A new sensitive and subunit-selective molecular tool for investigating protein kinase A in the brain

Despite cellular complexity, a limited number of small molecules act as intracellular second messengers. Protein kinase A (PKA) is the main transducer of the information carried by cyclic adenosine monophosphate (cAMP). Recently, cellular imaging has achieved major technical advancements, although the search for more specific and sensitive low-molecular-weight probes to explore subcellular events involving second messengers is still in progress. The convergent synthesis of a novel, fluorescent small molecule comprising the cAMP structure and a rhodamine-based fluorescent residue, connected through a flexible linker, is described here. The interaction motif of this compound with PKA was investigated in silico using a blind docking approach, comparing its theoretical binding energy with the one calculated for cAMP. Moreover, the predicted pharmacokinetic properties were also computed and discussed. The new probe was tested on three areas of the mouse central nervous system (parietal cerebral cortex, hippocampus, and cerebellar cortex) with different fixation methods demonstrating remarkable selectivity towards the PKA RIα subunit. The probe showed overall better performances when compared to other commercially available fluorescent cAMP analogues, acting at lower concentrations, and providing stable labeling.     

The relationship of CCR5 antagonists to CD4+ T-cell gain: a meta-regression of recent clinical trials in treatment-experienced HIV-infected patients

Purpose: Lower CD4+ T-cell counts are related to increased morbidity and mortality despite virologic suppression. CCR5 antagonists are associated with robust CD4+ T-cell responses. We examined the relationship of CCR5 antagonists to CD4+ T-cell gains. Design: Meta-regression of recent phase 2-3 trials evaluating new antiretroviral agents in treatment-experienced subjects. Methods: We analyzed the relationship of CCR5 antagonists to CD4+ T-cell count increase 24 weeks after initiating the new regimen using a linear model with generalized estimating equations controlling for differing rates of virologic suppression. Each treatment group was treated as a data point weighted by sample size. Results: We included 46 treatment groups from 17 trials (11 groups from 5 trials used CCR5 antagonists). Controlling for average baseline HIV-1 RNA and proportion of subjects achieving HIV-1 RNA <50 copies/mL, use of a CCR5 antagonist was associated with an additional significant CD4+ T-cell gain of +30/μL (95% CI, 19-42) at 24 weeks compared to treatment groups not using a CCR5 antagonist. Conclusions: Use of a CCR5 antagonist was associated with an enhanced CD4+ T-cell count response independent of virologic suppression. This observation supports further evaluation of CCR5 antagonists in patients with discordant immunologic and virologic responses to ART.     

Neutrophil chemotactic activity in human gastric secretions

To study levels of neutrophil chemotactic activity in human gastric secretions, these secretions were collected via the endoscope during elective esophagogastroduodenoscopy. Fresh samples were then prepared for the neutrophil chemotactic assay with the use of human peripheral neutrophils in modified Boyden chambers. Mean maximum chemotactic activity was 45.8% +/- 11.2% in patients with gastric inflammation compared with only 10.1% +/- 4.2% in patients with normal results of endoscopic examination. The chemotactic factors responsible for this chemotactic activity may play a role in the recruitment of neutrophils to areas of gastric mucosal injury.     

Quality of Life Following Surgery for Intracranial Meningiomas at Brigham and Women's Hosipital: A Study of 164 Patients Using a Modification of the Functional Assessment of Cancer Therapy–brain Questionnaire

The objective of this study was to determine the subjectively reported quality of life (QOL) of patients with meningiomas surgically treated. Demographic, medical and outcomes data on 164 patients were retrospectively analyzed with the use of the Brain Tumor Center database at the Brigham and Women's Hospital, Boston, MA. The patients were contacted via a telephone survey and were asked 26 standardized QOL questions based on a modification of the validated Functional Assessment of Cancer Therapy–Brain (FACT–BR) Study, which used only questions adjuvant to brain tumor patients.The patients ages ranged from 23 to 87 years. The mean follow-up time after intracranial surgery was 33 months and median follow-up time was 28 months, with a range of 0 to 165 months. Of those 164 patients still living, 95% (155) participated in the telephone survey. 80% reported being satisfied with their post-treatment quality of life; 86% reported that they could write, read, drive and return to work at their pre-morbid level of functioning; 87% described themselves as independent and able to act on their own initiatives.Our study found a high level of satisfaction for QOL in patients who have undergone surgery for intracranial meningiomas. Patients, by their own report, are able to lead independent, personally satisfying, meaningful and productive lives. This provides useful information to share with patients in discussions regarding surgical treatment of these lesions.     

Adapted changes in left ventricular structure and function in severe uncomplicated obesity

OBJECTIVE: A massive amount of fat tissue, as that observed in obese subjects with BMI over 50 kg/m(2), could affect cardiac morphology and performance, but few data on this issue are available. We sought to evaluate cardiac structure and function in uncomplicated severely obese subjects. RESEARCH METHODS AND PROCEDURES: We studied 55 uncomplicated severely obese patients, 40 women, 15 men, mean age 35.5 +/- 10.2 years, BMI 51.2 +/- 8.8 kg/m(2), range 43 to 81 kg/m(2), with a history of fat excess of at least 10 years, and 55 age-matched normal-weight subjects (40 women, 15 men, mean BMI 23.8 +/- 1.2 kg/m(2)) as a control group. Each subject underwent an echocardiogram to evaluate left ventricular (LV) mass and geometry and systolic and diastolic function. RESULTS: Severely obese subjects showed greater LV mass and indexed LV mass than normal-weight subjects (p < 0.01 for all parameters). Nevertheless, LV mass was appropriate for sex, height(2.7), and stroke work in most (77%) uncomplicated severely obese subjects. In addition, no significant difference in LV mass indices and LV mass appropriateness between obese subjects with BMI > or = 50 kg/m(2) and those with BMI < or = 50 kg/m(2) was found. Obese subjects also showed higher ejection fraction and midwall shortening than normal-weight subjects (p = 0.05 and p < 0.01, respectively), suggesting a hyperdynamic systolic function. No significant difference in systolic performance between obese subjects with BMI > or = 50 kg/m(2) and those with BMI < or = 50 kg/m(2) was seen. DISCUSSION: Our data show that uncomplicated severe obesity, despite the massive fat tissue amount, is associated largely with adapted and appropriate changes in cardiac structure and function.     

Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk

Metabolic syndrome is related to multiple cardiovascular risk factors. Visceral adipose tissue (VAT) plays a key role in metabolic syndrome. Easy detection of VAT could be an important tool to increase knowledge of metabolic syndrome. The objective of this study was to study the relationship of echocardiographic epicardial adipose tissue to anthropometric and clinical parameters of metabolic syndrome. We selected 72 consecutive subjects, 46.5 +/- 17.4 yr of age, with a body mass index between 22 and 47 kg/m(2). Each subject underwent transthoracic echocardiogram to measure epicardial fat thickness on right ventricle and magnetic resonance imaging to calculate visceral adipose tissue. Anthropometric, metabolic, and cardiac parameters were also evaluated. Echocardiographic epicardial adipose tissue showed a very good correlation with magnetic resonance imaging abdominal VAT and epicardial fat measurement (Bland-Altman plot and linear regression). Multiple regression analysis showed that waist circumference (r(2) = 0.428; P = 0.01), diastolic blood pressure (r(2) = 0. 387; P = 0.02), and fasting insulin (r(2) = 0.387; P = 0.03) were the strongest independent variables correlated with epicardial adipose tissue. Echocardiographic epicardial adipose tissue could be applied as an easy and reliable imaging indicator of VAT and cardiovascular risk.     

Intragastric Balloon or Diet Alone? A Retrospective Evaluation

BACKGROUND: Very few studies have reported results of the BioEnterics Intragastric Balloon (BIB(R)) at >/=12 months follow-up. The aim of this study is the retrospective evaluation of the results of BIB placement compared to diet regimen alone. METHODS: From January 2005 to June 2006, 130 outpatients underwent a structured diet plan with simple behavioral modification at our institutions. Controls (n = 130) were selected from the charts of patients who, during the same period, underwent BIB treatment. Patients in the outpatient group were given a structured balanced diet with a caloric intake between 1,000 and 1,200. The approximate macronutrient distribution, according the "Mediterranean diet," was 25% protein (at least 60 g/day), 20-25% lipids, and 50-55% carbohydrates. In the BIB group, patients received generic counseling for eating behavior. In both groups, we considered weight loss parameters (kilograms, percentage of excess weight loss [%EWL], body mass index [BMI], percentage of excess BMI loss [%EBL]) at 6 and 24 months from baseline and comorbidities at baseline and after 24 months. Results are expressed as mean+/-standard deviation. Statistical analysis was done by Student's t-test and chi (2)-test or Fisher's exact test. p < .05 was considered significant. RESULTS: At the time of BIB removal (6 months), significantly better results in terms of weight loss in kilograms (16.7 +/- 4.7 vs. 6.6 +/- 2.6; p < 0.01), BMI (35.4 +/- 11.2 vs. 38.9 +/- 12.1; p < 0.01), %EBL (38.5 +/- 16.1 Vs 18.6 +/- 14.3; p < 0.01), and %EWL (33.9 +/- 18 vs. 24.3 +/- 17.0; p < 0.01) were observed in patients treated by intragastric balloon as compared to diet-treated patients. At 24 months from baseline, patient dropout was 1/130 (0.7%) and 25/130 (19.2%) in the BIB and diet groups, respectively (p < 0.001). At this time, patients treated with intragastric balloon have tended to regain weight, whereas diet-treated patients have already regained most of lost weight. CONCLUSIONS: Although the strength of this study may be limited by its retrospective design, the results indicate that, in the short-to-medium term, BIB is significantly superior to diet in terms of weight loss.     

Achieving housestaff competence in emergency airway management using scenario based simulation training: comparison of attending vs housestaff trainers

STUDY OBJECTIVES: To evaluate a teaching protocol comparing a critical care attending to a housestaff team in training medical interns in initial airway management skills using a computer-controlled patient simulator (CPS) and scenario-based simulation training (SST). DESIGN: Prospective, randomized, controlled, unblinded trial. SETTING: Internal medicine residency training program in an urban teaching hospital. PARTICIPANTS: Forty-nine starting internal medicine interns in July 2003, all of whom had been certified in advanced cardiac life support in June 2003. INTERVENTIONS: All interns were tested and scored with a CPS while responding to a standardized respiratory arrest scenario. Random allocation to either training by a single experienced teaching attending or by a housestaff team occurred immediately following testing. All interns were retested using the same scenario 6 weeks following the initial training, and their clinical performance of airway management was scored during actual patient events throughout the year. MEASUREMENTS: Initial airway management was divided into specific scorable steps. For each intern, individual step scores and total scores were recorded before and after training. For 10 consecutive months following training, intern airway management scores were recorded for actual patient airway events. RESULTS: All starting medical interns demonstrated poor initial airway management skills. SST was effective in improving these skills, both on retesting with the patient simulator and in actual patient situations. Interns trained by a housestaff team performed as well as interns trained by the attending. CONCLUSIONS: SST is effective in training medical interns, and the results are equivalent whether the training is provided by an experienced teaching attending or by a housestaff training team.