Treatment of hot flashes with transdermal estradiol administration

A randomized prospective double blind study was performed to assess the ability of a transdermal therapeutic system (TTS) delivering estradiol (E2) to suppress hot flashes (HFs) in symptomatic postmenopausal women. Patients were given placebo or E2 in four doses for a 20-day period, and serum gonadotropin and estrogen levels and the occurrences of HFs were measured. Administration of placebo had no measurable effect on either estrogen or gonadotropin levels or the occurrence of HFs. A dose-response relationship was found between the rate of E2 administered and the circulating level of E2, with 25, 50, 100, and 200 micrograms/24 h dosages raising the mean E2 concentrations from mean baseline levels of 5-8 pg/ml to 18, 38, 73, and 100 pg/ml, respectively. Estrone levels also increased with TTS application, but to a lesser extent than did E2 levels. Dose-response reductions of FSH and LH with increasing amounts of E2 administration occurred, but gonadotropin levels were not lowered in any of the patients into the ranges found in premenopausal women. TTS application significantly suppressed the occurrence of HFs at the 50 micrograms/24 h dosage and higher. A significant negative correlation (r = 0.6045; P less than 0.001) between E2 levels and the rates of occurrence of HFs was found during hormone administration. Based on this regression, 50% and 100% reductions of HFs should occur at 61 and 122 pg/ml E2. These data indicate that the transdermal delivery of E2 with these systems significantly reduced the occurrence of HFs and allowed definition of the therapeutic range of hormone replacement in terms of lost ovarian function, as reflected by circulating E2 levels.     

Biochemical alterations associated with ALS

Our objective was to identify metabolic pathways affected by ALS using non-targeted metabolomics in plasma, comparing samples from healthy volunteers to those from ALS patients. This discovery could become the basis for the identification of therapeutic targets and diagnostic biomarkers of ALS. Two distinct cross-sectional studies were conducted. Plasma was collected from 62 (Study 1) and 99 (Study 2) participants meeting El Escorial criteria for possible, probable, or definite ALS; 69 (Study 1) and 48 (Study 2) healthy controls samples were collected. Global metabolic profiling was used to detect and evaluate biochemical signatures of ALS. Twenty-three metabolites were significantly altered in plasma from ALS patients in both studies. These metabolites include biochemicals in pathways associated with neuronal change, hypermetabolism, oxidative damage, and mitochondrial dysfunction, all of which are proposed disease mechanisms in ALS. The data also suggest possible hepatic dysfunction associated with ALS. In conclusion, the data presented here provide insight into the pathophysiology of ALS while suggesting promising areas of focus for future studies. The metabolomics approach can generate novel hypotheses regarding ALS disease mechanisms with the potential to identify therapeutic targets and novel diagnostic biomarkers.     

Antimicrobial activity of fosfomycin and tobramycin in combination against cystic fibrosis pathogens under aerobic and anaerobic conditions

BackgroundThere is a need for new antibiotics or combination of antibiotics that possess activity against increasingly resistant cystic fibrosis (CF) respiratory pathogens such as Pseudomonas aeruginosa and MRSA.MethodsThe antimicrobial activity of a novel 4:1 (w/w) fosfomycin:tobramycin (F:T) combination against CF respiratory pathogens under both aerobic and anaerobic conditions was determined by MIC, time-kill and biofilm studies, and compared with activity of fosfomycin and tobramycin, individually.ResultsF:T and fosfomycin had excellent activity against P. aeruginosa and were more active than tobramycin against P. aeruginosa under anaerobic conditions with lower MIC₅₀, MIC₉₀ and geometric mean values. F:T (p < 0.001) and fosfomycin (p < 0.001) MICs for P. aeruginosa were significantly lower under anaerobic conditions with tobramycin MICs significantly higher (p < 0.001). F:T and fosfomycin also had high activity against MRSA with both being more active than tobramycin. In time–kill studies, F:T was rapidly bactericidal against all 15 P. aeruginosa and 3/5 MRSA isolates tested. F:T also demonstrated bactericidal activity against P. aeruginosa grown in biofilm under both aerobic and anaerobic conditions.ConclusionsF:T has promising in vitro antimicrobial activity against MRSA and P. aeruginosa with greater activity under anaerobic conditions similar to those found in the CF lung.     

