Redox reactions are imperative to preserving cellular metabolism yet must be strictly regulated. Imbalances between reactive oxygen species (ROS) and antioxidants can initiate oxidative stress, which ...without proper resolve, can manifest into disease. In type 1 diabetes (T1D), T-cell-mediated autoimmune destruction of pancreatic β-cells is secondary to the primary invasion of macrophages and dendritic cells (DCs) into the islets. Macrophages/DCs, however, are activated by intercellular ROS from resident pancreatic phagocytes and intracellular ROS formed after receptor-ligand interactions via redox-dependent transcription factors such as NF-κB. Activated macrophages/DCs ferry β-cell antigens specifically to pancreatic lymph nodes, where they trigger reactive T cells through synapse formation and secretion of proinflammatory cytokines and more ROS. ROS generation, therefore, is pivotal in formulating both innate and adaptive immune responses accountable for islet cell autoimmunity. The importance of ROS/oxidative stress as well as potential for redox modulation in the context of T1D will be discussed.
Oxidative stress and persistent inflammation are exaggerated through chronic over-nutrition and a sedentary lifestyle, resulting in insulin resistance. In type 2 diabetes (T2D), impaired insulin ...signaling leads to hyperglycemia and long-term complications, including metabolic liver dysfunction, resulting in non-alcoholic fatty liver disease (NAFLD). The manganese metalloporphyrin superoxide dismustase (SOD) mimetic, manganese (III) meso-tetrakis (
-ethylpyridinium-2-yl) porphyrin (MnP), is an oxidoreductase known to scavenge reactive oxygen species (ROS) and decrease pro-inflammatory cytokine production, by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. We hypothesized that targeting oxidative stress-induced inflammation with MnP would assuage liver complications and enhance insulin sensitivity and glucose tolerance in a high-fat diet (HFD)-induced mouse model of T2D. During 12 weeks of feeding, we saw significant improvements in weight, hepatic steatosis, and biomarkers of liver dysfunction with redox modulation by MnP treatment in HFD-fed mice. Additionally, MnP treatment improved insulin sensitivity and glucose tolerance, while reducing serum insulin and leptin levels. We attribute these effects to redox modulation and inhibition of hepatic NF-κB activation, resulting in diminished ROS and pro-inflammatory cytokine production. This study highlights the importance of controlling oxidative stress and secondary inflammation in obesity-mediated insulin resistance and T2D. Our data confirm the role of NF-κB-mediated inflammation in the development of T2D, and demonstrate the efficacy of MnP in preventing the progression to disease by specifically improving liver pathology and hepatic insulin resistance in obesity.
To explore which modifiable lifestyle behaviors contribute to illness intrusiveness in persons with multiple sclerosis (MS).
Cohort study.
Community-based comprehensive MS center.
Adults with MS ...(N=154) who completed an online battery of self-report questionnaires.
Not applicable.
Illness intrusiveness was measured with the 13-item Illness Intrusiveness Ratings Scale. Lifestyle behaviors were measured using the respective components of the Simple Lifestyle Indicator Questionnaire (ie, Diet, Physical Activity, Alcohol, Smoking, and Life Stress) and self-reported body mass index (BMI).
After controlling for age, race, sex, disease duration, and level of physical disability ("disability"), life stress was associated with greater illness intrusiveness (b=4.65, P<.001), and physical activity was associated with less illness intrusiveness (b=-0.67, P=.009). Exploratory mediation analyses revealed physical activity had an indirect effect on illness intrusiveness through disability (b=-0.39, 95% CI: -0.68, -0.16). Conversely, disability also displayed an indirect effect on illness intrusiveness through physical activity (b=0.57, 95% CI: 0.12, 1.16).
Life stress and physical activity are 2 modifiable lifestyle behaviors that contribute to illness intrusiveness, with the latter also having an indirect effect through disability. These findings may help inform future behavioral interventions for improving health-related quality of life in persons with MS.
