A coronary heart disease risk model for predicting the effect of potent antiretroviral therapy in HIV-1 infected men

BACKGROUND: Many HIV-infected patients on highly active antiretroviral therapy (HAART) experience metabolic complications including dyslipidaemia and insulin resistance, which may increase their coronary heart disease (CHD) risk. We developed a prognostic model for CHD tailored to the changes in risk factors observed in patients starting HAART. METHODS: Data from five cohort studies (British Regional Heart Study, Caerphilly and Speedwell Studies, Framingham Offspring Study, Whitehall II) on 13,100 men aged 40-70 and 114,443 years of follow up were used. CHD was defined as myocardial infarction or death from CHD. Model fit was assessed using the Akaike Information Criterion; generalizability across cohorts was examined using internal-external cross-validation. RESULTS: A parametric model based on the Gompertz distribution generalized best. Variables included in the model were systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, triglyceride, glucose, diabetes mellitus, body mass index and smoking status. Compared with patients not on HAART, the estimated CHD hazard ratio (HR) for patients on HAART was 1.46 (95% CI 1.15-1.86) for moderate and 2.48 (95% CI 1.76-3.51) for severe metabolic complications. CONCLUSIONS: The change in the risk of CHD in HIV-infected men starting HAART can be estimated based on typical changes in risk factors, assuming that HRs estimated using data from non-infected men are applicable to HIV-infected men. Based on this model the risk of CHD is likely to increase, but increases may often be modest, and could be offset by lifestyle changes.

Stereology meets electron tomography: towards quantitative 3D electron microscopy

Stereological tools are the gold standard for accurate (i.e., unbiased) and precise quantification of any microscopic sample. The past decades have provided a broad spectrum of tools to estimate a variety of parameters such as volumes, surfaces, lengths, and numbers. Some of them require pairs of parallel sections that can be produced by either physical or optical sectioning, with optical sectioning being much more efficient when applicable. Unfortunately, transmission electron microscopy could not fully profit from these riches, mainly because of the large depth of field. Hence, optical sectioning was a long-time desire for electron microscopists. This desire was fulfilled with the development of electron tomography that yield stacks of slices from electron microscopic sections. Now, parallel optical slices of a previously unimagined small thickness (2-5 nm axial resolution) can be produced. These optical slices minimize problems related to overprojection effects, and allow for direct stereological analysis, e.g., volume estimation with the Cavalieri principle and number estimation with the optical disector method. Here, we demonstrate that the symbiosis of stereology and electron tomography is an easy and efficient way for quantitative analysis at the electron microscopic level. We call this approach quantitative 3D electron microscopy.

Efficacy of the combination of amlodipine and valsartan in patients with hypertension uncontrolled with previous monotherapy: the Exforge in Failure after Single Therapy (EX-FAST) study

In this randomized, double-blind, multicenter study, patients whose blood pressure (BP) was uncontrolled by monotherapy were switched directly to amlodipine/valsartan 5/160 mg (n=443) or 10/160 mg (n=451). After 16 weeks, BP control (levels <140/90 mm Hg or <130/80 mm Hg for diabetics) was achieved in 72.7% (95% confidence interval [CI], 68.6-76.9) of patients receiving amlodipine/valsartan 5/160 mg and in 74.8% (95% CI, 70.8-78.9) receiving amlodipine/valsartan 10/160 mg. Incremental reductions from baseline in mean sitting systolic and diastolic BP were significantly greater with the higher dose (20.0+/-0.7 vs 17.5+/-0.7 mm Hg; P=.0003 and 11.6+/-0.4 vs 10.4+/-0.4 mm Hg; P=.0046). Incremental BP reductions were also achieved with both regimens irrespective of previous monotherapy, hypertension severity, diabetic status, body mass index, and age. Peripheral edema was the most frequent adverse event. These results provide support for the BP-lowering benefits of complementary antihypertensive therapy with amlodipine and valsartan in patients with hypertension uncontrolled by previous monotherapy.

