Targeting hyperarousal: Mantram Repetition Program for PTSD in US veterans.

Background: Hyperarousal appears to play an important role in the development and maintenance of posttraumatic stress disorder (PTSD) symptoms, but current evidence-based treatments appear to address this symptom type less effectively than the other symptom clusters. The Mantram Repetition Program (MRP) is a meditation-based intervention that has previously been shown to improve symptoms of posttraumatic stress disorder (PTSD) and may be especially helpful for hyperarousal. If MRP is an effective tool for decreasing this often treatment-resistant symptom cluster, it may become an important clinical tool. Objective: The goal of this secondary analysis was to examine the effect of the MRP on hyperarousal and other PTSD symptom clusters and to examine hyperarousal as a mediator of treatment response. Method: Secondary analyses were conducted on data from a randomized controlled trial in which Veterans with PTSD (n = 173) were assigned to the MRP or a non-specific psychotherapy control and assessed pre-treatment, post-treatment and 8 weeks after treatment completion. The impact of the interventions on PTSD symptom clusters was examined, and time-lagged hierarchical linear modelling was applied to examine alternative mediation models. Results: All PTSD symptom clusters improved in both treatments. MRP led to greater reductions in hyperarousal at post-treatment (Hedge's g = 0.57) and follow-up (Hedge's g = 0.52), and in numbing at post-treatment (Hedge's g = 0.47). Hyperarousal mediated reductions in the composite of the other PTSD symptom clusters. Although the reverse model was significant as well, the effect was weaker in this direction. Conclusion: Interventions focused on the management of hyperarousal may play an important role in recovery from PTSD. The MRP appears efficacious in reducing hyperarousal, and thereby impacting other PTSD symptom clusters, as one pathway to facilitating recovery

HST/STIS Spectroscopy of the Lyman-Alpha Emission Line in the Central Dominant Galaxies in A426, A1795, and A2597: Constraints on Clouds in the Intracluster Medium

We report on HST/STIS spectra of the Lyman-alpha emission in the central dominant galaxies in three rich clusters of galaxies. We find evidence for a population of clouds in the intracluster medium.We detect 10 Ly-alpha absorption systems towards the nucleus of NGC1275 with columns of N(HI) 1E12-1E14 cm-2. The detected absorption features are most consistent with associated nuclear absorption systems. There is very little nuclear absorption at the systemic velocity in NGC1275. This implies that the large columns detected in the 21 cm line towards the parsec scale radio source avoid the line of sight to the nucleus. This gas may be located in a circumnuclear disk or torus. We detect at least one and possibly two absorption features towards the extended Ly-alpha in A426. We do not detect absorption towards the extended Ly-alpha emission in A1795, and A2597 with upper limits N(HI) 1E13 cm-2 for optically thin absorbers. Our data constrain the covering factor of any high column density gas in the ICM to be less than 25%. Our results suggest that the lack of observed intermediate temperature gas is not explained by obscuration. In addition, the low columns of gas on the 100 kpc scales in the ICM suggests that (1) the rate at which cold gas accumulates in the ICM on these scales is very low, and (2) the dense nebulae in the central 10 kpc must have cooled or been deposited in situ.Comment: 6 figure

Application of OMI Observations to a Space-Based Indicator of NOx and VOC Controls on Surface Ozone Formation

We investigated variations in the relative sensitivity of surface ozone formation in summer to precursor species concentrations of volatile organic compounds (VOCs) and nitrogen oxides (NOx) as inferred from the ratio of the tropospheric columns of formaldehyde to nitrogen dioxide (the "Ratio") from the Aura Ozone Monitoring Instrument (OMI). Our modeling study suggests that ozone formation decreases with reductions in VOCs at Ratios less than 1 and NOx at Ratios greater than 2; both NOx and VOC reductions may decrease ozone formation for Ratios between 1 and 2. Using this criteria. the OMI data indicate that ozone formation became: 1. more sensitive to NOx over most of the United States from 2005 to 2007 because of the substantial decrease in NOx emissions, primarily from stationary sources, and the concomitant decrease in the tropospheric column of NO2. and 2. more sensitive to NOx with increasing temperature, in part because emissions of highly reactive, biogenic isoprene increase with temperature, thus increasing the total VOC reactivity. In cities with relatively low isoprene emissions (e.g .. Chicago). the data clearly indicate that ozone formation became more sensitive to NOx from 2005 to 2007. In cities with relatively high isoprene emissions (e.g ., Atlanta), we found that the increase in the Ratio due to decreasing NOx emissions was not obvious as this signal was convolved with variations in the Ratio associated with the temperature dependence of isoprene emissions and, consequently, the formaldehyde concentration

