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.

Evaluating Patients With Suspected Nonepileptic Psychogenic Seizures

The authors evaluate 26 patients with suspected psychogenic non-epileptic seizures (PNES) who were referred to prolonged intensive video EEG (VEEG) in an epilepsy diagnostic center at the University of Sao Paulo, Brazil. Following the investigative protocol, 50% of the patients received a diagnosis of PNES, 15.4% of epilepsy, and 34.6% of associated PNES and epilepsy. In all patients in our series, PNES were the pseudo-neurological presentations of dissociative or conversion symptoms in patients presenting the following mental disorders: conversion disorder, somatization or undifferentiated somatoform disorder, dissociative disorder not otherwise specified, and posttraumatic stress disorder. Psychiatric comorbidities, mostly depressive disorders, were frequent. (The Journal of Neuropsychiatry and Clinical Neurosciences 2009; 21: 292-298)

Twenty seven-year experience with sternal cleft repair

Congenital sternal cleft is a rare disease, and primary repair in the neonatal period is its best management. In 1998 we presented three surgical techniques for sternal cleft correction, but since 1999 we have elected one of them as our procedure of choice. Our latest results are now presented. It is a review of 15 patients operated from October 1979 to December 2007. Surgical repair consisted of 3 sliding chondrotomies, 10 reconstructions basec on a `posterior sternal wall`, 1 reconstruction combined to Ravitch operation for pectus excavatum and 1 associated with total repair of Cantrell`s pentalogy. Data concerning epidemiological features, surgical reconstruction, aesthetic results, postoperative major complications, mortality and hospital stay, were collected from hospital charts. Follow-up ranged from 4 months to 27 years. All patients submitted to surgical, correction had a good aesthetic and functional result. Neither postoperative mortality nor major complication was observed. Two patients had subcutaneous fluid collection that prolonged the drainage duration. The mean hospital stay was 6 days. In conclusion, reconstructing sterna. cleft with a `posterior periosteal flap from sternal bars and chondral graft` is an effective option with good aesthetic and long-term functional results. (C) 2008 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Elevation of Uterine Basal Tone and Fetal Heart Rate Abnormalities After Labor Analgesia A Randomized Controlled Trial

OBJECTIVE: To estimate the effects of combined spinal-epidural and traditional epidural analgesia on uterine basal tone and its association with the occurrence of fetal heart rate (FHR) abnormalities. METHODS: Seventy-seven laboring patients who requested pain relief during labor were randomly assigned to combined spinal-epidural (n=41) or epidural analgesia (n=36). Uterine contractions and FHR were recorded 15 minutes before and after analgesia. Uterine tone was evaluated with intrauterine pressure catheter. Primary outcomes were the elevation of baseline uterine tone and occurrence of FHR prolonged decelerations or bradycardia after analgesia. The influence of other variables such as oxytocin use, hypotension, and speed of pain relief were estimated using a logistic regression model. RESULTS: The incidence of all outcomes was significantly greater in the combined spinal-epidural group compared with epidural: uterine hypertonus (17 compared with 6; P=.018), FHR abnormalities (13 compared with 2; P<.01), and both events simultaneously (11 compared with 1; P<.01). Logistic regression analysis showed the type of analgesia as the only independent predictor of uterine hypertonus (odds ratio 3.526, 95% confidence interval 1.21-10.36; P=.022). For the occurrence of FHR abnormalities, elevation of uterine tone was the independent predictor (odds ratio 18.624, 95% confidence interval 4.46-77.72; P<.001). Regression analysis also found a correlation between decrease on pain scores immediately after analgesia and the estimated probability of occurrence of hypertonus and FHR abnormalities. CONCLUSION: Combined spinal-epidural analgesia is associated with a significantly greater incidence of FHR abnormalities related to uterine hypertonus compared with epidural analgesia. The faster the pain relief after analgesia, the higher the probability of uterine hypertonus and FHR changes. CLINICAL TRIAL REGISTRATION: Umin Clinical Trials Registry, http://www.umin.ac.jp/ctr/index.htm, UMIN000001186

