Ranolazine Exerts Potent Effects on Atrial Electrical Properties and Abbreviates Atrial Fibrillation Duration in the Intact Porcine Heart

Introduction: In vitro studies and ambulatory ECG recordings from the MERLIN TIMI-36 clinical trial suggest that the novel antianginal agent ranolazine may have the potential to suppress atrial arrhythmias. However, there are no reports of effects of ranolazine on atrial electrophysiologic properties in large intact animals. Methods and Results: In 12 closed-chest anesthetized pigs, effects of intravenous ranolazine (similar to 9 mu M plasma concentration) on multisite atrial effective refractory period (ERP), conduction time (CT), and duration and inducibility of atrial fibrillation (AF) initiated by intrapericardial acetylcholine were investigated. Ranolazine increased ERP by a median of 45 ms (interquartile range 29-50 ms; P < 0.05, n = 6) in right and left atria compared to control at pacing cycle length (PCL) of 400 ms. However, ERP increased by only 28 (24-34) ms in right ventricle (P < 0.01, n = 6). Ranolazine increased atrial CT from 89 (71-109) ms to 98 (86-121) ms (P = 0.04, n = 6) at PCL of 400 ms. Ranolazine decreased AF duration from 894 (811-1220) seconds to 621 (549-761) seconds (P = 0.03, n = 6). AF was reinducible in 1 of 6 animals after termination with ranolazine compared with all 6 animals during control period (P = 0.07). Dominant frequency (DF) of AF was reduced by ranolazine in left atrium from 11.7 (10.7-20.5) Hz to 7.6 (2.9-8.8) Hz (P = 0.02, n = 6). Conclusions: Ranolazine, at therapeutic doses, increased atrial ERP to greater extent than ventricular ERP and prolonged atrial CT in a frequency-dependent manner in the porcine heart. AF duration and DF were also reduced by ranolazine. Potential role of ranolazine in AF management merits further investigation. (J Cardiovasc Electrophysiol, Vol. 20, pp. 796-802, July 2009).

Effects of biomass burning on nasal mucociliary clearance and mucus properties after sugarcane harvesting

Objective: Biofuel from sugarcane is widely produced in developing countries and is a clean and renewable alternative source of energy. However, sugarcane harvesting is mostly performed after biomass burning. The aim of this study was to evaluate the effects of harvesting after biomass burning on nasal mucociliary clearance and the nasal mucus properties of farm workers. Methods: Twenty seven sugarcane workers (21-45 years old) were evaluated at the end of two successive time-periods: first at the end of a 6-month harvesting period (harvesting), and then at the end of a 3-month period without harvesting (non-harvesting). Nasal mucociliary clearance was evaluated by the saccharine transit test, and mucus properties were analyzed using in vitro mucus contact angle and mucus transportability by sneeze. Arterial blood pressure, heart rate, respiratory rate, pulse oximetry, body temperature, associated illness, and exhaled carbon monoxide were registered. Results: Data are presented as mean values (95% confidence interval). The multivariate model analysis adjusted for age, body-mass index, smoking status and years of working with this agricultural practice showed that harvesting yielded prolonged saccharine transit test in 7.83 min (1.88-13.78), increased mucus contact angle in 8.68 degrees (3.18-14.17) and decreased transportability by sneeze in 32.12 mm (-44.83 to -19.42) compared with the non-harvesting period. No significant differences were detected in any of the clinical parameter at either time-period. Conclusion: Sugarcane harvesting after biomass burning negatively affects the first barrier of the respiratory system in farm workers by impairing nasal mucociliary clearance and inducing abnormal mucus properties. (C) 2011 Elsevier Inc. All rights reserved.

