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

http://ift.tt/2w3JeYS

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.

http://ift.tt/2vKE55n

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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Sleeping for two: The importance of good sleep during pregnancy

Publication date: Available online 12 August 2017
Source:Women and Birth
Author(s): Leandro Lucena, Cristina Frange, Sergio Tufik, Helena Hachul




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Midwives being ‘with woman’: An integrative review

Publication date: Available online 12 August 2017
Source:Women and Birth
Author(s): Zoe Bradfield, Ravani Duggan, Yvonne Hauck, Michelle Kelly
BackgroundMidwives being 'with woman' is embedded in professional philosophy, standards of practice and partnerships with women. In light of the centrality of being 'with woman' to the profession of midwifery, it is timely to review the literature to gain a contemporary understanding of this phenomenon.AimThis review synthesises research and theoretical literature to report on what is known and published about being 'with woman'.MethodsA five step framework for conducting an integrative literature reviews was employed. A comprehensive search strategy was utilised that incorporated exploration in electronic databases CINAHL, Scopus, Proquest, Science Direct and Pubmed. The initial search resulted in the retrieval of 2057 publications which were reduced to 32 through a systematic process.FindingsThe outcome of the review revealed three global themes and corresponding subthemes that encompassed 'with woman': (1) philosophy, incorporated two subthemes relating to midwifery philosophy and philosophy and models of care; (2) relationship, that included the relationship with women and the relationship with partners; and (3) practice, that captured midwifery presence, care across the childbirth continuum and practice that empowers women.ConclusionResearch and theoretical sources support the concept that being 'with woman' is a fundamental construct of midwifery practice as evident within the profession's philosophy. Findings suggest that the concept of midwives being 'with woman' is a dynamic and developing construct. The philosophy of being 'with woman' acts as an anchoring force to guide, inform and identify midwifery practice in the context of the rapidly changing modern maternity care landscapes. Gaps in knowledge and recommendations for further research are made.



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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).

http://ift.tt/2vKssLR

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.

http://ift.tt/2w3XIrX

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).

http://ift.tt/2vK3s7r

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.

http://ift.tt/2w3XFMN

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.

http://ift.tt/2vKMK7U

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.

http://ift.tt/2vKuyv0

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.

http://ift.tt/2w4cKxM

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.

http://ift.tt/2vKyZpZ

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.

http://ift.tt/2vKuFXt

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.

http://ift.tt/2w42gP0

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.

http://ift.tt/2vKhQfP

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.

http://ift.tt/2w3BKFq

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%).

http://ift.tt/2vKhQwl

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.

http://ift.tt/2w30td2

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).

http://ift.tt/2vKhPbL

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.

http://ift.tt/2fNYMcZ

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.

http://ift.tt/2fNYK4R

Incidental detection of two adult gravid filarial worms in breast: a case report

Microfilaria is a major public health problem in tropical and subtropical countries and is an endemic problem in India. Wuchereria bancrofti is the commonest filarial infection. In some lesions, microfilariae and...

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Bevacizumab in advanced lung cancer: state of the art

Future Oncology, Ahead of Print.


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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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Abernethy malformation associated with Caroli’s syndrome in a patient with a PKHD1 mutation: a case report

Abernethy malformation is a rare congenital anomaly characterised by the partial or complete absence of the portal vein and the subsequent development of an extrahepatic portosystemic shunt. Caroli's disease i...

http://ift.tt/2w3qpoB

The function of the thyroid gland in patients with multi-drug resistant tuberculosis

Multidrug-resistant tuberculosis (MDRTB) remains a health problem for many countries in the world. The share of MDRTB is 10–30% among newly diagnosed cases and 20–70% among relapses and treatment failure. The ...

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Pharmacokinetic interactions and dosing rationale for antiepileptic drugs in adults and children

Summary

Aim

Population pharmacokinetic modelling has been widely used across many therapeutic areas to identify sources of variability, which are incorporated into models as covariate factors. Despite numerous publications on pharmacokinetic (PK) drug-drug interactions (DDIs) between antiepileptic drugs (AEDs), such data are not used to support the dose rationale for polytherapy in the treatment of epileptic seizures. Here we assess the impact of DDIs on plasma concentrations and evaluate the need for AED dose adjustment.

Methods

Models describing the pharmacokinetics of carbamazepine, clobazam, clonazepam, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, valproic acid, and zonisamide in adult and paediatric patients were collected from the published literature and implemented in NONMEM v7.2. Taking current clinical practice into account, we explore simulation scenarios to characterise AED exposure in virtual patients receiving mono-, and polytherapy. Css, Cmax and Cmin were selected as parameters of interest for the purpose of this analysis.

Results

Our simulations show that DDIs can cause major changes in AED concentrations both in adults and children. When more than one AED is used, even larger changes are observed in the concentrations of the primary drug, leading to significant differences in Css between mono- and polytherapy for most AEDs. These results suggest that currently recommended dosing algorithms and titration procedures do not ensure attainment of appropriate therapeutic concentrations.

Conclusions

The effect of DDIs on AED exposure cannot be overlooked. Clinical guidelines must take into account such covariate effects and ensure appropriate dosing recommendations for adult and paediatric patients who require combination therapy.

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Adaptive Global Innovative Learning Environment for Glioblastoma: GBM AGILE

Glioblastoma (GBM) is a deadly disease with few effective therapies. While much has been learned about the molecular characteristics of the disease, this knowledge has not been translated into clinical improvements for patients. At the same time, many new therapies are being developed. Many of these therapies have potential biomarkers to identify responders. The result is an enormous amount of testable clinical questions that must be answered efficiently. The GBM Adaptive Global Innovative Learning Environment (GBM AGILE) is a novel, multi-arm, platform trial designed to address these challenges. It is the result of the collective work of over 130 oncologists, statisticians, pathologists, neurosurgeons, imagers, and translational and basic scientists from around the world. GBM AGILE is comprised of two stages. The first stage is a Bayesian adaptively randomized screening stage to identify effective therapies based on impact on overall survival compared with a common control. This stage also finds the population in which the therapy shows the most promise based on clinical indication and biomarker status. Highly effective therapies transition in an inferentially seamless manner in the identified population to a second confirmatory stage. The second stage uses fixed randomization to confirm the findings from the first stage in order to support registration. Therapeutic arms with biomarkers may be added to the trial over time while others complete testing. The design of GBM AGILE enables rapid clinical testing of new therapies and biomarkers to speed highly effective therapies to clinical practice.

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Personalized Medicine Based Approach to Model Patterns of Chemoresistance and Tumor Recurrence Using Ovarian Cancer Stem Cell Spheroids

Purpose: Chemoresistant ovarian cancers grow in suspension within the ascites fluid. In order to screen the effect of chemotherapeutics and biologics on resistant ovarian cancers with a personalized basis, we developed a 3D hanging drop spheroid platform. Experimental Design: We initiated spheroids with primary ALDH+ CD133+ ovarian cancer stem cells (OvCSCs) from different patient samples, and demonstrated that stem cell progeny from harvested spheroids was similar to the primary tumor. OvCSC spheroids were utilized to initiate tumors in immune-deficient mice. Drug responses to cisplatin and ALDH targeting compound or JAK2 inhibitor determined if the OvCSC population within the spheroids could be targeted. Cells that escaped therapy were isolated and used to initiate new spheroids and model tumor re-emergence in a personalized manner. Results: OvCSC spheroids from different patients exhibited varying, and personalized responses to chemotherapeutics. Xenografts were established from OvCSC spheroids, even with one single spheroid. Distinct responses to therapy were observed in distinct primary tumor xenografts similar to those observed in spheroids. Spheroids resistant to Cisplatin/ALDH inhibitor therapy had persistent, albeit lower ALDH expression and complete loss of CD133 expression while those resistant to cisplatin/JAK2 inhibitor therapy were enriched for ALDH+ cells. Conclusions: Our 3D hanging drop suspension platform can be used to propagate primary OvCSCs that represent individual patient tumors effectively by differentiating in vitro, and initiating tumors in mice. Therefore, our platform can be used to study cancer stem cell biology, and model tumor re-emergence to identify new targeted therapeutics from an effective personalized medicine standpoint.

http://ift.tt/2uRtqVj

Combined CDK4/6 and mTOR inhibition is synergistic against glioblastoma via multiple mechanisms