Hemorrhagic vesicle-bullous lesions in Henoch-Schonlein purpura and review of literature

Introduction: The characteristic feature of Henoch-Schonlein purpura (HSP) is palpable purpura, however hemorrhagic vesicles and blisters have been rarely reported. Case reports: From January 1983 to December 2007, 5079 patients were followed in our Pediatric Rheumatology Unit, 232 (4.6%) of them with the diagnosis of HSP. Three female patients (1.3%) presented hemorrhagic vesicles and bullous lesions associated with palpable purpura. In one case the lesions were severe and widespread, and in another they preceded the typical purpuric lesions. In both cases, skin biopsy disclosed leukocytoclastic vasculitis with IgA and C3 deposits. Two patients healed with residual lesions: ulcers in one case and skin hyperpigmentation in two of them. Discussion: Hemorrhagic vesicle-bullous lesions are rare in HSP This manifestation may represent a more severe and prolonged disease course with scars or may precede typical skin lesions.

A phase II study of UFT with leucovorin administered as a twice daily schedule in the treatment of patients with metastatic colorectal cancer

Prolonged infusions have been shown to be safer and potentially more effective than bolus regimens of 5-fluorouracil (5-FU) as treatment for metastatic colorectal cancer (mCRC). However, infusional 5-FU requires central venous access and costly infusion pumps. Oral fluoropyrimidines enable longer exposures to 5-FU with increased convenience. Tegafur - uracil (UFT) with leucovorin (LV) given thrice daily has improved safety plus comparable survival and response rates to bolus 5-FU/LV. We conducted a phase II clinical study in 98 patients with mCRC to evaluate if UFT with LV given twice daily provided comparable time to progression ( TTP), efficacy and tolerability to that reported for thrice daily in two phase III clinical studies. Secondary objectives included overall response rate ( ORR) and overall survival ( OS). Median TTP was 3.8 months, when compared with 3.5 months for thrice daily. The ORR ( 11%) and median OS ( 12.8 months) with twice daily administration were similar to that of thrice daily administration ( 12% and 12.4 months). The incidence of grade 3/4 treatment-related diarrhoea was 30% on the twice daily and 21% on the thrice daily schedule. These results suggest that twice daily administration has similar efficacy and tolerability to thrice daily administration and is an acceptable alternative for patients who would benefit from UFT with LV therapy.

Cardiovascular Risk and Clinical Factors in Athletes: 10 Years of Evaluation

DE MATOS, L. D. N. J., N. D. A. O. CALDEIRA, P. D. S. PERLINGEIRO, I. L. G. DOS SANTOS, C. E. NEGRAO and L. F. AZEVEDO. Cardiovascular Risk and Clinical Factors in Athletes: 10 Years of Evaluation. Med. Sci. Sports Exerc., Vol. 43, No. 6, pp. 943-950, 2011. Purpose: Preparticipation screening in athletes is a very current but controversial theme. Part of this controversy is due to the cost benefit, especially when the screening is merely used as a prevention of sudden cardiac death caused by rare and hereditary diseases. The purpose of this study was to describe the prevalence of preexisting diseases, cardiovascular risk factor for cardiovascular diseases development, and hematological profile in a population of amateur and professional athletes. Methods: Data of 623 athletes (529 men and 94 women), aged 13-77 yr, were analyzed to detect preexisting diseases. The variables total cholesterol, LDL, HDL, triglycerides, fasting glucose, body mass index, hemoglobin, hematocrit, and ferritin were analyzed in two groups according to age, that is, younger and older 35 yr old, and their prevalence (%) and distribution in quartiles were presented. chi(2) test and Pearson product-moment correlation coefficients between variables were applied, and P < 0.05 was adopted for significance. Results: Hypertension was the most prevalent preexisting diseases, although the data showed low prevalence of cardiomyopathy. Cardiovascular risk factors were prevalent in both genders. There were positive correlations between cardiovascular risk factors and age and between body mass index and lipid levels in male athletes. Also, there was a high prevalence of low ferritin levels for women, with positive correlation between the levels of hemoglobin and ferritin. Conclusions: In the present study, hypertension was the most prevalent diagnosed disease, and cardiovascular risk factors showed important prevalence, especially in athletes older than 35 yr. Although physical training represents a cardioprotective factor to the onset of cardiovascular disease, it does not exclude the prevalence of risk factors and diseases in athletes.

