Παρασκευή, 5 Ιανουαρίου 2018

Table of Contents



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Editorial Board



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Pneumocephalus and seizures following combined spinal-epidural for labor

Most cases of pneumocephalus following neuraxial blocks are associated with accidental dural puncture using loss of resistance to air for identification of the epidural space [1]. To our knowledge, there are no published reports in literature following use of saline for loss of resistance. We report the finding of simultaneous pneumocephalus and a cavernoma in a patient who received a combined spinal-epidural analgesia for labor, using loss of resistance to saline (LORS). The patient provided written consent for the authors to publish this report.

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Nasotracheal intubation through pharyngeal flap after pharyngeal flap construction

A 24-year-old woman provided her written consent to publish the details of her case. She had undergone multiple surgeries including pharyngeal flap construction for bilateral cleft lip and palate. All previous operations were performed under general anesthesia by oral intubation. In the present procedure, sagittal split ramus osteotomy under general anesthesia with nasotracheal intubation was planned. We obtained the three-dimensional morphological structure of the pharyngeal flap (Fig. 1). The measurements of the cross-section at the narrowest were 5.1×12.8mm for the left orifice and 3.2×13.2mm for the right.

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Clinical experiences of unilateral anterior sub-costal quadratus lumborum block for a nephrectomy

Among several quadratus lumborum (QL) blocks, an anterior sub-costal QL block is a new technique, and there are only a few reports of this new approach in the literature [1,2]. In this case, we reported two cases in which we used the anterior sub-costal QL block for a nephrectomy.

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Clinical effects of prophylactic use of phentolamine in patients undergoing pheochromocytoma surgery

To the Editor,

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Emergency insertion of the LMA protector airway in patients in the lateral position

The LMAR Protector™ Airway (Teleflex Medical Japan, Tokyo, Protector), a new type of second generation airway, has an integrated cuff pressure indicator that allows continuous cuff pressure monitoring at a glance [1,2]. Continuous cuff pressure monitoring contributes to safe management in the perioperative period in all situations. Here, we report two cases in which the Protector was inserted in an emergency situation with the patient in the lateral position.

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Respiratory effect of interscalene brachial plexus block vs combined infraclavicular plexus block with suprascapular nerve block for arthroscopic shoulder surgery

Shoulder surgery typically results in moderate to severe postoperative pain, especially within the first 24h after surgery. The interscalene nerve block (ISB) is one of the most effective analgesic techniques for shoulder surgery. A common adverse effect after ISB remains the occurrence of ipsilateral phrenic nerve block. In the literature [1] diaphragm-sparing nerve blocks alternative to ISB for shoulder surgery, such as supraclavicular block, distal nerve blocks, intraarticular analgesia, has been reported; recently [2] a new combination of suprascapular nerve block (SSB) and infraclavicular block (ICB) seemed to provide surgical anesthesia and satisfactory postoperative analgesia, but, the respiratory effects of this technique are still not well documented.

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Under pressure: Evaluating the role of intraoperative hemodynamics in postoperative acute kidney injury

In this issue of Journal of Clinical Anesthesia, Wu et al. describe their well-designed randomized trial investigating the impact of targeted mean arterial pressure (MAP) ranges on postoperative acute kidney injury (AKI) [1]. Their study is of pressing concern: postoperative AKI remains a source of shared apprehension among anesthesiologists, surgeons, and nephrologists, for which prevention and treatment strategies are a matter of ongoing debate. The healthcare burden of postoperative AKI is well-described: it is common, costly, and life-threatening.

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Incidence of lower-extremity muscle weakness after quadratus lumborum block

Since the original publication on the quadratus lumborum (QL) block in 2013, various approaches for QL block administration have been reported [1,2]. Lower-extremity muscle weakness after a posterior QL block has been reported as a complication [3]. However, there have been no reports of lower-extremity muscle weakness after a QL block using other approaches. We investigated the incidence of lower-extremity muscle weakness after each type of QL block.

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Bilateral adductor canal block catheters in patients undergoing simultaneous bilateral knee arthroplasty: A series of 17 patients

Continuous adductor canal blocks (ACB) have been shown to reduce pain with knee flexion, decrease opioid consumption, and enhance ambulation following total knee arthroplasty [1]. Of the patients who undergo bilateral knee arthroplasties, a small subset have the procedures performed during the same operative encounter rather than a staged procedure [2]. These patients present additional perioperative pain and rehabilitation challenges, in addition to a longer length of hospital stay [2,3]. Adequate analgesia is imperative for immediate postoperative rehabilitation; however, there is a paucity of research regarding regional techniques for simultaneous bilateral knee arthroplasty (SBKA).

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Lack of generalizability of observational studies' findings for turnover time reduction and growth in surgery based on the State of Iowa, where from one year to the next, most growth was attributable to surgeons performing only a few cases per week

Three observational studies at large teaching hospitals found that reducing turnover times resulted in the surgeons performing more cases. We sought to determine if these findings are generalizable to other hospitals, because, if so, reducing turnover times may be an important mechanism for hospitals to use for growing caseloads.

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Lidocaine post-nasal dripping (LPND): An easy way for awake nasal intubation

Several techniques of topical anesthesia for awake fiberoptic intubation (AFOI) have been described such as "spray as you go" [1,2], nebulization [2], atomization [3,4] transtracheal injection [5]. These require multiple complicated steps [1,2], specialized equipment [2–4], and are invasive [5].

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Severe type B lactic acidosis and insulin-resistant hyperglycemia related to cadaveric kidney transplantation

Lactic acidosis, increased lactate levels >2mmol/L with a high anion gap metabolic acidosis, commonly occurs due to hypoperfusion/hypoxia (type A) but may also arise due to other causes, often overlooked, such as thiamine deficiency (type B) [1]. We report the perioperative occurrence of severe type B lactic acidosis with insulin-resistant hyperglycemia related to cadaveric kidney transplantation and its rapid resolution after intravenous thiamine administration. Written consent was obtained from the patient.

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Use of dexmedetomidine in a cardiac intensive care unit

Delirium, pain and agitation, known as the "triad of Intensive Care Units (ICU)" [1] are very common in critical patients. At least 20% of patients develop delirium during their stay in the ICU, reaching 80% in those receiving mechanical ventilation [2]. There is a need to identify these patients for appropriate treatment and prevention, as this neuronal dysfunction is associated with increased mortality, length of hospitalization, dependency and disability at discharge [3,4].

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Videolaryngoscope versus Macintosh laryngoscope for tracheal intubation in adults with obesity: A systematic review and meta-analysis

Videolaryngoscopy has become more common since the 2000s. Despite several anecdotal reports in the literature, it remains unclear whether videolaryngoscopy is superior to direct Macintosh laryngoscopy for tracheal intubation in adults with obesity. This systematic review and meta-analysis focused on prospective randomised trials comparing videolaryngoscopes with the Macintosh laryngoscope for tracheal intubation in adults with obesity.

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Retroclavicular approach to infraclavicular brachial plexus block for distal radius fracture in a patient with implanted pacemaker

Patients with implanted pacemaker underwent upper limb surgery under regional anesthesia in the literature are rarely. We report a case of successful retroclavicular approach to infraclavicular brachial plexus block (RA-IBPB) in a patient with implanted pacemaker and with requiring open osteosynthesis due to distal radius fracture.

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Anesthetic management for laparoscopic sleeve gastrectomy to a child

Anesthesia for obese children undergoing weight loss surgery poses a challenge for the anesthetists given that this population has high risk of developing psychosocial and medical comorbidities such as pulmonary and cardiovascular disorders, hypertension, dyslipidemia, obstructive sleep apnea and type 2 diabetes mellitus [1–3].

