Cardalert : a portable, battery-operated, real-time arrhythmia detector and alarm system /

Vita.

Histone deacetylase inhibitors target diabetes via chromatin remodeling or as chemical chaperones?

Globally, obesity and diabetes (particularly type 2 diabetes) represents a major challenge to world health. Despite decades of intense research efforts, the genetic basis involved in diabetes pathogenesis & conditions associated with obesity are still poorly understood. Recent advances have led to exciting new developments implicating epigenetics as an important mechanism underpinning diabetes and obesity related disease. One epigenetic mechanism known as the "histone code" describes the idea that specific patterns of post-translational modifications to histones act like a molecular "code" recognised and used by non-histone proteins to regulate specific chromatin functions. One modification which has received significant attention is that of histone acetylation. The enzymes which regulate this modification are described as lysine acetyltransferases or KATs and histone deacetylases or HDACs. Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target. Some of the known inhibitors of HDACs (HDACi) have also been shown to act as "chemical chaperones" to alleviate diabetic symptoms. In this review, we discuss the available evidence concerning the roles of HDACs in regulating chaperone function and how this may have implications in the management of diabetes. © 2009 Bentham Science Publishers Ltd.

Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX) : an open-label randomised phase III trial

Background: Use of cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has the potential to increase survival in patients with advanced non-small-cell lung cancer. We therefore compared chemotherapy plus cetuximab with chemotherapy alone in patients with advanced EGFR-positive non-small-cell lung cancer. Methods: In a multinational, multicentre, open-label, phase III trial, chemotherapy-naive patients (≥18 years) with advanced EGFR-expressing histologically or cytologically proven stage wet IIIB or stage IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio to chemotherapy plus cetuximab or just chemotherapy. Chemotherapy was cisplatin 80 mg/m 2 intravenous infusion on day 1, and vinorelbine 25 mg/m 2 intravenous infusion on days 1 and 8 of every 3-week cycle) for up to six cycles. Cetuximab-at a starting dose of 400 mg/m 2 intravenous infusion over 2 h on day 1, and from day 8 onwards at 250 mg/m 2 over 1 h per week-was continued after the end of chemotherapy until disease progression or unacceptable toxicity had occurred. The primary endpoint was overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00148798. Findings: Between October, 2004, and January, 2006, 1125 patients were randomly assigned to chemotherapy plus cetuximab (n=557) or chemotherapy alone (n=568). Patients given chemotherapy plus cetuximab survived longer than those in the chemotherapy-alone group (median 11·3 months vs 10·1 months; hazard ratio for death 0·871 [95% CI 0·762-0·996]; p=0·044). The main cetuximab-related adverse event was acne-like rash (57 [10%] of 548, grade 3). Interpretation: Addition of cetuximab to platinum-based chemotherapy represents a new treatment option for patients with advanced non-small-cell lung cancer. Funding: Merck KGaA. © 2009 Elsevier Ltd. All rights reserved.

Toxicity profile of the immunomodulatory thalidomide analogue, lenalidomide : Phase I clinical trial of three dosing schedules in patients with solid malignancies

Thalidomide is an anti-angiogenic agent currently used to treat patients with malignant cachexia or multiple myeloma. Lenalidomide (CC-5013) is an immunomodulatory thalidomide analogue licensed in the United States of America (USA) for the treatment of a subtype of myelodysplastic syndrome. This two-centre, open-label phase I study evaluated dose-limiting toxicities in 55 patients with malignant solid tumours refractory to standard chemotherapies. Lenalidomide capsules were consumed once daily for 12 weeks according to one of the following three schedules: (I) 25 mg daily for the first 7 d, the daily dose increased by 25 mg each week up to a maximum daily dose of 150 mg; (II) 25 mg daily for 21 d followed by a 7-d rest period, the 4-week cycle repeated for 3 cycles; (III) 10 mg daily continuously. Twenty-six patients completed the study period. Two patients experienced a grade 3 hypersensitivity rash. Four patients in cohort I and 4 patients in cohort II suffered grade 3 or 4 neutropaenia. In 2 patients with predisposing medical factors, grade 3 cardiac dysrhythmia was recorded. Grade 1 neurotoxicity was detected in 6 patients. One complete and two partial radiological responses were measured by computed tomography scanning; 8 patients had stable disease after 12 weeks of treatment. Fifteen patients remained on treatment as named patients; 1 with metastatic melanoma remains in clinical remission 3.5 years from trial entry. This study indicates the tolerability and potential clinical efficacy of lenalidomide in patients with advanced solid tumours who have previously received multi-modality treatment. Depending on the extent of myelosuppressive pre-treatment, dose schedules (II) or (III) are advocated for large-scale trials of long-term administration. © 2006 Elsevier Ltd. All rights reserved.

