Il-1 beta breaks tolerance through inhibition of regulatory T cell function

IL-1 is a key proinflammatory driver of several autoimmune diseases including juvenile inflammatory arthritis, diseases with mutations in the NALP/cryopyrin complex and Crohn’s disease, and is genetically or clinically associated with many others. IL-1 is a pleiotropic proinflammatory cytokine; however the mechanisms by which increased IL-1 signaling promotes autoreactive T cell activity are not clear. Here we show that autoimmune-prone NOD and IL-1 receptor antagonist-deficient C57BL/6 mice both produce high levels of IL-1, which drives autoreactive effector cell expansion. IL-1beta drives proliferation and cytokine production by CD4+CD25+FoxP3– effector/memory T cells, attenuates CD4+CD25+FoxP3+ regulatory T cell function, and allows escape of CD4+CD25– autoreactive effectors from suppression. Thus, inflammation or constitutive overexpression of IL-1beta in a genetically predisposed host can promote autoreactive effector T cell expansion and function, which attenuates the ability of regulatory T cells to maintain tolerance to self.

Description of a New Model of Intestinal Denervation and In Situ Ischemia-Reperfusion Injury Using the Cecal Artery for Perfusion

Background. The main purpose of the present investigation was to describe a model of intestinal denervation and in situ intestinal ischemia-reperfusion injury in adult rats, with utilization of the distal branch of the superior mesenteric artery close to the cecum for perfusion. Methods. In the root of the mesentery, the mesenteric artery and vein were completely isolated. Close to the cecal valve, a lymphatic node served as the reference point for the localization of the cecal artery, which was cannulated for perfusion with cold lactated Ringer`s solution. One hundred adult male rats were utilized in the study. Results. In a pilot study, we demonstrated that the cold ischemia time was sufficient to promote histopathologic intestinal changes characteristic of ischemia-reperfusion injury. Among 88 operated animals, 62 (70.5%) survived the procedure. Conclusion. The experimental model described herein has the advantage of preserving the entire intestine, which makes it more suitable for studies of physiological and morphological alterations after intestinal transplantation.

Long-Term Pharmacotherapy for Obesity in Elderly Patients A Retrospective Evaluation of Medical Records from a Specialized Obesity Outpatient Clinic

Background: Obesity is a serious chronic disease and the prevalence of this condition is increasing among the elderly. Although the benefits of weight loss to improve control of associated diseases are well known in young adults, they are not in older patients. The use of anti-obesity drugs to promote weight loss is widespread in Brazil and other countries, and obesity specialists frequently prescribe medicines in doses and for durations previously unreported in the literature. Sibutramine, orlistat and amfepramone (diethylpropion) have been evaluated in clinical trials of more than 2 years` duration in adults, demonstrating safety and efficacy, but long-term studies in obesity treatment are absent for other drugs. The efficacy and safety of obesity pharmacotherapy among the elderly is unknown. Objective: To describe the experience of obesity pharmacotherapy in the elderly in a specialized obesity care setting in Brazil, with a focus on efficacy and safety. Methods: A retrospective evaluation was conducted on medical charts from an outpatient clinic of a specialized tertiary centre for the treatment of obesity. We included patients who had had at least one consultation between January and December 2007, were aged >= 60 years at the beginning of the treatment, had had at least 6 months of follow-up and had received a prescription of at least one potential weight-loss drug. Diagnoses reported on medical records were documented. Age, weight, height and body mass index (BMI) were recorded at admission, after 6, 12, 18 and 24 months, and at the last available visit. The medicines prescribed, together with the dose, duration of use, adverse effects and reasons for discontinuation, were documented. Results: The group consisted of 44 women (86%) and 7 men (14%), with a mean +/- SD age of 65.2 +/- 4.5 years, weight of 95.3 +/- 12.5 kg and BMI of 38.5 +/- 4.3 kg/m(2). The mean +/- SD time of follow-up was 39.3 +/- 26.4 months, and the mean weight loss was 6.65 kg (p < 0.01). After the first 6 months, the mean +/- SD weight loss was 5.7 +/- 3.8 kg (p < 0.0001). A smaller weight loss was seen between the 6th and 12th months, with no statistically significant change in weight thereafter. A weight loss of >= 5% was achieved by 64.71%, 63.64%, 62.16% and 69.70% in the 6th, 12th, 18th and 24th months, respectively, and a weight loss of >= 10% was achieved by 17.65%, 34.09%, 32.43% and 39.39% in the 6th, 12th, 18th and 24th months, respectively. The medicines prescribed were sibutramine, orlistat, fluoxetine, sertraline, topiramate, fenproporex, mazindol and amfepramone, alone or in combinations, concomitantly or sequentially. The reasons for discontinuation were lack of response (n = 13), loss of response (development of tolerance) [n= 11], lack of adherence (n = 14) and adverse effects (n= 14). One episode of atrial flutter occurred in a patient taking fenproporex. The weight-loss medications were generally well tolerated, and only transient adverse events were reported. Conclusions: Long-term pharmacotherapy for obesity was effective and well tolerated by this group of elderly patients.

