Modeling the effects of health status and the educational infrastructure on the cognitive development of Tanzanian schoolchildren.

This paper models the proximate determinants of school attendance and scores on cognitive and educational achievement tests and on school examinations of over 600 schoolchildren from the Control group of a randomized trial in Tanzania, where children in the Intervention group heavily infected with hookworm and schistosomiasis received treatment. The modeling approach used a random effects framework and incorporated the inter-relationships between school attendance and performance on various tests, controlling for children's health status, socioeconomic variables, grade level, and the educational infrastructure. The empirical results showed the importance of variables such as children's height and hemoglobin concentration for the scores, especially on educational achievement tests that are easy to implement in developing countries. Also, teacher experience and work assignments were significant predictors of the scores on educational achievement tests, and there was some evidence of multiplicative effects of children's heights and work assignments on the test scores. Lastly, some comparisons were made for changes in test scores of treated children in the Intervention group with the untreated children in the Control group.     

Valoración de parámetros clínicos y analíticos preoperatorios en apendicitis aguda complicada. Score para predecir apendicitis complicada

BackgroundTo analyze whether clinical and analytical parameters differ according to histopathology in cases of acute appendicitis (AA).MethodsThis is a retrospective, observational study including patients (>14 years of age) admitted for suspicion of AA from 1 April 2014 to 31 July 2016. Histopathology was divided into complicated (including perforated and gangrenous AA) and uncomplicated appendicitis (phlegmonous). Sex, age, temperature of patients on admission to the Emergency Department, symptom duration, preoperative white blood cell (WBC) count, neutrophil percentage, mean platelet volume (MPV), platelet distribution width (PDW), C-reactive protein (CRP) and hospital stay were compared in the two groups.ResultsThree hundred and thirty-five patients were analyzed, and 284 were included. Appendicitis was uncomplicated in 194 (68.3%) and complicated in 90 (31.7%). Age, symptom duration, neutrophil percentage, CRP and hospital stay were higher in the complicated AA group (P < .05). The mean differences between uncomplicated and complicated AA were: age 13.2 years (95% CI: 8.2-18.2), symptom duration 14.1 hours (95% CI: 6.3-21.9), neutrophil percentage 5.0% (95% CI: 3.2-6.8), CRP 73.6 mg/l (95% CI: 50.0-97.2) and hospital stay 2.2 days (95% CI: 1.4-3.0), with p<0.05 for all these variables. A model based on the preoperative parameters (age, symptom duration, neutrophil percentage and CRP) was calculated to predict the likelihood of complicated AA. The receiver operating characteristic (ROC) of the model had an area under the curve of 0.80 (95% CI 0.75-0.85).ConclusionThis model is able to diagnose complicated AA without the need for imaging techniques, although it must be validated with prospective analysis.     

Expression, localization, and function of the carnitine transporter octn2 (slc22a5) in human placenta.

L-carnitine is assumed to play an important role in fetal development, and there is evidence that carnitine is transported across the placenta. The protein involved in this transfer, however, has not been identified on a molecular level. We therefore characterized localization and function of the carnitine transporter OCTN2 in human placenta. Significant expression of OCTN2 mRNA was detected in human placenta applying real-time polymerase chain reaction technology. Confocal immunofluorescence microscopy using an antibody directed against the carboxy terminus of OCTN2 protein revealed that it is predominantly expressed in the apical membrane of syncytiotrophoblasts. This was confirmed by the costaining of organic anion-transporting polypeptide B and MRP2, which are known to be expressed mainly in the basal and apical syncytiotrophoblasts membrane, respectively. To further support this finding, we performed transport studies using basal and apical placenta membrane vesicles. We could demonstrate that the carnitine uptake into the apical vesicles was about eight times higher compared with the basal ones. Moreover, this uptake was sodium- and pH-dependent with an apparent K(m) value of 21 muM and inhibited by verapamil, which is in line with published data for recombinant OCTN2. Finally, experiments using trophoblasts in cell culture revealed that expression of OCTN2 paralleled human choriogonadotropin production and thus is modulated by cellular differentiation. In summary, we show expression and function of OCTN2 in human placenta. Moreover, several lines of evidence indicate that OCTN2 is localized in the apical membrane of syncytiotrophoblasts, thereby suggesting a major role in the uptake of carnitine during fetal development.     