Purpose: Glioblastoma (GBM) is a deadly brain tumor marked by dysregulated signaling and aberrant cell cycle control. Molecular analyses have identified that the CDK4/6-Rb-E2F axis is dysregulated in about 80% of GBMs. Single-agent CDK4/6 inhibitors have failed to provide durable responses in GBM, suggesting a need to combine them with other agents. We investigate the efficacy of the combination of CDK4/6 inhibition and mTOR inhibition against GBM. Experimental Design: Preclinical in vitro and in vivo assays using primary GBM cell lines were performed. Results: We show that the CDK4/6 inhibitor palbociclib suppresses the activity of downstream mediators of the mTOR pathway, leading to rebound mTOR activation that can be blocked by the mTOR inhibitor everolimus. We further show that mTOR inhibition with everolimus leads to activation of the Ras mediator Erk that is reversible with palbociclib. The combined treatment strongly disrupts GBM metabolism, resulting in significant apoptosis. Further increasing the utility of the combination for brain cancers, everolimus significantly increases the brain concentration of palbociclib. Conclusions: Our findings demonstrate that the combination of CDK4/6 and mTOR inhibition has therapeutic potential against GBM and suggest it should be evaluated in a clinical trial.

http://ift.tt/2whe2oO

Maintenance of CD8+ memory T lymphocytes in the spleen but not in the bone marrow is dependent on proliferation

It is current belief that numbers of CD8 memory T lymphocytes in the memory phase of an immune response are maintained by homeostatic proliferation. Here we compare the proliferation of CD8 memory T lymphocytes, generated by natural infections and by intentional immunization, in spleen and in bone marrow. 50% of CD8 memory T lymphocytes in the spleen are eliminated by cyclophosphamide within 14 days, indicating that numbers of at least 50% of splenic CD8 memory T lymphocytes are maintained by proliferation. Numbers of CD8 memory T lymphocytes in the bone marrow, however, were not affected by cyclophosphamide. This stability was independent of circulating CD8 memory T cells, blocked by FTY720, showing that bone marrow is a privileged site for the maintenance of memory T lymphocytes, as resident cells, resting in terms of proliferation.

This article is protected by copyright. All rights reserved

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Trastuzumab Biosimilar on Track for Approval [News in Brief]

As cancer biosimilars enter the market, experts predict moderately lower prices but wonder about long-term side effects.

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The Physiological and Metabolic Differences between Visceral and Subcutaneous Adipose Tissues in Nile Tilapia (Oreochromis niloticus)

Background: Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SCAT) have different structures and metabolic functions, and play different roles in the regulation of mammal systemic endocrine. However, little is known about morphology and physiological and metabolic functions between VAT and SCAT in fish. Methods: We compared the morphological, physiological and biochemical characteristics of VAT and SCAT in Nile Tilapia and measured their functions in energy intake flux, lipolytic ability, and gene expression patterns. Results: SCAT contained more large adipocytes and non-adipocytes than VAT in Nile tilapia. VAT had a higher lipid and was the primary site for lipid deposition. Conversely, SCAT had higher hormone-induced lipolytic activity. Furthermore, SCAT had a higher percentage of monounsaturated and lower polyunsaturated fatty acids than VAT. SCAT had higher mitochondrial DNA, gene expression for fatty acid β-oxidation, adipogenesis and brown adipose tissue characteristics, but it also had a lower gene expression for inflammation and adipocyte differentiation than VAT. Conclusions: SCAT and VAT have different morphological structures, as well as physiological and metabolic functions in fish. VAT is the preferable lipid deposition tissue, whereas SCAT exhibits higher lipid catabolic activity than VAT. General Significance: The physiological functions of SCAT in fish are commonly overlooked. The present study indicates SCAT has specific metabolic characteristics that differ VAT. The differences between VAT and SCAT should be considered in future metabolism studies using fish as models, either in biomedical or aquaculture studies.

http://ift.tt/2uRoEHm

Filling the void: a role for exercise induced BDNF and brain amyloid precursor protein processing

Inactivity, obesity, and insulin resistance are significant risk factors for the development of Alzheimer's disease (AD). Several studies have demonstrated that diet induced obesity, inactivity, and insulin resistance exacerbates neuropathological hallmarks of AD. The aggregation of beta-amyloid peptides is one of these hallmarks. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in amyloid precursor protein (APP) processing, leading to beta-amyloid peptide formation. Understanding how BACE1 content and activity is regulated is essential for establishing therapies aimed at reducing and/or slowing the progression of AD. Exercise training has proven to reduce the risk of AD as well as decrease beta-amyloid production and BACE1 content and/or activity. However, these long-term interventions also result in improvements in adiposity, circulating metabolites, glucose tolerance, and insulin sensitivity making it difficult to determine the direct effects of exercise on brain APP processing. This review highlights this large void in our knowledge and aims discusses our current understanding the direct of effect of exercise on beta-amyloid production. We have concentrated on the central role that brain-derived neurotrophic factor (BDNF) may play in mediating the direct effects of exercise on reducing brain BACE1 content and activity as well as beta-amyloid production. Future studies should aim to generate a greater understanding of how obesity and exercise can directly alter APP processing and AD related pathologies. This knowledge could provide evidence-based hypotheses for designing therapies to reduce the risk of AD and dementia.

http://ift.tt/2wgYFN4

Issue Highlights

Patients with recurrent or persistent symptoms of achalasia after Heller myotomy (HM) commonly undergo one of two procedures, namely redo myotomy or pneumatic dilation (PD). Peroral endoscopic myotomy (POEM) is another treatment option for these refractory patients, but data on the effectiveness and safety of this approach are limited. In this context, Ngamruengphong et al undertook this multicenter retrospective cohort study comparing the technical success, safety, and clinical efficacy of POEM for patients with prior HM as compared to those without previous surgery.

http://ift.tt/2fMNSEj

Meaning in life as a mediator between physical impairment and the wish to hasten death in patients with advanced cancer

Meaning in life (MiL) is a key factor for ensuring spiritual wellbeing and quality of life among patients with life-threatening illnesses. However, the role of MiL in relation to the wish to hasten death (WTHD) and its interaction with other physical and psychological factors in patients with advanced cancer has not yet been studied.

http://ift.tt/2wgWJUF

Public Opinion about the Future of the Affordable Care Act

In the early hours of Friday, July 28, the U.S. Senate closed debate on repealing and replacing the Affordable Care Act (ACA) without the passage of any piece of legislation and after rejecting the replacement bill previously passed by the House of Representatives. This public-opinion analysis…

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A Nicotine-Focused Framework for Public Health

Despite extraordinary progress in tobacco control and prevention, tobacco use remains the leading cause of preventable disease and death in the United States. Combustible cigarettes cause the overwhelming majority of tobacco-related disease and are responsible for more than 480,000 U.S. deaths each…

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Advances in Computed Tomography Vol.6,No.2 (June 2017)

Effectiveness of Endovascular Coil Embolization of Ruptured Hepatic Artery Pseudoaneurysm
Hepatic Artery, Pseudoaneurysm, Rupture, Embolization, Endovascular
Paper Information Full Paper: PDF (Size:4406KB)
DOI: 10.4236/act.2017.62002

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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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Ilizarov technique and limited surgical methods for correction of post-traumatic talipes equinovarus in children

Background

The objective of this study was to evaluate the efficacy and safety of using Ilizarov invasive distraction technique combined with limited surgical operations in the treatment of post-traumatic talipes equinovarus in children.

Methods

Eighteen cases of post-traumatic deformed feet in 15 patients who received the treatment of Ilizarov frame application, limited soft-tissue release or osteotomy were selected in this study. After removal of the frame, an ankle–foot orthosis was used continuously for another 6–12 months. Pre- and post-operatively, the International Clubfoot Study Group (ICFSG) score was employed to evaluate the gait and range of motion of the ankle joint. Radiographical assessment was also conducted.

Results

Patients were followed up for 22 (17–32) months. Ilizarov frame was applied for a mean duration of 5.5 (4–9) months. When it was removed, the gait was improved significantly in all the patients. The correction time was 6–8 weeks for patients who underwent soft-tissue release and 8–12 weeks for those with bone osteotomy. At the last follow-up assessment, the differences between pre- and post-operative plantar-flexion angle, dorsiflexion, motion of ankle joint and talocalcaneal angle were significant (all P < 0.05). The observed complications included wire-hole infection in one foot, toe contracture in one, residual deformity in three, recurrence of deformity in two and spastic ischaemia in one foot.

Conclusion

Our findings suggest that Ilizarov technique combined with limited surgical operation can be considered as an efficient and successful method for correction of post-traumatic talipes equinovarus in children.

