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https://www.readbyqxmd.com/read/28537398/discovery-of-clinical-candidate-2-2s-6s-2-phenyl-6-hydroxyadamantan-2-yl-1-3-hydroxyazetidin-1-yl-ethanone-bms-816336-an-orally-active-novel-selective-11%C3%AE-hydroxysteroid-dehydrogenase-type-1-inhibitor
#1
Xiang-Yang Ye, Stephanie Y Chen, Shung Wu, David S Yoon, Haixia Wang, Zhenqiu Hong, Stepen P O'Connor, Jun Li, James J Li, Lawrence L Kennedy, Steven J Walker, Akbar Nayeem, Steven Sheriff, Daniel M Camac, Vidyhashankar Ramamurthy, Paul E Morin, Rachel Zebo, Joseph R Taylor, Nathan N Morgan, Randolph P Ponticiello, Thomas Harrity, Atsu Apedo, Rajasree Golla, Ramakrishna Seethala, Mengmeng Wang, Timothy W Harper, Bogdan G Sleczka, Bin He, Mark Kirby, David K Leahy, Jianqing Li, Ronald L Hanson, Zhiwei Guo, Yi-Xin Li, John D DiMarco, Raymond Scaringe, Brad D Maxwell, Frederick Moulin, Joel C Barrish, David A Gordon, Jeffrey A Robl
BMS-816336 (6n-2), a hydroxyl-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme (IC50 3.0 nM) with >10000 fold selectivity over human 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). BMS-816336 exhibits a robust acute pharmacodynamic effects in cynomolgus monkeys (ED50 0.13 mpk) and in DIO mice. It is orally bioavailable (%F ranges from 20-72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans...
May 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28527054/understanding-migraine-as-a-cycling-brain-syndrome-reviewing-the-evidence-from-functional-imaging
#2
Arne May
Due to the clinical picture and also based on early imaging data (Weiller et al. Nat Med 1:658-660, 1995), the brainstem and midbrain structures have been intensely discussed as possible driving or generating structures in migraine. The fact that the brainstem activation persisted after treatment makes it unlikely that this activation was only due to increased activity of the endogenous anti-nociceptive system. It was consequently (and somewhat simplifying) coined the "migraine generator". Since then several studies have focussed on this region when investigating episodic, but also chronic migraine...
May 2017: Neurological Sciences
https://www.readbyqxmd.com/read/28510653/chronic-corticosterone-treatment-during-adolescence-has-significant-effects-on-metabolism-and-skeletal-development-in-male-c57bl6-n-mice
#3
Scott A Kinlein, Ziasmin Shahanoor, Russell D Romeo, Ilia N Karatsoreos
Glucocorticoids are potent modulators of metabolic and behavioral function. Their role as mediators in the "stress response" is well known, but arguably their primary physiological function is in the regulation of cellular and organismal metabolism. Disruption of normal glucocorticoid function is linked to metabolic disease, such as Cushing's syndrome. Glucocorticoids are also elevated in many forms of obesity, suggesting that there are bidirectional effects of these potent hormones on metabolism and metabolic function...
May 15, 2017: Endocrinology
https://www.readbyqxmd.com/read/28488756/cyclic-vomiting-syndrome-in-adults-and-children-a-hypothesis
#4
Sylvain Redon, Cécile Mareau, Eric Guedj, Anne Donnet
OBJECTIVE: To see how patients' clinical descriptions compare to the third classification of International Classification of Headache Disorders (ICHD-III beta). BACKGROUND: CVS is an episodic syndrome associated with migraine. It is a rare disorder of childhood and adulthood. New criteria are proposed in the third classification of International Classification of Headache Disorders. METHODS: This study describes children and adults' CVS characteristics at a French tertiary-care center, according to the ICHD-II and ICHD-III beta criteria...
May 10, 2017: Headache
https://www.readbyqxmd.com/read/28488608/epilepsy-surgery-in-children
#5
REVIEW
Sita Jayalakshmi, Sudhindra Vooturi, Swapan Gupta, Manas Panigrahi
Approximately 60% of all patients with epilepsy suffer from focal epilepsy syndromes. In approximately 15% of these patients, the seizures are not adequately controlled with anticonvulsive drugs, and such patients are potential candidates for surgical treatment and majority are children. Epilepsy surgery in children, who have been carefully chosen, can result in either seizure freedom or a marked (>90%) reduction in seizures in approximately two-third of children with intractable seizures. In the multimodality presurgical evaluation approach, sufficient concordance should be established among various independent investigations, thus identifying the location and extent of the epileptogenic zone with a high degree of confidence...
