Reasoning deficits among illicit drug users are associated with aspects of cannabis use

Background. Deficits in deductive reasoning have been observed among ecstasy/polydrug users. The present study seeks to investigate dose-related effects of specific drugs and whether these vary with the cognitive demands of the task. Methods. One hundred and five participants (mean age 21.33, S.D. 3.14; 77 females, 28 males) attempted to generate solutions for eight one-model syllogisms and one syllogism for which there was no valid conclusion (NVC). All of the one model syllogisms generated at least one valid conclusion and six generated two valid conclusions. In these six cases one of the conclusions was classified as common and the other as non-common. Results. The number of valid common inferences was negatively associated with aspects of short term cannabis use and with measures of IQ. The outcomes observed were more than simple post intoxication effects since cannabis use in the 10 days immediately before testing was unrelated to reasoning performance. Following adjustment for multiple comparisons, the number of non-common valid inferences was not significantly associated with any of the drug use measures. Conclusions. Recent cannabis use appears to impair the processes associated with generating valid common inferences while not affecting the production of non-common inferences. It is possible, therefore, that the two types of inference may recruit different executive resources which may differ in their susceptibility to cannabis-related effects

Early‐onset coenzyme Q10 deficiency associated with ataxia and respiratory chain dysfunction due to novel pathogenic COQ8A variants, including a large intragenic deletion

Coenzyme Q10 (CoQ10) deficiency is a clinically and genetically heterogeneous subtype of mitochondrial disease. We report two girls with ataxia and mitochondrial respiratory chain deficiency who were shown to have primary CoQ10 deficiency. Muscle histochemistry displayed signs of mitochondrial dysfunction—ragged red fibers, mitochondrial paracrystalline inclusions, and lipid deposits while biochemical analyses revealed complex II+III respiratory chain deficiencies. MRI brain demonstrated cerebral and cerebellar atrophy. Targeted molecular analysis identified a homozygous c.1015G>A, p.(Ala339Thr) COQ8A variant in subject 1, while subject 2 was found to harbor a single heterozygous c.1029_1030delinsCA variant predicting a p.Gln343_Val344delinsHisMet amino acid substitution. Subsequent investigations identified a large‐scale COQ8A deletion in trans to the c.1029_1030delinsCA allele. A skin biopsy facilitated cDNA studies that confirmed exon skipping in the fibroblast derived COQ8A mRNA transcript. This report expands the molecular genetic spectrum associated with COQ8A ‐related mitochondrial disease and highlights the importance of thorough investigation of candidate pathogenic variants to establish phase. Rapid diagnosis is of the utmost importance as patients may benefit from therapeutic CoQ10 supplementation

Risk Factors for Congenital Cryptorchidism in a Prospective Birth Cohort Study

Background: Risk factors for congenital cryptorchidism were investigated in a prospective birth cohort study in Denmark and Finland from 1997 to 2001. Methodology and Principal Findings: In total, 2,496 boys were examined for cryptorchidism at birth (cryptorchid/healthy: 128/2,368) and three months old (33/2,215). Information on risk factors was obtained antenatally (questionnaire/interview) or at birth from birth records. Use of nicotine substitutes during pregnancy (n = 40) and infertility treatment by intrauterine insemination (n = 49) were associated with an increased risk for cryptorchidism, adjusted odds ratio (95 % confidence interval) (OR (95%CI)) 3.04 (95%CI 1.00–9.27) and 3.01 (95%CI 1.27–7.15), respectively. No association was seen for mothers (n = 79) who had infertility treatment in form of intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF) treatment (OR 0.71 95%CI 0.21–2.38). In total, 728 (29%) reported to have smoked during pregnancy, however, no increased risk among maternal smokers was found. Furthermore, we found statistically significant associations between cryptorchidism and low birth weight, prematurity, being small for gestational age, substantial vaginal bleeding, and breech presentation, which are in accordance with other studies. Conclusions and Significance: Our study revealed two novel risk factors for cryptorchidism: intrauterine insemination and the use of nicotine substitutes in pregnancy. This suggests that cryptorchidism may not only be associated to geneti

Metformin Attenuates Palmitate-Induced Endoplasmic Reticulum Stress, Serine Phosphorylation of IRS-1 and Apoptosis in Rat Insulinoma Cells