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Modification of Human Umbilical Cord Blood Stem Cells Using Polyethylenimine Combined with Modified TAT Peptide to Enhance BMP-2 Production

With the emerging role of umbilical cord blood-derived mesenchymal stem cells (hUCB-MSC) for bone regeneration and delivery of therapeutic proteins, there is an increasing need for effective gene delivery systems to modify such cells. mTAT, a TAT peptide sequence bearing histidine and cysteine residues, has been successfully used for intracellular gene delivery. Using a gWiz-GFP plasmid, we demonstrated that polyethylenimine combined with mTAT (mTAT/PEI) displayed good transfection efficacy in hUCB-MSC. hUCB-MSC transfected with mTAT/PEI were shown to express more BMP-2 protein and mRNA, indicating the feasibility of using the cells as a BMP-2 delivery system. Importantly, compared to PEI25, a "gold standard" nonviral transfection polymer, mTAT/PEI had limited toxicity to the cells. Furthermore, we demonstrated enhanced osteogenic activity in vitro for BMP-2 expressing hUCB-MSC. These results provide encouraging evidence for the potential use of mTAT/PEI to genetically modify hUCB-MSC as an approach to enhance tissue regeneration.

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Validity of a Cochrane Systematic Review and meta-analysis for determining the safety of vitamin E

The public safety of α-tocopherol has been called in question by several meta-analyses which have raised concern among regulatory authorities. The objective of this study was to evaluate the Cochrane Database ...

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Blood pressure-lowering effect of Shinrin-yoku (Forest bathing): a systematic review and meta-analysis

Shinrin-yoku (experiencing the forest atmosphere or forest bathing) has received increasing attention from the perspective of preventive medicine in recent years. Some studies have rep...

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The protective effects of Resveratrol against radiation-induced intestinal injury

Intestinal injury is a potential cause of death after high-dose radiation exposure. The aim of the present study was to investigate the protective effects of resveratrol against radiation-induced small intesti...

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What Antibiotic Regimen Is Most Efficacious in Treating Pelvic Inflammatory Disease?

The authors included 37 randomized controlled trials for analysis, with patients from a wide range of inpatient and outpatient settings in different countries. Of these patients, investigators reported 81.1% with clinical cure. Overall, there were no differences in the rates of clinical cure or adverse effects requiring treatment discontinuation according to the 5 treatment regimens, although much of the evidence quality ranged from very low to moderate. One study at low risk for bias that compared azithromycin versus doxycycline among patients with mild to moderate pelvic inflammatory disease found that azithromycin was superior to doxycycline, with relative risk 1.35 (95% confidence interval 1.10 to 1.67; 133 subjects).

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Alterations in SCAI Expression during Cell Plasticity, Fibrosis and Cancer

Abstract

Suppressor of cancer cell invasion (SCAI) has been originally characterized as a tumor suppressor inhibiting metastasis in different human cancer cells, and it has been suggested that SCAI expression declines in tumors. The expression patterns and role of SCAI during physiological and pathophysiological processes is still poorly understood. Earlier we demonstrated that SCAI is regulating the epithelial-mesenchymal transition of proximal tubular epithelial cells, it is downregulated during renal fibrosis and it is overexpressed in Wilms' tumors. Here we bring further evidence for the involvement of SCAI during cell plasticity and we examine the prognostic value and expression patterns of SCAI in various tumors. SCAI prevented the activation of the SMA promoter induced by angiotensin II. SCAI expression decreased in a model of endothelial-mesenchymal transition and increased during iPS reprogramming of fibroblasts. During renal fibrosis SCAI expression declined, as evidenced in a rat model of renal transplant rejection and in TGF-β1 overexpressing transgenic mice. High expression of SCAI correlated with better survival in patients with breast and lung cancers. Intriguingly, in the case of other cancers (gastric, prostate, colorectal) high SCAI expression correlated with poor survival of patients. Finally, we bring evidence for SCAI overexpression in colorectal cancer patients, irrespective of stage or metastatic status of the disease, suggesting a diverse role of SCAI in various diseases and cancer.

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Minimally invasive surgical techniques for adult spinal deformity

Publication date: Available online 16 August 2017
Source:Seminars in Spine Surgery
Author(s): Blake M. Bodendorfer, Ryan S. Murray, Fred F. Mo
Minimally invasive surgery has become increasingly popular, utilizing smaller incisions in an effort to reduce morbidity associated with traditional approaches. Traditional correction of adult degenerative scoliosis is associated with significant risks and prolonged recovery. Surgeons should be cognizant of patient selection factors, approaches, risks, and outcomes of minimally invasive procedures, because they can be effective and desirable for the patient. This study reviews the current literature to summarize the most recent evidence available. Minimally invasive spinal deformity correction and hybrid constructs is a viable alternative to traditional open surgery.



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Treatment outcomes of patients with multidrug-resistant and extensively drug resistant tuberculosis in Hunan Province, China

The worldwide emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) has posed additional challenges for global tuberculosis (TB) control efforts, as limite...

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Mechanical Thrombectomy for Middle Cerebral Artery Division Occlusions: A Systematic Review and Meta-Analysis

Background: Middle cerebral artery division (M2) occlusion was significantly underrepresented in recent mechanical thrombectomy (MT) randomized controlled trials, and the approach to this disease remains heterogeneous. Objective: To conduct a systematic review and meta-analysis of outcomes at 90 days among patients undergoing MT for M2 middle cerebral artery (MCA) occlusions. Methods: Five clinical databases were searched from inception through September 2016. Observational studies reporting 90-day modified Rankin Scale scores for patients undergoing MT for M2 MCA occlusions with an M1 MCA control group were selected. The primary outcome of interest was good clinical outcome 90 days after MT of an M1 or M2 MCA occlusion. Secondary outcomes of interest included mortality and excellent clinical outcome, recanalization rates, significant intracerebral hemorrhage, and procedural complications. Results: A total of 323 publications were identified, and 237 potentially relevant articles were screened. Six studies were included in the analysis (M1 = 1,203, M2 = 258; total n = 1,461). We found no significant differences in good clinical outcomes (1.10 [95% CI, 0.83-1.44]), excellent clinical outcomes (1.07 [0.65-1.79]), mortality at 3 months (0.85 [0.58-1.24]), recanalization rates (1.06 [0.32-3.48]), and significant intracranial hemorrhage (1.19 [0.61-2.30]). Conclusions: MT of M2 MCA occlusions is as safe as that of main trunk MCA occlusions, and comparable in terms of clinical outcomes and hemorrhagic complications. Randomized clinical trials are needed to assess the impact of MT in patients with M2 occlusions, given that M1 MCA occlusions have different natural histories than M2 occlusions.
Intervent Neurol 2017;6:242-253

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Living Donor Kidney Transplantation in Atypical Hemolytic Uremic Syndrome: A Case Series

The development of complement inhibitors has greatly improved the outcome of patients with atypical hemolytic uremic syndrome (aHUS), making kidney transplantation a more feasible option. Although prophylactic eculizumab therapy may prevent recurrent disease after transplantation, its necessity for all transplant recipients is debated.

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Membranous Nephropathy and Intrarenal Extramedullary Hematopoiesis in a Patient With Myelofibrosis

Kidney disease in the setting of a hematologic malignancy is common, with the frequency and type of kidney disease varying depending on the specific malignancy. Various glomerular diseases and tumor infiltration of the kidneys have been reported in patients with lymphoproliferative disorders. Descriptions of kidney involvement in myeloproliferative disorders have been much rarer. We report a case of membranous nephropathy accompanied by kidney injury in a patient with primary myelofibrosis with additional features considered related to the patient's myeloproliferative disorder.

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Zenith Alpha Thoracic Endovascular Graft by Cook Medical: Class I Recall - Potential Formation of Thrombus Inside Device

Audience: Risk Manager, Cardiology, Surgery, Patient [Posted 08/16/2017] ISSUE: Cook Medical Inc. is recalling the Zenith Alpha Thoracic Endovascular Graft when used for the treatment of Blunt Traumatic Aortic Injury (BTAI) because blood clots...

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Zenith Alpha Thoracic Endovascular Graft by Cook Medical: Class I Recall - Potential Formation of Thrombus Inside Device

Audience: Risk Manager, Cardiology, Surgery, Patient [Posted 08/16/2017] ISSUE: Cook Medical Inc. is recalling the Zenith Alpha Thoracic Endovascular Graft when used for the treatment of Blunt Traumatic Aortic Injury (BTAI) because blood clots...