May 2017: Neurology India
https://www.readbyqxmd.com/read/28479374/cafeteria-diet-differentially-alters-the-expression-of-feeding-related-genes-through-dna-methylation-mechanisms-in-individual-hypothalamic-nuclei
#6
Gisela Paola Lazzarino, María Florencia Andreoli, María Florencia Rossetti, Cora Stoker, María Virgina Tschopp, Enrique Hugo Luque, Jorge Guillermo Ramos
We evaluated the effect of cafeteria diet (CAF) on the mRNA levels and DNA methylation state of feeding-related neuropeptides, and neurosteroidogenic enzymes in discrete hypothalamic nuclei. Besides, the expression of steroid hormone receptors was analyzed. Female rats fed with CAF from weaning increased their energy intake, body weight, and fat depots, but did not develop metabolic syndrome. The increase in energy intake was related to an orexigenic signal of paraventricular (PVN) and ventromedial (VMN) nuclei, given principally by upregulation of AgRP and NPY...
May 4, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28476224/molecular-and-genetic-aspects-of-congenital-isolated-hypogonadotropic-hypogonadism
#7
REVIEW
Lorena Guimaraes Lima Amato, Ana Claudia Latronico, Leticia Ferreira Gontijo Silveira
Congenital isolated hypogonadotropic hypogonadism (IHH) is a clinically and genetically heterogenous disorder characterized by abnormal synthesis, secretion, or action of gonadotropin-releasing hormone, a key hypothalamic decapeptide that orchestrates the reproductive axis. Several modes of inheritance have been identified. A growing list of causative genes has been implicated in the molecular pathogenesis of syndromic and nonsyndromic IHH, largely contributing for better understanding the complex neuroendocrine control of reproduction...
June 2017: Endocrinology and Metabolism Clinics of North America
https://www.readbyqxmd.com/read/28475119/oral-treatment-with-the-ghrelin-receptor-agonist-hm01-attenuates-cachexia-in-mice-bearing-colon-26-c26-tumors
#8
Fabienne O Villars, Claudio Pietra, Claudio Giuliano, Thomas A Lutz, Thomas Riediger
The gastrointestinal hormone ghrelin reduces energy expenditure and stimulates food intake. Ghrelin analogs are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to investigate whether oral treatment with the non-peptidergic ghrelin receptor agonist HM01 counteracts CACS in colon-26 (C26) tumor-bearing mice. The C26 tumor model is characterized by pronounced body weight (BW) loss and muscle wasting in the absence of severe anorexia. We analyzed the time course of BW loss, body composition, muscle mass, bone mineral density, and the cytokines interleukin-6 (IL-6) and macrophage-inhibitory cytokine-1 (MIC-1)...
May 5, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28472148/genetic-analysis-of-single-minded-1-gene-in-early-onset-severely-obese-children-and-adolescents
#9
Daniela Stanikova, Marek Buzga, Patrik Krumpolec, Martina Skopkova, Martina Surova, Barbara Ukropcova, Lubica Ticha, Miroslava Petrasova, Dominika Gabcova, Miroslava Huckova, Lucie Piskorova, Jan Bozensky, Marian Mokan, Jozef Ukropec, Ivona Zavacka, Iwar Klimes, Juraj Stanik, Daniela Gasperikova
BACKGROUND: Inactivating mutations of the hypothalamic transcription factor singleminded1 (SIM1) have been shown as a cause of early-onset severe obesity. However, to date, the contribution of SIM1 mutations to the obesity phenotype has only been studied in a few populations. In this study, we screened the functional regions of SIM1 in severely obese children of Slovak and Moravian descent to determine if genetic variants within SIM1 may influence the development of obesity in these populations...
2017: PloS One
https://www.readbyqxmd.com/read/28469924/anorexia-cachexia-syndrome-like-hypothalamic-neuroendocrine-dysfunction-in-a-patient-with-a-papillary-craniopharyngioma
#10
Lourdes Balcázar-Hernández, Guadalupe Vargas-Ortega, Yelitza Valverde-García, Victoria Mendoza-Zubieta, Baldomero González-Virla
The craniopharyngiomas are solid cystic suprasellar tumors that can present extension to adjacent structures, conditioning pituitary and hypothalamic dysfunction. Within hypothalamic neuroendocrine dysfunction, we can find obesity, behavioral changes, disturbed circadian rhythm and sleep irregularities, imbalances in the regulation of body temperature, thirst, heart rate and/or blood pressure and alterations in dietary intake (like anorexia). We present a rare case of anorexia-cachexia syndrome like a manifestation of neuroendocrine dysfunction in a patient with a papillary craniopharyngioma...
