Cognitive Behavioral Therapy for IBS: How Useful, How Often, and How Does It Work?

Abstract

Purpose of Review

While dietary and medical treatments are beneficial for specific GI symptoms for some IBS patients, they have an unsatisfactory track record for the full range of GI symptoms for more severe patients. A number of psychological interventions have been developed over the past two decades to help patients' self-manage symptoms. This review discusses the last 5 years of research on psychological treatments, with a focus on cognitive behavioral therapy (CBT) and hypnosis.

Recent Findings

Recent systematic reviews indicate that psychological interventions are efficacious and their gains are maintained long-term. Treatment gains are not a function of the number of sessions.

Summary

Psychological interventions are at least moderately efficacious treatments for IBS symptoms. Of different psychotherapies, CBT and hypnosis appear efficacious in minimal-contact formats (e.g., fewer sessions, phone contact). Research is still needed to identify theoretically relevant active ingredients that underlie treatment effects.

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Ablation Therapy for Barrett’s Esophagus: New Rules for Changing Times

Abstract

Purpose of Review

In this review, we discuss different endoscopic techniques in the eradication of Barrett's esophagus (BE) as well as some controversies in the field of treatment.

Recent Findings

Patients with T1a esophageal adenocarcinoma and BE of high-grade dysplasia should undergo endoscopic ablative therapy. The most studied technique to date is radiofrequency ablation. It can be combined with endoscopic mucosal resection in cases containing nodular and flat lesions. Cryotherapy and APC have shown promise with good efficacy and safety profiles so far, but are not mainstream as more studies are needed. Surveillance is still required post-ablation since recurrence is common. Low-grade dysplasia can be treated with either endo-ablative therapy or surveillance. Non-dysplastic BE treatment is controversial and so far, only surveillance is recommended. Research is ongoing to better risk stratify these patients.

Summary

Our ability to diagnose and treat BE has come a long way in the past few years with the goal of preventing its progression into malignancy. The advent of endoscopic techniques in the eradication of BE has provided a less invasive and safer modality of treatment as compared to surgical esophagectomy. Data in the form of randomized trials and high-volume registries has provided good evidence to support the efficacy of these techniques and their long-term durability.

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Cardiac action potential repolarization re-visited: early repolarization shows all-or-none behaviour

Abstract

In healthy mammalian hearts the action potential (AP) waveform initiates and modulates each contraction, or heartbeat. As a result, action potential height and duration are key physiological variables. In addition, rate-dependent changes in ventricular action potential duration (APD), and variations in APD at a fixed heart rate, are both reliable biomarkers of electrophysiological stability. Present guidelines for the likelihood that candidate drugs will increase arrhythmias rely on small changes in APD and Q-T intervals as criteria for Safety Pharmacology decisions. However, both of these measurements correspond to the final repolarization of the AP. Emerging clinical evidence also draws attention to the early repolarization phase of the action potential (and the J wave of the ECG) as a biomarker for arrhythmogenesis.

Here we provide mechanistic background to this Early Repolarization Syndrome by summarizing the evidence that both the initial depolarization and repolarization phases of the cardiac action potential can exhibit distinct time- and voltage-dependent thresholds; and demonstrating that both can show regenerative all-or-none behaviour. An important consequence of this is that not all of the dynamics of action potential repolarization in human ventricle can be captured by data from single myocytes when these results are expressed as 'repolarization reserve'. For example, the complex pattern of cell-to-cell current flow that is responsible for AP conduction (propagation) within the mammalian myocardium can change APD and the Q-T interval of the electrocardiogram as well as alter APD stability, and modulate responsiveness to pharmacological agents (such as Class III anti-arrhythmic drugs).

This article is protected by copyright. All rights reserved

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Engineering defined membrane-embedded elements of AMPA receptor induces opposing gating modulation by CNIH3 and stargazin

Abstract

During excitatory synaptic transmission, various structurally unrelated transmembrane auxiliary subunits control the function of AMPA receptors (AMPARs), but the underlying mechanisms remain unclear. We identified lipid-exposed residues in the transmembrane domain (TMD) of GluA2 subunit of AMPARs that are critical for the function of AMPAR auxiliary subunits, stargazin (Stg) and cornichon 3 (CNIH3). These residues are essential for stabilizing the AMPAR-CNIH3 complex in detergents and overlap with the contacts made between GluA2 TMD and Stg in the cryoEM structures. Mutating these residues had opposite effects on gating modulation and complex stability when Stg- and CNIH3-bound AMPARs were compared. Specifically, in detergent the GluA2-A793F formed unstable complex with CNIIH3 but in the membrane the GluA2-A793F-CNIH3 complex expressed a gain-of-function. In contrast, the GluA2-A793F-Stg complex was stable, but had diminished gating modulation. The GluA2-C528L destabilized AMPAR-CNIH3 complex but stabilized AMPAR-Stg complex, with overall loss-of-function in gating modulation. Furthermore, loss-of-function mutations in this TMD region cancelled the effects of a gain-of-function Stg carrying mutation in its extracellular loop, demonstrating that both the extracellular and the TMD elements contribute independently to gating modulation. The elements of AMPAR functionally recruited by auxiliary subunits are, therefore, located not only in the extracellular domains but also in the lipid accessible surface of the AMPAR. The TMD surface we defined is a potential target for auxiliary subunit specific compounds, because engineering of this hotspot induces opposing functional outcomes by Stg and CNIH3. The collection of mutant-phenotype mapping provides a framework for engineering AMPAR gating using auxiliary subunits.

This article is protected by copyright. All rights reserved

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The facial morphology in Down syndrome: A 3D comparison of patients with and without obstructive sleep apnea

Obstructive sleep apnea (OSA) occurs at a high prevalence in patients with Down syndrome (DS). A polysomnogram, which is often cumbersome and challenging, remains the gold standard method of diagnosing OSA. OSA in patients with DS is often attributed to skeletal and soft-tissue structural alterations that are characteristic of the DS phenotype; as such, we hypothesized that assessing anthropometric facial measurements may be predictive of OSA in patients with DS. We used the 3dMDface sterophotography system to capture and create 3D facial images, and we subsequently identified facial landmarks using a single, experienced investigator and utilizing proprietary software to calculate inter-landmark distances and angles. We compared our findings with similar data for neurotypically developing participants. We further compared the findings in participants with DS with and without OSA. Participants with DS had maxillomandibular hypoplasia with smaller ear, nose, and eye measurements compared to neurotypically developing peers. We found no statistically significant differences in 3D photogrammetric measurements between participants with DS with or without OSA.

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A splice-site variant in ANKRD11 associated with classical KBG syndrome

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Cystic kidneys in fetal Walker–Warburg syndrome with POMT2 mutation: Intrafamilial phenotypic variability in four siblings and review of literature

Walker–Warburg syndrome (WWS) is a severe form of congenital muscular dystrophy secondary to α-dystroglycanopathy with muscle, brain, and eye abnormalities often leading to death in the first weeks of life. It is transmitted in an autosomal recessive pattern, and has been linked to at least 15 different genes; including protein O-mannosyltransferase 1 (POMT1), protein O-mannosyltransferase 2 (POMT2), protein O-mannose beta-1,2-N acetylglucosaminyltransferase (POMGNT1), fukutin (FKTN), isoprenoid synthase domain-containing protein (ISPD), and other genes. We report on a consanguineous family with four consecutive siblings affected by this condition with lethal outcome in three (still birth), and termination of the fourth pregnancy based on antenatal MRI identification of brain and kidney anomalies that heralded proper and deep clinical phenotyping. The diagnosis of WWS was suggested based on the unique collective phenotype comprising brain anomalies in the form of lissencephaly, subcortical/subependymal heterotopia, and cerebellar hypoplasia shared by all four siblings; microphthalmia in one sibling; and large cystic kidneys in the fetus and another sibling. Other unshared neurological abnormalities included hydrocephalus and Dandy-Walker malformation. Whole exome sequencing of the fetus revealed a highly conserved missense mutation in POMT2 that is known to cause WWS with brain and eye anomalies.In conclusion, the heterogeneous clinical presentation in the four affected conceptions with POMT2 mutation expands the current clinical spectrum of POMT2-associated WWS to include large cystic kidneys; and confirms intra-familial variability in terms of brain, kidney, and eye anomalies.

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New intragenic rearrangements in non-Finnish mulibrey nanism

Prenatal growth is a complex dynamic process controlled by various genetic and environmental factors. Among genetic syndromes characterized by growth restriction, MULIBREY nanism represents a rare autosomal recessive condition presenting with severe pre- and post-natal growth failure, characteristic dysmorphic features but normal neurological development. The phenotype of MULIBREY nanism is variable and overlaps with others such as the Silver-Russell syndrome. We report here three patients in two distinct non-Finnish families from North France who were first suspected to have Silver–Russell syndrome which failed to be confirmed on molecular analyses. Clinical features in the three patients led us to also consider the diagnosis of MULIBREY nanism. Sequencing of the TRIM37 gene showed the three patients shared a novel nonsense mutation (c.181 C>T p.Arg61*) in a heterozygous state. Quantitative fluorescent multiplex PCR identified a new deletion of exons 15 and 16 in TRIM37 in one isolated patient and another deletion of exon 9 in two siblings. Breakpoints of both the deletions were localized in Alu sequences. Given the high number of Alu repeats, which predispose to gene rearrangements, one should always consider such genetic rearrangements in the molecular diagnosis of non-Finnish MULIBREY nanism patients. Early diagnosis of the disease would prompt careful cardiac follow up of such patients as cardiological complication is a characteristic feature of the MULIBREY nanism as described in this report.

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Diaphanospondylodysostosis and ischiospinal dysostosis, evidence for one disorder with variable expression in a patient who has survived to age 9 years

Diaphanospondylodysostosis (DSD) and ischiospinal dysostosis (ISD) are both rare skeletal dysplasias consisting of abnormal axial skeletal development but normal appendicular skeletal development. Both disorders recently have been found to result from mutations in the BMPER gene. We report a patient with one deletion and one mutation of the BMPER gene who has features most consistent with DSD but who has survived to age 9 years. Survival suggests that DSD and ISD reflect a spectrum of severity of one disease process.