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Quantification of Information Encoded by Gene Expression Levels During Lifespan Modulation Under Broad-range Dietary Restriction in C. elegans

Here, we present a framework to relate broad-range dietary restriction to gene expression and lifespan. We describe protocols for broad-range dietary restriction and for quantitative imaging of gene expression under this paradigm. We further outline computational analyses to reveal underlying information processing features of the genetic circuits involved in food-sensing.

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Analysis of RIM Expression and Function at Mouse Photoreceptor Ribbon Synapses

RAB3A-interacting molecule (RIM) proteins are important regulators of transmitter release from active zones. At conventional chemical synapses, RIMs contribute substantially to vesicle priming and docking and their loss reduces the readily releasable pool of synaptic vesicles by up to 75%. The priming function of RIMs is mediated via the formation of a tripartite complex with Munc13 and RAB3A, which brings synaptic vesicles in close proximity to Ca²⁺ channels and the fusion site and activates Munc13. We reported previously that, at mouse photoreceptor ribbon synapses, vesicle priming is Munc13 independent. In this study, we examined RIM expression, distribution, and function at male and female mouse photoreceptor ribbon synapses. We provide evidence that RIM1α and RIM1β are highly likely absent from mouse photoreceptors and that RIM2α is the major large RIM isoform present at photoreceptor ribbon synapses. We show that mouse photoreceptors predominantly express RIM2 variants that lack the interaction domain for Munc13. Loss of full-length RIM2α in a RIM2α mutant mouse only marginally perturbs photoreceptor synaptic transmission. Our findings therefore strongly argue for a priming mechanism at the photoreceptor ribbon synapse that is independent of the formation of a RIM–Munc13–RAB3A complex and thus provide further evidence for a fundamental difference between photoreceptor ribbon synapses and conventional chemical synapses in synaptic vesicle exocytosis.

SIGNIFICANCE STATEMENT RAB3A-interacting molecules 1 and 2 (RIM1/2) are essential regulators of exocytosis. At conventional chemical synapses, their function involves Ca²⁺ channel clustering and synaptic vesicle priming and docking through interactions with Munc13 and RAB3A, respectively. Examining wild-type and RIM2 mutant mice, we show here that the sensory photoreceptor ribbon synapses most likely lack RIM1 and predominantly express RIM2 variants that lack the interaction domain for Munc13. Our findings demonstrate that the photoreceptor-specific RIM variants are not essential for synaptic vesicle priming at photoreceptor ribbon synapses, which represents a fundamental difference between photoreceptor ribbon synapses and conventional chemical synapses with respect to synaptic vesicle priming mechanisms.

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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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Rapidly progressive intravascular primary effusion lymphoma in an HIV-positive renal transplant recipient

Summary

We describe the clinical and post-mortem findings of a case of rapidly progressive, ultimately fatal primary effusion lymphoma (PEL) arising in an HIV-positive man two years after renal transplantation. Disseminated multi-organ involvement associated with a peculiar intravascular pattern of growth, as seen in this case, has only been reported once previously. This is also, to our knowledge, the first detailed description of a lymphoma arising post-transplant in an HIV-positive patient.

This article is protected by copyright. All rights reserved.

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Chewing gum rapid test for inflammation

Dental implants occasionally entail complications: Six to fifteen percent of patients develop an inflammatory response in the years after receiving a dental implant. This is caused by bacteria destroying the soft tissue and the bone around the implant in the worst case.

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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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Inhibitory growth evaluation and apoptosis induction in MCF-7 cancer cells by new 5-aryl-2-butylthio-1,3,4-oxadiazole derivatives

Abstract

Background

Cancer has become one of the global health issues and it is the life-threatening disease characterized by unrestrained growth of cells. Despite various advances being adopted by chemotherapeutic management, the use of the current anticancer drugs such as Doxorubicin, Asparginase, Methotrexate, Vincristine remains limited due to high toxicity, side effects and developing drug resistance. Apoptosis is a crucial cellular process and improper regulation of apoptotic signaling pathways may lead to cancer formation. Subsequently, the synthesis of effective chemotherapeutic agents that can induce apoptosis in tumor cell has emerged as a significant approach in cancer drug discovery.

Methods

The goal of this work is to develop a potential antitumor agent exerting significant inhibitory effects on cancer cell and low cytotoxicity, for which we focused on the structural features of 1,3,4-oxadiazoles as it a privileged scaffold in modern medicinal chemistry and have the ability to inhibit growth factors, enzymes and kinases potentially involved in the attainment of cellular immortality and carcinogenesis.

Result

In vitro MTT screening assay showed the compound 5-aminophenyl-2-butylthio-1,3,4-oxadiazole (5e) showing the highest inhibitory effect against MCF-7 cancer cell with IC₅₀ value 10.05 ± 1.08 µM while it is much safer and less toxic on normal cell line (HEK-293). The dose-dependent treatment of MCF-7 cells with 5e resulted in inhibition of cell migration in the wound healing assay. The flow-cytometry analysis showed the cells arrested in G0/G1 phase of the cell cycle. Compound 5e induced apoptosis of MCF-7 cells was characterized using DAPI staining and Annexin V-PE/7-AAD dual binding assay. Reduction of NBT by compound 5e showed a reduced generation of ROS. Western blotting studies showed high activation of apoptotic protein Caspase3 and decrease in expression of anti-apoptotic protein BCL-2.

Conclusion

Based on the results of in vitro studies, it could be concluded that compound 5e showed a significant inhibitory growth effect on MCF-7 cells and have the potential to be developed as lead molecule and further structural modifications may result in promising new anticancer agents.

Graphical abstract

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Characterizing Cell Migration Within Three-dimensional In Vitro Wound Environments

The goal of this protocol is to evaluate the effect of pro- and anti-migratory factors on cell migration within a three-dimensional fibrin matrix.

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Lrig1+ gastric isthmal progenitor cells restore normal gastric lineage cells during damage recovery in adult mouse stomach

Objective

Lrig1 is a marker of proliferative and quiescent stem cells in the skin and intestine. We examined whether Lrig1-expressing cells are long-lived gastric progenitors in gastric glands in the mouse stomach. We also investigated how the Lrig1-expressing progenitor cells contribute to the regeneration of normal gastric mucosa by lineage commitment to parietal cells after acute gastric injury in mice.

Design

We performed lineage labelling using Lrig1-CreERT2/+;R26R-YFP/+ (Lrig1/YFP) or R26R-LacZ/+ (Lrig1/LacZ) mice to examine whether the Lrig1-YFP-marked cells are gastric progenitor cells. We studied whether Lrig1-YFP-marked cells give rise to normal gastric lineage cells in damaged mucosa using Lrig1/YFP mice after treatment with DMP-777 to induce acute injury. We also studied Lrig1-CreERT2/CreERT2 (Lrig1 knockout) mice to examine whether the Lrig1 protein is required for regeneration of gastric corpus mucosa after acute injury.

Results

Lrig1-YFP-marked cells give rise to gastric lineage epithelial cells both in the gastric corpus and antrum, in contrast to published results that Lgr5 only marks progenitor cells within the gastric antrum. Lrig1-YFP-marked cells contribute to replacement of damaged gastric oxyntic glands during the recovery phase after acute oxyntic atrophy in the gastric corpus. Lrig1 null mice recovered normally from acute gastric mucosal injury indicating that Lrig1 protein is not required for lineage differentiation. Lrig1+ isthmal progenitor cells did not contribute to transdifferentiating chief cell lineages after acute oxyntic atrophy.

Conclusions

Lrig1 marks gastric corpus epithelial progenitor cells capable of repopulating the damaged oxyntic mucosa by differentiating into normal gastric lineage cells in mouse stomach.

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Reassessment of gamma-glutamyl transpeptidase to platelet ratio (GPR): a large-sample, dynamic study based on liver biopsy in a Chinese population with chronic hepatitis B virus (HBV) infection

Recently, Lemoine and colleagues1 presented a novel marker of liver fibrosis, the gamma-glutamyl transpeptidase to platelet ratio (GPR), as a more accurate non-invasive marker than either the aspartate aminotransferase to platelet ratio index (APRI) or the fibrosis index based on four factors (FIB-4) for diagnosing liver fibrosis in patients with chronic hepatitis B virus (HBV) infection in West Africa, and a simple and inexpensive alternative to transient elastography and liver biopsy. Boyd and colleagues2 demonstrated good results for GPR in the diagnosis of liver fibrosis in patients with HBV/HIV co-infection in France. However, Stockdale and colleagues3 reported that in patients with HBV / human immunodeficiency virus (HIV) co-infection in West Africa, GPR showed poor correlation with transient elastography. Lemoine and colleagues4 subsequently responded that the diagnostic accuracy of GPR differed when using liver biopsy or transient elastography as the reference. These inconsistent opinions...

