The Bypass Angioplasty Revascularization Investigation 2 Diabetes Randomized Trial of Different Treatment Strategies in Type 2 Diabetes Mellitus With Stable Ischemic Heart Disease Impact of Treatment Strategy on Cardiac Mortality and Myocardial Infarction

Background-The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial in 2368 patients with stable ischemic heart disease assigned before randomization to percutaneous coronary intervention or coronary artery bypass grafting strata reported similar 5-year all-cause mortality rates with insulin sensitization versus insulin provision therapy and with a strategy of prompt initial coronary revascularization and intensive medical therapy or intensive medical therapy alone with revascularization reserved for clinical indication(s). In this report, we examine the predefined secondary end points of cardiac death and myocardial infarction (MI). Methods and Results-Outcome data were analyzed by intention to treat; the Kaplan-Meier method was used to assess 5-year event rates. Nominal P values are presented. During an average 5.3-year follow-up, there were 316 deaths (43% were attributed to cardiac causes) and 279 first MI events. Five-year cardiac mortality did not differ between revascularization plus intensive medical therapy (5.9%) and intensive medical therapy alone groups (5.7%; P = 0.38) or between insulin sensitization (5.7%) and insulin provision therapy (6%; P = 0.76). In the coronary artery bypass grafting stratum (n = 763), MI events were significantly less frequent in revascularization plus intensive medical therapy versus intensive medical therapy alone groups (10.0% versus 17.6%; P = 0.003), and the composite end points of all-cause death or MI (21.1% versus 29.2%; P = 0.010) and cardiac death or MI (P = 0.03) were also less frequent. Reduction in MI (P = 0.001) and cardiac death/MI (P = 0.002) was significant only in the insulin sensitization group. Conclusions-In many patients with type 2 diabetes mellitus and stable ischemic coronary disease in whom angina symptoms are controlled, similar to those enrolled in the percutaneous coronary intervention stratum, intensive medical therapy alone should be the first-line strategy. In patients with more extensive coronary disease, similar to those enrolled in the coronary artery bypass grafting stratum, prompt coronary artery bypass grafting, in the absence of contraindications, intensive medical therapy, and an insulin sensitization strategy appears to be a preferred therapeutic strategy to reduce the incidence of MI. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305. (Circulation. 2009;120:2529-2540.)

Creatine Activates Airway Epithelium in Asthma

Airway epithelium plays important roles in the pathophysiology of asthma. Creatine supplementation (Cr) was shown to increase asthma features in a murine model of allergic asthma; however, the role of the airway epithelium in this inflammatory response is not known. BALB/c mice were divided into control, creatine supplementation, ovalbumin-sensitized (OVA) and OVA plus creatine supplementation groups. OVA sensitization occurred on days 0, 14, 28 and 42, and ovalbumin challenge from days 21-53. Cr was also given on days 21-53. Total and differential cells counts in BALF were evaluated. Quantitative epithelial expression of interleukin (IL)-4, IL-5, IL-13, CCL11, CCL5, CCL2, iNOS, VCAM-1, ICAM-1, NF-kappa B, VEGF, TGF-beta, IGF-1, EGFR, TIMP-1, TIMP-2, MMP-9, MMP-12 and arginase II were performed. Cr increased the number of total cells and eosinophils in BALF, the epithelial content of goblet cells and the epithelial expression of IL-5, CCL2, iNOS, ICAM-1, NF-kappa B, TGF-beta, TIMP-1 and MMP-9 when compared to the control group (p < 0.05). Creatine supplementation also exacerbated goblet cell proliferation, and IL-5 and iNOS expression by epithelial cells compared to the OVA group (p < 0.01). Creatine up-regulates the pro-inflammatory cascade and remodelling process in this asthma model by modulating the expression of inflammatory mediators by epithelial cells.