Atrial assist device, a new alternative to lifelong anticoagulation?

OBJECTIVE: Atrial fibrillation is a very common heart arrhythmia, associated with a five-fold increase in the risk of embolic strokes. Treatment strategies encompass palliative drugs or surgical procedures all of which can restore sinus rhythm. Unfortunately, atria often fail to recover their mechanical function and patients therefore require lifelong anticoagulation therapy. A motorless volume displacing device (Atripump) based on artificial muscle technology, positioned on the external surface of atrium could avoid the need of oral anticoagulation and its haemorrhagic complications. An animal study was conducted in order to assess the haemodynamic effects that such a pump could provide. METHODS: Atripump is a dome-shape siliconecoated nitinol actuator sewn on the external surface of the atrium. It is driven by a pacemaker-like control unit. Five non-anticoagulated sheep were selected for this experiment. The right atrium was surgically exposed, the device sutured and connected. Haemodynamic parameters and intracardiac ultrasound (ICUS) data were recorded in each animal and under three conditions; baseline; atrial fibrillation (AF); atripump assisted AF (aaAF). RESULTS: In two animals, after 20 min of AF, small thrombi appeared in the right atrial appendix and were washed out once the pump was turned on. Assistance also enhanced atrial ejection fraction. 31% baseline; 5% during AF; 20% under aaAF. Right atrial systolic surfaces (cm2) were; 5.2 +/- 0.3 baseline; 6.2 +/- 0.1 AF; 5.4 +/- 0.3 aaAF. CONCLUSION: This compact and reliable pump seems to restore the atrial "kick" and prevents embolic events. It could avoid long-term anticoagulation therapy and open new hopes in the care of end-stage heart failure.

ACAO ANTIARRITMICA DA METOCLOPRAMIDA (PLASIL®) EM INTOXICACAO DIGITALICA EXPERIMENTAL. COMPARACAO COM A DIFENIL-HIDANTOINA

The antiarrhythmic action of metoclopramide in cardiac arrhythmias caused by toxic doses of desacetyl-lanatoside C and digitoxin was studied in dogs. A comparison was made between the efficacy of metoclopramide and diphenylhydantoin in arrhythmias caused by digitoxin. The results indicate that metoclopramide antagonized the arrhythmias induced by desacetyl-lanatoside C, while causing a transitory reversion of those induced by digitoxin in most of the experiments. Diphenylhydantoin failed to show an arrhythmic effect in the majority of the tested animals.

Eficácia e segurança do uso inalatório da adrenalina-L na laringite pós-intubação utilizada em associação com a dexametasona

Objective: to assess the efficacy and safety of the use of nebulized L-epinephrine associated with dexamethasone in post-intubation laryngitis. Method: we carried out a prospective, randomized, double-blind, placebo controlled study with two cohorts of patients with postintubation laryngitis graded 3 to 6 by Downes and Raphaely score and during two years. Our population was divided into two groups: A and B; both groups received intravenous dexamethasone and nebulized saline with (group B) and without (group A) L-epinephrine. The efficacy was assessed by Downes and Raphaely's score. The side effects of epinephrine were evaluated according to occurrence of arrhythmia, to increased blood pressure, and to average heart rate of group B in comparison to group A. Results: twenty-two patients were included in group A (average score = 4.8) and 19 in group B (average score = 5.2). During treatment, 3 patients in group A presented a score of 8 and were reintubated. This group also showed higher clinical scores than group B during the first two hours of the protocol; these results were not statistically significant. No side effects were observed due to epinephrine. The gasometric parameters were adequate in both groups, but better in the control group. Conclusions: we did not observe increased efficacy for the treatment of post-intubation laryngitis when nebulized L-epinephrine was used simultaneously with intravenous dexamethasone. Some indicators, however, did present a favorable trend when combined therapy was used and should be submitted to further evaluation.