Acute Toxic Leukoencephalopathy: Potential for Reversibility Clinically and on MRI With Diffusion-Weighted and FLAIR Imaging

OBJECTIVE. Toxic leukoencephalopathy may present acutely or subacutely with symmetrically reduced diffusion in the periventricular and supraventricular white matter, hereafter referred to as periventricular white matter. This entity may reverse both on imaging and clinically. However, a gathering together of the heterogeneous causes of this disorder as seen on MRI with diffusion-weighted imaging (DWI) and an analysis of their likelihood to reverse has not yet been performed. Our goals were to gather causes of acute or subacute toxic leukoencephalopathy that can present with reduced diffusion of periventricular white matter in order to promote recognition of this entity, to evaluate whether DWI with apparent diffusion coefficient (ADC) values can predict the extent of chronic FLAIR abnormality ( imaging reversibility), and to evaluate whether DWI can predict the clinical outcome ( clinical reversibility). MATERIALS AND METHODS. Two neuroradiologists retrospectively reviewed the MRI examinations of 39 patients with acute symptoms and reduced diffusion of periventricular white matter. The reviewers then scored the extent of abnormality on DWI and FLAIR. ADC ratios of affected white matter versus the unaffected periventricular white matter were obtained. Each patient`s clinical records were reviewed to determine the cause and clinical outcome. Histology findings were available in three patients. Correlations were calculated between the initial MRI markers and both the clinical course and the follow-up extent on FLAIR using Spearman`s correlation coefficient. RESULTS. Of the initial 39 patients, seven were excluded because of a nontoxic cause (hypoxic-ischemic encephalopathy [HIE] or congenital genetic disorders) or because of technical errors. In the remaining 32 patients, no correlation was noted between any of the initial MRI markers (percentage of ADC reduction, DWI extent, or FLAIR extent) with the clinical outcome. Three patients had histologic correlation. However, moderate correlation was seen between the extent of abnormality on initial FLAIR and the extent on follow-up FLAIR (r = 0.441, p = 0.047). Of the 13 patients who underwent repeat MRI at 21 days or longer, the reduced diffusion resolved in all but one. Significant differences were noted between ADC values in affected white matter versus unaffected periventricular white matter on initial (p < 0.0001) but not on follow-up MRI (p = 0.13), and in affected white matter on initial versus follow-up (p = 0.0014) in those individuals who underwent repeat imaging on the same magnet (n = 9), confirming resolution of the DWI abnormalities. CONCLUSION. Acute toxic leukoencephalopathy with reduced diffusion may be clinically reversible and radiologically reversible on DWI, and may also be reversible, but to a lesser degree, on FLAIR MRI. None of the imaging markers measured in this study appears to correlate with clinical outcome, which underscores the necessity for prompt recognition of this entity. Alerting the clinician to this potentially reversible syndrome can facilitate treatment and removal of the offending agent in the early stages.

Promoting physical activity to older adults: a preliminary evaluation of three general practice-based strategies

The aim of this study was to explore the feasibility of an exercise scientist (ES) working in general practice to promote physical activity (PA) to 55 to 70 year old adults. Participants were randomised into one of three groups: either brief verbal and written advice from a general practitioner (GP) (G1, N=9); or individualised counselling and follow-up telephone calls from an ES, either with (G3, N=8) or without a pedometer (G2, N=11). PA levels were assessed at week 1, after the 12-wk intervention and again at 24 weeks. After the 12-wk intervention, the average increase in PA was 116 (SD=237) min/wk; N=28, p < 0.001. Although there were no statistically significant between-group differences, the average increases in PA among G2 and G3 participants were 195 (SD=207) and 138 (SD=315) min/wk respectively, compared with no change (0.36, SD=157) in G1. After 24 weeks, average PA levels remained 56 (SD=129) min/wk higher than in week 1. The small numbers of participants in this feasibility study limit the power to detect significant differences between groups, but it would appear that individualised counselling and follow-up contact from an ES, with or without a pedometer, can result in substantial changes in PA levels. A larger study is now planned to confirm these findings.