Afghanistan connection : heroin production, distribution, and consumption

Heroin prices are a reflection of supply and demand, and similar to any other market, profits motivate participation. The intent of this research is to examine the change in Afghan opium production due to political conflict affecting Europe’s heroin market and government policies. If the Taliban remain in power, or a new Afghan government is formed, the changes will affect the heroin market in Europe to a certain degree. In the heroin market, the degree of change is dependent on many socioeconomic forces such as law enforcement, corruption, and proximity to Afghanistan. An econometric model that examines the degree of these socioeconomic effects has not been applied to the heroin trade in Afghanistan before. This research uses a two-stage least squares econometric model to reveal the supply and demand of heroin in 36 different countries from the Middle East to Western Europe in 2008. An application of the two-stage least squares model to the heroin market in Europe will attempt to predict the socioeconomic consequences of Afghanistan opium production.

Glomerular filtration rate estimates decrease during high altitude expedition but increase with Lake Louise acute mountain sickness scores

AIM: Acute mountain sickness (AMS) can result in pulmonary and cerebral oedema with overperfusion of microvascular beds, elevated hydrostatic capillary pressure, capillary leakage and consequent oedema as pathogenetic mechanisms. Data on changes in glomerular filtration rate (GFR) at altitudes above 5000 m are very limited. METHODS: Thirty-four healthy mountaineers, who were randomized to two acclimatization protocols, undertook an expedition on Muztagh Ata Mountain (7549 m) in China. Tests were performed at five altitudes: Zurich pre-expedition (PE, 450 m), base camp (BC, 4497 m), Camp 1 (C1, 5533 m), Camp 2 (C2, 6265 m) and Camp 3 (C3, 6865 m). Cystatin C- and creatinine-based (Mayo Clinic quadratic equation) GFR estimates (eGFR) were assessed together with Lake Louise AMS score and other tests. RESULTS: eGFR significantly decreased from PE to BC (P < 0.01). However, when analysing at changes between BC and C3, only cystatin C-based estimates indicated a significant decrease in GFR (P = 0.02). There was a linear decrease in eGFR from PE to C3, with a decrease of approx. 3.1 mL min(-1) 1.73 m(-2) per 1000 m increase in altitude. No differences between eGFR of the two groups with different acclimatization protocols could be observed. There was a significant association between eGFR and haematocrit (P = 0.01), whereas no significant association between eGFR and aldosterone, renin and brain natriuretic peptide could be observed. Finally, higher AMS scores were significantly associated with higher eGFR (P = 0.01). CONCLUSIONS: Renal function declines when ascending from low to high altitude. Cystatin C-based eGFR decreases during ascent in high altitude expedition but increases with AMS scores. For individuals with eGFR <40 mL min(-1) 1.73 m(-2), caution may be necessary when planning trips to high altitude above 4500 m above sea level.

Orbitale Fettgewebsatrophie bei lokaler Bimatoprost-Therapie - Kann Bimatoprost einen Enophthalmus verursachen?

PURPOSE: The aim of this communication is to report enophthalmos as a possible new adverse effect of topical bimatoprost treatment. PATIENTS AND METHODS: A retrospective case series of five glaucoma patients under long-term topical bimatoprost treatment was evaluated. Documentation with photo and Hertel exophthalmometry was reviewed. RESULTS: In all five patients a deep lid sulcus, reduced infraocular fat pads and enophthalmos-suspicious Hertel values were found (mean 11.9 mm; SD 2.4). Other aetiologies for enophthalmos were excluded anamnestically and by clinical examination. CONCLUSION: Bimatoprost may lead to an alteration of the eyelid with deepening of the lid sulcus and may also be responsible for an iatrogenic orbital fat atrophy. A possible mechanism of action might be the induction of apoptosis of orbital fibroblasts with a remodelling of the extracellular matrix. Prospective studies are necessary to confirm this cross-sectional observation.

