Compositionality for Quantitative Specifications

We provide a framework for compositional and iterative design and verification of systems with quantitative information, such as rewards, time or energy. It is based on disjunctive modal transition systems where we allow actions to bear various types of quantitative information. Throughout the design process the actions can be further refined and the information made more precise. We show how to compute the results of standard operations on the systems, including the quotient (residual), which has not been previously considered for quantitative non-deterministic systems. Our quantitative framework has close connections to the modal nu-calculus and is compositional with respect to general notions of distances between systems and the standard operations

Detection of the A189G mtDNA heteroplasmic mutation in relation to age in modern and ancient bones.

International audienceThe aim of this study was to demonstrate the presence of the A189G age-related point mutation on DNA extracted from bone. For this, a peptide nucleic acid (PNA)/DNA sequencing method which can determine an age threshold for the appearance of the mutation was used. Initially, work was done in muscle tissue in order to evaluate the sensitivity of the technique and afterwards in bone samples from the same individuals. This method was also applied to ancient bones from six well-preserved skeletal remains. The mutation was invariably found in muscle, and at a rate of up to 20% in individuals over 60 years old. In modern bones, the mutation was detected in individuals aged 38 years old or more, at a rate of up to 1%, but its occurrence was not systematic (only four out of ten of the individuals over 50 years old carried the heteroplasmy). For ancient bones, the mutation was also found in the oldest individuals according to osteologic markers. The study of this type of age-related mutation and a more complete understanding of its manifestation has potentially useful applications. Combined with traditional age markers, it could improve identification accuracy in forensic cases or in anthropological studies of ancient populations

High doses of medroxyprogesterone as the cause of disappearance of adherence of the zona pellucida to an oocyte

The zona pellucida (ZP) is an external glycoprotein membrane of oocytes of mammals and embryos in the early stage of their development. ZP first appears in growing ovarian follicles as an extracellular substance between the oocyte and granular cells. The zona pellucid markedly affects the development and maturation of the oocyte. The morphology of the ZP-oocyte complex allows a more precise determination of the oocyte maturity. According to numerous experimental studies, ZP is essential for preimplantation embryonic development of humans and other mammals. It prevents dispersion of blastomeres and enhances their mutual interactions. ZP is a dynamic structure responsible for the provision of nutrients to early forms of oocytes in mammals. The aim of the present study was untrastructural evaluation of the ZP-oocyte contact during inhibited ovulation. Female white rats (Wistar strain) received a suspension of medroxyprogesterone acetate (MPA) in incremental intramuscular bolus doses of 3.7 mg (therapeutic dose), 7.4 mg and 11.1 mg. The animals were decapitated 5 days after the administration of MPA. Ovarian sections were evaluated under a transmission electron microscope (TEM) Zeiss EM 900. Morphometric analysis of ZP was conducted using the cell imaging system by Olympus. In females exposed to therapeutic doses of MPA, ZP showed the structure of granular-fibrous reticulum of a medium electron density with single cytoplasmic processes originating from the surrounding structures. The oocyte cell membrane generated single, delicate processes directed toward ZP. Microvilli of the oocyte were short and thin. In the group receiving 7.4 mg of MPA, ZP had the structure of a delicate, loose granular-fibrous reticulum, and the oocyte cell membrane generated single microvilli directed toward ZP. In both those groups, the close ZP-oocyte contact was observed. Otherwise, in the group exposed to the highest MPA doses (11.1 mg), thicker and more numerous oocyte microvilli were found, which did not penetrate ZP matrix. They were dense, irregularly separated contour, forming a barrier between ZP and oocyte. The present findings are likely to suggest that MPA has inhibiting effects on the synthesis of binding proteins and causes the loss of the oocyte contact with ZP

Risk factors and in-hospital outcomes in stroke and myocardial infarction patients

BACKGROUND: Acute stroke (AS) and acute myocardial infarction (AMI) share major risk factors such as age, gender, and high blood pressure. The main objective of this study was to compare vascular risk factor profiles with in-hospital outcomes in AS and AMI patients. METHODS: We evaluated 486 consecutive patients who were admitted to Bjelovar General Hospital with diagnoses of AS (ischaemic stroke or intracerebral haemorrhage; N = 380) or AMI (N = 106) during a one year period. The frequency of risk factors and in-patient mortality rates were assessed in both groups. For statistical analysis we used t-tests and χ(2 )tests. RESULTS: AS patients were significantly older than AMI patients: the mean age for AS patients was 68.9 ± 9.1 years, and for AMI patients was 62.8 ± 11.7 years (p < 0.001). AMI was significantly more common than AS in patients younger than 65 years; 51% of this group had AMI and 26% had AS (p < 0.001). Hypertension was a more common risk factor in AS patients (69% AS patients vs. 58% AMI patients; p = 0.042). Patients who died did not differ significantly in age between the groups. In-patient mortality rates were significantly higher in AS than AMI cases (31% vs. 12%, p < 0.001 for all patients; 37% vs.5%, p < 0.001 for men). Women hospitalized for AMI were more likely to die in hospital than men (28% vs. 5%; p = 0.002). CONCLUSIONS: We found that age at the time of presentation was a significant differentiating factor between patients with AS and AMI. The only exceptions were women, whose ages at the onset of AS and AMI were similar. In contrast, patients who died did not differ significantly in age. We observed significantly higher inpatient mortality for men (when adjusted for age) than for women with AS. The five-fold higher in-patient mortality rate in women than in men with AMI is most likely to have resulted from other factors related to treatment