IL-1 beta breaks tolerance through expansion of CD25(+) effector T cells

IL-1 is a key proinflammatory driver of several autoimmune diseases including juvenile inflammatory arthritis, diseases with mutations in the NALP/cryopyrin complex and Crohn's disease, and is genetically or clinically associated with many others. IL-1 is a pleiotropic proinflammatory cytokine; however the mechanisms by which increased IL-1 signaling promotes autoreactive T cell activity are not clear. Here we show that autoimmune-prone NOD and IL-1 receptor antagonist-deficient C57BL/6 mice both produce high levels of IL-1, which drives autoreactive effector cell expansion. IL-1 beta drives proliferation and cytokine production by CD4(+)CD25(+)FoxP3(-) effector/memory T cells, attenuates CD4(+)CD25(+)FoxP3(+) regulatory T cell function, and allows escape of CD4(+)CD25(-) autoreactive effectors from suppression. Thus, inflammation or constitutive overexpression of IL-1 beta in a genetically predisposed host can promote autoreactive effector T cell expansion and function, which attenuates the ability of regulatory T cells to maintain tolerance to self.

Effect of the immunosuppressants on hepatocyte cells proliferation and apoptosis during liver regeneration after hepatectomy - molecular studies

The regeneration and remodeling of the transplanted liver is the result of hepatocyte proliferation and apoptosis (programmed cell death). The purpose of this study was to verify the influence of immunosuppressants on the expression levels of genes: IL-6 (regulator of hepatocyte proliferation), pro-apoptotic (Bak and Bax) and anti-apoptotic (Bcl-Xl and Bcl-2). 36 newborn suckling rats (age 5-7 days, weight 6-10 g) were divided into four groups: hepatectomy, hepatectomy plus methylprednisolone, hepatectomy plus CsA and hepatectomy plus Tac. The same experiments were performed in 24 weaning rats (age 21-23 days, weight 30-50 g). The animals were killed one day after the hepatectomy and the remnant livers were analyzed. The livers of all animals exhibited histological changes of liver regeneration. The immunosuppressants did not promote any alteration on IL-6 gene expression levels. Methylprednisolone and CsA increased the expression levels of Bak gene in newborn rats. However, methylprednisolone and Tac promoted increased expression levels of Bcl-2 in all groups. We hypothesize that these effects explain the efficacy of these drugs on the treatment of acute and chronic liver rejection as the expression of Bcl-2 in cholangiocytes is decreased as a consequence of bile duct lesions.

Nutrition-related habits and associated factors of Brazilian adolescents

To investigate the nutrition-related habits (NRH) of Brazilian adolescents and evaluate the associations with risk factors. Cross-sectional school-based was carried out among high school adolescents aged 14-18 years (n = 1,759) from public and private schools from two cities. The NRH were investigated by the weekly consumption of vegetables, fruit, sweet food and fried food. Risk factors investigated were: city, sex, age, socioeconomic status and nutritional status. In statistics, Poisson regression was used with robust variance adjustment. Data indicated low consumption of fruits and vegetables, 70.0 and 71.0%, respectively, and high consumption of sweets and fried food, 66.7 and 63%, respectively. Boys showed risk of inadequate intake of vegetables [prevalence ratios (PR) 1.10, 95% CI 1.01-1.16] and fruit (PR 1.09, 95% CI 1.01-1.16). Furthermore, adolescents who live in Maringa had greater likelihood of consuming vegetables and fruit (20 and 25%, respectively). However, they presented risk of inadequate consumption of sweets (PR 1.19, 95% CI 1.11-1.28) for adolescents who live in Presidente Prudente. We concluded that inadequate NRH show high prevalence among adolescents and indicate the need to employ educational strategies that promote the adoption of more healthy habits and behaviors.

Early Changes in Postprandial Gallbladder Emptying in Morbidly Obese Patients Undergoing Roux-en-Y Gastric Bypass: Correlation with the Occurrence of Biliary Sludge and Gallstones

Gallstones have been frequently diagnosed after Roux-en-Y gastric bypass (RYGBP). Gallbladder stasis associated with duodenal exclusion may play a role in their pathogenesis. Gallbladder emptying was studied before and on the 30th and 31st postoperative days (POD) after RYGBP in 20 morbidly obese patients. Gallbladder volume after fasting and every 15 min during a 2-h period following administration of a standard liquid meal was determined by sonography. On the 31st POD, the meal was administered through the gastrostomy in order to promote its transit through the duodenum. Fasting volume (FV), maximum ejection fraction (Max EF), and residual volume (RV) were determined. Biliary sludge and calculi were investigated after 1 and 6 months, respectively. FV was 39.4 +/- 20.2 ml, 50.1 +/- 22.7 ml, and 47.9 +/- 23.4 ml, respectively, for the preoperative and two postoperative assessments (P = 0.09). RV was 7.6 +/- 8.7 ml, 25.1 +/- 20.0 ml, and 24.6 +/- 20.9 ml; and Max EF was 80.5 +/- 20.9%, 54.3 +/- 21.4%, and 50.5 +/- 29.0%, respectively, for the pre-, postoral, and postgastrostomy infusion measurements. There was only a significant difference between the preoperative value and the two postoperative values (P < 0.001). Biliary sludge was detected in 65% of the patients and 46% of them subsequently developed gallstones. Gallbladder emptying became significantly compromised after RYGBP. This impairment was unrelated to duodenal exclusion but it was associated with biliary sludge and stone formation.