2017: Endocrinology, Diabetes & Metabolism Case Reports
https://www.readbyqxmd.com/read/28469921/gonadotrophin-abnormalities-in-an-infant-with-lowe-syndrome
#11
Bronwen E Warner, Carol D Inward, Christine P Burren
SUMMARY: This case, presenting with bilateral impalpable testes, illustrates the relevance of a broad differential disorders of sex development case management. It provides new insights on hypothalamic-pituitary-gonadal (HPG) axis and testicular function abnormalities in the multisystem disorder of Lowe syndrome. Lowe syndrome, also known as oculocerebrorenal syndrome, is a rare disorder characterised by eye abnormalities, central nervous system involvement and proximal renal tubular acidosis...
2017: Endocrinology, Diabetes & Metabolism Case Reports
https://www.readbyqxmd.com/read/28461749/treatment-resistant-lennox-gastaut-syndrome-therapeutic-trends-challenges-and-future-directions
#12
REVIEW
Adam P Ostendorf, Yu-Tze Ng
Lennox-Gastaut syndrome is a severe, childhood-onset electroclinical syndrome comprised of multiple seizure types, intellectual and behavioral disturbances and characteristic findings on electroencephalogram of slow spike and wave complexes and paroxysmal fast frequency activity. Profound morbidity often accompanies a common and severe seizure type, the drop attack. Seizures often remain refractory, or initial treatment efficacy fades. Few individuals are seizure free despite the development of multiple generations of antiseizure medications over decades and high-level evidence on several choices...
2017: Neuropsychiatric Disease and Treatment
https://www.readbyqxmd.com/read/28458903/using-kisspeptin-to-assess-gnrh-function-in-an-unusual-case-of-primary-amenorrhoea
#13
S Vimalesvaran, S Narayanaswamy, L Yang, J K Prague, A Buckley, A D Miras, S Franks, K Meeran, W S Dhillo
SUMMARY: Primary amenorrhoea is defined as the failure to commence menstruation by the age of 15 years, in the presence of normal secondary sexual development. The potential causes of primary amenorrhoea extend from structural to chromosomal abnormalities. Polycystic ovarian syndrome (PCOS) is a common cause of secondary amenorrhoea but an uncommon cause of primary amenorrhoea. An early and prompt diagnosis of PCOS is important, as up to 30% of these women are predisposed to glucose intolerance and obesity, with the subgroup of women presenting with primary amenorrhoea and PCOS displaying a higher incidence of metabolic dysfunction...
2017: Endocrinology, Diabetes & Metabolism Case Reports
https://www.readbyqxmd.com/read/28458232/cortisol-mediator-of-association-between-alzheimer-s-disease-and-diabetes-mellitus
#14
REVIEW
Elena Notarianni
Numerous epidemiologic studies have identified an independent association between Alzheimer's disease (AD) and diabetes mellitus (DM), which remains unexplained. This review contends that the association is mediated by mild hypercortisolemia that is manifested in AD by early stages, as empirical evidence indicates that hypercortisolemia is diabetogenic even at subclinical levels. Subclinical Cushing's syndrome is discussed as the paradigm. It is proposed that hypercortisolemia increases the risk of pre-diabetes and DM during early AD and the preceding decades...
April 23, 2017: Psychoneuroendocrinology
https://www.readbyqxmd.com/read/28449321/a-review-of-associated-controversies-surrounding-glucocorticoid-use-in-veterinary-emergency-and-critical-care
#15
Maya A Aharon, Jennifer E Prittie, Kate Buriko
OBJECTIVE: To review the literature in human and veterinary medicine regarding the indications for, efficacy of, and controversies surrounding glucocorticoid (GC) administration in the emergency and critical care (ECC) setting, and to provide an overview of the most commonly used synthetic GC formulations. MEDICATIONS: Synthetic GCs vary in GC and mineralocorticoid potency, hypothalamic pituitary axis suppression, duration of action, route of administration, and clinical indication for use...
