Role of nitric oxide in hyperpnea-induced bronchoconstriction and airway microvascular permeability in guinea pigs

The present study aimed to evaluate the role of nitric oxide (NO) on hyperpnea-induced bronchoconstriction (HIB) and airway microvascular hyperpermeability (AMP). Sixty-four guinea pigs were anesthetized, tracheotonnized, cannulated, and connected to animal ventilator to obtain pulmonary baseline respiratory system resistance (Rrs). Animals were then submitted to 5 minutes hyperpnea and Rrs was evaluated during 15 minutes after hyperpnea. AMP was evaluated by Evans blue dye (25 mg/kg) extravasation in airway tissues. Constitutive and inductible NO was evaluated by pretreating animals with N(G)-nitro-1-arginine methyl ester (I-NAME) (50 mg/kg), aminoguadinine (AG) (50 mg/kg), and I-arginine (100 mg/kg) and exhaled NO (NOex) was evaluated before and after drug administration and hyperpnea. The results show that I-NAME potentiated (57%) HIB and this effect was totally reversed by I-arginine pretreatment, whereas AG did not have effect on HIB. I-NAME decreased basal AMP (48%), but neither I-NAME nor AG had any effect on hyperpnea-induced AMP. NOex levels were decreased by 50% with I-NAME, effect that was reversed by I-arginine treatment. These results suggest that constitutive but not inducible NO could have a bronchoprotective effect on HIB in guinea pigs. The authors also observed that neither constitutive nor inducible NO seems to have any effect on hyperpnea-induced AMP.

Effects of proportional assisted ventilation on exercise performance in idiopathic pulmonary fibrosis patients

Background: Patients with idiopathic pulmonary fibrosis (IPF) present an important ventilatory (imitation reducing their exercise capacity. Non-invasive ventilatory support has been shown to improve exercise capacity in patients with obstructive diseases; however, its effect on IPF patients remains unknown. Objective: The present study assessed the effect of ventilatory support using proportional, assist ventilation (PAV) on exercise capacity in patients with IPF. Methods: Ten patients (61.2 +/- 9.2 year-old) were submitted to a cardiopulmonary exercise testing, plethysmography and three submaximal. exercise tests (60% of maximum load): without ventilatory support, with continuous positive airway pressure (CPAP) and PAV. Submaximal tests were performed randomly and exercise capacity, cardiovascular and ventilatory response as well as breathlessness subjective perception were evaluated. Lactate plasmatic levels were obtained before and after submaximal. exercise. Results: Our data show that patients presented a limited exercise capacity (9.7 +/- 3.8 mL O(2)/kg/min). Submaximal. test was increased in patients with PAV compared with CPAP and without ventilatory support (respectively, 11.1 +/- 8.8 min, 5.6 +/- 4.7 and 4.5 +/- 3.8 min; p < 0.05). An improved arterial oxygenation and lower subjective perception to effort was also observed in patients with IPF when exercise was performed with PAV (p < 0.05). IPF patients performing submaximal exercise with PAV also presented a lower heart rate during exercise, although systolic and diastolic pressures were not different among submaximal tests. Our results suggest that PAV can increase exercise tolerance and decrease dyspnoea and cardiac effort in patients with idiopathic pulmonary fibrosis. (C) 2009 Elsevier Ltd. All rights reserved.

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.

Effect of aquatic respiratory exercise-based program in patients with fibromyalgia