Exercise Reduces Effects of Creatine on Lung

We recently demonstrated that creatine supplementation increased some features of lung allergic sensitization in mice. On the other hand, other studies have shown that aerobic exercise inhibited allergic airway inflammation and remodeling. We hypothesized that aerobic exercise may decrease the exacerbatory effects of the creatine supplementation in a murine model of asthma. Balb/c mice were divided into six groups: Control, Creatine (Cr), Low Intensity Exercise + Creatine (Low + Cr), Ovalbumin (OVA), Ovalbumin + Creatine (OVA + Cr) and Ovalbumin + Creatine + Low Intensity Exercise (OVA + Cr + Low). OVA-sensitized groups were sensitized with OVA intraperitoneal injections (days 0, 14, 28, and 42). Aerosol challenge (OVA 1 %) and Cr treatment (0.5 g/kg/day) were initiated on Day 21 until Day 53. Low intensity exercise began on day 22 and was sustained until day 50. Low intensity exercise in the presence of creatine supplementation in sensitized mice resulted in a decreased number of eosinophils in BALF (p < 0.001) and in the airways (P < 0.001), and a decreased density of inflammatory cells positive to IL-4 (p < 0.001) and IL-5 (p < 0.001), airway collagen (p < 0.001) and elastic fibers (p < 0.001) content, airway smooth muscle thickness (p < 0.001) and bronchoconstriction index (p < 0.05) when compared with OVA + Cr group. These results suggest that aerobic exercise reduces the exacerbatory effects of creatine supplementation in chronically sensitized mice.

Impact of Nervous System Hyperalgesia on Pain, Disability, and Quality of Life in Patients With Knee Osteoarthritis: A Controlled Analysis

Objective. Refractory, disabling pain associated with knee osteoarthritis (OA) is usually treated with total knee replacement. However, pain in these patients might be associated with central nervous sensitization rather than peripheral inflammation and injury. We evaluated the presence of hyperalgesia in patients scheduled for a total knee replacement due to knee osteoarthritis with refractory pain, and we assessed the impact of pressure pain threshold measurements (PPT) on pain, disability, and quality of life of these patients. Methods. Sixty-two female patients were compared with 22 age-matched healthy controls without reported pain for the last year. PPT was measured at the lower extremities subcutaneous dermatomes, over the vastus medialis, adductor longus, rectus femoris, vastus lateralis, tibialis anterior, peroneus longus, iliacus, quadratus lumborum and popliteus muscles and at the supraspinous ligaments from L1-L5, over the L5-S1 and S1-S2 sacral areas and at the pes anserinus bursae and patellar tendon. Results. Patients with knee OA had significantly lower PPT over all evaluated structures versus healthy control subjects (P < 0.001). Lower PPT values were correlated with higher pain intensity, higher disability scores, and with poorer quality of life, except for the role-emotional and general health status. Combined PPT values over the patellar tendon, at the S2 subcutaneous dermatome and at the adductor longus muscle were the best predictors for visual analog scale and Western Ontario and McMaster Universities Osteoarthritis Index pain scores. Conclusion. Patients with pain due to osteoarthritis who were scheduled for total knee replacement showed hyperalgesia of nervous system origin that negatively impacted pain, knee functional capacity, and most aspects of quality of life.

Loss of the Ca2+/calmodulin-dependent protein kinase type IV in dopaminoceptive neurons enhances behavioral effects of cocaine

The persistent nature of addiction has been associated with activity-induced plasticity of neurons within the striatum and nucleus accumbens (NAc). To identify the molecular processes leading to these adaptations, we performed Cre/loxP-mediated genetic ablations of two key regulators of gene expression in response to activity, the Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) and its postulated main target, the cAMP-responsive element binding protein (CREB). We found that acute cocaine-induced gene expression in the striatum was largely unaffected by the loss of CaMKIV. On the behavioral level, mice lacking CaMKIV in dopaminoceptive neurons displayed increased sensitivity to cocaine as evidenced by augmented expression of locomotor sensitization and enhanced conditioned place preference and reinstatement after extinction. However, the loss of CREB in the forebrain had no effect on either of these behaviors, even though it robustly blunted acute cocaine-induced transcription. To test the relevance of these observations for addiction in humans, we performed an association study of CAMK4 and CREB promoter polymorphisms with cocaine addiction in a large sample of addicts. We found that a single nucleotide polymorphism in the CAMK4 promoter was significantly associated with cocaine addiction, whereas variations in the CREB promoter regions did not correlate with drug abuse. These findings reveal a critical role for CaMKIV in the development and persistence of cocaine-induced behaviors, through mechanisms dissociated from acute effects on gene expression and CREB-dependent transcription.

