AIMTo develop a new synthetic route for olmesartan medoxomil.

METHODSOlmesartan medoxomil was prepared from ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate via hydrolysis and lactonization to afford 4,4- dimethyl-2-propyl-4,6-dihydrofuro [3,4-d]-1H-imidazole-6-one which was condensed with 2-(triphenylmethyl)-5-[4'-(bromomethylbiphenyl)-2-yl] tetrazole, followed by esterification with 4-chloromethyl-5-methyl-1,3-dioxol-2-one, and deprotection. The chemical structure of the major impurity in condensation reaction is the regio-isomer in the imidazole moiety, and confirmed by single crystal X-ray diffraction. The corresponding regio-isomer of olmesartan medoxomil was synthesized from the impurity by similar method. Optimization of the condensation conditions reduced the impurity to a negligible quantity.

RESULTSSynthesis of olmesartan medoxomil by the new route gave a product of 60% yield and above 99.0% purity. The content of olmesartan medoxomil regio-isomer was effectively controlled to less than 0.1%.

CONCLUSIONA novel synthetic route for olmesartan medoxomil was developed successfully. The olmesartan medoxomil regio-isomer is reported for the first time.

Angiotensin II Type 1 Receptor Blockers ; chemical synthesis ; chemistry ; Animals ; Antihypertensive Agents ; chemical synthesis ; chemistry ; pharmacology ; Blood Pressure ; drug effects ; Imidazoles ; chemical synthesis ; chemistry ; pharmacology ; Molecular Structure ; Olmesartan Medoxomil ; Rats ; Stereoisomerism ; Tetrazoles ; chemical synthesis ; chemistry ; pharmacology

Hematopoietic progenitor kinase 1 ( HPK1 ) , also known as MAP4K1 , is a serine/threonine protein kinase and a member of the MAP4K family of mammalian Ste20-related pro¬tein kinases.Recent studies have found that HPK1 is assoeiated with the occurrence and progression of a variety of tumors, and may play an important role in some malignant tumors.This pa¬ per reviews the HPK1 signaling pathway, its relationship with tumor and drug development progress, so as to provide referenee for the research of HPK1 protein kinase.

Objective To analyze the molecular characteristics of the newly isolated two Japanese encephalitis virus strains(JEV) in Wuhan. Methods The mosquitoes were collected in Wuhan from April to October in 2009. The envelope (E) protein gene of JEV was detected using RT-PCR and sequenced.Sequence comparisons and phylogenetic analysis were conducted using DNAstar and MegAlign. Results Two Japanese encephalitis virus (JEV) strains (WHJX09-9, WHJX09-10 ) were isolated from Culex tritaeniorhynchus among 16 mosquito pools and identified as genotype I. The result showed that the homology of the two strains was 98. 9％ in nucleotides and 100％ in deduced amines. The comparison between the new genotype 1 JEV strains and live attenuated vaccine strain SA14-14-2 in E gene showed that the homology of nucleotide sequence was 87.4％ and 87.9％ ,the homology of amino acid was 96. 9％ (totol 15 amino acid were different) in E gene. The mutation sites of amino acid distributed among three different coding domain,but no antigen binding site and neurotoxin-involved site of amino acid were changed. Conclusion Wuhan had appeared a new genotype of JEV which was different from the former strain isolated in Wuhan,the new JEV strains still had neurotoxicity but had high homology with the vaccine strains adopted in Wuhan. The vaccine could still be adopted to prevent Japanese encephalitis if steps were take to eradicate mosquitos at the same time. laboratory surveillance were also an important task to build an early-warning mechanism against JEV.

OBJECTIVETo study the prevalence and clinical characteristics of the A to G mutation at nucleotide 3243 of the mitochondrial tRNA(Leu(UUR)) gene in familial diabetes in Shanghai, Jiangsu and Zhejiang Province of China.

METHODSThe mt3243 A to G mutation in 770 randomly selected, unrelated probands of diabetic pedigrees were screened by PCR-RFLP technique and PCR-direct sequencing. Genetic and clinical analyses were further performed in the probands and their family members.

