Smoking cessation during alcohol treatment: a randomized trial of combination nicotine patch plus nicotine gum

Aims   The primary aim was to compare the efficacy of smoking cessation treatment using a combination of active nicotine patch plus active nicotine gum versus therapy consisting of active nicotine patch plus placebo gum in a sample of alcohol-dependent tobacco smokers in an early phase of out-patient alcohol treatment. A secondary aim was to determine whether or not there were any carry-over effects of combination nicotine replacement on drinking outcomes.
Design   Small-scale randomized double-blind placebo-controlled clinical trial with 1-year smoking and drinking outcome assessment.
Setting   Two out-patient substance abuse clinics provided a treatment platform of behavioral alcohol and smoking treatment delivered in 3 months of weekly sessions followed by three monthly booster sessions.
Participants   Participants were 96 men and women with a diagnosis of alcohol abuse or dependence and smoking 15 or more cigarettes per day.
Intervention   All participants received open-label transdermal nicotine patches and were randomized to receive either 2 mg nicotine gum or placebo gum under double-blind conditions.
Findings   Analysis of 1-year follow-up data revealed that patients receiving nicotine patch plus active gum had better smoking outcomes than those receiving patch plus placebo gum on measures of time to smoking relapse and prolonged abstinence at 12 months. Alcohol outcomes were not significantly different across medication conditions.
Conclusions   Results of this study were consistent with results of larger trials of smokers without alcohol problems, showing that combination therapy (nicotine patch plus gum) is more effective than monotherapy (nicotine patch) for smoking cessation.     

Membrane-associated farnesylated UCH-L1 promotes α-synuclein neurotoxicity and is a therapeutic target for Parkinson's disease

Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is linked to Parkinson's disease (PD) and memory and is selectively expressed in neurons at high levels. Its expression pattern suggests a function distinct from that of its widely expressed homolog UCH-L3. We report here that, in contrast to UCH-L3, UCH-L1 exists in a membrane-associated form (UCH-L1^M) in addition to the commonly studied soluble form. C-terminal farnesylation promotes the association of UCH-L1 with cellular membranes, including the endoplasmic reticulum. The amount of UCH-L1^M in transfected cells is shown to correlate with the intracellular level of α-synuclein, a protein whose accumulation is associated with neurotoxicity and the development of PD. Reduction of UCH-L1^M in cell culture models of α-synuclein toxicity by treatment with a farnesyltransferase inhibitor (FTI-277) reduces α-synuclein levels and increases cell viability. Proteasome function is not affected by UCH-L1^M, suggesting that it may negatively regulate the lysosomal degradation of α-synuclein. Therefore, inhibition of UCH-L1 farnesylation may be a therapeutic strategy for slowing the progression of PD and related synucleinopathies.     

Global deletion of thrombospondin-1 increases cardiac and skeletal muscle capillarity and exercise capacity in mice

Thrombospondin-1 (TSP-1) is a known inhibitor of angiogenesis; however, a skeletal muscle phenotype of TSP-1 null mice has not been investigated. The purposes of this study were to compare and contrast TSP-1 null and wild-type mice by examining the following: (1) capillarity in the skeletal and cardiac muscles; (2) fibre type composition and oxidative enzyme activity in the hindlimb; and (3) the consequences of TSP-1 gene deletion for exercise capacity. In TSP-1 null mice, maximal running speed was 11% greater and time to exhaustion during submaximal endurance running was 67% greater compared with wild-type mice. Morphometric analyses revealed that TSP-1 null mice had higher ( P < 0.05) capillarity in the heart and skeletal muscle than wild-type mice, whereas no differences for fibre type composition or oxidative enzyme activity were present between the two groups. Cardiac function, as measured by transthoracic echocardiography, revealed no difference in myocardial contractility but greater left ventricular end-diastolic and systolic dimensions, corresponding to an elevated heart mass in the TSP-1 null mice. The results of this study indicate that TSP-1 is an important endogenous negative regulator of angiogenesis that prevents excessive capillarization in the heart and skeletal muscles. The increased capillarity alone was sufficient to increase ( P < 0.05) exercise capacity. These data demonstrate that the capillary-to-muscle interface is a critical factor that limits oxygen transport during exercise.     

From the Cover: Loss of phosphatidylinositol 4-kinase 2α activity causes late onset degeneration of spinal cord axons

Phosphoinositide (PI) lipids are intracellular membrane signaling intermediates and effectors produced by localized PI kinase and phosphatase activities. Although many signaling roles of PI kinases have been identified in cultured cell lines, transgenic animal studies have produced unexpected insight into the in vivo functions of specific PI 3- and 5-kinases, but no mammalian PI 4-kinase (PI4K) knockout has previously been reported. Prior studies using cultured cells implicated the PI4K2α isozyme in diverse functions, including receptor signaling, ion channel regulation, endosomal trafficking, and regulated secretion. We now show that despite these important functions, mice lacking PI4K2α kinase activity initially appear normal. However, adult Pi4k2a^GT/GT animals develop a progressive neurological disease characterized by tremor, limb weakness, urinary incontinence, and premature mortality. Histological analysis of aged Pi4k2a^GT/GT animals revealed lipofuscin-like deposition and gliosis in the cerebellum, and loss of Purkinje cells. Peripheral nerves are essentially normal, but massive axonal degeneration was found in the spinal cord in both ascending and descending tracts. These results reveal a previously undescribed role for aberrant PI signaling in neurological disease that resembles autosomal recessive hereditary spastic paraplegia.     