Guillain-Barré Syndrome and Preceding Infection with Campylobacter, Influenza and Epstein-Barr Virus in the General Practice Research Database

BACKGROUND: A number of infectious agents have previously been suggested as risk factors for the development of Guillain-Barré syndrome (GBS), but robust epidemiologic evidence for these associations is lacking. METHODS AND FINDINGS: We conducted a nested case-control study using data from the United Kingdom General Practice Research Database between 1991 and 2001. Controls were matched to cases on general practice clinic, sex, year of birth and date of outcome diagnosis in their matched case. We found positive associations between GBS and infection with Campylobacter, Epstein-Barr virus and influenza-like illness in the previous two months, as well as evidence of a protective effect of influenza vaccination. After correction for under-ascertainment of Campylobacter infection, the excess risk of GBS following Campylobacter enteritis was 60-fold and 20% of GBS cases were attributable to this pathogen. CONCLUSIONS: Our findings indicate a far greater excess risk of GBS among Campylobacter enteritis patients than previously reported by retrospective serological studies. In addition, they confirm previously suggested associations between infection due to Epstein-Barr virus infection and influenza-like illness and GBS. Finally, we report evidence of a protective effect of influenza vaccination on GBS risk, which may be mediated through protection against influenza disease, or result from a lower likelihood of vaccination among those with recent infection. Cohort studies of GBS incidence in this population would help to clarify the burden of GBS due to influenza, and any potential protective effect of influenza vaccination

A multi-ethnic study of a PNPLA3 gene variant and its association with disease severity in non-alcoholic fatty liver disease

The adiponutrin (PNPLA3) rs738409 polymorphism has been found to be associated with susceptibility to non-alcoholic fatty liver disease (NAFLD) in various cohorts. We further investigated the association of this polymorphism with non-alcoholic steatohepatitis (NASH) severity and with histological features of NAFLD. A total of 144 biopsy-proven NAFLD patients and 198 controls were genotyped for PNPLA3 gene polymorphism (rs738409 C>G). The biopsy specimens were histologically graded by a qualified pathologist. We observed an association of G allele with susceptibility to NAFLD in the pooled subjects (OR 2.34, 95% CI 1.69–3.24, p < 0.0001), and following stratification, in each of the three ethnic subgroups, namely Chinese, Indian and Malay (OR 1.94, 95% CI 1.12–3.37, p = 0.018; OR 3.51, 95% CI 1.69–7.26, p = 0.001 and OR 2.05, 95% CI 1.25–3.35, p = 0.005, respectively). The G allele is associated with susceptibility to NASH (OR 2.64, 95% CI 1.85–3.75, p < 0.0001), with NASH severity (OR 1.85, 95% CI 1.05–3.26, p = 0.035) and with presence of fibrosis (OR 1.95, 95% CI 1.17–3.26, p = 0.013) but not with simple steatosis nor with other histological parameters. Although the serum triglyceride level is significantly higher in NAFLD patients compared to controls, the G allele is associated with decreased level of triglycerides (p = 0.029) in the NAFLD patients. Overall, the rs738409 G allele is associated with severity of NASH and occurence of fibrosis in patients with NAFLD

Autistic behavior in boys with fragile X syndrome: social approach and HPA-axis dysfunction

The primary goal of this study was to examine environmental and neuroendocrine factors that convey increased risk for elevated autistic behavior in boys with Fragile X syndrome (FXS). This study involves three related analyses: (1) examination of multiple dimensions of social approach behaviors and how they vary over time, (2) investigation of mean levels and modulation of salivary cortisol levels in response to social interaction, and (3) examination of the relationship of social approach and autistic behaviors to salivary cortisol. Poor social approach and elevated baseline and regulation cortisol are discernible traits that distinguish boys with FXS and ASD from boys with FXS only and from typically developing boys. In addition, blunted cortisol change is associated with increased severity of autistic behaviors only within the FXS and ASD group. Boys with FXS and ASD have distinct behavioral and neuroendocrine profiles that differentiate them from those with FXS alone and typically developing boys

Characterizing Ligand-Gated Ion Channel Receptors with Genetically Encoded Ca++ Sensors

We present a cell based system and experimental approach to characterize agonist and antagonist selectivity for ligand-gated ion channels (LGIC) by developing sensor cells stably expressing a Ca2+ permeable LGIC and a genetically encoded Förster (or fluorescence) resonance energy transfer (FRET)-based calcium sensor. In particular, we describe separate lines with human α7 and human α4β2 nicotinic acetylcholine receptors, mouse 5-HT3A serotonin receptors and a chimera of human α7/mouse 5-HT3A receptors. Complete concentration-response curves for agonists and Schild plots of antagonists were generated from these sensors and the results validate known pharmacology of the receptors tested. Concentration-response relations can be generated from either the initial rate or maximal amplitudes of FRET-signal. Although assaying at a medium throughput level, this pharmacological fluorescence detection technique employs a clonal line for stability and has versatility for screening laboratory generated congeners as agonists or antagonists on multiple subtypes of ligand-gated ion channels. The clonal sensor lines are also compatible with in vivo usage to measure indirectly receptor activation by endogenous neurotransmitters