几种手性药物对映体的HPLC分离与生物样品分析

使用ＣＨＩＲＡＬ－ＡＧＰ柱，通过优化色谱条件，以ＨＰＬＣ法对３种手性药物ＳＦＺ－４７〔（±）－３Ｈ－１，２－二氢－２－（４－甲基苯胺基）－甲基－１－吡咯里嗪酮〕，ＫＭＢＺ－００９〔（±）－反式－４－苯基－５－（邻氯苄基）－吡咯烷酮－２〕和地丙苯酮〔（±）－２′－（２－羟基－３－（特戊胺基）丙氧基）－３－苯基苯丙基酮〕进行了对映体的直接分离，达到良好的分离效果．在此基础上测试了动物血浆样品中ＳＦＺ－４７的对映体，对其药物动力学的对映体选择性进行了初步研究．     

Genomic Localization and Nucleotide Sequence of a lef-8 Gene of the Spodoptera Littoralis Nucleopolyhedrovirus

A gene similar to lef-8 of the Autographa californica (Ac) nucleopolyhedrovirus (MNPV) was identified in the Spodoptera littoralis (Spli) MNPV. The SpliMNPV lef-8-like gene was localized on the genomic map between 26.9 and 29 map units and is flanked by a chitinase gene and p47 gene. This gene arrangement differs from that of similar genes in the AcMNPV genome, where the lef-8 gene is located about 62 kbp from the chitinase gene and about 7 kbp from the p47 gene. Sequence analyses of the lef-8 gene revealed an ORF of 2730 nucleotides, predicted to encode a protein with M _r 104876. The putative protein is 60.9% identical to the AcMNPV LEF-8 and contains an identical sequence of a conserved motif of DNA-dependent RNA polymerases. Sequences downstream of the lef-8 gene contain two sequence repeats which resemble a repeated motif of the SpliMNPV enhancer element and other repetitive sequences from the viral genome. This revised version was published online in July 2006 with corrections to the Cover Date.     

Involvement of programmed cell death in preimplantation embryo demise

Fragmentation is frequently observed in animal and human embryosobtained via in-vitro fertilization (IVF), and is known to beassociated with decreased pregnancy rates and poor survivalfollowing cryopreservation. We postulate that embryo fragmentationis a consequence of activated programmed cell death (PCD) andsubsequent apoptosis and discuss evidence of morphological,histological and biochemical features compatible with the occurrenceof PCD in preimplantation embryos. If PCD is an underlying causeof the high incidence of the fragmentation seen in human pre-embryos,it remains to be determined whether this is reflective of thenatural incidence of lethal chromo somes in the human populationor due to the IVF procedure and culture conditions.     

Interrelationship between secretion, protein phosphorylation and intracellular Ca2+ concentration in platelets stimulated by thrombin or thromboxane A2 analogue

The interrelationship between ATP-secretion, protein phosphorylation and intracellular Ca²⁺ concentration ([Ca²⁺]i) was studied in both ³²P and quin 2 loaded human platelets stimulated by thrombin or thromboxane A₂ analogue (STA₂). In platelets stimulated by thrombin, the degree of 47,000 dalton polypeptides (P47) phosphorylation was observed in completely dose-related manner, regardless of the amount of [Ca²⁺]i. In the same condition, the degree of myosin light chain (P20) phosphorylation, however, was well correlated with ATP secretion and [Ca²⁺]i, when platelets were stimulated by lower dose of thrombin. The similar results were obtained in platelets stimulated by STA₂. These findings suggested that P20, but not P47, phosphorylation in activated platelets is mediated by a rise of [Ca²⁺]i and is well correlated with the secretory reaction. It was unlikely that P47 phosphorylation plays any role in promoting platelet activation.     

Molecular basis for treating endometriosis with aromatase inhibitors

Although treatment of one unusually aggressive case of postmenopausal endometriosis with an aromatase inhibitor has been strikingly successful, large clinical trials are required to establish whether aromatase inhibitors will have a significant role in the medical management of endometriosis. Introduction of aromatase inhibitors into the treatment of endometriosis underscores the importance of basic research leading to the development of novel strategies in reproductive disorders. It was shown earlier that aromatase activity was not detectable in normal endometrium. Aromatase, however, is expressed inappropriately in endometriosis and stimulated by prostaglandin E2. Aromatase activity gives rise to local biosynthesis of oestrogen, which, in turn, stimulates prostaglandin E2 production, thus establishing a positive feedback cycle. This favours accumulation of oestrogen and prostaglandins in endometriosis, which is an inflammatory disorder dependent on oestrogen for growth.     