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Analysis of learning curves in gastroscopy training: the need for composite measures for defining competence

We read with interest and commend the study by Ward and colleagues which explores the learning curve in gastroscopy.1 The authors apply a D2 intubation rate of >95% as a proxy marker of trainee competency, and conclude that 187–200 procedures are sufficient to achieve this, in line with Joint Advisory Group (JAG) certification criteria.2 We would like to debate the following points with the authors.

While we agree that D2 intubation and J-maneouvre reflect procedural completion and rely on motor skill, we argue that this stand-alone measure is insufficient to define competence. Competence is defined by the American Society for Gastrointestinal Endoscopy as the 'minimal level of skill, knowledge and/or expertise derived through training and experience that is required to safely and proficiently perform a task or procedure'.3 Thus, competence is not merely a destination-orientated end point; it is reliant on a combination of technical...

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Plausibility criteria for putative pathophysiological mechanisms in functional gastrointestinal disorders: a consensus of experts

Background and aims

The functional gastrointestinal disorders (FGIDs) are extremely common conditions associated with a considerable personal, social and health economic burden. Managing FGIDs in clinical practice is challenging because of the uncertainty of symptom-based diagnosis, the high frequency of overlap between these conditions and the limited efficacy of available therapies. It has often been argued that successful drug development and management of FGIDs requires knowledge of the underlying pathophysiology. Numerous and highly variable candidate pathophysiological mechanisms have been implicated in the generation of FGID symptoms, but there is no current consensus on how to best define the relevance of these disturbances.

Methods

A group of international experts on FGIDs developed plausibility criteria that should be fulfilled by relevant pathophysiological mechanisms in FGIDs.

Results

Five criteria are proposed: (1) the presence of the abnormality in a subset of patients, (2) temporal association between proposed mechanism and symptom(s), (3) correlation between the level of impairment of the mechanism and symptom(s), (4) induction of the symptom(s) by provoking the pathophysiological abnormality in healthy subjects and (5) treatment response by a therapy specifically correcting the underlying disorder or congruent natural history of symptoms and dysfunction in the absence of specific therapy. Based on strength of evidence for these five criteria according to the Grading of Recommendations Assessment, Development and Evaluation system, a plausibility score can be calculated for each mechanism.

Conclusion

Evaluation of the strength of evidence for candidate pathophysiological abnormalities fulfilling these five plausibility criteria will help to identify the most relevant mechanisms to target for novel diagnostic approaches and for the development of new therapies.

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Serum ghrelin is associated with risk of colorectal adenocarcinomas in the ATBC study

Background

Colorectal cancers are the third most common cancers in women and men in the USA. While dietary and lifestyle factors such as Western diet, physical inactivity and obesity have been linked to an increased risk of this malignancy, the mechanisms for these associations are unclear. GI hormones, including ghrelin, are involved in energy balance by mediating appetite and metabolism; however, the association between ghrelin and colorectal cancer has not been studied.

Methods

We conducted a case–control study nested within the all-male Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish smokers (aged 50–69 years) to examine serum ghrelin concentration and colorectal cancer risk. Data from 284 colon and 239 rectal cancers and 523 controls (matched on age, date of blood draw and serum availability) were analysed. ORs and 95% CIs were calculated using multivariable (conditional) logistic regression.

Results

Overall, low-serum ghrelin was significantly associated with increased risk of colorectal cancer (Q1 vs Q4: OR:1.57, 95% CI 1.05 to 2.34). For individuals developing tumours within 10 years of blood draw, those in the lowest quartile of serum ghrelin concentrations were statistically significantly more likely to develop colorectal cancers than those with higher serum ghrelin concentrations (OR: 10.86, 95% CI 5.01 to 23.55). However, for individuals with tumours developing more than 20 years after blood draw, low-serum ghrelin concentrations were associated with a decreased risk of colorectal cancer relative to those with the highest serum ghrelin concentrations (OR: 0.26, 95% CI 0.11 to 0.64).

Conclusion

Low-serum ghrelin was associated with an increased colorectal cancer risk within 10 years of blood draw with a decreased risk for developing colorectal cancer more than 20 years after blood draw. These results suggest that ghrelin concentrations may vary across the carcinogenic process.

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Too hard to swallow!

Introduction

An 80-year-old woman presented with a 4-month history of intermittent oropharyngeal dysphagia and aspiration, particularly after eating peas. She had no significant medical history and denied additional symptomatology. Gastroscopy revealed a smooth lesion arising in the pharynx abutting the epiglottis (figure 1) but was otherwise unremarkable. Pillow sign was negative. No neck masses were palpable on examination after endoscopy.

Question

What is the endoscopic finding and what are the differential diagnoses?

How will you manage it?

Answer

Endoscopically, there was an extrinsic posterior hypopharyngeal mass with normal mucosa. Differential diagnoses include: lymphoma, lipoma, cystic lesions, schwannoma and anterior cervical osteophyte. The patient underwent barium swallow and X-ray (figure 2), which confirmed pharyngeal compression by anterior cervical osteophytes at the level of C3-C4 with ossification of the anterior longitudinal ligament (ALL) down to C7. ALL ossification affecting ≥4 contiguous vertebrae, with preserved intervertebral disc height, is a hallmark of diffuse...

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Preferential Disruption of Prefrontal GABAergic Function by Nanomolar Concentrations of the {alpha}7nACh Negative Modulator Kynurenic Acid

Increased concentrations of kynurenic acid (KYNA) in the prefrontal cortex (PFC) are thought to contribute to the development of cognitive deficits observed in schizophrenia. Although this view is consistent with preclinical studies showing a negative impact of prefrontal KYNA elevation on executive function, the mechanism underlying such a disruption remains unclear. Here, we measured changes in local field potential (LFP) responses to ventral hippocampal stimulation in vivo and conducted whole-cell patch-clamp recordings in brain slices to reveal how nanomolar concentrations of KYNA alter synaptic transmission in the PFC of male adult rats. Our data show that prefrontal infusions of KYNA attenuated the inhibitory component of PFC LFP responses, a disruption that resulted from local blockade of α7-nicotinic acetylcholine receptors (α7nAChR). At the cellular level, we found that the inhibitory action exerted by KYNA in the PFC occurred primarily at local GABAergic synapses through an α7nAChR-dependent presynaptic mechanism. As a result, the excitatory–inhibitory ratio of synaptic transmission becomes imbalanced in a manner that correlates highly with the level of GABAergic suppression by KYNA. Finally, prefrontal infusion of a GABA_AR positive allosteric modulator was sufficient to overcome the disrupting effect of KYNA and normalized the pattern of LFP inhibition in the PFC. Thus, the preferential inhibitory effect of KYNA on prefrontal GABAergic transmission could contribute to the onset of cognitive deficits observed in schizophrenia because proper GABAergic control of PFC output is one key mechanism for supporting such cortical functions.

SIGNIFICANCE STATEMENT Brain kynurenic acid (KYNA) is an astrocyte-derived metabolite and its abnormal elevation in the prefrontal cortex (PFC) is thought to impair cognitive functions in individuals with schizophrenia. However, the mechanism underlying the disrupting effect of KYNA remains unclear. Here we found that KYNA biases the excitatory–inhibitory balance of prefrontal synaptic activity toward a state of disinhibition. Such disruption emerges as a result of a preferential suppression of local GABAergic transmission by KYNA via presynaptic inhibition of α7-nicotinic acetylcholine receptor signaling. Therefore, the degree of GABAergic dysregulation in the PFC could be a clinically relevant contributing factor for the onset of cognitive deficits resulting from abnormal increases of cortical KYNA.