Induction of Indoleamine 2,3-Dioxygenase by Gene Delivery in Allogeneic Islets Prolongs Allograft Survival

Indoleamine 2,3-dioxygenase (IDO), an enzyme that plays a critical role in fetomaternal tolerance, exerts immunoregulatory functions suppressing T-cell responses. The aims of this study were to promote IDO expression in rat islets using a nonviral gene transfer approach, and to analyze the effect of the in vivo induction of IDO in a model of allogeneic islet transplantation. The IDO cDNA was isolated from rat placenta, subcloned into a plasmid and transfected into rat islets using Lipofectamine. The efficiency of transfection was confirmed by qRT-PCR and functional analysis. The in vivo effect of IDO expression was analyzed in streptozotocin-induced diabetic Lewis rats transplanted with allogeneic islets under the renal capsule. Transplantation of IDO-allogeneic islets reversed diabetes and maintained metabolic control, in contrast to transplantation of allogeneic nontransfected islets, which failed shortly after transplantation in all animals. Graft survival of allograft islets transfected with IDO transplanted without any immunosuppression was superior to that observed in diabetic rats receiving nontransfected islets. These data demonstrated that IDO expression induced in islets by lipofection improved metabolic control of streptozotocin-diabetic rats and prolonged allograft survival.

Myelin proteolipid protein expressed in COS-1 cells is targeted to actin-associated surfaces

The compact myelin sheath represents one of the largest expanses of membrane-membrane contact in the body and, in the central nervous system, requires the myelin proteolipid protein (PLP) for assembly, To determine whether the molecular properties of PLP promote membrane adhesion and direct its subcellular localization in the absence of oligodendrocyte-specific targeting mechanisms, PLP was expressed in COS-I fibroblasts, Immunofluorescence staining indicated that PUP was translated effectively, transited the rough endoplasmic reticulum and Golgi apparatus, was delivered to the cell surface, and was endocytosed, In the plasma membrane, the PLP distribution was patchy and only sporadically coincided with sites of membrane-membrane contact between PLP-expressing cells, PLP was not randomly distributed, however, but correlated closely with microfilament locations in leading edge membranes and microvilli, as demonstrated by phalloidin double labeling, Our results indicate that even in non-myelinating cells, PLP can be concentrated in membranes associated with movement and growth, and suggest possible roles for the actin cytoskeleton in PLP localization, As PLP, DM20, and the DM20-like M6 protein all associate with actin-enriched membranes, this may be a common feature of PLP/DM20 gene family members. (C) 1997 Wiley-Liss, Inc.

Hemodynamic response in one session of strength exercise with and without electrostimulation in heart failure patients: A randomized controlled trial

Background: Studies have investigated the influence of neuromuscular electrostimulation on the exercise/muscle capacity of patients with heart failure (HF), but the hemodynamic overload has never been investigated. The aim of our study was to evaluate the heart rate (HR), systolic and diastolic blood pressures in one session of strength exercises with and without neuromuscular electrostimulation (quadriceps) in HF patients and in healthy subjects. Methods: Ten (50% male) HF patients and healthy subjects performed three sets of eight repetitions with and without neuromuscular electrostimulation randomly, with one week between sessions. Throughout, electromyography was performed to guarantee the electrostimulation was effective. The hemodynamic variables were measured at rest, again immediately after the end of each set of exercises, and during the recovery period. Results: Systolic and diastolic blood pressures did not change during each set of exercises among either the HF patients or the controls. Without electrostimulation: among the controls, the HR corresponding to the first (85 +/- 13 bpm, p = 0.002), second (84 +/- 10 bpm, p < 0.001), third (89 +/- 17, p < 0.001) sets and recuperation (83 +/- 16 bpm, p = 0.012) were different compared to the resting HR (77 bpm). Moreover, the recuperation was different to the third set (0.018). Among HF patients, the HR corresponding to the first (84 +/- 9 bpm, p = 0.041) and third (84 +/- 10 bpm, p = 0.036) sets were different compared to the resting HR (80 +/- 7 bpm), but this increase of 4 bpm is clinically irrelevant to HF. With electrostimulation: among the controls, the HR corresponding to the third set (84 +/- 9 bpm) was different compared to the resting HR (80 +/- 7 bmp, p = 0.016). Among HF patients, there were no statistical differences between the sets. The procedure was well tolerated and no subjects reported muscle pain after 24 hours. Conclusions: One session of strength exercises with and without neuromuscular electrostimulation does not promote a hemodynamic overload in HF patients. (Cardiol J 2011; 18,1: 39-46)

