Genetic determinants of chronic oxaliplatin‐induced peripheral neurotoxicity: a genome‐wide study replication and meta‐analysis

We aimed at validating the role of genetic variants identified by a recent genome‐wide association study (GWAS) as determinants of chronic oxaliplatin‐induced peripheral neurotoxicity (OXAIPN). Eight polymorphisms (rs10486003, rs2338, rs843748, rs797519, rs4936453, rs12023000, rs17140129, and rs6924717) were genotyped in a total of 150 colorectal cancer patients of Caucasian origin receiving oxaliplatin‐based chemotherapy. The severity grade of chronic OXAIPN was assessed by NCI‐CTC criteria and the clinical version of the Total Neuropathy Score^© (TNSc^©). None of the polymorphisms investigated was found associated with grade ≥ 2 chronic OXAIPN (NCI‐CTC criteria), while a nominal association emerged for ACYP2 rs843748 when using the TNSc^© scale (dominant model: odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.10–0.75, P = 0.008). In the combined analysis of this results with data of the two previously published studies which assessed chronic OXAIPN by NCI‐CTC criteria, evidence suggestive of association with chronic OXAIPN (NCI‐CTC criteria) was found for ACYP2 rs843748 (dominant model: OR: 2.40, 95%CI: 1.40–5.24, P = 0.027), which, however, did not remain significant after correction for multiple testing (threshold P‐value <0.00625). These findings suggest a minor role of the single nucleotide polymorphisms (SNPs) investigated as genetic determinants of chronic OXAIPN. These results also highlight the importance of replication studies with meta‐analysis for validation of GWAS findings.     

Development and aging of cortical thickness correspond to genetic organization patterns

There is a growing realization that early life influences have lasting impact on brain function and structure. Recent research has demonstrated that genetic relationships in adults can be used to parcellate the cortex into regions of maximal shared genetic influence, and a major hypothesis is that genetically programmed neurodevelopmental events cause a lasting impact on the organization of the cerebral cortex observable decades later. Here we tested how developmental and lifespan changes in cortical thickness fit the underlying genetic organizational principles of cortical thickness in a longitudinal sample of 974 participants between 4.1 and 88.5 y of age with a total of 1,633 scans, including 773 scans from children below 12 y. Genetic clustering of cortical thickness was based on an independent dataset of 406 adult twins. Developmental and adult age-related changes in cortical thickness followed closely the genetic organization of the cerebral cortex, with change rates varying as a function of genetic similarity between regions. Cortical regions with overlapping genetic architecture showed correlated developmental and adult age change trajectories and vice versa for regions with low genetic overlap. Thus, effects of genes on regional variations in cortical thickness in middle age can be traced to regional differences in neurodevelopmental change rates and extrapolated to further adult aging-related cortical thinning. This finding suggests that genetic factors contribute to cortical changes through life and calls for a lifespan perspective in research aimed at identifying the genetic and environmental determinants of cortical development and aging.There is a growing realization that events during development impact brain and cognition throughout the entire lifespan (1). For instance, the major portion of the relationship between cortical thickness and IQ in old age can be explained by childhood IQ (2), and genotype may explain a substantial part of the lifetime stability in intelligence (3). Effects of genes on the organization of the cortex have been shown in adults (4–6), but it is unknown whether and how regional differences in cortical development correspond to these regional genetic subdivisions.Although consensus has not been reached for the exact trajectories, cortical thickness as measured by MRI appears to decrease in childhood (7–12). The exact foundation for this thinning is not known, as MRI provides merely representations of the underlying neurobiology, and available histological data cannot with certainty be used to guide interpretations of MRI results. Although speculative, apparent thickness decrease may be grounded in factors such as synaptic pruning and intracortical myelination, although the link between established synaptic processes (13–15) and cortical thickness has not been empirically confirmed. After childhood, cortical thinning continues throughout the remainder of the lifespan, speculated to reflect neuronal shrinkage and reductions in number of spines and synapses (16), although similar to development, we lack data to support a direct connection between cortical thinning and specific neurobiological events.It has been demonstrated that genetic correlations between thickness in different surface locations can be used to parcellate the adult cortex into regions of maximal shared genetic influence (4). This result can be interpreted according to the hypothesis that genetically programmed neurodevelopmental events cause lasting impact on the organization of the cerebral cortex detectable decades later (4–6). Here we tested how developmental and lifespan changes fit the genetic organization of cortical thickness in a large longitudinal sample with 1,633 scans from 974 participants between 4.1 and 88.5 y of age, including 773 scans from children below 12 y Genetically based subdivisions of cortical thickness from an independent dataset of 406 twins (4) were applied to the data, yielding 12 separate regions under maximum control of shared genetic influences. We hypothesized that thickness in cortical regions with overlapping genetic architecture would show similar developmental and adult age change trajectories and dissimilar trajectories for regions with low genetic overlap.     