Genetic heterogeneity in Finnish hereditary prostate cancer using ordered subset analysis

Prostate cancer (PrCa) is the most common male cancer in developed countries and the second most common cause of cancer death after lung cancer. We recently reported a genome-wide linkage scan in 69 Finnish hereditary PrCa (HPC) families, which replicated the HPC9 locus on 17q21-q22 and identified a locus on 2q37. The aim of this study was to identify and to detect other loci linked to HPC. Here we used ordered subset analysis (OSA), conditioned on nonparametric linkage to these loci to detect other loci linked to HPC in subsets of families, but not the overall sample. We analyzed the families based on their evidence for linkage to chromosome 2, chromosome 17 and a maximum score using the strongest evidence of linkage from either of the two loci. Significant linkage to a 5-cM linkage interval with a peak OSA nonparametric allele-sharing LOD score of 4.876 on Xq26.3-q27 (ΔLOD=3.193, empirical P=0.009) was observed in a subset of 41 families weakly linked to 2q37, overlapping the HPCX1 locus. Two peaks that were novel to the analysis combining linkage evidence from both primary loci were identified; 18q12.1-q12.2 (OSA LOD=2.541, ΔLOD=1.651, P=0.03) and 22q11.1-q11.21 (OSA LOD=2.395, ΔLOD=2.36, P=0.006), which is close to HPC6. Using OSA allows us to find additional loci linked to HPC in subsets of families, and underlines the complex genetic heterogeneity of HPC even in highly aggregated families.     

Effects of caffeinated vs. non-caffeinated alcoholic beverage on next-day hangover incidence and severity,perceived sleep quality,and alertness

Aims

Beliefs about the effects of mixing caffeine and alcohol on hangover or sleep may play a role in motivation to consume these mixtures; therefore, information is needed about actual effects. We investigated whether intoxication with caffeinated vs. non-caffeinated beer differentially affected perceived sleep quality, sleepiness, and hangover incidence and severity the next morning.

Methods

University students (89%) and recent graduate drinkers were randomized to receive: (1) beer with the equivalent of 69 mg caffeine/12 oz glass of regular beer (n = 28) or (2) beer without caffeine (n = 36), in sufficient quantity to attain a BrAC of 0.12 g%. After an 8-h supervised sleep period, participants completed measures of hangover, sleep quality, sleep latency and time asleep, and sleepiness.

Results

While caffeinated beer improved perceived sleep quality, effect sizes were greater for morning alertness than for quality while sleeping, with no effect on sleep latency or total sleep time. No effects were seen on hangover incidence or severity.

Conclusions

Mixing caffeine and alcohol does not significantly impair amount of sleep or sleep latency, hangover, or sleepiness the morning after drinking to intoxication in this population.     

The NLRP3 inflammasome inhibitor OLT1177 rescues cognitive impairment in a mouse model of Alzheimer’s disease

Numerous studies demonstrate that neuroinflammation is a key player in the progression of Alzheimer’s disease (AD). Interleukin (IL)-1β is a main inducer of inflammation and therefore a prime target for therapeutic options. The inactive IL-1β precursor requires processing by the the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome into a mature and active form. Studies have shown that IL-1β is up-regulated in brains of patients with AD, and that genetic inactivation of the NLRP3 inflammasome improves behavioral tests and synaptic plasticity phenotypes in a murine model of the disease. In the present study, we analyzed the effect of pharmacological inhibition of the NLRP3 inflammasome using dapansutrile (OLT1177), an oral NLRP3-specific inhibitor that is safe in humans. Six-month-old WT and APP/PS1 mice were fed with standard mouse chow or OLT1177-enriched chow for 3 mo. The Morris water maze test revealed an impaired learning and memory ability of 9-mo-old APP/PS1 mice (P = 0.001), which was completely rescued by OLT1177 fed to mice (P = 0.008 to untreated APP/PS1). Furthermore, our findings revealed that 3 mo of OLT1177 diet can rescue synaptic plasticity in this mouse model of AD (P = 0.007 to untreated APP/PS1). In addition, microglia were less activated (P = 0.07) and the number of plaques was reduced in the cortex (P = 0.03) following NLRP3 inhibition with OLT1177 administration. We also observed an OLT1177 dose-dependent normalization of plasma metabolic markers of AD to those of WT mice. This study suggests the therapeutic potential of treating neuroinflammation with an oral inhibitor of the NLRP3 inflammasome.