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The role of IQSEC2 in syndromic intellectual disability: Narrowing the diagnostic odyssey

While X-linked intellectual disability (XLID) syndromes pose a diagnostic challenge for clinicians, an increasing number of recognized disorders and their genetic etiologies are providing answers for patients and their families. The availability of clinical exome sequencing is broadening the ability to identify mutations in genes previously unrecognized as causing XLID. In recent years, the IQSEC2 gene, located at Xp11.22, has emerged as the cause of multiple cases of both nonsyndromic and syndromic XLID. Herein we present a case series of six individuals (five males, one female) with intellectual disability and seizures found to have alterations in IQSEC2. In all cases, the diagnostic odyssey was extensive and expensive, often including invasive testing such as muscle biopsies, before ultimately reaching the diagnosis. We report these cases to demonstrate the exhaustive work-up prior to finding the changes in IQSEC2 gene, recommend that this gene be considered earlier in the diagnostic evaluation of individuals with global developmental delay, microcephaly, and severe, intractable epilepsy, and support the use of intellectual disability panels including IQSEC2 in the first-line evaluation of these patients.

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O210 Abnormal movements mimicking tremor in amyotrophic hands in adults

Adult patients presenting with slowly progressive hand weakness and wasting (HWW) without signs of upper motor neuron involvement and unconvincing cervical MRI signs of disk protrusion are a diagnostic challenge. Clinical and electrophysiological follow-up is needed to reach the most probable diagnosis.

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P244 Normal cortical modulation of subcortical structures is altered in cervical dystonia

Blink reflex (BR) is obtained after different kinds of stimuli, such as trigeminal supraorbial branch stimulation (trigeminal BR, TBR) or median nerve stimulation at wrist (hand-evoked BR, HBR). Inhibition of TBR occurs when a preceding subthreshold stimulus is applied before trigeminal stimulation (prepulse inhibition, PPI). In healthy subjects, magnitude of HBR is increased and magnitude of PPI of TBR is decreased if the stimulated hand is positioned in the peripersonal space (PPS). Here, we aimed to investigate the changes of HBR and PPI of the TBR in PPS to understand alterations of cortical modulations of subcortical structures in cervical dystonia.

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P243 Functional connectivity analysis of cortico-cortical evoked potentials

The electrical stimulation of the cortical tissue can evoke early (N1) and late (N2) cortico-cortical evoked potential (CCEP) components. In this study, we applied functional connectivity analysis to investigate the attenuation and network topology induced by electrical stimulation. We also compared the synchronization and network topology in case of stimulations inside and outside the epileptic zone (EZ).

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P322 Fully automated R-peak detection algorithm for patients with epilepsy: First step towards portable seizure detector

Earlier studies have shown that short term heart rate variability (HRV) analysis of ECG is a promising biomarker for detection of epileptic seizures. A precise and accurate automatic R-peak detection algorithm is a necessity in a real-time, continuous measurement of HRV, in a portable ECG device.

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P253 Knowledge of electromyography (EMG) among sub-Saharan African patients - A pilot survey

Electromyography (EMG) is one of the common diagnostic procedure in neurology but still scarce in sub-Saharan Africa (SSA).

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O1-6-12. Cauda equina conduction time as a test for lumber spinal stenosis

We examined the cauda equina conduction time (CECT) in 20 patients (11 male), average age, 73years, low back pain therapy criterion score of Japan orthopaedic Association (JOA score), 17 points, and Oswestry Disability Index (ODI), 19 points and aged matched 17 healthy volunteers. Magnetic Augmented Translumbosacral Stimulation (MTATS) at L1 and S1 levels elicited a compound muscle action potential (CMAP) recordable from bilateral abductor hallucis muscle. We calculated the CECT as the difference between the latencies of CAMPs elicited by stimulation at L1 and S1 level.

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P290 Reduced hand dexterity in parkinson’s disease patients is associated with impaired intracortical inhibition

To check whether hand dexterity in Parkinson's disease (PD) patients is linked with motor cortex excitability and plasticity.

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O2-6-06. The role of gaze in performing the trail making test

We studied the role of gaze in performing the trail-making test (TMT) in eight normal subjects, a task frequently used to assess frontal executive function in neurological patients. TMT was presented on a touch-panel monitor placed in front of the subjects, on which they were asked to connect the presented numbers with their fingers in an ascending order (version A), or with the added task of alternately connecting between the numbers and letters in ascending and alphabetical orders (version B), respectively.

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P219 Cortical excitability in Dystrophia Myotonica type 1

Dystrophia Myotonica type 1 (DM1) is characterized by distal muscle weakness, atrophy, myotonia and CNS involvement. Electrophysiological assessment of CNS involvement in DM1 patient refers to multimodal evoked potential studies. Herein we investigated the function of central motor pathways in DM1 patients by transcranial magnetic stimulation (TMS) and the possible relationships with disease duration, muscular impairment and MRI findings.

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O2-6-08. Mechanism of forelimb motor function restoration after cervical spinal cord hemisection in rats: Electorophysiological verification

The objective of this study was to electrophysiologically assess corticospinal tracts of adult rats and recovery of motor function of their forelimbs after cervical cord hemisection. Of 39 adult rats used, compound muscle action potentials (CMAPs) of forelimbs of 15 rats were evaluated, before they received left C5 segmental hemisection of the spinal cord, by stimulating the pyramid of medulla oblongata on one side using an exciting microelectrode. All 15 rats exhibited contralateral electrical activity, but their CMAPs disappeared after hemisection.

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P306 Motor cortex tRNS reduce pain and improve affective and cognitive impairment in patients with fibromyalgia: Preliminary results of a randomized sham-controlled trial

Fibromyalgia (FMS) is a clinical syndrome characterized by widespread musculoskeletal pain, chronic fatigue, cognitive deficit, sleep and mood disorders. Most pharmacological therapies showed limited effectiveness and there's need for new effective and well tolerated therapeutic tools. Recently, transcranial direct-current stimulation (tDCS) of motor cortex showed able to reduce pain, while dorsolateral prefrontal cortex (DLPFC) tDCS improved anxiety, depression and cognitive impairment in FMS. A new application, random noise stimulation (tRNS), using randomly changing alternating currents, showed very recently ability to ameliorate working memory and pain in limited series of FMS and neuropathic pain patients.

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O-2-6-15. Immediate effects of anodal tDCS combined with patterned electrical stimulation on gait performance in patients with stroke

Anodal transcranial direct current stimulation (tDCS) combined with patterned electrical stimulation (PES) modulates spinal reciprocal inhibition and improves the ankle movement in patients with incomplete spinal cord injury (Yamaguchi et al., 2016). This study aimed to examine the immediate effects of anodal tDCS combined with PES on gait performance in patients with stroke. Twelve patients with subacute stroke participated in this double-masked, sham-controlled cross-over study. They randomly participated in the following sessions on separate days: (1) anodal tDCS+PES; (2) anodal tDCS+sham PES; (3) sham tDCS+PES.

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P270 An unusual demyelinating neuropathy in a patient with defects in the DCTN1 gene

An unusual case of genetic disturbance resulting in an unusual neuropathy.

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O2-6-21. Comparison of muscle ultrasound findings between demyelinating neuropathy and axonopathy

Denervation causes increased echo intensity (EI) and decreased muscle thickness (MT) on muscle ultrasound (MUS). Chronic inflammatory demyelinating polyneuropathy (CIDP) does not present with denervation unless secondary axonal degeneration occurs. Hence, few MUS changes would occur compared to amyotrophic lateral sclerosis (ALS). The abductor pollicis brevis, abductor digiti minimi, and first dorsal interosseous muscles of 12 patients with CIDP and 13 patients with ALS were examined. There were no significant differences in Medical Research Council scales of each muscle between the CIDP and ALS group.

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P237 Axonal excitability findings in type 1 diabetes mellitus – Median nerve versus tibial nerve comparison

Length dependent peripheral neuropathy is the most common complication of diabetes mellitus (DM). As no curative treatment for diabetic polyneuropathy (DMP) is available, its prevention and early detection is very important. Axonal excitability is defined as the capability of nodal and paranodal pathological changes in DMP. The aim of present study was to determine alterations in axonal excitability findings in tibial nerve by comparing median nerve axonal excitability findings in Type 1 DMP.

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O-2-6-26. Effects of sleep on the epileptiform discharge in benign adult familial myoclonus epilepsy (BAFME)

Epileptiform discharges often increase in most epilepsy types. This study sought to clarify the effects of sleep modification on cortical irritability in benign adult familial myoclonus epilepsy (BAFME). We retrospectively reviewed 31 conventional electroencephalographies (EEGs) of 12 BAFME patients and analyzed epileptiform discharges during the awake and sleep periods of 6 EEGs in 5 BAFME patients (5 women, mean age: 49.6±20.3years). Using conventional EEG analysis, EEG was classified into awake (66.6%) and light sleep stages (Stage I and II) (33.4%).

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P330 Event-related potential combined with middle latency somatosensory evoked potential improve the prediction of awakening from coma

To determine the evaluation day that evoked potentials (EPs) best correlates with wakening outcome for comatose patients; to determine whether middle latency somatosensory evoked potential (MLSEP) combined with event-related potential (ERP) improved the prediction of awakening.

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O3-6-04. Optogenetically induced motor evoked potentials in mice

Optogenetics is a powerful tool that utilizes light to control neurons genetically modified to express light-sensitive ion channels. This innovative technology, which allows for the activation or silencing of neurons on a millisecond time-scale, can be aimed at specific cell types, preventing the manipulation of cells that fall outside a target population. As such, optogenetics has the potential to improve impaired brain networks without side effects commonly associated with alternative strategies (e.g., electrical stimulation).

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P314 Two distinct phenotypes of corticomotor hand representation in human motor cortex

Transcranial magnetic stimulation (TMS) can be used to map the corticomotor representations of hand muscles in the precentral motor-cortex (PMC). The spatial peak of the corticomotor representations is often not located in the primary motor cortex (M1HAND), but shows an anterior shift towards the dorsal premotor cortex (PMd). Here we used magnetic resonance imaging (MRI) to test the hypothesis that the PMC shows different structural and functional properties in individuals with a clear "premotor" representation compared to individuals with a preponderant "primary-motor" representation of hand muscles.