RESULTSThirteen diabetic patients (13/770, 1.69%) with mt3243 A to G mutation were detected. Eleven diabetic patients and 8 normal glucose tolerance (NGT) first-degree relatives of these 13 probands were also found bearing the mutation. Seventeen patients were associated with sensory hearing loss. In the 24 patients harboring the mutation, the majority had lower body mass index (BMI), 18 showed typical maternal inheritance, 15 had sensory hearing loss, 13 had insulin resistance and 14 required insulin therapy due to secondary failure to oral hypoglycemic agents.

CONCLUSIONThe mutation of mt3243 A to G in the mitochondrial tRNA(Leu(UUR)) gene is an important cause of diabetes in Shanghai, Jiangsu and Zhejiang Province of China. Mitochondrial gene mutation diabetes (MDM) is clinically characterized by early onset, emaciation, maternal inheritance, sensorineural hearing loss, and lower islet beta cell function, and some have insulin resistance.

Asian Continental Ancestry Group ; genetics ; China ; epidemiology ; DNA, Mitochondrial ; genetics ; Deafness ; genetics ; Diabetes Mellitus ; genetics ; Genetic Testing ; Hearing Loss, Sensorineural ; genetics ; Humans ; Insulin Resistance ; genetics ; Molecular Sequence Data ; Mutation ; Prevalence ; RNA, Transfer, Amino Acyl ; genetics

OBJECTIVETo compare the therapeutic effect and indication between standard large trauma craniotomy and routine craniotomy.

METHODSThere were 97 patients in the standard large trauma craniotomy group and 110 patients in the routine craniotomy group. The mortality, postoperative ICP (intracranial pressure), ratio of pupil rebound, complication and results of six month follow-up after operation were compared between the two groups.

RESULTSFifteen patients (15.6%) died in the standard large trauma craniotomy group and 30 (27.7%) in the routine craniotomy group. The postoperative mean ICP was 3.75 kPa+/-1.89 kPa in the standard large trauma craniotomy group and 5.11 kPa+/-1.57 kPa in the routine craniotomy group. The pupil rebound was found in 47 patients (61.0%) in the standard large trauma craniotomy group and in 41 patients (46.1%) in the routine craniotomy group (P<0.01). The rate of complication was lower in the standard large trauma craniotomy group, but no obvious difference in long-term therapeutic effect was found between the two groups.

CONCLUSIONSStandard large trauma craniotomy can attenuate brain hernia and the mortality of the patients with acute subdural hematoma. The incidence of complication can also be decreased. But the long term life quality of the patients can not be improved.

Acute Disease ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Chi-Square Distribution ; Craniotomy ; standards ; Female ; Follow-Up Studies ; Hematoma, Subdural ; mortality ; surgery ; Humans ; Intracranial Pressure ; Male ; Middle Aged ; Quality of Life ; Treatment Outcome

OBJECTIVETo present a new neurovascular island flap for fingertip reconstruction.

METHODSBased on the transverse palmar branch of the digital artery, this flap was designed on the volar side of a digit and reversed to repair the fingertip defects.

RESULTS12 fingers in 11 patients were reconstructed using this flap. Of them, 11 flaps survived and one necrosed. The contour of the reconstructed fingers looked well.

CONCLUSIONThis new neurovascular island flap provides excellent padding and sensation for fingertip reconstruction. The technique is simple.

Adolescent ; Adult ; Female ; Finger Injuries ; surgery ; Fingers ; blood supply ; surgery ; Humans ; Male ; Middle Aged ; Reconstructive Surgical Procedures ; methods ; Skin Transplantation ; Surgical Flaps ; blood supply ; Young Adult

