Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia

Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated de novo mutation (p.Cys188Trp) in the GABAA receptor Cl− channel γ-1 subunit (GABRG1) exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na+ and Ca+ channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca2+ channel Cav3.2 (CACNA1H). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis

Intensive enteral nutrition is ineffective for individuals with severe alcoholic hepatitis treated with corticosteroids.

peer reviewedBACKGROUND & AIMS: Severe alcoholic hepatitis (AH) is a lifethreatening disease for which adequate oral nutritional support is recommended. We performed a randomized controlled trial to determine whether the combination of corticosteroid and intensive enteral nutrition therapy is more effective than corticosteroid therapy alone in patients with severe AH. METHODS: We enrolled 136 heavy consumers of alcohol (age, 18–75 y) with recent onset of jaundice and biopsy-proven severe AH in our study, performed at 18 hospitals in Belgium and 2 in France, from February 2010 through February 2013. Subjects were assigned randomly (1:1) to groups that received either intensive enteral nutrition plus methylprednisolone or conventional nutrition plus methylprednisolone (controls). In the intensive enteral nutrition group, enteral nutrition was given via feeding tube for 14 days. The primary end point was patient survival for 6 months. RESULTS: In an intention-to-treat analysis, we found no significant difference between groups in 6-month cumulative mortality: 44.4% of patients died in the intensive enteral nutrition group (95% confidence interval [CI], 32.2%–55.9%) and 52.1% of controls died (95% CI, 39.4%– 63.4%) (P ¼ .406). The enteral feeding tube was withdrawn prematurely from 48.5% of patients, and serious adverse events considered to be related to enteral nutrition occurred in 5 patients. Regardless of group, a greater proportion of patients with a daily calorie intake less than 21.5 kcal/kg/day died (65.8%; 95% CI, 48.8–78.4) than patients with a higher intake of calories (33.1%; 95% CI, 23.1%–43.4%) (P < .001). CONCLUSIONS: In a randomized trial of patients with severe AH treated with corticosteroids, we found that intensive enteral nutrition was difficult to implement and did not increase survival. However, low daily energy intake was associated with greater mortality, so adequate nutritional intake should be a main goal for treatment

Calcium Dependent CAMTA1 in Adult Stem Cell Commitment to a Myocardial Lineage

The phenotype of somatic cells has recently been found to be reversible. Direct reprogramming of one cell type into another has been achieved with transduction and over expression of exogenous defined transcription factors emphasizing their role in specifying cell fate. To discover early and novel endogenous transcription factors that may have a role in adult-derived stem cell acquisition of a cardiomyocyte phenotype, mesenchymal stem cells from human and mouse bone marrow and rat liver were co-cultured with neonatal cardiomyocytes as an in vitro cardiogenic microenvironment. Cell-cell communications develop between the two cell types as early as 24 hrs in co-culture and are required for elaboration of a myocardial phenotype in the stem cells 8-16 days later. These intercellular communications are associated with novel Ca(2+) oscillations in the stem cells that are synchronous with the Ca(2+) transients in adjacent cardiomyocytes and are detected in the stem cells as early as 24-48 hrs in co-culture. Early and significant up-regulation of Ca(2+)-dependent effectors, CAMTA1 and RCAN1 ensues before a myocardial program is activated. CAMTA1 loss-of-function minimizes the activation of the cardiac gene program in the stem cells. While the expression of RCAN1 suggests involvement of the well-characterized calcineurin-NFAT pathway as a response to a Ca(2+) signal, the CAMTA1 up-regulated expression as a response to such a signal in the stem cells was unknown. Cell-cell communications between the stem cells and adjacent cardiomyocytes induce Ca(2+) signals that activate a myocardial gene program in the stem cells via a novel and early Ca(2+)-dependent intermediate, up-regulation of CAMTA1

Subcellular Location of PKA Controls Striatal Plasticity: Stochastic Simulations in Spiny Dendrites

Dopamine release in the striatum has been implicated in various forms of reward dependent learning. Dopamine leads to production of cAMP and activation of protein kinase A (PKA), which are involved in striatal synaptic plasticity and learning. PKA and its protein targets are not diffusely located throughout the neuron, but are confined to various subcellular compartments by anchoring molecules such as A-Kinase Anchoring Proteins (AKAPs). Experiments have shown that blocking the interaction of PKA with AKAPs disrupts its subcellular location and prevents LTP in the hippocampus and striatum; however, these experiments have not revealed whether the critical function of anchoring is to locate PKA near the cAMP that activates it or near its targets, such as AMPA receptors located in the post-synaptic density. We have developed a large scale stochastic reaction-diffusion model of signaling pathways in a medium spiny projection neuron dendrite with spines, based on published biochemical measurements, to investigate this question and to evaluate whether dopamine signaling exhibits spatial specificity post-synaptically. The model was stimulated with dopamine pulses mimicking those recorded in response to reward. Simulations show that PKA colocalization with adenylate cyclase, either in the spine head or in the dendrite, leads to greater phosphorylation of DARPP-32 Thr34 and AMPA receptor GluA1 Ser845 than when PKA is anchored away from adenylate cyclase. Simulations further demonstrate that though cAMP exhibits a strong spatial gradient, diffusible DARPP-32 facilitates the spread of PKA activity, suggesting that additional inactivation mechanisms are required to produce spatial specificity of PKA activity