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O3-6-21. Time-dependent changes in intraoperative monitoring findings during microvascular decompression for hemifacial spasm

We analyzed time-dependent changes in the intraoperative monitoring of abnormal muscle responses (AMRs) and facial motor evoked potentials (FMEPs) elicited by transcranial electrical stimulation during microvascular decompression (MVD) in 26 patients with hemifacial spasm. In the orbicularis oculi muscle, the AMRs disappeared in 11 patients before MVD, in six after MVD, and in three during dural closure. The AMRs persisted in six patients. FMEP amplitudes decreased to less than 50% in two patients before MVD, in four after MVD, and in six during dural closure.

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Muscle Proprioceptors in Adult Rat: Mechanosensory Signaling and Synapse Distribution in Spinal Cord

Abstract The characteristic signaling and intra-spinal projections of muscle proprioceptors best described in the cat are often generalized across mammalian species. However, species-dependent adaptations within this system seem necessary to accommodate asymmetric scaling of length, velocity, and force information required by the physics of movement. In the present study we report mechanosensory responses and intraspinal destinations of three classes of muscle proprioceptors. Proprioceptors from triceps surae muscles in adult female Wistar rats anesthetized with isoflurane were physiologically classified as muscle spindle group Ia or II or as tendon organ group Ib afferents, studied for their firing responses to passive-muscle stretch, and in some cases, labeled and imaged for axon projections and varicosities in spinal segments. Afferent projections and the laminar distributions of provisional synapses in rats closely resembled those found in cat. Afferent signaling of muscle kinematics was also similar to reports on cat, but rat Ib afferents fired robustly during passive muscle stretch and Ia afferents displayed an exaggerated dynamic response, even after accounting for locomotor scaling. These differences in mechanosensory signaling by muscle proprioceptors may represent adaptations for movement control in different animal species.

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Field repetition and local mapping in the hippocampus and medial entorhinal cortex

Hippocampal place cells support spatial cognition and are thought to form the neural substrate of a global 'cognitive map'. A widely held view is that parts of the hippocampus also underlie the ability to separate patterns, or to provide different neural codes for distinct environments. However, a number of studies have shown that in environments composed of multiple, repeating compartments, place cells and other spatially modulated neurons show the same activity in each local area. This repetition of firing fields may reflect pattern completion, and may make it difficult for animals to distinguish similar local environments. In this review we will (a) highlight some of the navigation difficulties encountered by humans in repetitive environments, (b) summarise literature demonstrating that place and grid cells represent local and not global space, and (c) attempt to explain the origin of these phenomena. We argue that the repetition of firing fields can be a useful tool for understanding of the relationship between grid cells in the entorhinal cortex and place cells in the hippocampus, the spatial inputs shared by these cells, and the propagation of spatially-related signals through these structures.

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Asymmetric vestibular stimulation reveals persistent disruption of motion perception in unilateral vestibular lesions

Self-motion perception was studied in patients with unilateral vestibular lesions (UVL) due to acute vestibular neuritis at 1 week, 4, 8 and 12 months after the acute episode. We assessed vestibularly-mediated self-motion perception by measuring the error in reproducing the position of a remembered visual target at the end of 4 cycles of asymmetric whole-body rotation. The oscillatory stimulus consists of a slow (0.09Hz) and a fast (0.38Hz) half cycle. A large error was present in UVL patients when the slow half cycle was delivered towards the lesion side, but minimal towards the healthy side. This asymmetry diminished over time, but it remained abnormally large at 12 months. In contrast, vestibulo-ocular reflex responses showed a large direction-dependent error only initially, then they normalized. Normalization also occurred for conventional reflex vestibular measures (caloric tests, subjective visual vertical and head shaking nystagmus) and for perceptual function during symmetric rotation. Vestibular-related handicap, measured with the Dizziness Handicap Inventory (DHI) at 12 months, correlated with self-motion perception asymmetry but not with abnormalities in vestibulo-ocular function. We conclude that 1) a persistent self-motion perceptual bias is revealed by asymmetric rotation in UVLs despite vestibulo-ocular function becoming symmetric over time 2) this dissociation is caused by differential perceptual-reflex adaptation to high and low frequency rotations when these are combined as with our asymmetric stimulus 3) the findings imply differential central compensation for vestibulo-perceptual and vestibulo-ocular reflex functions 4) self-motion perception disruption may mediate long-term vestibular-related handicap in UVL patients.

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Variance in exposed perturbations impairs retention of visuomotor adaptation

Sensorimotor control requires an accurate estimate of the state of the body. The brain optimizes state estimation by combining sensory signals with predictions of the sensory consequences of motor commands using a forward model. Given that both sensory signals and predictions are uncertain (i.e. noisy), the brain optimally weights the relative reliance on each source of information during adaptation. In support, it is known that uncertainty in the sensory predictions influences the rate and generalization of visuomotor adaptation. We investigated whether uncertainty in the sensory predictions affects the retention of a new visuomotor relationship. This was done by exposing three separate groups to a visuomotor rotation whose mean was common at 15° CCW but whose variance around the mean differed (i.e. SD of 0°, 3.2° or 4.5°). Retention was assessed by measuring the persistence of the adapted behaviour in a no vision phase. Results revealed that mean reach direction late in adaptation was similar across groups, suggesting it depended mainly upon the mean of exposed rotations and was robust to differences in variance. However, retention differed across groups, with higher levels of variance being associated with a more rapid reversion toward non-adapted behaviour. A control experiment ruled out that differences in retention were accounted for by differences in success rates. Exposure to variable rotations may have increased the uncertainty in sensory predictions, making the adapted forward model more labile and susceptible to change or decay.

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State-dependent Sensorimotor Gating in a Rhythmic Motor System

Sensory feedback influences motor circuits and/or their projection neuron inputs to adjust ongoing motor activity, but its efficacy varies. Currently, less is known about regulation of sensory feedback onto projection neurons that control downstream motor circuits than about sensory regulation of the motor circuit neurons themselves. Here, we tested whether sensory feedback onto projection neurons is sensitive only to activation of a motor system, or also to the modulatory state underlying that activation, using the crab Cancer borealis stomatogastric nervous system. We examined how proprioceptor neurons (gastropyloric receptors, GPRs) influence the gastric mill (chewing) circuit neurons and the projection neurons (MCN1, CPN2) which drive the gastric mill rhythm (GMR). During gastric mill rhythms triggered by the VCN mechanosensory neurons, GPR was shown previously to influence gastric mill circuit neurons but its excitation of MCN1/CPN2 was absent. Here we tested whether GPR effects on MCN1/CPN2 are also absent during gastric mill rhythms triggered by the peptidergic POC neurons. The VCN and POC pathways both trigger lasting MCN1/CPN2 activation, but their distinct influence on circuit feedback to these neurons produces different gastric mill motor patterns. We show that GPR excites MCN1 and CPN2 during the POC-GMR, altering their firing rates and activity patterns. This action changes both phases of the POC-GMR, whereas GPR only alters one phase of the VCN-GMR. Thus, sensory feedback to projection neurons can be gated as a function of the modulatory state of an active motor system, not simply switched on/off with the onset of motor activity.

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Perception of the dynamic visual vertical during sinusoidal linear motion.

The vestibular system provides information for spatial orientation. However, this information is ambiguous: because the otoliths sense the gravito-inertial force, they cannot distinguish gravitational and inertial components. As a consequence, prolonged linear acceleration of the head can be interpreted as tilt, referred to as the somatogravic effect. Previous modeling work suggests that the brain disambiguates the otolith signal according to the rules of Bayesian inference, combining noisy canal cues with the a priori assumption that prolonged linear accelerations are unlikely. Within this modeling framework the noise of the vestibular signals affects the dynamic characteristics of the tilt percept during linear whole-body motion. To test this prediction, we devised a novel paradigm to psychometrically characterize the dynamic visual vertical - as a proxy for the tilt percept - during passive sinusoidal linear motion along the inter-aural axis (0.33Hz motion frequency, 1.75m/s2 peak acceleration, 80cm displacement). While subjects (n=10) kept fixation on a central body-fixed light, a line was briefly flashed (5ms) at different phases of the motion, the orientation of which had to be judged relative to gravity. Consistent with the model's prediction, subjects showed a phase-dependent modulation of the dynamic visual vertical, with a subject-specific phase-shift with respect to the imposed acceleration signal. The magnitude of this modulation was smaller than predicted, suggesting a contribution of non-vestibular signals to the dynamic visual vertical. Despite their dampening effect, our findings may point to a link between the noise components in the vestibular system and the characteristics of dynamic visual vertical.

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Intermittent apnea elicits inactivity-induced phrenic motor facilitation via a retinoic acid- and protein synthesis-dependent pathway

Respiratory motoneuron pools must provide rhythmic inspiratory drive that is robust and reliable, yet dynamic enough to respond to respiratory challenges. One form of plasticity that is hypothesized to contribute to motor output stability by sensing and responding to inadequate respiratory neural activity is inactivity-induced phrenic motor facilitation (iPMF), an increase in inspiratory output triggered by a reduction in phrenic synaptic inputs. Evidence suggests that mechanisms giving rise to iPMF differ depending on the pattern of reduced respiratory neural activity (i.e. neural apnea). A prolonged neural apnea elicits iPMF via a spinal TNFα-induced increase in atypical PKC activity, but little is known regarding mechanisms that elicit iPMF following intermittent neural apnea. We tested the hypothesis that iPMF triggered by intermittent neural apnea requires retinoic acid and protein synthesis. Phrenic nerve activity was recorded in urethane anesthetized and ventilated rats treated intrathecally with an inhibitor of retinoic acid synthesis (DEAB), a protein synthesis inhibitor (emetine) or vehicle (aCSF) prior to intermittent (5 episodes, ~1.25 min each) or prolonged (30 min) neural apnea. Both DEAB and emetine abolished iPMF elicited by intermittent neural apnea, but had no effect on iPMF elicited by a prolonged neural apnea. Thus, different patterns of reduced respiratory neural activity elicit phenotypically similar iPMF via distinct spinal mechanisms. Understanding mechanisms that allow respiratory motoneurons to dynamically tune their output may have important implications in the context of respiratory control disorders that involve varied patterns of reduced respiratory neural activity, such as central sleep apnea and spinal cord injury.