HDL atheroprotection by aerobic exercise training in type 2 diabetes mellitus

Purpose: In this study we analyzed the role played by aerobic exercise training in the plasma lipoprotein profile, prebeta 1-HDL concentration, and in the in vitro HDL3 ability to remove cholesterol from macrophages and inhibit LDL oxidation in type 2 diabetes mellitus (DM) patients and control subjects, in the fasting and postprandial states. Methods: Healthy controls (HTC, N = 11; 1 M/10 F) and subjects with type 2 diabetes mellitus (DMT, N = 11; 3M/ 8F) were engaged in a 4-month aerobic training program, and compared with a group of sedentary subjects with type 2 diabetes mellitus (DMS, N = 10; 4 M/6 F). All groups were submitted to an oral fat load test to analyze all parameters, both at the beginning of the investigation protocol (basal) and at the end of the study period (final). Results: Exercising did not modify body weight, BMI, plasma concentrations of total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides (TG), glucose, insulin, or HOMA-IR, but it reduced the waist circumference. The HDL3 Composition did not change, and its ability to remove cell cholesterol was unaltered by aerobic training. In DMT but not in HTC, aerobic training improved 15% the HDL3 protective effect against LDL maximal oxidation rate in the fasting state, and reduced 24% the plasma prebeta 1-HDL concentration in the postprandial state, suggesting an enhanced prebeta 1-HDL conversion into larger, more mature HDL particles. In this regard, regular aerobic exercise enriched HDL2 with TG in the fasting and postprandial states in HTC and in the fasting phase in DMT. Conclusion: Our results show that aerobic exercise training in diabetes mellitus improves the HDL efficiency against LDL oxidation and favors HDL maturation. These findings were independent of changes in insulin resistance and of the rise of plasma HDL cholesterol concentration.

Obesity, estrone, and coronary artery disease in postmenopausal women

Objectives: The link between obesity and endogenous estrogen with coronary artery disease (CAD) in postmenopausal women is uncertain. In this prospective study we analyzed the association of body mass index (BMI) and blood levels of estrone in postmenopausal women with known CAD or with a high risk factor score for CAD. Methods: Participants were 251 female clinic patients aged 50-90 years who were postmenopausal and not using estrogen therapy. Clinical and behavioral characteristics and fasting blood for estrone and heart disease risk factors were collected at baseline, and again at I and 2 years. Women were grouped according to their BMI (kg/m(2)) as normal (18.5 <= BMI < 25), overweight (25 <= BMI < 30) or obese (BMI >= 30), and by low and high estrone levels (< 15 and >= 15 pg/mL, respectively). Fatal and nonfatal events were recorded for 2 years after baseline. Results: Women with a low estrone level were older, thinner, and had less hypertension, diabetes, and lower triglyceride and glucose levels. BMI was positively associated with estrone levels, hypertension, and diabetes and inversely associated with HDL cholesterol. There were 14 deaths, 8 attributed to CAD. The Kaplan-Meier survival curve showed a nonsignificant trend (p = 0.074) of greater all cause mortality in women with low estrone levels (< 15 mL). In this model, adjusted for BMI, age [OR 1.08; p = 0.03], C-reactive protein [OR = 1.24; p = 0.024] and hypertension [OR = 6.22; p = 0.003] were independent predictors of all cause mortality. Conclusions: Postmenopausal women with low estrone levels (< 15 pg/mL) had a trend for increased mortality over the next 2 years. Larger, longer studies are needed. (c) 2008 Elsevier Ireland Ltd. All rights reserved.

