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1.
The role of new adipokines in gestational diabetes mellitus pathogenesis.
Mierzyński, R, Poniedziałek-Czajkowska, E, Dłuski, D, Leszczyńska-Gorzelak, B
Ginekologia polska. 2018;(4):221-26
Abstract
Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition dur-ing pregnancy. Explanation of the GDM pathogenesis is important due to preventing gestational complications. During pregnancy there are significant changes in maternal metabolism. Many of these changes are influenced by different adi-pokines produced in the placenta and adipose tissue. The exact role of adipokines in the pathogenesis of GDM remains still unknown. Several adipokines have been analysed throughout gestation and their levels have been suggested as biomarkers of maternal-perinatal outcomes. Some of them have been postulated as significant in the pathogenesis of pregnancy complications like GDM. This report aims to review some of the recent topics of adipokine research that may be of particular importance in patho-physiology and diagnosis of gestational diabetes mellitus. Because of manuscript length limitations, after thorough literature review and in view of the recent evidence, we focus on the one of the most well-known adipokine: adiponectin, and not so well-studied: nesfatin-1, chemerin, ghrelin, and CTRP 1.
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Novel GLI3 variant causing overlapped Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS) phenotype with agenesis of gallbladder and pancreas.
Ito, S, Kitazawa, R, Haraguchi, R, Kondo, T, Ouchi, A, Ueda, Y, Kitazawa, S
Diagnostic pathology. 2018;(1):1
Abstract
BACKGROUND A proper balance between the activator and the repressor form of GLI3, a zinc-finger transcription factor downstream of hedgehog signaling, is essential for proper development of various organs during development. Mutations in different domains of the GLI3 gene underlie several congenital diseases including Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS). CASE PRESENTATION Here, we describe the case of an overlapped phenotype of these syndromes with agenesis of the gallbladder and the pancreas, bearing a c.2155 C > T novel likely pathogenic variant of GLI3 gene by missense point mutation causing p.P719S at the proteolytic cleavage site. CONCLUSIONS Although agenesis of the gallbladder and the pancreas is uncommon in GLI3 morphopathy, a slight difference in the gradient or the balance between activator and repressor in this case may hinder sophisticated spatial and sequential hedgehog signaling that is essential for proper development of gallbladder and pancreas from endodermal buds.
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Human erythrocytes release ATP by a novel pathway involving VDAC oligomerization independent of pannexin-1.
Marginedas-Freixa, I, Alvarez, CL, Moras, M, Leal Denis, MF, Hattab, C, Halle, F, Bihel, F, Mouro-Chanteloup, I, Lefevre, SD, Le Van Kim, C, et al
Scientific reports. 2018;(1):11384
Abstract
We previously demonstrated that the translocase protein TSPO2 together with the voltage-dependent anion channel (VDAC) and adenine nucleotide transporter (ANT) were involved in a membrane transport complex in human red blood cells (RBCs). Because VDAC was proposed as a channel mediating ATP release in RBCs, we used TSPO ligands together with VDAC and ANT inhibitors to test this hypothesis. ATP release was activated by TSPO ligands, and blocked by inhibitors of VDAC and ANT, while it was insensitive to pannexin-1 blockers. TSPO ligand increased extracellular ATP (ATPe) concentration by 24-59% over the basal values, displaying an acute increase in [ATPe] to a maximal value, which remained constant thereafter. ATPe kinetics were compatible with VDAC mediating a fast but transient ATP efflux. ATP release was strongly inhibited by PKC and PKA inhibitors as well as by depleting intracellular cAMP or extracellular Ca2+, suggesting a mechanism involving protein kinases. TSPO ligands favoured VDAC polymerization yielding significantly higher densities of oligomeric bands than in unstimulated cells. Polymerization was partially inhibited by decreasing Ca2+ and cAMP contents. The present results show that TSPO ligands induce polymerization of VDAC, coupled to activation of ATP release by a supramolecular complex involving VDAC, TSPO2 and ANT.
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Mini-review: Update on the genetics of schizophrenia.
Coelewij, L, Curtis, D
Annals of human genetics. 2018;(5):239-243
Abstract
A number of important findings have recently emerged relevant to identifying genetic risk factors for schizophrenia. Findings using common variants point towards gene sets of interest and also demonstrate an overlap with other psychiatric and nonpsychiatric disorders. Imputation of variants of the gene for complement component 4 (C4) from GWAS data has shown that the predicted expression of the C4A product is associated with schizophrenia risk. Very rare variants disrupting SETD1A, RBM12 or NRXN1 have a large effect on risk. Other rare, damaging variants are enriched in genes that are loss of function intolerant and/or whose products localise to the synapse. These and particular copy number variants can result in increased risk of schizophrenia but also of other neurodevelopmental disorders. The findings for C4 and NRXN1 may be especially helpful for elucidating the biological mechanisms that can lead to disease.