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Ketorolac dose-response for acute pain is well known and the safety rules for adequate prescribing are clear

The study by Duttchen et al. [1] shows almost no difference in analgesic efficacy when comparing 15 and 30mg of IV ketorolac given intraoperatively to provide postoperative pain relief. In the discussion, the authors indicate that another 2017 study performed in an emergency department similarly showed that in patients with acute pain 10, 15 and 30mg are of similar analgesic efficacy [2], suggesting that these data are new.

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Takotsubo cardiomyopathy complicating thoracoabdominal aortic aneurysm repair

We describe the management of a patient with symptomatic spinal cord hypoperfusion after thoracoabdominal aortic aneurysm repair, where the neurological insult and associated emotional stress precipitated Takotsubo cardiomyopathy. Transthoracic Echocardiography showed akinetic mid and apical left ventricular segments, while basal segments were spared. Emergent coronary angiography ruled out acute coronary syndrome. Excess catecholamines have been postulated as a contributing mechanism to the disease, therefore, catecholamines were avoided to prevent further myocardial injury.

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High Prevalence and Temporal Variation of Extended Spectrum β-Lactamase–Producing Bacteria in Urban Swedish Mallards

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


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Unintended Side Effects of Transformation Are Very Rare in Cryptococcus neoformans

Received wisdom in the field of fungal biology holds that the process of editing a genome by transformation and homologous recombination is inherently mutagenic. However, that belief is based on circumstantial evidence. We provide the first direct measurement of the effects of transformation on a fungal genome by sequencing the genomes of 29 transformants and 30 untransformed controls to high coverage. Contrary to the received wisdom, our results show that transformation of DNA segments flanked by long targeting sequences, followed by homologous recombination and selection for a drug marker, is extremely safe. If a transformation deletes a gene, that may create selective pressure for a few compensatory mutations, but even when we deleted a gene we found fewer than two point mutations per deletion strain, on average. We also tested these strains for changes in gene expression and found only a few genes that were consistently differentially expressed between wild type and strains modified by genomic insertion of a drug resistance marker. As part of our report, we provide the assembled genome sequence of the commonly used laboratory strain Cryptococcus neoformans var. grubii strain KN99α.



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Local Anesthetic Systemic Toxicity: A Review of Recent Case Reports and Registries

This review summarizes presenting features, management, and outcomes of local anesthetic systemic toxicity (LAST) from published cases and those submitted to online registries capturing use of intravenous lipid emulsion (ILE) therapy. The results of single-center and multicenter registries and epidemiologic studies complement this information. Between March 2014 and November 2016, 47 separate cases of LAST were described in 35 peer-reviewed articles. Local anesthetic systemic toxicity events occurred as a result of penile blocks (23%), local infiltration (17%), and upper/lower extremity, torso, and neuraxial blockade. Twenty-two patients (47%) were treated with ILE, and 2 patients (4.3%) died. During the same time period, 11 cases submitted to lipidrescue.org were treated with ILE and survived. The incidence of LAST reported in registries is 0.03% or 0.27 (95% confidence interval, 0.21–0.35) per 1000 peripheral nerve blocks (denominator of 251,325). Seizure (53% and 61% from case reports and registries, respectively) was the most common presenting feature. Accepted for publication October 9, 2017. Address correspondence to: Marina Gitman, MD, Department of Anesthesiology, College of Medicine, University of Illinois, 1740 W Taylor St, Suite 3200 W, Chicago, IL 60612 (e-mail: gitman@uic.edu). The authors declare no conflict of interest. Copyright © 2018 by American Society of Regional Anesthesia and Pain Medicine.

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A novel noninvasive index for the prediction of moderate to severe fibrosis in chronic hepatitis B patients

The evaluation of liver fibrosis stages is essential for the clinical management of chronic hepatitis B (CHB).

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A novel noninvasive index for the prediction of moderate to severe fibrosis in chronic hepatitis B patients

The evaluation of liver fibrosis stages is essential for the clinical management of chronic hepatitis B (CHB).

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The efficacy of pre-operative preparation with intravenous iron and/or erythropoietin in anaemic patients undergoing orthopaedic surgery: An observational study

BACKGROUND Pre-operative anaemia and transfusion are common among patients undergoing elective orthopaedic surgery. Application of 'patient blood management' might be the most effective way to reduce both anaemia and transfusion. Pre-operative administration of iron and/or erythropoietin (EPO) is one of the cornerstones of the first pillar of patient blood management, but in a daily clinical setting, efficacy and long-term safety of this measure have not been analysed thoroughly to date. OBJECTIVE To investigate the influence of pre-operative preparation (PREP) of patients with iron and/or EPO on peri-operative transfusion needs and long-term survival. DESIGN AND METHODS This was a single-centre, retrospective study. After approval of our local ethics committee, data of 5518 patients who received total hip or total knee replacement between 2008 and 2014 were included. Patients receiving iron and/or EPO were included in the PREP group, whereas patients without iron and/or EPO were included in the no preparation group. From the full data set, a bias-reduced subset of 662 patients was obtained by means of propensity score-matching to compare peri-operative red blood cell utilisation and long-term survival of patients between groups. RESULTS Patients in the PREP group needed a lower number of units of red blood cells than patients in the no preparation group (0.2 ± 0.8 vs. 0.5 ± 1.3, P 

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Effect of pressure-controlled inverse ratio ventilation on dead space during robot-assisted laparoscopic radical prostatectomy: A randomised crossover study of three different ventilator modes

BACKGROUND Pressure-controlled inverse inspiratory to expiratory ratio ventilation (PC-IRV) is thought to be beneficial for reducing the dead space volume. OBJECTIVE To investigate the effects of PC-IRV on the components of dead space during robot-assisted laparoscopic radical prostatectomy (RLRP). DESIGN A randomised crossover study of three different ventilator modes. SETTING A single university hospital from September 2014 to April 2015. PATIENTS Twenty consecutive study participants undergoing RLRP. INTERVENTIONS Patients were ventilated sequentially with three different modes in random order for 30 min: volume control ventilation (VCV; inspiratory to expiratory ratio 0.5), pressure control ventilation (PCV; inspiratory to expiratory ratio 0.5) and PC-IRV. Inverse inspiratory to expiratory ratio was adjusted individually by observing the expiratory flow-time wave to prevent the risk of dynamic pulmonary hyperinflation. MAIN OUTCOME MEASURES The primary outcome included physiological dead space (VDphys), airway dead space (VDaw), alveolar dead space (VDalv) and shunt dead space (VDshunt). VDphys was calculated by Enghoff's method. We also analysed respiratory dead space (VDresp) and VDaw using a novel analytical method. Then, VDalv and VDshunt were calculated by VDalv = VDresp − VDaw and VDshunt = VDphys − VDresp, respectively. RESULTS The VDphys/expired tidal volume (VTE) ratio in PC-IRV (29.2 ± 4.7%) was significantly reduced compared with that in VCV (43 ± 8.5%) and in PCV (35.9 ± 3.9%). The VDshunt/VTE in PC-IRV was significantly smaller than that in VCV and PCV. VDaw/VTE in PC-IRV was also significantly smaller than that in VCV but not that in PCV. There was no significant change in VDalv/VTE. CONCLUSION PC-IRV with the inspiratory to expiratory ratio individually adjusted by the expiratory flow-time wave decreased VDphys/VTE in patients undergoing RLRP. TRIAL REGISTRATION University Hospital Medical Information Network in Japan 000014004. Correspondence to Go Hirabayashi, MD, Department of Anaesthesiology, Mizonokuchi Hospital, Teikyo University School of Medicine, 3–8–3 Mizonokuchi, Takatsu-ku, Kawasaki, Kanagawa 213–8507, Japan Tel: +81 44 844 3333; fax: +81 44 844 3390; e-mail: hirabayashi1967@gmail.com Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://ift.tt/2ylyqmW). © 2018 European Society of Anaesthesiology