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Gamma Oscillations in the Rat Ventral Striatum Originate in the Piriform Cortex

Local field potentials (LFPs) recorded from the human and rodent ventral striatum (vStr) exhibit prominent, behaviorally relevant gamma-band oscillations. These oscillations are related to local spiking activity and transiently synchronize with anatomically related areas, suggesting a possible role in organizing vStr activity. However, the origin of vStr gamma is unknown. We recorded vStr gamma oscillations across a 1.4 mm² grid spanned by 64 recording electrodes as male rats rested and foraged for rewards, revealing a highly consistent power gradient originating in the adjacent piriform cortex. Phase differences across the vStr were consistently small (<15°) and current source density analysis further confirmed the absence of local sink-source pairs in the vStr. Reversible occlusions of the ipsilateral (but not contralateral) nostril, known to abolish gamma oscillations in the piriform cortex, strongly reduced vStr gamma power and the occurrence of transient gamma-band events. These results imply that local circuitry is not a major contributor to gamma oscillations in the vStr LFP and that piriform cortex is an important driver of gamma-band oscillations in the vStr and associated limbic areas.

SIGNIFICANCE STATEMENT The ventral striatum (vStr) is an area of anatomical convergence in circuits underlying motivated behavior, but it remains unclear how its inputs from different sources interact. A major proposal about how neural circuits may switch dynamically between convergent inputs is through temporal organization reflected in local field potential (LFP) oscillations. Our results show that, in the rat, the mechanisms controlling gamma-band oscillations in the vStr LFP are primarily located in the in the adjacent piriform cortex rather than in the vStr itself, providing a novel interpretation of previous rodent work on gamma oscillations in the vStr and related circuits and an important consideration for future work seeking to use oscillations in these areas as biomarkers for behavioral and neurological disorders.

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Electrophysiological Evidence That the Retrosplenial Cortex Displays a Strong and Specific Activation Phased with Hippocampal Theta during Paradoxical (REM) Sleep

It is widely accepted that cortical neurons are similarly more activated during waking and paradoxical sleep (PS; aka REM) than during slow-wave sleep (SWS). However, we recently reported using Fos labeling that only a few limbic cortical structures including the retrosplenial cortex (RSC) and anterior cingulate cortex (ACA) contain a large number of neurons activated during PS hypersomnia. Our aim in the present study was to record local field potentials and unit activity from these two structures across all vigilance states in freely moving male rats to determine whether the RSC and the ACA are electrophysiologically specifically active during basal PS episodes. We found that theta power was significantly higher during PS than during active waking (aWK) similarly in the RSC and hippocampus (HPC) but not in ACA. Phase–amplitude coupling between HPC theta and gamma oscillations strongly and specifically increased in RSC during PS compared with aWK. It did not occur in ACA. Further, 68% and 43% of the units recorded in the RSC and ACA were significantly more active during PS than during aWK and SWS, respectively. In addition, neuronal discharge of RSC but not of ACA neurons increased just after the peak of hippocampal theta wave. Our results show for the first time that RSC neurons display enhanced spiking in synchrony with theta specifically during PS. We propose that activation of RSC neurons specifically during PS may play a role in the offline consolidation of spatial memories, and in the generation of vivid perceptual scenery during dreaming.

SIGNIFICANCE STATEMENT Fifty years ago, Michel Jouvet used the term paradoxical to define REM sleep because of the simultaneous occurrence of a cortical activation similar to waking accompanied by muscle atonia. However, we recently demonstrated using functional neuroanatomy that only a few limbic structures including the retrosplenial cortex (RSC) and anterior cingulate cortex (ACA) are activated during PS. In the present study, we show for the first time that the RSC and ACA contain neurons firing more during PS than in any other state. Further, RSC neurons are firing in phase with the hippocampal theta rhythm. These data indicate that the RSC is very active during PS and could play a key role in memory consolidation taking place during this state.

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Columnar Segregation of Magnocellular and Parvocellular Streams in Human Extrastriate Cortex

Magnocellular versus parvocellular (M-P) streams are fundamental to the organization of macaque visual cortex. Segregated, paired M-P streams extend from retina through LGN into V1. The M stream extends further into area V5/MT, and parts of V2. However, elsewhere in visual cortex, it remains unclear whether M-P-derived information (1) becomes intermixed or (2) remains segregated in M-P-dominated columns and neurons. Here we tested whether M-P streams exist in extrastriate cortical columns, in 8 human subjects (4 female). We acquired high-resolution fMRI at high field (7T), testing for M- and P-influenced columns within each of four cortical areas (V2, V3, V3A, and V4), based on known functional distinctions in M-P streams in macaque: (1) color versus luminance, (2) binocular disparity, (3) luminance contrast sensitivity, (4) peak spatial frequency, and (5) color/spatial interactions. Additional measurements of resting state activity (eyes closed) tested for segregated functional connections between these columns. We found M- and P-like functions and connections within and between segregated cortical columns in V2, V3, and (in most experiments) area V4. Area V3A was dominated by the M stream, without significant influence from the P stream. These results suggest that M-P streams exist, and extend through, specific columns in early/middle stages of human extrastriate cortex.

SIGNIFICANCE STATEMENT The magnocellular and parvocellular (M-P) streams are fundamental components of primate visual cortical organization. These streams segregate both anatomical and functional properties in parallel, from retina through primary visual cortex. However, in most higher-order cortical sites, it is unknown whether such M-P streams exist and/or what form those streams would take. Moreover, it is unknown whether M-P streams exist in human cortex. Here, fMRI evidence measured at high field (7T) and high resolution revealed segregated M-P streams in four areas of human extrastriate cortex. These results suggest that M-P information is processed in segregated parallel channels throughout much of human visual cortex; the M-P streams are more than a convenient sorting property in earlier stages of the visual system.

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Antagonistic Serotonergic and Octopaminergic Neural Circuits Mediate Food-Dependent Locomotory Behavior in Caenorhabditis elegans

Biogenic amines are conserved signaling molecules that link food cues to behavior and metabolism in a wide variety of organisms. In the nematode Caenorhabditis elegans, the biogenic amines serotonin (5-HT) and octopamine regulate a number of food-related behaviors. Using a novel method for long-term quantitative behavioral imaging, we show that 5-HT and octopamine jointly influence locomotor activity and quiescence in feeding and fasting hermaphrodites, and we define the neural circuits through which this modulation occurs. We show that 5-HT produced by the ADF neurons acts via the SER-5 receptor in muscles and neurons to suppress quiescent behavior and promote roaming in fasting worms, whereas 5-HT produced by the NSM neurons acts on the MOD-1 receptor in AIY neurons to promote low-amplitude locomotor behavior characteristic of well fed animals. Octopamine, produced by the RIC neurons, acts via SER-3 and SER-6 receptors in SIA neurons to promote roaming behaviors characteristic of fasting animals. We find that 5-HT signaling is required for animals to assume food-appropriate behavior, whereas octopamine signaling is required for animals to assume fasting-appropriate behavior. The requirement for both neurotransmitters in both the feeding and fasting states enables increased behavioral adaptability. Our results define the molecular and neural pathways through which parallel biogenic amine signaling tunes behavior appropriately to nutrient conditions.

SIGNIFICANCE STATEMENT Animals adjust behavior in response to environmental changes, such as fluctuations in food abundance, to maximize survival and reproduction. Biogenic amines, such as like serotonin, are conserved neurotransmitters that regulate behavior and metabolism in relation to energy status. Disruptions of biogenic amine signaling contribute to human neurological diseases of mood, appetite, and movement. In this study, we investigated the roles of the biogenic amines serotonin and octopamine in regulating locomotion behaviors associated with feeding and fasting in the roundworm Caenorhabditis elegans. We identified neural circuits through which these signals work to govern behavior. Understanding the molecular pathways through which biogenic amines function in model organisms may improve our understanding of dysfunctions of appetite and behavior found in mammals, including humans.

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Reduced histone H3 K27 trimethylation is encountered in about 50% of atypical teratoid/rhabdoid tumors (AT/RT) but is not associated with molecular subgroup status and outcome

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A Protocol for Using Gene Set Enrichment Analysis to Identify the Appropriate Animal Model for Translational Research

We provide a standardized protocol for the use of gene set enrichment analysis of transcriptomic data to identify an ideal mouse model for translational research. This protocol can be used with DNA microarray and RNA sequencing data and can further be extended to other omics data if data are available.

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Table of Content Volume 56, Number 10, October 2017

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Aligning Digital CD8+ Scoring and Targeted Next-Generation Sequencing with PD-L1 Expression: A Pragmatic Approach in Early-Stage Squamous Cell Lung Carcinoma

Abstract

Aims

To study PD-L1 expression, tumour-infiltrating T lymphocytes (TILs) and the molecular context in patients with early-stage squamous cell lung carcinomas (SCCs).

