Neural Regeneration Research (Neural Regen Res)

Bridging larger gaps in peripheral nerves using neural prosthetics and physical therapeutic agents Muhammad Sana Ullah Sahar, Matthew Barton, Geoffrey Douglas Tansley Neural Regeneration Research 2019 14(7):1109-1115 Peripheral nerve injuries are relatively common and can be caused by a variety of traumatic events such as motor vehicle accidents. They can lead to long-term disability, pain, and financial burden, and contribute to poor quality of life. In this review, we systematically analyze the contemporary literature on peripheral nerve gap management using nerve prostheses in conjunction with physical therapeutic agents. The use of nerve prostheses to assist nerve regeneration across large gaps (> 30 mm) has revolutionized neural surgery. The materials used for nerve prostheses have been greatly refined, making them suitable for repairing large nerve gaps. However, research on peripheral nerve gap management using nerve prostheses reports inconsistent functional outcomes, especially when prostheses are integrated with physical therapeutic agents, and thus warrants careful investigation. This review explores the effectiveness of nerve prostheses for bridging large nerve gaps and then addresses their use in combination with physical therapeutic agents.

Magnesium: Pathophysiological mechanisms and potential therapeutic roles in intracerebral hemorrhage Jason J Chang, Rocco Armonda, Nitin Goyal, Adam S Arthur Neural Regeneration Research 2019 14(7):1116-1121 Intracerebral hemorrhage (ICH) remains the second-most common form of stroke with high morbidity and mortality. ICH can be divided into two pathophysiological stages: an acute primary phase, including hematoma volume expansion, and a subacute secondary phase consisting of blood-brain barrier disruption and perihematomal edema expansion. To date, all major trials for ICH have targeted the primary phase with therapies designed to reduce hematoma expansion through blood pressure control, surgical evacuation, and hemostasis. However, none of these trials has resulted in improved clinical outcomes. Magnesium is a ubiquitous element that also plays roles in vasodilation, hemostasis, and blood-brain barrier preservation. Animal models have highlighted potential therapeutic roles for magnesium in neurological diseases specifically targeting these pathophysiological mechanisms. Retrospective studies have also demonstrated inverse associations between admission magnesium levels and hematoma volume, hematoma expansion, and clinical outcome in patients with ICH. These associations, coupled with the multifactorial role of magnesium that targets both primary and secondary phases of ICH, suggest that magnesium may be a viable target of study in future ICH studies.

Network-centric medicine for peripheral nerve injury: Treating the whole to boost endogenous mechanisms of neuroprotection and regeneration David Romeo-Guitart, Caty Casas Neural Regeneration Research 2019 14(7):1122-1128 Peripheral nerve injuries caused by accidents may lead to paralysis, sensory disturbances, anaesthesia, and lack of autonomic functions. Functional recovery after disconnection of the motoneuronal soma from target tissue with proximal rupture of axons is determined by several factors: motoneuronal soma viability, proper axonal sprouting across inhibitory zones and elongation toward specific muscle, effective synapse contact rebuilding, and prevention of muscle atrophy. Therapies, such as adjuvant drugs with pleiotropic effects, that promote functional recovery after peripheral nerve injury are needed. Toward this aim, we designed a drug discovery workflow based on a network-centric molecular vision using unbiased proteomic data and neural artificial computational tools. Our focus is on boosting intrinsic capabilities of neurons for neuroprotection; this is in contrast to the common approach based on suppression of a pathobiological pathway known to be associated with disease condition. Using our workflow, we discovered neuroheal, a combination of two repurposed drugs that promotes motoneuronal soma neuroprotection, is anti-inflammatory, enhances axonal regeneration after axotomy, and reduces muscle atrophy. This drug discovery workflow has thus yielded a therapy that is close to its clinical application.

Exogenous neural stem cell transplantation for cerebral ischemia Ling-Yi Liao, Benson Wui-Man Lau, Dalinda Isabel Sánchez-Vidaña, Qiang Gao Neural Regeneration Research 2019 14(7):1129-1137 Cerebral ischemic injury is the main manifestation of stroke, and its incidence in stroke patients is 70–80%. Although ischemic stroke can be treated with tissue-type plasminogen activator, its time window of effectiveness is narrow. Therefore, the incidence of paralysis, hypoesthesia, aphasia, dysphagia, and cognitive impairment caused by cerebral ischemia is high. Nerve tissue regeneration can promote the recovery of the aforementioned dysfunction. Neural stem cells can participate in the reconstruction of the damaged nervous system and promote the recovery of nervous function during self-repair of damaged brain tissue. Neural stem cell transplantation for ischemic stroke has been a hot topic for more than 10 years. This review discusses the treatment of ischemic stroke with neural stem cells, as well as the mechanisms of their involvement in stroke treatment.

Potential therapeutic molecular targets for blood-brain barrier disruption after subarachnoid hemorrhage Hideki Kanamaru, Hidenori Suzuki Neural Regeneration Research 2019 14(7):1138-1143 Aneurysmal subarachnoid hemorrhage remains serious hemorrhagic stroke with high morbidities and mortalities. Aneurysm rupture causes arterial bleeding-induced mechanical brain tissue injuries and elevated intracranial pressure, followed by global cerebral ischemia. Post-subarachnoid hemorrhage ischemia, tissue injuries as well as extravasated blood components and the breakdown products activate microglia, astrocytes and Toll-like receptor 4, and disrupt blood-brain barrier associated with the induction of many inflammatory and other cascades. Once blood-brain barrier is disrupted, brain tissues are directly exposed to harmful blood contents and immune cells, which aggravate brain injuries furthermore. Blood-brain barrier disruption after subarachnoid hemorrhage may be developed by a variety of mechanisms including endothelial cell apoptosis and disruption of tight junction proteins. Many molecules and pathways have been reported to disrupt the blood-brain barrier after subarachnoid hemorrhage, but the exact mechanisms remain unclear. Multiple independent and/or interconnected signaling pathways may be involved in blood-brain barrier disruption after subarachnoid hemorrhage. This review provides recent understandings of the mechanisms and the potential therapeutic targets of blood-brain barrier disruption after subarachnoid hemorrhage.

Choroid plexus tumor necrosis factor receptor 1: A new neuroinflammatory piece of the complex Alzheimer's disease puzzle Sophie Steeland, Roosmarijn E Vandenbroucke Neural Regeneration Research 2019 14(7):1144-1147 Due to the aging of the population and despite the enormous scientific effort, Alzheimer’s disease remains one of the biggest medical and pharmaceutical challenges in current medicine. Novel insights highlight the importance of neuroinflammation as an undeniable player in the onset and progression of Alzheimer’s disease. Tumor necrosis factor is a master inflammatory cytokine that signals via tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2, but that also regulates several brain functions in health and disease. However, clinical trials investigating drugs that interfere with the tumor necrosis factor pathway in Alzheimer’s disease led to inconclusive results, partially because not only the pro-inflammatory tumor necrosis factor/tumor necrosis factor receptor 1, but also the beneficial tumor necrosis factor/tumor necrosis factor receptor 2 signaling was antagonized in these trials. We recently found that tumor necrosis factor is the main upregulated cytokine in the choroid plexus of Alzheimer’s disease patients, signaling via tumor necrosis factor receptor 1. In agreement with this, choroidal tumor necrosis factor/tumor necrosis factor receptor 1 signaling was also upregulated in different Alzheimer’s disease mouse models. Interestingly, both genetic and nanobody-based pharmacological blockage of tumor necrosis factor receptor 1 signaling was accompanied by favorable effects on Alzheimer’s disease-associated inflammation, choroidal morphology and cognitive functioning. Here, we briefly summarize the detrimental effects that can be mediated by tumor necrosis factor/tumor necrosis factor receptor 1 signaling in (early) Alzheimer’s disease, and the consequences this might have on the disease progression. As the main hypothesis in Alzheimer’s disease clinical trials is still based on the amyloid beta-cascade, the importance of Alzheimer’s disease-associated neuroinflammation urge the development of novel therapeutic strategies that might be effective in the early stages of Alzheimer’s disease and prevent the irreversible neurodegeneration and resulting memory decline.

Transcriptional dysregulation in neurodegenerative diseases: Who tipped the balance of Yin Yang 1 in the brain? Zhefan Stephen Chen, Ho Yin Edwin Chan Neural Regeneration Research 2019 14(7):1148-1151 Yin Yang 1 (YY1) is a multi-functional transcription factor that regulates gene expression in a range of cell types, including neurons. It controls neuronal differentiation, as well as neuronal specification and migration during the development of the mammalian nervous system. Besides, YY1 also mediates the transcription of genes that are required for neuronal survival. An impairment of the transcriptional function of YY1 causes neuronal death. This review summarizes recent research findings that unveil the dysfunction of YY1 in multiple neurodegenerative disorders. The expression of disease proteins perturbs the function of YY1 via distinct molecular mechanisms, including recruitment to protein aggregates, protein degradation and aberrant nuclear/cytoplasmic shuttling. Understanding the pathogenic roles of YY1 will further broaden our knowledge of the disease mechanisms in distinct neurodegenerative disorders.