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Face percept formation in human ventral temporal cortex

Loci in ventral temporal cortex are selectively active while viewing faces and other objects, but it remains unclear whether these areas represent accumulation of simple visual information, or processing of intact percept. We measured broadband electrocorticographic changes from implanted electrodes on the ventral temporal brain surface while showing patients noise-degraded images of faces and houses. In a subset of posterior fusiform gyrus face-selective regions, cortical activity decreased parametrically with noise increase, until the perceptual threshold. At noise levels higher than the perceptual threshold, and for house stimuli, activity remained at baseline. We propose that this convergence of proportional and thresholded response may identify active areas where face percepts are extracted from simple visual features. These loci exist within a topological structure of face percept formation in the human ventral visual stream, preceded by category non-selective activity in peri-calcarine early visual areas, and in concert with all-or-nothing activity in post-perceptual sub-regions of the ventral temporal lobe. This topological organization suggests a physiological basis for the anatomy of face perception, explaining different perceptual deficits following temporal lobe injury.

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Environmental Stress Affects the Formation of Staphylococcus aureus Persisters Tolerant to Antibiotics

Microbial Drug Resistance , Vol. 0, No. 0.


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Detection of First-Line Drug Resistance Mutations and Drug–Protein Interaction Dynamics from Tuberculosis Patients in South India

Microbial Drug Resistance , Vol. 0, No. 0.


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Meeting Report on Experimental Approaches to Evolution and Ecology Using Yeast and Other Model Systems

The fourth EMBO-sponsored conference on Experimental Approaches to Evolution and Ecology Using Yeast and Other Model Systems (http://ift.tt/2i8FKi0), was held at the EMBL in Heidelberg, Germany, October 19-23, 2016. The conference was organized by Judith Berman (Tel Aviv University), Maitreya Dunham (University of Washington), Jun-Yi Leu (Academia Sinica), and Lars Steinmetz (EMBL Heidelberg and Stanford University). The meeting attracted ~120 researchers from 28 countries and covered a wide range of topics in the fields of genetics, evolutionary biology, and ecology with a unifying focus on yeast as a model system. Attendees enjoyed the Keith Haring inspired yeast florescence microscopy artwork (Figure 1), a unique feature of the meeting since its inception, and the one-minute flash talks that catalyzed discussions at two vibrant poster sessions. The meeting coincided with the 20th anniversary of the publication describing the sequence of the first eukaryotic genome, Saccharomyces cerevisiae (Goffeau et al. 1996). Many of the conference talks focused on important questions about what is contained in the genome, how genomes evolve, and the architecture and behavior of communities of phenotypically and genotypically diverse microorganisms. Here, we summarize highlights of the research talks around these themes. Nearly all presentations focused on novel findings, and we refer the reader to relevant manuscripts that have subsequently been published.

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Comparison of transforaminal lumbar interbody fusion outcomes in patients receiving rhBMP-2 versus autograft

Recombinant human bone morphogenetic protein 2 (rhBMP-2) plays a pivotal role in complex spine surgery. Despite its limited approval, the off-label use of rhBMP-2 is prevalent, particularly in transforaminal lumbar interbody fusions (TLIF)

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On gender roles in spine surgery

In our recent article, "Gender trends in authorship of spine related academic literature – a 39 year perspective", we demonstrated that while female authorship is increasing over time, women still only make up about 14% of senior authors. Furthermore, women are half as likely to continue publishing longer than 5 years and, as senior authors, publish half as many articles as men do. These numbers are astonishing, but they only tell part of the story; we must rely on the experiences of females in spine surgery to further understand the underlying truths behind the gender disparities.

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Preventable diagnostic errors in fatal cervical spine injuries: a nationwide register-based study from 1987 to 2010

Fall-induced injuries in patients are increasing in number and they often lead to serious consequences, such as cervical spine injuries (CSI). CSI diagnostics remain a challenge despite improved radiological services.

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Using spinopelvic parameters to estimate residual lumbar lordosis assuming previous lumbosacral fusion – a study of normative values

Pelvic Incidence (PI) = Pelvic Tilt (PT) + Sacral Slope (SS) is an established trigonometric equation which can be expanded from studying the fixed pelvis with the spine to a fixed spinopelvic complex with the remnant spine, in scenarios of spinopelvic fusion or ankylosis. For a fixed spinopelvic complex, we propose the equation termed: Lumbar Incidence (LI) = Lumbar Tilt (LT) + Lumbar Slope (LS).

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Depression is associated with the long-term outcome of lumbar spinal stenosis surgery: a 10-year follow-up study

Depression is associated with greater postoperative disability in lumbar spinal stenosis (LSS) patients. No previous studies have reported the association in a 10-year follow-up.

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EMS student awarded national scholarship

GRAND RAPIDS, Mich. — The staff at Platinum Educational Group understands the struggles and obstacles that are presented to students obtaining higher education in the healthcare industries. In 2015, Platinum Educational Group launched its inaugural scholarships program geared at EMS students. In 2016, the company expanded its product line to include the Nursing and Allied Health fields. It only ...

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Increasing Parental Knowledge Related to the Human Papillomavirus (HPV) Vaccine

The purposes of this study were to evaluate parental attitudes toward general vaccination protocols and increase parental knowledge of the human papilloma virus (HPV) vaccine.

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The Financial Impact of a Hospital-Based Care Coordination Program for Children With Special Health Care Needs

Care coordination programs are important in caring for medically complex pediatric patients, particularly for children with special health care needs. This study is a retrospective financial analysis of a hospital-based care coordination program involving one procedural subgroup of children with special health care needs: those receiving pediatric tracheostomy. Hospital records were reviewed for patients who received a tracheostomy at a large Midwestern U.S. hospital from 1999 through 2015. The population was divided into two subgroups: patients who received a tracheostomy before the development of a care coordination program and patients who received a tracheostomy after enrollment in the care coordination program.

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Paramedic - UCHealth

At UCHealth, we do things differently We believe in something different: a focus on the individuality of every person. In big ways and small, we exist to improve the extraordinary lives of all those we serve. As Colorado's largest and most innovative health care system, we as a team deliver on the commitment to provide the best possible experience for our patients and their families. We foster a true ...

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EMS leaders honored at Pinnacle EMS leadership forum

By EMS1 Staff BOCA RATON, Fla. —Three EMS leaders were honored at the 12th annual Pinnacle EMS Leadership Forum for their efforts in advancing EMS as a profession. MedStar Mobile Healthcare Executive Director Doug Hooten and Regional EMS Authority Integrated Services COO Brenda Staffan were presented with the Pinnacle EMS Leadership Award. "With their teams at their respective organizations ...

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Emergency Reporting partners with StreetWise Response Software for EMS and fire agencies

Emergency Reporting's integration with StreetWise links the data used or produced in the apparatus during a response with data stored in a department's records, significantly improving accuracy, situational awareness, safety and efficiency during emergency response. BELLINGHAM, Wash. — Emergency Reporting (ER), a leading provider of Fire & EMS records management software, is pleased ...

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Continuing chronic beta-blockade in the acute phase of severe sepsis and septic shock is associated with decreased mortality rates up to 90 days

Abstract

Background. There is growing evidence that beta-blockade may reduce mortality in selected patients with sepsis. However, it is unclear if a pre-existing, chronic oral beta-blocker therapy should be continued or discontinued during the acute phase of severe sepsis and septic shock.Methods. The present secondary analysis of a prospective observational single centre trial compared patient and treatment characteristics, length of stay and mortality rates between adult patients with severe sepsis or septic shock, in whom chronic beta-blocker therapy was continued or discontinued, respectively. The acute phase was defined as the period ranging from two days before to three days after disease onset. Multivariable Cox regression analysis was performed to compare survival outcomes in patients with pre-existing chronic beta-blockade.Results. A total of 296 patients with severe sepsis or septic shock and pre-existing, chronic oral beta-blocker therapy were included. Chronic beta-blocker medication was discontinued during the acute phase of sepsis in 129 patients and continued in 167 patients. Continuation of beta-blocker therapy was significantly associated with decreased hospital (P=0.03), 28-day (P=0.04) and 90-day mortality rates (40.7% vs 52.7%; P=0.046) in contrast to beta-blocker cessation. The differences in survival functions were validated by a Log-rank test (P=0.01). Multivariable analysis identified the continuation of chronic beta-blocker therapy as an independent predictor of improved survival rates (HR = 0.67, 95%-CI (0.48, 0.95), P=0.03).Conclusions. Continuing pre-existing chronic beta-blockade might be associated with decreased mortality rates up to 90 days in septic patients.

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Epidemiology of sepsis and septic shock in critical care units: comparison between sepsis-2 and sepsis-3 populations using a national critical care database

Abstract

Background: New sepsis and septic shock definitions could change the epidemiology of sepsis because of differences in criteria. We therefore compared the sepsis populations identified by the old and new definitions.Methods: We used a high-quality, national, intensive care unit (ICU) database of 654 918 consecutive admissions to 189 adult ICUs in England, from January 2011 to December 2015. Primary outcome was acute hospital mortality. We compared old (Sepsis-2) and new (Sepsis-3) incidence, outcomes, trends in outcomes, and predictive validity of sepsis and septic shock populations.Results: From among 197 724 Sepsis-2 severe sepsis and 197 142 Sepsis-3 sepsis cases, we identified 153 257 Sepsis-2 septic shock and 39 262 Sepsis-3 septic shock cases. The extrapolated population incidence of Sepsis-3 sepsis and Sepsis-3 septic shock was 101.8 and 19.3 per 100 000 person-years, respectively, in 2015. Sepsis-2 severe sepsis and Sepsis-3 sepsis had similar incidence, similar mortality and showed significant risk-adjusted improvements in mortality over time. Sepsis-3 septic shock had a much higher Acute Physiology And Chronic Health Evaluation II (APACHE II) score, greater mortality and no risk-adjusted trends in mortality improvement compared with Sepsis-2 septic shock. ICU admissions identified either as Sepsis-3 sepsis or septic shock and as Sepsis-2 severe sepsis or septic shock had significantly greater risk-adjusted odds of death compared with non-sepsis admissions (P<0.001). The predictive validity was greatest for Sepsis-3 septic shock.Conclusions: In an ICU database, compared with Sepsis-2, Sepsis-3 identifies a similar sepsis population with 92% overlap and much smaller septic shock population with improved predictive validity.