Lipotoxicity refers to cellular dysfunctions caused by elevated free fatty acid levels playing a central role in the development and progression of obesity related diseases. Saturated fatty acids cause insulin resistance and reduce insulin production in the pancreatic islets, thereby generating a vicious cycle, which potentially culminates in type 2 diabetes. The underlying endoplasmic reticulum (ER) stress response can lead to even β-cell death (lipoapoptosis). Since improvement of β-cell viability is a promising anti-diabetic strategy, the protective effect of metformin, a known insulin sensitizer was studied in rat insulinoma cells. Assessment of palmitate-induced lipoapoptosis by fluorescent microscopy and by detection of caspase-3 showed a significant decrease in metformin treated cells. Attenuation of β-cell lipotoxicity was also revealed by lower induction/activation of various ER stress markers, e.g. phosphorylation of eukaryotic initiation factor 2α (eIF2α), c-Jun N-terminal kinase (JNK), insulin receptor substrate-1 (IRS-1) and induction of CCAAT/enhancer binding protein homologous protein (CHOP). Our results indicate that the β-cell protective activity of metformin in lipotoxicity can be at least partly attributed to suppression of ER stress

Wolcott-Rallison syndrome

Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disease, characterized by neonatal/early-onset non-autoimmune insulin-requiring diabetes associated with skeletal dysplasia and growth retardation. Fewer than 60 cases have been described in the literature, although WRS is now recognised as the most frequent cause of neonatal/early-onset diabetes in patients with consanguineous parents. Typically, diabetes occurs before six months of age, and skeletal dysplasia is diagnosed within the first year or two of life. Other manifestations vary between patients in their nature and severity and include frequent episodes of acute liver failure, renal dysfunction, exocrine pancreas insufficiency, intellectual deficit, hypothyroidism, neutropenia and recurrent infections. Bone fractures may be frequent. WRS is caused by mutations in the gene encoding eukaryotic translation initiation factor 2α kinase 3 (EIF2AK3), also known as PKR-like endoplasmic reticulum kinase (PERK). PERK is an endoplasmic reticulum (ER) transmembrane protein, which plays a key role in translation control during the unfolded protein response. ER dysfunction is central to the disease processes. The disease variability appears to be independent of the nature of the EIF2AK3 mutations, with the possible exception of an older age at onset; other factors may include other genes, exposure to environmental factors and disease management. WRS should be suspected in any infant who presents with permanent neonatal diabetes associated with skeletal dysplasia and/or episodes of acute liver failure. Molecular genetic testing confirms the diagnosis. Early diagnosis is recommended, in order to ensure rapid intervention for episodes of hepatic failure, which is the most life threatening complication. WRS should be differentiated from other forms of neonatal/early-onset insulin-dependent diabetes based on clinical presentation and genetic testing. Genetic counselling and antenatal diagnosis is recommended for parents of a WRS patient with confirmed EIF2AK3 mutation. Close therapeutic monitoring of diabetes and treatment with an insulin pump are recommended because of the risk of acute episodes of hypoglycaemia and ketoacidosis. Interventions under general anaesthesia increase the risk of acute aggravation, because of the toxicity of anaesthetics, and should be avoided. Prognosis is poor and most patients die at a young age. Intervention strategies targeting ER dysfunction provide hope for future therapy and prevention

The Correlation between Mixing Length and Metallicity on the Giant Branch: Implications for Ages in the Gaia Era

In the updated APOGEE-Kepler catalog, we have asteroseismic and spectroscopic data for over 3000 first ascent red giants. Given the size and accuracy of this sample, these data offer an unprecedented test of the accuracy of stellar models on the post-main-sequence. When we compare these data to theoretical predictions, we find a metallicity dependent temperature offset with a slope of around 100 K per dex in metallicity. We find that this effect is present in all model grids tested, and that theoretical uncertainties in the models, correlated spectroscopic errors, and shifts in the asteroseismic mass scale are insufficient to explain this effect. Stellar models can be brought into agreement with the data if a metallicity-dependent convective mixing length is used, with Delta alpha(ML), YREC similar to 0.2 per dex in metallicity, a trend inconsistent with the predictions of three-dimensional stellar convection simulations. If this effect is not taken into account, isochrone ages for red giants from the Gaia data will be off by as much as a factor of two even at modest deviations from solar metallicity ([Fe/H]- -0.5)

