Searching for candidate genes for male infertility

<abstract>Aim: We describe an approach to search for candidate genes for male infertility using the two human genome databases: the public University of California at Santa Cruz (UCSC) and private Celera databases which list known and predicted gene sequences and provide related information such as gene function, tissue expression, known mutations and single nucleotide polymorphisms (SNPs). Methods and Results: To demonstrate this in silico research, the following male infertility candidate genes were selected: (1) human BOULE, mutations of which may lead to germ cell arrest at the primary spermatocyte stage, (2) mutations of casein kinase 2 alpha genes which may cause globozoospermia, (3) DMR-N9 which is possibly involved in the spermatogenic defect of myotonic dystrophy and (4) several testes expressed genes at or near the breakpoints of a balanced translocation associated with hypospermatogenesis. We indicate how information derived from the human genome databases can be used to confirm these candidate genes may be pathogenic by studying RNA expression in tissue arrays using in situ hybridization and gene sequencing. Conclusion: The paper explains the new approach to discovering genetic causes of male infertility using information about the human genome.

Dexmedetomidine Promotes Angiogenesis and Vasculogenic Mimicry in Human Hepatocellular Carcinoma through α^(2)-AR/HIF-1α/VEGFA Pathway

Objective Dexmedetomidine(DEX),the most specificα^(2)-adrenergic receptor agonist widely used for its sedative and analgesic properties,has been reported to upregulate HIF-1αexpression to protect hypoxic and ischemic tissues.However,it is largely unclear whether DEX can also upregulate Hypoxiainducible factor-1 alpha(HIF-1α)expression and its downstream vascular endothelial growth factor-A(VEGFA)in cancer tissues with oxygen-deficient tumor microenvironment.Methods We used SMMC-7721 cells,MHCC97-H cells,and a mouse model of orthotopic hepatic carcinoma to explore the effect of DEX on angiogenesis and vasculogenic mimicry(VM)and its mechanism.Under normoxic(20%O^(2))and hypoxic(1%O^(2))conditions,DEX was used to intervene cells,and yohimbine was used to rescue them.Results The results showed that DEX promoted angiogenesis and VM in human liver cancer cells within a certain dose range,and the addition of yohimbine inhibited this effect.DEX could activate HIF-1α/VEGFA pathway,which was further verified by silencing HIF-1α.Consistently,in vivo results also showed that DEX can up-regulate HIF-1α/VEGFA expression,and enhance the number of VM channels and microvessel density(MVD).Conclusion We believe that HIF-1α/VEGFA might be an important signaling pathway by which DEX promotes angiogenesis and VM formation in human hepatocellular carcinoma,whereasα^(2)-adrenergic receptor mediation might be the critical mechanisms.

严重与轻度少精症患者精液中非整倍体发生率的比较及其对卵母细胞单精子显微注射后妊娠结局的影响

Objective: To determine the incidence of disomy and diploidy for chromosomes 18, X, and Y in the sperm samples of severe oligozoospermic (< 5 ×106 spermatozoa/mL) and oligozoospermic (5-20 ×106 spermatozoa/mL) men undergoing intracytoplasmic sperm injection (ICSI) and to evaluate the influence of sperm aneuploidy on pregnancy outcome. Design: Prospective study. Setting: Infertility clinic and genetic laboratory. Patient(s): Fifteen patients with severe oligozoospermia, 15 patients with oligozoospermia, and 10 normal fertile donors. Intervention(s): Fluorescence in-situ hybridization (FISH) performed on sperm samples. Main Outcome Measure(s): The frequency of disomy and diploidy for chromosomes 18, X, and Y was analyzed using FISH, and the clinical outcome after ICSI was correlated. Result(s): Significantly greater frequencies of XY, YY disomy and diploidy were observed in severe oligozoospermic men compared with oligozoospermic and normozoospermic men. Although the fertilization rate was similar, the pregnancy rate was higher in the group with oligozoospermia versus severe oligozoospermia. Conclusion(s): This study demonstrated the presence of an elevated sperm aneuploidy rate in patients with low semen quality. Additionally, the data show a negative influence of sperm chromosome abnormalities on ICSI outcome.

改良的胚胎冷冻保存法增加解冻后的存活率同时提高种植率

Objective: To achieve maximum post-thaw survival of frozen embryos. Design: Historical controlled study. Setting: Hospital-based fertility center. Patient(s): One hundred forty-five patients whose embryos were frozen and thawed according to the standard method, and 56 patients whose embryos were frozen and thawed according to a modified method. Intervention( s): Modifications were made to the various steps of cryopreservation: freezing and thawing solutions, loading of embryos into the straws, and warming rates. Main Outcome Measure(s): Post-thaw survival, implantation, and pregnancy rates. Result(s): With the modified method, 138 (93%) of the 149 embryos thawed for 56 patients survived freezing, and 79.8%had all their blastomeres intact, which is almost double the result obtained (41.8%) for patients whose embryos were thawed with the standard method. The implantation and pregnancy rates were also significantly higher with the modified method compared with the standard method. Conclusion(s) : Greater post-thaw embryo survival was achieved, with a concomitant increase in implantation and pregnancy rates, by modifying the various steps in the standard cryopreservation methodology. This has important implications in IVF practice.

A Prospective, Multicentric, Post Marketing Surveillance to Evaluate Efficacy & Safety of Ranitidine HCl (150 & 300 mg IR/CR) in Indian Patients with Gastroesophageal Reflux Disease (PROGRADE)

Purpose: Ranitidine hydrochloride (HCl) remains an important medication for treating acid-peptic ailments such as Gastroesophageal reflux disease (GERD). The main objective of this Post Marketing Surveillance (PMS) clinical study was to test the efficacy and safety of Ranitidine HCl in Indian patients suffering from GERD. Patients and Methods: Data of 2446 patients (1307 males;1121 females) from 21 centers across India were analyzed. Patients received either of the three treatments: Ranitidine HCl 150 mg twice a day (BID) (ARM-A), Ranitidine HCl 300 mg once daily (OD) or BID (ARM-B), and Ranitidine HCl 300 mg OD (ARM-C). Gastroesophageal Reflux Disease Symptom Assessment Scale (GSAS) score and Heartburn Severity score were used to assess the drug’s efficacy. The adverse events reported by patients or investigators were analyzed to assess the safety profile of Ranitidine. Results: Of the 2446 subjects screened, 2428 were enrolled. There was a significant reduction in GSAS scores from baseline to the end of the study visit in all three ARMs. The GSAS scores reduced from 2.02 to 0.23 in ARM-A, 2.01 to 0.24 in ARM-B, and 2.07 to 0.26 in ARM-C patients. In ARM A, 72.82% had 24 hours heartburn-free days, and 66.89% had 7 consecutive heartburn-free days, which was more significant than the other two ARMs. 128 (5.27%) patients reported ADRs due to Ranitidine HCl at different doses. The most frequently reported ADR was constipation (17.18%), followed by oliguria (14.06%), cold (13.28%), and dysuria (12.5%). Of 128 ADRs, 113 (88.28%) were mild, and only 11 (8.59%) ADRs were related to the study drug. No severe ADRs were reported during the study. Conclusion: Ranitidine HCl 150/300 mg tablet was found to be an effective and safe H2-receptor antagonist for treating GERD in Indian Patients.