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Frontal alpha-delta EEG does not preclude volitional response during anaesthesia: prospective cohort study of the isolated forearm technique

Abstract

Background: The isolated forearm test (IFT) is the gold standard test of connected consciousness (awareness of the environment) during anaesthesia. The frontal alpha-delta EEG pattern (seen in slow wave sleep) is widely held to indicate anaesthetic-induced unconsciousness. A priori we proposed that one responder with the frontal alpha-delta EEG pattern would falsify this concept.Methods: Frontal EEG was recorded in a subset of patients from three centres participating in an international multicentre study of IFT responsiveness following tracheal intubation. Raw EEG waveforms were analysed for power–frequency spectra, depth-of-anaesthesia indices, permutation entropy, slow wave activity saturation and alpha-delta amplitude-phase coupling.Results: Volitional responses to verbal command occurred in six out of 90 patients. Three responses occurred immediately following intubation in patients (from Sites 1 and 2) exhibiting an alpha-delta dominant (delta power >20 dB, alpha power >10 dB) EEG pattern. The power–frequency spectra obtained during these responses were similar to those of non-responders (P>0.05) at those sites. A further three responses occurred in (Site 3) patients not exhibiting the classic alpha-delta EEG pattern; these responses occurred later relative to intubation, and in patients had been co-administered ketamine and less volatile anaesthetic compared with Site 1 and 2 patients. None of the derived depth-of-anaesthesia indices could robustly discrimate IFT responders and non-responders.Conclusions: Connected consciousness can occur in the presence of the frontal alpha-delta EEG pattern during anaesthesia. Frontal EEG parameters do not readily discriminate volitional responsiveness (a marker of connected consciousness) and unresponsiveness during anaesthesia.Clinical trial registration: NCT02248623

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Prehabilitation

1I052A073J03

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Listen: Jessie Senini reflects on the day that changed her paramedic career

By EMS1 Staff NEW ORLEANS — A paramedic and EMS1.com comic strip artist discussed her work experiences on a podcast. "White Shirts" creator Jessi Senini was featured on the Medic2Medic podcast to talk about her journey from Montana to New Orleans to start her EMS adventure. Senini talks about the one day that changed her EMS career, as well as the effects of stress and burnout. You ...

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Elevated Expression of RPA3 Is Involved in Gastric Cancer Tumorigenesis and Associated with Poor Patient Survival

Abstract

Background

The replication protein A3 (RPA3) is a component of the RPA protein complex, which plays an essential role in multiple processes of DNA metabolism.

Aims

However, the involvement of RPA3 in gastric cancer tumorigenesis has not yet been investigated.

Methods

We stably knocked down RPA3 expression using short hairpin RNA in AGS cell line, and performed cell growth, colony formation and soft agar assays. Xenograft experiments were performed to examine tumor promoting properties of RPA3 in vivo. The qRT-PCR and immunohistochemistry were performed to evaluate RPA3 expression levels in 37 and 12 pairs of gastric cancer patient samples, respectively. Association between RPA3 expression and survival was evaluated in an independent cohort of 85 gastric cancer patients.

Results

Downregulation of RPA3 inhibited cell growth, clonogenicity and soft agar growth in AGS cells. Decreased expression of RPA3 significantly reduced tumor growth rate in AGS xenografts. In addition, RPA3 was upregulated in cancerous tissues compared with matched noncancerous adjacent tissues in gastric cancer patients. High expression of RPA3 was associated with poor patient survival.

Conclusion

Upregulation of RPA3 is involved in gastric cancer tumorigenesis and is associated with poorer patient survival. RPA3 represents a new therapeutic target of gastric cancer and serves as a potential prognostic biomarker for patient survival in gastric cancer.

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Evolution of Clinical Behavior in Crohn’s Disease: Factors Associated with Complicated Disease and Surgery

Abstract

Background

The phenotypic expression of Crohn's disease may vary over time. Establishment of Crohn's disease phenotypes is important for definition of patient care strategies.

Aims

The aim of the study was to evaluate the long-term evolution of patients based on disease phenotypes and the main factors associated with this evolution.

Methods

Data from 179 patients were collected from a unicentric prospective database. Montreal classification was employed. Kaplan–Meier method was used to estimate the cumulative probability of complication development and surgery. Poisson regression for multivariate analysis was applied. The Local Institutional Review Board approved the research.

Results

Female: 54.2%. Mean age at diagnosis: 32.7 (±13.7) years. Behavior at presentation: inflammatory 62.0%, stricturing 24.6%, penetrating 13.4%; perianal disease: 31.8%; median follow-up time: 65.2 months (IQR 31.0–108.8). Behavior at follow-up period end: inflammatory 43.6%, stricturing 38.0%, penetrating 18.4%; perianal disease: 46.4%. Cumulative probability of being complication free in 5, 10, and 20 years: 86.3, 66.4, and 52.2%, respectively. Cumulative probability of being surgery free in 5, 10, and 20 years: 87.3, 79.2, and 64.1%, respectively. L1 and L4 locations, use of immunosuppressive therapy, smoking, number of hospitalization/patient-year, abdominal surgery, age at diagnosis <40 years, and biological therapy were the factors associated with changes in phenotype or development of complications and perianal disease.

Conclusion

Clinical behavior altered in about one-third of patients. The most frequent complication was a change to stricturing pattern. Disease location, current smoker, immunosuppressive therapy use, hospitalization, and abdominal surgery were factors associated with an unfavorable clinical evolution.

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BMI Is a Risk Factor for Colorectal Cancer Mortality

Abstract

Background

The relationship between dietary and lifestyle risk factors and long-term mortality from colorectal cancer is poorly understood. Several factors, such as obesity, intakes of red meat, and use of aspirin, have been reported to be associated with risk of colorectal cancer mortality, though these findings have not been replicated in all studies to date.

Methods

In the Minnesota Colon Cancer Control Study, 46,551 participants 50–80 years old were randomly assigned to usual care (control) or annual or biennial screening by fecal occult blood testing. Colon cancer mortality was assessed after 30 years of follow-up. Dietary intake and lifestyle risk factors were assessed by questionnaire at baseline.

Results

Age [hazard ratio (HR) 1.09; 95% CI 1.07, −1.11], male sex (HR 1.25; 95% CI 1.01, 1.57), and higher body mass index (BMI) (HR 1.03; 95% CI 1.00–1.05) increased the risk of CRC mortality, while undergoing screening for CRC was associated with a reduced risk of colorectal cancer mortality (HR 0.76; 95% CI 0.61–0.94 and 0.67; 95% CI 0.53–0.83 for biennial and annual screening, respectively). Intakes of grains, meats, proteins, coffee, alcohol, aspirin, fiber, fruits, and vegetables were not associated with colorectal cancer mortality.

Conclusions

Our study confirms the relationship between BMI and long-term colorectal cancer mortality. Modulation of BMI may reduce risk of CRC mortality.

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Obesity, Metabolic Syndrome, and Cardiovascular Risk in Gluten-Free Followers Without Celiac Disease in the United States: Results from the National Health and Nutrition Examination Survey 2009–2014

Abstract

Background

Despite unclear benefits of gluten-free diets (GFD) in the general population, gluten-free followers without medical indications are driving the market. Few studies have investigated health benefits of GFD in the general population.

Aims

To estimate metabolic and cardiovascular disease (CVD) risk profiles among gluten-free followers without celiac disease (CD).

Methods

Data were obtained from the National Health and Nutrition Examination Survey (NHANES) 2009–2014. There were 13,523 persons without CD who had GFD information. People with known CVD were excluded. We compared gluten-free followers without CD and the general population by selective metabolic and CVD risk profiles using survey-weighted generalized logistic regression.

Results

There were 155 gluten-free followers without CD and CVD, corresponding to a weighted prevalence of 1.3% (3.2 million Americans). Gluten-free followers tended to be women and have a smaller waist circumference and higher HDL cholesterol. They also had a lower BMI with a borderline p value (0.053) and significant self-reported weight loss (−1.33 kg) over one year. Moreover, gluten-free followers were more likely to consider their weight appropriate. There was no statistical difference by age, smoking, hypertension, total cholesterol, triglyceride cholesterol, HbA1c, or fasting glucose. Despite a lower probability of having metabolic syndrome (33.0 vs 38.5%) and lower 10-year CVD risk score (4.52 vs 5.70%) in gluten-free followers, there was no statistical difference.

Conclusions

Although being on a GFD may be beneficial in weight management, there was no significant difference in terms of prevalence of metabolic syndrome and CVD risk score in gluten-free followers without CD.

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Neonatal fractures as a presenting feature of LMOD3-associated congenital myopathy

Nemaline myopathy is a rare inherited disorder characterized by weakness, hypotonia, and depressed deep tendon reflexes. It is clinically and genetically heterogeneous, with the most severe phenotype presenting as perinatal akinesia, severe muscle weakness, feeding difficulties and respiratory failure, leading to early mortality. Pathogenic variants in 12 genes, encoding components of the sarcomere or factors related to myogenesis, have been reported in patients affected with the disorder. Here, we describe an early, lethal presentation of decreased fetal movements, hypotonia, muscle weakness, and neonatal respiratory failure requiring ventilator support in three siblings from a consanguineous family. All exhibited perinatal fractures, and thus, a skeletal dysplasia was considered as possibly contributing to the phenotype. However, whole exome sequencing revealed a homozygous, loss-of-function pathogenic variant in LMOD3, which has recently been associated with nemaline myopathy and, in a subset of patients, perinatal fractures. This case demonstrates the importance of considering congenital neuromuscular disorders in the differential diagnosis of perinatal fractures.