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Exploring the use of educational material about shoulder dysfunction: a Quality Improvement project in people with ALS

Shoulder pain is a common secondary complication of amyotrophic lateral sclerosis (ALS) that can contribute to functional decline and decreased participation in daily activities. The purpose of this study was to assess the effectiveness of an educational brochure aimed at improving knowledge regarding shoulder pain and dysfunction in people with ALS. Participants completed a pre-intervention survey with questions regarding their knowledge of how ALS may affect their shoulders. After completing the pre-survey, they were mailed a brochure that described shoulder health and range of motion and stretching exercises. Four weeks after receiving the brochure, participants were then asked to determine the effectiveness of the educational materials in terms of impact on shoulder-related knowledge and self-efficacy with regards to prevention of shoulder pain and dysfunction. More than 50% of participants reported pain, decreased range of motion, or weakness in at least one shoulder since being diagnosed with ALS. All participants were interested in receiving educational materials and all agreed that the brochure was easy to interpret and understand, with most (87%) reporting it was helpful. Educational brochures are one strategy to improve awareness about shoulder health and to educate ALS patients about exercises that may help reduce shoulder pain and dysfunction. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Funding: Sabrina Paganoni has been funded by the NIH (Career Development Award 2K12HD001097-16). The authors report no conflicts of interest. *Corresponding author: Sabrina Paganoni, MD, PhD, Harvard Medical School, Neurological Clinical Research Institute (NCRI), Massachusetts General Hospital, 165 Cambridge St, Suite 600, Boston, MA 02114, Ph: (617) 643-3452; Fax: (617) 724-7290. Email: spaganoni@partners.org Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Abulia due to injury of the prefrontocaudate tract in a stroke patient

No abstract available

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Adding HRV biofeedback to psychotherapy increases heart rate variability and improves the treatment of major depressive disorder

Publication date: Available online 5 January 2018
Source:International Journal of Psychophysiology
Author(s): Yoko Tsui Caldwell, Patrick R. Steffen
Heart rate variability (HRV) is a significant marker of health outcomes with decreased HRV predicting increased disease risk. HRV is decreased in major depressive disorder (MDD) but existing treatments for depression do not return heart rate variability to normal levels even with successful treatment of depression. Heart rate variability biofeedback (HRVB) increases heart rate variability but no studies to date have examined whether combining HRVB with psychotherapy improves outcome in MDD treatment. The present study used a randomized controlled design to compare the effects of HRVB combined with psychotherapy on MDD relative to a psychotherapy treatment as usual group and to a non-depressed control group. The HRVB+psychotherapy group showed a larger increase in HRV and a larger decrease in depressive symptoms relative to the other groups over a six-week period, whereas the psychotherapy group only did not improve HRV. Results support the supplementation of psychotherapy with HRVB in the treatment of MDD.



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Pa. EMS agency gets equipped with body armor

"You never know what you're getting into on a daily basis," Chief Robert Weidner said. "I'd rather come home to my family at the end of a shift"

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Effect of Age and Sex on Hospital Readmission in Traumatic Brain Injury

Publication date: Available online 4 January 2018
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Chih-Ying Li, Amol Karmarkar, Deepak Adhikari, Kenneth Ottenbacher, Yong-Fang Kuo
ObjectiveTo investigate the impact of age and sex on 30-, 60- and 90-day hospital readmission after acute hospital discharge for individuals with traumatic brain injury (TBI).DesignRetrospective cohort study.SettingAcute hospitals and post-acute discharge settingsParticipantsFrom the 2013 Nationwide Readmissions Database, we retrieved information on 52,877 individuals with diagnosis-related group codes of TBI. We included only those alive at index acute discharge and excluded those discharged with same-day readmission. We divided our sample into four age groups: 18-40, 41-65, 66-75 and 76+ years old.InterventionsNA.Main Outcome Measure(s)All-cause hospital readmission.ResultsSex differences in 30-, 60- and 90-day hospital readmission were found for all age groups (all p<.05). The largest sex differences in hospital readmission were in the two oldest groups (66-75, 76+). For both sexes, the oldest group (76+) had the highest adjusted 90-day readmission risk [e.g., 90-day readmission: Odds Ratio (OR) = 2.32 (2.01-2.69) for males; OR=1.96 (1.59-2.43) for females]. Among those readmitted within 90 days, the youngest group (18-40 years) had the highest cumulative readmission percent (35% for both sexes) within the first week post-hospital discharge.ConclusionAge and sex were significantly associated with hospital readmission during the first 90 days post-discharge in our TBI sample. Specifically, those aged 66-75 or 76+ had the highest readmission risk over 90 days for both sexes. The findings suggest that clinicians should consider age and sex in discharge planning and for the entire episode of care for the TBI population.



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Neurodynamic techniques versus “sham” therapy in the treatment of carpal tunnel syndrome; a randomized placebo-controlled trial

Publication date: Available online 4 January 2018
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Tomasz Wolny, Paweł Linek
ObjectivesTo evaluate the efficacy of neurodynamic techniques used as the sole therapeutic component compared with "sham" therapy in the treatment of mild and moderatecarpal tunnel syndromes (CTS).DesignSingle blinded, randomized placebo-controlled trial.SettingSeveral medical clinics in the south of Poland.ParticipantsVolunteer sample of 150 patients diagnosed with CTS.Main Outcome MeasuresSymptom severity (SSS) and Functional status (FSS) of Boston Carpal Tunnel Questionnaire (BCTQ).InterventionNeurodynamic techniques were used in the NT (neurodynamic techniques) group, and "sham" therapy was used in the ST ("sham" therapy) group.In neurodynamic techniques, the neurodynamic sequence were used and sliding and tension techniques were used. In "sham"therapy, no neurodynamic sequences were used and therapeutic procedures were performed in an intermediate position. Therapy was conducted twice weekly for a total of 20 therapy sessions.ResultsA baseline assessment revealed no inter-group differences in all examined parameters (p>0.05). After therapy, there was statisticant intra-group improvement in NCS (sensory and motor conduction velocity, motor latency) only for the NT group (p<0.01). After therapy, intra-group statisticant changes also occurred for the NT group in pain assessment, 2PD, SSS and FSS (in all cases p<0.01). There were no group differences in assessment of grip and pinch strength(p>0.05).ConclusionThe use of neurodynamic techniques has a better therapeutic effect compared to "sham" therapy in the treatment of mild and moderate forms of CTS.



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Dose and duration of opioid use in propensity score matched, privately insured opioid users with and without spinal cord injury

Publication date: Available online 4 January 2018
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Brittany N. Hand, James S. Krause, Kit N. Simpson
ObjectiveThe objectives were to: 1) compare the opioid utilization patterns in opioid users with spinal cord injury (SCI) to a propensity score matched general population of opioid users without SCI and 2) identify characteristics of persons with SCI associated with long-term and/or high-dose use of opioids.DesignQuasi-experimental analysis of archival dataSettingData used for the analysis were derived from Thompson Reuters MarketScan® Commercial Claims and Encounters Databases for the years 2012-2013.ParticipantsParticipants (aged 18-64 years) included 1,454 opioid users with SCI and 1,454 propensity score matched opioid users without SCI. The cohorts were matched using demographics including comorbidities, hospital admissions, age, gender, and geographic region.Interventionsn/aMain Outcome MeasuresMedical and pharmacy claims from 2012-2013 MarketScan data were analyzed to characterize whether persons were short term (<90 days) or long-term (≥90 days) opioid users and whether persons had high (≥120 mg) or low (<120 mg) average daily morphine equivalents.ResultsResults indicated persons with SCI were significantly more likely to be long-term users of low-dose short-acting opioids (p<0.0001) and more likely to be on high morphine equivalent doses of long-acting opioids (p<0.0001) than matched controls. Among persons with SCI, those with lumbar/sacral injuries had more days' supply of high-dose long-acting opioids than did persons with thoracic or cervical injuries.ConclusionPersons with SCI are prescribed opioids for longer durations of time and at higher morphine equivalent doses than controls, which may increase risk of opioid dependence or adverse drug events. Findings should be considered in the development of practice guidelines for alternate pain management options or opioid dependence interventions for persons with SCI.



