that might inhibit the autoimmune response and may be involved in the beneficial effect on beta cell destruction in Type 1 diabetes.

Critical reduction in beta-cell mass results in two distinct outcomes over time. Adaptation with impaired glucose tolerance or decompensated diabetes.

We have proposed that hyperglycemia-induced dedifferentiation of beta-cells is a critical factor for the loss of insulin secretory function in diabetes. Here we examined the effects of the duration of hyperglycemia on gene expression in islets of partially pancreatectomized (Px) rats. Islets were isolated, and mRNA was extracted from rats 4 and 14 weeks after Px or sham Px surgery. Px rats developed different degrees of hyperglycemia; low hyperglycemia was assigned to Px rats with fed blood glucose levels less than 150 mg/dl, and high hyperglycemia was assigned above 150 mg/dl. beta-Cell hypertrophy was present at both 4 and 14 weeks. At the same time points, high hyperglycemia rats showed a global alteration in gene expression with decreased mRNA for insulin, IAPP, islet-associated transcription factors (pancreatic and duodenal homeobox-1, BETA2/NeuroD, Nkx6.1, and hepatocyte nuclear factor 1 alpha), beta-cell metabolic enzymes (glucose transporter 2, glucokinase, mitochondrial glycerol phosphate dehydrogenase, and pyruvate carboxylase), and ion channels/pumps (Kir6.2, VDCC beta, and sarcoplasmic reticulum Ca(2+)-ATPase 3). Conversely, genes normally suppressed in beta-cells, such as lactate dehydrogenase-A, hexokinase I, glucose-6-phosphatase, stress genes (heme oxygenase-1, A20, and Fas), and the transcription factor c-Myc, were markedly increased. In contrast, gene expression in low hyperglycemia rats was only minimally changed at 4 weeks but significantly changed at 14 weeks, indicating that even low levels of hyperglycemia induce beta-cell dedifferentiation over time. In addition, whereas 2 weeks of correction of hyperglycemia completely reverses the changes in gene expression of Px rats at 4 weeks, the changes at 14 weeks were only partially reversed, indicating that the phenotype becomes resistant to reversal in the long term. In conclusion, chronic hyperglycemia induces a progressive loss of beta-cell phenotype with decreased expression of beta-cell-associated genes and increased expression of normally suppressed genes, these changes being present with even minimal levels of hyperglycemia. Thus, both the severity and duration of hyperglycemia appear to contribute to the deterioration of the beta-cell phenotype found in diabetes.