Do antibiotic-impregnated shunts in hydrocephalus therapy reduce the risk of infection? An observational study in 258 patients

Background  

Shunt infection in hydrocephalus patients is a severe, even life-threatening complication. Antibiotic-impregnated shunts (AIS) have been developed in an attempt to reduce rate of shunt infection. The study was performed to analyze if AIS can diminish the rate of shunt infection. The pathogenic nature of shunt infection in patients with AIS systems and those without antibiotic impregnated shunts (non-AIS) was compared.     

Calculation of individual cardiovascular risk in a primary prevention setting shows a high number of patients with a high risk score

On occasion of the annual convention of the European Society of Cardiology, general awareness was used to stage an event to inform the public about cardiovascular risk and cardiovascular disease. After the measurement of blood pressure, HDL and total cholesterol and after answering questions on smoking and medication visitors received a printout showing their individual calculated cardiovascular event rate over the next ten years. For the calculation of the expected event rate, the algorithm of the Adult Treatment Panel III was used. Of the 43,500 visitors 1513 were screened, 651 male, 862 female. Of those screened in this primary prevention setting 143 male (22.07%) and 9 female (1.02%) had an expected cardiovascular event rate of 20% or more over the next ten years requiring immediate action according to the current guidelines. The calculated risk scores are considerably lower than would be expected in a representative sample from the population. This indicates that patients with a high cardiovascular risk possibly do not take part in unstructured primary screening events.     

ICD-Therapie

Sudden cardiac death (SCD) remains the leading common cause for overall mortality in the industrialized world. Although prediction of SCD is considered a necessary prerequisite for its effective prevention and therapy, hard criteria for that goal are difficult to identify. A number of clinical trials were conducted to define the role of implantable cardioverter-defibrillators (ICDs) in preventing SCD. In addition to its undisputed value in secondary prevention of SCD, study results have proven a reduction of mortality through ICDs in patients with both ischemic and non-ischemic cardiomyopathy and a reduced left ventricular ejection fraction (EF). To date, national and international guidelines help us to apply standard ICD indications in patients with structural or hereditary heart diseases that are associated with increased SCD risk. Yet we know that our strategies currently in use for selecting patients who require ICD therapy are imperfect and leave a large number of high-risk patients unprotected. Therefore, the best possible risk assessment should be used in each individual case for optimal SCD prevention without unnecessary device implantation.     

Effect of Chronic Alcoholism on Human Muscle Glycogen and Glucose Metabolism

To determine the effect of alcohol on carbohydrate metabolism, 48 human muscle biopsies from chronic alcoholics were studied. The level of glycogen and the activities of the enzymes catalyzing glycogen and glucose metabolism were analyzed. Chronic alcohol intake produced an increase in glycogen concentration and a decrease in pyruvate kinase activity before the first signs of myopathy appeared. When myopathy was present, glycogen decreased. These changes may contribute to the decline in skeletal muscle performance in these patients.     

New shift models for doctors in a large German University Neurosurgery Department: how they comply with the European Working Time Directive 3 years after implementation

Background

Due to the European Working Time Directive (EWTD) and a new collective agreement for doctors working at University hospitals in 2006 new shift models had to be designed in the Department of Neurosurgery of the University Hospital Tübingen, Germany. The aim of the study was to show the fit of the models regarding the average weekly working time limits (aWTL), the daily maximum of 10-h working time (10-h dWT), and the staff expenditures 3 years after implementation.

Methods

The new shift model was implemented in 2008, and hence planning and documentation were done electronically. Adherence to the work schedules was measured, and aWTL adherence rates were compared. The relative number of 10-h dWT violations in 2009 and 2010 was analysed. Staff costs relative to performance before and after implementation were calculated and tested using analysis of variance (ANOVA). Four other departments without alteration of shift models served as a control group in cost trend analysis.

Results

In 2010 all doctors in the Department of Neurosurgery were able to stay within the limit of 54 h/week; one doctor without opt-out exceeded the 48 h/week limit (50.1 h/week). The median per capita rate of 10-h dWT violations in 2009 was 20.3 % of all eligible working days and further declined to 10.7 % in 2010 (p?Conclusions After implementation of the new shift model, current monitoring and properly matching modifications led to long-term stability in complying with the EWTD regulations without increasing costs for staff expenditures.     

Successful postoperative activation of an adjustable annuloplasty ring (MiCardia) in recurrent ischemic mitral valve regurgitation

We report the case of a 73-year-old patient with severe ischemic mitral regurgitation (MR). She subsequently underwent combined coronary artery revascularization and mitral valve annuloplasty using the adjustable enCorSQ device (MiCardia Corporation, Irvine, CA). Three months later she experienced recurrent symptomatic severe MR. Accessing the subcutaneous lead, activation and downsizing of the device within 45 seconds resulted in trace MR. The result was unchanged 1 month later.