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Bettina Balint, Niccolò E Mencacci, Enza Maria Valente, Antonio Pisani, John Rothwell, Joseph Jankovic, Marie Vidailhet, Kailash P Bhatia
Dystonia is a neurological condition characterized by abnormal involuntary movements or postures owing to sustained or intermittent muscle contractions. Dystonia can be the manifesting neurological sign of many disorders, either in isolation (isolated dystonia) or with additional signs (combined dystonia). The main focus of this Primer is forms of isolated dystonia of idiopathic or genetic aetiology. These disorders differ in manifestations and severity but can affect all age groups and lead to substantial disability and impaired quality of life...
September 20, 2018: Nature Reviews. Disease Primers
Zhiqi Tang, Lijuan Liu, Yujie Guo, Guoxiong Deng, Meixiang Chen, Jinru Wei
The present study examined whether exendin‑4 (Ex4) can improve the endothelial dysfunction of apolipoprotein E knockout (APOE‑KO) mice fed a high‑cholesterol diet and the potential mechanism by which it acts. Genetically wild‑type (WT) C57BL/6 mice and APOE‑KO mice of C57BL/6 background, were each randomly assigned to receive either Ex4 treatment (Ex4‑treated, for 8 weeks) or not (control). The 4 groups were fed the same high‑cholesterol diet for 8 weeks. The following were measured at the end of the eighth week: Endothelium‑dependent vasodilation of the arteries; plasma nitric oxide (NO) and metabolic index; levels of endothelial NO synthase (eNOS); phosphorylated eNOS (p‑eNOS; Ser‑1,177); guanosine triphosphate cyclohydrolase‑1 (GCH1); and tetrahydrobiopterin (THB)...
September 2018: Molecular Medicine Reports
Nilanjana Sadhu, Ellie H Jhun, Yingwei Yao, Ying He, Robert E Molokie, Diana J Wilkie, Zaijie Jim Wang
The multidimensional nature of pain in sickle cell disease (SCD) has rendered its therapeutic management extremely challenging. In this study, we explored the role of five single nucleotide polymorphisms (SNPs) of candidate gene GCH1 in SCD pain. Composite pain index (CPI) scores and acute care utilization rates were used as phenotype markers. Rs8007267 was associated with chronic pain (additive model: B = -3.76, p = 0.037; dominant model: B = -5.61, p = 0.021) and rs3783641 (additive model: incident rate ratio [IRR] = 1...
July 19, 2018: Experimental Hematology
Nana Li, Ping Yu, Bin Rao, Ying Deng, Yixiong Guo, Yushan Huang, Lijie Ding, Jun Zhu, Huanming Yang, Jian Wang, Jian Guo, Fang Chen, Zhen Liu
Background The overall incidence of hyperphenylalaninemia (HPA) in China is 1:11,763, with tetrahydrobiopterin (BH4) deficiency accounting for 8.55% of patients with HPA in the mainland. Much progress has been made in the diagnosis and treatment of BH4 deficiency with the introduction of neonatal screening in China. However, the screening rate is still low and screening is not universally available. Methods A total of 44 BH4-deficient patients were enrolled in this study, of which 39 were diagnosed with BH4 deficiency, while the remaining five showed typical characteristics of BH4 deficiency at a later period...
August 28, 2018: Journal of Pediatric Endocrinology & Metabolism: JPEM
Toshiharu Nagatsu, Akira Nakashima, Hiroshi Ichinose, Kazuto Kobayashi
Parkinson's disease (PD) is an aging-related movement disorder mainly caused by a deficiency of neurotransmitter dopamine (DA) in the striatum of the brain and is considered to be due to progressive degeneration of nigro-striatal DA neurons. Most PD is sporadic without family history (sPD), and there are only a few percent of cases of young-onset familial PD (fPD, PARKs) with the chromosomal locations and the genes identified. Tyrosine hydroxylase (TH), tetrahydrobiopterin (BH4)-dependent and iron-containing monooxygenase, catalyzes the conversion of L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), which is the initial and rate-limiting step in the biosynthesis of catecholamines (DA, noradrenaline, and adrenaline)...