Objective: This study assessed the effects of an aquatic respiratory exercise-based program in patients with fibromyalgia (FMS). Methods: Forty women, aged between 20 and 60 years, were randomly assigned into two groups of 20 patients: the aquatic respiratory exercise-based program (ARG) and the control group (CTL). The ARG group performed the exercise program for 1 h, four times a week, for 4 weeks which included: (i) warming-Lip; (ii) respiratory exercises, consisting of five different breathing patterns, along With upper, lower limbs and trunk movements (45 min); and (iii) relaxation exercises. Both groups were included in supervised recreational activities of 1 h, once a week, for 4 weeks. Questionnaires were applied before and after intervention to assess quality of life and functional capacity (SF-36, Fibromyalgia Impact Questionnaire [FIQ]), anxiety (Hamilton Anxiety Scale [HAS]), and quality of sleep (Pittsburg Sleep Quality Index [PSQI]). Number of tender points and pain (Visual Analogue Scale [VAS]) were also evaluated. Results: At baseline there was no difference between the two groups, including number of tender points and questionnaire responses. After intervention, the ARG group, compared with the CTL group, showed improvement in SF-36 scores (physical functioning P = 0.001, bodily pain 1) = 0.001, vitality P = 0.009, social functioning P = 0.001, emotional role P = 0.001), in FIQ (total score P = 0.049, work missed P = 0.036, fatigue P = 0.013, morning tiredness P = 0.007) plus in VAS-pain (P = 0.029), VAS-dyspnea (P = 0.04), anxiety (HAS P = 0.005) and quality of sleep (PSQI P = 0.004). Conclusions: The short-term aquatic respiratory exercise-based program improved pain, quality of life, functional capacity, anxiety and quality of sleep in patients with FMS and may be a relevant addition to the treatment of these patients.

Improvement of Insulin Resistance and Reduction of Cardiovascular Risk Among Obese Patients with Type 2 Diabetes with the Duodenojejunal Bypass Liner

This study aims to evaluate the effectiveness of the duodenojejunal bypass liner (DJBL) in the improvement of insulin resistance and reduction of cardiovascular risk among morbidly obese patients with type 2 diabetes mellitus, using the triglyceride/high-density lipoprotein (HDL) cholesterol ratio, percentage of weight loss, and glycemic control. We used the TG/HDL ratio with a cutoff value of 3.5 to identify patients with insulin resistance. The value of the initial ratio was compared with the ratio obtained 6 months after implantation to evaluate whether an improvement in insulin resistance occurred. We also evaluated the improvement of glycated hemoglobin levels and the weight loss resulted from the use of the device and correlated that with the improvement of the TG/HDL ratio. All patients implanted with the device presented a statistically significant reduction of the HbA1c levels, with most patients (70.3%) obtaining diabetes control with HbA1c levels lower than 7% at the end of the study. All patients also presented a significant weight reduction, with an average loss of 12.6% of their initial weight. We observed an important improvement in insulin resistance and metabolic syndrome, with a significant reduction of the TG/HDL ratio from 5.75 to 4.36 (p < 0.001) and 42.6% of the patients presenting a TG/HDL ratio lower than 3.5 at the end of the study. The DJBL, when used for a period of 6 months, is effective in the control of diabetes, weight loss, improvement of insulin resistance, and decrease of cardiovascular risk among morbidly obese patients with type 2 diabetes mellitus.

Antiretroviral Drug Resistance in a Respondent-Driven Sample of HIV-Infected Men Who Have Sex With Men in Brazil

Background: There are few studies on HIV subtypes and primary and secondary antiretroviral drug resistance (ADR) in community-recruited samples in Brazil. We analyzed HIV clade diversity and prevalence of mutations associated with ADR in men who have sex with men in all five regions of Brazil. Methods: Using respondent-driven sampling, we recruited 3515 men who have sex with men in nine cities: 299 (9.5%) were HIV-positive; 143 subjects had adequate genotyping and epidemiologic data. Forty-four (30.8%) subjects were antiretroviral therapy-experienced (AE) and 99 (69.2%) antiretroviral therapy-naive (AN). We sequenced the reverse transcriptase and protease regions of the virus and analyzed them for drug resistant mutations using World Health Organization guidelines. Results: The most common subtypes were B (81.8%), C (7.7%), and recombinant forms (6.9%). The overall prevalence of primary ADR resistance was 21.4% (i.e. among the AN) and secondary ADR was 35.8% (i.e. among the AE). The prevalence of resistance to protease inhibitors was 3.9% (AN) and 4.4% (AE); to nucleoside reverse transcriptase inhibitors 15.0% (AN) and 31.0% (AE) and to nonnucleoside reverse transcriptase inhibitors 5.5% (AN) and 13.2% (AE). The most common resistance mutation for nucleoside reverse transcriptase inhibitors was 184V (17 cases) and for nonnucleoside reverse transcriptase inhibitors 103N (16 cases). Conclusions: Our data suggest a high level of both primary and secondary ADR in men who have sex with men in Brazil. Additional studies are needed to identify the correlates and causes of antiretroviral therapy resistance to limit the development of resistance among those in care and the transmission of resistant strains in the wider epidemic.