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5.
Novel transmitters in brain stem vagal neurocircuitry: new players on the pitch.
Bülbül, M, Travagli, RA
American journal of physiology. Gastrointestinal and liver physiology. 2018;(1):G20-G26
Abstract
The last few decades have seen a major increase in the number of neurotransmitters and neuropeptides recognized as playing a role in brain stem neurocircuits, including those involved in homeostatic functions such as stress responsiveness, gastrointestinal motility, feeding, and/or arousal/wakefulness. This minireview will focus on the known physiological role of three of these novel neuropeptides, i.e., apelin, nesfatin-1, and neuropeptide-S, with a special emphasis on their hypothetical roles in vagal signaling related to gastrointestinal motor functions.
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Precision therapy for epilepsy due to KCNT1 mutations: A randomized trial of oral quinidine.
Mullen, SA, Carney, PW, Roten, A, Ching, M, Lightfoot, PA, Churilov, L, Nair, U, Li, M, Berkovic, SF, Petrou, S, et al
Neurology. 2018;(1):e67-e72
Abstract
OBJECTIVE To evaluate quinidine as a precision therapy for severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1. METHODS A single-center, inpatient, order-randomized, blinded, placebo-controlled, crossover trial of oral quinidine included 6 patients with severe autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) due to KCNT1 mutation. Order was block randomized and blinded. Four-day treatment blocks were used with a 2-day washout between. Dose started at 900 mg over 3 divided doses then, in subsequent participants, was reduced to 600 mg, then 300 mg. Primary outcome was seizure frequency measured on continuous video-EEG in those completing the trial. RESULTS Prolonged QT interval occurred in the first 2 patients at doses of 900 and 600 mg quinidine per day, respectively, despite serum quinidine levels well below the therapeutic range (0.61 and 0.51 μg/mL, reference range 1.3-5.0 μg/mL). Four patients completed treatment with 300 mg/d without adverse events. Patients completing the trial had very frequent seizures (mean 14 per day, SD 7, median 13, interquartile range 10-18). Seizures per day were nonsignificantly increased by quinidine (median 2, 95% confidence interval -1.5 to +5, p = 0.15) and no patient had a 50% seizure reduction. CONCLUSION Quinidine did not show efficacy in adults and teenagers with ADNFLE. Dose-limiting cardiac side effects were observed even in the presence of low measured serum quinidine levels. Although small, this trial suggests use of quinidine in ADNFLE is likely to be ineffective coupled with considerable cardiac risks. CLINICAL TRIALS REGISTRATION Australian Therapeutic Goods Administration Clinical Trial Registry (trial number 2015/0151). CLASSIFICATION OF EVIDENCE This study provides Class II evidence that for persons with severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1, quinidine does not significantly reduce seizure frequency.
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7.
Arc - An endogenous neuronal retrovirus?
Shepherd, JD
Seminars in cell & developmental biology. 2018;:73-78
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Abstract
The neuronal gene Arc is essential for long-lasting information storage in the mammalian brain and has been implicated in various neurological disorders. However, little is known about Arc's evolutionary origins. Recent studies suggest that mammalian Arc originated from a vertebrate lineage of Ty3/gypsy retrotransposons, which are also ancestral to retroviruses. In particular, Arc contains homology to the Gag polyprotein that forms the viral capsid and is essential for viral infectivity. This surprising connection raises the intriguing possibility that Arc may share molecular characteristics of retroviruses.
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Effect of Ascertainment Bias on Estimates of Patient Mortality in Inherited Cardiac Diseases.
Nannenberg, EA, van Rijsingen, IAW, van der Zwaag, PA, van den Berg, MP, van Tintelen, JP, Tanck, MWT, Ackerman, MJ, Wilde, AAM, Christiaans, I
Circulation. Genomic and precision medicine. 2018;(10):e001797
Abstract
BACKGROUND Accurate estimates of survival are indispensable for cardiologists, clinical geneticists, and genetic counselors dealing with families with an inherited cardiac disease. However, a bias towards a more severe disease with a worse outcome in the first publications may not accurately represent the actual survival forecast. We, therefore, evaluated the effect of ascertainment bias on survival in 3 different inherited cardiac diseases (idiopathic ventricular fibrillation, SCN5A overlap syndrome, and arrhythmogenic cardiomyopathy) caused by a founder mutation. METHODS We collected mortality data from mutation-positive subjects with either DPP6-associated idiopathic ventricular fibrillation, SCN5A overlap syndrome, and PLN-R14del-mediated arrhythmogenic cardiomyopathy >2 to 10 years of ongoing clinical/cascade genetic screening. RESULTS The median age of survival in DPP6 mutation-positive subjects increased from 44.6 years in the original cohort from 2008 (n=60; 95% CI, 36.8-52.4 years) to 68.2 years in the extended cohort from 2012 (n=235; 95% CI, 64.6-71.7 years; P<0.001). In the SCN5A overlap syndrome, survival increased from 56.1 years in 1999 (n=86; 95% CI, 48.0-64.2 years) to 69.7 years in 2009 (n=197; 95% CI, 61.3-78.2 years; P=0.049). In PLN-R14del positive patients, the median age of survival increased from 63.5 years in 2010 (n=89; 95% CI, 59.1-68.0 years) to 65.2 years in 2012 (n=370; 95% CI, 62.0-68.3 years; P=0.046). CONCLUSIONS The median age of survival in 3 different inherited cardiac diseases with an established pathogenic substrate significantly increased once genetic testing and cascade screening extended, after the first publication that elucidated the discovery of the disease-susceptibility gene/mutation. This underscores the direct and negative influence of ascertainment bias on survival forecasts and the importance of ongoing clinical/genetic follow-up to establish the most accurate disease prognosis for genetically mediated heart diseases.