To investigate the influence of Anxin granules combined with tirofiban on acute myocardial infarction (AMI) Patients after elective percutaneous coronary intervention (PCI). One hundred and twenty AMI patients were randomly divided into treatment group and control group. The patients in the two groups were all given Tirofiban 30mins before PCI . The treatment group was added Anxin granules 30 mins before and after PCI. Tissue factor (TF) and von willebrand factor (vWF) were tested at 6 hours after operation. Syndromatology alteration of traditional Chinese medicine (TCM) and bleeding complications were observed at 4 weeks after operation. Both TF and vWF at 6 hours after operation of the treatment group was lower than the control group significantly (P < 0.01), while the condition of myocardial ischemia at 90 mins after operation of the treatment group was better than control group with significance. The syndromatology alteration of TCM especially spontaneous perspiration and hypodynamia of the treatment group were improved significantly compared to control group 4 weeks after operation. All patients in both groups had no bleeding complications and thrombopenia. The study suggests that Anxin granules combined with tirofiba can improve the clinical efficacy and the endothelial function of AMI patients after PCI with no increase in bleeding events.
Aged ; Angioplasty, Balloon, Coronary ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Humans ; Middle Aged ; Myocardial Infarction ; complications ; metabolism ; surgery ; Postoperative Hemorrhage ; drug therapy ; etiology ; metabolism ; prevention & control ; Thromboplastin ; metabolism ; von Willebrand Factor ; metabolism

OBJECTIVETo investigate the prevalence of mutations and sequence variations of glucokinase gene GCK in Chinese early-onset diabetes population.

METHODSThe study was conducted in 174 unrelated Chinese residents, including 80 nondiabetic controls, 94 probands of early-onset diabetes pedigree. Direct sequencing was performed to screen all 10 exons of glucokinase gene, including promoter and exon/intron junctions.

RESULTSNo mutations were identified in coding region, but several previously reported sequence variants were identified. 5'-untranslated region of exon 1a, 84 bp upstream of the translation initiation site GGCGG to GGGGG(early-onset diabetes group G allele frequency 0.106 vs control group 0.075, P=0.355); IVS1b+12 (A-->T) (early-onset diabetes group T allele frequency 0.005 vs non-identity of this variation in control group); IVS 5+29 (G-->T) (early-onset diabetes group T allele frequency 0.027 vs control group 0.019, P=0.731); IVS 9+8 (T-->C) (early-onset diabetes group C allele frequency 0.585 vs 0.694, P=0.044). A novel variation IVS 9+49 (G-->A) (early-onset diabetes group A allele frequency 0.011 vs control 0.006, P=1.000) was identified. There were no significant relationships of the exon 1a 5'-untransted region -84 bp(C-->G), IVS 5+29 (G-->T), IVS 9+8 (T-->C) and IVS 9+49 (G-->A) variants of GCK gene to the clinical variables such as plasma glucose, insulin, C-peptide and fasting lipid profile.

CONCLUSIONThe prevalence of structural mutations in glucokinase gene responsible for early-onset diabetes appears to be rare among Chinese patients.

Adult ; Base Sequence ; DNA Mutational Analysis ; Diabetes Mellitus, Type 2 ; blood ; genetics ; Female ; Genetic Predisposition to Disease ; genetics ; Glucokinase ; genetics ; Humans ; Lipids ; blood ; Male ; Mutation ; Pedigree ; Polymerase Chain Reaction

OBJECTIVETo investigate the dynamic expression of hypoxia inducible factor-1alpha (HIF-1alpha) and its clinical values in hepatocellular carcinoma (HCC).

METHODSThe dynamic changes of liver pathology, HIF-1alpha transcription and expression were observed through the hepatoma model. The self-control specimens from 35 human HCC patients were collected and the expression, cellular distribution, and clinicopathological features of HIF-1alpha and its gene was analyzed by immunohistochemistry, western blotting and nested- PCR, respectively.

RESULTSBoth levels of hepatic HIF-1alpha and HIF-1alpha mRNA expression increased during the HCC development course. The incidence of HIF-1alpha and the ratio of HIF-1alpha to beta-actin was 0% and 0.16+/-0.02 in the control rats, 77.8% and 0.29+/-0.04 in the denatured rats, 88.9% and 0.52+/-0.03 in the precancerous rats, and 100% and 0.84+/-0.02 in the cancerous rats respectively, with significant difference between the control group and any of the experimental groups (P = 0.000). The positive HIF-1alpha was brown and granule-like and mainly presented in cytoplasm and few in nucleus. The incidence of HIF-1alpha was 80% (28/35) in HCC and 100% (35/35) in its surrounding tissues. The clinical pathological features indicated HIF-1alpha expression associated with tumor size and differentiation degree the of HCC. No correlation was found between HIF-1alpha and tumor numbers or positive-HBsAg.