Identification and chromosomal localization of one locus of Leishmania (L.) major related with resistance to itraconazole

Ergosterol is an important compound responsible to maintain integrity and fluidity of Leishmania spp. membranes. Starting from an overexpression/selection method, our group has isolated and mapped nine different loci of Leishmania (L.) major related to resistance against two inhibitors of the ergosterol biosynthesis pathway, terbinafine (TBF) and itraconazole (ITZ). Individual functional analysis after overexpression induction of these loci in the presence of TBF and/or ITZ [or the ITZ analog ketoconazole (CTZ)] have shown low but significant levels of resistance after transfection into L. major wild-type parasites. In this work, we have shown the insert mapping and chromosomal identification of one of these loci (cosItz2). Functional analysis experiments associated with chromosomal localization by comparison at genomic database allowed us to identify two prospective gene-protein systems not related to the ergosterol biosynthesis and capable to confer wild-type cells resistance to ITZ-CTZ after transfection. We expected that this approach can open new insights for a better understanding of mechanisms of ITZ-CTZ action and resistance in Leishmania resulting in new strategies for the leishmaniasis treatment.

The challenge of multidrug resistance: The treatment of gram-negative rod infections

Infections caused by multidrug-resistant gram-negative bacteria are an increasing problem worldwide. Treatment of these microorganisms is a challenge because resistance limits dramatically therapeutic options. In this review, we discuss data of in vitro susceptibility and clinical studies of possible agents for the management of these infections. Currently, published data are limited, and there are no randomized clinical trials involving the treatment of infections caused by multidrug-resistant gram-negative rods. For imipenem-resistant Acinetobacter spp., most studied options are polymyxins and sulbactam. No newer antimicrobials active against Pseudomonas aeruginosa are available or under investigation. Tigecycline presents a broad spectrum of activity in vitro but has been studied mainly as treatment of community-acquired infections, as has ertapenem. They are potential options against extended-spectrum P-lactamase-producing Enterobacteriaceae, and tigecycline may be useful in treating Acinetobacter infections.

Impact of antimicrobial resistance on the treatment and outcome of patients with sepsis

Antimicrobial therapy is one of the main stones of sepsis therapy. A recent study of septic shock patients showed that each hour of delay in antimicrobial administration during the ensuing 6 h after the onset of hypotension was associated with a decrease in survival rates. However, many questions regarding the impact of infection caused by antimicrobial-resistant pathogens on the mortality of patients with sepsis still need to be clarified. There is a lack of fair studies in the literature. Most studies have had inadequate sample size, inadequate adjustment for predictors of adverse outcomes, and inadequate definition of appropriate antibiotic therapy. Despite the fact that appropriate therapy is essential to treat sepsis, it seems that severity of underlying diseases and comorbidities are more important than resistance, although the studies were not well designed to examine the real impact of resistance on outcome. Finally, new technologies such as microarray that can identify different microorganisms, genes of resistance, and virulence in a few hours might have a great impact on the treatment of sepsis due to antimicrobial-resistant pathogens in the future.

Effects of estradiol and norethisterone on lipids, insulin resistance and carotid flow