Breast cancer risk with postmenopausal hormonal treatment

This review was designed to determine from the best evidence whether there is an association between postmenopausal hormonal treatment and breast cancer risk. Also, if there is an association, does it vary according to duration and cessation of use, type of regimen, type of hormonal product or route of administration; whether there is a differential effect on risk of lobular and ductal cancer; and whether hormone treatment is associated with breast cancers that have better prognostic factors? Data sources for the review included Medline, the Cochrane Database of Systematic Reviews (Cochrane Library, 2005) and reference lists in the identified citations. Eligible citations addressed invasive breast cancer risk among postmenopausal women and involved use of the estrogen products with or without progestin that are used as treatment for menopausal symptoms. Abstracted data were demographic groupings, categories of hormone use, categories of breast cancer, two-by-two tables of exposure and outcome and adjusted odds ratios, relative risks (RRs) or hazard rates. Average estimates of risk were weighted by the inverse variance method, or if heterogeneous, using a random effects model. The average risk of invasive breast cancer with estrogen use was 0.79 [95% confidence interval (95% CI) = 0.61-1.02] in four randomized trials involving 12 643 women. The average breast cancer risk with estrogen-progestin use was 1.24 (95% CI = 1.03-1.50) in four randomized trials involving 19 756 women. The average risks reported in recent epidemiological studies were higher: 1.18 (95% CI = 1.01-1.38) with current use of estrogen alone and 1.70 (95% CI = 1.36-2.17) with current use of estrogen-progestin. The association of breast cancer with current use was stronger than the association with ever use, which includes past use. For past use, the increased breast cancer risk diminished soon after discontinuing hormones and normalized within 5 years. Reasonably adequate data do not show that breast cancer risk varies significantly with different types of estrogen or progestin preparations, lower dosages or different routes of administration, although there is a small difference between sequential and continuous progestin regimens. Epidemiological studies indicate that estrogen-progestin use increases risk of lobular more than ductal breast cancer, but the number of studies and cases of lobular cancer remains limited. Among important prognostic factors, the stage and grade in breast cancers associated with hormone use [corrected] do not differ significantly from those in non-users, but breast cancers in estrogen-progestin users are significantly more likely to be estrogen receptor (ER) positive. In conclusion, valid evidence from randomized controlled trials (RCTs) indicates that breast cancer risk is increased with estrogen-progestin use more than with estrogen alone. Epidemiological evidence involving more than 1.5 million women agrees broadly with the trial findings. Although new studies are unlikely to alter the key findings about overall breast cancer risk, research is needed, however, to determine the role of progestin, evaluate the risk of lobular cancer and delineate effects of hormone use on receptor presence, prognosis and mortality in breast cancer.     

Trends in the incidence of cryptorchidism and hypospadias, and methodological limitations of registry-based data

Cryptorchidism and hypospadias share possible risk factors, such as intrauterine growth retardation. According to the data collected by the International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS), apparently increasing trends in the incidence of hypospadias were found in Sweden during the 1960s, and in Norway, Denmark, England and Hungary during the 1970s. In Norway and Denmark, the increase continued in the 1980s, while in the USA it has continued from the 1970s to the 1990s. Finland has shown a lower reported rate of hypospadias than other Nordic countries. However, it is difficult to make comparisons between countries because of variable inclusion criteria. Furthermore, the reliability of the data depends on correct ascertainment and reporting of the cases. The ICBDMS has also collected data on cryptorchidism, but these appear to be unreliable because of a discrepancy with the data from cohort studies. According to two comparable English studies, the incidence of cryptorchidism in full-term boys approximately doubled between the 1950s and the 1980s. Regionally there are large differences: e.g. in Finland the incidence of cryptorchidism is clearly lower than in Denmark. Regional and temporal trends may help to identify environmental factors that might be associated with these disorders.     

Premature ovarian failure

Premature ovarian failure (POF) causing hypergonadotrophic hypogonadism occurs in 1% of women. In majority of cases the underlying cause is not identified. The known causes include: (a) Genetic aberrations, which could involve the X chromosome or autosomes. A large number of genes have been screened as candidates for causing POF; however, few clear causal mutations have been identified. (b) Autoimmune ovarian damage, as suggested by the observed association of POF with other autoimmune disorders. Anti-ovarian antibodies are reported in POF by several studies, but their specificity and pathogenic role are questionable. (c) Iatrogenic following surgical, radiotherapeutic or chemotherapeutic interventions as in malignancies. (d) Environmental factors like viral infections and toxins for whom no clear mechanism is known. The diagnosis is based on finding of amenorrhoea before age 40 associated with FSH levels in the menopausal range. Screening for associated autoimmune disorders and karyotyping, particularly in early onset disease, constitute part of the diagnostic work-up. There is no role of ovarian biopsy or ultrasound in making the diagnosis. Management essentially involves hormone replacement and infertility treatment, the only proven means for the latter being assisted conception with donated oocytes. Embryo cryopreservation, ovarian tissue cryopreservation and oocyte cryopreservation hold promise in cases where ovarian failure is foreseeable as in women undergoing cancer treatments.     

Sperm pathology: a step beyond descriptive morphology. Origin, characterization and fertility potential of abnormal sperm phenotypes in infertile men

Sperm pathology is presented as the discipline of characterizing structural and functional deficiencies in abnormal spermatozoa. This concept complements that of sperm morphology mainly concerned with the appearance of spermatozoa. These two notions collaborate in providing correlations of prognostic value with sperm fertilizing capacity, explaining the mechanisms of sperm inefficiency, suggesting strategies to improve fertilization and opening a door to molecular genetic studies. Phenotypes of genetic origin involving sperm heads, flagella and the neck region are presented describing their clinical manifestations, sperm structure, cytochemistry and genetic background. When available, animal models are used to highlight possible genetic mechanisms. Sperm pathologies secondary to andrological conditions or environmental factors are described, stressing the non-specific nature of the sperm response to noxious agents. The available literature on the prognostic value of sperm pathologies in ICSI is also reviewed. Flagellar anomalies bear a good prognosis, but those affecting the acrosome, sperm chromatin and the neck region entail an increasing chance of failure, which highlights the differential roles played by specific sperm components in fertilization, implantation and early embryonic development. A final discussion is devoted to genetic counselling and the risks involved in using immotile or abnormal spermatozoa in assisted reproduction.