Genome-wide association study identifies breast cancer risk variant at 10q21.2: results from the Asia Breast Cancer Consortium

Although approximately 20 common genetic susceptibility loci have been identified for breast cancer risk through genome-wide association studies (GWASs), genetic risk variants reported to date explain only a small fraction of heritability for this common cancer. We conducted a four-stage GWAS including 17 153 cases and 16 943 controls among East-Asian women to search for new genetic risk factors for breast cancer. After analyzing 684 457 SNPs in 2062 cases and 2066 controls (Stage I), we selected for replication among 5969 Chinese women (4146 cases and 1823 controls) the top 49 SNPs that had neither been reported previously nor were in strong linkage disequilibrium with reported SNPs (Stage II). Three SNPs were further evaluated in up to 13 152 Chinese and Japanese women (6436 cases and 6716 controls) (Stage III). Finally, two SNPs were evaluated in 10 847 Korean women (4509 cases and 6338 controls) (Stage IV). SNP rs10822013 on chromosome 10q21.2, located in the zinc finger protein 365 (ZNF365) gene, showed a consistent association with breast cancer risk in all four stages with a combined per-risk allele odds ratio of 1.10 (95% CI: 1.07-1.14) (P-value for trend = 5.87 × 10(-9)). In vitro electrophoretic mobility shift assays demonstrated the potential functional significance of rs10822013. Our results strongly implicate rs10822013 at 10q21.2 as a genetic risk variant for breast cancer among East-Asian women.     

Type 2 diabetes,polycystic ovary syndrome and the insulin resistance syndrome in adolescents: Are they one big iceberg?

Obesity in children may cause overt clinical disease in childhood. The complex endocrine and metabolic changes of obesity and insulin resistance in adolescents result in hyperinsulinemia, dyslipidemia, hypertension, steatohepatitis, glucose intolerance, type 2 diabetes, acanthosis nigricans and ovarian hyperandrogenemia, commonly known as polycystic ovarian syndrome (PCOS). Type 2 diabetes and PCOS in adolescents are new endocrine diseases in this age group that require unique approaches to diagnosis and treatment. The direct correlation between duration of disease and control of the disease, and subsequent long term complications of these two diseases, predict serious morbidity in young adult life for the affected adolescents. Pediatricians have an important role in the prevention, diagnosis and treatment of obesity, insulin resistance syndrome, type 2 diabetes and PCOS.     

原发性免疫性血小板减少症的研究和诊治:国际共识报告

(接上期472页)达那唑:是一种作用较弱的雄激素,口服剂量为每次200mg,每天2～4次(每天10～15 mg/kg).57例脾切除术后的ITP患者中,反应率为60%～67%(血小板＞50×109/L,持续2个月以上).老年女性和脾切后的患者效果最好.氨苯砜:是一种中等强度的肾上腺皮质激素类药物,常以每次75～100 mg、每天1次口服.对一线肾上腺皮质激素治疗无反应的患者,氨苯砜可使脾切除术推迟32个月以上(证据水平Ⅱb).然而,脾切除术后患者对该药的反应率较低.     

The Influence of Two Different Invitation Letters on Chlamydia Testing Participation: Randomized Controlled Trial

Background

In the Netherlands, screening for chlamydia (the most prevalent sexually transmitted infection worldwide) is a relatively simple and free procedure. Via an invitation letter sent by the public health services (PHS), people are asked to visit a website to request a test kit. They can then do a chlamydia test at home, send it anonymously to a laboratory, and, within two weeks, they can review their test results online and be treated by their general practitioner or the PHS. Unfortunately, the participation rates are low and the process is believed to be not (cost-) effective.

Objective

The objective of this study was to assess whether the low participation rate of screening for chlamydia at home, via an invitation letter asking to visit a website and request a test kit, could be improved by optimizing the invitation letter through systematically applied behavior change theories and evidence.

Methods

The original letter and a revised letter were randomly sent out to 13,551 citizens, 16 to 29 years old, in a Dutch municipality. Using behavior change theories, the revised letter sought to increase motivation to conduct chlamydia screening tests. The revised letter was tailored to beliefs that were found in earlier studies: risk perception, advantages and disadvantages (attitude), moral norm, social influence, and response- and self-efficacy. Revisions to the new letter also sought to avoid possible unwanted resistance caused when people feel pressured, and included prompts to trigger the desired behavior.

Results

No significant differences in test package requests were found between the two letters. There were also no differences between the original and revised letters in the rates of returned tests (11.80%, 581/4922 vs 11.07%, 549/4961) or positive test results (4.8%, 23/484 vs 4.1%, 19/460). It is evident that the new letter did not improve participation compared to the original letter.

Conclusions

It is clear that the approach of inviting the target population through a letter does not lead to higher participation rates for chlamydia screening. Other approaches have to be developed and pilot tested.     