Effects of Ginkgo biloba extract EGb761 on neural differentiation of stem cells offer new hope for neurological disease treatment Chao Ren, Yong-Qiang Ji, Hong Liu, Zhe Wang, Jia-Hui Wang, Cai-Yi Zhang, Li-Na Guan, Pei-Yuan Yin Neural Regeneration Research 2019 14(7):1152-1157 Stem cell transplantation has brought new hope for the treatment of neurological diseases. The key to stem cell therapy lies in inducing the specific differentiation of stem cells into nerve cells. Because the differentiation of stem cells in vitro and in vivo is affected by multiple factors, the final differentiation outcome is strongly associated with the microenvironment in which the stem cells are located. Accordingly, the optimal microenvironment for inducing stem cell differentiation is a hot topic. EGb761 is extracted from the leaves of the Ginkgo biloba tree. It is used worldwide and is becoming one of the focuses of stem cell research. Studies have shown that EGb761 can antagonize oxygen free radicals, stabilize cell membranes, promote neurogenesis and synaptogenesis, increase the level of brain-derived neurotrophic factors, and replicate the environment required during the differentiation of stem cells into nerve cells. This offers the possibility of using EGb761 to induce the differentiation of stem cells, facilitating stem cell transplantation. To provide a comprehensive reference for the future application of EGb761 in stem cell therapy, we reviewed studies investigating the influence of EGb761 on stem cells. These started with the composition and neuropharmacology of EGb761, and eventually led to the finding that EGb761 and some of its important components play important roles in the differentiation of stem cells and the protection of a beneficial microenvironment for stem cell transplantation.

Amelioration of Alzheimer's disease pathology and cognitive deficits by immunomodulatory agents in animal models of Alzheimer's disease Bridget Martinez, Philip V Peplow Neural Regeneration Research 2019 14(7):1158-1176 The most common age-related neurodegenerative disease is Alzheimer’s disease (AD) characterized by aggregated amyloid-β (Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles, together with loss of cholinergic neurons, synaptic alterations, and chronic inflammation within the brain. These lead to progressive impairment of cognitive function. There is evidence of innate immune activation in AD with microgliosis. Classically-activated microglia (M1 state) secrete inflammatory and neurotoxic mediators, and peripheral immune cells are recruited to inflammation sites in the brain. The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects. Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials. Treatment with immunomodulatory/anti-inflammatory agents early in the disease process, while not preventive, is able to inhibit the inflammatory consequences of both Aβ and tau aggregation. The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD. The majority of the animal studies reviewed had used transgenic models of early-onset AD. More effort needs to be given to creat models of late-onset AD. The effects of a combinational therapy involving two or more of the tested pharmaceutical agents, or one of these agents given in conjunction with one of the cell-based therapies, in an aged animal model of AD would warrant investigation.

Precision medicine in pantothenate kinase-associated neurodegeneration Mónica Alvarez-Cordoba, Marina Villanueva-Paz, Irene Villalón-García, Suleva Povea-Cabello, Juan M Suárez-Rivero, Marta Talaverón-Rey, Javier Abril-Jaramillo, Ana Belén Vintimilla-Tosi, José A Sánchez-Alcázar Neural Regeneration Research 2019 14(7):1177-1185 Neurodegeneration with brain iron accumulation is a broad term that describes a heterogeneous group of progressive and invalidating neurologic disorders in which iron deposits in certain brain areas, mainly the basal ganglia. The predominant clinical symptoms include spasticity, progressive dystonia, Parkinson’s disease-like symptoms, neuropsychiatric alterations, and retinal degeneration. Among the neurodegeneration with brain iron accumulation disorders, the most frequent subtype is pantothenate kinase-associated neurodegeneration (PKAN) caused by defects in the gene encoding the enzyme pantothenate kinase 2 (PANK2) which catalyzed the first reaction of the coenzyme A biosynthesis pathway. Currently there is no effective treatment to prevent the inexorable course of these disorders. The aim of this review is to open up a discussion on the utility of using cellular models derived from patients as a valuable tool for the development of precision medicine in PKAN. Recently, we have described that dermal fibroblasts obtained from PKAN patients can manifest the main pathological changes of the disease such as intracellular iron accumulation accompanied by large amounts of lipofuscin granules, mitochondrial dysfunction and a pronounced increase of markers of oxidative stress. In addition, PKAN fibroblasts showed a morphological senescence-like phenotype. Interestingly, pantothenate supplementation, the substrate of the PANK2 enzyme, corrected all pathophysiological alterations in responder PKAN fibroblasts with low/residual PANK2 enzyme expression. However, pantothenate treatment had no favourable effect on PKAN fibroblasts harbouring mutations associated with the expression of a truncated/incomplete protein. The correction of pathological alterations by pantothenate in individual mutations was also verified in induced neurons obtained by direct reprograming of PKAN fibroblasts. Our observations indicate that pantothenate supplementation can increase/stabilize the expression levels of PANK2 in specific mutations. Fibroblasts and induced neurons derived from patients can provide a useful tool for recognizing PKAN patients who can respond to pantothenate treatment. The presence of low but significant PANK2 expression which can be increased in particular mutations gives valuable information which can support the treatment with high dose of pantothenate. The evaluation of personalized treatments in vitro of fibroblasts and neuronal cells derived from PKAN patients with a wide range of pharmacological options currently available, and monitoring its effect on the pathophysiological changes, can help for a better therapeutic strategy. In addition, these cell models will be also useful for testing the efficacy of new therapeutic options developed in the future.

Mediterranean diet, alkaline water may be as effective as PPIs for laryngopharyngeal reflux

Alkaline water is water that's less acidic than regular tap water. This means it is rich in alkalizing compounds, including calcium, silica, potassium, magnesium, and bicarbonate.https://www.precisionnutrition.com/alkaline-water-legit-or-hoax

Seeing little relief with PPIs for patients, study author looked to dietary treatment for LPR

Treatment of laryngopharyngeal reflux (LPR) with alkaline water and the Mediterranean diet may be as effective as treatment with proton-pump inhibitors (PPIs), according to research published online in JAMA Otolaryngology–Head & Neck Surgery in September. Like gastroesophageal reflux disease, a similar condition, LPR occurs when acidic gastric juices in the stomach back up into the esophagus, but in LPR, the gastric juices reach the throat, resulting in symptoms such as hoarseness, sore throat, cough, and excessive mucous. 

In the study, researchers conducted a retrospective medical c­hart review comparing the change in Reflux Symptom Index (RSI) in two groups of patients, those treated between 2010 and 2012 with PPIs and standard reflux precautions and those treated between 2013 and 2015 with a plant-based Mediterranean diet and alkaline water that had a pH of at least 8. The team found that 54.1% of patients in the PPI group achieved a clinically meaningful reduction of at least 6 points, but 62.5% in the dietary group achieved similar results. Furthermore, those in the dietary group achieved a greater reduction in RSI: 39.8% compared with 27.2% in the PPI group.

"It's pretty clear that this data suggests that we, as health care professionals, need to start getting patients educated so they understand how important a role diet plays," said study lead author Craig H. Zalvan, MD, FACS, chief of otolaryngology and medical director at The Institute for Voice and Swallowing Disorders at Phelps Hospital in Sleepy Hollow, NY.

Zalvan said he thought to study dietary treatment for LPR after seeing that a sizable number of patients don't get much relief with PPIs.

"The standard of care for LPR has always been PPIs, and many of my patients got better with them, but a bunch didn't. At most it helps about 50% of patients," Zalvan said. "I looked at chronic diseases like heart disease, diabetes, and stroke, and their successful treatment with a plant-based diet, so I thought there's got to be a better way to treat LPR with diet [as well] and not have people constantly taking pills."

Zalvan added that the idea to incorporate alkaline water into treatment stemmed from prior research conducted by Jaime Koufman, MD, at the Voice Institute of New York in New York City, which suggests that alkaline water may benefit patients with reflux because it deactivates pepsin and acts as an acid buffer.

Zalvan said that as medication experts and readily accessible members of the health care team, pharmacists can help boost the signal about treatment options for LPR.

"Pharmacists can reinforce that PPIs are meant to be short-term medications for an acute problem, and that in order to get off them, diet will play a major part," Zalvan said. "If patients come to me and I say they should try diet, and then they go to the pharmacy and the pharmacist says they should try diet, patients are more likely to try diet."