CONCLUSIONSHIF-1alpha expression is associated with occurrence and development of HCC, and is perhaps a target molecule for HCC therapy.

Adult ; Aged ; Animals ; Carcinoma, Hepatocellular ; metabolism ; pathology ; Female ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; metabolism ; Liver ; metabolism ; pathology ; Liver Neoplasms ; metabolism ; pathology ; Male ; Middle Aged ; RNA, Messenger ; genetics ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo investigate the analgesic and sedative effects of inhaling a mixture of nitrous oxide and oxygen on burn patient during and after dressing change.

METHODSA total of 240 burn patients hospitalized in the Institute of Burn Research of Changhai Hospital Affiliated to the Second Military Medical University, Department of Burns of the First People's Hospital in Zhengzhou, and Department of Burns and Plastic Surgery of General Hospital of Ningxia Medical University from October 2011 to September 2012 were enrolled in our study, and they were all in accordance with the inclusion criteria. The 240 patients were divided into control group (n = 60, treated with inhalation of oxygen during dressing change) and treatment group (n = 180, treated with inhalation of a mixture of 65% nitrous oxide and oxygen during dressing change) according to the computer-generated list of random number. The other treatments in control group and treatment group were the same. Before, during, and after dressing change, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), oxygen saturation (SO2), and adverse effects were observed. The degree of pain and anxiety felt by the patients were respectively evaluated with the visual analogue scale (VAS) and Chinese version of the burn specific pain anxiety scale (C-BSPAS) at the same time points as above. Data were processed with analysis of covariance, chi-square test, analysis of variance, and rank sum test.

RESULTSThere were no significant differences between control group and treatment group in the levels of HR, SBP, DBP, and SO2 before dressing change (with F values respectively 0.76, 0.06, 1.11, 0.70, P values all above 0.05). Compared with those of control group, the levels of HR, SBP, DBP, and SO2 in treatment group were significantly ameliorated during dressing change (with F values respectively 81.78, 146.36, 226.44, 205.62, P values all below 0.01). After dressing change, the levels of DBP in the two groups were close (F = 0.31, P > 0.05), but the levels of HR, SBP, and SO2 showed statistical differences (with F values respectively 7.02, 8.69, 12.23, P < 0.05 or P < 0.01). Before dressing change, the VAS scores were approximate between control group and treatment group (Z = 0.21, P > 0.05). Compared with those in control group (9.4 ± 0.7, 1.7 ± 2.5), the VAS scores were significantly lowered in treatment group during and after dressing change (1.6 ± 1.3, 0.7 ± 1.1, with Z values respectively 11.84, 3.35, P values all below 0.01). There was no significant difference in C-BSPAS score between control group and treatment group before dressing change (Z = 0.62, P > 0.05). Compared with those in control group (75 ± 13, 73 ± 12), the C-BSPAS scores in treatment group were decreased during and after dressing change (9 ± 15, 9 ± 14, with Z values respectively 11.91, 12.28, P values all below 0.01). There were no obvious adverse effects in two groups before, during, and after dressing change.

CONCLUSIONSA mixture of nitrous oxide and oxygen seems to have obvious analgesic and sedative effects on burn patients during dressing change, and it can be widely used.

Administration, Inhalation ; Adolescent ; Adult ; Aged ; Analgesia ; methods ; Bandages ; Burns ; surgery ; Female ; Humans ; Hypnotics and Sedatives ; administration & dosage ; therapeutic use ; Male ; Middle Aged ; Nitrous Oxide ; administration & dosage ; therapeutic use ; Oxygen ; administration & dosage ; therapeutic use ; Young Adult