High prevalence of ACE DD genotype among north Indian end stage renal disease patients

BACKGROUND: The Renin-Angiotensin system (RAS) is a key regulator of both blood pressure and kidney functions and their interaction. In such a situation, genetic variability in the genes of different components of RAS is likely to contribute for its heterogeneous association in the renal disease patients. Angiotensin converting enzyme-1 (ACE-1) is an important component of RAS which determines the vasoactive peptide Angiotensin-II. METHODS: In the present study, we have investigated 127 ESRD patients and 150 normal healthy controls from north India to deduce the association between ACE gene polymorphism and ESRD. The inclusion criteria for patients included a constantly elevated serum creatinine level above normal range (ranging from 3.4 to 15.8) and further the patients were recommended for renal transplantation. A total of 150 normal healthy controls were also genotyped for ACE I/D polymorphism. The criterion of defining control sample as normal was totally based on the absence of any kidney disease determined from the serum creatinin level. Genotyping of ACE I/D were assayed by polymerase chain reaction (PCR) based DNA amplification using specific flanking primers Based on the method described elsewhere. RESULTS: The difference of DD and II genotypes was found highly significant among the two groups (p = 0.025; OR = 3.524; 95%CI = 1.54-8.07). The combined genotype DD v/s ID+II comparison validated that DD genotype is a high risk genotype for ESRD (p = 0.001; OR = 5.74; 95%CI limit = 3.4-8.5). However, no correlation was obtained for different biochemical parameters of lipid profile and renal function among DD and non DD genotype. Interestingly, ~87% of the DD ESRD patients were found hypertensive in comparison to the 65% patients of non DD genotype CONCLUSION: Based on these observations we conclude that ACE DD genotype implicate a strong possible role in the hypertensive state and in renal damage among north Indians. The study will help in predetermining the timing, type and doses of anti-hypertensive therapy for ESRD patients

Predicted contextual modulation varies with distance from pinwheel centers in the orientation preference map

In the primary visual cortex (V1) of some mammals, columns of neurons with the full range of orientation preferences converge at the center of a pinwheel-like arrangement, the ‘pinwheel center' (PWC). Because a neuron receives abundant inputs from nearby neurons, the neuron's position on the cortical map likely has a significant impact on its responses to the layout of orientations inside and outside its classical receptive field (CRF). To understand the positional specificity of responses, we constructed a computational model based on orientation preference maps in monkey V1 and hypothetical neuronal connections. The model simulations showed that neurons near PWCs displayed weaker but detectable orientation selectivity within their CRFs, and strongly reduced contextual modulation from extra-CRF stimuli, than neurons distant from PWCs. We suggest that neurons near PWCs robustly extract local orientation within their CRF embedded in visual scenes, and that contextual information is processed in regions distant from PWCs

Inhaled corticosteroids in childhood asthma: the story continues

Inhaled corticosteroids (ICS) are the most effective anti-inflammatory drugs for the treatment of persistent asthma in children. Treatment with ICS decreases asthma mortality and morbidity, reduces symptoms, improves lung function, reduces bronchial hyperresponsiveness and reduces the number of exacerbations. The efficacy of ICS in preschool wheezing is controversial. A recent task force from the European Respiratory Society on preschool wheeze defined two different phenotypes: episodic viral wheeze, wheeze that occurs only during respiratory viral infections, and multiple-trigger wheeze, where wheeze also occurs in between viral episodes. Treatment with ICS appears to be more efficacious in the latter phenotype. Small particle ICS may offer a potential benefit in preschool children because of the favourable spray characteristics. However, the efficacy of small particle ICS in preschool children has not yet been evaluated in prospective clinical trials. The use of ICS in school children with asthma is safe with regard to systemic side effects on the hypothalamic–pituitary–adrenal axis, growth and bone metabolism, when used in low to medium doses. Although safety data in wheezing preschoolers is limited, the data are reassuring. Also for this age group, adverse events tend to be minimal when the ICS is used in appropriate doses

Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials

Background Change in albuminuria has strong biological plausibility as a surrogate endpoint for progression of chronic kidney disease, but empirical evidence to support its validity is lacking. We aimed to determine the association between treatment effects on early changes in albuminuria and treatment effects on clinical endpoints and surrograte endpoints, to inform the use of albuminuria as a surrogate endpoint in future randomised controlled trials. Methods In this meta-analysis, we searched PubMed for publications in English from Jan 1, 1946, to Dec 15, 2016, using search terms including “chronic kidney disease”, “chronic renal insufficiency”, “albuminuria”, “proteinuria”, and “randomized controlled trial”; key inclusion criteria were quantifiable measurements of albuminuria or proteinuria at baseline and within 12 months of follow-up and information on the incidence of end-stage kidney disease. We requested use of individual patient data from the authors of eligible studies. For all studies that the authors agreed to participate and that had sufficient data, we estimated treatment effects on 6-month change in albuminuria and the composite clinical endpoint of treated end-stage kidney disease, estimated glomerular filtration rate of less than 15 mL/min per 1·73 m2, or doubling of serum creatinine. We used a Bayesian mixed-effects meta-regression analysis to relate the treatment effects on albuminuria to those on the clinical endpoint across studies and developed a prediction model for the treatment effect on the clinical endpoint on the basis of the treatment effect on albuminuria. Findings We identified 41 eligible treatment comparisons from randomised trials (referred to as studies) that provided sufficient patient-level data on 29 979 participants (21 206 [71%] with diabetes). Over a median follow-up of 3·4 years (IQR 2·3–4·2), 3935 (13%) participants reached the composite clinical endpoint. Across all studies, with a meta-regression slope of 0·89 (95% Bayesian credible interval [BCI] 0·13–1·70), each 30% decrease in geometric mean albuminuria by the treatment relative to the control was associated with an average 27% lower hazard for the clinical endpoint (95% BCI 5–45%; median R2 0·47, 95% BCI 0·02–0·96). The association strengthened after restricting analyses to patients with baseline albuminuria of more than 30 mg/g (ie, 3·4 mg/mmol; R2 0·72, 0·05–0·99]). For future trials, the model predicts that treatments that decrease the geometric mean albuminuria to 0·7 (ie, 30% decrease in albuminuria) relative to the control will provide an average hazard ratio (HR) for the clinical endpoint of 0·68, and 95% of sufficiently large studies would have HRs between 0·47 and 0·95. Interpretation Our results support a role for change in albuminuria as a surrogate endpoint for the progression of chronic kidney disease, particularly in patients with high baseline albuminuria; for patients with low baseline levels of albuminuria this association is less certain