May 2017: Journal of Veterinary Emergency and Critical Care
https://www.readbyqxmd.com/read/28448550/priority-target-conditions-for-algorithms-for-monitoring-children-s-growth-interdisciplinary-consensus
#16
Pauline Scherdel, Rachel Reynaud, Christine Pietrement, Jean-François Salaün, Marc Bellaïche, Michel Arnould, Bertrand Chevallier, Hugues Piloquet, Emmanuel Jobez, Jacques Cheymol, Emmanuelle Bichara, Barbara Heude, Martin Chalumeau
BACKGROUND: Growth monitoring of apparently healthy children aims at early detection of serious conditions through the use of both clinical expertise and algorithms that define abnormal growth. Optimization of growth monitoring requires standardization of the definition of abnormal growth, and the selection of the priority target conditions is a prerequisite of such standardization. OBJECTIVE: To obtain a consensus about the priority target conditions for algorithms monitoring children's growth...
2017: PloS One
https://www.readbyqxmd.com/read/28448064/changes-in-thyroid-hormone-concentrations-during-neonatal-extracorporeal-membrane-oxygenation
#17
L Leeuwen, A F J van Heijst, J van Rosmalen, Y B de Rijke, L W J E Beurskens, D Tibboel, E L T van den Akker, H IJsselstijn
OBJECTIVE: Thyroid hormone concentrations can be disturbed during critical illness. Our aim was to determine changes in thyroid hormone concentrations during neonatal extracorporeal membrane oxygenation (ECMO). STUDY DESIGN: We included 21 ECMO-treated neonates. Age-specific s.d. scores (SDS) of free and total thyroxine (FT4; TT4), reverse and total triiodothyronine (rT3; TT3), thyroid-stimulating hormone (TSH) and thyroxine-binding globulin (TBG) were determined at six fixed time-points...
April 27, 2017: Journal of Perinatology: Official Journal of the California Perinatal Association
https://www.readbyqxmd.com/read/28434547/stress-dose-corticosteroid-versus-placebo-in-neonatal-cardiac-operations-a-randomized-controlled-trial
#18
Pertti K Suominen, Juho Keski-Nisula, Tiina Ojala, Paula Rautiainen, Timo Jahnukainen, Johanna Hästbacka, Pertti J Neuvonen, Olli Pitkänen, Jussi Niemelä, Anu Kaskinen, Jukka Salminen, Risto Lapatto
BACKGROUND: Corticosteroids can improve the hemodynamic status of neonates with postoperative low cardiac output syndrome after cardiac operations. This study compared a prophylactically administered stress-dose corticosteroid (SDC) regimen against placebo on inflammation, adrenocortical function, and hemodynamic outcome. METHODS: Forty neonates undergoing elective open heart operations were randomized into two groups. The SDC group received perioperatively 2 mg/kg methylprednisolone, and 6 hours after the operation, a hydrocortisone infusion (0...
April 20, 2017: Annals of Thoracic Surgery
https://www.readbyqxmd.com/read/28433974/hypoactive-hypoalert-behaviour-and-thalamic-hypometabolism-due-to-intracranial-hypotension
#19
Seamus Kearney, Peter Flynn, Simon Hughes, Wendy Spence, Mark Owen McCarron
A 47-year-old man presented with a 9-year history of a hypoalert hypoactive behaviour syndrome, caused by the deep brain swelling variant of spontaneous intracranial hypotension. Along with apathy with retained cognition, he had stable ataxia, impaired upgaze and episodes of central apnoea. MRI brain showed a sagging brainstem, pointed ventricles and reduced angle between the vein of Galen and the straight sinus, but no meningeal enhancement or subdural collections. A dopamine transporter scan showed preganglionic dopamine receptor deficiency; a fluorodeoxy glucose positron emission tomography scan showed bilateral hypothalamic hypometabolism...
April 22, 2017: Practical Neurology
https://www.readbyqxmd.com/read/28432042/syndrome-of-inappropriate-antidiuretic-hormone-accompanied-by-bilateral-hypothalamic-and-anterior-thalamic-lesions-with-serum-antiaquaporin-4-antibody
#20
Kosuke Inoue, Takahiro Nakayama, Aya Kamisawa, Jun Saito
We described a rare case of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and severe unconsciousness accompanied by bilateral hypothalamic and anterior thalamic lesions with positive serum antiaquaporin 4 (AQP4) antibody. A 29-year-old man was admitted to our hospital due to the subacute progression of an unconscious state. He was observed to be hyponatraemic secondary to SIADH. Brain MRI showed bilateral hypothalamic and anterior thalamic lesions. Anti-AQP4 antibody was detected in his serum...
April 20, 2017: BMJ Case Reports
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