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The pregnancy in neurofibromatosis 1: A retrospective register-based total population study

The objective of this retrospective total population study was to form a view of the pregnancies of the patients with neurofibromatosis type 1 (NF1). A cohort of 1,410 Finnish patients with NF1 was acquired by searching NF1-related inpatient and outpatient hospital visits and confirming the diagnoses by reviewing the medical records. Ten matched control persons per patient with NF1 were collected from Population Register Centre. Study persons were linked to data from Medical Birth Register and Care Register for Health Care through the personal identity code. Cesarean deliveries, hypertension/preeclampsia, and placental abruptions were more common among mothers with NF1 with adjusted odds ratios of 2.24 (95%CI 1.63–3.07), 1.96 (95%CI 1.18–3.24), and 13.40 (95%CI 4.26–42.13), respectively. The adjusted mean pregnancy duration was 0.65 (95%CI 0.42–0.88) weeks shorter among the mothers with NF1 than in the control group consisting of non-NF1 mothers giving birth to a non-NF1 child. The pregnancies of non-NF1 mothers giving birth to a NF1 child were 0.43 (95%CI 0.24–0.62) weeks shorter than in the control group. In summary, NF1 of the mother was associated with a shortened pregnancy and increased pregnancy complications. Also, the NF1 of the fetus slightly shortened pregnancy. Since mothers with NF1 are at increased risk for pregnancy complications, careful evaluation of their pregnancies is warranted.

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Continuous hypomethylation of the KCNQ1OT1:TSS-DMR in monochorionic twins discordant for Beckwith-Wiedemann syndrome

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Challenges of developing and conducting clinical trials in rare disorders

Rare disease drug development is a rapidly expanding field. Clinical researchers in rare diseases face many challenges when conducting trials in small populations. Disease natural history is often poorly understood and the ability to detect clinically meaningful outcomes requires understanding of their rate of occurrence and variability, both of which contribute to difficulties in powering a study. Standard trial designs are not optimized to obtain adequate safety and efficacy data from small numbers of patients, so alternative designs (enrichment, crossover, adaptive, N-of 1) need to be considered. The affected patients can be hard to identify, especially early in the course of their disease, are generally geographically dispersed, and are often children. Trials are frequently conducted on an international scale and may be subject to complex or multiple regulatory agency oversights and may be affected by local customs, cultures, and practices. A basic understanding of the FDA programs supporting development of drugs for rare diseases is provided by this review and the role of early consultation with the FDA is emphasized. Of recent FDA New Molecular Entities (NME) approvals, 41% (17 approvals) in 2014, 47% (21 approvals) in 2015, and 41% (9 approvals) in 2016 were for rare disease indications. Through effective interactions and collaborations with physicians, institutions, and patient groups, sponsors have been successful in bringing new treatments to market for individuals affected by rare diseases. Challenges to drug development have been overcome through the focused efforts of patients/families, non-profit patient advocacy groups, drug developers, and regulatory authorities.

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Progressive macrothrombocytopenia and hearing loss in a large family with DIAPH1 related disease

In this study, we describe a Japanese family with progressive hearing loss and macrothrombocytopenia. Using next-generation and Sanger sequencing analyses, we identified a heterozygous variant in exon 27 of the DIAPH1 gene (NM_005219), c.3637C>T, p.R1213X. All patients in the family had sensorineural hearing loss and macrothrombocytopenia. None of the patients exhibited a tendency to bleed. No pathogenic variants were found in the MYH9 gene. Hearing loss began with high-frequency loss during early childhood and progressed to severe hearing loss involving all frequencies. Analyses of the mean platelet volume and platelet distribution width indicated that the macrothrombocytopenia is progressive in patients with DIAPH1 related disease.There are no reports describing progressive macrothrombocytopenia in patients with pathogenic variants of DIAPH1. Thus, progressive macrothrombocytopenia may be a novel feature of deafness patients with pathogenic variants in DIAPH1.

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Estimation of live birth and population prevalence of Down syndrome in nine U.S. states

For all of the U.S. states with sufficient data, we estimated live birth and population prevalences for Down syndrome (DS). As social service resources vary between states, such data are important for public policy discussions and state planning. We predicted the actual and nonselective live birth prevalence, and population prevalence, for DS in nine U.S. states based on publicly available datasets from the Centers for Disease Control and Prevention and the Integrated Public Use Microdata Series. As of 2010, we estimated a population size for people with DS of 4,554 in MA (population prevalence 1 in 1,440), 6,101 in NJ (1 in 1,443), 14,315 in NY (1 in 1,355), 9,739 in IL (1 in 1,319), 4,354 in IN (1 in 1,491), 7,295 in MI (1 in 1,354), 9,099 in FL (1 in 2,071), 3,014 in KY (1 in 1,442), and 3,596 in AZ (1 in 1,784). The number of people living with DS has steadily increased from 1950 until 2010 in these nine U.S. states. Population prevalence would have been higher absent DS-related elective terminations. Racial and ethnic groups, other than non-Hispanic whites, comprise a growing proportion within these DS communities, particularly among younger-aged persons.

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Preaxial polydactyly in an individual with Wiedemann-Steiner syndrome caused by a novel nonsense mutation in KMT2A

Wiedemann-Steiner syndrome (WDSTS) is an autosomal dominant disorder characterized by hypertrichosis, intellectual disability, and dysmorphic facial appearances (down-slanted vertically narrow palpebral fissures, wide nasal bridge, broad nasal tip, and thick eyebrows). In 2012, Jones and co-workers identified heterozygous mutations in KMT2A (lysine methyltransferase 2A) as the molecular cause of WDSTS. Although the phenotype of this syndrome continues to expand, the associated features are not fully understood. Here, we report WDSTS in a 12-year-old Japanese boy with a novel nonsense mutation in KMT2A. He had right preaxial polydactyly, which has not been previously reported in WDSTS. We could not identify a causal relationship between the KMT2A mutation and preaxial polydactyly, and cannot exclude the preaxial polydactyly is a simple coincidence. We summarized the clinical features of WDSTS associated with KMT2A mutation and discussed the cardinal symptoms in detail.

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A novel heterozygous mutation in FGFR2 gene causing Pfeiffer syndrome

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Prevalence of gastrointestinal symptoms in Angelman syndrome

Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability, expressive speech impairment, movement disorder, epilepsy, and a happy demeanor. Children with AS are frequently reported to be poor feeders during infancy and as having gastrointestinal issues such as constipation, reflux, and abnormal food related behaviors throughout their lifetime. To assess the prevalence of gastrointestinal disorders in individuals with AS, we retrospectively analyzed medical records of 120 individuals seen at the Angelman Syndrome Clinic at Massachusetts General Hospital and 43 individuals seen at the University of North Carolina Comprehensive Angelman Clinic. The majority of patients' medical records indicated at least one symptom of gastrointestinal dysfunction, with constipation and gastroesophageal reflux disease (GERD) the most common. Other gastrointestinal issues reported were cyclic vomiting episodes, difficulty swallowing, excessive swallowing, and eosinophilic esophagitis. Upper gastrointestinal symptoms such as GERD, swallowing difficulties, cyclic vomiting, and eosinophilic esophagitis were more common in those with deletions and uniparental disomy, likely related to the involvement of multiple genes and subsequent hypotonia. The frequency of constipation is consistent among all genetic subtypes while early feeding issues appear to mainly affect those with deletions. Caregivers and healthcare providers should be aware of the high prevalence of these issues, as proper treatment may improve not only gastrointestinal dysfunction but also sleep and behavioral issues.

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Clinical and molecular characterization of de novo loss of function variants in HNRNPU

DNA alterations in the 1q43-q44 region are associated with syndromic neurodevelopmental disorders characterized by global developmental delay, intellectual disability, dysmorphic features, microcephaly, seizures, and agenesis of the corpus callosum. HNRNPU is located within the 1q43-q44 region and mutations in the gene have been reported in patients with early infantile epileptic encephalopathy. Here, we report on the clinical presentation of four patients with de novo heterozygous HNRNPU loss-of-function mutations detected by clinical whole exome sequencing: c.651_660del (p.Gly218Alafs*118), c.1089G>A (p.Trp363*), c.1714C>T (p.Arg572*), and c.2270_2271del (p.Pro757Argfs*7). All patients shared similar clinical features as previously reported including seizures, global developmental delay, intellectual disability, variable neurologic regression, behavior issues, and dysmorphic facial features. Features including heart defects and kidney abnormalities were not reported in our patients. These findings expands the clinical spectrum of HNRNPU-related disorder and shows that HNRNPU contributes to a subset of the clinical phenotypes associated with the contiguous 1q43-q44 deletion syndrome.

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Interstitial deletion 5p14.1-p15.2 and 5q14.3-q23.2 in a patient with clubfoot, blepharophimosis, arthrogryposis, and multiple congenital abnormalities

Interstitial deletions of the short and long arms of chromosome 5 are rare cytogenetic abnormalities. The 5p distal deletion is a genetic disorder characterized by a high-pitched cat-like cry, microcephaly, epicanthal folds, micrognathia, severe intellectual disability and motor delays. Previously, more than 46 patients with the 5q deletion have been reported. Here, we report de novo interstitial deletions involving 5p14.1–p15.2 and 5q14.3–q23.2 in a patient with multiple congenital abnormalities, including blepharophimosis, arthrogryposis, short neck, round face, pelvic kidney, agenesis of the corpus callosum, and clubfoot. The deletions were characterized using GTG banding and aCGH microarray analysis. Concurrent 5p and 5q interstitial deletions in humans have not been previously reported. We also discussed the relationship between the 5q deleted region and clubfeet.

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Epilepsy in fragile-X-syndrome mimicking panayiotopoulos syndrome: Description of three patients

Fragile-X-syndrome is the most common cause of inherited intellectual disability. Epilepsy is reported to occur in 10–20% of individuals with Fragile-X-syndrome. A frequent seizure/electroencephalogram (EEG) pattern resembles that of benign rolandic epilepsy. We describe the clinical features, EEG findings and evolution in three patients affected by Fragile-X-syndrome and epilepsy mimicking Panayiotopoulos syndrome. Age at seizure onset was between 4 and about 7 years. Seizures pattern comprised a constellation of autonomic symptoms with unilateral deviation of the eyes and ictal syncope. Duration of the seizures could be brief or lengthy. Interictal EEGs revealed functional multifocal abnormalities. The evolution was benign in all patients with seizures remission before the age of 14. This observation expands the spectrum of benign epileptic phenotypes present in Fragile-X-syndrome and may be quite helpful in guiding anticonvulsant management and counseling families as to expectations regarding seizure remission.