We discuss design issues related to the extensive use of Enclosed Layout Transistors (ELT's) and guard rings in deep submicron CMOS technologies in order to improve radiation tolerance of ASIC's ...designed for the LHC experiments (the Large Hadron Collider at present under construction at CERN). We present novel aspects related to the use of ELT's: noise measured before and after irradiation up to 100 Mrad (SiO/sub 2/), a model to calculate the W/L ratio and matching properties of these devices. Some conclusions concerning the density and the speed of IC's conceived with this design approach are finally drawn.
Using a new database on Italian wines rated by the Guida dei Vini di Veronelli from 2004 to 2009, we show that the tasters' quality evaluations are affected by two sources of personal bias, namely ...generosity and personal preferences towards certain types of wine characteristics.
Villa Marelli Institute (VMI), Niguarda Ca'Granda Hospital, Milan, Italy.
A recent report on the fatal side effects of isoniazid preventive therapy (IPT) from the United States has re-ignited ...discussion on the safety of this intervention.
To evaluate IPT feasibility, treatment completion and adverse events (AE) and their determinants under field conditions.
Data from consecutive subjects undergoing IPT at the VMI were recorded in an electronic database from 1992 to 2009. Logistic regression analysis was performed to detect completion and AE determinants.
A total of 11,963 patients were included in the study. AE (odds ratio OR 2.70, 95%CI 2.22-3.28) and human immunodeficiency virus positive status (OR 5.20, 95%CI 2.10-12.93) were the main determinants of treatment interruption among Italians, while social weakness (no housing/job; OR 2.88, 95%CI 2.43-3.42), AEs (OR 1.33, 95%CI 1.15-1.53, 2.22-3.28) and screening in undocumented subjects (OR 1.20, 95%CI 1.01-1.44) prevailed among foreigners. Age was the main determinant of transaminase increase (OR 1.03, 95%CI 1.03-1.04), as were AEs of the gastrointestinal (OR 1.02, 95%CI 1.02-1.03), central nervous (OR 1.02, 95%CI 1.02-1.05) and peripheral nervous systems (OR 1.04, 95%CI 1.02-1.05).
This analysis demonstrates the feasibility and safety of IPT, with determinants of interruption and AEs being predictable and addressable.
As a result of less than optimal outcomes the use of islet allografts as a standard insulin replacement therapy is limited to adults with a history of extreme glucose dysregulation and hypoglycemia ...unawareness. In this study, we examined the use of prophylactic immunotherapy to prevent islet allograft rejection in the absence of antirejection drugs. Our protocol to achieve allograft acceptance used a negative vaccination strategy that is comprised of apoptotic donor cells delivered in Incomplete Freund's Adjuvant (IFA) 1 week prior to islet transplantation. The goal of this new protocol is to elicit hyporesponsiveness to alloantigen prior to islet transplantation. First, we examined our protocol without islet allograft transplants and determined that the negative vaccination was not globally immunosuppressive or immunostimulatory. Islet allograft experiments using fully MHC-mismatched islet donors and recipients demonstrated that the negative vaccination strategy induced long-term islet allograft acceptance. Upon rechallenge with alloantigen, the negative vaccination protocol successfully achieved hyporesponsiveness. In addition, the microenvironment at the site of the tolerant allograft revealed a decrease in proinflammatory mediators (IFN-γ, TNF-α) and an increase in the anti-inflammatory mediator IL-10, as well as increased expression of the master regulator of T-regulatory cells, FOXP3. Our data suggest that pretreating allograft recipients with apoptotic donor alloantigen delivered in IFA induced long-term islet allograft acceptance and glycemic control by introducing alloantigen to the recipient immune system in a nonimmunostimulatory manner prior to transplant.
The aim of the study was to assess the effects of varying the pressurisation rate during noninvasive pressure support ventilation on patients' breathing pattern, inspiratory effort, arterial blood ...gases, tolerance to ventilation and amount of air leakage. A total of 15 chronic obstructive pulmonary disease patients recovering from an acute episode of hypercapnic acute respiratory failure were studied during four randomised trials with different levels of pressurisation rate. No significant changes were observed in breathing pattern and arterial blood gases between the different runs. The pressure time product of the diaphragm, an estimate of its metabolic consumption, was significantly lower with all pressurisation rates than with spontaneous breathing, but was significantly lowest with the fastest rate. However, air leak, assessed by the ratio between expired and inspired tidal volumes, increased and the patients' tolerance of ventilation, measured using a standardised scale, was significantly poorer with the fastest pressurisation rate. In chronic obstructive pulmonary disease patients recovering from an episode of acute hypercapnic respiratory failure and ventilated with noninvasive pressure support ventilation, different pressurisation rates resulted in different reductions in the pressure time product of the diaphragm; this reduction was greater with the fastest rate, but was accompanied by significant air leaks and poor tolerance.