July 11, 2018: Journal of Neural Transmission
Lamia Heikal, Anna Starr, Dania Hussein, Jesus Prieto-Lloret, Phil Aaronson, Lea Ann Dailey, Manasi Nandi
Reduced nitric oxide (NO) bioavailability correlates with impaired cardiovascular function. NO is extremely labile and has been challenging to develop as a therapeutic agent. However, NO bioavailability could be enhanced by pharmacologically targeting endogenous NO regulatory pathways. Tetrahydrobiopterin, an essential cofactor for NO production, is synthesized by GTP cyclohydrolase-1 (GCH1), which complexes with GCH1 feedback regulatory protein (GFRP). The dietary amino acid l-phenylalanine activates this complex, elevating vascular BH4 ...
June 2018: JACC. Basic to Translational Science
X Yang, H Zhang, J Shang, G Liu, T Xia, C Zhao, G Sun, H Dou
Dogs were domesticated by human and originated from wolves. Their evolutionary relationships have attracted much scientific interest due to their genetic affinity but different habitats. To identify the differences between dogs and wolves associated with domestication, we analysed the blood transcriptomes of wolves and dogs by RNA-Seq. We obtained a total of 30.87 Gb of raw reads from two dogs and three wolves using RNA-Seq technology. Comparisons of the wolf and dog transcriptomes revealed 524 genes differentially expressed genes between them...
August 2018: Animal Genetics
Hiroyo Yoshino, Kenya Nishioka, Yuanzhe Li, Yutaka Oji, Genko Oyama, Taku Hatano, Yutaka Machida, Yasushi Shimo, Arisa Hayashida, Aya Ikeda, Kaoru Mogushi, Yasuro Shibagaki, Ai Hosaka, Hiroshi Iwanaga, Junko Fujitake, Takekazu Ohi, Daigo Miyazaki, Yoshiki Sekijima, Mitsuaki Oki, Hirofumi Kusaka, Ken-Ichi Fujimoto, Yoshikazu Ugawa, Manabu Funayama, Nobutaka Hattori
Guanosine triphosphate cyclohydrolase I (GCH1) mutations are associated with increased risk for dopa-responsive dystonia (DRD) and Parkinson's disease (PD). Herein, we investigated the frequency of GCH1 mutations and clinical symptoms in patients with clinically diagnosed PD and DRD. We used the Sanger method to screen entire exons in 268 patients with PD and 26 patients with DRD, with the examinations of brain magnetic resonance imaging scans, striatal dopamine transporter scans, and [123 I] metaiodobenzylguanidine (MIBG) myocardiac scintigraphy scans...
August 2018: Journal of Neurology
Maija Kalliomäki, Anne-Li Lind, Alfhild Grönbladh, Ulf Gunnarsson, Gabriel Sandblom, Torsten Gordh, Fred Nyberg
Aim of investigation Persistent postoperative pain of some extent is seen in about 20% of patients after surgical operations, while 80% heal without chronic pain. The type of chronic pain that arises is mainly neuropathic, and is suggested to be in part regulated by genetic factors. In order to study the possible involvement of some candidate genes suggested to be involved in the processing of pain (BDNF, CACNA2D2, ORPM1, GRIK 3, GCH1 and TNF-α ), we performed a genetic association study in a well characterized clinical material of patients that had undergone surgery for inguinal hernia (n = 189)...
December 29, 2017: Scandinavian Journal of Pain
Arafat Nasser, Lisbeth Birk Møller
Background A great proportion of the variation in pain experience and chronicity is caused by heritable factors. Within the last decades several candidate genes have been discovered either increasing or decreasing pain sensitivity or the risk of chronic pain in humans. One of the most studied genes is the GCH1 gene coding for the enzyme GTP cyclohydrolase 1 (GCH1). GCH1 catalyses the initial and rate-limiting step in the biosynthesis of tetrahydrobiopterin (BH4). The main function of BH4 is regulation of monoamine and nitric oxide biosynthesis, all involved in nociceptive signalling...