Methods and results

The study included samples from 40 patients (discovery cohort) and 29 patients (validation cohort) diagnosed with early-stage SCC. PD-L1 immunohistochemistry (IHC) was performed with three commercially available clones (E1L3N, SP263 and SP142). CD8⁺ TILs were scored with a digital algorithm. All tumours were analyzed with targeted next-generation sequencing (NGS). Additionally, TP53 mutations were investigated with direct sequencing. In both cohorts, we observed a significant association between CD8⁺ TILs density and high PD-L1 IHC expression in tumour cells (TCs). Furthermore, high SP142 PD-L1 expression in immune cells (ICs) was also significantly associated with CD8⁺ TILs density. Therefore, CD8⁺ TILs density discriminated between patients with high versus low PD-L1 IHC expression with excellent sensitivity and specificity. Interestingly, the highest percentages of PD-L1 positive TCs with the three antibodies were found in samples with CDK6 amplification, with high amplification of CMYC or with CCND1-PIK3CA co-amplification. High SP142 PD-L1 IHC expression in ICs showed a non-significant correlation with TP53 mutations. Conversely, most cases with FGFR1 amplification were negative for all PD-L1 clones.

Conclusions

Our preliminary results support the use of digital CD8⁺ TILs scoring and targeted NGS alongside PD-L1 expression. The approach presented herein could help define patients with SCCs candidates to immune checkpoints inhibitors.

This article is protected by copyright. All rights reserved.

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Application of the Condensed Protocol for the NIA-AA guidelines for the neuropathologic assessment of Alzheimer's disease in an academic clinical practice

Abstract

Aims

In response to concerns regarding resource expenditures required to fully implement the 2012 NIA-AA Sponsored Guidelines for the neuropathologic assessment of Alzheimer's disease (AD), we previously developed a sensitive and cost-reducing Condensed Protocol (CP) at the University of Washington (UW) Alzheimer's Disease Research Center (ADRC) that consolidated the recommended NIA-AA protocol into fewer cassettes requiring fewer immunohistochemical stains. The CP was not designed to replace NIA-AA protocols, but instead to make the NIA-AA criteria accessible to clinical and forensic neuropathology practices where resources limit full implementation of NIA-AA guidelines.

Methods and Results

In this regard, we developed practical criteria to instigate CP sampling and immunostaining, and applied these criteria in an academic clinical neuropathological practice. Over the course of one year, 73 cases were sampled using the CP; of those, 53 (72.6%) contained histologic features that prompted CP workup. We found that the CP resulted in increased identification of AD and Lewy body disease neuropathologic changes from what was expected using a clinical history-driven workup alone, while saving approximately $900 per case.

Conclusions

This study demonstrates the feasibility and cost-savings of the CP applied to a clinical autopsy practice, and highlights potentially unrecognized neurodegenerative disease processes in the general aging community.

This article is protected by copyright. All rights reserved.

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Iterative robust adaptive beamforming

The minimum power distortionless response beamformer has a good interference rejection capability, but the desired signal will be suppressed if signal steering vector or data covariance matrix is not precise. ...

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O -(2-[ 18 F]fluoroethyl)- l -tyrosine PET in gliomas: influence of data processing in different centres

Abstract

Background

PET using O-(2-[¹⁸F]fluoroethyl)-l-tyrosine (¹⁸F-FET) is an established method for brain tumour diagnostics, but data processing varies in different centres. This study analyses the influence of methodological differences between two centres for tumour characterization with ¹⁸F-FET PET using the same PET scanner.

Methodological differences between centres A and B in the evaluation of ¹⁸F-FET PET data were identified for (1) framing of PET dynamic data, (2) data reconstruction, (3) cut-off values for tumour delineation to determine tumour-to-brain ratios (TBR) and tumour volume (T_vol) and (4) ROI definition to determine time activity curves (TACs) in the tumour. Based on the ¹⁸F-FET PET data of 40 patients with untreated cerebral gliomas (20 WHO grade II, 10 WHO grade III, 10 WHO grade IV), the effect of different data processing in the two centres on TBR_mean, TBR_max, T_vol, time-to-peak (TTP) and slope of the TAC was compared. Further, the effect on tumour grading was evaluated by ROC analysis.

Results

Significant differences between centres A and B were found especially for TBR_max (2.84 ± 0.99 versus 3.34 ± 1.13; p < 0.001), T_vol (1.14 ± 1.28 versus 1.51 ± 1.44; p < 0.001) and TTP (22.4 ± 8.3 min versus 30.8 ± 6.3 min; p < 0.001) and minor differences for TBR_mean and slope. Tumour grading was not influenced by different data processing.

Conclusions

Variable data processing of ¹⁸F-FET PET in different centres leads to significant differences especially for TBR_max and T_vol. A standardization of data processing and evaluation is needed to make ¹⁸F-FET PET comparable between different centres.

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A human PET study of [ 11 C]HMS011, a potential radioligand for AMPA receptors

Abstract

Background

α-Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor is a primary mediator of fast glutamatergic excitatory signaling in the brain and has been implicated in diverse neuropsychiatric diseases. We recently developed a novel positron emission tomography (PET) ligand, 2-(1-(3-([¹¹C]methylamino)phenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl) benzonitrile ([¹¹C]HMS011). This compound is a radiolabelled derivative of perampanel, an antiepileptic drug acting on AMPA receptors, and was demonstrated to have promising in vivo properties in the rat and monkey brains. In the current study, we performed a human PET study using [¹¹C]HMS011 to evaluate its safety and kinetics.

Four healthy male subjects underwent a 120-min PET scan after injection of [¹¹C]HMS011. Arterial blood sampling and metabolite analysis were performed to obtain parent input functions for three of the subjects using high-performance liquid chromatography. Regional distribution volumes (V _Ts) were calculated based on kinetic models with and without considering radiometabolite in the brain. The binding was also quantified using a reference tissue model with white matter as reference.

Results

Brain uptake of [¹¹C]HMS011 was observed quickly after the injection, followed by a rapid clearance. Three hydrophilic and one lipophilic radiometabolites appeared in the plasma, with notable individual variability. The kinetics in the brain with apparent radioactivity retention suggested that the lipophilic radiometabolite could enter the brain. A dual-input graphical model, an analytical model designed in consideration of a radiometabolite entering the brain, well described the kinetics of [¹¹C]HMS011. A reference tissue model showed small radioligand binding potential (BP*_ND) values in the cortical regions (BP*_ND = 0–0.15). These data suggested specific binding component of [¹¹C]HMS011 in the brain.

Conclusions

Kinetic analyses support some specific binding of [¹¹C]HMS011 in the human cortex. However, this ligand may not be suitable for practical AMPA receptor PET imaging due to the small dynamic range and metabolite in the brain.

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Aggressive haematological malignancies

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Anaphylactoid Purpura Associated with Streptococcal Cellulitis: A Case Report and Literature Review

A 54-year-old Japanese man noticed painful swelling and redness of his left leg. He was admitted for treatment of cellulitis, which was accompanied with increased anti-streptolysin O and anti-streptokinase titers in his clinical course. After Piperacillin/Tazobactam administration, the skin lesion resolved. However, the patient then developed arthritis, palpable purpura, and intermittent abdominal pain, later found to be secondary to a severe duodenal ulcer. He was diagnosed with cellulitis-associated anaphylactoid purpura and was given prednisolone, which dramatically improved his symptoms. The anaphylactoid purpura was likely caused by Streptococcus-induced cellulitis, which was successfully treated with prednisolone. Association between these diseases is rare.

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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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Annexin A2 could enhance multidrug resistance by regulating NF-κB signaling pathway in pediatric neuroblastoma

Abstract

Background

Chemotherapy is one of major therapeutic regimens for neuroblastoma (NB) in children. However, recurrence and metastasis associated with poor prognosis caused by acquired multidrug resistance remains a challenge. There is a great need to achieve new insight into the molecular mechanism of drug resistance in NB. The aim of this study is to identify novel drug sensitivity-related biomarkers as well as new therapeutic targets to overcome chemoresistance.

Methods

We proteome-wide quantitatively compared protein expression of two NB cell lines with different drug sensitivities, isolated from the same patient prior to and following chemotherapy. Annexin A2 (ANXA2) emerged as a key factor contributing to drug resistance in NB. Then, we assessed the correlation of ANXA2 expression and clinical characteristics using a tissue microarray. Further, the roles of ANXA2 in chemoresistance for NB and the underlying mechanisms were studied by using short hairpin RNA (shRNA) in vitro and vivo.