Abstract Background Muscle weakness is common and significantly affects persons with multiple sclerosis (PwMS), with dysfunction in upper limb (UL) muscle groups occurring in approximately 60% of ...PwMS. Objective To develop gender‐specific regression‐based prediction equations, with 95% confidence intervals for maximal bilateral UL isometric strength (shoulder abduction and adduction, wrist flexion and extension) and hand grip strength in PwMS. Design Cross‐sectional study. Setting Comprehensive MS center. Participants 256 PwMS. Interventions Not Applicable. Main Outcome Measures Shoulder abduction and adduction and wrist flexion and extension isometric strength (Biodex System 4 Pro Dynamometer) and hand grip strength (Jamar handheld dynamometer) were measured. Disease characteristics (disability and disease duration) and demographics (age, height, and weight) were collected. Regression‐based predictive equations were generated for the UL muscle groups for each gender and limb, using age, height, weight, disability, and disease duration as covariates. Variables were compared between genders using the Mann–Whitney U test. Maximal voluntary contraction (MVC) reference values (mean ± SD) were reported based on age (<30, 30–39, 40–49, 50–59, 60–69 years) and disability (mild, moderate, severe ambulant, and severe nonambulant) for each gender and limb. Results Regression‐based equations were developed for both genders' strongest and weakest limb, accounting for age, height, weight, disability, and disease duration. MVC was higher in men than women ( p < .001) in all muscle groups. Overall, MVC was significantly related to age in 14, height in 5, weight in 6, disability in 14, and disease duration in none of the 20 models. Conclusion This is the first study to provide regression‐based prediction equations for strongest and weakest MVC of UL muscle groups and demonstrated an inverse relationship between MVC with disability and age. Regression‐based reference strength values can help clinicians understand muscular strength along a spectrum of PwMS and can aid in goal setting and education for realistic outcomes.
Cognitive impairment, difficulty performing basic activities of daily living (ADLs) and instrumental ADLs (IADLs), depression, and fatigue are common among individuals with multiple sclerosis (MS). ...Some associations between these symptoms are known; however, many of their relationships remain unclear. This study investigated the contributions of subjective and objective cognition, depressive symptom severity, and fatigue on ADLs and IADLs.
Participants (N = 217) were individuals with MS from a comprehensive MS center, participating in a larger study characterizing upper extremity function in MS. Outcome measures of ADL and IADL abilities were the Functional Status Index-Assistance (FSI-A) and Functional Status Index-Difficulty (FSI-D) and the Test D'évaluation Des Membres Supérieurs de Personnes Âgées (TEMPA). Predictors were objective cognition (Symbol Digit Modalities Test; SDMT), subjective cognition (Performance Scales
-Cognition; PS-C), depressive symptom severity (Center for Epidemiologic Studies Depression Scale; CES-D-10), and fatigue (Modified Fatigue Impact Scale; MFIS-5). Correlations were conducted, followed by hierarchal linear regressions. The SDMT and PS-C were entered into separate models.
After controlling for demographics, the SDMT significantly predicted the TEMPA and FSI-A, while the PS-C predicted only the FSI-D. The CES-D-10 predicted the FSI-D even after accounting for PS-C and SDMT, while the MFIS-5 only predicted the FSI-D when the SDMT was included. Neither the CES-D-10 nor MFIS-5 significantly predicted the FSI-A or TEMPA.
The way an individual with MS perceived their symptoms significantly contributed to their reported difficulty with functional tasks, while only their objective cognitive functioning predicted ADL and IADL performance and the level of assistance they would require.
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