Is alcohol a cofactor of HIV and AIDS? Evidence from immunological and behavioral studies

The authors aim to critically examine empirical research on the effects of alcohol on HIV and AIDS from the immunological and behavioral fields. In vitro immunological studies demonstrate that social drinking increases the susceptibility of human cells to HIV infection. Animal studies show that acute and chronic alcohol ingestion increases rare of progression from retrovirus to clinical illness. In humans with HIV, no experimental evidence shows that alcohol is a cofactor of AIDS. Findings from behavioral studies show that a link between social drinking and risk of HIV is weak. No experimental evidence demonstrates that chronic drinking influences rate and course of disease progression to AIDS in humans who are HIV+. It is premature to promote the role of alcohol as a cofactor in HIV and AIDS.

NFAT1 transcription factor is central in the regulation of tissue microenvironment for tumor metastasis

Members of the nuclear factor of activated T cell (NFAT) family of transcription factors were originally described in T lymphocytes but later shown to be expressed in several immune and non-immune cell types. NFAT proteins can modulate cellular transformation intrinsically, and NFAT-deficient (NFAT1-/-) mice are indeed more susceptible to transformation than wild-type counterparts. However, the contribution of an NFAT1-/- microenvironment to tumor progression has not been studied. We have addressed this question by inoculating NFAT1-/- mice with B16F10 melanoma cells intravenously, an established model of tumor homing and growth. Surprisingly, NFAT1-/- animals sustained less tumor growth in the lungs after melanoma inoculation than wild-type counterparts. Even though melanoma cells equally colonize NFAT1-/- and wild-type lungs, tumors do not progress in the absence of NFAT1 expression. A massive mononuclear perivascular infiltrate and reduced expression of TGF-beta in the absence of NFAT1 suggested a role for tumor-infiltrating immune cells and the cytokine milieu. However, these processes are independent of an IL-4-induced regulatory tumor microenvironment, since lack of this cytokine does not alter the phenotype in NFAT1-/- animals. Bone marrow chimera experiments meant to differentiate the contributions of stromal and infiltrating cells to tumor progression demonstrated that NFAT1-induced susceptibility to pulmonary tumor growth depends on NFAT1-expressing parenchyma rather than on bone marrow-derived cells. These results suggest an important role for NFAT1 in radio-resistant tumor-associated parenchyma, which is independent of the anti-tumor immune response and Th1 versus Th2 cytokine milieu established by the cancer cells, but able to promote site-specific tumor growth.

Short-term specialized enteral diet fails to attenuate malnutrition impairment of experimental open wound acute healing

Objective: We assessed the effect of enteral refeeding on the morphology, gene expression, and contraction of acute open wounds in previously malnourished rats using two different enteral diets. Methods: Adult male isogenic Lewis rats divided into two groups (eutrophic, n = 30; and previously malnourished, 12-15% body weight loss, n = 27) were subjected to cutaneous dorsal wounds and gastrostomy. Control rats received a standard oral diet (AIN-93M chow) plus enteral saline solution. Subject rats received chow plus a standard enteral diet or an enteral diet enriched with arginine and antioxidants. On post-trauma days 7 and 14, wound granulation tissue samples were collected for morphologic analysis using hematoxylin and eosin and picrosirius stain or immunohistochemistry slides and real-time polymerase chain reaction for collagen I and III gene expression. Wound contraction was also evaluated by comparing wound images from days 0,7, and 14. Results: Malnourished control rats had increased intensity and duration of wound inflammation, impaired increase of fibroblast cells contingent on post-trauma days 7 to 14, decreased expression of collagen III, and less wound contraction compared with eutrophic control rats. A specialized enteral diet did not improve wound healing of malnourished rats but did promote wound contraction at post-trauma day 7 in eutrophic rats. Conclusion: Short-term enteral refeeding, even with a specialized diet, failed to protect previously wounded malnourished rats from a prolonged inflammatory phase and impaired healing. (C) 2010 Elsevier Inc. All rights reserved.