Results

First in total, over 6000 proteins were identified, and there were about 460 significantly regulated proteins which were up- or down-regulated by greater than two folds. We screened out ANXA2 which was upregulated by more than 12-fold in the chemoresistant NB cell line, and it might be involved in the drug resistance of NB. Then, using a tissue chip containing 42 clinical NB samples, we found that strong expression of ANXA2 was closely associated with advanced stage, greater number of chemotherapy cycles, tumor metastasis and poor prognosis. Following knockdown of ANXA2 in NB cell line SK-N-BE(2) using shRNA, we demonstrate enhanced drug sensitivity for doxorubicin (2.77-fold) and etoposide (7.87-fold) compared with control. Pro-apoptotic genes such as AIF and cleaved-PARP were upregulated. Inhibiting ANXA2 expression attenuated transcriptional activity of NF-κB via down-regulated nuclear translocation of subunit p50. Finally, simulated chemotherapy in a xenograft NB nude mouse model suggests that ANXA2 knockdown could improve clinical results in vivo.

Conclusion

Our profiling data provided a rich source for further study of the molecular mechanisms of acquired drug resistance in NB. Further study may determine the role of ANXA2 as a prognostic biomarker and a potential therapeutic target for patients with multidrug-resistant NB.

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Recommendations for biomarker testing in epithelial ovarian cancer: a National Consensus Statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology

Abstract

Because of advances in the understanding of histological and molecular characteristics in ovarian cancer, it is now possible to recognize the existence of five subtypes, which in turn has allowed a more refined therapeutic approach and better design of clinical trials. Each of these five subtypes has specific histological features and a particular biomarker expression, as well as mutations in different genes, some of which have prognostic and predictive value. CA125 and HE4 are examples of ovarian cancer biomarkers used in the diagnosis and follow-up of these malignancies. Currently, somatic or germinal mutations on BRCA1 and BRCA2 genes are the most important biomarkers in epithelial ovarian cancer having prognostic and predictive value. This article will review the histological and molecular characteristics of the five subtypes of ovarian cancer, describing the most important biomarkers and mutations that can guide in diagnosis, screening and tailored treatment strategy.

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New Neurotensin analogue radiolabeled by 99mTechnetium as a potential agent for tumor identification

Abstract

Introduction

It has been shown that more than 75% of ductal pancreatic adenocarcinomas are overexpress neurotensin (NT) receptors. Overexpression of NT receptors has been reported in various human tumor types. Hence, a non-invasive diagnosis and staging method could be very beneficial. In this work, we describe radiolabeling and evaluation of new neurotensin analogues to target neurotensin receptor-positive tumors such as pancreatic carcinoma.

Methods

Radiolabeling was performed at 95°C for 10 min using^99mTc in the presence of tricine/EDDA exchange labeling. Radiochemical yield analysis involved ITLC and HPLC methods. A binding assay test was carried out in nine different concentrations of labeled neurotensin analogues in HT-29 cells. Radiopeptide-specific binding and internalization were studied in NT receptors expressing HT-29 cells. Biodistribution studies were performed in tumor-free BALB/c mice and HT-29 xenografted tumor-bearing nude mice.

Result

The peptide was efficiently labeled by ^99mTc with high radiochemical yields (> 98%). The radioconjugate was thoroughly stable in the solution and human serum even for 24 h. The radiolabeled peptide showed high affinity (32.66 ±4.01 nM) and specificity internalization (>%18 after 4 h) to HT-29 cells. The radiopeptide efficiently showed tumor size and location in tumor-bearing nude mice. In biodistribution, a receptor-specific uptake of radiopeptide was observed in neurotensin receptor-positive organs such as intestine. Uptake in the tumor was 4.59 ±0.23%ID/g after 2 h.

Conclusion

Owing to excellent stability, high affinity, rapid blood clearance, low accumulation in non-target organs, and high uptake in tumor, the ^99mTc–HYNIC-peptide is a potential agent for targeting of NTR-overexpressing tumor cells in clinical surroundings.

This article is protected by copyright. All rights reserved.

Radiochemical purity of radiopeptide was high .Radiopeptide showed high affinity, specificity internalization to HT-29 cells and it efficiently showed tumor size and location in tumor-bearing nude mice. In biodistribution, receptor-specific uptake of radiopeptide was observed in neurotensin receptor-positive organs such as tumor and intestine.

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Impact of new generation hormone-therapy on cognitive function in elderly patients treated for a metastatic prostate cancer: Cog-Pro trial protocol

Abstract

Background

New generation hormone-therapies (NGHT) targeting the androgen signalling pathway are nowadays proposed to elderly patients with metastatic castration-resistant prostate cancer (CRPCa). The impact of these treatments on cognitive function has never been evaluated whereas cognitive impairment may have an impact on the autonomy and the treatment adherence. The aim of this study is to prospectively assess the incidence of cognitive impairment in elderly men after treatment by NGHT for a metastatic CRPCa.

Methods/design

The Cog-Pro study is a multicentre longitudinal study including CRPCa patients ≥70 years old treated with NGHT (n = 134), control metastatic prostate cancer patients without castration resistance treated with first generation androgen deprivation therapy (n = 55), and healthy participants (n = 33), matched on age and education. Cognitive, geriatric and quality of life assessment and biological tests will be performed at baseline, 3, 6 and 12 months after start of the treatment (inclusion time). The primary endpoint is the proportion of elderly patients receiving a NGHT who will experience a decline in cognitive performances within 3 months after study enrollment. Secondary endpoints concern: autonomy, quality of life, anxiety, depression, cognitive reserve, adherence to hormone-therapy, comparison of the cognitive impact of 2 different NGHT (abiraterone acetate and enzalutamide), impact of co-morbidities and biological assessments.

Discussion

Evaluating, understanding and analyzing the incidence, severity of cognitive impairments and their impact on quality of life, autonomy and adherence in this group of patients with advanced disease is a challenge. This study should help to improve cancer care of elderly patients and secure the use of oral treatments as the risk of non-observance does exist. Our results will provide up-to date information for patients and caregivers on impact of these treatments on cognitive function in order to help the physicians in the choice of the treatment.

Trial registration

NCT02907372, registered: July 26, 2016.

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Randomized study comparing full dose monotherapy (S-1 followed by irinotecan) and reduced dose combination therapy (S-1/oxaliplatin followed by S-1/irinotecan) as initial therapy for older patients with metastatic colorectal cancer: NORDIC 9

Abstract

Background

Metastatic colorectal cancer (mCRC) is a disease of older age, but there is a relative lack of knowledge about effects of chemotherapy in older patients as they are under-represented in clinical trials. Little data can guide whether the strategy in older mCRC patients should be a sequential full-dose monotherapy chemotherapy approach or a dose-reduced combination chemotherapy approach. The oral 5FU prodrug S-1 seems to have less side effects than capecitabine and should be an optimal drug for older patients, but few data are available. Improved geriatric assessments are needed to select which older patients should receive therapy.

Methods

The NORDIC 9 trial is a Nordic multicenter randomized phase II study comparing full dose monotherapy (S-1 30 mg/m² twice daily days 1–14 every 3 weeks, followed by second line irinotecan 250–350 mg/m² iv day 1 every 3 weeks or 180–250 mg/m² iv day 1 every 2 weeks) with reduced dose combination therapy (S-1 20 mg/m² days 1–14 + oxaliplatin 100 mg/m² iv day 1 every 3 weeks, followed by second line S-1 20 mg/m² days 1–14 + irinotecan 180 mg/m² day 1 every 3 week) for older patients (≥70 years) with mCRC who are not candidates for full-dose standard combination therapy. Additional bevacizumab (7.5 mg/kg) is optional in first-line. Blood samples and tumor tissue will be collected to investigate predictive markers. Geriatric screening tools (G-8, VES-13, Timed-Up-and-Go and Handgrip strength), Charlson Comorbidty Index and quality of life (EORTC QLQ-C30) will be evaluated as predictors of efficacy and toxicity. The target sample size is 150 patients.

The primary endpoint is progression-free survival and secondary endpoints are time-to-failure of strategy, overall survival, response rate, toxicity, and correlations between biomarkers, pre-treatment characteristics and geriatric assessments.

Discussion

The study will add knowledge on how to treat older mCRC patients who are not candidates for standard combination therapy. Furthermore it may provide understanding of efficacy and tolerability of chemotherapy in older cancer patients and thus offer a better chance for tailored treatment strategies in these patients.

Trial registration

EU Clinical Trial Register, EudraCT no. 2014–000394-39. Registered 05 May 2014.

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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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