Probiotics and ileitis: Could augmentation of TNF/NFκB activity be the answer?

Probiotics have gained tremendous popularity amongst individuals searching for alternative and "natural" means to promote intestinal health. It has been suggested that the probiotic formulation VSL#3 promotes several aspects of intestinal health including attenuation of inflammatory bowel diseases (IBD). Although a definitive mechanism of action has not been clearly identified, it is generally accepted that probiotics suppress development of chronic inflammation by inhibiting activation of various inflammatory signaling pathways. This concept however needs to be revisited in light of a recent publication by Pagnini et al. showing that VSL#3 prevents development of ileitis through activation of NFκB and production of the prototypical inflammatory cytokine TNFα.     

IκBα polymorphism at promoter region (rs2233408) influences the susceptibility of gastric cancer in Chinese

Background  

Nuclear factor of kappa B inhibitor alpha (IκBα) protein is implicated in regulating a variety of cellular process from inflammation to tumorigenesis. The objective of this study was to investigate the susceptibility of rs2233408 T/C genotype in the promoter region of IκBα to gastric cancer and the association of this polymorphism with clinicopathologic variables in gastric cancer patients.     

Hepatitis B and the infected health care worker: Public safety at what cost?

Public safety and the right of the health care worker to practise without prejudice based on underlying illness may be at odds for those affected by the hepatitis B virus (HBV). Nevertheless, HBV does not preclude entry into a health care profession, and the risk of transmission from health care worker to patient is not uniform across the spectrum of health care fields. In the present article, the authors present an overview of the literature regarding transmission of HBV from the health care worker to the patient, and the current recommendations that vary from province to province within Canada. The establishment of national guidelines to standardize monitoring of HBV infection among health care workers would improve health care workplace safety and patient care.     

GLUT2 protein at the rat proximal tubule brush border membrane correlates with protein kinase C (PKC)-βl and plasma glucose concentration

Aims/hypothesis GLUT2 is the main renal glucose transporter upregulated by hyperglycaemia, when it becomes detectable at the brush border membrane (BBM). Since glucose-induced protein kinase C (PKC) activation in the kidney is linked to diabetic nephropathy, we investigated the effect of glycaemic status on the protein levels of PKC isoforms α, βI, βII, δ and ɛ in the proximal tubule, as well as the relationship between them and changes in GLUT2 production at the BBM. Methods Plasma glucose concentrations were modulated in rats by treatment with nicotinamide 15 min prior to induction of diabetes with streptozotocin. Levels of GLUT2 protein and PKC isoforms in BBM were measured by western blotting. Additionally, the role of calcium signalling and PKC activation on facilitative glucose transport was examined by measuring glucose uptake in BBM vesicles prepared from proximal tubules that had been incubated either with thapsigargin, which increases cytosolic calcium, or with the PKC activator phorbol 12-myristate,13-acetate (PMA). Results Thapsigargin and PMA enhanced GLUT-mediated glucose uptake, but had no effect on sodium-dependent glucose transport. Diabetes significantly increased the protein levels of GLUT2 and PKC-βI at the BBM. Levels of GLUT2 and PKC-βI correlated positively with plasma glucose concentration. Diabetes had no effect on BBM levels of α, βII, δ or ɛ isoforms of PKC. Conclusions/interpretation Enhanced GLUT2-mediated glucose transport across the proximal tubule BBM during diabetic hyperglycaemia is closely associated with increased PKC-βI. Thus, altered levels of GLUT2 and PKC-βI proteins in the BBM may be important factors in the pathogenic processes underlying diabetic renal injury. A. K. Goestemeyer and J. Marks contributed equally to the study.     

Could stent design affect platelet activation? Results of the Platelet Activation in STenting (PAST) Study

Platelet activation induced by coronary artery stenting may be related to stent design. In a prospective, randomized pilot study of 54 elective patients, platelet activation was analyzed before and at 2 hours, 24 hours, 5 days and 30 days post-implantation of either a closed-cell (NIR) or open-cell (TETRA) stent. Platelet activation was less following NIR implantation as indicated by reduced aggregation to 5 mol adenosine diphosphate at 30 days (32.3 6.1% versus 94.5 18.9%; p = 0.02) and reduced expression of multiple surface markers (log mean fluorescence intensity): at 2 hours, CD 107a (22 13 versus 18 5; p = 0.045); at 24 hours, CD 31 (136 48 versus 110 48; p = 0.04), CD 151 (104 45 versus 91 31; p = 0.048), platelet leukocyte aggregates (95 40 versus 77 24; p = 0.018), and CD 107a (24 12 versus 17 4; p = 0.03); and at 30 days, CD 151 (99 33 versus 81 32; p = 0.03), platelet leukocyte aggregates (84 35 versus 72 31; p = 0.045) and PAC-1 (88 91 versus 72 30; p = 0.025). Ex vivo studies in explanted swine hearts revealed that the NIR stent produced less intimal prolapse and thus a smoother stent-vessel wall interface than the TETRA stent. In this pilot study, platelet activation was greater during the 30 days following implantation of an open-cell versus a closed-cell stent. This finding may be related to superior scaffolding, resulting in a smoother luminal contour after implantation of a closed-cell stent.     

