Anti-epileptic effect of Ganoderma lucidum polysaccharides by inhibition of intracellular calcium accumulation and stimulation of expression of CaMKII a in epileptic hippocampal neurons

Purpose: To investigate the mechanism of the anti-epileptic effect of Ganoderma lucidum polysaccharides (GLP), the changes of intracellular calcium and CaMK II a expression in a model of epileptic neurons were investigated. Method: Primary hippocampal neurons were divided into: 1) Control group, neurons were cultured with Neurobasal medium, for 3 hours; 2) Model group I: neurons were incubated with Mg2+ free medium for 3 hours; 3) Model group II: neurons were incubated with Mg2+ free medium for 3 hours then cultured with the normal medium for a further 3 hours; 4) GLP group I: neurons were incubated with Mg2+ free medium containing GLP (0.375 mg/ml) for 3 hours; 5) GLP group II: neurons were incubated with Mg2+ free medium for 3 hours then cultured with a normal culture medium containing GLP for a further 3 hours. The CaMK II a protein expression was assessed by Western-blot. Ca2+ turnover in neurons was assessed using Fluo-3/AM which was added into the replacement medium and Ca2+ turnover was observed under a laser scanning confocal microscope. Results: The CaMK II a expression in the model groups was less than in the control groups, however, in the GLP groups, it was higher than that observed in the model group. Ca2+ fluorescence intensity in GLP group I was significantly lower than that in model group I after 30 seconds, while in GLP group II, it was reduced significantly compared to model group II after 5 minutes. Conclusion: GLP may inhibit calcium overload and promote CaMK II a expression to protect epileptic neuron

Diabetes Mellitus and Mortality after Acute Coronary Syndrome as a First or Recurrent Cardiovascular Event

Diabetes Mellitus (DM) is associated with adverse cardiovascular prognosis. However, the risk associated with DM may vary between individuals according to their overall cardiovascular risk burden. Therefore, we aimed to determine whether DM is associated with poor outcome in patients presenting with Acute Coronary Syndrome (ACS) according to the index episode being a first or recurrent cardiovascular event.We conducted a retrospective analysis of a prospective cohort study involving 2499 consecutively admitted patients with confirmed ACS in 11 UK hospitals during 2003. Usual care was provided for all participants. Demographic factors, co-morbidity and treatment (during admission and at discharge) factors were recorded. The primary outcome was all cause mortality (median 2 year follow up), compared for cohorts with and without DM according to their prior cardiovascular disease (CVD) disease status. Adjusted analyses were performed with Cox proportional hazards regression analysis. Within the entire cohort, DM was associated with an unadjusted 45% increase in mortality. However, in patients free of a history of CVD, mortality of those with and without DM was similar (18.8% and 19.7% respectively; p = 0.74). In the group with CVD, mortality of patients with DM was significantly higher than those without DM (46.7% and 33.2% respectively; p<0.001). The age and sex adjusted interaction between DM and CVD in predicting mortality was highly significant (p = 0.002) and persisted after accounting for comorbidities and treatment factors (p = 0.006). Of patients free of CVD, DM was associated with smaller elevation of Troponin I (p<0.001). However in patients with pre-existing CVD Troponin I was similar (p = 0.992).DM is only associated with worse outcome after ACS in patients with a pre-existing history of CVD. Differences in the severity of myocyte necrosis may account for this. Further investigation is required, though our findings suggest that aggressive primary prevention of CVD in patients with DM may have beneficially modified their first presentation with (and mortality after) ACS

Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification

Digital Media Use: Differences and Inequalities in Relation to Class and Age

This paper takes a national perspective on issues of digital media use. The paper draws upon the OfCom Media Literacy 2013 survey to explore how digital media use varies in regard to two major social variables – class and age. Both class and age feature predominantly in UK policy on digital access and use. Class and age are invoked as either things that create barriers to access or as issues to be addressed and managed through using digital media. Despite the large body of work on the 'digital divide' there is a more limited literature that explicitly addresses class. The paper seeks to act as an empirical reference point for the development of further debate around the links between class and digital media use. The paper presents a factor analysis of the OfCom data that identifies five main areas of digital media use. These five factors are then subjected to a multiple analysis of variance to explore the effects across, between and within age and class categories. A cluster analysis based on the factors identifies seven main 'User Types' that are again compared across class and age. The paper finds that class and age act relatively independently as predicators of digital media use and neither compound nor mitigate each other's effects. Importantly the paper notes that the greatest levels and breadth of Internet use can be found in NRS social class groups AB and to an extent C1. In contrast the greatest levels of non-use and limited use can be found in NRS social class groups DE. In conclusion the paper notes that age still acts as the major explanatory variable for overall use and some specific types of use, but that class also independently acts to explain patterns of digital media use. As a result any simplistic policy expectations that digital access and use issues will become less relevant as age demographics change have to be questioned