Evaluation of cardiac rhythm in dogs treated with levamisole hydrochloride using 24-hour ambulatory electrocardiography

The objective of this study was to evaluate the electrocardiographic alterations in the cardiac rhythm in dogs treated with levamisole hydrochloride over a period of 24 hours. Thirty-six mixed-breed dogs, both male and female, all clinically healthy, were used in the experiment. The dogs were divided into 6 groups with 6 dogs in each group, according to dosage and route of administration. The Holter test was initiated immediately after the treatment, and was maintained for 24 hours. In the group treated with 10 mg/kg by way of subcutaneous injection, one of them showed ventricular premature complexes, sometimes isolated and other times in pairs, and ventricular tachycardia, concentrated mainly in the first hour after administration of the drug. In the group of 6 animals treated subcutaneously with 25mg/kg, four showed isolated ventricular premature complexes, ventricular bigeminy and trigeminy, mainly during the first 2 hours after administration of the drug. All the animals in the other groups showed sinus arrhythmia followed by sinus arrest. The disturbances in the cardiac rhythm observed in clinically healthy animals treated with levamisole hydrochloride, indicate that it is preferable to avoid subcutaneous administration of levamisole hydrochloride and that the oral administration of the drug should be done with caution. © 2003 Elsevier B.V. All rights reserved.

Anthracycline-induced cardiotoxicity

The anthracyclines constitute a group of drugs widely used for the treatment of a variety of human tumors. However, the development of irreversible cardiotoxicity has limited their use. Anthracycline-induced cardiotoxicity can persist for years with no clinical symptoms. However, its prognosis becomes poor after the development of overt heart failure, possibly even worse than ischemic or idiopathic dilated cardiomyopathies. Due to the successful action of anthracyclines as chemotherapic agents, several strategies have been tried to prevent/ attenuate their side effects. Although anthracycline-induced injury appears to be multifactorial, a common denominator among most of the proposed mechanisms is cellular damage mediated by reactive oxygen species. However, it remains controversial as to whether antioxidants can prevent such side effects given that different mechanisms may be involved in acute versus chronic toxicity. The present review applies a multisided approach to the critical evaluation of various hypotheses proposed over the last decade on the role of oxidative stress in cardiotoxicity induced by doxorubicin, the most used anthracycline agent. The clinical diagnosis and treatment is also discussed. © 2008 Bentham Science Publishers Ltd.

Sudden cardiac death athletes: a systematic review

Previous events evidence that sudden cardiac death (SCD) in athletes is still a reality and it keeps challenging cardiologists. Considering the importance of SCD in athletes and the requisite for an update of this matter, we endeavored to describe SCD in athletes. The Medline (via PubMed) and SciELO databases were searched using the subject keywords sudden death, athletes and mortality. The incidence of SCD is expected at one case for each 200,000 young athletes per year. Overall it is resulted of complex dealings of factors such as arrhythmogenic substrate, regulator and triggers factors. In great part of deaths caused by heart disease in athletes younger than 35 years old investigations evidence cardiac congenital abnormalities. Athletes above 35 years old possibly die due to impairments of coronary heart disease, frequently caused by atherosclerosis. Myocardial ischemia and myocardial infarction are responsible for the most cases of SCD above this age (80%). Pre-participatory athletes' evaluation helps to recognize situations that may put the athlete's life in risk including cardiovascular diseases. In summary, cardiologic examinations of athletes' pre-competition routine is an important way to minimize the risk of SCD. © 2010 Ferreira et al; licensee BioMed Central Ltd.

