RESUMO
Protein arginine methyltransferases (PRMTs) catalyze the methylation of the terminal nitrogen atoms of the guanidino group of arginine of protein substrates. The aberrant expression of these methyltransferases is linked to various diseases, making them promising therapeutic targets. Currently, PRMT inhibitors are at different stages of clinical development, which validated their significance as drug targets. Structural Genomics Consortium (SGC) has reported several small fragment inhibitors as Class I PRMT inhibitors, which can be the starting point for rational drug development. Herein, we report the successful application of a fragment-based approach toward the discovery of selective Class I PRMT inhibitors. Structure-based ligand optimization was performed by strategic incorporation of fragment hits on the drug-like quinazoline core and subsequent fragment growth in the desired orientation towards identified hydrophobic shelf. A clear SAR was established, and the lead compounds 55 and 56 displayed potent inhibition of Class I PRMTs with IC50 values of 92 nM and 37 nM against PRMT4. We report the systematic development of potent Class I PRMT inhibitors with good potency and about 100-fold selectivity when tested against a panel of 31 human DNA, RNA, and protein lysine and arginine methyltransferases. These improved small molecules will provide new options for the development of novel potent and selective PRMT4 inhibitors.
Assuntos
Desenho de Fármacos , Proteína-Arginina N-Metiltransferases , Humanos , Desenvolvimento de Medicamentos , Arginina , CatáliseRESUMO
OBJECTIVE@#To observe the clinical efficacy of chiropractic plus plum-blossom needling combined with flexibility training for attention deficit in mentally-retarded adolescents.@*METHODS@#Thirty adolescents with mild mental retardation were randomly divided into a medical rehabilitation plus flexibility training group (10 cases, 2 cases dropped off), a flexibility training group (10 cases, 1 case dropped off) and a control group (10 cases). The patients in the flexibility training group received flexibility training, once every other day, 3 times a week for 12 weeks. The patients in the medical rehabilitation plus flexibility training group received chiropractic and plum-blossom needling at Baihui (GV 20) and Sishencong (EX-HN 1) on the basis of the treatment in the flexibility training group, once every other day, 3 times a week for 12 weeks. The patients in the control group did not receive any targeted physical training and medical rehabilitation. Tobii Pro Spectrum eye movement instrument was used to test the attention concentration (T), attention span (M), attention transfer (γ%) and attention distribution (η).@*RESULTS@#Compared before treatment, T and M in the medical rehabilitation plus flexibility training group and the flexibility training group were increased after treatment (P<0.01, P<0.05), and γ% in the medical rehabilitation plus flexibility training group was increased after treatment (P<0.05). The increasing range of T, M and γ% in the medical rehabilitation plus flexibility training group and the flexibility training group was greater than that in the control group (P<0.01), and the increasing range of T and γ% in the medical rehabilitation plus flexibility training group was greater than that in the flexibility training group (P<0.05).@*CONCLUSION@#The chiropractic plus plum blossom needling combined with flexibility training can improve the attention deficit in mentally-retarded adolescents.
Assuntos
Adolescente , Humanos , Terapia por Acupuntura , Quiroprática , Flores , Prunus domestica , Procedimentos Cirúrgicos VascularesRESUMO
Current states of traumatic eye injury are reviewed in terms of epidemiology in the developing countries and developed countries, causes of the trauma, eye injury types, traumatic eye injury diagnostic methods and treatments. Trauma-caused vision-threatening conditions such as open global injury, traumatic optic neuropathy and proliferative vitreoretinopathy are particularly discussed. Also the most updated clinic research in China as Eye Injury Vitrectomy Study is discussed. At the end, the current achievements and research in traumatic eye injury in the world are summerized.
Assuntos
Humanos , China , Traumatismos Oculares , Diagnóstico por Imagem , Terapêutica , Traumatismos do Nervo Óptico , Terapêutica , Vitrectomia , Vitreorretinopatia Proliferativa , TerapêuticaRESUMO
Background Recently,the number of randomized controlled trials on ophthalmic diseases that published in international journals from mainland China has increased gradually.There is no systematic summary in this field.Objective To systematically search and analyze the distribution of ophthalmic diseases related randomized controlled trials (RCT) published in SCI journals from mainland China up to November,2012.Methods The search was performed on Pubmed using “Ophthalmology”,“Eye” and all of their inferior subjective terms,with type of literature being limited as randomized controlled trial,and country as China.All retrieved papers were screened,data extracted and analyzed.Results There were 68 ophthalmic diseases related RCT papers published from mainland China since 1989.After 2005,the number of RCT papers from mainland China increased quickly with 7 in 2006,11 in 2009,and 15 in 2011.The 68 RCT papers were focused on cataract,optometry,glaucoma,corneal and conjunctival diseases,ophthalmic immune and pharmacology,and fundus diseases.The RCT papers were published in a total of 35 SCI journals including most kinds of ophthalmic journals such as Ophthalmology,IOVS and a few journals on other specialty.The journal Clin Experiment Ophthalmol had the maximum RCT papers from China (8 papers).The 68 RCT papers came from 26 departments in mainland China,mainly from the hospitals affiliated to medical university in Guangzhou,Beijing,Shanghai,Wenzhou and Hangzhou.Conclusions The number of ophthalmic diseases related RCT papers published in SCI journals from mainland China increased continuously.The papers were mainly focused on cataract,optomctry and glaucoma.The number of these papers,however,was still small and imbalance between districts existed.