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Expanding spectrum of contactin-associated protein 2 (CASPR2) autoimmunity-syndrome of parkinsonism and ataxia.
Kannoth, S, Nambiar, V, Gopinath, S, Anandakuttan, A, Mathai, A, Rajan, PK
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2018;(3):455-460
Abstract
Contactin-associated protein 2 (CASPR2) antibodies are originally associated with Morvan's syndrome and peripheral nerve hyper excitability. Our objective was to study retrospectively the clinical spectrum of CASPR2 antibody-positive patients in our hospital. This is a retrospective observational study. Patients treated at the Amrita Institute of Medical Sciences from May 2013 to April 2016, who were tested positive for CASPR2 antibodies, were included. A total of 1584 samples were tested in the neuroimmunology laboratory during the study period for voltage-gated potassium channel (VGKC) complex antibodies-leucine-rich glioma-inactivated protein 1 (LGI1) and CASPR2 antibodies. Thirty-four were positive for LGI1, 13 were positive for CASPR2, and 7 were for both (total 54-3.4% positivity). Of these 54 cases, 11 were treated in our hospital. Seven were positive for LGI1, three for CASPR2, and one for both. The patient who had both CASPR2 and LGI1 antibody positive had Morvan's syndrome. One patient with CASPR2 had neuromyotonia. The other patient was admitted with status epilepticus with a syndrome of parkinsonism and ataxia. The third patient had encephalopathy and myoclonus with a syndrome of parkinsonism and ataxia. Two of them underwent siddha treatment for other ailments prior to the onset of the disease for other ailments. Our short series shows the expanding spectrum of CASPR2 autoimmunity. Syndrome of parkinsonism and ataxia is an important manifestation of CASPR2 autoimmunity where we can offer a definitive treatment.
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LGI1, CASPR2 and related antibodies: a molecular evolution of the phenotypes.
Binks, SNM, Klein, CJ, Waters, P, Pittock, SJ, Irani, SR
Journal of neurology, neurosurgery, and psychiatry. 2018;(5):526-534
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Abstract
Recent biochemical observations have helped redefine antigenic components within the voltage-gated potassium channel (VGKC) complex. The related autoantibodies may be now divided into likely pathogenic entities, which target the extracellular domains of leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2), and species that target intracellular neuronal components and are likely non-pathogenic. This distinction has enhanced clinical practice as direct determination of LGI1 and CASPR2 antibodies offers optimal sensitivity and specificity. In this review, we describe and compare the clinical features associated with pathogenic LGI1 and CASPR2 antibodies, illustrate emerging laboratory techniques for antibody determination and describe the immunological mechanisms that may mediate antibody-induced pathology. We highlight marked clinical overlaps between patients with either LGI1 or CASPR2 antibodies that include frequent focal seizures, prominent amnesia, dysautonomia, neuromyotonia and neuropathic pain. Although occurring at differing rates, these commonalities are striking and only faciobrachial dystonic seizures reliably differentiate these two conditions. Furthermore, the coexistence of both LGI1 and CASPR2 antibodies in an individual occurs surprisingly frequently. Patients with either antibody respond well to immunotherapies, although systematic studies are required to determine the magnitude of the effect beyond placebo. Finally, data have suggested that CASPR2 and LGI1 modulation via genetic or autoimmune mechanisms may share common intermediate molecules. Taken together, the biochemical distinction of antigenic targets has led to important clinical advances for patient care. However, the striking syndrome similarities, coexistence of two otherwise rare antibodies and molecular insights suggest the VGKC complex may yet be a common functional effector of antibody action. Hence, we argue for a molecular evolution alongside a clinical and phenotypic re-evaluation.