Effects of Oropharyngeal Exercises on Patients with Moderate Obstructive Sleep Apnea Syndrome

Rationale: Upper airway muscle function plays a major role in maintenance of the upper airway patency and contributes to the genesis of obstructive sleep apnea syndrome (OSAS). Preliminary results suggested that oropharyngeal exercises derived from speech therapy may be an effective treatment option for patients with moderate OSAS. Objectives: To determine the impact of oropharyngeal exercises in patients with moderate OSAS. Methods: Thirty-one patients with moderate OSAS were randomized to 3 months of daily (similar to 30 min) sham therapy (n = 15, control) or a set of oropharyngeal exercises (n = 16), consisting of exercises involving the tongue, soft palate, and lateral pharyngeal wall. Measurements and Main Results: Anthropometric measurements, snoring frequency (range 0-4), intensity (1-3), Epworth daytime sleepiness (0-24) and Pittsburgh sleep quality (0-21) questionnaires, and full polysomnography were performed at baseline and at study conclusion. Body mass index and abdominal circumference of the entire group were 30.3 +/- 3.4 kg/m(2) and 101.4 +/- 9.0 cm, respectively, and did not change significantly over the study period. No significant change occurred in the control group in all variables. In contrast, patients randomized to oropharyngeal exercises had a significant decrease (P < 0.05) in neck circumference (39.6 +/- 3.6 vs. 38.5 +/- 4.0 cm), snoring frequency (4 [4-4] vs. 3 [1.5-3.5]), snoring intensity (3 [3-4] vs. 1 [1-2]), daytime sleepiness (14 +/- 5 vs. 8 +/- 6), sleep quality score (10.2 +/- 3.7vs. 6.9 +/- 2.5), and OSAS severity (apnea-hypopnea index, 22.4 +/- 4.8 vs. 13.7 +/- 8.5 events/h). Changes in neck circumference correlated inversely with changes in apnea-hypopnea index (r = 0.59; P < 0.001). Conclusions: Oropharyngeal exercises significantly reduce OSAS severity and symptoms and represent a promising treatment for moderate OSAS. Clinical trial registered with www.clinicaltrials.gov (NCT 00660777).

Protein disulfide isomerase overexpression in vascular smooth muscle cells induces spontaneous preemptive NADPH oxidase activation and Nox1 mRNA expression: Effects of nitrosothiol exposure

Mechanisms regulating NADPH oxidase remain open and include the redox chaperone protein disulfide isomerase (PDI). Here, we further investigated PDI effects on vascular NADPH oxidase. VSMC transfected with wild-type PDI (wt-PDI) OF PDI mutated in all four redox cysteines (mut-PDI) enhanced (2.5-fold) basal cellular ROS production and membrane NADPH oxidase activity, with 3-fold increase in Nox1, but not Nox4 mRNA. However, further ROS production, NADPH oxidase activity and Nox1 mRNA increase triggered by angiotensin-II (AngII) were totally lost with PDI overexpression, suggesting preemptive Nox1 activation in such cells. PDI overexpression increased Nox4 mRNA after AngII stimulus, although without parallel ROS increase. We also show that Nox inhibition by the nitric oxide donor GSNO is independent of PDI. PDI silencing decreased specifically Nox1 mRNA and protein, confirming that PDI may regulate Nox1 at transcriptional level in VSMC. Such data further strengthen the role of PDI as novel NADPH oxidase regulator. (C) 2009 Elsevier Inc. All rights reserved.

Effects of Chronic Exposure to Crack Cocaine on the Respiratory Tract of Mice

Smoked cocaine (crack cocaine) causes several forms of injury to the respiratory tract, including asthma exacerbations, lung edema and hemorrhage, and nasal mucosal alterations. Few studies, however, have assessed respiratory tract pathology in habitual users of crack cocaine. Here, we describe the histological alterations in the respiratory tract of mice caused by chronic inhalation of crack cocaine. Twenty 2-month-old BALB/c mice were exposed to the smoke of 5 g crack cocaine in an inhalation chamber once a day for two months and compared to controls (n = 10). We then morphometrically analyzed nose and bronchiolar epithelial alterations, bronchiolar and alveolar macrophage cell density, alveolar hemosiderin content, and in addition determined the vasoconstriction index and the wall thickness of pulmonary arteries. The serum cocaine level was 212.5 ng/mL after a single inhalation. The mucus content of the nasal epithelium increased in crack-exposed animals, and the nasal and bronchial epithelium thickness decreased significantly. The alveolar hemosiderin content and the alveolar and bronchiolar macrophage cell density increased in animals exposed to crack. The vasoconstriction index increased in the pulmonary arteries of the exposed group. Chronic crack cocaine inhalation causes extensive histological changes along the entire respiratory tract.