RESUMO
<p><b>OBJECTIVE</b>To observe the therapeutic efficacy and the mechanism of Chinese medicine eye-patch with invigorating blood circulation and detoxification on asthenopia.</p><p><b>METHODS</b>A total of 180 rabbits were subjected to three tests, namely the skin microcirculation, the microvascular regeneration in the skin and the skin temperature change, with 60 rabbits for each test. The rabbits in each test were randomly and equally divided into three groups: the normal control group was treated with physiological saline on naked back once per day, the low dose group was treated with the eye-patch on naked back for 15 min once per day, while the high dose group was treated for three times per day. Forty Hartley guinea pigs were randomly and equally divided into four groups for the muscle tone test: the normal control group was treated with physiological saline on naked back, the model group was treated without any medication, the low dose group was treated with the eye-patch on naked back for 10 min once per day, while the high dose group was treated for three times per day. All treatments were continued for 14 days until the termination of the test. The microcirculatory blood flow was observed by using a video-microscopy system. The histological sections were used to detect the microvascular regeneration by observing the expression of factor VIII. The temperature changes on the skin surface were measured by using infrared thermometer, and the muscle tone was tested by the electromyography.</p><p><b>RESULTS</b>In compare with the normal or the model group, the improvement in the skin microcirculation and the blood vascular regeneration, and the decreasing in the muscle tone in low dose and high dose groups were statistically significant with confident level at P<0.05.</p><p><b>CONCLUSIONS</b>The eye-patch with invigorating blood circulation and detoxification has great enhancement in blood vascular regeneration and skin microcirculation, and great improvement in the indexes for muscle tone. The study explains certain therapeutic efficacy and mechanism of the eye-patch and shows that it could reduce the symptoms for patients with asthenopia.</p>
Assuntos
Animais , Coelhos , Astenopia , Tratamento Farmacológico , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas , Farmacologia , Usos Terapêuticos , Cobaias , Microcirculação , Substâncias Protetoras , Farmacologia , Usos Terapêuticos , Regeneração , Fluxo Sanguíneo Regional , Pele , Temperatura CutâneaRESUMO
<p><b>BACKGROUND</b>Screening for amblyopia at earliest is important for early treatment and better prognosis. This study aimed to evaluate the validity of uncorrected distant and near visual acuity (VA) and stereoacuity for screening amblyopia in grade-1 students in primary school in central China.</p><p><b>METHODS</b>By stratified cluster sampling, 3112 grade-1 students from 11 Anyang primary schools were selected for the study. All the participants underwent uncorrected distant and near VA, stereopsis test, cycloplegic refraction, best corrected VA (BCVA), cover test, and ocular movement examination. VA was measured with a logarithm of the minimum angle of resolution (logMAR) chart. Stereoacuity was measured with the Lang II stereo card and TNO test. Amblyopia was defined as the BCVA less than or equal to 0.1 logMAR units of any eye in the absence of significant pathological abnormalities. The sensitivity, specificity, and positive and negative predictive value of uncorrected VA and stereoacuity for amblyopia were analyzed.</p><p><b>RESULTS</b>Out of the 3112 eligible students, 2893 (92.96%) completed the examinations. The average age of the students was (7.10 ± 0.41) years. Screened by distant VA with low cutoff (logMAR 0.1), high cutoff (logMAR 0.0), and near VA (logMAR 0.0), 31.64%, 73.18%, and 50.23% students were abnormal, respectively. Screened by stereopsis test, only 4.69% students were abnormal. Diagnosed by a senior pediatric ophthalmologist, 61 students had amblyopia. The sensitivities of distant VA with low/high cutoff and near VA were 92.31%, 100%, and 80.77%, respectively, whereas that of stereoacuity by TNO test was 15.38%. Simultaneous testing of either two of the three tests improved the sensitivity.</p><p><b>CONCLUSIONS</b>Distant VA test of high cutoff alone displays a high sensitivity but a low specificity. Simultaneous testing of distant VA of low cutoff and stereoacuity is a better choice to balance between sensitivity and specificity.</p>
Assuntos
Criança , Pré-Escolar , Feminino , Humanos , Masculino , Ambliopia , Diagnóstico , China , Percepção de Profundidade , Instituições Acadêmicas , Seleção Visual , Acuidade Visual , FisiologiaRESUMO
OBJECTIVE: Visual search is an important attention process that precedes the information processing. Visual search also mediates the relationship between cognition function (attention) and social cognition (such as facial expression identification). However, the association between visual attention and social cognition in patients with schizophrenia remains unknown. The purposes of this study were to examine the differences in visual search performance and facial expression identification between patients with schizophrenia and normal controls, and to explore the relationship between visual search performance and facial expression identification in patients with schizophrenia. METHODS: Fourteen patients with schizophrenia (mean age=46.36+/-6.74) and 15 normal controls (mean age=40.87+/-9.33) participated this study. The visual search task, including feature search and conjunction search, and Japanese and Caucasian Facial Expression of Emotion were administered. RESULTS: Patients with schizophrenia had worse visual search performance both in feature search and conjunction search than normal controls, as well as had worse facial expression identification, especially in surprised and sadness. In addition, there were negative associations between visual search performance and facial expression identification in patients with schizophrenia, especially in surprised and sadness. However, this phenomenon was not showed in normal controls. CONCLUSION: Patients with schizophrenia who had visual search deficits had the impairment on facial expression identification. Increasing ability of visual search and facial expression identification may improve their social function and interpersonal relationship.