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MicroRNA Tissue Atlas of the Malaria Mosquito Anopheles gambiae

Anopheles gambiae mosquitoes transmit the human malaria parasite Plasmodium falciparum, which causes the majority of fatal malaria cases worldwide. The hematophagous lifestyle defines mosquito reproductive biology and is exploited by P. falciparum for its own sexual reproduction and transmission. The two main phases of the mosquito reproductive cycle, previtellogenic (PV) and postblood meal (PBM), shape its capacity to transmit malaria. Transition between these phases is tightly coordinated to ensure homeostasis between mosquito tissues and successful reproduction. One layer of control is provided by microRNAs (miRNAs), well-known regulators of blood meal digestion and egg development in Aedes mosquitoes. Here, we report a global overview of tissue-specific miRNAs (miRNA) expression during the PV and PBM phases and identify miRNAs regulated during PV to PBM transition. The observed coordinated changes in the expression levels of a set of miRNAs in the energy-storing tissues suggest a role in the regulation of blood meal-induced metabolic changes.



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The Substrates of Nonsense-Mediated mRNA Decay in Caenorhabditis elegans

Nonsense-mediated mRNA decay (NMD) is a conserved pathway that strongly influences eukaryotic gene expression. Inactivating or inhibiting NMD affects the abundance of a substantial fraction of the transcriptome in numerous species. Transcripts whose abundance is altered in NMD-deficient cells may represent either direct substrates of NMD or indirect effects of inhibiting NMD. We present a genome-wide investigation of the direct substrates of NMD in Caenorhabditis elegans. Our goals were (i) to identify mRNA substrates of NMD and (ii) to distinguish those mRNAs from others whose abundance is indirectly influenced by the absence of NMD. We previously demonstrated that Upf1p/SMG-2, the central effector of NMD in all studied eukaryotes, preferentially associates with mRNAs that contain premature translation termination codons. We used this preferential association to distinguish direct from indirect effects by coupling immunopurification of Upf1/SMG-2 with high-throughput mRNA sequencing of NMD-deficient mutants and NMD-proficient controls. We identify 680 substrates of NMD, 171 of which contain novel spliced forms that (i) include sequences of annotated introns and (ii) have not been previously documented in the C. elegans transcriptome. NMD degrades unproductively spliced mRNAs with sufficient efficiency in NMD-proficient strains that such mRNAs were not previously known. Two classes of genes are enriched among the identified NMD substrates: (i) mRNAs of expressed pseudogenes and (ii) mRNAs of gene families whose gene number has recently expanded in the C. elegans genome. Our results identify novel NMD substrates and provide a context for understanding NMD's role in normal gene expression and genome evolution.



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The Complexities and Nuances of Analyzing the Genome of Drosophila ananassae and Its Wolbachia Endosymbiont

In "Retrotransposons Are the Major Contributors to the Expansion of the Drosophila ananassae Muller F Element," Leung et al. (2017) improved contigs attributed to the Muller F element from the original CAF1 assembly, and used them to conclude that most of the sequence expansion of the fourth chromosome of D. ananassae is due to a higher transposon load than previously thought, but is not due to Wolbachia DNA integrations. While we do not disagree with the first conclusion, the authors base their second conclusion on the lack of homology detected between their improved CAF1 genome assembly attributed to D. ananassae and reference Wolbachia genomes. While the consensus CAF1 genome assembly lacks any sequence similarity to the reference genome of the Wolbachia endosymbiont of Drosophila melanogaster (wMel), numerous studies from multiple laboratories provide experimental support for a large lateral/horizontal gene transfer (LGT) of a Wolbachia genome into this D. ananassae line. As such, we strongly suspect that the original whole genome assembly was either constructed after the removal of all Wolbachia reads, or that Wolbachia sequences were directly removed from the contigs in the CAF1 assembly. Hence, Leung et al. (2017) could not have identified the Wolbachia LGT using the CAF1 assembly. This manuscript by Leung et al. (2017) highlights that an assembly of the Wolbachia sequence reads and their mate pairs was erroneously attributed solely to the Wolbachia endosymbiont, albeit before we understood the extent of LGT in D. ananassae. As such, we recommend that the sequences deposited at the National Center for Biotechnology Information (NCBI) under PRJNA13365 should not be attributed to Wolbachia endosymbiont of D. ananassae, but should have their taxonomy reclassified by NCBI as "Unclassified sequences." As our knowledge about genome biology improves, we need to reconsider and reanalyze earlier genomes removing the prejudice introduced from now defunct paradigms.



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A Single Residue Mutation in the G{alpha}q Subunit of the G Protein Complex Causes Blindness in Drosophila

Heterotrimeric G proteins play central roles in many signaling pathways, including the phototransduction cascade in animals. However, the degree of involvement of the G protein subunit Gαq is not clear since animals with previously reported strong loss-of-function mutations remain responsive to light stimuli. We recovered a new allele of q in Drosophila that abolishes light response in a conventional electroretinogram assay, and reduces sensitivity in whole-cell recordings of dissociated cells by at least five orders of magnitude. In addition, mutant eyes demonstrate a rapid rate of degeneration in the presence of light. Our new allele is likely the strongest hypomorph described to date. Interestingly, the mutant protein is produced in the eyes but carries a single amino acid change of a conserved hydrophobic residue that has been assigned to the interface of interaction between Gαq and its downstream effector, PLC. Our study has thus uncovered possibly the first point mutation that specifically affects this interaction in vivo.



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Response to the Letter to the Editor by Dunning Hotopp and Klasson



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Caenorhabditis elegans DBL-1/BMP Regulates Lipid Accumulation via Interaction with Insulin Signaling

Metabolic homeostasis is coordinately controlled by diverse inputs. Understanding these regulatory networks is vital to combating metabolic disorders. The nematode Caenorhabditis elegans has emerged as a powerful, genetically tractable model system for the discovery of lipid regulatory mechanisms. Here we introduce DBL-1, the C. elegans homolog of bone morphogenetic protein 2/4 (BMP2/4), as a significant regulator of lipid homeostasis. We used neutral lipid staining and a lipid droplet marker to demonstrate that both increases and decreases in DBL-1/BMP signaling result in reduced lipid stores and lipid droplet count. We find that lipid droplet size, however, correlates positively with the level of DBL-1/BMP signaling. Regulation of lipid accumulation in the intestine occurs through non-cell-autonomous signaling, since expression of SMA-3, a Smad signal transducer, in the epidermis (hypodermis) is sufficient to rescue the loss of lipid accumulation. Finally, genetic evidence indicates that DBL-1/BMP functions upstream of Insulin/IGF-1 Signaling in lipid metabolism. We conclude that BMP signaling regulates lipid metabolism in C. elegans through interorgan signaling to the Insulin pathway, shedding light on a less well-studied regulatory mechanism for metabolic homeostasis.