For the full article, please visit www.pharmacytoday.org for the November 2017 issue of Pharmacy Today.

Deciphering the Genetics of Major End-Use Quality Traits in Wheat

Improving the end-use quality traits is one of the primary objectives in wheat breeding programs. In the current study, a population of 127 recombinant inbred lines (RILs) derived from a cross between Glenn (PI-639273) and Traverse (PI-642780) was developed and used to identify quantitative trait loci (QTL) for 16 end-use quality traits in wheat. The phenotyping of these 16 traits was performed in nine environments in North Dakota, USA. The genotyping for the RIL population was conducted using the wheat Illumina iSelect 90K SNP assay. A high-density genetic linkage map consisting of 7,963 SNP markers identified a total of 76 additive QTL (A-QTL) and 73 digenic epistatic QTL (DE-QTL) associated with these traits. Overall, 12 stable major A-QTL and three stable DE-QTL were identified for these traits, suggesting that both A-QTL and DE-QTL played an important role in controlling end-use quality traits in wheat. The most significant A-QTL (AQ.MMLPT.ndsu.1B) was detected on chromosome 1B for mixograph middle line peak time. The AQ.MMLPT.ndsu.1B A-QTL was located very close to the position of the Glu-B1 gene encoding for a subunit of high molecular weight glutenin and explained up to 24.43% of phenotypic variation for mixograph MID line peak time. A total of 23 co-localized QTL loci were detected, suggesting the possibility of the simultaneous improvement of the end-use quality traits through selection procedures in wheat breeding programs. Overall, the information provided in this study could be used in marker-assisted selection to increase selection efficiency and to improve the end-use quality in wheat.

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High-Density Linkage Map and QTLs for Growth in Snapper (Chrysophrys auratus)

Characterizing the genetic variation underlying phenotypic traits is a central objective in biological research. This research has been hampered in the past by the limited genomic resources available for most non-model species. However, recent advances in sequencing technologies and related genotyping methods are rapidly changing this. Here we report the use of genome-wide SNP data from the ecologically and commercially important marine fish species Chrysophrys auratus (snapper) to 1) construct the first linkage map for this species, 2) scan for growth QTLs, and 3) search for putative candidate genes in the surrounding QTL regions. The newly constructed linkage map contained ~11K SNP markers and is one of the densest maps to date in the fish family Sparidae. Comparisons with genome scaffolds of the recently assembled snapper genome indicated that marker placement was mostly consistent between the scaffolds and linkage map (R = 0.7), but that at fine scales (< 5 cM) some precision limitations occurred. Of the 24 linkage groups, which likely reflect the 24 chromosomes of this species, three were found to contain QTLs with genome-wide significance for growth-related traits. A scan of 13 candidate growth genes located the growth hormone, myogenin, and parvalbumin genes within 5.3, 9.6, and 25.0 cM of these QTLs, respectively. The linkage map and QTLs found in this study will advance the investigation of genome structure and aquaculture breeding efforts in this and related species.

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Evolution of the Highly Repetitive PEVK Region of Titin Across Mammals

The protein titin plays a key role in vertebrate muscle where it acts like a giant molecular spring. Despite its importance and conservation over vertebrate evolution, a lack of high quality annotations in non-model species makes comparative evolutionary studies of titin challenging. The PEVK region of titin-named for its high proportion of Pro-Glu-Val-Lys amino acids-is particularly difficult to annotate due to its abundance of alternatively spliced isoforms and short, highly repetitive exons. To understand PEVK evolution across mammals, we developed a bioinformatics tool, PEVK_Finder, to annotate PEVK exons from genomic sequences of titin and applied it to a diverse set of mammals. PEVK_Finder consistently outperforms standard annotation tools across a broad range of conditions and improves annotations of the PEVK region in non-model mammalian species. We find that the PEVK region can be divided into two subregions (PEVK-N, PEVK-C) with distinct patterns of evolutionary constraint and divergence. The bipartite nature of the PEVK region has implications for titin diversification. In the PEVK-N region, certain exons are conserved and may be essential, but natural selection also acts on particular codons. In the PEVK-C, exons are more homogenous and length variation of the PEVK region may provide the raw material for evolutionary adaptation in titin function. The PEVK-C region can be further divided into a highly repetitive region (PEVK-CA) and one that is more variable (PEVK-CB). Taken together, we find that the very complexity that makes titin a challenge for annotation tools may also promote evolutionary adaptation.

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Dentin hypersensitivity monitored by cold air quantitative sensory testing

Abstract

Background

Quantification of dentin hypersensitivity (DH) is challenging and requires standardized, graded stimulation by natural‐like stimuli.

Objective

The present study aimed at identifying DH subjects and longitudinally monitoring their pain thresholds by cold air quantitative sensory testing (QST).

Methods

Subject recruitment started with an online DH questionnaire. Respondents were screened by dental air stimulation. Sensitizing and habituating subjects were excluded. A recently developed stimulation device was employed for cold air QST. Single tooth DH was verified by applying an equi‐intense stimulus to a control tooth. Descriptive statistics were applied for subject characteristics. Mean values were calculated for the stimulation parameters temperature and air flow. Reliability of temperatures for detecting pain and for evoking moderate pain over multiple time points within a three weeks period were analyzed by two‐way random single and average measures intra‐class correlation coefficients.

Results

353 persons completed the online DH questionnaire of which 117 were screened. 44 passed the screening, yet 15 were excluded for various reasons. 29 subjects were monitored by QST across three weeks. Results revealed a high intra‐individual stability of the temperature inducing moderate to strong pain intensity (MPI) (single measures ICC of T_MPI 0.83, p < 0.001). Mean T_MPI was ‐13.69 °C, yet it highly varied among the 29 subjects (SD±10.04 °C).

Conclusions

Using a novel approach, namely dental QST based on cold air stimuli, we present evidence for temporally stable DH perceptions over a three weeks period. The method fulfills international guideline requirements and is recommendable for obtaining valid results when testing various interventions for DH management.

This article is protected by copyright. All rights reserved.

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Management of Peutz-Jeghers Syndrome in Children and Adolescents: A Position Paper From the ESPGHAN Polyposis Working Group

Peutz-Jeghers syndrome (PJS) is a well-described inherited syndrome, characterized by the development of gastrointestinal polyps, and characteristic mucocutaneous freckling. Development of small bowel intestinal polyps may lead to intussusception in children may require emergency laparotomy with potential loss of bowel. Gastrointestinal polyps may lead to bleeding and anemia. This European Society for Paediatric Gastroenterology Hepatology and Nutrition position paper provides a guide for diagnosis, assessment, and management of PJS in children and adolescents and guidance on avoiding complications from PJS or from the endoscopic procedures performed on these patients. This is the first position paper regarding PJS published by European Society for Paediatric Gastroenterology Hepatology and Nutrition. Literature from PubMed, Medline, and Embase was reviewed and in the absence of evidence, recommendations reflect the opinion of pediatric and adult experts involved in the care of polyposis syndromes. Because many of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, some of the recommendations are based on expert opinion. This position paper will be helpful in the appropriate management and timing of procedures in children and adolescents with PJS.

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Recanalization of Chronic Extrahepatic Portal Vein Obstruction in Pediatric Patients Using a Minilaparotomy Approach

Purpose: Extrahepatic portal vein obstruction (EHPVO) is the most frequent cause of portal hypertension in children. Some patients are not amenable to meso-Rex bypass and alternative surgeries do not restore physiologic flow. We aim to demonstrate the feasibility and safety of minilaparotomy for recanalization of chronic EHPVO. Methods: This 2013–2015 single-center, retrospective review included pediatric patients with chronic EHPVO who underwent minilaparotomy, mesenteric vein access, and attempted recanalization of the occluded portal vein. Outcomes included portal patency, resolution of variceal bleeding, size and number of varices, spleen size, and platelet count. Results: There were 6 EHPVO patients. The median age was 9.9 years and median duration of EHPVO was 7 years (3–16 years). EHPVO etiologies were liver transplantation (50%), idiopathic (33%), and umbilical vein catheterization (17%). Four patients (67%) had successful portal vein recanalization and stenting. At last follow-up [median 3.1 years (2.2–4.3 years)] all successfully recanalized patients had patent portal vein stents and resolution of varices and variceal bleeding. The median reduction in spleen size was 26%, with improvement in platelet counts (50–310/μL). The 2 patients with an idiopathic etiology may have never had a main extrahepatic portal vein based on imaging, and both were unable to be recanalized. Conclusions: Recanalization and stenting of a prolonged occlusion of the portal vein via a minilaparotomy approach is feasible, safe, and may provide an alternative to shunt surgery or endoscopic therapy in selected patients.