Denosumab reduces the risk of osteoporotic fractures in postmenopausal women, particularly in those with moderate to high fracture risk as assessed with FRAX

Denosumab has been shown to reduce the incidence of vertebral, nonvertebral, and hip fractures. The aim of the current study was to determine whether the antifracture efficacy of denosumab was dependent on baseline fracture probability assessed by FRAX. The primary data of the phase 3 FREEDOM study of the effects of denosumab in women with postmenopausal osteoporosis were used to compute country-specific probabilities using the FRAX tool (version 3.2). The outcome variable comprised all clinical osteoporotic fractures (including clinical vertebral fractures). Interactions between fracture probability and efficacy were explored by Poisson regression. At baseline, the median 10-year probability of a major osteoporotic fracture (with bone mineral density) was approximately 15% and for hip fracture was approximately 5% in both groups. In the simplest model adjusted for age and fracture probability, treatment with denosumab over 3 years was associated with a 32% (95% confidence interval [CI] 20% to 42%) decrease in clinical osteoporotic fractures. Denosumab reduced fracture risk to a greater extent in those at moderate to high risk. For example, at 10% probability, denosumab decreased fracture risk by 11% (p = 0.629), whereas at 30% probability (90th percentile of study population) the reduction was 50% (p = 0.001). The reduction in fracture was independent of prior fracture, parental history of hip fracture, or secondary causes of osteoporosis. A low body mass index (BMI) was associated with greater efficacy. Denosumab significantly decreased the risk of clinical osteoporotic fractures in postmenopausal women. Overall, the efficacy of denosumab was greater in those at moderate to high risk of fracture as assessed by FRAX.     

Modernizing the treatment of venous thoracic outlet syndrome

This study aims to quantify the management and outcomes of patients treated for venous thoracic outlet syndrome (vTOS) over a seven-year period. A retrospective case-note review of all patients undergoing first rib resection at a regional vascular unit between January 1, 2002 and December 31, 2009 was performed. Treatment pathways and outcomes recorded as freedom from symptoms and venous patency were analyzed. Thirty-five patients were identified with vTOS. Ninety-one percent of patients had patent veins at discharge from clinical follow-up and were symptom-free at a median of 44 months. Patients treated within seven days of symptoms (94.7 versus 85.7, P = 0.060), with catheter-directed thrombolysis (94 versus 87.5% P = 0.702) and excision of first rib in less than 30 days (100 versus 85.7%, P = 0.002), had improved symptom-free rates. In conclusion, early referral, immediate catheter-directed thrombolysis, perioperative balloon venoplasty and early thoracic outlet decompression may provide a suitable model for improving outcomes in vTOS.     

Automated Assessment of Exclusion Criteria for DXA Lumbar Spine Scans

Modern bone densitometry systems using dual-energy X-ray absorptiometry (DXA) automatically analyze lumbar spine scans and provide clinically important information concerning spine bone mineral density (BMD) and fracture risk. Lumbar spine BMD accurately reflects skeletal health and fracture risk in most cases, but degenerative diseases associated with aging may lead to the formation of reactive bone (osteophytes) and other confounding conditions that elevate BMD without a concomitant increase in bone strength or decrease in fracture risk. Automated densitometry software known as computer-aided densitometry (CAD) (GE Medical Systems Lunar) assists the user in identifying scans with common acquisition and analysis irregularities known to influence BMD values. Visual examination of 231 female spine scans measured with DXA found abnormal conditions that could influence BMD results in 29% of scans. The sensitivity and specificity of several criteria for identifying scans with conditions that could influence BMD were determined. A good criterion for identifying scans with abnormal conditions was a T-score difference of greater than 0.9 or 1.0 between L1-L4 mean and individual vertebrae. Criteria for excluding affected vertebrae were determined. Exclusion of affected vertebrae resulted in a mean BMD decrease of nearly 0.6 SD (T-score) among affected scans.     

Arterio-Ureteric Fistula Following Iliac Angioplasty

Arterio-ureteric fistulae are rare but can be associated with significant morbidity and mortality. We describe a novel case in which an arterio-ureteric fistula occurred as a complication following external iliac artery angioplasty and stenting, in a patient who had undergone previous pelvic surgery, radiotherapy, ureteric stenting, and urinary diversion surgery. Prompt recognition enabled successful endovascular management using a covered stent.     

Hand surface area--do racial differences exist?

The patient's own palm is used as a template in assessing small patchy burns and is traditionally believed to be 1% of body surface area. This does alter with the patient's age, sex and BMI and there have been suggestions that it can also differ between ethnic groups. We undertook this study to see if there were any differences in the hand surface area between Caucasians, Orientals and Asians. It was done by tracing the hand outline and calculating the surface area. The study showed that there was no significant difference between the three ethnic groups in terms of hand surface area.