A comparison between diuretics and angiotensin-receptor blocker agents in patients with stage I hypertension (PREVER-treatment trial): Study protocol for a randomized double-blind controlled trial

Background: Cardiovascular disease is the leading cause of death in Brazil, and hypertension is its major risk factor. The benefit of its drug treatment to prevent major cardiovascular events was consistently demonstrated. Angiotensin-receptor blockers (ARB) have been the preferential drugs in the management of hypertension worldwide, despite the absence of any consistent evidence of advantage over older agents, and the concern that they may be associated with lower renal protection and risk for cancer. Diuretics are as efficacious as other agents, are well tolerated, have longer duration of action and low cost, but have been scarcely compared with ARBs. A study comparing diuretic and ARB is therefore warranted.Methods/design: This is a randomized, double-blind, clinical trial, comparing the association of chlorthalidone and amiloride with losartan as first drug option in patients aged 30 to 70 years, with stage I hypertension. The primary outcomes will be variation of blood pressure by time, adverse events and development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG. The secondary outcomes will be fatal or non-fatal cardiovascular events: myocardial infarction, stroke, heart failure, evidence of new subclinical atherosclerosis and sudden death. The study will last 18 months. The sample size will be of 1200 participants for group in order to confer enough power to test for all primary outcomes. The project was approved by the Ethics committee of each participating institution.Discussion: The putative pleiotropic effects of ARB agents, particularly renal protection, have been disputed, and they have been scarcely compared with diuretics in large clinical trials, despite that they have been at least as efficacious as newer agents in managing hypertension. Even if the null hypothesis is not rejected, the information will be useful for health care policy to treat hypertension in Brazil. Clinical trials registration number: ClinicalTrials.gov: NCT00971165. © 2011 Fuchs et al; licensee BioMed Central Ltd.

Adverse drug reaction as cause of hospital admission of elderly people: a pilot study

The objective of this study was to estimate the prevalence of adverse drug reactions (ADR) related to hospital admission of elderly people, identifying the use of potentially inappropriate medication (PIM), the ADR and the risk factors associated with the hospitalization. A cross-sectional study was conducted in a private hospital of São Paulo State, Brazil. All patients aged ≥ 60 years, admitted in the general practice ward in May 2006 were interviewed about the drugs used and the symptoms/complaints that resulted in hospitalization. More than a half (54.5 %) of elderly hospitalizations were related with ADR. The therapeutic classes involved with ADR were: cardiovascular (37.7 %), central nervous (34.6 %) and respiratory (5.7 %). The ADR observed were disorders in circulatory (28.4 %), digestive (20.0 %) and respiratory (18.9 %) tracts. 27 elderly had made PIM and in 20 of them this was the cause of hospitalization. Polypharmacy was an ADR risk factor (p = 0.021).These data allows the healthcare professionals upgrade, qualifying them in pharmcovigilance.

American visceral leishmaniasis: Factors associated with lethality in the state of São Paulo, Brazil

Objectives. To identify factors associated with death in visceral leishmaniasis (VL) cases. Patients and Methodology. We evaluated prognostic factors for death from VL in São Paulo state, Brazil, from 1999 to 2005. A prognostic study nested in a clinical cohort was carried out by data analysis of 376 medical files. A comparison between VL fatal cases and survivors was performed for clinical, laboratory, and biological features. Association between variables and death was assessed by univariate analysis, and the multiple logistic regression model was used to determine adjusted odds ratio for death, controlling confounding factors. Results. Data analysis identified 53 fatal cases out of 376 patients, between 1999 and 2005 in São Paulo state. Lethality was 14.1 (53/376), being higher in patients older than fifty years. The main causes of death were sepsis, bleeding, liver failure, and cardiotoxicity due to treatment. Variables significantly associated with death were severe anemia, bleeding, heart failure, jaundice, diarrhea, fever for more than sixty days, age older than fifty years, and antibiotic use. Conclusion. Educational health measures are needed for the general population and continuing education programs for health professionals working in the affected areas with the purpose of identifying and treating early cases, thus preventing the disease evolution towards death. © 2012 Geraldine Madalosso et al.

Evaluating the effectiveness of Bayesian feature selection

A practical Bayesian approach for inference in neural network models has been available for ten years, and yet it is not used frequently in medical applications. In this chapter we show how both regularisation and feature selection can bring significant benefits in diagnostic tasks through two case studies: heart arrhythmia classification based on ECG data and the prognosis of lupus. In the first of these, the number of variables was reduced by two thirds without significantly affecting performance, while in the second, only the Bayesian models had an acceptable accuracy. In both tasks, neural networks outperformed other pattern recognition approaches.