Mycophenolate mofetil (MMF): firing at the atherosclerotic plaque from different angles?

Atherosclerosis is characterized by a persistent, low-grade inflammatory state in which immune cell activation is inseparably linked to plaque formation and destabilization. The T-lymphocyte in particular has emerged as a pivotal player throughout the course of atherogenesis. As a consequence, the concept that immune modulation is a suitable target for cardiovascular prevention is currently an important focus of research. Mycophenolate mofetil (MMF) has emerged as a non-competitive inhibitor of inosine monophosphate dehydrogenase (IMPDH) that exerts cytostatic effects, particularly on proliferating T-lymphocytes. In addition, MMF has other immune-modulating effects, such as downregulation of the expression of adhesion molecules and attenuation of monocyte and macrophage responses. Given the added benefit that MMF is well tolerated, this immunosuppressive agent constitutes an attractive candidate for the modulation of inflammatory activation in atherogenesis. The present review provides an overview of the potential anti-atherogenic properties of MMF.     

Does sodium hyaluronate- and carboxymethylcellulose-based bioresorbable membrane (Seprafilm) decrease operative time for loop ileostomy closure?

Background

Adhesions can result in serious clinical complications and make ileostomy closure, which is relatively simple procedure into a complicated and prolonged one. The use of sodium hyaluronate and carboxymethyl cellulose membrane (Seprafilm®) was proven to significantly reduce the postoperative adhesions at the site of application. The aim of this study was to assess the incidence and severity of adhesions around a loop ileostomy and to analyze the lenght of time and morbidity for mobilization at the time of ileostomy closure with and without the use of Seprafilm.

Methods

Twenty-nine surgeons from 15 institutions participated in this multicenter prospective randomized study. 191 patients with loop ileostomy construction were randomly assigned to either receive Seprafilm under the midline incision and around the stoma (Group I), only under the midline incision (Group II), or not to receive Seprafilm (Group III). At ileostomy closure, adhesions were quantified and graded; operative morbidity was also measured.

Results

All 3 groups were comparable relative to gender, mean age and number of patients with prior operations (26, 25 and 19, respectively). Group II patients were significantly more likely to have pre-existing adhesions than Group III patients (30.6% vs. 14.1%, p=0.025). At stoma mobilization, significantly more patients in Group III than in Group I had adhesions around the stoma (95.2% vs. 82.3%, p=0.021). Mean operative times were 27, 25, and 28 minutes, respectively (p=0.38), with significant differences among sites. There was no significant difference in the number of patients needing myotomy or enterotomy (29, 27 and 24 patients, respectively), nor in the number of postoperative complications (7, 9 and 7 patients, respectively).

Conclusions

When consistently applied, Seprafilm significantly decreased adhesion formation around the stoma but not operative times without any increase in the need for myotomy or enterotomy. These findings were not seen in the overall study population possibly due to the large number of surgeons using a variety of application techniques.     

Vitamin B(12) deficiency and incontinence: is there an association?

BACKGROUND: This study investigated the relationship between B(12) (cobalamin) levels and incontinence in older outpatients using secondary data analysis. METHODS: Between 1991 and 1999, there were 929 patients (258 men and 671 women) for whom urinary incontinence (UI), fecal incontinence (FI), and B(12) were prospectively recorded. Covariates included race, gender, age, medications, Mini-Mental State Examination, modified illness rating, and instrumental activities of daily living (IADLs). RESULTS: Some form of incontinence (UI or FI or both) was found in 41% of subjects, isolated UI in 34%, double incontinence (DI) in 12%, and isolated FI in 4%. Having UI increased the risk of also having FI (p <.0001). Serum B(12) levels of 300 pg/ml or less were not predictive of isolated UI or isolated FI. However, in logistic regression, DI was predicted by B(12) (odds ratio [OR] = 2.113, p =.0094), IADLs (OR = 0.810, p <.0001), cathartics/laxative use (OR = 1.902, p =.126), and diuretic use (OR = 2.226, p =.006). Considering isolated UI in women, higher IADLs reduced risk of UI (OR = 0.956, p =.002), while diuretics (OR = 1.481, p =.041) and antihistamines (OR = 1.909, p =.046) both increased risk of UI. In men, only use of anticonvulsant medications (OR = 4.529, p =.023) increased risk of isolated UI. Greater physical illness in both genders increased risk of isolated FI (OR = 1.204, p =.006). CONCLUSIONS: These findings suggest that serum B(12) at levels of 300 pg/ml or less are not associated with isolated UI or isolated FI but may play a role in DI. A possible association of low B(12) levels with DI is intriguing because of the implications for treatment and prevention. More immediately, medication side effects should be considered when evaluating this problem.     

Does reduced membrane lipid fluidity underlie the altered thrombin-induced expression of integrin α(IIb)β(3) and PADGEM-140 in membranes of platelets from diabetic juveniles?