Effects of bromazepam in frontal theta activity on the performance of a sensorimotor integration task: A quantitative electroencephalography study

Our objective is to verify the modulatory effects of bromazepam on EEG theta absolute power when subjects were submitted to a visuomotor task (i.e., car driver task). Sample was composed of 14 students (9 males and 5 females), right handed, with ages varying between 23 and 42 years (mean = 32.5 +/- 9.5), absence of mental or physical impairments, no psychoactive or psychotropic substance use and no neuromuscular disorders (screened by a clinical examination). The results showed an interaction between condition and electrodes (p=0.034) in favor of F8 electrode compared with F7 in both experimental conditions (t-test; p=0.001). Additionally, main effects were observed for condition (p=0.001), period (p=0.001) and electrodes (p=0.031) in favor of F4 electrode compared with F3. In conclusion, Br 6 mg of bromazepam may interfere in sensorimotor processes in the task performance in an unpredictable scenario allowing that certain visuospatial factors were predominant. Therefore, the results may reflect that bromazepam effects influence the performance of the involved areas because of the acquisition and integration of sensory stimuli processes until the development of a motor behavior based on the same stimuli. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Reduced gray matter volume in ventral prefrontal cortex but not amygdala in bipolar disorder: Significant effects of gender and trait anxiety

Neuroimaging studies in bipolar disorder report gray matter volume (GMV) abnormalities in neural regions implicated in emotion regulation. This includes a reduction in ventral/orbital medial prefrontal cortex (OMPFC) GMV and, inconsistently, increases in amygdala GMV. We aimed to examine OMPFC and amygdala GMV in bipolar disorder type 1 patients (BPI) versus healthy control participants (HC), and the potential confounding effects of gender, clinical and illness history variables and psychotropic medication upon any group differences that were demonstrated in OMPFC and amygdala GMV Images were acquired from 27 BPI (17 euthymic, 10 depressed) and 28 age- and gender-matched HC in a 3T Siemens scanner. Data were analyzed with SPM5 using voxel-based morphometry (VBM) to assess main effects of diagnostic group and gender upon whole brain (WB) GMV. Post-hoc analyses were subsequently performed using SPSS to examine the extent to which clinical and illness history variables and psychotropic medication contributed to GMV abnormalities in BPI in a priori and non-a priori regions has demonstrated by the above VBM analyses. BPI showed reduced GMV in bilateral posteromedial rectal gyrus (PMRG), but no abnormalities in amygdala GMV. BPI also showed reduced GMV in two non-a priori regions: left parahippocampal gyrus and left putamen. For left PMRG GMV, there was a significant group by gender by trait anxiety interaction. GMV was significantly reduced in male low-trait anxiety BPI versus male low-trait anxiety HC, and in high-versus low-trait anxiety male BPI. Our results show that in BPI there were significant effects of gender and trait-anxiety, with male BPI and those high in trait-anxiety showing reduced left PMRG GMV. PMRG is part of medial prefrontal network implicated in visceromotor and emotion regulation. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Optimizing Medical Therapy of Acromegaly: Beneficial Effects of Cabergoline in Patients Uncontrolled with Long-Acting Release Octreotide

