Dual Pathology in a Patient with Right Lower Quadrant Pain

Meckel diverticula are remnants of the omphalomesenteric duct. They have 2% incidence in the general population, are usually asymptomatic, and tend to be diagnosed incidentally. The generally held principle had been that asymptomatic cases do not require resection, as exemplified by a 2008 systematic review of over 200 studies. However, a recent series reported an increased risk of malignancies, and recommended mandatory resection. We present a case of Meckel diverticulitis with concurrent infiltrative appendiceal carcinoid in a patient with right lower quadrant pain.     

Interleukin-3, GM-CSF, and TPA induce distinct phosphorylation events in an interleukin 3-dependent multipotential cell line

The mechanism of action of the hemopoietic growth factor, murine interleukin-3 (mIL-3), was investigated using an mIL-3-dependent multipotential hematopoietic cell line, B6SUtA1. Murine granulocyte- macrophage colony-stimulating factor (mGM-CSF) was as potent as mIL-3 in stimulating these cells. In addition, sodium orthovanadate, an inhibitor of phosphotyrosine phosphatase, and 12-O-tetradecanoyl- phorbol-13-acetate (TPA), a known activator of protein kinase C, also stimulated DNA synthesis in these cells, suggesting that protein phosphorylation might be involved in the mechanism of action of mIL-3 and mGM-CSF. To assess this possibility, intact B6SUtA1 cells exposed for brief periods to mIL-3, mGM-CSF, and TPA were analyzed for changes in phosphorylation patterns using metabolic 32P-labeling and antibodies to phosphotyrosine. Both mIL-3 and mGM-CSF induced the serine-specific phosphorylation of a 68-Kd cytosolic protein, whereas all three agents stimulated the serine-specific phosphorylation of a 68-Kd membrane protein. Furthermore, mIL-3 stimulated tyrosine phosphorylation of the 68-Kd membrane protein, as well as of 140-, 90-, 55, and 40-Kd proteins. The 90-Kd protein was also tyrosine phosphorylated in response to mGM-CSF. These phosphotyrosine containing proteins were not detected in TPA-treated cells. These results indicate that protein phosphorylations on tyrosine and serine residues occur in B6SUtA1 cells following short-term incubation with mIL-3 or mGM-CSF and that most of these phosphorylation events are mediated by kinases other than protein kinase C (PkC).     

Annexin A1, formyl peptide receptor,and NOX1 orchestrate epithelial repair

N-formyl peptide receptors (FPRs) are critical regulators of host defense in phagocytes and are also expressed in epithelia. FPR signaling and function have been extensively studied in phagocytes, yet their functional biology in epithelia is poorly understood. We describe a novel intestinal epithelial FPR signaling pathway that is activated by an endogenous FPR ligand, annexin A1 (ANXA1), and its cleavage product Ac2-26, which mediate activation of ROS by an epithelial NADPH oxidase, NOX1. We show that epithelial cell migration was regulated by this signaling cascade through oxidative inactivation of the regulatory phosphatases PTEN and PTP-PEST, with consequent activation of focal adhesion kinase (FAK) and paxillin. In vivo studies using intestinal epithelial specific Nox1^–/–IEC and AnxA1^–/– mice demonstrated defects in intestinal mucosal wound repair, while systemic administration of ANXA1 promoted wound recovery in a NOX1-dependent fashion. Additionally, increased ANXA1 expression was observed in the intestinal epithelium and infiltrating leukocytes in the mucosa of ulcerative colitis patients compared with normal intestinal mucosa. Our findings delineate a novel epithelial FPR1/NOX1-dependent redox signaling pathway that promotes mucosal wound repair.     