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NASPGHAN Distinguished Service Award 2018: Michael Narkewicz

No abstract available

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Intracellular Localization of Microbial Transglutaminase and Its Influence on the Transport of Gliadin in Enterocytes

Objective: Celiac disease (CD) is a systemic inflammatory disorder, characterized by the destruction of duodenal epithelium. The CD8+ T cells involved are associated with cross-presentation. In addition to other factors, the rising prevalence of CD might be induced by microbial transglutaminase (mTG) an enzyme frequently used in food production that shares enzymatic and antigenic properties of tissue transglutaminase (TG2), the autoantigen in CD. We hypothesized that mTG and gliadin are transported into the endoplasmic reticulum (ER), indicating cross-presentation of both antigens. Methods: Apical incubation of duodenal biopsies from CD and control patients was performed with mTG alone or with mTG and simultaneously with Frazer's fraction. Evaluation was carried out by immunofluorescence and electron microscopy. Results: Approximately 6% to 9% of the intracellular mTG and gliadin were transported to the ER of enterocytes. RACE cells (Rapid uptake of Antigen into the Cytosol of Enterocytes) displayed an enhanced antigen uptake into a dilated ER. mTG strongly localized at the basolateral membrane and the lamina propria. Conclusions: mTG and gliadin are transported to the ER of enterocytes and to a greater extent to the ER of RACE cells, suggesting cross-presentation of exogenous antigens. The strong localization of mTG at the basolateral membrane and the lamina propria may also indicate a potential antigenic interaction with cells of the immune system. Since mTG may not only been taken up with food stuffs but could also be released by bacteria within the intestinal microbiota, further investigations are needed regarding the role of mTG in CD pathogenesis.

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2018 AAP Murray Davidson Award: David Piccoli

No abstract available

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Are All Breast-fed Infants Equal? Clustering Metabolomics Data to Identify Predictive Risk Clusters for Childhood Obesity

Objectives: Fetal and early life represent a period of developmental plasticity during which metabolic pathways are modified by environmental and nutritional cues. Little is known on the pathways underlying this multifactorial complex. We explored whether 6 months old breast-fed infants could be clustered into metabolically similar groups and that those metabotypes could be used to predict later obesity risk. Methods: Plasma samples were obtained from 183 breast-fed infants aged 6 months participating in the European multicenter Childhood Obesity Project study. We measured amino acids along with polar lipid concentrations (acylcarnitines, lysophosphatidylcholines, phosphatidylcholines, sphingomyelins). We determined the metabotypes using a Bayesian agglomerative clustering method and investigated the properties of these clusters with respect to clinical, programming, and metabolic factors up to 6 years of age. Results: We identified 20 metabolite clusters comprising 1 to 39 children. Phosphatidylcholines predominantly influenced the clustering process. In the largest clusters (n ≥ 14), large differences existed for birth length (unadjusted P 

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Master Educator Award 2018: B U.K. Li, MD

No abstract available

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Dehydrated Hereditary Stomatocytosis Presenting as Severe Perinatal Ascites and Cholestasis

No abstract available

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Promoting and Protecting Breast-feeding: The Importance of Good Quality Data

No abstract available

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The Frequency of Lysosomal Acid Lipase Deficiency in Children With Unexplained Liver Disease

Objectives: Evidence suggests that lysosomal acid lipase deficiency (LAL-D) is often underdiagnosed because symptoms may be nonspecific. We aimed to investigate the prevalence of LAL-D in children with unexplained liver disease and to identify demographic and clinical features with a prospective, multicenter, cross-sectional study. Methods: Patients (aged 3 months–18 years) who had unexplained transaminase elevation, unexplained hepatomegaly or hepatosplenomegaly, obesity-unrelated liver steatosis, biopsy-proven cryptogenic fibrosis and cirrhosis, or liver transplantation for cryptogenic cirrhosis were enrolled. A Web-based electronic data collection system was used. LAL activity (nmol/punch/h) was measured using the dried blood spot method and classified as LAL-D ( 0.37). A second dried blood spot sample was obtained from patients with intermediate LAL activity for confirmation of the result. Results: A total of 810 children (median age 5.6 years) from 795 families were enrolled. The reasons for enrollment were unexplained transaminase elevation (62%), unexplained organomegaly (45%), obesity-unrelated liver steatosis (26%), cryptogenic fibrosis and cirrhosis (6%), and liver transplantation for cryptogenic cirrhosis (

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Biologics and Surgery in Inflammatory Bowel Disease: Learning at the Cutting Edge

No abstract available

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Systematic Review of Probiotics for Cystic Fibrosis Patients: Moving Forward

Background: Cystic fibrosis (CF) is associated with chronic respiratory disease and pancreatic insufficiency and results in the malabsorption of nutrients and intestinal inflammation. There is evidence that probiotic supplementation may impact the gastrointestinal and respiratory microbiota. This study aimed to categorize current evidence regarding the effects of supplementing with probiotics in CF patients on gastrointestinal and respiratory outcomes according to the type of intervention. Methods: The initial database search included all identified studies according to the recommendations of the Cochrane Collaboration, regardless of language, publication date or design. Studies were categorized by probiotic strain (Lactobacillus reuteri; Lactobacillus rhamnosus GG or a mix of strains); dosage (low dosage if 109 CFU); and duration of intervention (1, 3, 6, or 12 months). Assessment of quality was performed based on the Cochrane risk of bias criteria and the Downs & Black checklist. Results: A total of 205 studies were identified; however, only 9 met the criteria for inclusion. The studies were considered to have a high risk of bias, hampering the possibility of performing a meta-analysis. Eighty percent of the studies (4 of 5) reported a positive result for intestinal inflammation, and another 4 studies (4 of 5) reported a positive result for pulmonary exacerbation frequency, regardless of the treatment approach. Conclusions: The present data indicate a promising future for probiotic use in cystic fibrosis, which has an impact on exacerbations and intestinal inflammation; however, further studies of standardized therapeutic interventions are required.

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Training in Endoscopy: Coaching, Deliberate Practice, and Reflection

No abstract available

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Resting Energy Expenditure in Patients With Familial Dysautonomia: A Preliminary Study

Objectives: Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy characterized by chronic lung disease and cyclic vomiting due to hyper-adrenergic crises. Most FD patients are in a depleted nutritional state; however, the phenotype of the disease is quite different between patients, as for the severity of lung disease and the intensity and frequency of these pathognomonic crises. In this study we wanted to investigate whether resting energy expenditure (REE) levels are increased in this population, and if correlations exist between REE levels and phenotype severity. Methods: Data was collected from 12 FD patients (6/6 m/f). REE measurements were conducted by indirect calorimeter. Measured REE % predicted were correlated with pulmonary function, severity of the scoliosis, serum C-reactive protein, yearly frequency of hyperadrenergic crisis, hospital admissions and the use of nocturnal noninvasive positive pressure ventilation. Results: Mean REE was 112 ±13% predicted with 50% being in a hypermetabolic state (REE/HB > 110%). Body mass index (BMI) was below normal range in 75% of patients, and reduced energy intake was also decreased in 75%. No significant correlations to disease severity factors were found. When dividing the subjects to REE levels above or below 125% predicted, Patients with REE above 125% predicted presented with significantly lower inspiratory capacity (42.7% predicted vs 62.8% predicted; P = 0.04). Conclusions: Hypermetabolic state was described in 50% of FD patients. The Low BMI is explained by combination of relative anorexia and increased REE. The REE levels are related to the underling respiratory disease.

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Conceptual Model of Lean Body Mass in Pediatric Inflammatory Bowel Disease

Youth with inflammatory bowel disease (IBD) demonstrate deficits in lean mass (LM) placing them at increased risk for future health problems, including reduction of bone mass and impaired bone architecture. Research suggests that deficits in LM are multifactorial, including influences from the disease and its treatment, and health behaviors such as diet and physical activity. Based on a systematic literature review examining factors related to LM deficits in IBD, this article presents a conceptual model to explain the development of LM in youth with IBD. The model considers predictors of LM across 4 domains: demographic; medical; diet; and physical activity. Much existing research is cross-sectional, but suggests multiple factors work together to promote or inhibit LM accrual in youth with IBD. The conceptual model, developed based on empirical findings to date, can be used to understand and further elucidate the process through which LM is developed and maintained, to inform the development of empirically supported clinical interventions, and to guide future research objectives and priorities.