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Mating Design and Genetic Structure of a Multi-Parent Advanced Generation Intercross (MAGIC) Population of Sorghum (Sorghum bicolor (L.) Moench)

Multi-parent advanced generation intercross (MAGIC) populations are powerful next-generation mapping resources. We describe here the mating design and structure of the first MAGIC population in sorghum, and test its utility for mapping. The population was developed by intercrossing 19 diverse founder lines through a series of paired crosses with a genetic male sterile (MS) source, followed by 10 generations of random mating. At the final stage of random mating, 1000 random fertile plants in the population were identified and subjected to six generations of selfing to produce 1000 immortal MAGIC inbred lines. The development of this sorghum MAGIC population took over 15 yr. Genotyping-by-sequencing (GBS) of a subset of 200 MAGIC lines identified 79,728 SNPs, spanning high gene-rich regions. Proportion of SNPs per chromosome ranged from 6 to 15%. Structure analyses produced no evidence of population stratification, portraying the desirability of this population for genome-wide association studies (GWAS). The 19 founders formed three clusters, each with considerable genetic diversity. Further analysis showed that 73% of founder alleles segregated in the MAGIC population. Linkage disequilibrium (LD) patterns depicted the MAGIC population to be highly recombined, with LD decaying to r2$$\le $$ 0.2 at 40 kb and down to r2$$\le $$ 0.1 at 220 kb. GWAS detected two known plant height genes, DWARF1 (chromosome 9) and DWARF3 (chromosome 7), and a potentially new plant height quantitative trait locus (QTL) (QTL-6) on chromosome 6. The MAGIC population was found to be rich in allelic content with high fragmentation of its genome, making it fit for both gene mapping and effective marker-assisted breeding.



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Rapid Gene Family Evolution of a Nematode Sperm Protein Despite Sequence Hyper-conservation

Reproductive proteins are often observed to be the most rapidly evolving elements within eukaryotic genomes. The major sperm protein (MSP) is unique to the phylum Nematoda and is required for proper sperm locomotion and fertilization. Here, we annotate the MSP gene family and analyze their molecular evolution in 10 representative species across Nematoda. We show that MSPs are hyper-conserved across the phylum, having maintained an amino acid sequence identity of 83.5–97.7% for over 500 million years. This extremely slow rate of evolution makes MSPs some of the most highly conserved genes yet identified. However, at the gene family level, we show hyper-variability in both gene copy number and genomic position within species, suggesting rapid, lineage-specific gene family evolution. Additionally, we find evidence that extensive gene conversion contributes to the maintenance of sequence identity within chromosome-level clusters of MSP genes. Thus, while not conforming to the standard expectation for the evolution of reproductive proteins, our analysis of the molecular evolution of the MSP gene family is nonetheless consistent with the widely repeatable observation that reproductive proteins evolve rapidly, in this case in terms of the genomic properties of gene structure, copy number, and genomic organization. This unusual evolutionary pattern is likely generated by strong pleiotropic constraints acting on these genes at the sequence level, balanced against expansion at the level of the whole gene family.



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A Deconvolution Protocol for ChIP-Seq Reveals Analogous Enhancer Structures on the Mouse and Human Ribosomal RNA Genes

The combination of Chromatin Immunoprecipitation and Massively Parallel Sequencing, or ChIP-Seq, has greatly advanced our genome-wide understanding of chromatin and enhancer structures. However, its resolution at any given genetic locus is limited by several factors. In applying ChIP-Seq to the study of the ribosomal RNA genes, we found that a major limitation to resolution was imposed by the underlying variability in sequence coverage that very often dominates the protein–DNA interaction profiles. Here, we describe a simple numerical deconvolution approach that, in large part, corrects for this variability, and significantly improves both the resolution and quantitation of protein–DNA interaction maps deduced from ChIP-Seq data. This approach has allowed us to determine the in vivo organization of the RNA polymerase I preinitiation complexes that form at the promoters and enhancers of the mouse (Mus musculus) and human (Homo sapiens) ribosomal RNA genes, and to reveal a phased binding of the HMG-box factor UBF across the rDNA. The data identify and map a "Spacer Promoter" and associated stalled polymerase in the intergenic spacer of the human ribosomal RNA genes, and reveal a very similar enhancer structure to that found in rodents and lower vertebrates.



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Restorer-of-Fertility Mutations Recovered in Transposon-Active Lines of S Male-Sterile Maize

Mitochondria execute key pathways of central metabolism and serve as cellular sensing and signaling entities, functions that depend upon interactions between mitochondrial and nuclear genetic systems. This is exemplified in cytoplasmic male sterility type S (CMS-S) of Zea mays, where novel mitochondrial open reading frames are associated with a pollen collapse phenotype, but nuclear restorer-of-fertility (restorer) mutations rescue pollen function. To better understand these genetic interactions, we screened Activator-Dissociation (Ac-Ds), Enhancer/Suppressor-mutator (En/Spm), and Mutator (Mu) transposon-active CMS-S stocks to recover new restorer mutants. The frequency of restorer mutations increased in transposon-active stocks compared to transposon-inactive stocks, but most mutants recovered from Ac-Ds and En/Spm stocks were unstable, reverting upon backcrossing to CMS-S inbred lines. However, 10 independent restorer mutations recovered from CMS-S Mu transposon stocks were stable upon backcrossing. Many restorer mutations condition seed-lethal phenotypes that provide a convenient test for allelism. Eight such mutants recovered in this study included one pair of allelic mutations that were also allelic to the previously described rfl2-1 mutant. Targeted analysis of mitochondrial proteins by immunoblot identified two features that consistently distinguished restored CMS-S pollen from comparably staged, normal-cytoplasm, nonmutant pollen: increased abundance of nuclear-encoded alternative oxidase relative to mitochondria-encoded cytochrome oxidase and decreased abundance of mitochondria-encoded ATP synthase subunit 1 compared to nuclear-encoded ATP synthase subunit 2. CMS-S restorer mutants thus revealed a metabolic plasticity in maize pollen, and further study of these mutants will provide new insights into mitochondrial functions that are critical to pollen and seed development.



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Genome-Wide Mapping of Decay Factor-mRNA Interactions in Yeast Identifies Nutrient-Responsive Transcripts as Targets of the Deadenylase Ccr4

The Ccr4 (carbon catabolite repression 4)-Not complex is a major regulator of stress responses that controls gene expression at multiple levels, from transcription to mRNA decay. Ccr4, a "core" subunit of the complex, is the main cytoplasmic deadenylase in Saccharomyces cerevisiae; however, its mRNA targets have not been mapped on a genome-wide scale. Here, we describe a genome-wide approach, RNA immunoprecipitation (RIP) high-throughput sequencing (RIP-seq), to identify the RNAs bound to Ccr4, and two proteins that associate with it, Dhh1 and Puf5. All three proteins were preferentially bound to lowly abundant mRNAs, most often at the 3' end of the transcript. Furthermore, Ccr4, Dhh1, and Puf5 are recruited to mRNAs that are targeted by other RNA-binding proteins that promote decay and mRNA transport, and inhibit translation. Although Ccr4-Not regulates mRNA transcription and decay, Ccr4 recruitment to mRNAs correlates better with decay rates, suggesting it imparts greater control over transcript abundance through decay. Ccr4-enriched mRNAs are refractory to control by the other deadenylase complex in yeast, Pan2/3, suggesting a division of labor between these deadenylation complexes. Finally, Ccr4 and Dhh1 associate with mRNAs whose abundance increases during nutrient starvation, and those that fluctuate during metabolic and oxygen consumption cycles, which explains the known genetic connections between these factors and nutrient utilization and stress pathways.