In diabetic patients, where the membrane lipid microviscosity of blood platelets is altered, the availability of platelet membrane receptors may change concomitantly. Platelet hypersensitivity in diabetic subjects was previously hypothesized to result from the nonenzymatic glycosylation-induced loss in platelet membrane fluidity. In our present study juvenile type 1 diabetic subjects were compared with their relevant controls with respect to thrombin-stimulated platelet activation in relation to glycation-induced impairments of platelet membrane dynamics. Our results indicate that: (a) the mean steady-state fluorescence polarization (p) of both 1,6-diphenyl-1,3,5-hexatriene (DPH) and 1-anilino-8-naphthalenesulphonate (ANS) in membranes from diabetic subjects were significantly greater than for control subjects, thus indicating reduced membrane lipid fluidity in diabetic platelets in various membrane regions; (b) the significantly higher [(3)H]NaBH(4) reduction, indicating the increased attachment of glucose to protein amino groups, was attributed to the proteins extracted from diabetic platelet membranes; (c) CD62-positive resting platelets were not significantly more abundant in diabetic patients; (d) basically, unaltered amounts of PADGEM-140 membrane antigen (CD62) copies were detected in resting diabetic platelets; (e) significantly higher numbers of membrane glycoprotein β(3) were found in diabetic platelets; (f) thrombin-induced elevations in the expression of CD61 (β(3)) and CD62 (PADGEM-140) occurred to much higher extent in platelets of diabetic patients, thus pointing to more profound activation of diabetic platelets by thrombin; (g) the total amounts of platelet membrane glycoprotein β(3) was significantly reduced in platelet lysates from diabetic subjects. We conclude that glycation-induced rigidization of platelet membranes might hypersensitize diabetic platelets to aggregating agents by rendering platelet membrane receptors more exposed to the external environment. Thus, thrombin may bind more efficiently to the exposed glycoprotein receptors (due to glycation) in diabetic platelets. Such excessive exposure and displacements toward the external environment might favour the accelerated shedding of some membrane proteins in diabetic platelets. We further suggest that their subsequent replacements would render platelet intrinsic storage pools exhausted and thus, might explain the diminished total amount of β(3) found in platelets of diabetic patients.     

What is the efficiency of ATP signaling from erythrocytes to regulate distribution of O(2) supply within the microvasculature?

Erythrocytes appear to be ideal sensors for regulating microvascular O(2) supply as they release the potent vasodilator ATP in an O(2) saturation-dependent manner. Whether erythrocytes play a significant role in regulating O(2) supply in the complex environment of diffusional O(2) exchange among capillaries, arterioles, and venules, depends on the efficiency with which erythrocytes signal the vascular endothelium. If one assumes that the distribution of purinergic receptors is uniform throughout the microvasculature, then the most efficient site for signaling should occur in capillaries, where the erythrocyte membrane is in close proximity to the endothelium. ATP released from erythrocytes would diffuse a short distance to P(2y) receptors inducing an increase in blood flow, possibly the result of endothelial hyperpolarization. We hypothesize that this hyperpolarization varies across the capillary bed depending upon erythrocyte supply rate and the flux of O(2) from these erythrocytes to support O(2) metabolism. This would suggest that the capillary bed would be the most effective site for erythrocytes to communicate tissue oxygen needs. Electrically coupled endothelial cells conduct the integrated signal upstream where arterioles adjust vascular resistance, thus enabling ATP released from erythrocytes to regulate the magnitude and distribution of O(2) supply to individual capillary networks.     

Fatty acids acutely enhance insulin-induced oxidative stress and cause insulin resistance by increasing mitochondrial reactive oxygen species (ROS) generation and nuclear factor-κB inhibitor (IκB)–nuclear factor-κB (NFκB) activation in rat muscle,in the absence of mitochondrial dysfunction

Aims/hypothesis  

Insulin effects reportedly involve reactive oxygen species (ROS) and oxidative stress in vitro, but skeletal muscle oxidative stress is an emerging negative regulator of insulin action following high-fat feeding. NEFA may enhance oxidative stress and insulin resistance. We investigated the acute impact of insulin with or without NEFA elevation on muscle ROS generation and insulin signalling, and the potential association with altered muscle mitochondrial function.     

Combining Antiplatelet and Antithrombotic Therapy (Triple Therapy): What Are the Risks and Benefits?

Most patients with mechanical heart valves and many patients with atrial fibrillation will require long-term anticoagulation therapy. For patients with mechanical prosthetic valves, only warfarin is indicated. However, for patients with nonvalvular atrial fibrillation who are at increased risk for embolic stroke, one of the newer antithrombotic medications, such as rivaroxaban, dabigatran, and apixaban, also can be used. Patients with indications for antithrombotic therapy often will have coexisting vascular disease, such as coronary artery disease, requiring concomitant antiplatelet therapy with aspirin alone or more commonly with a dual antiplatelet regimen, aspirin and clopidogrel, or prasugrel or ticagrelor. The risks and benefits of this approach are still not well defined, and current guidelines have included recommendations based primarily on expert opinion.