Variants in PPP3R1 and MAPT are associated with more rapid functional decline in Alzheimer's disease: The Cache County Dementia Progression Study

BackgroundSingle-nucleotide polymorphisms (SNPs) located in the gene encoding the regulatory subunit of the protein phosphatase 2B (PPP3R1, rs1868402) and the microtubule-associated protein tau (MAPT, rs3785883) gene were recently associated with higher cerebrospinal fluid (CSF) tau levels in samples from the Knight Alzheimer's Disease Research Center at Washington University (WU) and Alzheimer's Disease Neuroimaging Initiative (ADNI). In these same samples, these SNPs were also associated with faster functional decline, or progression of Alzheimer's disease (AD) as measured by the Clinical Dementia Rating sum of boxes scores (CDR-sb). We attempted to validate the latter association in an independent, population-based sample of incident AD cases from the Cache County Dementia Progression Study (DPS).MethodsAll 92 AD cases from the DPS with a global CDR-sb ≤1 (mild) at initial clinical assessment who were later assessed on CDR-sb data on at least two other time points were genotyped at the two SNPs of interest (rs1868402 and rs3785883). We used linear mixed models to estimate associations between these SNPs and CDR-sb trajectory. All analyses were performed using Proc Mixed in SAS.ResultsAlthough we observed no association between rs3785883 or rs1868402 alone and change in CDR-sb (P > .10), there was a significant association between a combined genotype model and change in CDR-sb: carriers of the high-risk genotypes at both loci progressed >2.9 times faster than noncarriers (P = .015). When data from DPS were combined with previously published data from WU and ADNI, change in CDR-sb was 30% faster for each copy of the high-risk allele at rs3785883 (P = .0082) and carriers of both high-risk genotypes at both loci progressed 6 times faster (P < .0001) than all others combined.ConclusionsWe replicate a previous report by Cruchaga et al that specific variations in rs3785883 and rs1868402 are associated with accelerated progression of AD. Further characterization of this association will provide a better understanding of how genetic factors influence the rate of progression of AD and could provide novel insights into preventative and therapeutic strategies.     

Reservoir and excess pressures predict cardiovascular events in high-risk patients

Background

Analysis of the arterial pressure curve plays an increasing role in cardiovascular risk stratification. Measures of wave reflection and aortic stiffness have been identified as independent predictors of risk. Their determination is usually based on wave propagation models of the circulation. Another modeling approach relies on modified Windkessel models, where pressure curves can be divided into reservoir and excess pressure. Little is known of their prognostic value.

Methods and results

The aim of this study is to evaluate the predictive value of parameters gained from reservoir theory applied to aortic pressure curves in a cohort of high-risk patients. Furthermore the relation of these parameters to those from wave separation analysis is investigated.Central pressure curves from 674 patients with preserved ejection fraction, measured by radial tonometry and a validated transfer function, were analyzed. A high correlation between the amplitudes of backward traveling pressure waves and reservoir pressures was found (R = 0.97). Various parameters calculated from the reservoir and excess pressure waveforms predicted cardiovascular events in univariate Cox proportional hazards modeling. In a multivariate model including several other risk factors such as brachial blood pressure, the amplitude of reservoir pressure remained a significant predictor (HR = 1.37 per SD, p = 0.016).

Conclusions

Based on very different models, parameters from reservoir theory and wave separation analysis are closely related and can predict cardiovascular events to a similar extent. Although Windkessel models cannot describe all of the physiological properties of the arterial system, they can be useful to analyze its behavior and to predict cardiovascular events.     

Early left ventricular abnormality/dysfunction in obese children affected by NAFLD

Background and aimsAlthough it is generally accepted that non alcoholic fatty liver disease (NAFLD) is linked to increased risk of cardiovascular disease, the presence of abnormalities in cardiac function among NAFLD children is limited and controversial. Aim of the study was to detect cardiac abnormalities/dysfunction in a paediatric population of NAFLD.Methods and resultsAnthropometric, laboratory, cardiovascular fitness, 24 h blood pressure monitoring and Doppler echocardiography parameters were obtained in 50 untreated children (37 males; mean age 12.2 + 2.5) with biopsy-proven NAFLD.Abnormalities in both cardiac function and geometry could be identified in the whole study population: prevalence of about 35% in left ventricular hypertrophy, 14% of concentric remodelling and 16% of left atrial dilatation. Furthermore children with NAFLD (NAS score <5) showed lower cardiac alterations compared to NASH patients (NAS score >5). After adjusting for age, sex and BMI, a positive correlation was found only between LV mass and NAS score (p < 0.001).ConclusionOur results suggest that cardiac dysfunction can be detectable early in NAFLD children and this is not linked to cardiovascular and metabolic alteration, other than to liver damage. Although as a preliminary stage, we can speculate a possible direct relationship between liver and heart steatosis, already occurring during childhood.     