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Pneumatosis Cystoides Intestinalis

No abstract available

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Clinical Safety and Utility of Pediatric Balloon-assisted Enteroscopy: A Multicenter Prospective Study in Japan

Objectives: The benefit of balloon-assisted enteroscopy (BAE) had been recently documented in pediatric patients, but previous reports are based on single institution experiences. We evaluated the feasibility of pediatric BAE in 8 tertiary referral hospitals throughout Japan. Methods: This was a prospective, multi-institutional study. Patients younger than 18 years were enrolled between April 2014 and March 2017 to undergo double-balloon or single-balloon enteroscopy. Data were collected prospectively using a standardized questionnaire. Results: We enrolled 79 pediatric patients (96 procedures, 70 boys, 26 girls; median age 12.7 years, range 1–17 years). Antegrade (oral-route) BAE was performed in 20 procedures (lowest body weight 12.9 kg, youngest age 3.7 years), and retrograde (anal-route) BAE in 76 (lowest body weight 10.8 kg, youngest age 1.6 years). Severe adverse events were associated with BAE in 2 patients: 1 with hemorrhage due to polypectomy and 1 with pancreatitis after double-balloon endoscopic retrograde cholangioscopy. No intestinal perforation was reported. Procedure duration of oral-route BAE for diagnosis was significantly longer than anal-route for diagnosis (P 

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2018 Harry Shwachman Award

No abstract available

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Can Pediatric Endoscopists Accurately Assess Their Clinical Competency? A Comparison Across Skill Levels

Background: Assessment is critical to support pediatric endoscopy training. Although trainee engagement in assessment is encouraged, the use of self-assessment and its accuracy among pediatric endoscopists is not well described. We aimed to determine the self-assessment accuracy of novice, intermediate, and experienced pediatric endoscopists. Methods: Novice (performed 1000) pediatric endoscopists from 3 North American academic teaching hospitals each performed a clinical colonoscopy. Endoscopists were assessed in real-time by 2 experienced endoscopists using the Gastrointestinal Endoscopy Competency Assessment Tool for Pediatric Colonoscopy (GiECATKIDS). In addition, participants self-assessed their performance using the same instrument. Self-assessment accuracy between the externally assessed and self-assessed scores was evaluated using absolute difference scores, intraclass correlation coefficients, and Bland-Altman analyses. Results: Forty-seven endoscopists participated (21 novices, 16 intermediates, and 10 experienced). Overall, there was moderate agreement of externally assessed and self-assessed GiECATKIDS total scores with an intraclass correlation coefficient of 0.72 (95% confidence interval, 0.55–0.83). The absolute difference scores among the 3 groups were significantly different (P = 0.005), with experienced endoscopists demonstrating a more accurate self-assessment compared to novices (P = 0.003). Bland-Altman plots revealed that novice endoscopists' self-assessed scores tended to be higher than their externally assessed scores, indicating they overestimated their performance. Conclusions: We found that endoscopic experience was positively associated with self-assessment accuracy among pediatric endoscopists. Novices were inaccurate in assessing their endoscopic competence and were prone to overestimation of their performances. Our findings suggest novices may benefit from targeted interventions aimed at improving their insight and self-awareness.

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Prevalence of Celiac Disease in a Long-term Study of a Spanish At-genetic-risk Cohort From the General Population

Objectives: To perform long-term celiac disease (CD) screening in an HLA-DQ2 (+) cohort from the general population and to assess the influence of risk genotypes on its development. Methods: In 2004, an HLA-DQ2 (+) cohort was selected. After the first CD screening at age 2 to 3 years, we performed a follow-up screening 8 to 10 years later. Antitransglutaminase 2 antibodies were determined using a rapid test kit. Results were confirmed by serum IgA antitransglutaminase 2 and IgA endomysial antibody determination. CD diagnosis was carried out by intestinal biopsies. Four HLA-DQ2 genotypic groups were used: G1: DQ2.5/DQ2.5 (G1A) or DQ2.5/ DQ2.2 (G1B); G2: DQ2.2/DQ7.5 (DQ2.5 trans); G3: DQ2.5/ X; G4: DQ2.2/X. Results: CD prevalence after 10 years of follow-up was 5.8% (95% confidence interval 3.8–8.7). One of every 3 HLA-DQ2(+) children carried at least 1 haplotype DQ2.2 or DQ7. The homozygous genotype DQ2.5/DQ2.5 and the HLA-DQ2.5 trans genotype increased CD risk 4- and 3-fold, respectively. The homozygous genotype DQ2.5/ DQ2.2 did not increase the CD risk. Children carrying G1 or G2 genotypes were diagnosed with CD earlier and more frequently during the follow-up compare with those carrying G3 or G4 genotypes. Approximately 81% of children with spontaneous antibody negativization after the first screening maintained negative antibodies. Conclusions: A repeated screening of at-risk children during their follow-up allowed us to diagnose new CD cases. In our cohort, HLA- DQ2.5 trans genotype conferred a higher risk in the development of CD than HLA- DQ2.5/DQ2.2. The majority of children with potential CD and CD autoimmunity at 10 years of age remained healthy.

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Ultrasound-Guided Botulinum Toxin Injections in Cervical Dystonia Needs Prompt Muscle Selection, Appropriate Dosage, and Precise Guidance

No abstract available

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Acute Phase Predictors of 6-Month Functional Outcome in Italian Stroke Patients Eligible for In-Hospital Rehabilitation: Erratum

No abstract available

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Effects of Video Games–Based Task-Oriented Activity Training (Xbox 360 Kinect) on Activity Performance and Participation in Patients With Juvenile Idiopathic Arthritis: A Randomized Clinical Trial

Objective The aim of the study was to compare the effects of two different task-oriented activity training programs on activity performance and participation in children/adolescents with juvenile idiopathic arthritis. Design Sixty-two patients were randomized into group I and group II for task-oriented activity training. In group I, activities of daily living were practiced using real materials from daily life, and in group II, activities of daily living were practiced using video-based games (Xbox 360 Kinect) for 3 d/wk for 8 wks. Pain by the Numeric Rating Scale, upper limb muscle, grip, and pinch strengths by a dynamometer, activity performance and participation by the Childhood Health Assessment Questionnaire, Canadian Occupational Performance Measure, and Duruoz Hand Index were evaluated. Results After treatment in both groups, significant changes were found in the Numeric Rating Scale, muscle strength, grips strength, Childhood Health Assessment Questionnaire, Canadian Occupational Performance Measure, and Duruoz Hand Index (P

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Quantification and Description of Physical Exercise Performance

No abstract available

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Amputee Locomotion: Joint Moment Adaptations to Running Speed Using Running-Specific Prostheses after Unilateral Transtibial Amputation

Objective The objective of this study was to investigate three-dimensional lower extremity joint moment differences between limbs and speed influences on these differences in individuals with lower extremity amputations using running-specific prostheses. Design Eight individuals with unilateral transtibial amputations and 8 control subjects with no amputations ran overground at three constant velocities (2.5, 3.0, and 3.5 m/sec). A 2 × 2 × 3 (group × leg × speed) repeated-measures analysis of variance with Bonferroni adjustments determined statistical significance. Results The prosthetic limb generated significantly greater peak ankle plantarflexion moments and smaller peak ankle varus, knee stance extension, knee swing flexion, knee internal rotation, hip stance flexion, hip swing flexion, hip swing extension, hip valgus, and hip external rotation moments than the intact limb did. The intact limb had greater peak hip external rotation moments than control limbs did, but all other peak moments were similar between these limbs. Increases in peak hip stance and knee swing flexion moments associated with speed were greater in the intact limb than in the prosthetic limb. Conclusion Individuals with amputation relied on the intact limb more than the prosthetic limb to run at a particular speed when wearing running-specific prostheses, but the intact joints were not overloaded relative to the control limbs.

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2018 AJPM&R Reviewers

No abstract available

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V-Mart, a Virtual Reality Grocery Store: A Focus Group Study of a Promising Intervention for Mild Traumatic Brain Injury and Posttraumatic Stress Disorder

Objective This study examined the potential usability, relevance, and acceptability of V-Mart, a virtual reality grocery store as an assessment and intervention tool for veterans with mild traumatic brain injury. Design Six focus groups were conducted for a 2-yr period to assess perceptions from the following three key stakeholders: therapists, veterans with neither mild traumatic brain injury nor posttraumatic stress disorder, and veterans with mild traumatic brain injury with or without posttraumatic stress disorder (mild traumatic brain injury/posttraumatic stress disorder). The System Usability Scale was applied as an objective measure of usability. Transcripts from the six focus groups were subjected to thematic analyses using the constant, comparative method. Results The focus groups indicated that V-Mart was perceived as highly usable, relevant, and acceptable. Early technical problems were resolved satisfactorily. Therapists indicated that they would use an application such as V-Mart if it were available. The veterans with neither mild traumatic brain injury nor posttraumatic stress disorder felt that it was realistic and likely to be useful, as did the veterans with mild traumatic brain injury/posttraumatic stress disorder. The System Usability Scale mean follow-up scores ranged from 71.4 to 86.0, surpassing the threshold for acceptable usability in health care settings. Conclusions Focus group and System Usability Scale data indicate that the V-Mart has great potential as an assessment tool and intervention for veterans with mild traumatic brain injury/posttraumatic stress disorder. Further development and clinical trials are warranted.