Guidelines for the management of hypertensive disorders of pregnancy 2008

This is the Executive Summary of updated guidelines developed by the Society of Obstetric Medicine of Australia and New Zealand for the management of hypertensive diseases of pregnancy. They address a number of challenging areas including the definition of severe hypertension, the use of automated blood pressure monitors, the definition of non-proteinuric pre-eclampsia and measuring proteinuria. Controversial management issues are addressed such as the treatment of severe hypertension and other significant manifestations of pre-eclampsia, the role of expectant management in pre-eclampsia remote from term, thromboprophylaxis, appropriate fluid therapy, the role of prophylactic magnesium sulfate and anaesthetic issues for women with pre-eclampsia. The guidelines stress the need for experienced team management for women with pre-eclampsia and mandatory hospital protocols for treatment of hypertension and eclampsia. New areas addressed in the guidelines include recommended protocols for maternal and fetal investigation of women with hypertension, preconception management for women at risk of pre-eclampsia, auditing outcomes in women with hypertensive diseases of pregnancy and long-term screening for women with previous pre-eclampsia.     

Clinical and epidemiologic features of group a streptococcal pneumonia in Ontario,Canada

BACKGROUND: Since the 1960s, group A streptococcus (GAS) has accounted for less than 1% of cases of community-acquired pneumonia. During the past 2 decades there has been a resurgence of invasive GAS infection, but no large study of GAS pneumonia has been performed. METHODS: To determine the clinical and epidemiologic features of GAS pneumonia, we conducted prospective, population-based surveillance of all invasive GAS infection in residents of Ontario from January 1, 1992, through December 31, 1999. RESULTS: Of 2079 cases of invasive GAS infection, 222 (11%) represented GAS pneumonia. The incidence of GAS pneumonia ranged from 0.16 per 100 000 in 1992 to 0.35 per 100 000 in 1999. Most cases were community acquired (81%). Forty-four percent of nursing home-acquired cases occurred during outbreaks. The case fatality rate was 38% for GAS pneumonia, compared with 12% for the entire cohort with invasive GAS infection and 26% for patients with necrotizing fasciitis. The presence of streptococcal toxic shock syndrome (odds ratio, 19; 95% confidence interval, 8.4-42; P =.001) and increasing age (odds ratio per decade, 1.45; 95% confidence interval, 1.2-1.7; P<.001) were associated with fatal outcome. Time to death was rapid, with a median of 2 days despite antimicrobial therapy and supportive measures. CONCLUSIONS: Group A streptococcal pneumonia is a common form of invasive GAS disease but remains an uncommon cause of community-acquired pneumonia. Progression is rapid despite appropriate therapy. The incidence is similar to, and the case fatality rate higher than, that of necrotizing fasciitis.     

Leukocytosis and adverse hospital outcomes after acute myocardial infarction

An elevated white blood cell (WBC) count at the time of hospital presentation is associated with increased mortality after acute myocardial infarction (AMI). The association between WBC count and the development of clinically significant complications of AMI and death during hospitalization for AMI is, however, less clear. The objectives of this observational study were to examine the association between baseline WBC count, the development of heart failure, cardiogenic shock, and death during hospitalization for AMI from a more generalizable community-wide perspective. The study sample consisted of adult residents of all ages from the Worcester, Massachusetts, metropolitan area (1990 census estimate 437,000) hospitalized with confirmed AMI at all greater Worcester medical centers. The study population consisted of 3,796 men and 2,734 women of all ages hospitalized with validated AMI, in 12 annual periods between 1986 and 1999, aggregated into quintiles based on WBC count obtained at the time of hospital admission. In multivariable-adjusted regression analyses controlling for potentially confounding demographic and clinical factors, patients in the uppermost quintiles of WBC count were at increased risk for heart failure (odds ratio [OR] 2.77, 95% confidence interval [CI] 2.33 to 3.31), cardiogenic shock (OR 2.82, 95% CI 2.05 to 3.87), and hospital death (OR 2.14, 95% CI 1.66 to 2.76). The results of our large observational study suggest that the peripheral total leukocyte count is strongly associated with the development of heart failure, cardiogenic shock, and death during hospitalization for AMI. These findings suggest that the WBC count should be considered an important prognostic factor associated with adverse hospital outcomes in patients with AMI.     

Early Breastfeeding Cessation Among HIV-Infected and HIV-Uninfected Women in Western Cape Province,South Africa

As part of the Mother-Infant Health Study, we describe infant feeding practices among HIV-infected and HIV-uninfected mothers over a 12-month period when the Western Cape Province prevention of mother-to-child transmission (PMTCT) program was transitioning from a policy of exclusive formula feeding to one of exclusive breastfeeding. Two hundred pairs of mother and HIV-uninfected infant were included in the analysis, among whom 81 women were HIV uninfected and breastfeeding. Of the 119 HIV-infected mothers, 50 (42%) were breastfeeding and 69 (58%) were formula feeding. HIV-infected mothers predominantly breastfed for 8.14 (7.71–15.86) weeks; HIV-uninfected mothers predominantly breastfed for 8.29 (8.0–16.0) weeks; and HIV-infected mothers predominantly formula fed for 50.29 (36.43–51.43) weeks. A woman’s HIV status had no influence on the time to stopping predominant breastfeeding (P?=?0.20). Our findings suggest suboptimal duration of breastfeeding among both HIV-infected and HIV-uninfected mothers. Providing support for all mothers postdelivery, regardless of their HIV status, may improve breastfeeding practices.