Objectives: To evaluate the lipid profile, insulin resistance and vasomotricity, and the interaction between these factors, in postmenopausal women receiving hormone therapy. Methods: A prospective, randomized, double-blind study was carried out in which 77 postmenopausal women received one of the three treatment regimens: (A) 2 mg oral micronized estradiol (E(2)) (n = 25); (B) 2 mg oral E(2) + 1 mg oral norethisterone acetate (NETA) (n = 28); or Q placebo (n = 24), daily for 6 months. Evaluations were carried out at baseline and at the end of treatment on lipid and lipoprotein profiles, homeostasis model assessment of insulin resistance (HOMA-IR) and pulsatility index (PI) of the internal carotid artery by Doppler ultrasonography. Results: Mean increases of 15.6% and 2.4% and a reduction of 6.4% in high-density lipoprotein (HDL) levels were found for the E(2), E(2) + NETA and placebo groups, respectively. Reductions of 9.5% and 3.7% and an increase of 12.1% in low-density lipoprotein (LDL), and reductions of 20.0% and 3.8% and an increase of 28.8% in the LDL:HDL ratio were found for the E(2), E(2) + NETA and placebo groups, respectively (p < 0.001 in all cases). Insulin levels and HOMA-IR decreased 12.8% and 12.3% in the E2 group and increased 12.9% and 16.0% in the E(2) + NETA group (p < 0.05), respectively. Carotid PI following treatment was 1.18 +/- 0.23, 1.38 +/- 0.20 and 1.41 +/- 0.21 for the E(2), E(2) + NETA and placebo groups, respectively (p = 0.0006). Conclusions: Oral estrogen therapy led to an improvement in lipid profile, insulin resistance and carotid blood flow, which was cancelled when NETA was associated. (c) 2008 Elsevier Ireland Ltd. All rights reserved.

Benefits of exercise training in diabetic rats persist after three weeks of detraining

Regarding all benefits of exercise training, a question remains: how long are these benefits kept? This study evaluated the effect of 3-week detraining after 10 weeks of training in STZ-diabetic rats. Male Wistar rats were assigned into: sedentary controls, trained controls, trained-detrained controls. sedentary diabetic, trained diabetic and trained-detrained diabetic. Arterial pressure (AP) and heart rate (HR) were recorded by a data acquisition system. Baroreflex sensitivity (BRS) was evaluated by HR responses to AP changes induced by infusion of vasoactive drugs. Intrinsic heart rate (IHR), sympathetic tonus (ST) and vagal tonus (VT) were evaluated by pharmacological blockade with atenolol and atropine. Spectral analysis of systolic AP and HR variabilities (HRV) was performed to estimate autonomic modulation to the heart and vessels. Diabetes cardiovascular and autonomic dysfunctions were reversed by exercise training and partially maintained in the 3-week detraining period. In controls, training decreased AP and HR and improved BRS. changes that returned to baseline values after detraining. IHR and VT were improved in trained diabetic rats and remained in detrained diabetic ones. LF component of HRV decreased in trained control group. In diabetics. exercise training improved variance, and absolute LF and HF components of HRV. Only HF was maintained in detrained diabetic group. Moreover, there was an inverse relationship between plasma glucose and the absolute HF component of HRV. These changes probably determined the different survival rate of 80% in diabetic detrained and 51% in diabetic sedentary rats. (c) 2008 Elsevier B.V. All rights reserved.

Distinct resistance mutation and polymorphism acquisition in HIV-1 protease of subtypes B and F1 from children and adult patients under virological failure

The goal of this work was to compare the differences between human immunodeficiency Virus type 1 (HIV-1) of B and F1 Subtypes in the acquisition of major and rninot- protease inhibitor (P1)-associated resistance mutations and of other polymorphisms at the protease (PR) gene, through a cross sectional Study. PR sequences from subtypes B and F1 isolates matched according to P1 exposure time from Brazilian patients were included in this study. Sequences were separated in four groups: 24 and 90 from children and 141 and 99 from adults infected with isolates of subtypes F1 and B, respectively. For comparison, 211 subype B and 79 subtype F1 PR sequences from drug-naive individuals Were included. Demographic and clinical data were similar among B- and F1-infected patients. In untreated patients, Mutations L1OV, K20R, and M361 were more frequent in subtype F1, while L63P, A7IT, and V771 were more prevalent in Subtype B. In treated patients, K20M, D30N, G73S, 184V, and L90M, were More prevalent in subtype B, and K20T and N88S Were more prevalent in Subtype F1. A higher proportion of subtype F1 than Of subtype B Strains Containing other polymorphisms was observed. V82L mutation was Present With increased frequency in isolates from children compared to isolates from adults infected with both subtypes. We could observe a faster resistance emergence in children than in adults, during treatment with protease inhibitors. This data provided evidence that, although rates of overall drug resistance do not differ between subtypes B and F1, the former accumulates resistance at higher proportion in specific amino acid positions of protease when compared to the latter. (c) 2008 Elsevier B.V. All rights reserved.