Evaluating the safety profile of focused ultrasound and microbubble-mediated treatments to increase blood-brain barrier permeability

Introduction: Treatment of several diseases of the brain are complicated by the presence of the skull and the blood-brain barrier (BBB). Focused ultrasound (FUS) and microbubble (MB)-mediated BBB treatment is a minimally invasive method to transiently increase the permeability of blood vessels in targeted brain areas. It can be used as a general delivery system to increase the concentration of therapeutic agents in the brain parenchyma.

Areas covered: Over the past two decades, the safety of using FUS+MBs to deliver agents across the BBB has been interrogated through various methods of imaging, histology, biochemical assays, and behavior analyses. Here we provide an overview of the factors that affect the safety profile of these treatments, describe methods by which FUS+MB treatments are controlled, and discuss data that have informed the assessment of treatment risks.

Expert opinion: There remains a need to assess the risks associated with clinically relevant treatment strategies, specifically repeated FUS+MB treatments, with and without therapeutic agent delivery. Additionally, efforts to develop metrics by which FUS+MB treatments can be easily compared across studies would facilitate a more rapid consensus on the risks associated with this intervention.     

Depressive symptoms and heart rate variability in postmenopausal women

BACKGROUND: Depressive symptoms have been associated with increased cardiac morbidity and mortality rates, but the pathophysiologic mechanism linking depressive symptoms to cardiovascular outcome has yet to be fully understood. Lower heart rate variability has also been associated with increased risk of cardiac events in healthy individuals and in patients with coronary artery disease. Findings regarding a relationship between depressive symptoms and heart rate variability that could explain increased cardiovascular risk have been inconsistent across studies. METHODS: As an ancillary study to the Women's Health Initiative Observational Study, 3372 postmenopausal women aged 50 to 83 years were enrolled for further evaluation using 24-hour ambulatory electrocardiographic monitoring. A shortened version of the Center for Epidemiological Studies Depression Scale and the Diagnostic Interview Schedule were administered. Women with adequate electrocardiographic data and depressive symptom information and without coronary artery disease were analyzed (n = 2627). RESULTS: Two hundred sixty-nine women (10.2%) had depressive symptoms as measured using the 2 instruments. Women with depressive symptoms had a higher mean +/- SD heart rate (77.4 +/- 9.6 vs 75.5 +/- 8.5 beats/min) and lower heart rate variability than women without depressive symptoms. All differences remained significant after adjusting for age (P<.01). CONCLUSIONS: Women with depressive symptoms had significant reductions in heart rate variability and higher heart rates, suggestive of increased sympathetic tone. These findings may contribute to the increased cardiac morbidity and mortality rates associated with depression in other studies.     

Role of Dietary Protein and Thiamine Intakes on Cognitive Function in Healthy Older People: A Systematic Review

The effectiveness of nutritional interventions to prevent and maintain cognitive functioning in older adults has been gaining interest due to global population ageing. A systematic literature review was conducted to obtain and appraise relevant studies on the effects of dietary protein or thiamine on cognitive function in healthy older adults. Studies that reported on the use of nutritional supplementations and/or populations with significant cognitive impairment were excluded. Seventeen eligible studies were included. Evidence supporting an association between higher protein and/or thiamine intakes and better cognitive function is weak. There was no evidence to support the role of specific protein food sources, such as types of meat, on cognitive function. Some cross-sectional and case-control studies reported better cognition in those with higher dietary thiamine intakes, but the data remains inconclusive. Adequate protein and thiamine intake is more likely associated with achieving a good overall nutritional status which affects cognitive function rather than single nutrients. A lack of experimental studies in this area prevents the translation of these dietary messages for optimal cognitive functioning and delaying the decline in cognition with advancing age.     

Drug abuse and responsible fathering: a comparative study of men enrolled in methadone maintenance treatment

AIM: Because very little is known about the parenting of drug-abusing men, this study was designed to document ways that drug abuse contributes to compromise of responsible fathering. DESIGN, SETTING, PARTICIPANTS: Generalized linear models and data representing different dimensions of responsible fathering were used to clarify ways that the fathering of 106 men receiving methadone maintenance treatment differed from that of 118 men living in the same community with no history of alcohol or drug abuse. MEASUREMENT: Men who enrolled in the study completed two structured interviews and a battery of five self-report measures selected to document current and historical dimensions of responsible fathering. FINDINGS: When the opioid-dependent fathers were compared to the other fathers, there were significant differences in: (i) economic resources to support family formation; (ii) patterns of pair-bonding; (iii) patterns of procreation; and (iv) parenting behavior. When fathering of the youngest biological child was examined, the opioid-dependent fathers confirmed few differences in historical dimensions of fathering, but they reported significant differences in current dimensions reflecting: (i) constricted personal definitions of the fathering role; (ii) poorer relationships with biological mothers; (iii) less frequent residence with the child; (iv) less frequent provision of financial support; (v) less involvement in positive parenting; (vi) poorer appraisal of self as a father; and (vii) less satisfaction as a father. CONCLUSIONS: The findings highlight ways that drug abuse contributes to compromise of responsible fathering, and they raise questions about ways that the drug abuse treatment system might better address parenting as a treatment issue for men.     

Alpha 2 macroglobulin state in acute pancreatitis. Raised values of alpha 2 macroglobulin-protease complexes in severe and mild attacks.