Loss of the ciliary protein Chibby1 in mice leads to exocrine pancreatic degeneration and pancreatitis

Primary cilia protrude from the apical surface of many cell types and act as a sensory organelle that regulates diverse biological processes ranging from chemo- and mechanosensation to signaling. Ciliary dysfunction is associated with a wide array of genetic disorders, known as ciliopathies. Polycystic lesions are commonly found in the kidney, liver, and pancreas of ciliopathy patients and mouse models. However, the pathogenesis of the pancreatic phenotype remains poorly understood. Chibby1 (Cby1), a small conserved coiled-coil protein, localizes to the ciliary base and plays a crucial role in ciliogenesis. Here, we report that Cby1-knockout (KO) mice develop severe exocrine pancreatic atrophy with dilated ducts during early postnatal development. A significant reduction in the number and length of cilia was observed in Cby1-KO pancreta. In the adult Cby1-KO pancreas, inflammatory cell infiltration and fibrosis were noticeable. Intriguingly, Cby1-KO acinar cells showed an accumulation of zymogen granules (ZGs) with altered polarity. Moreover, isolated acini from Cby1-KO pancreas exhibited defective ZG secretion in vitro. Collectively, our results suggest that, upon loss of Cby1, concomitant with ciliary defects, acinar cells accumulate ZGs due to defective exocytosis, leading to cell death and progressive exocrine pancreatic degeneration after birth

Cord compression defined by MRI is the driving factor behind the decision to operate in Degenerative Cervical Myelopathy despite poor correlation with disease severity.

OBJECTIVES:The mainstay treatment for Degenerative Cervical Myelopathy (DCM) is surgical decompression. Not all cases, however, are suitable for surgery. Recent international guidelines advise surgery for moderate to severe disease as well as progressive mild disease. The goal of this study was to examine the factors in current practice that drive the decision to operate in DCM. STUDY DESIGN:Retrospective cohort study. METHODS:1 year of cervical spine MRI scans (N = 1123) were reviewed to identify patients with DCM with sufficient clinical documentation (N = 39). Variables at surgical assessment were recorded: age, sex, clinical signs and symptoms of DCM, disease severity, and quantitative MRI measures of cord compression. Bivariate correlations were used to compare each variable with the decision to offer the patient an operation. Subsequent multivariable analysis incorporated all significant bivariate correlations. RESULTS:Of the 39 patients identified, 25 (64%) were offered an operation. The decision to operate was significantly associated with narrower non-pathological canal and cord diameters as well as cord compression ratio, explaining 50% of the variance. In a multivariable model, only cord compression ratio was significant (p = 0.017). Examination findings, symptoms, functional disability, disease severity, disease progression, and demographic factors were all non-significant. CONCLUSIONS:Cord compression emerged as the main factor in surgical decision-making prior to the publication of recent guidelines. Newly identified predictors of post-operative outcome were not significantly associated with decision to operate

Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy.

Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes

Simultaneous quantification of 12 different nucleotides and nucleosides released from renal epithelium and in human urine samples using ion-pair reversed-phase HPLC

Nucleotides and nucleosides are not only involved in cellular metabolism but also act extracellularly via P1 and P2 receptors, to elicit a wide variety of physiological and pathophysiological responses through paracrine and autocrine signalling pathways. For the first time, we have used an ion-pair reversed-phase high-performance liquid chromatography ultraviolet (UV)-coupled method to rapidly and simultaneously quantify 12 different nucleotides and nucleosides (adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, adenosine, uridine triphosphate, uridine diphosphate, uridine monophosphate, uridine, guanosine triphosphate, guanosine diphosphate, guanosine monophosphate, guanosine): (1) released from a mouse renal cell line (M1 cortical collecting duct) and (2) in human biological samples (i.e., urine). To facilitate analysis of urine samples, a solid-phase extraction step was incorporated (overall recovery rate ? 98 %). All samples were analyzed following injection (100 ?l) into a Synergi Polar-RP 80 Å (250 × 4.6 mm) reversed-phase column with a particle size of 10 ?m, protected with a guard column. A gradient elution profile was run with a mobile phase (phosphate buffer plus ion-pairing agent tetrabutylammonium hydrogen sulfate; pH 6) in 2-30 % acetonitrile (v/v) for 35 min (including equilibration time) at 1 ml min(-1) flow rate. Eluted compounds were detected by UV absorbance at 254 nm and quantified using standard curves for nucleotide and nucleoside mixtures of known concentration. Following validation (specificity, linearity, limits of detection and quantitation, system precision, accuracy, and intermediate precision parameters), this protocol was successfully and reproducibly used to quantify picomolar to nanomolar concentrations of nucleosides and nucleotides in isotonic and hypotonic cell buffers that transiently bathed M1 cells, and urine samples from normal subjects and overactive bladder patients