Alzheimer’s disease (AD) and other related neurodegenerative diseases leading to dementia represent an enormous burden for the society and health economies. AD patients suffer progressive cognitive and functional deficits often for many years, which result in a heavy burden to patients, families, and the public health system. In fact, in 2015 an estimated 46.8 million people worldwide were living with dementia, which could extend to 131.5 million by 2050 (1). Rising prevalence and mortality rates in combination with a lack of effective treatments lead to enormous costs to society. Research on AD in the last decades has focused on the pathological hallmarks and cellular deposits of amyloid-β (Aβ) peptides and neurofibrils (2). Recently, there has been increased evidence supporting a central role of the immune system in the progression or even the origin of the disease (3–5). In this respect, it is noteworthy that it has been known since 1989 that levels of interleukin (IL)-1β, one of the main mediators of innate immune response, are elevated in brains of patients with AD and can be associated with the progression and onset of AD (6–11). Additionally, it was shown that the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome (12, 13), a multisubunit complex important for the maturation of IL-1β, is activated by Aβ peptides, leading to an overproduction of IL-1β, neuroinflammation, and cognitive impairment (14, 15). Inhibition of the NLRP3 inflammasome and the subsequent reduced IL-1β production can be linked to a change in the phenotype of microglia, the innate immune cells in the brain. Heneka et al. (16) pointed out the important role of the NLRP3 inflammasome/caspase-1 axis in AD pathogenesis by demonstrating significant improvements (e.g., in cognition) in APP/PS1 mice (a mouse model for AD) when crossed with NLRP3^−/− animals. The APP/PS1 mice express a human amyloid precursor protein (APP) and human presenilin-1 (PS1), leading to the accumulation of Aβ peptides, neuroinflammation, and cognitive impairment (17).OLT1177 (rINN: dapansutrile) is a new chemical entity small molecule that specifically targets the NLRP3 inflammasome and prevents the activation of caspase-1 and the maturation and release of IL-1β (18). OLT1177 has been shown to be well tolerated in animals and humans (18) and is currently in phase 2 clinical studies for the treatment of inflammatory conditions, such as osteoarthritis (topical gel dosage form) and inflammatory diseases, such as acute gout flare (oral capsule dosage form), among other diseases (19).In this study, we used the APP/PS1 mouse model of AD to investigate the effects of OLT1177 as an acute, oral pharmacological intervention (17). Six-month-old WT and APP/PS1ΔE9 mice consumed ad libitum OLT1177 in feed pellets (∼0, 500, or 1,000 mg/kg/d based on feed concentrations of 0, 3.75 or 7.5 g of OLT1177 per kilogram of feed; hereafter referred to as 3.75 or 7.5 g/kg OLT1177) for the treatment duration of 3 mo. APP/PS1 mice treated with OLT1177 showed rescue effects in various assessments, ranging from improved cognitive function to overall reduction in proinflammatory cytokines in the brain, suggesting the potential benefits of pharmaceutically blocking NLRP3 signaling in AD.     

Identification and characterization of a novel mutation c.1090G>T (G325W) and nine common mutant alleles leading to Gaucher disease in Spanish patients

BACKGROUND: Gaucher disease is an autosomal recessive disorder resulting from mutations in the glucocerebrosidase gene (GBA). The lack of full genotype/phenotype correlation complicates counseling regarding clinical outcome and treatment recommendations. SUBJECTS AND METHODS: Several mutations in the human beta-glucosidase gene associated with Gaucher disease in 16 Spanish families were identified utilizing a combination of methods: enzymatic restriction, PCR-SSCP, and sequence analyses. Expression studies were performed following the introduction of the mutagenized human acid beta-glucosidase cDNA into COS-1 cells, and the residual enzyme activities of the mutant protein were measured and compared with the normal cDNA. RESULTS: The identified mutations and corresponding residual enzyme activities of the expressed protein are as follows: c.517A>C (T134P), 1%; c.721G>A (G202R), 17%; c.1090G>T (G325W), 13.9%; c.1093G>A (E326K), 26%; c.1208G>A (S364N), 4.1%; c.1226A>G (N370S), 17,8%; c.1246G>A (G377S), 17.6%; c.1289C>T (P391L), 8.5%; c.1448T>C (L444P), 3%; and c.1504C>T (R463C), 24.5%. CONCLUSIONS: Site-directed mutagenesis and expression in COS-1 cells are useful methods to increase our understanding of causality in Gaucher disease and the correlation between disease severity, gene defects, and residual enzyme activity. Our study demonstrates the functional consequences of the identified human beta-glucosidase mutations (T134P, S364N, G377S, P391L, and G325W) and provide evidence for the molecular and biochemical basis of Gaucher disease, among patients of Spanish ancestry.