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The Influence of Genetic Stability on Aspergillus fumigatus Virulence and Azole Resistance

Genetic stability is extremely important for the survival of every living organism, and a very complex set of genes has evolved to cope with DNA repair upon DNA damage. Here, we investigated the Aspergillus fumigatus AtmA (Ataxia-telangiectasia mutated, ATM) and AtrA kinases, and how they impact virulence and the evolution of azole resistance. We demonstrated that A. fumigatus atmA and atrA null mutants are haploid and have a discrete chromosomal polymorphism. The atmA and atrA strains are sensitive to several DNA-damaging agents, but surprisingly both strains were more resistant than the wild-type strain to paraquat, menadione, and hydrogen peroxide. The atmA and atrA genes showed synthetic lethality emphasizing the cooperation between both enzymes and their consequent redundancy. The lack of atmA and atrA does not cause any significant virulence reduction in A. fumigatus in a neutropenic murine model of invasive pulmonary aspergillosis and in the invertebrate alternative model Galleria mellonela. Wild-type, atmA, and atrA populations that were previously transferred 10 times in minimal medium (MM) in the absence of voriconazole have not shown any significant changes in drug resistance acquisition. In contrast, atmA and atrA populations that similarly evolved in the presence of a subinhibitory concentration of voriconazole showed an ~5–10-fold increase when compared to the original minimal inhibitory concentration (MIC) values. There are discrete alterations in the voriconazole target Cyp51A/Erg11A or cyp51/erg11 and/or Cdr1B efflux transporter overexpression that do not seem to be the main mechanisms to explain voriconazole resistance in these evolved populations. Taken together, these results suggest that genetic instability caused by atmA and atrA mutations can confer an adaptive advantage, mainly in the intensity of voriconazole resistance acquisition.



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Rapid and Efficient CRISPR/Cas9-Based Mating-Type Switching of Saccharomyces cerevisiae

Rapid and highly efficient mating-type switching of Saccharomyces cerevisiae enables a wide variety of genetic manipulations, such as the construction of strains, for instance, isogenic haploid pairs of both mating-types, diploids and polyploids. We used the CRISPR/Cas9 system to generate a double-strand break at the MAT locus and, in a single cotransformation, both haploid and diploid cells were switched to the specified mating-type at ~80% efficiency. The mating-type of strains carrying either rod or ring chromosome III were switched, including those lacking HMLα and HMRa cryptic mating loci. Furthermore, we transplanted the synthetic yeast chromosome V to build a haploid polysynthetic chromosome strain by using this method together with an endoreduplication intercross strategy. The CRISPR/Cas9 mating-type switching method will be useful in building the complete synthetic yeast (Sc2.0) genome. Importantly, it is a generally useful method to build polyploids of a defined genotype and generally expedites strain construction, for example, in the construction of fully a/a/α/α isogenic tetraploids.



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Severe Fertility Effects of sheepish Sperm Caused by Failure To Enter Female Sperm Storage Organs in Drosophila melanogaster

In Drosophila, mature sperm are transferred from males to females during copulation, stored in the sperm storage organs of females, and then utilized for fertilization. Here, we report a gene named sheepish (shps) of Drosophila melanogaster that is essential for sperm storage in females. shps mutant males, although producing morphologically normal and motile sperm that are effectively transferred to females, produce very few offspring. Direct counts of sperm indicated that the primary defect was correlated to failure of shps sperm to migrate into the female sperm storage organs. Increased sperm motion parameters were seen in the control after transfer to females, whereas sperm from shps males have characteristics of the motion parameters different from the control. The few sperm that occasionally entered the female sperm storage organs showed no obvious defects in fertilization and early embryo development. The female postmating responses after copulation with shps males appeared normal, at least with respect to conformational changes of uterus, mating plug formation, and female remating rates. The shps gene encodes a protein with homology to amine oxidases, including as observed in mammals, with a transmembrane region at the C-terminal end. The shps mutation was characterized by a nonsense replacement in the third exon of CG13611, and shps was rescued by transformants of the wild-type copy of CG13611. Thus, shps may define a new class of gene responsible for sperm storage.



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Genotyping by Sequencing in Almond: SNP Discovery, Linkage Mapping, and Marker Design

In crop plant genetics, linkage maps provide the basis for the mapping of loci that affect important traits and for the selection of markers to be applied in crop improvement. In outcrossing species such as almond (Prunus dulcis Mill. D. A. Webb), application of a double pseudotestcross mapping approach to the F1 progeny of a biparental cross leads to the construction of a linkage map for each parent. Here, we report on the application of genotyping by sequencing to discover and map single nucleotide polymorphisms in the almond cultivars "Nonpareil" and "Lauranne." Allele-specific marker assays were developed for 309 tag pairs. Application of these assays to 231 Nonpareil x Lauranne F1 progeny provided robust linkage maps for each parent. Analysis of phenotypic data for shell hardness demonstrated the utility of these maps for quantitative trait locus mapping. Comparison of these maps to the peach genome assembly confirmed high synteny and collinearity between the peach and almond genomes. The marker assays were applied to progeny from several other Nonpareil crosses, providing the basis for a composite linkage map of Nonpareil. Applications of the assays to a panel of almond clones and a panel of rootstocks used for almond production demonstrated the broad applicability of the markers and provide subsets of markers that could be used to discriminate among accessions. The sequence-based linkage maps and single nucleotide polymorphism assays presented here could be useful resources for the genetic analysis and genetic improvement of almond.



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Rice TSV3 Encoding Obg-Like GTPase Protein Is Essential for Chloroplast Development During the Early Leaf Stage Under Cold Stress

The Spo0B-associated GTP-binding (Obg) proteins are essential for the viability of nearly all bacteria. However, the detailed roles of Obg proteins in higher plants have not yet been elucidated. In this study, we identified a novel rice (Oryza sativa L.) thermo-sensitive virescent mutant (tsv3) that displayed an albino phenotype at 20° before the three-leaf stage while being a normal green at 32° or even at 20° after the four-leaf stage. The mutant phenotype was consistent with altered chlorophyll content and chloroplast structure in leaves. Map-based cloning and complementation experiments showed that TSV3 encoded a small GTP-binding protein. Subcellular localization studies revealed that TSV3 was localized to the chloroplasts. Expression of TSV3 was high in leaves and weak or undetectable in other tissues, suggesting a tissue-specific expression of TSV3. In the tsv3 mutant, expression levels of genes associated with the biogenesis of the chloroplast ribosome 50S subunit were severely decreased at the three-leaf stage under cold stress (20°), but could be recovered to normal levels at a higher temperature (32°). These observations suggest that the rice nuclear-encoded TSV3 plays important roles in chloroplast development at the early leaf stage under cold stress.



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RNA-Sequencing of Drosophila melanogaster Head Tissue on High-Sugar and High-Fat Diets

Obesity has been shown to increase risk for cardiovascular disease and type-2 diabetes. In addition, it has been implicated in aggravation of neurological conditions such as Alzheimer's. In the model organism Drosophila melanogaster, a physiological state mimicking diet-induced obesity can be induced by subjecting fruit flies to a solid medium disproportionately higher in sugar than protein, or that has been supplemented with a rich source of saturated fat. These flies can exhibit increased circulating glucose levels, increased triglyceride content, insulin-like peptide resistance, and behavior indicative of neurological decline. We subjected flies to variants of the high-sugar diet, high-fat diet, or normal (control) diet, followed by a total RNA extraction from fly heads of each diet group for the purpose of Poly-A selected RNA-Sequencing. Our objective was to identify the effects of obesogenic diets on transcriptome patterns, how they differed between obesogenic diets, and identify genes that may relate to pathogenesis accompanying an obesity-like state. Gene ontology analysis indicated an overrepresentation of affected genes associated with immunity, metabolism, and hemocyanin in the high-fat diet group, and CHK, cell cycle activity, and DNA binding and transcription in the high-sugar diet group. Our results also indicate differences in the effects of the high-fat diet and high-sugar diet on expression profiles in head tissue of flies, despite the reportedly similar phenotypic impacts of the diets. The impacted genes, and how they may relate to pathogenesis in the Drosophila obesity-like state, warrant further experimental investigation.



