Mrgprd Enhances Excitability in Specific Populations of Cutaneous Murine Polymodal Nociceptors

The Mas-related G protein-coupled receptor D (Mrgprd) is selectively expressed in nonpeptidergic nociceptors that innervate the outer layers of mammalian skin. The function of Mrgprd in nociceptive neurons and the physiologically relevant somatosensory stimuli that activate Mrgprd^-expressing (Mrgprd^+) neurons are currently unknown. To address these issues, we studied three Mrgprd knock-in mouse lines using an ex vivo somatosensory preparation to examine the role of the Mrgprd receptor and Mrgprd+ afferents in cutaneous somatosensation. In mouse hairy skin, Mrgprd, as marked by expression of green fluorescent protein reporters, was expressed predominantly in the population of nonpeptidergic, TRPV1-negative, C-polymodal nociceptors. In mice lacking Mrgprd, this population of nociceptors exhibited decreased sensitivity to cold, heat, and mechanical stimuli. Additionally, in vitro patch-clamp studies were performed on cultured dorsal root ganglion neurons from Mrgprd^(–/–) and Mrgprd^(+/–) mice. These studies revealed a higher rheobase in neurons from Mrgprd^(–/–) mice than from Mrgprd^(+/–) mice. Furthermore, the application of the Mrgprd ligand β-alanine significantly reduced the rheobase and increased the firing rate in neurons from Mrgprd^(+/–) mice but was without effect in neurons from Mrgprd^(–/–) mice. Our results demonstrate that Mrgprd influences the excitability of polymodal nonpeptidergic nociceptors to mechanical and thermal stimuli

Plains Tectonism on Venus: The Deformation Belts of Lavinia Planitia

High-resolution radar images from the Magellan spacecraft have revealed the first details of the morphology of the Lavinia Planitia region of Venus. A number of geologic units can be distinguished, including volcanic plains units with a range of ages. Transecting these plains over much of the Lavinia region are two types of generally orthogonal features that we interpret to be compressional wrinkle ridges and extensional grooves. The dominant tectonic features of Lavinia are broad elevated belts of intense deformation that transect the plains with complex geometry. They are many tens to a few hundred kilometers wide, as much as 1000 km long, and elevated hundreds of meters above the surrounding plains. Two classes of deformation belts are seen in the Lavinia region. “Ridge belts” are composed of parallel ridges, each a few hundred meters in elevation, that we interpret to be folds. Typical fold spacings are 5–10 km. “Fracture belts” are dominated instead by intense faulting, with faults in some instances paired to form narrow grabens. There is also some evidence for modest amounts of horizontal shear distributed across both ridge and fracture belts. Crosscutting relationships among the belts show there to be a range in belt ages. In western Lavinia in particular, many ridge and fracture belts appear to bear a relationship to the much smaller wrinkle ridges and grooves on the surrounding plains: Ridge morphology tends to dominate belts that lie more nearly parallel to local plains wrinkle ridges, and fracture morphology tends to dominate belts that lie more nearly parallel to local plains grooves. We use simple models to explore the formation of ridge and fracture belts. We show that convective motions in the mantle can couple to the crust to cause horizontal stresses of a magnitude sufficient to induce the formation of deformation belts like those observed in Lavinia. We also use the small-scale wavelengths of deformation observed within individual ridge belts to place an approximate lower limit on the venusian thermal gradient in the Lavinia region at the time of deformation

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

BOB CAT: a Large-Scale Review and Delphi Consensus for Management of Barrett’s Esophagus With No Dysplasia, Indefinite for, or Low-Grade Dysplasia