Alcohol-associated admissions to an adult intensive care unit: an audit

BACKGROUND AND OBJECTIVE: Excessive alcohol consumption is a major cause for premature death and preventable ill health in the whole population. We set out to audit admissions to the intensive care unit (ICU) of our large teaching hospital with respect to alcohol-related admissions. METHODS: A prospective audit was conducted into alcohol-associated admissions to our university hospital adult ICU over 12 months. The following data were collected for each patient admitted: age, gender, diagnosis and amount of alcohol consumption, APACHE II score, and the probability of death. RESULTS: Patients with definite alcohol consumption constituted 39.1% (124 patients) of all admissions (317 patients) to the ICU. In Group 1 (89 patients), the admission was directly associated with alcohol consumption, which included heavy alcohol consumption. Group 2 (35 patients) consisted of 'social drinkers'; and Group 3 was composed of patients who denied any alcohol intake. Group 1 had a high median APACHE II score of 19 (range 4-35) and a significantly higher mortality rate (41.6%) than Group 3 (18.4%, P < 0.001) or the entire sample studied (23.7%, P < 0.001). The results also demonstrated an incidence of pneumonia of 29.2% (26 patients) in alcohol-associated admissions compared with 22.8% (eight patients) in Group 2 and 21.8% (19 patients) in Group 3. Trauma admissions amounted to 11.4% of the patients studied (24/211 patients), 17 (70.8%) of whom were directly associated with alcohol and it included 11 pedestrians. CONCLUSIONS: Alcohol may play a major role in the admission and mortality of ICU patients. Further investigations are warranted because our sample size is so small.     

��-Cell Failure in Diet-Induced Obese Mice Stratified According to Body Weight Gain: Secretory Dysfunction and Altered Islet Lipid Metabolism Without Steatosis or Reduced ��-Cell Mass

OBJECTIVE

C57Bl/6 mice develop obesity and mild hyperglycemia when fed a high-fat diet (HFD). Although diet-induced obesity (DIO) is a widely studied model of type 2 diabetes, little is known about β-cell failure in these mice.

RESEARCH DESIGN AND METHODS

DIO mice were separated in two groups according to body weight gain: low- and high-HFD responders (LDR and HDR). We examined whether mild hyperglycemia in HDR mice is due to reduced β-cell mass or function and studied islet metabolism and signaling.

RESULTS

HDR mice were more obese, hyperinsulinemic, insulin resistant, and hyperglycemic and showed a more altered plasma lipid profile than LDR. LDR mice largely compensated insulin resistance, whereas HDR showed perturbed glucose homeostasis. Neither LDR nor HDR mice showed reduced β-cell mass, altered islet glucose metabolism, and triglyceride deposition. Insulin secretion in response to glucose, KCl, and arginine was impaired in LDR and almost abolished in HDR islets. Palmitate partially restored glucose- and KCl-stimulated secretion. The glucose-induced rise in ATP was reduced in both DIO groups, and the glucose-induced rise in Ca²⁺ was reduced in HDR islets relatively to LDR. Glucose-stimulated lipolysis was decreased in LDR and HDR islets, whereas fat oxidation was increased in HDR islets only. Fatty acid esterification processes were markedly diminished, and free cholesterol accumulated in HDR islets.