April 1, 2014: Scandinavian Journal of Pain
Surawee Chuaiphichai, Victoria S Rashbrook, Ashley B Hale, Lucy Trelfa, Jyoti Patel, Eileen McNeill, Craig A Lygate, Keith M Channon, Gillian Douglas
GTPCH (GTP cyclohydrolase 1, encoded by Gch1 ) is required for the synthesis of tetrahydrobiopterin; a critical regulator of endothelial NO synthase function. We have previously shown that mice with selective loss of Gch1 in endothelial cells have mild vascular dysfunction, but the consequences of endothelial cell tetrahydrobiopterin deficiency in vascular disease pathogenesis are unknown. We investigated the pathological consequence of Ang (angiotensin) II infusion in endothelial cell Gch1 deficient ( Gch1 fl/fl Tie2cre) mice...
July 2018: Hypertension
Jun Ma, Lin Wang, Ying-Mai Yang, Xin-Hua Wan
BACKGROUND: Dystonia is a movement disorder with high clinical and genetic heterogeneity. Molecular diagnosis is important for an accurate diagnosis of dystonia. Targeted gene capture sequencing has been an effective method for screening multiple candidate genes simultaneously. This method, however, has been rarely reported to be used with dystonia patients. OBJECTIVES AND METHODS: To assess the effectiveness of the targeted gene capture sequencing in dystonia, we performed custom target gene capture followed by next-generation sequencing in dystonia patients from China...
July 15, 2018: Journal of the Neurological Sciences
Lingdan Chen, Chunli Liu, Dejun Sun, Tao Wang, Li Zhao, Wenli Chen, Mingjie Yuan, Jian Wang, Wenju Lu
Objective: Peripheral arterial disease (PAD) patients with diabetes mellitus suffer from impaired neovascularization after ischemia which results in poorer outcomes. MicroRNA (miR)-133a is excessively expressed in endothelial cells under diabetic conditions. Here, we test whether diabetes-induced miR-133a up-regulation is involved in the impaired capability of neovascularization in experimental PAD models. Methods and results: MiR-133a level was measured by quantitative RT-PCR and showed a higher expression level in the ischemic muscle from diabetic mice when compared with nondiabetic mice...
August 31, 2018: Bioscience Reports
Ya-Ping Yan, Bo Zhang, Ting Shen, Xiao-Li Si, Zhang-Yu Guo, Jun Tian, Cong-Ying Xu, Bao-Rong Zhang
Whole-exome sequencing of Parkinson's disease (PD) patients has revealed that the frequency of GTP-cyclohydrolase I (GCH1) variants was significantly higher in patients than in controls. GCH1 rs11158026 was also found to increase the risk of PD. To investigate genetic contribution of dopa-responsive dystonia-related genes to PD, GCH1, and tyrosine hydroxylase (TH) were tested in PD patients. A total of 859 study subjects comprising 421 patients with PD and 438 controls were recruited. For GCH1 gene, one known variant (c...
August 2018: Neurobiology of Aging
Marian Acevedo-Alvarez, Judy Yeh, Lery Alvarez-Lugo, Ming Lu, Nitin Sukumar, Warren G Hill, Toby C Chai
AIMS: Symptoms from overactive bladder (OAB) and cystitis secondary to urinary tract infection (UTI) can be similar in post-menopausal women. Effects of ovariectomy (OVX) on voiding behavior after lipopolysaccharide (LPS) intravesical exposure (surrogate for cystitis) in mice were measured. Urothelial genes associated with micturition changes were identified. METHODS: Female C57BL6/J mice underwent OVX or sham surgeries (n = 10 for each). Voiding spot assays (VSA) were performed prior to surgery, 4 weeks post-surgery, and each time after 3 consecutive days of transurethral instillation of LPS...