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Morphological Changes of the Median Nerve After Carpal Tunnel Release in a Median Nerve Lipofibromatous Hamartoma

No abstract available

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An Investigation of Pressure Profiles and Wearer Comfort During Walking With a Transtibial Hydrocast Socket

Objective The aims of the study were to conduct an investigation of the transtibial hydrocast socket interface pressures during walking and to explore potential relationships between pressures experienced and resultant wearer comfort. Design In this cross-sectional study, pressure data at the limb and hydrocast socket interface during walking were collected from 16 users of hydrocast sockets. The pressures at this interface were described by location, magnitude, and duration for all participants and were compared between the most and least comfortable participants. Results High pressures were found about the bony prominences of the residual limb, especially the tibial crest of the anterior distal region. Factors identified as potentially causing discomfort (P 0.80) were high peak pressures at the anterior proximal region and longer durations of submaximal loading at the lateral proximal region and the anterior and medial distal regions. High pressure variability at the anterior proximal region may also contribute to discomfort (P = 0.106, d = 0.88). Conclusions The hydrocast socket interface pressures have been described for a cohort of users. A number of differences were found in the pressure profiles of the most and least comfortable participants. These differences suggest trends between the identified pressure parameters and resultant wearer comfort. Future studies should confirm these exploratory results.

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Multisystem Balance Training Reduces Injurious Fall Risk in Parkinson Disease: A Randomized Trial

Previous studies have shown that balance training could reduce falls in people with Parkinson disease. However, it remains unclear whether exercise can reduce injurious falls. The objective of present study was to determine whether multisystem balance training could reduce injurious falls and modify targeted fall risk factors in Parkinson disease nonfallers and single fallers. Participants were randomly assigned to an 8-wk balance group (experimental, n = 41) or an upper limbs group (control, n = 43). Outcomes examined at posttraining and 12-mo follow-up were: (1) injurious fall risk (ratio of noninjurious fallers to injurious fallers); (2) two potential fall risk factors based on Balance Evaluation Systems Test scores and dual-task timed-up-and-go times. At posttraining, results indicated that there were no injurious falls, and fewer experimental participants were found in high fall risk cohorts based on Balance Evaluation Systems Test scores and dual-task timed-up-and-go times (P

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Motor Control Training Compared With Transcutaneous Electrical Nerve Stimulation in Patients With Disc Herniation With Associated Radiculopathy: A Randomized Controlled Trial

Objective The aim of the study was to compare the effectiveness of motor control training and transcutaneous electrical nerve stimulation in relieving pain, reducing functional disability, and improving transversus abdominis activation in patients with lumbar disc herniation with associated radiculopathy. Design This is a randomized controlled trial. Methods Forty patients diagnosed with lumbar disc herniation were randomly divided into two groups: motor control training group (n = 20) and transcutaneous electrical nerve stimulation group (n = 20). Interventions The motor control training group and transcutaneous electrical nerve stimulation group attended 60 mini sessions twice a week for 8 wks, totaling to 16 sessions. Main Outcome Measures The main outcome measures are pain, functional disability, and transversus abdominis activation capacity. Results Differences between both groups were observed after 8 wks, favoring the motor control training group. Motor control training was more effective than transcutaneous electrical nerve stimulation in relieving pain (mean difference = 3.3 points, 95% confidence interval = 2.12–4.48), reducing functional disability (mean difference = 8.4 points, 95% confidence interval = 5.44–11.36), improving the quality of pain (mean difference = 17 points, 95% confidence interval = 7.93–26.07), sensory quality of pain (mean difference = 10.3 points, 95% confidence interval = 5.55–15.05), and transversus abdominis activation (mean difference = 1.5 points, 95% confidence interval = 0.90–2.10). Conclusions The results suggest that motor control training is more effective than transcutaneous electrical nerve stimulation with respect to relieving pain, reducing functional disability, and improving transversus abdominis activation in patients with lumbar disc herniation.

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Can Botulinum Toxin Help Prevent Migraine in Adults?: A Cochrane Review Summary With Commentary

No abstract available

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The Effectiveness of Group-Based Physiotherapy-Led Behavioral Psychological Interventions on Adults With Chronic Low Back Pain: A Systematic Review and Meta-Analysis

Group-based physiotherapy-led behavioral psychological interventions (GPBPIs) are an emerging treatment for chronic low back pain, but the efficacy of these interventions is uncertain. A review of relevant randomized controlled trials and a meta-analysis was conducted to evaluate the effectiveness of GPBPIs on pain relief in adults with chronic low back pain. Literature databases, Google Scholar, bibliographies, and other relevant sources were searched. Thirteen intervention studies (13) published from 1998 to 2013 were included. The meta-analysis was conducted using RevMan software in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. In reviewing the short- (

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Mechanical In-exsufflation-Expiratory Flows as Indication for Tracheostomy Tube Decannulation: Case Studies

Mechanical insufflation exsufflation-expiratory flows (MIE-EFs) correlate with upper airway patency. Patients dependent on continuous noninvasive ventilatory support with severe spinal muscular atrophy type 1, now over 20 yrs old, have used MIE sufficiently effectively along with continuous noninvasive ventilatory support to avoid tracheotomy indefinitely. Although MIE-EFs can apparently decrease in amyotrophic lateral sclerosis to necessitate tracheotomy, they can increase over time and remain effective in all spinal muscular atrophy types. Two cases demonstrate an association between increasing MIE-EF and, ultimately, successful decannulation of a patient with spinal muscular atrophy type 2 who was continuous tracheostomy mechanical ventilation dependent and a patient with obesity hypoventilation syndrome. Only when MIE-EF increased to exceed 200 l/min did the decannulations succeed. Definitive noninvasive management (continuous noninvasive ventilatory support) of these patients may be possible only when MIE is effective, and the greater the MIE-EF, the greater its effectiveness. Thus, increasing MIE-EF can signal resolution of upper airway obstruction sufficiently to permit decannulation whether a patient is ventilator dependent or not.

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Hypothesis Testing in Superiority, Noninferiority, and Equivalence Clinical Trials: Implications in Physical Medicine and Rehabilitation

In medical research, it is important to be able to examine whether there is a significant difference between two samples. With this, establishing an appropriate hypothesis is a critical, basic step for correct interpretation of results in inferential statistical data analysis. It is important to note that the aim of hypothesis testing is not to "accept" or "reject" the null hypothesis but to gauge the likelihood that the observed difference is genuine if the null hypothesis is true. Traditionally, the null hypothesis assumes that there is no statistically significant difference between the two groups. It has become more difficult to develop new treatments that are better than the standard of care. This review article summarizes and explains the methodology of the different types of clinical trials regarding the relevant basic statistical concepts and hypothesis testing.

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Author’s Response to Letter to the Editor on “Ultrasound-Guided Botulinum Toxin Injections in Cervical Dystonia Needs Prompt Muscle Selection, Appropriate Dosage, and Precise Guidance”

No abstract available

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Improving Outcomes in Oncological Colorectal Surgery by Prehabilitation

Introduction The cornerstone in the treatment of colorectal cancer is surgery. A surgical event poses a significant risk of decreased functional decline and impaired health-related quality of life. Prehabilitation is defined as the multimodal preoperative enhancement of a patient's condition. It may serve as a strategy to improve postoperative outcomes. Prehabilitation requires a multidisciplinary effort of medical health care professionals and a behavioral change of the patient. Methods The goal of prehabilitation is threefold: (1) to reduce postoperative complications, (2) to enhance and accelerate the recovery of the patient, and (3) to improve overall quality of life. In this article, we introduce the FIT model illustrating a possible framework toward the implementation of both evidence-based and tailor-made prehabilitation for patients undergoing surgery for colorectal cancer. Results The model is composed of three pillars: "facts" (how to screen patients and evidence on what content to prescribe), "integration" (data of own questionnaires assessing motivation of patients and specialists), and finally "tools" (which outcome measurements to use). Discussion Developing implementable methods and defining standardized outcome instruments will help establish a solid base for patient-centered prehabilitation programs. Any party introducing prehabilitation requiring multidisciplinary teamwork and behavioral change can potentially use this framework.