Assuntos
Humanos , Povo Asiático , Processamento Eletrônico de Dados , Cognição , Expressão Facial , EsquizofreniaRESUMO
Background Whether the wearing of bifocal lenses can delay the development of myopia in school childhood is in controversy.To assess the effect of bifocal lenses using evidence-based medicine method is of important significance.Objective Present study was to compare the effect of bifocal lenses with single vision lenses in retarding myopia progression in school-aged myopic children.Methods This was a evidence-based medicine study.The systematical literature search was performed from MEDLINE(1966 to October 2010),EMBASE(1974 to October 2010),Cochrane Library,Chinese Biomedical Database(1978 to October 2010),and Chinese Clinical Trial Registry combined with hand searching of related bibliographies of journals and books were applied to collect the randomized-controlled clinical trial about bifocal lenses.Screening,evaluation and data extraction of the retrieved literature were performed by two investigators independently.Mata-analysis was used to assess the progression of refraction and axial length among included randomized clinical trials.Results Three high-quality randomized-controlled clinical trials meeting the inclusion criterion were included in this meta-analysis.The results showed that the weighted mean difference in progression of refraction was 0.22D between bifocal lenses and single vision lenses(95% CI:-0.24-0.67),and the difference was statistical insignificance(P=0.35).The weighted mean difference in progression of refraction during the follow-up durations of 6,12,18,24 and >30 months were 0.15(95% CI:-0.09-0.38),0.17(95% CI:-0.05-0.39),0.42(95% CI:-0.14-0.98),0.23(95% CI:-0.21-0.66) and 0.03(95% CI:-0.40-0.46),respectively without statistical significance.The weighted mean difference in elongation of axial length between two interventions was -0.17mm(95% CI:-0.26-0.08) with a statistically significance(P=0.000).Conclusion Based on currently available studies,bifocal lenses could not significantly slow the progression of myopia in myopic school-aged children in comparison with single vision lenses.Because only few high-quality studies are currently available,this conclusion need to be supported by more large-sample-size clinical trials.
RESUMO
<p><b>OBJECTIVE</b>To investigate the relationship between the polymorphisms of UGT1A6 genes and anti-tuberculosis drug induced hepatic-injury (ADIH).</p><p><b>METHODS</b>202 cases and 239 controls were collected and a case-control study was conducted. Information on related risk factors of tuberculosis was collected. The genotypes of UGT1A6-19T/G, UGT1A6-308C/A and UGT1A6-541A/G genetic polymorphisms were detected by polymerase chain reaction and restriction fragment length polymorphism technique (PCR-RFLP) in patients received anti-tuberculosis therapy. The Hha I, Dpn II and Nsi I enzyme were employed. Univariate and multivariate conditional logistic analyses were conducted using SPSS13.0 for windows software.</p><p><b></b>RESULTS</p><p><b>RESULTS</b>The allele frequency of gene UGT1A6-19T/T, UGT1A6-19T/G, UGT1A6-19G/G, GT1A6-308C/C, UGT1A6-308C/A, UGT1A6-308A/A, UGT1A6-541AA, UGT1A6-541A/G and UGT1A6-541G/G in ADIH group were 51.5%, 39.6%, 8.9%, 52.0%, 40.6%, 7.4%, 57.9%, 33.7%, 8.4% and 71.1%, 25.5%, 3.3%, 79.1%, 19.2%, 1.7%, 79.5%, 19.2%, 1.3% in control group, respectively. Univariate analysis demonstrated that the frequency of UGT1A6-19T/G, UGT1A6-308C/A and UGT1A6-541A/G genotype in cases were significantly higher than that in controls (P less than 0.05).</p><p><b>CONCLUSION</b>A positive association is found between UGT1A6 genotype and the occurrence of ADIH. The synergetic effect is proved on susceptibility to pulmonary tuberculosis between UGT1A6 mutant genotypes.</p>