Different strains of mice present distinct lung tissue mechanics and extracellular matrix composition in a model of chronic allergic asthma

The impact of genetic factors on asthma is well recognized but poorly understood. We tested the hypothesis that different mouse strains present different lung tissue strip mechanics in a model of chronic allergic asthma and that these mechanical differences may be potentially related to changes of extracellular matrix composition and/or contractile elements in lung parenchyma. Oscillatory mechanics were analysed before and after acetylcholine (ACh) in C57BL/10, BALB/c, and A/J mice, subjected or not to ovalbumin sensitization and challenge. In controls, tissue elastance (E) and resistance (R), collagen and elastic fibres` content, and alpha-actin were higher in A/J compared to BALB/c mice, which, in turn, were more elevated than in C57BL/10. A similar response pattern was observed in ovalbumin-challenged animals irrespective of mouse strain. E and R augmented more in ovalbumin-challenged A/J [E: 22%, R: 18%] than C57BL/10 mice [E: 9.4%, R: 11 %] after ACh In conclusion, lung parenchyma remodelled differently yielding distinct in vitro mechanics according to mouse strain. (C) 2008 Elsevier B.V. All rights reserved.

Airway epithelium mediates the anti-inflammatory effects of exercise on asthma

Airway epithelium plays an important role in the asthma physiopathology. Aerobic exercise decreases Th2 response in murine models of allergic asthma, but its effects on the structure and activation of airway epithelium in asthma are unknown. BALB/c mice were divided into control, aerobic exercise, ovalbumin-sensitized and ovalbumin-sensitized plus aerobic exercise groups. Ovalbumin sensitization occurred on days 0, 14, 28, 42, and aerosol challenge from day 21 to day 50. Aerobic exercise started on day 22 and ended on day 50. Total cells and eosinophils were reduced in ovalbumin-sensitized group submitted to aerobic exercise. Aerobic exercise also reduced the oxidative and nitrosative stress and the epithelial expression of Th2 cytokines, chemokines, adhesion molecules, growth factors and NF-kB and P2X7 receptor. Additionally, aerobic exercise increased the epithelial expression of IL-10 in non-sensitized and sensitized animals. These findings contribute to the understanding of the beneficial effects of aerobic exercise for chronic allergic airway inflammation, suggesting an immune-regulatory role of exercise on airway epithelium. (C) 2011 Elsevier B.V. All rights reserved.

CpG-Induced Th1-Type Response in the Downmodulation of Early Development of Allergy and Inhibition of B7 Expression on T Cells of Newborn Mice

Several differences have been described between neonatal and adult immune responses. The predisposition in early life to Th2-type response or tolerance makes it a susceptible period for infections and allergic sensitization. The aim of this work was to evaluate the effects of CpG-containing oligodeoxynucleotides on neonatal and adult immunization with ovalbumin and Blomia tropicalis extract and compare the CpG effects on B and T cells of neonatal and adult mice. Mice that received CpG showed reduced immunoglobulin E (IgE) antibody production in both neonatal and adult periods, in parallel to increased IgG2a antibody levels. We observed that spleen cells of mice that received CpG in early life produced increased amounts of interferon-gamma upon anti-CD3 stimulation. Negative regulation of IgE response was more pronounced in adult than neonate mice; further, CpG decreased anaphylactic antiovalbumin IgG1 only in adults. Also, an upregulation of toll-like receptor 9 expression was detected in adult B cells, but not in neonatal, upon CpG stimuli. Neonatal B cells showed enhanced interleukin (IL)-10 expression and decreased IL-6 levels than adult B cells in response to CpG. When we analyzed in vitro activation of CD4+ T cells, an increased expression of B7 molecules on T cells in neonates was suppressed by CpG. Altogether, we verified qualitative and quantitative evidences regarding CpG effect on neonatal and adult allergens immunizations, which points to the importance of understanding neonatal immune system to establish immunomodulatory strategies for prevention of allergic diseases.

Allergic rhinitis in the child and associated comorbidities

Allergic rhinitis (AR) typically presents after the second year of life, but the exact prevalence in early life is unknown. AR affects 10-30% of the population, with the greatest frequency found in children and adolescents. It appears that the prevalence has increased in the pediatric population. As the childs` immune system develops between the 1st and 4th yr of life, those with an atopic predisposition begin to express allergic disease with a clear Th(2) response to allergen exposure, resulting in symptoms. In pediatric AR, two or more seasons of pollen exposure are generally needed for sensitization, so allergy testing to seasonal allergens (trees, grasses, and weeds) should be conducted after the age of 2 or 3 years. Sensitization to perennial allergens (animals, dust mites, and cockroaches) may manifest several months after exposure. Classification of AR includes measurement of frequency and duration of symptoms. Intermittent AR is defined as symptoms for < 4 days/wk or < 4 consecutive weeks. Persistent AR is defined as occurring for more than 4 days/wk and more than 4 consecutive weeks. AR is associated with impairments in quality of life, sleep disorders, emotional problems, and impairment in activities such as work and school productivity and social functioning. AR can also be graded in severity - either mild or moderate/severe. There are comorbidities associated with AR. The chronic effects of the inflammatory process affect lungs, ears, growth, and others. AR can induce medical complications, learning problems and sleep-related complaints, such as obstructive sleep apnea syndrome and chronic and acute sinusitis, acute otitis media, serous otitis media, and aggravation of adenoidal hypertrophy and asthma.

