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Author (up) Burnett, L.C.; LeDuc, C.A.; Sulsona, C.R.; Paull, D.; Rausch, R.; Eddiry, S.; Carli, J.F.M.; Morabito, M.V.; Skowronski, A.A.; Hubner, G.; Zimmer, M.; Wang, L.; Day, R.; Levy, B.; Fennoy, I.; Dubern, B.; Poitou, C.; Clement, K.; Butler, M.G.; Rosenbaum, M.; Salles, J.P.; Tauber, M.; Driscoll, D.J.; Egli, D.; Leibel, R.L. url  doi
openurl 
  Title Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome Type Journal Article
  Year 2017 Publication The Journal of Clinical Investigation Abbreviated Journal J Clin Invest  
  Volume 127 Issue 1 Pages 293-305  
  Keywords  
  Abstract Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central hypogonadism, and low growth hormone (GH). Rare microdeletions in PWS patients define a 91-kb minimum critical deletion region encompassing 3 genes, including the noncoding RNA gene SNORD116. Here, we found that protein and transcript levels of nescient helix loop helix 2 (NHLH2) and the prohormone convertase PC1 (encoded by PCSK1) were reduced in PWS patient induced pluripotent stem cell-derived (iPSC-derived) neurons. Moreover, Nhlh2 and Pcsk1 expression were reduced in hypothalami of fasted Snord116 paternal knockout (Snord116p-/m+) mice. Hypothalamic Agrp and Npy remained elevated following refeeding in association with relative hyperphagia in Snord116p-/m+ mice. Nhlh2-deficient mice display growth deficiencies as adolescents and hypogonadism, hyperphagia, and obesity as adults. Nhlh2 has also been shown to promote Pcsk1 expression. Humans and mice deficient in PC1 display hyperphagic obesity, hypogonadism, decreased GH, and hypoinsulinemic diabetes due to impaired prohormone processing. Here, we found that Snord116p-/m+ mice displayed in vivo functional defects in prohormone processing of proinsulin, pro-GH-releasing hormone, and proghrelin in association with reductions in islet, hypothalamic, and stomach PC1 content. Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency.  
  Address  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0021-9738 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:27941249; PMCID:PMC5199710 Approved no  
  Call Number refbase @ user @ Serial 16636  
Permanent link to this record
 

 
Author (up) Chu J.; Bruyninckx F.; Neuhauser D.V. url  openurl
  Title Autonomic components of complex regional pain syndrome (CRPS) are favourably affected by electrical twitch-obtaining intramuscular stimulation (ETOIMS): Effects on blood pressure and heart rate Type Journal Article
  Year 2017 Publication BMJ Innov. Abbreviated Journal  
  Volume 3 Issue 3 Pages 176-187  
  Keywords analgesia; article; autonomic neuropathy; backache; blood pressure; clinical article; complex regional pain syndrome; controlled study; diastolic blood pressure; electrical twitch obtaining intramuscular stimulation; electromagnetism; electrostimulation; fatigue; health insurance; heart rate; human; male; muscle hypertonia; muscle twitch; nuclear magnetic resonance imaging; outcome assessment; priority journal; pulse pressure; pulse rate; range of motion; supersensitivity; systolic blood pressure; transcranial magnetic stimulation  
  Abstract Introduction Favourable pain relief results on evoking autonomous twitches at myofascial trigger points with Electrical Twitch Obtaining Intramuscular Stimulation (ETOIMS). Aim To document autonomic nervous system (ANS) dysfunction in Complex Regional Pain Syndrome (CRPS) from blood pressure (BP) and pulse/heart rate changes with ETOIMS. Methods and materials A patient with persistent pain regularly received serial ETOIMS sessions of 60, 90, 120 or >=150 min over 24 months. Outcome measures include BP: systolic, diastolic, pulse pressure and pulse/heart rate, pre-session/immediate-post-session summed differences (SDPPP index), and pain reduction. His results were compared with that of two other patients and one normal control. Each individual represented the following maximal elicitable twitch forces (TWF) graded 1-5: maximum TWF2: control subject; maximum TWF3: CRPS patient with suspected ANS dysfunction; and maximum TWF4 and TWF5: two patients with respective slow-fatigue and fast-fatigue twitches who during ETOIMS had autonomous twitching at local and remote myotomes simultaneously from denervation supersensitivity. ETOIMS results between TWFs were compared using one-way analysis of variance test. Results The patients showed immediate significant pain reduction, BP and pulse/heart rate changes/reduction(s) except for diastolic BP in the TWF5 patient. TWF2 control subject had diastolic BP reduction with ETOIMS but not with rest. Linear regression showed TWF grade to be the most significant variable in pain reduction, more so than the number of treatments, session duration and treatment interval. TWF grade was the most important variable in significantly reducing outcome measures, especially pulse/heart rate. Unlike others, the TWF3 patient had distinctive reductions in SDPPP index. Conclusions Measuring BP and pulse/heart rate is clinically practical for alerting ANS dysfunction maintained CRPS. SDPPP index (>=26) and pulse/heart rate (>=8) reductions with almost every ETOIMS treatment, plus inability to evoke autonomous twitches due to pain-induced muscle hypertonicity, are pathognomonic of this problem.  