Viability of partially damaged human embryos after cryopreservation

In our centre, embryos are judged to have survived cryopreservation if at least half of the initial number of blastomeres remain intact. Therefore both fully intact and partially damaged embryos are transferred. The aim of this study was to investigate the viability of partially damaged human embryos after cryopreservation. We retrospectively analysed the implantation and in-vivo development of embryos which were either fully intact or had lost some blastomeres after cryopreservation. Oocytes were collected following stimulation with the gonadotrophin-releasing hormone (GnRH)-agonist Buserelin and human menopausal gonadotrophin. Supernumerary multicellular embryos with not more than 20% of their volume filled with anucleate fragments were frozen on day 2 or day 3 of the cycle using a slow cooling procedure with dimethylsulphoxide as the cryoprotectant. Following slow thawing, 431 fully intact embryos were transferred in 314 embryo transfer procedures and 488 partially damaged embryos were transferred in 327 such procedures. The percentage of gestational sacs with fetal heartbeat obtained after transfer of fully intact embryos was almost three times higher than that after transfer of partially damaged embryos (11.4 versus 3.5%). Forty-five children (birth rate 10% per embryo transfer) were born after transfer of fully intact embryos and 14 after transfer of embryos from which some blastomeres had been lost following cryopreservation. In conclusion, although children have been delivered after transfer of partially damaged embryos, the aim of a cryopreservation programme must be to obtain fully intact embryos after thawing.      

The GAP-related domain of tuberin, the product of the TSC2 gene, is a target for missense mutations in tuberous sclerosis

Tuberous sclerosis is an autosomal dominant trait in which the dysregulation of cellular proliferation and differentiation results in the development of hamartomatous growths in many organs. The TSC2 gene is one of two genes determining tuberous sclerosis. Inactivating germline mutations of TSC2 in patients with tuberous sclerosis and somatic loss of heterozygosity at the TSC2 locus in the associated hamartomas indicate that TSC2 functions as a tumour suppressor gene and that loss of function is critical to expression of the tuberous sclerosis phenotype. The TSC2 product, tuberin, has a region of homology with the GTPase activating protein rap1GAP and stimulates the GTPase activity of rap1a and rab5a in vitro. Here we show that the region of homology between tuberin and human rap1GAP and the murine GAP mSpa1 is more extensive than previously reported and spans approximately 160 amino acid residues encoded within exons 34-38 of the TSC2 gene. Single strand conformation polymorphism analysis of these exons in 173 unrelated patients with tuberous sclerosis and direct sequencing of variant conformers together with study of additional family members enabled characterisation of disease associated mutations in 14 cases. Missense mutations, which occurred in exons 36, 37 and 38 were identified in eight cases, four of whom shared the same recurrent change P1675L. Each of the five different missense mutations identified was shown to occur de novo in at least one sporadic case of tuberous sclerosis. The high proportion of missense mutations detected in the region of the TSC2 gene encoding the GAP-related domain supports its key role in the regulation of cellular growth.      

Relationship between serum follicle stimulating hormone in the male and standard sperm parameters, and the results of intracytoplasmic sperm injection

Serum follicle stimulating hormone (FSH) is routinely measured when evaluating the infertile male for intracytoplasmic sperm injection (ICSI). However, among the sperm parameters, only its relationship with sperm concentration is well documented. Few investigations concern the relationship between FSH and sperm motility and morphology, and the results of ICSI. A retrospective study of 316 couples who underwent ICSI was carried out to determine the relationships between serum FSH concentrations in the male and (i) standard sperm parameters_(concentration, motility and morphology) and (ii) fertilization, cleavage, pregnancy and implantation rates after ICSI. There was an inverse correlation with sperm concentration and total motility but no relationship was found with progressive motility and sperm morphology. Neither was any relationship found between serum FSH and fertilization, cleavage, pregnancy and implantation rates, and the results of ICSI. These findings suggest the need to review the routine measurement of serum FSH in the infertile male when ICSI is the planned treatment procedure.      

Immune reconstitution inflammatory syndrome in association with HIV/AIDS and tuberculosis: Views over hidden possibilities

Background  

CD4+ T lymphocyte (CD4) cell count testing is the standard method for determining eligibility for antiretroviral therapy (ART), but is not widely available in sub-Saharan Africa. Total lymphocyte counts (TLCs) have not proven sufficiently accurate in identifying subjects with low CD4 counts. We developed clinical algorithms using TLCs, hemoglobin (Hb), and body mass index (BMI) to identify patients who require ART.     

Bronchoscopic aspiration and bronchoalveolar lavage in the diagnosis of sputum smear-negative pulmonary tuberculosis

The ability to make a definitive diagnosis in sputum smear-negative pulmonary tuberculosis by bronchoscopic aspiration, bronchoalveolar lavage (BAL), and examination of postbronchoscopy sputum were compared. Thirty-four patients with lesions on chest x-rays suspected of being pulmonary tuberculosis were entered into the study. The diagnosis of pulmonary tuberculosis was subsequently confirmed in 28 patients and the method of arriving at the final diagnosis was analyzed. A positive acid-fast bacilli (AFB) smear result was obtained in 4/28 (14%) of cases by a combination of bronchoscopic techniques and postbronchoscopy sputum examination. Prebronchoscopy sputum culture was positive in 12/28 (43%). Combined with bronchoscopy specimens, a positive AFB culture result was obtained in 26/28 (93%). Sputum examination, bronchoscopic aspiration, and BAL are complementary techniques and together they give a high yield of definitive diagnosis of pulmonary tuberculosis.