CONCLUSIONS

β-Cell failure in HDR mice is not due to reduced β-cell mass and glucose metabolism or steatosis but to a secretory dysfunction that is possibly due to altered ATP/Ca²⁺ and lipid signaling, as well as free cholesterol deposition.While insulin resistance is a common feature in most obese subjects, insulin secretion is increased to compensate for its reduced action and normoglycemia is maintained (1,2). In obese type 2 diabetes subjects, however, β-cell compensation fails due to marked impairment of glucose-stimulated insulin secretion (GSIS), often with reduced β-cell mass (2). The relationship between β-cell function and mass as causative factors in β-cell failure and diabetes progression is debated, with emphasis on the relevance of “functional β-cell mass” rather than total mass (2). Increased adiposity leads to elevated circulating free fatty acids (FFAs) and triglycerides, and in vitro and in vivo studies have indicated a causative role for dyslipidemia in insulin resistance (1,3). Although FFAs are necessary for the amplification of GSIS, their excess supply may also have a role in β-cell failure (4), as prolonged elevation of FFA levels both in vivo and in vitro cause β-cell dysfunction (5,6) and, at least in vitro, apoptosis (7).At least part of the β-cell compensation to insulin resistance is due to an increase in β-cell mass (4). Either long-term high-fat diet (HFD) (8) or a short-term lipid infusion (9) can result in increased β-cell mass without augmentation of GSIS, indicating that β-cell function and mass are not necessarily linked. Rodent studies have indicated that HFD leads to increased β-cell mass (8), which is also observed in normoglycemic obese individuals (10). Unclear at present is the dynamics between the factors driving compensatory increase in β-cell mass and function and those reducing them through the various stages of type 2 diabetes development, particularly as FFA may do both. Genetic islet susceptibility may be a critical determinant of these dynamics, both in humans and animal models (4,11,12).Even though studies employing genetically modified models (e.g., Zucker Diabetic Fatty rats, db/db mice) have helped in understanding some of these pathological processes (13–16), several of these models are of extreme nature, with rapid development of pronounced type 2 diabetes. These models, therefore, differ from human obesity-linked type 2 diabetes, which usually develops more gradually. In an attempt to gain insight into the basis of β-cell failure in a mild model of diabetes, we recently developed a new model of type 2 diabetes, the 60% pancreatectomized obese hyperlipidemic Zucker Fatty rat (14). In this model, severe β-cell dysfunction was found without any evidence of a falling β-cell mass or islet steatosis (14). More detailed examination of the pancreatectomized Zucker Fatty rat islets showed marked depletion of insulin stores and altered glycerolipid metabolism (14). The Zucker Fatty rat, as opposed to the Zucker Diabetic Fatty rat, however, does not have genetic predisposition to diabetes, as it maintains normoglycemia despite severe obesity-related insulin resistance (4). The diet-induced obese (DIO) C57BL/6 mouse gradually develops hyperglycemia (17). This suggests that DIO islets are unable to fully compensate for the obesity-related insulin resistance, as occurs in human type 2 diabetes.In the present study, we investigated β-cell dysfunction in DIO mice stratified into two groups according to the effect of HFD on body weight: the low responders to HFD (LDR) were less obese, developed intermediate severity of insulin resistance, and had only mild impairment in glycemia. The high responders to HFD (HDR) were more obese, insulin resistant, and hyperinsulinemic and were clearly hyperglycemic. Thus, the LDR and HDR groups allowed for analysis and comparison of islet β-cell mass and function in response to different levels of insulin resistance with corresponding very mild perturbation of glucose homeostasis and overt but mild hyperglycemia, respectively. When extended to obese humans, these two groups correspond to the pre-diabetes and early diabetes situations.     

Intravenous urography in urinary tract surveillance in carcinoma of the bladder.

AIMS: The need for intravenous urography (IVU) in upper tract surveillance for primary transitional cell carcinoma (TCC) of the bladder is contentious. We reviewed our intensive screening policy in the follow-up of these patients to ascertain if such a policy is required and if specific groups could be identified to rationalise this protocol. METHODS: Review of the clinical and radiological data on 174 patients with a diagnosis of primary TCC of the bladder attending a teaching hospital urology department. RESULTS: Eight upper tract 'lesions' were identified: six TCC and two false-positive examinations using IVU. No link was demonstrable between upper tract recurrence and tumour stage, grade or multiplicity at diagnosis. All had recurrent bladder tumour but four of the six upper tract tumours occurred at 72 months or later. Twenty-nine patients over the study period developed either a dilated pelvi-calyceal system or a non-functioning kidney detected on IVU. CONCLUSIONS: Upper tract TCC can present late and patients with early bladder recurrence and those who do not show a reduction in bladder tumour number at follow-up cystoscopy are most at risk. IVU can probably be safely abandoned in those without local recurrence at 24 months. IVU is sensitive but not specific for upper tract tumour but also yields other relevant clinical information concerning the renal tract. Screening for upper tract metachronous disease should therefore be confined to those with recurrent transitional cell carcinoma of the bladder.