  Address J. Chu, Department of Physical Medicine and Rehabilitation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 2055-642x ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number refbase @ admin @ Serial 17126  
Permanent link to this record
 

 
Author (up) Chu J.; Bruyninckx F.; Neuhauser D.V. url  openurl
  Title Autonomic components of complex regional pain syndrome (CRPS) are favourably affected by electrical twitch-obtaining intramuscular stimulation (ETOIMS): Effects on blood pressure and heart rate Type Journal Article
  Year 2017 Publication BMJ Innov. Abbreviated Journal  
  Volume 3 Issue 3 Pages 176-187  
  Keywords analgesia; article; autonomic neuropathy; backache; blood pressure; clinical article; complex regional pain syndrome; controlled study; diastolic blood pressure; electrical twitch obtaining intramuscular stimulation; electromagnetism; electrostimulation; fatigue; health insurance; heart rate; human; male; muscle hypertonia; muscle twitch; nuclear magnetic resonance imaging; outcome assessment; priority journal; pulse pressure; pulse rate; range of motion; supersensitivity; systolic blood pressure; transcranial magnetic stimulation  
  Abstract Introduction Favourable pain relief results on evoking autonomous twitches at myofascial trigger points with Electrical Twitch Obtaining Intramuscular Stimulation (ETOIMS). Aim To document autonomic nervous system (ANS) dysfunction in Complex Regional Pain Syndrome (CRPS) from blood pressure (BP) and pulse/heart rate changes with ETOIMS. Methods and materials A patient with persistent pain regularly received serial ETOIMS sessions of 60, 90, 120 or >=150 min over 24 months. Outcome measures include BP: systolic, diastolic, pulse pressure and pulse/heart rate, pre-session/immediate-post-session summed differences (SDPPP index), and pain reduction. His results were compared with that of two other patients and one normal control. Each individual represented the following maximal elicitable twitch forces (TWF) graded 1-5: maximum TWF2: control subject; maximum TWF3: CRPS patient with suspected ANS dysfunction; and maximum TWF4 and TWF5: two patients with respective slow-fatigue and fast-fatigue twitches who during ETOIMS had autonomous twitching at local and remote myotomes simultaneously from denervation supersensitivity. ETOIMS results between TWFs were compared using one-way analysis of variance test. Results The patients showed immediate significant pain reduction, BP and pulse/heart rate changes/reduction(s) except for diastolic BP in the TWF5 patient. TWF2 control subject had diastolic BP reduction with ETOIMS but not with rest. Linear regression showed TWF grade to be the most significant variable in pain reduction, more so than the number of treatments, session duration and treatment interval. TWF grade was the most important variable in significantly reducing outcome measures, especially pulse/heart rate. Unlike others, the TWF3 patient had distinctive reductions in SDPPP index. Conclusions Measuring BP and pulse/heart rate is clinically practical for alerting ANS dysfunction maintained CRPS. SDPPP index (>=26) and pulse/heart rate (>=8) reductions with almost every ETOIMS treatment, plus inability to evoke autonomous twitches due to pain-induced muscle hypertonicity, are pathognomonic of this problem.  