Homogeneous analysis of globular clusters from the APOGEE survey with the BACCHUS code – II. The Southern clusters and overview

We investigate the Fe, C, N, O, Mg, Al, Si, K, Ca, Ce, and Nd abundances of 2283 red giant stars in 31 globular clusters from high-resolution spectra observed in both the Northern and Southern hemisphere by the SDSS-IV APOGEE-2 survey. This unprecedented homogeneous data set, largest to date, allows us to discuss the intrinsic Fe spread, the shape, and statistics of Al-Mg and N-C anti-correlations as a function of cluster mass, luminosity, age, and metallicity for all 31 clusters. We find that the Fe spread does not depend on these parameters within our uncertainties including cluster metallicity, contradicting earlier observations. We do not confirm the metallicity variations previously observed in M22 and NGC 1851. Some clusters show a bimodal Al distribution, while others exhibit a continuous distribution as has been previously reported in the literature. We confirm more than two populations in ω Cen and NGC 6752, and find new ones in M79. We discuss the scatter of Al by implementing a correction to the standard chemical evolution of Al in the Milky Way. After correction, its dependence on cluster mass is increased suggesting that the extent of Al enrichment as a function of mass was suppressed before the correction. We observe a turnover in the Mg-Al anticorrelation at very low Mg in ω Cen, similar to the pattern previously reported in M15 and M92. ω Cen may also have a weak K-Mg anticorrelation, and if confirmed, it would be only the third cluster known to show such a pattern

Tissue- and hormone- dependent progesterone receptor distribution in the rat uterus

BACKGROUND: Estradiol (E2) and progesterone (P) are well known regulators of progesterone receptor (PR) expression in the rat uterus. However, it is not known which receptor subtypes are involved. Little knowledge exist about possible differences in PR regulation through ERalpha or ERbeta, and whether the PR subtypes are differently regulated depending on ER type bound. Thus, in the present study PR immunostaining has been examined in uteri of ovariectomized (ovx) rats after different treatments of estrogen and P, in comparison with that in immature, cycling, and pregnant animals. METHODS: The uteri were collected from 1) ovx rats treated with E2 and/or P; 2) immature rats, intact cycling rats and animals pregnant day 8 and 18; 3) ovx rats treated with E2 or an estrogen receptor (ER)alpha agonist or an ERbeta agonist. Two antibodies were used, one detecting PRA+B and another one specific for PRB. Real-time PCR was used to determine mRNA levels for PRAB and PRB in experiment 3. RESULTS: In stroma and myometrium faint staining was detected in ovx controls (OvxC), whereas E2 treatment resulted in strong staining. In contrast to this, in luminal epithelium (LE) the staining was strong in the OvxC group, whereas E2 treatment during the last 24 hrs before sacrifice caused a decrease. Similar to OvxC the LE of the immature animals was strongly stained. In the pregnant rats LE was negative, well in agreement with the results seen after E2 treatment. In the pregnant animals the stroma and decidua was strongly stained for PRAB, but only faint for PRB, indicating that PRA is the most expressed isoform in this state. The increase in stromal and myometrial immunostaining after E2 treatment was also found after treatment with the ERalpha agonist PPT. The ERbeta agonist DPN caused a decrease of the PR mRNA levels, which was also found for PRAB and PRB immunostaining in the GE. CONCLUSION: Stromal and myometrial PRAB levels are increased via ERalpha, as shown by treatment with E2 and the ERalpha agonist PPT, while the levels in LE are decreased. The uterine stroma of pregnant rats strongly expressed PRAB, but very little PRB, which is different to E2 treated ovx animals where both PRAB and PRB are strongly expressed. The ERbeta agonist DPN decreased the mRNA levels of PRAB and PRB, as well as the PRAB protein level in GE. These results suggest that ERbeta signals mainly down-regulate PR levels in the epithelial cells. ERalpha, on the other hand, up-regulates PR levels in the stroma and myometrium while it decreased them in LE. Thus, the effects from E2 and PPT on the mRNA levels, as determined by PCR, could be annihilated since they are increased and decreased depending on cell type. The distribution and amount of PR isoforms strongly depend on the hormonal milieu and cell type within the rat uterus