Background: Previous data indicate a beneficial effect of cabergoline (CAB) association to somatostatin analogs (SA) in acromegalics resistant to SA monotherapy. Objective: To assess the efficacy of CAB association on acromegalics with high IGF-I on stable long-acting release octreotide (OCT-LAR) (30 mg/28 days). Design, Subjects and Methods: 34 patients (17 male, 25-85 years, 33 macroadenomas) were enrolled in this prospective study. OCT-LAR was administered as primary (n = 4) and as secondary (n = 30) treatment: after surgery (n = 16), after surgery + radiotherapy (RT) (n = 11), and after RT only (n = 3). Duration of OCT-LAR therapy prior to CAB was 24 8 12 months. The immunohistochemical features of the tumors disclosed GH/PRL co-secretion in 11/21 patients. 13 patients had high PRL levels prior to CAB. The initial CAB dose was 1.5 mg/week. No IGF-I normalization led to a dose increase to 3.5 mg/week. The OCT-LAR dose was kept stable during treatment. IGF-I, GH and PRL levels were compared before and after CAB association. OCT-LAR was withdrawn in patients who achieved IGF-I normalization, in order to assess the influence of CAB. Results: Comparing OCT-LAR to OCT-LAR/CAB treatment, there was a significant decrease in mean GH, IGF-I, %ULNR- IGF-I and PRL levels. During OCT-LAR/CAB treatment, IGF-I normalized in 19 patients (56%). IGF-I normalization was correlated to lowest IGF-I levels on OCT-LAR monotherapy, but not to baseline PRL levels or GH/PRL co-expression. OCT-LAR withdrawn in all who had achieved IGF-I normalization on combined therapy resulted in IGF-I elevation to abnormal levels in all patients. Gastro intestinal symptoms were reported by 12 patients. Conclusion: OCT-LAR and CAB association has been shown to be an effective alternative therapy for those acromegalics who still have active acromegaly despite monotherapy with SA, mainly for those with lower pretreatment IGF-I concentrations. According to previous studies, the beneficial effects of CAB occur even when pretreatment PRL is normal and/or there is no tumor GH/PRL co-expression. Copyright (C) 2009 S. Karger AG, Basel

Do the Effects of Pentoxifylline on the Inflammatory Process and Pancreatic Infection Justify Its Use in Acute Pancreatitis?

Severe acute pancreatitis is associated with high morbidity and mortality rates. At the present time, no specific therapy has been shown to be uniformly effective in reducing morbidity and mortality in this disease. The aim of this study was to determine the effects of pentoxifylline on the pancreatic and systemic inflammatory process, pancreatic infection, and mortality rate in severe acute pancreatitis in rats. Methods: One hundred and twenty male Wistar rats were divided into 3 groups: sham, pancreatitis, and pentoxifylline (acute pancreatitis induction plus administration of 25 mg/kg pentoxifylline). Inflammatory response was measured by histological studies, inflammatory cytokine production (IL-6, IL-10, and TNF-alpha), and mortality rate. Pancreatic infection was evaluated by bacterial cultures expressed in colony-forming units per gram. Results: Pentoxifylline-treated animals had a statistically significant reduction of inflammatory cytokine levels, pancreatic histological damage, occurrence of bacterial translocation and pancreatic infection (p < 0.05), associated with a significant reduction in mortality rate. Conclusions: Pentoxifylline administration in this experimental model of acute pancreatitis reduces local and systemic inflammatory responses and decreases the pancreatic infection and the mortality rate. Copyright (C) 2009 S. Karger AG, Basel and IAP

Additive Effects of Obstructive Sleep Apnea and Hypertension on Early Markers of Carotid Atherosclerosis

Obstructive sleep apnea (OSA) has emerged as an independent risk factor for atherosclerosis. However, OSA is frequently associated with several risk factors for atherosclerosis, including hypertension (HTN). The impact of OSA and HTN alone compared with the association of both conditions on carotid atherosclerosis is not understood. We studied 94 middle-aged participants free of smoking and diabetes mellitus who were divided into 4 groups: controls (n = 22), OSA (n = 25), HTN (n = 20), and OSA + HTN (n = 27). All of the participants underwent polysomnography and carotid measurements of intima-media thickness, diameter, and distensibility with an echo-tracking device. Compared with controls, intima-media thickness and carotid diameter were similarly higher in OSA (713 +/- 117 and 7117 +/- 805 mu m), and HTN groups (713 +/- 182 and 7191 +/- 818 mu m), with a further significant increase in OSA + HTN patients (837 +/- 181 and 7927 +/- 821 mu m, respectively; P < 0.01). Carotid distensibility was significantly lower in HTN (P < 0.05) and OSA + HTN subjects (P < 0.001) compared with controls. In the OSA + HTN group, carotid distensibility was significantly lower than in the OSA group and controls (P < 0.05 for each comparison). Multivariate analysis showed that intima-media thickness was positively related to systolic blood pressure and apnea-hypopnea index. Apnea-hypopnea index was the only factor related to carotid diameter. Age and systolic blood pressure were independently related to carotid distensibility. In conclusion, the association of OSA and HTN has additive effects on markers of carotid atherosclerosis. Because early markers of carotid atherosclerosis predict future cardiovascular events, including not only stroke but also myocardial infarction, these findings may help to explain the increased risk of cardiovascular disease in patients with OSA. (Hypertension. 2009; 53: 64-69.)