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Windshield Wiper in the Shoulder: Ultrasound Imaging for the Proximal Rotator Cuff Interval

No abstract available

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Palm Oil and Beta-Palmitate in Infant Formula - A Position Paper by the ESPGHAN Committee on Nutrition

Background: Palm oil (PO) is used in infant formulas in order to achieve palmitic acid (PA) levels similar to those in human milk. PA in PO is esterified predominantly at the SN-1,3 position of triacylglycerol (TAG), and infant formulas are now available in which a greater proportion of PA is in the SN-2 position (typical configuration in human milk). Since there are some concerns about the use of PO, we aimed to review literature on health effects of PO and SN-2-palmitate in infant formulas. Methods: PubMed and Cochrane Database of Systematic Reviews were systematically searched for relevant studies on possible beneficial effects or harms of either PO or SN-2-palmitate in infant formula on various health outcomes. Results: We identified 12 relevant studies using PO and 21 studies using SN-2-palmitate. Published studies have variable methodology, subject characteristics and some are underpowered for the key outcomes. PO is associated with harder stools and SN-2-palmitate use may lead to softer stool consistency. Bone effects seem to be short-lasting. For some outcomes (infant colic, faecal microbiota, lipid metabolism), the number of studies is very limited and summary evidence inconclusive. Growth of infants is not influenced. There are no studies published on the effect on markers of later diseases. Conclusions: There is insufficient evidence to suggest that PO should be avoided as a source of fat in infant formulas for health reasons. Inclusion of high SN-2-palmitate fat blend in infant formulas may have short-term effects on stool consistency but cannot be considered essential. Address correspondence and reprint requests to Jiri Bronsky, MD, PhD, Assoc. Prof. of Paediatrics Gastroenterology and Nutrition Unit, Department of Paediatrics, University Hospital Motol, V Uvalu 84, 15006, Prague 5, Czech Republic (e-mail: jiri.bronsky@gmail.com). Received 22 October, 2018 Accepted 4 February, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.jpgn.org). Secretary of CoN: # Iva Hojsak Chair of CoN: ¤Magnus Domellöf Conflicts of Interest: MF conducted a trial using beta-palmitate which was funded by Industry (Cow & Gate, now Nutricia; in 1995) and has received honoraria for attending two Consultancy meetings with Enzymotec (a company involved in the manufacture of beta-palmitate for infant formulas). Authors report following conflicts of interest outside the submitted work: JB reports personal fees and non-financial support from AbbVie, Nutricia, Biocodex, personal fees from MSD, Nestlé, Ferring, Walmark. CC received research funding from ORDESA Laboratories and Abbott Nutrition. NE reports receipt of grants/research supports from National Institutes for Health Research (UK), Prolacta, Bioscience (US) and Danone Early life Nutrition. He also served as member of Advisory board for Danone Early life Nutrition and received payment/honorarium for lectures from Danone Early life Nutrition, Nestle Nutrition Institute, Baxter and Fresenius Kabi. KG reports personal fees from Nutricia, research grants and personal fees from Nestle and Nutricia and personal fees from Dr Falk. IH reports receipt of payment/honorarium for lectures from BioGaia, Nutricia, Nestle, GM pharma and receipt of payment/honorarium for consultation from Farmas,Chr Hansen. JH reports receipt of grants/research supports from Nutricia Advanced Medical Nutrition Netherlands and Danone Medical care (global). FI has participated as a clinical investigator and/or consultant and/or speaker for Arla Food, Biogaia, Nestle, Nestle Nutrition Institute, Wyeth, Danone and Abbott. AL received lecture fees and/or non-financial support from Baxter, Fresenius, Nestle [Combining Acute Accent] and Mead Johnson Nutrition. NFM acknowledges support of the Slovenian Research Agency (P3–0395: Nutrition and Public Health; L3-8213, L3-7538). CM reports receipt of grants/research supports from European Commission Innovation Fund Denmark, Nordea-fonden, Arla Foods, Chr. Hansen, USDEC, Gate Foundation. SJM reports receipt of grants/research supports from DSM Nutritional Products, she served as member of advisory board and received payment/honorarium for consultation from Baxter and received payment/honorarium for lectures from Baxter and Fresenius Kabi. EV reports grant/research support from Nutricia Italia Spa, Nestle Health Science - Vitaflo Italy, FoodAR srl Italy, PIAM Pharma and Integrative Care. RV reports no conflict of interest. MD has recived speaker fees from Baxter, Fresenius, Semper, Abbvie, Nestlé and research support from Baxter and Prolacta. © 2019 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Anti-Saccharomyces Cerevisiae Antibodies as a Prognostic Biomarker in Children with Crohn's disease

Objective: Although anti-saccharomyces cerevisiae antibodies (ASCA) could be a useful biomarker in differentiating Crohn's disease (CD) from ulcerative colitis (UC), their role as prognostic markers in children with CD has been under-investigated. This longitudinal prospective observational study aimed to assess the prognostic value of ASCA status among children with CD managed using biologics. Methods: The study population comprised of children with inflammatory bowel disease (IBD) diagnosed with CD from 2012 to 2018. Cox-regression model with adjustment for a priori covariates was used to examine the response to anti-tumor necrosis factor (TNF) biological therapy among ASCA positive patients in comparison to ASCA negative patients. Results: There were 273 measurements available from the study cohort comprising of children with CD, who were followed up for a median duration of 14 months (IQR 5-42). ASCA positive patients had a higher risk for moderate to severe clinical disease (odds ratio (OR) 2.88; 95% confidence interval (CI) 1.2–7.55) and extensive endoscopic distribution (OR 3.30; CI 1.12–9.74) at baseline in comparison to ASCA negative patients respectively. In comparison to ASCA IgG negative patients, ASCA IgG positive patients who were treated with biologics had a significantly lower relapse rate (aHR 0.12; CI 0.02–0.93). Ten (14%) patients had an unstable ASCA value with either ASCA IgA or ASCA IgG status changing from positive to negative or vice versa. Conclusions: ASCA positive children with CD present with more extensive (endoscopic) and clinically severe disease. ASCA IgG is a useful prognostic marker among children with CD who receive biologics. Address correspondence and reprint requests to Wael El-Matary, MBBCh, MD, MSc, FRCPCH, FRCPC, Dr. Head, Section of Pediatric Gastroenterology. Professor, Department of Pediatric and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, AE 408 Children's Hospital, Health Sciences Centre, 840 Sherbrook St., Winnipeg, Manitoba, R3A 1S1, Canada (e-mail: welmatary@exchange.hsc.mb.ca). Received 20 October, 2018 Revised 13 December, 2018 Accepted 16 January, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.jpgn.org). Abin Chandrakumar and Michael Georgy: Shared first authors. Conflict of Interest: Dr. El-Matary served as an advisory board member for both Janssen Canada and AbbVie Canada. He also received research support for Janssen Canada. © 2019 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Pediatric Endoscopy Practice Patterns in the United States, Canada and Mexico

Background & Aims: Endoscopic procedures are important for diagnosis and management of many gastrointestinal, liver and biliary conditions in children. Therapeutic endoscopy procedures, including ERCP, are performed less frequently in children relative to adults. However, a formal study to evaluate institutional volumes and practice patterns for advanced therapeutic pediatric endoscopy procedures has not been previously undertaken. Methods: A self-administered 16-question (5-minute) online survey assessing practice patterns for performance of pediatric endoscopy procedures was distributed to all registered North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) programs. Results were analyzed using descriptive statistics and thematic analysis of free-text comments. Results: Respondents from 82.9% of NASPGHAN centers completed this survey. Responses revealed that EGD/colonoscopy are performed at the vast majority of centers (>90%), with most performing >50/year. Therapeutic endoscopy procedures are performed less frequently in the pediatric population, with 18.97% reporting that ERCP is not performed at their institution. Where ERCP is performed, 91.38% reported

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Free-Breathing MRI Assessment of Body Composition in Healthy and Overweight Children: An Observational Study

Objective: Conventional, breath-holding magnetic resonance imaging (MRI) assesses body composition by measuring fat volumes and proton density fat fraction (PDFF). However, breath-holding MRI is not always feasible in children. This study's objective was to use free-breathing MRI to quantify visceral and subcutaneous fat volumes and PDFFs and correlate these measurements with hepatic PDFF. Methods: This was an observational, hypothesis-forming study that enrolled two groups of children (ages 6–17 years), healthy children and overweight children with presumed non-alcoholic fatty liver disease. Free-breathing MRI was used to measure visceral and subcutaneous fat volumes and PDFFs, and hepatic PDFF. Imaging biomarkers were compared between groups, and correlations coefficients (r) and coefficients of determination (R2) were calculated. Results: When compared to the control group (n = 10), the overweight group (n = 9) had greater mean visceral (1843 vs. 329 cm3, p 