Intranasal Corticosteroid Administration Reduces Nonspecific Bronchial Hyperresponsiveness and Improves Asthma Symptoms

Introduction. Rhinitis and asthma are currently recognized as manifestations of a single syndrome, the chronic allergic respiratory syndrome. Nearly all individuals with asthma have rhinitis, and severe rhinitis has been associated with worse outcomes in asthma patients. Intranasal treatment has been reported to be beneficial for the lower airways. Methods. This was a randomized, double-blind, placebo-controlled study. The objective was to evaluate the effects that treatment with intranasal beclomethasone dipropionate (BDP; 400 g/d) has on nasal and bronchial symptoms, as well as on lung function test results and bronchial responsiveness to histamine in patients with allergic rhinitis and asthma. We evaluated 33 patients, divided into two groups: treatment (n = 17); and placebo (n = 16). Over the course of the 125-day study period, each patient reported daily rhinitis and asthma symptoms, as well as the need for additional medication. All patients were submitted to spirometry and histamine challenge at baseline and at each subsequent evaluation (on days 50 and 75). Results. In comparison with the patients in the placebo group, those in the BDP treatment group presented significantly fewer nasal symptoms on day 50 and fewer asthma symptoms on day 75 (p 0.01 for both); required rescue medications less often; and presented a significantly lower degree of bronchial responsiveness to histamine on day 75 (p 0.01). Conclusion. In this study, intranasal BDP was effective in treating rhinitis as well as asthma. The benefits for the lower airways were observed only after prolonged treatment and might be better evaluated through nonspecific bronchial challenge.

Enterohormonal changes after digestive adaptation: Five-year results of a surgical proposal to treat obesity and associated diseases

Background Recent physiological knowledge allows the design of bariatric procedures that aim at neuroendocrine changes instead of at restriction and malabsorption. Digestive adaptation is a surgical technique for obesity based in this rationale. Methods The technique includes a sleeve gastrectomy, an omentectomy and a jejunectomy that leaves initial jejunum and small bowel totaling at least 3 m (still within normal variation of adult human bowel length). Fasting ghrelin and resistin and fasting and postprandial GLP-1 and PYY were measured pre- and postoperatively. Results Patients: 228 patients with initial body mass index (BMI) varying from 35 to 51 kg/m(2); follow-up: I to 5 years; average EBMIL% was 79.7% in the first year; 77.7% in the second year; 71.6% in the third year; 68.9% in the fourth year. Patients present early satiety and major improvement in presurgical comorbidities, especially diabetes. Fasting ghrelin and resistin were significantly reduced (P<0.05); GLP-1 and PYY response to food ingestion was enhanced (P<0.05). Surgical complications (4.4%) were resolved without sequela and without mortality. There was neither diarrhea nor detected malabsorption. Conclusions Based on physiological and supported by evolutionary data, this procedure creates a proportionally reduced gastrointestinal (GI) tract that amplifies postprandial neuroendocrine responses. It leaves basic GI functions unharmed. It reduces production of ghrelin and resistin and takes more nutrients to be absorbed distally enhancing GLP-1 and PYY secretion. Diabetes was improved significantly without duodenal exclusion. The patients do not present symptoms nor need nutritional support or drug medication because of the procedure, which is safe to perform.

PHOSPHODIESTERASE-4 INHIBITION REDUCES PROTEOLYSIS AND ATROGENES EXPRESSION IN RAT SKELETAL MUSCLES

Phosphodiesterase (PDE) inhibition reduces skeletal muscle atrophy, but the underlying molecular mechanism remains unclear. We used microdialysis to investigate the effects of different PDE inhibitors on interstitial tyrosine concentration as well as proteolytic activity and atrogenes expression in isolated rat muscle. Rolipram, a PDE-4-selective inhibitor, reduced the interstitial tyrosine concentration and rates of muscle protein degradation. The rolipram-induced muscle cAMP increase was accompanied by a decrease in ubiquitin proteasome system (UPS) activity and atrogin-1 mRNA, a ubiquitin-ligase involved in muscle atrophy. This effect was not associated with Akt phosphorylation but was partially blocked by a protein kinase A inhibitor. Fasting increased atrogin-1, MuRF-1 and LC3b expression, and these effects were markedly suppressed by rolipram. Our data suggest that activation of cAMP signaling by PDE-4 blockade leads to inhibition of UPS activity and atrogenes expression independently of Akt. These findings are important for identifying novel approaches to attenuate muscle atrophy. Muscle Nerve 44: 371-381, 2011