The effects of bromazepam over the temporo-parietal areas during the performance of a visuomotor task: A qEEG study

This study investigated the effects of bromazepam on qEEG when 14 healthy subjects were asked to perform a visuomotor task (i.e., motor vehicle driving task). The subjects were exposed to two experimental conditions: the placebo (PL) and 6 mg of bromazepam (Br 6 mg), following a randomized, double-blind design on different days. Specifically, we observe absolute power extracted from qEEG data for theta band. We expected to see a decrease in absolute theta power in the temporal and parietal areas due to the influence of bromazepam for the experimental group when compared with the placebo group. We found a main effect for the condition factor for electrodes T3, T4, P3 and P4. We also observed a main effect for the period factor for electrodes P3 and P4. We observed that the ingestion of 6 mg of bromazepam induces different patterns in theta power at the temporal and parietal sites. We concluded that 6 mg of bromazepam was an important factor in the fluctuation of the activities in the temporal and parietal areas. We then hypothesize about the specific role of this drug during the execution of a visuomotor task and within the sensorimotor integration process. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Systemic and Local Inflammation in Peritoneal Dialysis: Mechanisms, Biomarkers and Effects on Outcome

Thanks to the technological development in peritoneal dialysis (PD) during the last three decades, the most important problem nowadays for the nephrologists is the maintenance of the long-term function of the peritoneal membrane. Although PD may exert an early survival benefit as compared with hemodialysis (HD), long-term PD is often associated with histopathological alterations in the peritoneal membrane that are linked to peritoneal ultrafiltration deficit and increased mortality risk. These alterations are closely related to the presence of a chronic activated (local and systemic) inflammatory response. PD itself may have other factors associated that could further modulate the inflammatory response, such as the bioincompatibility of dialysis solutions, fluid overload and changes in the body composition. Understanding the pathophysiology of inflammation in PD is essential for the adoption of adequate strategies to improve both membrane and patient survival. Copyright (C) 2009 S. Karger AG, Basel

Effects of ambient levels of air pollution generated by traffic on birth and placental weights in mice

Objective: To examine whether there is an association between fetal and/or placental weight and exposure to ambient levels of air pollution in mice. Design: Chronic experiments on mice that were exposed to polluted vs. clean air. Setting: Environmental exposure to atmospheric pollution. Animal(S): Female Swiss mice (n = 70) were maintained at different stages of gestation in an exposure chamber located at an intersection with heavy traffic in a major city in Brazil. Control mice were maintained in a similar chamber, located adjacent to the exposure chamber but equipped with filters for particles and reactive gases. Intervention(s): Animals were divided into six groups as follows: no exposure, exposure to a polluted chamber throughout gestation, exposure to a polluted chamber during the 1st week of pregnancy, exposure to a polluted chamber during the 2nd and 3rd weeks, exposure to a polluted chamber during the 1st and 2nd week, and exposure to a polluted chamber during the 3rd week. Main Outcome Measure(S): At the end of the gestational period, the determination of fetal and placental weight was performed after cesarean section. Result(s): Exposure to air pollution during the 1st week of pregnancy promoted a significant reduction in fetal weight. Mice exposed to polluted air, in any phase of gestation, presented with lower placental weight in comparison to mice maintained in clean chambers. Conclusion(s): Exposure to ambient levels of traffic pollution at early phases of gestation is a determinant for decreased final fetal weight. Placental weight is reduced with exposure to air pollution at any phase of gestation. (Fertil Steril (R) 2008;90:1921-4. (C)2008 by American Society for Reproductive Medicine.)