Anaphylactic reaction induced by a polysulfone/polyvinylpyrrolidone membrane in the 10th session of hemodialysis with the same dialyzer

The majority of severe hypersensitivity reactions in hemodialysis patients have occurred due to sensitization to ethylene oxide or to nonbiocompatible membrane dialyzers. The use of polysulfone dialyzers rarely causes hypersensitivity reactions. In the present study, we describe a case of severe life-threatening reactions induced by polysulfone dialyzers (from different manufacturers subjected to a variety of sterilization methods), which occurred after 9 sessions of hemodialysis with the same prescription, exemplifying the complexity of such reactions.

Prospective analysis between the therapy of immunosuppressive medication and allogeneic microchimerism after liver transplantation

After liver transplantation, migration of donor-derived hematopoietic cells to recipient can be detected in pheripheral blood. This state is termed microchimerism. The aim of this study was to investigate prospectively the presence of allogeneic microchimerism, the occurrence of acute cellular rejection and the level of immunosuppression in transplanted patients. Microchimerism occurrence between 10 days and 12 months after liver transplantation was analyzed in 47 patients aged between 15 and 65 by a two-stage nested PCR/SSP technique to detect donor MHC HLA-DR gene specifically. A pre-transplant blood sample was colleted from each patient to serve as individual negative control. Microchimerism was demonstrated in 32 (68%) of the 47 patients; of these, only 10 patients (31.2%) presented rejection. Early microchimerism was observed in 25 patients (78.12%) and late microchimerism in 7 patients (21.8%). Among the patients with microchimerism, 14 were given CyA and 18 were given FK506. In the group without microchimerism, 12 patients were given CyA and 03 were given FK506. There was a significant association between the presence of microchimerism and the absence of rejection (p=0.02) and also between microchimerism and the type of immunosuppression used. Our data indicate that microchimerism and probably differentiation of donor-derived leukocytes can have relevant immunologic effects both in terms of sensitization of recipient and in terms of immunomodulation toward tolerance induction. (C) 2008 Elsevier B.V. All rights reserved.

Respiratory Infection, Exposure to Mouse Allergen and Breastfeeding: Role in Recurrent Wheezing in Early Life

Background: Environmental factors may influence the development of allergen sensitization and asthma. The aim of this study was to evaluate the role of endotoxin and allergen exposure in early life as a risk factor for recurrent wheezing. Methods: One hundred and four infants from low-income families, at high risk of asthma, were enrolled at birth. Dust samples were collected from the bedding and bedroom floor within 6 months after birth. Recurrent wheezing was defined as 3 or more wheezing episodes in the past year. Endotoxin was determined by Limulus amebocyte lysate assay, and major indoor allergens were quantitated by ELISA in dust extracts. IgE antibodies were measured by ImmunoCAP at 30 months of age. Results: At 30 months, 51 of the 99 infants who completed the study (51.5%) had recurrent wheezing. Respiratory infection was strongly associated with recurrent wheezing (OR 6.67, 95% CI 1.96-22.72), whereas exclusive breastfeeding for at least 1 month was a protective factor (OR 0.09, 95% CI 0.01-0.51). Exposure to high levels of mouse allergen was more frequent among non-recurrent wheezers, approaching significance (OR 0.12, 95% CI 0.01-1.13; p=0.064). None of the children were sensitized to mouse. Sensitization to mite was found in 26/90 (28.8%) children, with no association with recurrent wheezing. Conclusion: Respiratory infection was strongly associated with recurrent wheezing in the first 30 months of life, in children at high risk of asthma, living in a socially deprived community in Brazil. Copyright (C) 2009 S. Karger AG, Basel

Sensitisation to aeroallergens in Brazilian adolescents living at the periphery of large subtropical urban centres