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Effect of Ketoprofen and ATB-352 on the Immature Human Intestine: Identification of Responders and Non-Responders

Background and Objective: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a broad spectrum of life-threatening adverse effects on the immature gastrointestinal tract. NSAID derivatives exploiting the beneficial effects of biologically active gases, such as hydrogen sulfide (H2S), have been developed. Herein, we determined the effects of ketoprofen and ATB-352, a H2S-releasing ketoprofen derivative, on selected metabolic pathways previously identified to be significantly altered by indomethacin in the human immature intestine. Methods: Ketoprofen and ATB-352 were tested on human mid-gestation small intestinal explants maintained in a serum-free organ culture system for 48 h. The expression levels of the representative genes involved in selected metabolic pathways were measured by real-time PCR after a treatment of 48 hours. Results: Tested at a concentration that allows more than 80% inhibition of PGE2 production, ketoprofen was found to be less damaging than indomethacin at an equivalent dosage. However, based on the inducibility of cyclooxygenase-2 transcript expression, we were able to discriminate between responder individuals in which the deleterious effects observed with indomethacin were attenuated, and non-responder specimens in which the effects were similar to those observed with indomethacin. ATB-352 did not induce significant changes compared to ketoprofen on these metabolic pathways. Conclusions: These results show less damaging effects of ketoprofen compared to indomethacin on the immature intestine and indicate that the intestinal response to this NSAID significantly varies between individuals. However the results did not allow us to demonstrate a specific beneficial effect of H2S release in organ culture. Address correspondence and reprint requests to Jean-François Beaulieu, Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4 (. e-mail: Jean-Francois.Beaulieu@USherbrooke.ca). This is an open-access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https://ift.tt/1eRPUFd Received 17 July, 2018 Accepted 15 January, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.jpgn.org). Conflicts of Interest and Source of Funding: This work was supported by grants from the Canadian Institutes of Health Research and the Star Foundation. JFB was the recipient of the Canada Research Chair in Intestinal Physiopathology. JLW is Chief Scientific Officer for Antibe Therapeutics Inc. JLW's research is supported by an operating grant from the Canadian Institutes of Health Research. Author list and roles: Marie-Pier Thibault conducted a significant part of the work and to the drafting of the manuscript and contributed to the design of the study and interpretation of the data. Éric Tremblay contributed to the design of the study, interpretation of the data and revision of the manuscript. John L. Wallace contributed to specific aspects of the design of the study and revision of the manuscript. Jean-François Beaulieu contributed to the design of the study, interpretation of the data, and revising the manuscript. All authors approved the final version of the manuscript to be published. © 2019 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Disruption of the PTHLH regulatory landscape results in features consistent with hyperparathyroid disease

Parathyroid hormone like hormone (PTHLH) signaling is essential for the proper formation of bone and its elevation or disruption has been directly implicated in several different skeletal dysplasias. We report a patient with a 2.802 Mb deletion upstream of the PTHLH coding sequence who presents with multiple fractures, metaphyseal changes, and overall features consistent with hyperparathyroid like disease. Analysis of the deleted region revealed the loss of putative regulatory regions adjacent to PTHLH and the possible gain of a limb enhancer. Furthermore, PTHLH expression appeared to be mis‐regulated in fibroblasts derived from the patient. Altogether, we find that the disruption of the regulatory landscape of PTHLH likely results in its inappropriate expression and this novel clinical presentation.

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Cytosine methylation of mitochondrial DNA at CpG sequences impacts transcription factor A DNA binding and transcription

Publication date: Available online 23 February 2019

Source: Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms

Author(s): Vishantie Dostal, Mair E.A. Churchill

Abstract

In eukaryotes, cytosine methylation of nuclear DNA at CpG sequences (^5mCpG) regulates epigenetic inheritance through alterations in chromatin structure. However, mitochondria lack nucleosomal chromatin, therefore the molecular mechanisms by which ^5mCpG influences mitochondria must be different and are as yet unknown. Mitochondrial Transcription Factor A (TFAM) is both the primary DNA-compacting protein in the mitochondrial DNA (mtDNA) nucleoid and a transcription-initiation factor. TFAM must encounter hundreds of CpGs in mtDNA, so the occurrence of ^5mCpG has the potential to impact TFAM-DNA recognition. We used biophysical approaches to determine whether ^5mCpG alters any TFAM-dependent activities. ^5mCpG in the heavy strand promoter (HSP1) increased the binding affinity of TFAM and induced TFAM multimerization with increased cooperativity compared to nonmethylated DNA. However, ^5mCpG had no apparent effect on TFAM-dependent DNA compaction. Additionally, ^5mCpG had a clear and context-dependent effect on transcription initiating from the three mitochondrial promoters. Taken together, our findings demonstrate that ^5mCpG in the mitochondrial promoter region does impact TFAM-dependent activities in vitro.

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Coming full circle in cancer

Coming full circle in cancer

Coming full circle in cancer, Published online: 25 February 2019; doi:10.1038/s41576-019-0104-8

Three new studies characterize circular RNAs in cancer, with potential functional roles and clinical implications as biomarkers.

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The genome-wide landscape of small insertion and deletion mutations in Monopterus albus

Publication date: Available online 23 February 2019

Source: Journal of Genetics and Genomics

Author(s): Feng Chen, Fengling lai, Majing Luo, Yu-San Han, Hanhua Cheng, Rongjia Zhou

Abstract

Insertion and deletion (indel) mutations, which can trigger single nucleotide substitutions on the flanking regions of genes, may generate abundant materials for disease defense, reproduction, species survival and evolution. However, genetic and evolutionary mechanisms of indels remain elusive. We establish a comparative genome-transcriptome-alignment approach for a large-scale identification of indels in Monopterus population. Over 2000 indels in 1738 indel genes, including 1‒21 bp deletions and 1‒15 bp insertions, were detected. Each indel gene had ∼1.1 deletions/insertions, and 2‒4 alleles in population. Frequencies of deletions were prominently higher than those of insertions on both genome and population levels. Most of the indels led to in frame mutations with multiples of three and majorly occurred in non-domain regions, indicating functional constraint or tolerance of the indels. All indel genes showed higher expression levels than non-indel genes during sex reversal. Slide window analysis of global expression levels in gonads showed a significant positive correlation with indel density in the genome. Moreover, indel genes were evolutionarily conserved and evolved slowly compared to non-indel genes. Notably, population genetic structure of indels revealed divergent evolution of Monopterus population, as bottleneck effect of biogeographic isolation by Taiwan Strait.

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Distinct functions of Trio GEF domains in axon outgrowth of cerebellar granule neurons

Publication date: Available online 23 February 2019

Source: Journal of Genetics and Genomics

Author(s): Tao Tao, Jie Sun, Yajing Peng, Pei Wang, Xin Chen, Wei Zhao, Yeqiong Li, Lisha Wei, Wei Wang, Yan-Yan Zheng, Ye Wang, Xuena Zhang, Min-Sheng Zhu

Abstract

As a critical guanine nucleotide exchange factor (GEF) regulating neurite outgrowth, Trio coordinates multiple processes of cytoskeletal dynamics through activating Rac1, Cdc42 and RhoA small GTPases by two GEF domains, but the in vivo roles of these GEF domains and corresponding downstream effectors have not been determined yet. We established multiple lines of knockout mice and assessed the respective roles of Trio GEF domains and Rac1 in axon outgrowth. Knockout of total Trio in cerebellar granule neurons (CGNs) led to an impaired F-actin rearrangement of growth cone and hence a retarded neurite outgrowth. Such a retardation was reproduced by inhibition of GEF1 domain or knockdown of Cdc42 and restored apparently by introduction of active Cdc42. As Rac1 deficiency did not affect the neurite outgrowth of CGNs, we suggested that Trio GEF1-mediated Cdc42 activation was required for neurite outgrowth. We established a GEF2-knockout line with deletion of all Trio isoforms except a cerebella-specific Trio8, a short isoform of Trio without GEF2 domain, and used this line as a GEF2-deficient animal model. The GEF2-deficient CGNs had a normal neurite outgrowth but abolished Netrin-1-promoted growth, without affecting Netrin-1 induced Rac1 activation. We thus suggested that Trio GEF1-mediated Cdc42 activation rather than Rac1 activation drives the F-actin dynamics necessary for neurite outgrowth, while GEF2 functions in Netrin-1-promoted neurite elongation. Our results delineated the distinct roles of Trio GEF domains in neurite outgrowth, which is instructive to understand the pathogenesis of clinical Trio-related neurodevelopmental disorders.

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Comment on: “Effects of Carbohydrate Mouth Rinse on Cycling Time Trial Performance: A Systematic Review and Meta-Analysis”

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