Application of ANN modeling techniques in the prediction of the diameter of PCL/gelatin nanofibers in environmental and medical studies

Prediction of the diameter of a nanofiber is very difficult, owing to complexity of the interactions of the parameters which have an impact on the diameter and the fact that there is no comprehensive method to predict the diameter of a nanofiber. Therefore, the aim of this study was to compare the multi-layer perceptron (MLP), radial basis function (RBF), and support vector machine (SVM) models to develop mathematical models for the diameter prediction of poly(ε-caprolactone) (PCL)/gelatin (Gt) nanofibers. Four parameters, namely, the weight ratio, applied voltage, injection rate, and distance, were considered as input data. Then, a prediction of the diameter for the nanofiber model (PDNFM) was developed using data mining techniques such as MLP, RBFNN, and SVM. The PDNFM_MLP is introduced as the most accurate model to predict the diameter of PCL/Gt nanofibers on the basis of costs and time-saving. According to the results of the sensitivity analysis, the value of the PCL/Gt weight ratio is the most significant input which influences PDNFM_MLP in PCL/Gt electrospinning. Therefore, the PDNFM model, using a decision support system (DSS) tool can easily predict the diameter of PCL/Gt nanofibers prior to electrospinning.

A new tool for prediction the diameter of nanofibers is presented: the use of adaptive modeling techniques to predict fiber diameter and study the impact of electrospinning process parameters on electrospinning fiber diameter.     

Trends in reporting injury as a cause of death among people with epilepsy in the U.S., 1981–2010

PurposeTo examine trends in reporting injury as a cause of death among people with epilepsy in the U.S. during the past three decades.MethodWe analyzed the U.S. multiple causes of death data from death certificates in 1981–2010 to compare rate and odds ratios (OR) of reporting injury as cause of death among cases with vs. without mention of epilepsy across years.ResultsThe trends in reporting epilepsy with and without injury were similar in most age groups but were inconsistent in most external causes of injury. The OR of reporting injury was 1.02 (95% confidence intervals (CI) 0.97–1.07) in 1981–1985 and decreased to 0.52 (95% CI 0.48–0.55) in 2006–2010. The decline in OR was prominent among people aged 15–24 followed by people aged 25–44. For the five external causes of injury, the OR of suffocation and drowning were 6.32 (95% CI 5.91–6.75) and 5.64 (95% CI 5.16–6.16) in 1981–1985 and decreased to 3.03 (95% CI 2.74–3.35) and 2.56 (95% CI 2.18–3.00) in 2006–2010. The OR for poisoning and traffic crashes were 0.70 (95% CI 0.57–0.85) and 0.08 (95% CI 0.07–0.09) in 1981–1985 and 0.21 (95% CI 0.18–0.25) and 0.06 (95% CI 0.05–0.08) in 2006–2010.ConclusionThe risk of fatal injury among people with epilepsy decreased drastically during the past three decades in most age groups and for most external causes of injury except falls. People with epilepsy had lower risks of dying from injury due to poisoning or traffic crashes, had higher risks of dying from suffocation and drowning.     

Neurodevelopmental and behavioral effects of nonylphenol exposure during gestational and breastfeeding period on F1 rats

Nonylphenols (NP) are endocrine-disruptors known to be widely present in our environment. This study evaluated the effects of 4-n-NP on neurobehavioral development and memory capacity after perinatal exposure on the offspring rats. Dams were gavaged with 4-n-NP (0, 50 and 200 mg/kg/day) from gestational day 5 to postnatal day (PND) 21. Dams exposed to the higher dose lost weight during gestation and had a longer gestational duration. Juvenile female pups of the 200 mg 4-n-NP/kg/day group were lighter. Their thyroid somatic index (TSI) was also affected. For male pups, a decrease of TSI at weaning for the 200 mg 4-n-NP/kg/day group and an increase of GSI for the 50 mg 4-n-NP/kg/day group were observed. Physical maturation (incisives and eyes) were likewise affected. In open field (OF) tests, females were more active than males. In the first OF (PND 36), a treatment effect was observed only for males, particularly for the high dose group, which became as active as females. The second OF (PND 71) showed few differences between groups (treated vs control), the gender difference whatever the dose was not abolished. In the Morris Water Maze test, the study of the first 30 s showed that females (200 mg/kg/day) were mainly affected. Their performances were improved by 4-n-NP. These effects were particularly important for the first short-term memory test and observed to a lesser extent in the second evaluation of the long-term memory (PND 69). These data showed that perinatal 4-n-NP exposure induced behavioral and neuro-developmental impairments from 50 mg/kg/day.