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Global Transcriptome Sequencing Reveals Molecular Profiles of Summer Diapause Induction Stage of Onion Maggot, Delia antiqua (Diptera: Anthomyiidae)

The onion maggot, Delia antiqua, is a worldwide subterranean pest and can enter diapause during the summer and winter seasons. The molecular regulation of the ontogenesis transition remains largely unknown. Here we used high-throughput RNA sequencing to identify candidate genes and processes linked to summer diapause (SD) induction by comparing the transcriptome differences between the most sensitive larval developmental stage of SD and nondiapause (ND). Nine pairwise comparisons were performed, and significantly differentially regulated transcripts were identified. Several functional terms related to lipid, carbohydrate, and energy metabolism, environmental adaption, immune response, and aging were enriched during the most sensitive SD induction period. A subset of genes, including circadian clock genes, were expressed differentially under diapause induction conditions, and there was much more variation in the most sensitive period of ND- than SD-destined larvae. These expression variations probably resulted in a deep restructuring of metabolic pathways. Potential regulatory elements of SD induction including genes related to lipid, carbohydrate, energy metabolism, and environmental adaption. Collectively, our results suggest the circadian clock is one of the key drivers for integrating environmental signals into the SD induction. Our transcriptome analysis provides insight into the fundamental role of the circadian clock in SD induction in this important model insect species, and contributes to the in-depth elucidation of the molecular regulation mechanism of insect diapause induction.



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Comparison of ChIP-Seq Data and a Reference Motif Set for Human KRAB C2H2 Zinc Finger Proteins

KRAB C2H2 zinc finger proteins (KZNFs) are the largest and most diverse family of human transcription factors, likely due to diversifying selection driven by novel endogenous retroelements (EREs), but the vast majority lack binding motifs or functional data. Two recent studies analyzed a majority of the human KZNFs using either ChIP-seq (60 proteins) or ChIP-exo (221 proteins) in the same cell type (HEK293). The ChIP-exo paper did not describe binding motifs, however. Thirty-nine proteins are represented in both studies, enabling the systematic comparison of the data sets presented here. Typically, only a minority of peaks overlap, but the two studies nonetheless display significant similarity in ERE binding for 32/39, and yield highly similar DNA binding motifs for 23 and related motifs for 34 (MoSBAT similarity score >0.5 and >0.2, respectively). Thus, there is overall (albeit imperfect) agreement between the two studies. For the 242 proteins represented in at least one study, we selected a highest-confidence motif for each protein, utilizing several motif-derivation approaches, and evaluating motifs within and across data sets. Peaks for the majority (158) are enriched (96% with AUC >0.6 predicting peak vs. nonpeak) for a motif that is supported by the C2H2 "recognition code," consistent with intrinsic sequence specificity driving DNA binding in cells. An additional 63 yield motifs enriched in peaks, but not supported by the recognition code, which could reflect indirect binding. Altogether, these analyses validate both data sets, and provide a reference motif set with associated quality metrics.



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Egg Case Silk Gene Sequences from Argiope Spiders: Evidence for Multiple Loci and a Loss of Function Between Paralogs

Spiders swath their eggs with silk to protect developing embryos and hatchlings. Egg case silks, like other fibrous spider silks, are primarily composed of proteins called spidroins (spidroin = spider-fibroin). Silks, and thus spidroins, are important throughout the lives of spiders, yet the evolution of spidroin genes has been relatively understudied. Spidroin genes are notoriously difficult to sequence because they are typically very long (≥ 10 kb of coding sequence) and highly repetitive. Here, we investigate the evolution of spider silk genes through long-read sequencing of Bacterial Artificial Chromosome (BAC) clones. We demonstrate that the silver garden spider Argiope argentata has multiple egg case spidroin loci with a loss of function at one locus. We also use degenerate PCR primers to search the genomic DNA of congeneric species and find evidence for multiple egg case spidroin loci in other Argiope spiders. Comparative analyses show that these multiple loci are more similar at the nucleotide level within a species than between species. This pattern is consistent with concerted evolution homogenizing gene copies within a genome. More complicated explanations include convergent evolution or recent independent gene duplications within each species.



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Multicenter observational study on functional bowel disorders diagnosed using Rome III diagnostic criteria in Japan

Abstract

Background

The Rome III diagnostic criteria had been used to diagnose functional gastrointestinal disorders (FGIDs) world wide, and functional bowel disorders (FBDs) including irritable bowel syndrome (IBS) have recently attracted the attention of Japanese physicians. However, there have been few reports on the prevalence of FBDs diagnosed by the Rome III diagnostic criteria.

Aims

The aim of this study was to determine the prevalence of FBDs diagnosed according to the diagnostic criteria of Rome III in Japan.

Patients and methods

All patients who were booked for colonoscopy were enrolled from eight institutions in Japan. This study was a prospective observational study in the period from April 2013 to December 2013. Patients filled out FGID questionnaires of Rome III when they were waiting for colonoscopy.

Results

Data for 1200 patients who underwent colonoscopy were analyzed. A total of 547 patients (45.6%) were diagnosed with FBDs. Out of those patients, 9.1% had IBS. According to the Rome III diagnostic criteria, 134 patients (11.2%) had functional bloating (FB), 73 (6.1%) had functional constipation (FC), 40 (3.3%) had functional diarrhea (FD), and 191 (15.9%) had unspecified functional bowel disorder (UFBD). Patients with FBDs had significantly higher rates of almost all symptoms (abdominal pain, hard or lumpy stools, loose or watery stools, and bloating) than those in the controls.

Conclusions

In Japan, the prevalence of FBDs and IBS is high, similar to that in the US. Many patients with FBDs have multiple symptoms.



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The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management

Abstract

Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment—auditory neuropathy (AN). All patients were clinically suspected of CAPOS and had hearing problems. In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected. In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients.



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Efficacy of 125 I Versus Non- 125 I Combined with Transcatheter Arterial Chemoembolization for the Treatment of Unresectable Hepatocellular Carcinoma with Obstructive Jaundice

Abstract

Purpose

To compare the therapeutic effects of 125I versus non-125I combined with transcatheter arterial chemoembolization (TACE) for the treatment of unresectable hepatocellular carcinoma (HCC) with obstructive jaundice.

Methods

A retrospective analysis was conducted using the records of 54 consecutive patients who were initially diagnosed with HCC with obstructive jaundice between May 2009 and July 2016. Twenty-one cases (group A) were treated with percutaneous transhepatic biliary drainage (PTBD) followed by 125I radioactive seed strip implantation through the PTBD tube. After the total serum bilirubin level was reduced to normal and the liver function recovered to Child–Pugh class A or early B, TACE was conducted. In 33 cases (group B) PTBD was performed in combination with TACE without applying the 125I radioactive seeds. The duration of biliary patency and survival were analyzed.

Results

The technical success rate in both groups was 100%. The median biliary patency time was 6.000 ± 0.315 months (95% CI 5.382–6.618 months) in group A and 4.000 ± 0.572 months (95% CI 2.879–5.121 months) in group B; the two groups were significantly different (P = 0.001). The median survival was 11.000 ± 0.864 months (95% CI 9.306–12.694 months) in group A and 9.000 ± 0.528 months (95% CI 7.965–10.035 months) in group B; the two groups were significantly different (P = 0.022).

Conclusions

The combination of 125I with TACE was more effective than TACE without the radioactive seeds for treating patients with unresectable HCC with obstructive jaundice. Future prospective trials with larger samples will be required to validate these results.



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Clinical significance of germline copy number variation in susceptibility of human diseases

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Publication date: Available online 5 January 2018
Source:Journal of Genetics and Genomics
Author(s): Liwen Hu, Xinyue Yao, Hairong Huang, Zhong Guo, Xi Chen, Yang Xu, Yi Shen, Biao Xu, Demin Li
Germline copy number variation (CNV) is considered to be an important form of human genetic polymorphisms. Previous studies have identified amounts of copy number variations in human genome by advanced technologies, such as comparative genomic hybridization, single nucleotide genotyping, and high-throughput sequencing. CNV is speculated to be derived from multiple mechanisms, such as nonallelic homologous recombination (NAHR) and nonhomologous end-joining (NHEJ). CNVs cover a much larger genome scale than single nucleotide polymorphisms (SNP), and may alter gene expression levels by means of gene dosage, gene fusion, gene disruption, and long-range regulation effects, thus affecting individual phenotypes and playing crucial roles in human pathogenesis. The number of studies linking CNVs with common complex diseases has increased dramatically in recent years. Here, we provide a comprehensive review of the current understanding of germline CNVs, and summarize the association of germline CNVs with the susceptibility to a wide variety of human diseases that were identified in recent years. We also propose potential issues that should be addressed in future studies.