Constraining the Physical Parameters of the Circumstellar Disk of chi Ophiuchi

We present a numerical model describing a circularly symmetric gaseous disk around the Be star chi Ophiuchi. The model is constrained by long-baseline interferometric observations that are sensitive to the H-alpha Balmer line emission from the disk. For the first time our interferometric observations spatially resolve the inner region of the circumstellar disk around chi Ophiuchi and we use these results to place a constraint on the physical extent of the H-alpha-emitting region. We demonstrate how this in turn results in very specific constraints on the parameters that describe the variation of the gas density as a function of radial distance from the central star.Comment: Accepted for publication in Ap

A Study of Pi Aquarii During a Quasi-normal Star Phase: Refined Fundamental Parameters and Evidence for Binarity

We present the results of recent multicolor photometric and high-resolution spectroscopic observations of the bright Be star Pi Aquarii. Observational data collected from the literature were used to study the star's variations over the last four decades. The star is identified with the IR sources F22227+0107 in the IRAS Faint Point Source catalog and MSX5_G066.0066-44.7392 in the MSX catalog. The variations in near-IR brightness of Pi Aqr are found to be among the largest reported for Be stars. Since 1996, the star has shown only weak signs of circumstellar emission, which has allowed us to refine the fundamental stellar parameters: A_V=0.15 mag., T_eff=24000K, log g=3.9, and M_V=-2.95 mag. A weak emission component of the H-alpha line has been detected during the recent quasi-normal star phase. From analysis of the H-alpha line profiles, we find anti-phased radial velocity variations of the emission component and the photospheric absorption, with a period of 84.1 days and semi-amplitudes of 101.4 and 16.7 km/s, respectively. This result suggests that Pi Aqr may be a binary system consisting of stars with masses of M_1 sin^{3}i = 12.4 M_sun, M_2 sin^{3}i = 2.0 M_sun. We also estimate the orbital inclination angle to be between 50 and 75 degrees. We suggest that the photometric, spectroscopic, and polarimetric variations observed during the second half of the 20th century may be due to variable mass transfer between the binary components.Comment: 26 pages (including 8 figs, 2 tables), accepted by Ap

Assessment of coronary artery disease and calcified coronary plaque burden by computed tomography in patients with and without diabetes mellitus

Purpose: To compare the coronary atherosclerotic burden in patients with and without type-2 diabetes using CT Coronary Angiography (CTCA). Methods and Materials: 147 diabetic (mean age: 65 ± 10 years; male: 89) and 979 nondiabetic patients (mean age: 61 ± 13 years; male: 567) without a history of coronary artery disease (CAD) underwent CTCA. The per-patient number of diseased coronary segments was determined and each diseased segment was classified as showing obstructive lesion (luminal narrowing >50%) or not. Coronary calcium scoring (CCS) was assessed too. Results: Diabetics showed a higher number of diseased segments (4.1 ± 4.2 vs. 2.1 ± 3.0; p 400 (p < 0.001), obstructive CAD (37% vs. 18% of patients; p < 0.0001), and fewer normal coronary arteries (20% vs. 42%; p < 0.0001), as compared to nondiabetics. The percentage of patients with obstructive CAD paralleled increasing CCS in both groups. Diabetics with CCS ≤ 10 had a higher prevalence of coronary plaque (39.6% vs. 24.5%, p = 0.003) and obstructive CAD (12.5% vs. 3.8%, p = 0.01). Among patients with CCS ≤ 10 all diabetics with obstructive CAD had a zero CCS and one patient was asymptomatic. Conclusions: Diabetes was associated with higher coronary plaque burden. The present study demonstrates that the absence of coronary calcification does not exclude obstructive CAD especially in diabetics

Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome

Background: Pathogenic variants of GNB5 encoding the β5 subunit of the guanine nucleotide-binding protein cause IDDCA syndrome, an autosomal recessive neurodevelopmental disorder associated with cognitive disability and cardiac arrhythmia, particularly severe bradycardia. Methods: We used echocardiography and telemetric ECG recordings to investigate consequences of Gnb5 loss in mouse. Results: We delineated a key role of Gnb5 in heart sinus conduction and showed that Gnb5-inhibitory signalling is essential for parasympathetic control of heart rate (HR) and maintenance of the sympathovagal balance. Gnb5-/- mice were smaller and had a smaller heart than Gnb5+/+ and Gnb5+/-, but exhibited better cardiac function. Lower autonomic nervous system modulation through diminished parasympathetic control and greater sympathetic regulation resulted in a higher baseline HR in Gnb5-/- mice. In contrast, Gnb5-/- mice exhibited profound bradycardia on treatment with carbachol, while sympathetic modulation of the cardiac stimulation was not altered. Concordantly, transcriptome study pinpointed altered expression of genes involved in cardiac muscle contractility in atria and ventricles of knocked-out mice. Homozygous Gnb5 loss resulted in significantly higher frequencies of sinus arrhythmias. Moreover, we described 13 affected individuals, increasing the IDDCA cohort to 44 patients. Conclusions: Our data demonstrate that loss of negative regulation of the inhibitory G-protein signalling causes HR perturbations in Gnb5-/- mice, an effect mainly driven by impaired parasympathetic activity. We anticipate that unravelling the mechanism of Gnb5 signalling in the autonomic control of the heart will pave the way for future drug screening