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Paternal transmission of a FMR1 full mutation allele

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID) and autism. In most of cases, the molecular basis of this syndrome is a CGG repeat expansion in the 5′ untranslated region of the FMR1 gene. It is inherited as an X linked dominant trait, with a reduced penetrance (80% for males and 30% for females). Full mutation (FM) expansion from premutated alleles (PM) is only acquired via maternal meiosis, while paternal transmission always remains in the PM range. We present a 16-year-old girl with a mild fragile X syndrome phenotype. FMR1 gene study showed that the patient inherited a mosaic premutation-full mutation with an unmethylated uninterrupted allele (175, >200 CGG) from her father. The father showed an 88 CGG uninterrupted unmethylated allele in blood and sperm cells. To our knowledge, this is the first case of a FMR1 mosaic premutation-full mutation allele inherited from a PM father. In our opinion, the most likely explanation could be a postzygotic somatic expansion. We can conclude that in rare cases of a child with a full mutation whose mother does not carry a premutation, the possibility of paternal transmission should be considered.

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Bone marrow failure syndrome caused by homozygous frameshift mutation in the ERCC6L2 gene

Abstract

Inherited bone marrow failure syndromes (IBMFS) are group of disorders that lead to inadequate production of blood cells. Mutations in genes involved in telomere maintenance, DNA repair, and the cell cycle cause IBMFS. ERCC6L2 gene mutations have been associated with bone marrow failure that includes developmental delay and microcephaly. We report two cases of bone marrow failure with no extra-hematopoietic manifestations in patients from unrelated families with a homozygous truncating mutation in ERCC6L2. Bone marrow failure without developmental delay or microcephaly with ERCC6L2 mutation has not been previously described.

Presentation of wild type and predicted mutated forms of ERCC6L2 protein in patients with inherited bone marrow failure syndrome. A) A full length ERCC6L2 protein consists of 1561 amino acids. The DEXDc domain binds ATP and Helicase domain catalyzes the DNA remodeling. B) The c. 1457del(p.(Ile486fs)) mutation, described in this study, results in premature stop codon, leading to truncation of the protein and total lack of helicase domain. C) and D) schematically describe the two truncating mutations described previously. C) by Tummala et al. Am J Hum Genet. 2014;94(2):246-256 and D) by Tummala et al. and Zhang et al., J Exp Med. 2016;213(6):1011-1028.

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Radiotherapy for mucosa-associated lymphoid tissue (MALT) lymphoma of the rectum: a case report

Abstract

Extra-nodal mucosa-associated lymphoid tissue (MALT) lymphoma is frequently involved with the upper gastrointestinal tract, but rarely involved with the rectum. We report a case of rectal MALT lymphoma treated by radiotherapy (RT) alone. A 74-year-old woman with lower abdominal pain was diagnosed with MALT lymphoma by endoscopic mucosal resection (EMR). She was diagnosed as stage IE (Ann Arbor) MALT lymphoma by diagnostic work-up and review of EMR specimens. Definitive RT was performed with curative intent, totaling 30 Gy in 15 fractions. Complete response was confirmed by colonoscopy after RT with no progression observed at 5 years. Definitive RT is effective for rectal MALT lymphoma.

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A case of pancreatic cancer with severe vomiting treated by endoscopic ultrasound-guided celiac ganglia neurolysis

Abstract

A 50-year-old man with advanced pancreatic cancer was admitted for intractable severe vomiting 5–6 times a day, continuing over a week. He had been treated for advanced pancreatic cancer with chemotherapy for 6 months, and had undergone self-expandable metalic stent placement for obstructive jaundice due to the pancreatic cancer 4 months before admission. No abnormal findings suggesting gastrointestinal obstruction or brain metastasis were revealed on diagnostic imaging. We performed endoscopic ultrasound-guided celiac ganglia neurolysis twice by injecting ethanol into the celiac ganglion. After the treatments, the vomiting disappeared, and his eating habits gradually returned to normal. The patient died 7 months after treatment due to the advanced pancreatic cancer without recurrence of the vomiting.

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Overexpression of Topoisomerase 2-Alpha Confers a Poor Prognosis in Pancreatic Adenocarcinoma Identified by Co-Expression Analysis

Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of human cancer-related death in the developed countries. Its progression and prognosis are influenced by a complex network of gene interactions.

Aims

The purpose of this study is to explore key genes associated with pancreatic ductal adenocarcinoma and to predict the possible mechanisms.

Methods

A weighted gene co-expression network was constructed to identify gene modules associated with the progression of PDAC.

Results

In the significant module (R ² = 0.30), a total of 20 network hub genes were identified, 6 of which were also hub nodes in the protein–protein interaction network of the module genes. In validation, TOP2A has a higher correlation than other hub genes. Also, in the test set (n = 118), TOP2A was more highly expressed in PDAC than normal pancreas samples (P < 0.001). What is more, gene set enrichment analysis demonstrated that eight gene sets (n = 118), "nucleotide excision repair," "P53 signaling pathway," "proteasome," "mismatch repair," "homologous recombination," "DNA replication," "cell cycle," and "base excision repair," were enriched (FDR < 0.05). In gene ontology analysis, TOP2A in the enriched set was associated with cell cycle and cell division. Furthermore, survival analysis indicated that higher expression of TOP2A resulted in the lower overall survival time as well as disease-free survival time.

Conclusion

TOP2A was identified in association with the progression and prognosis of PDAC probably by regulating cell cycle and p53 signaling pathway.

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Mosapride Stabilizes Intestinal Microbiota to Reduce Bacterial Translocation and Endotoxemia in CCl 4 -Induced Cirrhotic Rats

Abstract

Background

Impaired intestinal motility may lead to the disruption of gut microbiota equilibrium, which in turn facilitates bacterial translocation (BT) and endotoxemia in cirrhosis. We evaluated the influence of mosapride, a prokinetic agent, on BT and DNA fingerprints of gut microbiota in cirrhotic rats.

Methods

A rat model of cirrhosis was set up via subcutaneous injection of carbon tetrachloride (CCl₄). The portal pressure, liver and intestinal damage, plasma endotoxin, BT, and intestinal transit rate (ITR) of cirrhotic rats were determined. Fecal DNA fingerprints were obtained by ERIC-PCR. The expressions of tight junction proteins were evaluated by western blotting.

Results

Mosapride treatment to cirrhotic rats significantly reduced the plasma endotoxin level and incidence of BT, accompanied by increased ITR. Cirrhotic rats (including those treated with mosapride) suffered from BT exhibited significantly lower ITR than those who are free of BT. Pearson coefficient indicated a significant and negative correlation between the plasma endotoxin level and ITR. The genomic fingerprints of intestinal microbiota from the three groups fell into three distinctive clusters. In the mosapride-treated group, Shannon's index was remarkably increased compared to the model group. Significantly positive correlation was detected between Shannon's index and ITR. Mosapride did not improve hepatic and intestinal damages and ileal expressions of occludin and ZO-1.

Conclusions

Mosapride significantly increases intestinal motility in cirrhotic rats, thus to recover the disordered intestinal microbiota, finally resulting in decreased plasma endotoxin and BT.

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Tumor Volume Doubling Time as a Dynamic Prognostic Marker for Patients with Hepatocellular Carcinoma

Abstract

Background and Aims

To evaluate the clinical value of tumor growth rate in hepatocellular carcinoma (HCC) patients, we investigated the growth rate of HCC by calculating the tumor volume doubling time (TVDT) and its impact on survival and recurrence.

Methods

A retrospective cohort study of 269 HCC patients who underwent two or more pretreatment imaging studies of computed tomography or magnetic resonance imaging was performed. Tumor growth rate and TVDT were calculated by comparing tumor volumes between imaging studies. Clinical parameters independently related to a TVDT of <2 months were evaluated. After dividing patients into slow-growing (159 patients with TVDT >2 months) and rapid-growing (110 patients with TVDT <2 months) groups, we compared the groups in terms of their survival and recurrence outcomes. The response to transarterial chemoembolization (TACE) was evaluated according to TVDT.

Results

The median tumor growth rate and TVDT were 37.5%/month and 2.37 months, respectively. By logistic regression analyses, a high Child–Pugh score, small initial tumor diameter, gross vascular invasion, and tumor multiplicity were found to be independently associated with a TVDT of <2 months (P < 0.05). Patients in the rapid-growing group had lower survival rates and higher recurrence rates (P < 0.05). The response to TACE was worse in the rapid-growing group (P < 0.05).

Conclusions

A fast HCC growth rate is associated with poor liver function and aggressive tumor biology. HCC patients with shorter TVDTs exhibit poorer survival and recurrence outcomes as well as a poor response to TACE.

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Covered Esophageal Stenting Is Effective for Symptomatic Gastric Lumen Narrowing and Related Complications Following Laparoscopic Sleeve Gastrectomy

Abstract

Background and Study Aims

Laparoscopic sleeve gastrectomy (LSG) is gaining popularity in treating morbid obesity. Prior studies showed a 3.5% risk of gastric sleeve stenosis (GSS). There is no consensus on how to treat these patients, and the role of endoscopic therapy has been addressed in only a few studies. We aim to assess the efficacy and safety of endoscopic stenting in the management of GSS following LSG.

Patients and Methods

Retrospective data were reviewed from July 2009 to November 2013. Patients were referred for endoscopic therapy for symptoms or imaging findings suggestive of gastric leak or narrowing following LSG. Endoscopic therapy included the use of fully covered self-expanding esophageal metal stents (FCSEMS) in addition to over-the-scope clip system (OTSC) when necessary.

Results

All 27 patients were females with mean age of 40 years; six patients were excluded from the study. Major symptom was nausea and vomiting in 57% of the patients. Five of 21 patients had concomitant leaks. All 21 patients underwent FCSEMS placement, and four out of five patients (80%) with concomitant leak had OTSC. The success rate in both groups for resolution of stricture and leak was 100%, and no surgical intervention was required. There were no immediate or delayed complications of endoscopic therapy. Median follow-up of 6 months was available for 20/21 patients. Among patients with gastric leak, 80% had resolution of their symptoms compared with 93% of patients with GSS.