Crotamine toxicity and efficacy in mouse models of melanoma

Objectives: Selective anticancer cell activity for both cell-penetrating and cationic antimicrobial peptides has previously been reported. As crotamine possesses activities similar to both of these, this study investigates crotamine`s anticancer toxicity in vitro and in vivo. Research design and methods: In vitro cancer cell viability was evaluated after treatment with 1 and 5 mu g/ml of crotamine. In vivo crotamine cytotoxic effects in C57Bl/6J mice bearing B16-F10 primary cutaneous melanoma were tested, with two groups each containing 35 mice. The crotamine-treated group received 1 mu g/day of crotamine per animal, subcutaneously which was well tolerated; the untreated group received a placebo. Results: Crotamine at 5 mu g/ml was lethal to B16-F10, Mia PaCa-2 and SK-Mel-28 cells and inoffensive to normal cells. In vivo crotamine treatment over 21 days significantly delayed tumor implantation, inhibited tumor growth and prolonged the lifespan of the mice. Mice in the crotamine-treated group survived at significantly higher rates (n = 30/35) than those in the untreated group (n = 7/35) (significance calculated with the Kaplan-Meier estimator). The average tumor weight in the untreated group was 4.60 g but was only about 0.27 g in the crotamine-treated mice, if detectable. Conclusions: These data warrant further exploration of crotamine as a tumor inhibition compound.

Mechanisms Involved in 3 `,5 `-Cyclic Adenosine Monophosphate-Mediated Inhibition of the Ubiquitin-Proteasome System in Skeletal Muscle

Although it is well known that catecholamines inhibit skeletal muscle protein degradation, the molecular underlying mechanism remains unclear. This study was undertaken to investigate the role of beta(2)-adrenoceptors (AR) and cAMP in regulating the ubiquitin-proteasome system (UPS) in skeletal muscle. We report that increased levels of cAMP in isolated muscles, promoted by the cAMP phosphodiesterase inhibitor isobutyl methylxanthine was accompanied by decreased activity of the UPS, levels of ubiquitin-protein conjugates, and expression of atrogin-1, a key ubiquitin-protein ligase involved in muscle atrophy. In cultured myotubes, atrogin-1 induction after dexamethasone treatment was completely prevented by isobutyl methylxanthine. Furthermore, administration of clenbuterol, a selective beta(2)-agonist, to mice increased muscle cAMP levels and suppressed the fasting-induced expression of atrogin-1 and MuRF-1, atrogin-1 mRNA being much more responsive to clenbuterol. Moreover, clenbuterol increased the phosphorylation of muscle Akt and Foxo3a in fasted rats. Similar responses were observed in muscles exposed to dibutyryl-cAMP. The stimulatory effect of clenbuterol on cAMP and Akt was abolished in muscles from beta(2)-AR knockout mice. The suppressive effect of beta(2)-agonist on atrogin-1 was not mediated by PGC-1 alpha (peroxisome proliferator-activated receptor-gamma coactivator 1 alpha known to be induced by beta(2)-agonists and previously shown to inhibit atrogin-1 expression), because food-deprived PGC-1 alpha knockout mice were still sensitive to clenbuterol. These findings suggest that the cAMP increase induced by stimulation of beta(2)-AR in skeletal muscles from fasted mice is possibly the mechanism by which catecholamines suppress atrogin-1 and the UPS, this effect being mediated via phosphorylation of Akt and thus inactivation of Foxo3. (Endocrinology 150: 5395-5404, 2009)