Plasma values of C reactive protein, alpha 1 proteinase inhibitor, alpha 2 macroglobulin, and complexed alpha 2 macroglobulin have been determined in serial samples from 27 patients with acute pancreatitis. Complexed alpha 2 macroglobulin was measured by a novel enzyme linked immunosorbent assay with a monoclonal antibody specific for the complexed form. Patients with severe illness had lower concentrations of total alpha 2 macroglobulin and higher concentrations of complexed alpha 2 macroglobulin than those with mild illness, and in the majority of severe attacks the abnormal amounts of complexed alpha 2 macroglobulin were present throughout the eight days of the study. The proportion of total alpha 2 macroglobulin in the uncomplexed form, however, was generally greater than 90%, and in 26% of the mild cases completely normal concentrations of uncomplexed alpha 2 macroglobulin (greater than 99% of total) were found throughout the eight days of the study. This suggests that exhaustion of alpha 2 macroglobulin in plasma is unlikely to be a major factor in the pathogenesis of acute pancreatitis.     

Substance abuse history predicts depression and relapse status among cocaine abusers

This study examined the relationships between lifetime years of cocaine, alcohol, and marijuana use prior to entry into residential treatment for primary cocaine dependence and (a) intake depression levels, and (b) levels of cocaine use in the six months after completing treatment. Years of education, age, and lifetime years of cocaine and alcohol use contributed significantly to predicting depression levels. Lifetime years of alcohol use alone predicted cocaine use during the six months post-treatment.     

An audit of the treatment of cancer of the oesophagus.

The treatment of cancer of the oesophagus in The General Infirmary at Leeds between the years 1975 and 1988 was reviewed. All cases with histologically proved cancer of the oesophagus were included, data being obtained from case notes, theatre operation books, endoscopy records, pathology records, and the Yorkshire Cancer Registry. Three hundred and sixteen patients were identified. Demographic details, mode of presentation, preoperative investigations, surgical management, methods of palliation, and survival data were entered into a database. The male to female ratio was 3:2 and the median age at presentation was 69 years (range 35-96). Surgical exploration was carried out in 134 of 316 patients (42%). Resection of the tumour, whether curative or palliative, was possible in 106 of 134 patients (79%). Operative (30 day) mortality was 27%. In 22 of 134 patients (16%), only intubation of the tumour was possible, while six patients (5%) had a thoracotomy or laparotomy alone. Median survival of the 106 patients after surgical resection was 292 days (range 0-14.2 years) and seven of them (7%) were still alive five years later. Of the remaining 182 patients (58%) who were not operated upon, 36 patients (11%) had a radical course of radiotherapy with a median survival of 175 days (range 80-453) and 146 patients (46%) either had endoscopic intubation (n = 64) or received no specific treatment (n = 82) with a median survival of 106 days (1-725) and 91 days (1-358) respectively. None of the 182 patients who did not have surgical treatment was alive at five years.     

Efficacy and safety of sibutramine in obese white and African American patients with hypertension: a 1-year, double-blind, placebo-controlled, multicenter trial

BACKGROUND: Obesity is a highly prevalent medical condition and is commonly accompanied by hypertension. This study assessed the efficacy and safety of treatment with sibutramine hydrochloride for promoting and maintaining weight loss in obese patients with controlled hypertension, including a subset analysis of African American patients. PATIENTS AND METHODS: Obese patients with a body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) between 27 and 40 and a history of hypertension controlled with a calcium channel blocker (with or without concomitant thiazide diuretic treatment) were randomized to receive sibutramine (n = 150) or placebo (n = 74) with minimal behavioral intervention for 52 weeks. African Americans constituted 36% of enrolled patients. Efficacy assessments were body weight and related parameters (BMI and waist and hip circumferences), metabolic parameters (serum levels of triglycerides, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], total cholesterol, glucose, and uric acid), and quality-of-life measures. Safety assessments included recording of blood pressure, pulse rate, adverse events, and reasons for discontinuation. RESULTS: For patients receiving sibutramine, weight loss occurred during the first 6 months of the trial and was maintained to the end of the 12-month treatment period. Among patients receiving sibutramine, 40.1% lost 5% or more of body weight (5% responders) and 13.4% lost 10% or more of body weight (10% responders) compared with 8.7% and 4.3% of patients in the placebo group, respectively (P<.05). Changes in body weight were similar among African Americans and whites. Sibutramine-induced weight loss was associated with significant improvements in serum levels of triglycerides, HDL-C, glucose, and uric acid. Waist circumference and quality-of-life measures also improved significantly in patients receiving sibutramine. Sibutramine-treated patients had small but statistically significant mean increases in diastolic blood pressure (2.0 mm Hg) and pulse rate (4.9 beats/min) compared with placebo-treated patients (-1.3 mm Hg and 0.0 beats/min; P<.05); these changes were similar among African Americans and whites. Most adverse events were mild to moderate in severity and transient. The most common adverse event resulting in discontinuation among patients receiving sibutramine was hypertension (5.3% of patients receiving sibutramine vs 1.4% of patients receiving placebo). CONCLUSIONS: In obese patients with controlled hypertension, sibutramine was an effective and well-tolerated treatment for weight loss and maintenance. Sibutramine-induced weight loss resulted in improvements in serum levels of triglycerides, HDL-C, uric acid, and glucose, and in waist circumference and quality-of-life measures. Blood pressure and heart rate increased by a small amount. Efficacy and safety profiles for sibutramine among African American and white obese patients with controlled hypertension were similar.