  Address J. Chu, Department of Physical Medicine and Rehabilitation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 2055-642x ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number refbase @ admin @ Serial 17128  
Permanent link to this record
 

 
Author (up) Kueppers, F.; Sanders, C. url  doi
openurl 
  Title State-of-the-art testing for alpha-1 antitrypsin deficiency Type Journal Article
  Year 2017 Publication Allergy and Asthma Proceedings Abbreviated Journal Allergy Asthma Proc  
  Volume 38 Issue 2 Pages 108-114  
  Keywords Asthma/diagnosis; Diagnosis, Differential; Genetic Testing/economics/*methods; Genotype; Genotyping Techniques; High-Throughput Nucleotide Sequencing/economics/*methods; Humans; Sequence Analysis, DNA/economics/methods; alpha 1-Antitrypsin/blood/*genetics; alpha 1-Antitrypsin Deficiency/blood/*diagnosis/genetics  
  Abstract BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition characterized by low serum levels of the protein alpha-1 antitrypsin. Because there are no unique clinical symptoms that point to a definitive diagnosis of AATD, laboratory testing is crucial to differentiate this disease from others. OBJECTIVE: To summarize advances in laboratory techniques used to test for AATD. METHODS: Data were sourced from a nonsystematic literature review of MEDLINE and the author's personal literature collection, and by checking reference lists of sourced articles. RESULTS: Since the original description of AATD by Laurell and Eriksson in 1963, testing methods have undergone major changes. Currently, alpha-1 antitrypsin protein is quantified by immunologic measurement in serum, and the phenotype is characterized by isoelectric focusing and/or targeted genotyping of predefined mutations. In addition, whole-gene sequencing of the gene SERPINA1 can be undertaken. However, this is costly and generally used only if targeted genotyping cannot conclusively identify the variant. The introduction of next-generation sequencing (NGS), which enables rapid and accurate sequencing of large quantities of DNA fragments in a single reaction, may help reduce costs. With its increasing availability, NGS may begin to appear in testing protocols. Clinical guidelines recommend that patients are tested for AATD if they have chronic irreversible airflow obstruction, especially those with early onset disease or a positive family history of AATD. Despite this, AATD is still underrecognized, and significant delays exist between symptom onset and diagnosis. CONCLUSION: Traditional testing practices have limitations. Screening programs that incorporate NGS are the most comprehensive methods available for accurate diagnosis of AATD.  
  Address  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1088-5412 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28120746 Approved no  
  Call Number refbase @ user @ Serial 17101  
Permanent link to this record
 

 
Author (up) Lacovich, V.; Espindola, S.L.; Alloatti, M.; Pozo Devoto, V.; Cromberg, L.E.; Carna, M.E.; Forte, G.; Gallo, J.-M.; Bruno, L.; Stokin, G.B.; Avale, M.E.; Falzone, T.L. url  doi
openurl 
  Title Tau Isoforms Imbalance Impairs the Axonal Transport of the Amyloid Precursor Protein in Human Neurons Type Journal Article
  Year 2017 Publication The Journal of Neuroscience : the Official Journal of the Society for Neuroscience Abbreviated Journal J Neurosci  
  Volume 37 Issue 1 Pages 58-69  
  Keywords App; Alzheimer's; axonal transport; splicing; tau; tauopathies  
  Abstract Tau, as a microtubule (MT)-associated protein, participates in key neuronal functions such as the regulation of MT dynamics, axonal transport, and neurite outgrowth. Alternative splicing of exon 10 in the tau primary transcript gives rise to protein isoforms with three (3R) or four (4R) MT binding repeats. Although tau isoforms are balanced in the normal adult human brain, imbalances in 3R:4R ratio have been tightly associated with the pathogenesis of several neurodegenerative disorders, yet the underlying molecular mechanisms remain elusive. Several studies exploiting tau overexpression and/or mutations suggested that perturbations in tau metabolism impair axonal transport. Nevertheless, no physiological model has yet demonstrated the consequences of altering the endogenous relative content of tau isoforms over axonal transport regulation. Here, we addressed this issue using a trans-splicing strategy that allows modulating tau exon 10 inclusion/exclusion in differentiated human-derived neurons. Upon changes in 3R:4R tau relative content, neurons showed no morphological changes, but live imaging studies revealed that the dynamics of the amyloid precursor protein (APP) were significantly impaired. Single trajectory analyses of the moving vesicles showed that predominance of 3R tau favored the anterograde movement of APP vesicles, increasing anterograde run lengths and reducing retrograde runs and segmental velocities. Conversely, the imbalance toward the 4R isoform promoted a retrograde bias by a significant reduction of anterograde velocities. These findings suggest that changes in 3R:4R tau ratio has an impact on the regulation of axonal transport and specifically in APP dynamics, which might link tau isoform imbalances with APP abnormal metabolism in neurodegenerative processes. SIGNIFICANCE STATEMENT: The tau protein has a relevant role in the transport of cargos throughout neurons. Dysfunction in tau metabolism underlies several neurological disorders leading to dementia. In the adult human brain, two tau isoforms are found in equal amounts, whereas changes in such equilibrium have been associated with neurodegenerative diseases. We investigated the role of tau in human neurons in culture and found that perturbations in the endogenous balance of tau isoforms were sufficient to impair the transport of the Alzheimer's disease-related amyloid precursor protein (APP), although neuronal morphology was normal. Our results provide evidence of a direct relationship between tau isoform imbalance and defects in axonal transport, which induce an abnormal APP metabolism with important implications in neurodegeneration.  
  Address Instituto de Biologia y Medicina Experimental (IBYME-CONICET), Buenos Aires C1428ADN, Argentina  
  Corporate Author Thesis  
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  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0270-6474 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28053030 Approved no  
  Call Number refbase @ user @ Serial 16630  
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