Therapeutic strategies to slow chronic kidney disease progression

Childhood chronic kidney disease commonly progresses toward end-stage renal failure, largely independent of the underlying disorder, once a critical impairment of renal function has occurred. Hypertension and proteinuria are the most important independent risk factors for renal disease progression. Therefore, current therapeutic strategies to prevent progression aim at controlling blood pressure and reducing urinary protein excretion. Renin-angiotensin-system (RAS) antagonists preserve kidney function not only by lowering blood pressure but also by their antiproteinuric, antifibrotic, and anti-inflammatory properties. Intensified blood pressure control, probably aiming for a target blood pressure below the 75th percentile, may exert additional renoprotective effects. Other factors contributing in a multifactorial manner to renal disease progression include dyslipidemia, anemia, and disorders of mineral metabolism. Measures to preserve renal function should therefore also comprise the maintenance of hemoglobin, serum lipid, and calcium-phosphorus ion product levels in the normal range

Development of a quality indicator set to measure and improve quality of ICU care for patients with traumatic brain injury

BackgroundWe aimed to develop a set of quality indicators for patients with traumatic brain injury (TBI) in intensive care units (ICUs) across Europe and to explore barriers and facilitators for implementation of these quality indicators.MethodsA preliminary list of 66 quality indicators was developed, based on current guidelines, existing practice variation, and clinical expertise in TBI management at the ICU. Eight TBI experts of the Advisory Committee preselected the quality indicators during a first Delphi round. A larger Europe-wide expert panel was recruited for the next two Delphi rounds. Quality indicator definitions were evaluated on four criteria: validity (better performance on the indicator reflects better processes of care and leads to better patient outcome), feasibility (data are available or easy to obtain), discriminability (variability in clinical practice), and actionability (professionals can act based on the indicator). Experts scored indicators on a 5-point Likert scale delivered by an electronic survey tool.ResultsThe expert panel consisted of 50 experts from 18 countries across Europe, mostly intensivists (N=24, 48%) and neurosurgeons (N=7, 14%). Experts agreed on a final set of 42 indicators to assess quality of ICU care: 17 structure indicators, 16 process indicators, and 9 outcome indicators. Experts are motivated to implement this finally proposed set (N=49, 98%) and indicated routine measurement in registries (N=41, 82%), benchmarking (N=42, 84%), and quality improvement programs (N=41, 82%) as future steps. Administrative burden was indicated as the most important barrier for implementation of the indicator set (N=48, 98%).ConclusionsThis Delphi consensus study gives insight in which quality indicators have the potential to improve quality of TBI care at European ICUs. The proposed quality indicator set is recommended to be used across Europe for registry purposes to gain insight in current ICU practices and outcomes of patients with TBI. This indicator set may become an important tool to support benchmarking and quality improvement programs for patients with TBI in the future

Valproic acid toxicokinetics:Serial hemodialysis and hemoperfusion

The toxicity and pharmacokinetic properties of a drug determine whether hemodialysis and/or hemoperfusion are indicated in acute intoxications. Valproic acid is considered unremovable by hemodialysis because of the high protein binding of 90%-95%. A 27-year-old male with a history of seizures was admitted to the emergency room because of coma, hypernatriemia, and respiratory failure caused by an intoxication with a large dose of valproic acid. At admission; the plasma valproic acid level was 1414 mg/L (9.9 mmol/L) (therapeutic range: 50-100 mg/L (350-700 umol/L). The anion gap was 26 mmol/L (normal <12-14 mmol/L) and corresponded fairly well with this valproic acid level. Because of the potential toxicity of this high valproic acid level serial hemodialysis and hemoperfusion was performed. The first session was done with a charcoal column and the second session with a resin column. The patient recovered during the course of treatment. The valproic acid plasma clearances during treatment were: 80 mL/min (hemodialysis); 40 mL/min (hemoperfusion by charcoal) and 80 mL/min (hemoperfusion by resin, only in the first hour). The protein binding of valproic acid in plasma was only 32% at the start and was 54% at the end of the two sessions. In this specific case of a severe valproic acid intoxication, saturated protein binding resulted in an increased fraction of unbound valproic acid. This made hemodialysis an effective treatment, while hemoperfusion was relatively less effective because of saturation of the column. In conclusion, the toxicokinetics of valproate are quite different from the pharmacokinetics at therapeutic levels. The anion gap and protein binding are important parameters in toxicokinetics