OBJECTIVES: Barrett’s esophagus (BE) is a common premalignant lesion for which surveillance is recommended. This strategy is limited by considerable variations in clinical practice. We conducted an international, multidisciplinary, systematic search and evidence-based review of BE and provided consensus recommendations for clinical use in patients with nondysplastic, indefinite, and low-grade dysplasia (LGD). METHODS: We defined the scope, proposed statements, and searched electronic databases, yielding 20,558 publications that were screened, selected online, and formed the evidence base. We used a Delphi consensus process, with an 80% agreement threshold, using GRADE (Grading of Recommendations Assessment, Development and Evaluation) to categorize the quality of evidence and strength of recommendations. RESULTS: In total, 80% of respondents agreed with 55 of 127 statements in the final voting rounds. Population endoscopic screening is not recommended and screening should target only very high-risk cases of males aged over 60 years with chronic uncontrolled reflux. A new international definition of BE was agreed upon. For any degree of dysplasia, at least two specialist gastrointestinal (GI) pathologists are required. Risk factors for cancer include male gender, length of BE, and central obesity. Endoscopic resection should be used for visible, nodular areas. Surveillance is not recommended for <5 years of life expectancy. Management strategies for indefinite dysplasia (IND) and LGD were identified, including a de-escalation strategy for lower-risk patients and escalation to intervention with follow-up for higher-risk patients. CONCLUSIONS: In this uniquely large consensus process in gastroenterology, we made key clinical recommendations for the escalation/de-escalation of BE in clinical practice. We made strong recommendations for the prioritization of future research

Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus.

BACKGROUND & AIMS: Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. METHODS: We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. RESULTS: We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 × 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 × 10(-9)). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 × 10(-9)). CONCLUSIONS: We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response

Transcriptional and Post-Transcriptional Regulation of SPAST, the Gene Most Frequently Mutated in Hereditary Spastic Paraplegia

Hereditary spastic paraplegias (HSPs) comprise a group of neurodegenerative disorders that are characterized by progressive spasticity of the lower extremities, due to axonal degeneration in the corticospinal motor tracts. HSPs are genetically heterogeneous and show autosomal dominant inheritance in ∼70–80% of cases, with additional cases being recessive or X-linked. The most common type of HSP is SPG4 with mutations in the SPAST gene, encoding spastin, which occurs in 40% of dominantly inherited cases and in ∼10% of sporadic cases. Both loss-of-function and dominant-negative mutation mechanisms have been described for SPG4, suggesting that precise or stoichiometric levels of spastin are necessary for biological function. Therefore, we hypothesized that regulatory mechanisms controlling expression of SPAST are important determinants of spastin biology, and if altered, could contribute to the development and progression of the disease. To examine the transcriptional and post-transcriptional regulation of SPAST, we used molecular phylogenetic methods to identify conserved sequences for putative transcription factor binding sites and miRNA targeting motifs in the SPAST promoter and 3′-UTR, respectively. By a variety of molecular methods, we demonstrate that SPAST transcription is positively regulated by NRF1 and SOX11. Furthermore, we show that miR-96 and miR-182 negatively regulate SPAST by effects on mRNA stability and protein level. These transcriptional and miRNA regulatory mechanisms provide new functional targets for mutation screening and therapeutic targeting in HSP

Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response

Quality indicators for patients with traumatic brain injury in European intensive care units

Background: The aim of this study is to validate a previously published consensus-based quality indicator set for the management of patients with traumatic brain injury (TBI) at intensive care units (ICUs) in Europe and to study its potential for quality measur

Changing care pathways and between-center practice variations in intensive care for traumatic brain injury across Europe

Purpose: To describe ICU stay, selected management aspects, and outcome of Intensive Care Unit (ICU) patients with traumatic brain injury (TBI) in Europe, and to quantify variation across centers. Methods: This is a prospective observational multicenter study conducted across 18 countries in Europe and Israel. Admission characteristics, clinical data, and outcome were described at patient- and center levels. Between-center variation in the total ICU population was quantified with the median odds ratio (MOR), with correction for case-mix and random variation between centers. Results: A total of 2138 patients were admitted to the ICU, with median age of 49 years; 36% of which were mild TBI (Glasgow Coma Scale; GCS 13–15). Within, 72 h 636 (30%) were discharged and 128 (6%) died. Early deaths and long-stay patients (> 72 h) had more severe injuries based on the GCS and neuroimaging characteristics, compared with short-stay patients. Long-stay patients received more monitoring and were treated at higher intensity, and experienced worse 6-month outcome compared to short-stay patients. Between-center variations were prominent in the proportion of short-stay patients (MOR = 2.3, p < 0.001), use of intracranial pressure (ICP) monitoring (MOR = 2.5, p < 0.001) and aggressive treatme