Conclusions

Endoscopic therapy for LSG-related GSS or leaks with FCSEMS is highly effective and safe.

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NF-E2-Related Factor 2 Suppresses Intestinal Fibrosis by Inhibiting Reactive Oxygen Species-Dependent TGF-β1/SMADs Pathway

Abstract

Background and Aims

This study aimed to evaluate the antifibrotic effects of NF-E2-Related Factor 2 (Nrf2) on intestinal fibrosis. Intestinal fibrosis is a common complication of Crohn's disease; however, its mechanism of intestinal fibrosis is largely unclear.

Methods

BALB/c mice received 2,4,6-trinitrobenzene sulfonic acid weekly via intrarectal injections to induce chronic fibrotic colitis. They also diet containing received 1% (w/w) tert-butylhydroquinone (tBHQ), which is an agonist of Nrf2. Human intestinal fibroblasts (CCD-18Co cells) were pretreated with tBHQ or si-Nrf2 followed by stimulation with transforming growth factor-β1 (TGF-β1), which transformed the cells into myofibroblasts. The main fibrosis markers such as α-smooth muscle actin, collagen I, tissue inhibitor of metalloproteinase-1, and TGF-β1/SMADs signaling pathway were detected by quantitative real-time RT-PCR, immunohistochemical analysis, and Western blot analysis. Levels of cellular reactive oxygen species (ROS) were detected by dichlorodihydrofluorescein diacetate.

Results

tBHQ suppressed the intestinal fibrosis through the TGF-β1/SMADs signaling pathway in TNBS-induced colitis and CCD-18Co cells. Moreover, Nrf2 knockdown enhanced the TGF-β1-induced differentiation of CCD-18Co cells. ROS significantly increased in TGF-β1-stimulated CCD-18Co cells. Pretreatment with H₂O₂, the primary component of ROS, was demonstrated to block the effect of tBHQ on reducing the expression of TGF-β1. Moreover, scavenging ROS by N-acetyl cysteine could inhibit the increasing expression of TGF-β1 promoted by Nrf2 knockdown.

Conclusions

The results suggested that Nrf2 suppressed intestinal fibrosis by inhibiting ROS/TGF-β1/SMADs pathway in vivo and in vitro.

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Perceptions of the Inpatient Training Experience: A Nationwide Survey of Gastroenterology Program Directors and Fellows

Abstract

Background

Inpatient training is a key component of gastroenterology (GI) fellowship programs nationwide, yet little is known about perceptions of the inpatient training experience.

Aim

To compare the content, objectives and quality of the inpatient training experience as perceived by program directors (PD) and fellows in US ACGME-accredited GI fellowship programs.

Methods

We conducted a nationwide, online-based survey of GI PDs and fellows at the conclusion of the 2016 academic year. We queried participants about (1) the current models of inpatient training, (2) the content, objectives, and quality of the inpatient training experience, and (3) the frequency and quality of educational activities on the inpatient service. We analyzed five-point Likert items and rank assessments as continuous variables by an independent t test and compared proportions using the Chi-square test.

Results

Survey response rate was 48.4% (75/155) for PDs and a total of 194 fellows completed the survey, with both groups reporting the general GI consult team (>90%) as the primary model of inpatient training. PDs and fellows agreed on the ranking of all queried responsibilities of the inpatient fellow to develop during the inpatient service. However, fellows indicated that attendings spent less time teaching and provided less formal feedback than that perceived by PDs (p < 0.0001). PDs rated the overall quality of the inpatient training experience (p < 0.0001) and education on the wards (p = 0.0003) as better than overall ratings by fellows.

Conclusion

Although GI fellows and PDs agree on the importance of specific fellow responsibilities on the inpatient service, fellows report experiencing less teaching and feedback from attendings than that perceived by PDs. Committing more time to education and assessment may improve fellows' perceptions of the inpatient training experience.

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Efficacy and safety of ledipasvir/sofosbuvir with ribavirin in chronic hepatitis C patients who failed daclatasvir/asunaprevir therapy: pilot study

Abstract

Background

In Japan, daclatasvir (DCV) and asunaprevir (ASV) therapy was the first IFN-free treatment to be approved, and thousands of patients have since been successfully treated, with an SVR rate of around 90%. The converse, however, is that around 10% of patients fail to achieve viral eradication and must be retreated using a different approach. This study is to evaluate treatment efficacy of ledipasvir/sofosbuvir and ribavirin in patients who failed to respond to DCV and ASV therapy.

Methods

Thirty patients were treated with 12 weeks of ledipasvir/sofosbuvir and ribavirin. We evaluated the rate of sustained virological response 12 weeks after the end of treatment (SVR₁₂) and examined the incidence of adverse events during ledipasvir/sofosbuvir and ribavirin treatment. NS5A and NS5B resistance-associated variants (RAVs) in treatment failure cases were examined.

Results

The overall SVR₁₂ rate was 86.7% (26/30). Large decreases in mean log₁₀ HCV RNA levels were observed in patients without cirrhosis, and the SVR₁₂ rate for these patients was 100% (12/12). In cases of cirrhosis, SVR₁₂ rate was 72.2% (13/18). The common factors in treatment failure cases were the presence of liver cirrhosis and both NS5A L31M/I and Y93H RAVs. The frequency of RAVs did not change before and after treatment among patients who relapsed.

Conclusion

Ledipasvir/sofosbuvir with ribavirin is an effective retreatment option for patients with chronic hepatitis C who failed to respond to prior daclatasvir and asunaprevir therapy.

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The tumor-stromal ratio as a strong prognosticator for advanced gastric cancer patients: proposal of a new TSNM staging system

Abstract

Background

Insufficient attention is paid to the underlying tumor microenvironment (TME) evolution, that resulting in tumor heterogeneity and driving differences in cancer aggressiveness and treatment outcomes. The morphological evaluation of the proportion of the stroma at the most invasive part of primary tumor (tumor-stromal ratio, TSR) in cancer is gaining momentum as evidence strengthens for the clinical relevance.

Methods

Tissue samples from the most invasive part of the primary gastric cancer (GC) of 494 patients were analyzed for their TSR, and a new TSNM (tumor-stromal node metastasis) staging system based on patho-biological behaviors was established and assessed.

Results

TSR is a new and strong independent prognostic factor for GC patients. The likelihood of tumor invasion is increased significantly for patients in the stromal-high subgroup compared to those in the stromal-low subgroup (P = 0.011). The discrimination ability of TSR was not less than the TNM staging system and was better in patients with stages I and II GC. We integrated the TSR parameter into the TNM staging system and proposed a new TSNM staging system creatively. There were three new subgroups (IC, IIC, IIID). There were four major groups and 10 subgroups in the TSNM system. The difference in overall survival (OS) was statistically significant among all TSNM system (P < 0.005 for all). Deep analyses revealed well predictive performance of the TSNM (P < 0.001).

Conclusions

This study confirms the TSR as a TME prognostic factor for GC. TSR is a candidate TME parameter that could easily be implemented in routine pathology diagnostics, and the TSNM staging system has been established to optimize risk stratification for GC. The value of the TSNM staging system should be validated in further prospective study.

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Chronic morphine reduces the readily releasable pool of GABA, a presynaptic mechanism of opioid tolerance

Abstract

The midbrain periaqueductal grey (PAG) plays a critical role in tolerance to the analgesic actions of opioids such as morphine. While numerous studies have identified the postsynaptic adaptations induced by chronic morphine treatment in this and other brain regions, the presence of presynaptic adaptations remains uncertain. We examined GABAergic synaptic transmission within rat PAG brain slices from animals which underwent a low dose morphine treatment protocol which produces tolerance, but not withdrawal. Evoked GABAergic IPSCs (inhibitory postsynaptic currents) were less in morphine compared to control saline treated animals. Postsynaptic GABA_A receptor mediated currents and desensitisation, presynaptic release probability (P_r), and inhibition by endogenous neurotransmitters were similar in morphine and saline treated animals. By contrast, the effective size of the ready releasable pool (RRP) was smaller in morphine treated animals. While the μ-opioid agonist DAMGO produced a reduction in P_r and RRP size in saline treated animals, it only reduced P_r in morphine treated animals. Consequently, DAMGO-induced inhibition of evoked IPSCs during short burst stimulation was less in morphine, compared to saline treated animals. These results indicate that low dose chronic morphine treatment reduces presynaptic μ-opioid inhibition by reducing the size of the pool of vesicles available for action potential dependent release. This novel presynaptic adaptation may provide important insights into the development of efficacious pain therapies that can circumvent the development of opioid tolerance.

This article is protected by copyright. All rights reserved

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Intraepithelial lymphocyte immunophenotype: a useful tool in the diagnosis of celiac disease

Abstract

According to new ESPGHAN guidelines, gluten challenge is considered necessary when there is doubt about the initial diagnosis of celiac disease (CD). The main aim of this study was to quantify intraepithelial lymphocyte (IEL) immunophenotype on celiac patients on gluten-containing diet (GCD) compared to those on gluten-free diet (GFD). Another aim was to evaluate the clinical utility of IELs in the CD diagnosis, especially in selected patients on GFD where diagnostic uncertainty remains. IEL immunophenotype (TCRγδ and NK-like IELs) were studied by flow cytometry in 111 children with CD (81 children with CD on GCD and 30 celiac patients on GFD) and a control group (10 children). Duration of GFD was 5.4 ± 1.6 years. TCRγδ IELs in celiac patients receiving a GCD or GFD were significantly higher (p < 0.001) than in the control group. NK-like IELs in patients receiving a GCD or GFD were significantly lower than in the control group (p < 0.001). We observed a permanent decrease of NK-like IELs and an increment of TCRγδ IELs after following an adequate establishment and compliance of a long-term GFD in celiac patients. Recognition of IELs changes in the intestinal mucosa on celiac patients after long-term establishment of a GFD could constitute a useful tool for CD diagnosis in various situations: in which there is doubt about the initial diagnosis and repeat biopsy is necessary (avoiding the need of gluten challenges), and in those patients with symptoms/signs suggestive of CD who maintain a low gluten diet.

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The Italian Compassionate use of Sofosbuvir (ITACOPS) observational cohort study for the treatment of recurrent hepatitis C: Clinical and virological outcomes

Transplant International

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