April 23, 2018: Neurourology and Urodynamics
Ming Zou, Rui Li, Jian-Yong Wang, Ke Wang, Ya-Nan Wang, Yang Li, Fei-Xue Ji, Sheng-Nan Sun, Shi-Shi Huang, Hui-Hui Fan, Chen-Ping Huang, Xiong Zhang, Jian-Hong Zhu
A recent large-scale European-originated genome-wide association data meta-analysis followed by a replication study identified 6 new risk loci for Parkinson's disease (PD), which include rs10797576/SIPA1L2, rs117896735/INPP5F, rs329648/MIR4697, rs11158026/GCH1, rs2414739/VPS13C, and rs8118008/DDRGK1. However, whether these new loci are associated with PD in Asian populations remain elusive. The INPP5F is nonpolymorphic in Asians. The present study aimed to understand the effects of the other 5 new loci in a Han Chinese population comprising 579 sporadic PD patients and 642 controls...
August 2018: Neurobiology of Aging
Gillian Douglas, Ashley B Hale, Jyoti Patel, Surawee Chuaiphichai, Ayman Al Haj Zen, Victoria S Rashbrook, Lucy Trelfa, Mark J Crabtree, Eileen McNeill, Keith M Channon
Aims: GTP cyclohydrolase I catalyses the first and rate-limiting reaction in the synthesis of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthases (NOS). Both eNOS and iNOS have been implicated in the progression of atherosclerosis, with opposing effects in eNOS and iNOS knockout mice. However, the pathophysiologic requirement for BH4 in regulating both eNOS and iNOS function, and the effects of loss of BH4 on the progression of atherosclerosis remains unknown. Methods and results: Hyperlipidemic mice deficient in Gch1 in endothelial cells and leucocytes were generated by crossing Gch1fl/flTie2cre mice with ApoE-/- mice...
August 1, 2018: Cardiovascular Research
Elsa Krim, Jerome Aupy, Fabienne Clot, Mickael Bonnan, Pierre Burbaud, Dominique Guehl
No abstract text is available yet for this article.
April 2018: Neurology. Genetics
Ruifang Wang, Nan Shen, Jun Ye, Lianshu Han, Wenjuan Qiu, Huiwen Zhang, Lili Liang, Yu Sun, Yanjie Fan, Lili Wang, Yu Wang, Zhuwen Gong, Huili Liu, Jianguo Wang, Hui Yan, Nenad Blau, Xuefan Gu, Yongguo Yu
BACKGROUND: Hyperphenylalaninemia (HPA) is an inherited metabolic disorder that is caused by a deficiency of phenylalanine hydroxylase (PAH) or tetrahydrobiopterin. The prevalence of HPA varies widely around the world. METHODS: A spectrum of HPA candidate genes in 1020 Chinese HPA patients was reported. Sanger sequencing, next generation sequencing (NGS), multiplex ligation-dependent probe amplification (MLPA) and quantitative real-time PCR (qRT-PCR) were applied to precisely molecular diagnose HPA patients...
June 2018: Clinica Chimica Acta; International Journal of Clinical Chemistry
Yi Ching Weng, Chun Chieh Wang, Yih Ru Wu
The typical clinical presentation of dopa-responsive dystonia, which is also called Segawa disease, is a young age of onset, with predominance in females, diurnal fluctuation of lower limb dystonia, and fair response to low-dose levodopa. This disease has both autosomal dominant and autosomal recessive inheritance. Autosomal dominant Segawa disease is caused by GCH1 mutation on chromosome 14q22.1-q22.2. Here, we report the case of a male patient with genetically confirmed Segawa disease and atypical presentations including no diurnal symptom fluctuation and insufficient response to levodopa...
February 2018: Brain and Behavior
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