Tree species diversity and utilities in a contracting lowland hillside rainforest fragment in Central Vietnam

Abstract Background Within the highly bio-diverse ‘Northern Vietnam Lowland Rain Forests Ecoregion’ only small, and mostly highly modified forestlands persist within vast exotic-species plantations. The aim of this study was to elucidate vegetation patterns of a secondary hillside rainforest remnant (elevation 120–330 m, 76 ha) as an outcome of natural processes, and anthropogenic processes linked to changing forest values. Methods In the rainforest remnant tree species and various bio-physical parameters (relating to soils and terrain) were surveyed on forty 20 m × 20 m sized plots. The forest's vegetation patterns and tree diversity were analysed using dendrograms, canonical correspondence analysis, and other statistical tools. Results Forest tree species richness was high (172 in the survey, 94 per hectare), including many endemic species (>16%; some recently described). Vegetation patterns and diversity were largely explained by topography, with colline/sub-montane species present mainly along hillside ridges, and lowland/humid-tropical species predominant on lower slopes. Scarcity of high-value timber species reflected past logging, whereas abundance of light-demanding species, and species valued for fruits, provided evidence of human-aided forest restoration and ‘enrichment’ in terms of useful trees. Exhaustion of sought-after forest products, and decreasing appreciation of non-wood products concurred with further encroachment of exotic plantations in between 2010 and 2015. Regeneration of rare tree species was reduced probably due to forest isolation. Conclusions Despite long-term anthropogenic influences, remnant forests in the lowlands of Vietnam can harbor high plant biodiversity, including many endangered species. Various successive future changes (vanishing species, generalist dominance, and associated forest structural-qualitative changes) are, however, expected to occur in small forest fragments. Lowland forest biodiversity can only be maintained if forest fragments maintain a certain size and/or are connected via corridors to larger forest networks. Preservation of the forests may be fostered using new economic incentive schemes

Microsomal function in hepatitis B surface antigen healthy carriers: assessment of cytochrome P450 1A2 activity by the 14C-caffeine breath test.

The hepatitis B surface antigen (HBsAg) carrier state is associated with changes in hepatocellular function involving the cytochrome P450 (CYP) system. Among this system, CYP1A2 enzyme plays an important role in chemical carcinogenesis and in the metabolism of several drugs. We have thus investigated CYP1A2 function using two 14C-caffeine breath tests (3-methyl-14C; C3BT and 7-methyl-14C caffeine; C7BT) in 12 HBsAg healthy carriers and 8 healthy volunteers matched for 14C-aminopyrine breath test values. HBsAg carriers exhibited lower C3- and C7BT values than normal controls. This difference, however, did not reach statistical significance except for C7BT values normalised for aminopyrine breath test values. Our data thus do not support the association between viral presence and CYP1A2 dysfunction

Les manifestations digestives de la maladie de Steinert. Analyse de 19 cas dont 10 avec symptômes digestifs.

We studied digestive manifestations occurring during follow-up of 19 cases of myotonic dystrophy. GI symptoms occurred in 10 patients (53%), mainly dysphagia (n = 7). In patients undergoing investigations (n = 7), their digestive troubles were probably or definitively related to the neurological disease in 6 cases. Upper GI endoscopy was normal in 5 dysphagic patients. The oesophageal manometry was abnormal in 3 of 4 patients. Complications developed in 3 cases (16%). One patient presented two episodes of spontaneous pneumoperitoneum. A second one developed a chronic colonic pseudo-obstruction with megacolon treated by subtotal colectomy. Manometric studies revealed oesophageal aperistalsis, low amplitude of gastro-jejunal contractions but persistence of migrating motor complexes and a normal recto-anal reflex. A third patient developed an acute pseudo-obstruction with ischemic colitis. In conclusion, myotonic dystrophy frequently disturbs digestive tract motility and may cause complications such as intestinal pseudo-obstruction

Hybrid III-V/silicon micro-lasers based on resonant cavity reflectors

We present a novel approach to design compact, single mode, hybrid 111-V/silicon microlasers. At both ends of the 111-V laser cavity, silicon gratings are operated in a resonant regime to allow high reflection over a short distance. We have verified this technique numerically andfound that, for a thick bonding layer of350 nm, more than 93% reflection can be obtained over a distance of less than 20 pm

Calcium - a life and death signal

One of the most versatile and universal signalling agents in the human body is the calcium ion, Ca2+. How does this simple ion act during cell birth, life and death, and how does it regulate so many different cellular processes