A clinical genetic method to identify mechanisms by which pain causes depression and anxiety

BACKGROUND: Pain patients are often depressed and anxious, and benefit less from psychotropic drugs than pain-free patients. We hypothesize that this partial resistance is due to the unique neurochemical contribution to mood by afferent pain projections through the spino-parabrachial-hypothalamic-amygdalar systems and their projections to other mood-mediating systems. New psychotropic drugs for pain patients might target molecules in such brain systems. We propose a method to prioritize molecular targets by studying polymorphic genes in cohorts of patients undergoing surgical procedures associated with a variable pain relief response. We seek molecules that show a significant statistical interaction between (1) the amount of surgical pain relief, and (2) the alleles of the gene, on depression and anxiety during the first postoperative year. RESULTS: We collected DNA from 280 patients with sciatica due to a lumbar disc herniation, 162 treated surgically and 118 non-surgically, who had been followed for 10 years in the Maine Lumbar Spine Study, a large, prospective, observational study. In patients whose pain was reduced >25% by surgery, symptoms of depression and anxiety, assessed with the SF-36 Mental Health Scale, improved briskly at the first postoperative measurement. In patients with little or no surgical pain reduction, mood scores stayed about the same on average. There was large inter-individual variability at each level of residual pain. Polymorphisms in three pre-specified pain-mood candidate genes, catechol-O-methyl transferase (COMT), serotonin transporter, and brain-derived neurotrophic factor (BDNF) were not associated with late postoperative mood or with a pain-gene interaction on mood. Although the sample size did not provide enough power to persuasively search through a larger number of genes, an exploratory survey of 25 other genes provides illustrations of pain-gene interactions on postoperative mood – the mu opioid receptor for short-term effects of acute sciatica on mood, and the galanin-2 receptor for effects of unrelieved post-discectomy pain on mood one year after surgery. CONCLUSION: Genomic analysis of longitudinal studies of pain, depression, and anxiety in patients undergoing pain-relieving surgery may help to identify molecules through which pain alters mood. Detection of alleles with modest-sized effects will require larger cohorts

Evolution of an Eurasian Avian-like Influenza Virus in Naïve and Vaccinated Pigs

Influenza viruses are characterized by an ability to cross species boundaries and evade host immunity, sometimes with devastating consequences. The 2009 pandemic of H1N1 influenza A virus highlights the importance of pigs in influenza emergence, particularly as intermediate hosts by which avian viruses adapt to mammals before emerging in humans. Although segment reassortment has commonly been associated with influenza emergence, an expanded host-range is also likely to be associated with the accumulation of specific beneficial point mutations. To better understand the mechanisms that shape the genetic diversity of avian-like viruses in pigs, we studied the evolutionary dynamics of an Eurasian Avian-like swine influenza virus (EA-SIV) in naïve and vaccinated pigs linked by natural transmission. We analyzed multiple clones of the hemagglutinin 1 (HA1) gene derived from consecutive daily viral populations. Strikingly, we observed both transient and fixed changes in the consensus sequence along the transmission chain. Hence, the mutational spectrum of intra-host EA-SIV populations is highly dynamic and allele fixation can occur with extreme rapidity. In addition, mutations that could potentially alter host-range and antigenicity were transmitted between animals and mixed infections were commonplace, even in vaccinated pigs. Finally, we repeatedly detected distinct stop codons in virus samples from co-housed pigs, suggesting that they persisted within hosts and were transmitted among them. This implies that mutations that reduce viral fitness in one host, but which could lead to fitness benefits in a novel host, can circulate at low frequencies