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Occurrence of Jaundice Following Simultaneous Ursodeoxycholic Acid Cessation and Obeticholic Acid Initiation



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Variable role of carotid bodies in cardiovascular responses to exercise, hypoxia and hypercapnia in spontaneously hypertensive rats

Abstract

The carotid body has recently emerged as a promising therapeutic target for treating cardiovascular disease, however the potential impact of carotid bodies removal on the dynamic cardiovascular responses to acute stressors such as exercise, hypoxia and hypercapnia in hypertension is an important safety consideration that has not been studied. We first validated a novel surgical approach to selectively resect the carotid bodies bilaterally (CBR) sparing the carotid sinus baroreflex. Second, we evaluated the impact of CBR on the cardiovascular responses to exercise, hypoxia and hypercapnia in the conscious, chronically instrumented spontaneously hypertensive (SH) rats. Our results confirm that our CBR technique successfully and selectively abolished the chemoreflex, whilst preserving carotid baroreflex function. CBR produced a sustained fall in arterial pressure in the SH rat of ∼20 mmHg that persisted across both dark and light phases (P < 0.001), with baroreflex function curves resetting around lower arterial pressure levels. The cardiovascular and respiratory responses to moderate forced exercise were similar between CBR and Sham. In contrast, CBR abolished the pressor response to hypoxia seen in Sham animals, although the increases in heart rate and respiration were similar between Sham and CBR groups. Both the pressor and respiratory responses to 7% hypercapnia were augmented after CBR (P < 0.05) compared to sham. Our finding that the carotid bodies play a critical role in maintaining arterial pressure during hypoxia has important implications when considering resection therapy of the carotid body in disease states such as hypertension as well as heart failure with sleep apnoea.

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Dietary branched chain amino acids and metabolic health: when less is more

Abstract

Within obesity research it is almost axiomatic that the consumption of adequate protein is healthy. A large body of work suggests that high protein diets reduce food intake, while maintaining protein intake but reducing caloric intake promotes fat loss while sustaining lean mass.

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Layer-specific E/I balances during neuronal synchronization in the visual cortex

Abstract

Rhythmic activity can synchronize neural ensembles within and across cortical layers. While gamma band rhythmicity has been observed in all layers, the laminar sources and functional impacts of neuronal synchronization in the cortex remain incompletely understood. Here, layer-specific optogenetic stimulation demonstrates that populations of excitatory neurons in any cortical layer of the mouse's primary visual cortex are sufficient to powerfully entrain neuronal oscillations in the gamma band. Within each layer, inhibition balances excitation and keeps activity in check. Across layers, translaminar output overcomes inhibition and drives downstream firing. These data establish that rhythm-generating circuits exist in all principle layers of the cortex, but provide layer-specific balances of excitation and inhibition that may dynamically shape the flow of information through cortical circuits. These data might help explain how E/I balances across cortical layers shape information processing, and shed light on the diverse nature and functional impacts of cortical gamma rhythms.



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Protein kinase D activation induces mitochondrial fragmentation and dysfunction in cardiomyocytes

Abstract

Regulation of mitochondrial morphology is crucial for the maintenance of physiological functions in many cell types including cardiomyocytes. Small and fragmented mitochondria are frequently observed in pathological condition, but it is still unclear which cardiac signalling pathway is responsible for regulating the abnormal mitochondrial morphology in cardiomyocytes. Here we demonstrate that a downstream kinase of Gq-protein coupled receptor (GqPCR) signalling, protein kinase D (PKD), mediates pathophysiological modifications in mitochondrial morphology and function, which consequently contribute to the activation of apoptotic signalling. We show that GqPCR stimulation induced by α1-adrenergic stimulation mediates mitochondrial fragmentation in a fission- and PKD-dependent manner in H9c2 cardiac myoblasts and rat neonatal cardiomyocytes. Upon GqPCR stimulation, PKD translocates from the cytoplasm to the outer mitochondrial membrane (OMM) and phosphorylates a mitochondrial fission protein, dynamin-like protein 1 (DLP1) at S637. PKD-dependent phosphorylation of DLP1 initiates DLP1 association with the OMM, which then enhances mitochondrial fragmentation, mitochondrial superoxide generation, mitochondrial permeability transition pore opening and apoptotic signalling. Finally, we demonstrate that DLP1 phosphorylation at S637 by PKD occurs in vivo using ventricular tissues from transgenic mice with cardiac-specific overexpression of constitutively active Gαq protein. In conclusion, GqPCR-PKD signalling induces mitochondrial fragmentation and dysfunction via PKD-dependent DLP1 phosphorylation in cardiomyocytes. This study is the first to identify a novel PKD-specific substrate, DLP1 in mitochondria as well as the functional role of PKD in cardiac mitochondria. Elucidation of these molecular mechanisms by which PKD-dependent enhanced fission mediates cardiac mitochondrial injury will provide novel insight into the relationship among mitochondrial form, function, and GqPCR signalling.

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A novel pathogenic MYH3 mutation in a child with Sheldon–Hall syndrome and vertebral fusions

Sheldon–Hall syndrome (SHS) is the most common of the distal arthrogryposes (DAs), a group of disorders characterized by congenital non-progressive contractures. Patients with SHS present with contractures of the limbs and a distinctive triangular facies with prominent nasolabial folds. Calcaneovalgus deformity is frequent, as well as camptodactyly and ulnar deviation. Causative mutations in at least four different genes have been reported (MYH3, TNNI2, TPM2, and TNNT3). MYH3 plays a pivotal role in fetal muscle development and mutations in this gene are associated with Freeman–Sheldon syndrome, distal arthrogryposis 8 (DA8), and autosomal dominant spondylocarpotarsal synostosis. The last two disorders are characterized by skeletal abnormalities, in particular bony fusions. The observation that MYH3 may be mutated in these syndromes has suggested the involvement of this gene in bone development. We report the case of a boy with a novel pathogenic MYH3 mutation, presenting with the classical clinical features of SHS in association with unilateral carpal bone fusion and multiple vertebral fusions. This distinctive phenotype has never been reported in the literature so far and expands the phenotypic spectrum of SHS, endorsing the clinical variability of patients with MYH3-related disorders. Our findings also support a role for MYH3 in both muscle and bone development, suggesting a phenotypic continuum in MYH3-related disorders.



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Large-cell neuroendocrine carcinoma arising from a gastritis cystica polyposa

Abstract

Gastritis cystica polyposa is a polypoid lesion that arises from the gastric mucosa at the gastrojejunal anastomotic site and is characterized by cystic dilation of the gastric glands. A 78-year-old man who underwent distal gastrectomy for a gastric ulcer with Billroth II reconstruction approximately 40 years previously, exhibited a gastritis cystica polyposa at the anastomotic site. Ulceration was observed on an annual endoscopic examination. Endoscopic ultrasonography revealed a submucosal hypoechoic mass with multiple cystic lesions. Gastrectomy was performed and histological examination revealed a large-cell neuroendocrine carcinoma with cystic dilation of the gastric glands. Here, we report the first case of a large-cell neuroendocrine carcinoma arising from a gastritis cystica polyposa. Endoscopic ultrasonography was effective at diagnosing a submucosal hypoechoic mass with cystic dilation of the gastric glands.



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