Objectives: To evaluate the sensitization to aeroallergens determined by skin prick test (SPT) in Brazilian adolescents, and to correlate its positivity with the diagnosis of asthma and/or rhinitis based on the written questionnaire (WQ) of ISAAC phase III study. Patients and Methods: A total of 996 adolescents (387 boys) were selected by systematic samples. A standard allergen extracts panel (positive/negative control, D pteronyssinus [Dpt], P americana [Pal, B germanica [Bg], dog, cat, fungal and grass mix) was used and its positivity compared with positive responses to asthma, rhinitis or both. Results: Positive SPT to at least one allergen was observed in 466 adolescents (46.8 %), with sensitisation to Dpt in 79.1 %. Positivity to more than one allergen occurred in 232 students (49.8 %). The frequency of positive SPTs was significantly higher among adolescents with asthma (OR = 2.16), rhinitis (OR = 1.69), and asthma and rhinitis (OR = 2.03). Positive SPT to four or more allergens were higher among asthmatics (OR = 2.6) and among adolescents with asthma and rhinitis (OR = 3). Conclusions: A high sensitisation rate to aeroallergens was observed, significantly higher among those with asthma, rhinitis or a combination of both, especially in multiple sensitisations.

Salicylates dilate blood vessels through inhibiting PYK2-mediated RhoA/Rho-kinase activation

Aims Compared with other non-steroid anti-inflammatory drugs (NSAIDs), aspirin is not correlated to hypertension. It has been shown that aspirin has unique vasodilator action in vivo, offering an explanation for the unique blood pressure effect of aspirin. In the present study, we investigate the mechanism whereby salicylates (aspirin and sodium salicylate) dilate blood vessels. Methods and results Rat aortic or mesenteric arterial rings were used to test the vascular effect of salicylates and other NSAIDs. RhoA translocation and the phosphorylation of MYPT1, the regulatory subunit of myosin light chain phosphatase, were measured by western blot, as evidenced for RhoA/Rho-kinase activation. Salicylates, but not other NSAIDs, relaxed contraction induced by most tested constrictors except for calyculin A, indicating that RhoA/Rho-kinase-mediated calcium sensitization is involved. The involvement of RhoA/Rho kinase in vasodilation by salicylates was confirmed by measurements of RhoA translocation and MYPT1 phosphorylation. The calculated half maximal inhibitory concentration (IC(50)) of vasodilation was apparently higher than that of cyclooxygenase inhibition, but comparable to that of proline-rich tyrosine kinase 2 (PYK2) inhibition. Over-expression of PYK2 induced RhoA translocation and MYPT1 phosphorylation, and these effects were markedly inhibited by sodium salicylate treatment. Consistent with the ex vitro vascular effects, sodium salicylate acutely decreased blood pressure in spontaneous hypertensive rats but not in Wistar Kyoto rats. Conclusion Salicylates dilate blood vessels through inhibiting PYK2-mediated RhoA/Rho-kinase activation and thus lower blood pressure.

The role of PKA and PKC epsilon pathways in prostaglandin E(2)-mediated hypernociception

Background and purpose: Protein kinase (PK) A and the epsilon isoform of PKC (PKC epsilon) are involved in the development of hypernociception (increased sensitivity to noxious or innocuous stimuli) in several animal models of acute and persistent inflammatory pain. The present study evaluated the contribution of PKA and PKC epsilon to the development of prostaglandin E(2) (PGE(2))-induced mechanical hypernociception. Experimental approach: Prostaglandin E(2)-induced mechanical hypernociception was assessed by constant pressure rat paw test. The activation of PKA or PKC epsilon was evaluated by radioactive enzymic assay in the dorsal root ganglia (DRG) of sensory neurons from the hind paws. Key results: Hypernociception induced by PGE(2) (100 ng) by intraplantar (i.pl.) injection, was reduced by i.pl. treatment with inhibitors of PKA [A-kinase-anchoring protein St-Ht31 inhibitor peptide (AKAPI)], PKC epsilon (PKC epsilon I) or adenylyl cyclase. PKA activity was essential in the early phase of the induction of hypernociception, whereas PKC activity was involved in the maintenance of the later phase of hypernociception. In the DRG (L4-L5), activity of PKA increased at 30 min after injection of PGE(2) but PKC activity increased only after 180 min. Moreover, i.pl. injection of the catalytic subunit of PKA induced hypernociception which was markedly reduced by pretreatment with an inhibitor of PKC epsilon, while the hypernociception induced by paw injection of PKC epsilon agonist was not affected by an inhibitor of PKA (AKAPI). Conclusions and implications: Taken together, these findings are consistent with the suggestion that PKA activates PKC epsilon, which is a novel mechanism of interaction between these kinases during the development of PGE(2)-induced mechanical hypernociception.