The effects of human herpesvirus 8 infection and interferon-gamma response in cutaneous lesions of Kaposi sarcoma differ among human immunodeficiency virus-infected and uninfected individuals

Background Kaposi sarcoma (KS) is associated with human herpesvirus 8 (HHV-8). The cutaneous immune response in this tumour is not well established and a better understanding is necessary. Objectives To evaluate the HHV-8 expression and immune response in cutaneous lesions of classic KS (CKS) and AIDS-associated KS (AIDS-KS). Methods We performed a quantitative immunohistochemical study of cells expressing HHV-8 latency-associated nuclear antigen (LANA), CD4, CD8 and interferon (IFN)-gamma in skin lesions from patients with CKS and AIDS-KS (with or without highly active antiretroviral therapy, HAART). Results CKS showed higher LANA expression compared with AIDS-KS, regardless of HAART. We also found higher LANA expression in nodules compared with patch/plaque lesions. The tissue CD4+ cell proportion was lower in AIDS-KS patients without HAART than in patients with CKS. In CKS lesions, CD4+ and CD8+ cells expressed IFN-gamma, as shown by double immunostaining. AIDS-KS presented low numbers of IFN-gamma-expressing cells. CD8+ cell numbers were similar in all groups, which appeared unrelated to the clinical or epidemiological type of KS. Conclusions. Our quantitative data on the pattern of KS lesions in selected groups of patients, as shown by in situ immune response, demonstrated a CD4+ T-cell involvement associated with IFN-gamma, an environment of immune response-modified human immunodeficiency virus (HIV) infection. In our sample, the promotion of KS in patients without HIV appears to be related to higher HHV-8 load or virulence than in those with AIDS. This higher resistance may be explained by a sustained immune response against this herpesvirus, that is only partially restored but effective after HAART.

EFFECTS OF A POTENT PEROXYNITRITE DECOMPOSITION CATALYST IN MURINE MODELS OF ENDOTOXEMIA AND SEPSIS

Excessive free-radical production due to various bacterial components released during bacterial infection has been linked to cell death and tissue injury. Peroxynitrite is a highly reactive oxidant produced by the combination of nitric oxide (NO) and superoxide anion, which has been implicated in cell death and tissue injury in various forms of critical illness. Pharmacological decomposition of peroxynitrite may represent a potential therapeutic approach in diseases associated with the overproduction of NO and superoxide. In the present study, we tested the effect of a potent peroxynitrite decomposition catalyst in murine models of endotoxemia and sepsis. Mice were injected i.p. with LPS 40 mg/kg with or without FP15 [Fe(III) tetrakis-2-(N-triethylene glycol monomethyl ether) pyridyl porphyrin] (0.1, 0.3, 1, 3, or 10 mg/kg per hour). Mice were killed 12 h later, followed by the harvesting of samples from the lung, liver, and gut for malondialdehyde and myeloperoxidase measurements. In other subsets of animals, blood samples were obtained by cardiac puncture at 1.5, 4, and 8 h after LPS administration for cytokine (TNF-alpha, IL-1 beta, and IL-10), nitrite/nitrate, alanine aminotransferase, and blood urea nitrogen measurements. Endotoxemic animals showed an increase in survival from 25% to 80% at the FP15 doses of 0.3 and 1 mg/kg per hour. The same dose of FP15 had no effect on plasma levels of nitrite/nitrate. There was a reduction in liver and lung malondialdehyde in the endotoxemic animals pretreated with FP15, as well as in hepatic myeloperoxidase and biochemical markers of liver and kidney damage (alanine aminotransferase and blood urea nitrogen). In a bacterial model of sepsis induced by cecal ligation and puncture, FP15 treatment (0.3 mg/kg per day) significantly protected against mortality. The current data support the view that peroxynitrite is a critical factor mediating liver, gut, and lung injury in endotoxemia and septic shock: its pharmacological neutralization may be of therapeutic benefit.