Quality of life in survivors after cervical artery dissection

BACKGROUND AND PURPOSE: Little data exists about longterm outcome, quality of life (QOL) and its predictors after spontaneous cervical artery dissections (sCAD). METHODS: Clinical and radiological data of 114 patients with sCAD were collected prospectively. Six patients died within 3 months, the remaining 108 were contacted after a mean of 1498 days (range: 379-3455), 99 survivors (92 %) replied. QOL, assessed with the stroke-specific QOL scale (SSQOL), and functional abilities, measured with modified Rankin Scale (mRS) were compared, and predictors of QOL were analyzed. Subgroup analyses were performed for patients with ischemic stroke, those with isolated local symptoms or transient ischemic symptoms and those without significant disabilities (mRS 0-1) at follow-up. RESULTS: Seventy-one of 99 patients (72 %) had no significant disability, but only 53 (54 %) reported a good QOL (SS-QOL > or = 4). Compared to the self-rated premorbid QOL of all patients, SS-QOL was impaired after sCAD (p < 0.001); impairment of QOL was observed in patients with ischemic stroke (p < 0.001), in patients with isolated local or transient ischemic symptoms (p < 0.038) and those without significant disabilities at follow-up (p = 0.013). Nevertheless, low mRS was associated with better overall QOL (Kendall's tau > 0.5). High National Institute of Health Stroke Scale score on admission and higher age were independent predictors of impaired QOL (p < 0.05). CONCLUSION: QOL is impaired in almost half of long-term survivors after sCAD, even in patients with local or transient symptoms or without functional disability. Impairment of QOL is a surprisingly frequent long-term sequela after sCAD and deserves attention as an outcome measure in these patients.

Serine residues 994 and 1023/25 are important for insulin receptor kinase inhibition by protein kinase C isoforms beta2 and theta

AIMS/HYPOTHESIS: Inhibition of the signalling function of the human insulin receptor (HIR) is one of the principle mechanisms which induce cellular insulin resistance. It is speculated that serine residues in the insulin receptor beta-subunit are involved in receptor inhibition either as inhibitory phosphorylation sites or as part of receptor domains which bind inhibitory proteins or tyrosine phosphatases. As reported earlier we prepared 16 serine to alanine point mutations of the HIR and found that serine to alanine mutants HIR-994 and HIR-1023/25 showed increased tyrosine autophosphorylation when expressed in human embryonic kidney (HEK) 293 cells. In this study we examined whether these mutant receptors have a different susceptibility to inhibition by serine kinases or an altered tyrosine kinase activity. METHODS: Tyrosine kinase assay and transfection studies. RESULTS: In an in vitro kinase assay using IRS-1 as a substrate we could detect a higher intrinsic tyrosine kinase activity of both receptor constructs. Additionally, a higher capacity to phosphorylate the adapter protein Shc in intact cells was seen. To test the inhibition by serine kinases, the receptor constructs were expressed in HEK 293 cells together with IRS-1 and protein kinase C isoforms beta2 and theta. Phorbol ester stimulation of these cells reduced wild-type receptor autophosphorylation to 58 % or 55 % of the insulin simulated state, respectively. This inhibitory effect was not observed with HIR-994 and HIR-1023/25, although all other tested HIR mutants showed similar inhibition induced by protein kinase C. CONCLUSION/INTERPRETATION: The data suggest that the HIR-domain which contains the serine residues 994 and 1023/25 is important for the inhibitory effect of protein kinase C isoforms beta2 and theta on insulin receptor autophosphorylation.

Complications following radical cystectomy for bladder cancer in the elderly

CONTEXT: The incidence of bladder cancer increases with advancing age. Considering the increasing life expectancy and the increasing proportion of elderly people in the general population, radical cystectomy will be considered for a growing number of elderly patients who suffer from muscle-invasive or recurrent bladder cancer. OBJECTIVE: This article reviews contemporary complication and mortality rates after radical cystectomy in elderly patients and the relationship between age and short-term outcome after this procedure. EVIDENCE ACQUISITION: A literature review was performed using the PubMed database with combinations of the following keywords cystectomy, elderly, complications, and comorbidity. English-language articles published in the year 2000 or later were reviewed. Papers were included in this review if the authors investigated any relationship between age and complication rates with radical cystectomy for bladder cancer or if they reported complication rates stratified by age groups. EVIDENCE SYNTHESIS: Perioperative morbidity and mortality are increased and continence rates after orthotopic urinary diversion are impaired in elderly patients undergoing radical cystectomy. Complications are frequent in this population, particularly when an extended postoperative period (90 d instead of 30 d) is considered. CONCLUSIONS: Although age alone does not preclude radical cystectomy for muscle-invasive or recurrent bladder cancer or for certain types of urinary diversion, careful surveillance is required, even after the first 30 d after surgery. Excellent perioperative management may contribute to the prevention of morbidity and mortality of radical cystectomy, supplementary to the skills of the surgeon, and is probably a reason for the better perioperative results obtained in high-volume centers.