SCA6 is caused by moderate CAG expansion in the alpha1A-voltage- dependent calcium channel gene

Recently, moderate (CAG)>20 repeat expansions in the alpha1A-voltage- dependent calcium channel gene (CACNL1A4) have been identified in a previously unmapped type of SCA which has been named SCA6. We investigated the (CAG)n repeat length of the CACNL1A4 gene in 733 patients with sporadic ataxia and in 46 German families with dominantly inherited SCA which do not harbor the SCA1, SCA2, or MJD1/SCA3 mutation, respectively. The SCA6 (CAG)n expansion was identified in 32 patients most frequently with late manifestation of the disease. The (CAG)n stretch of the affected allele varied between 22 and 28 trinucleotide units and is therefore the shortest trinucleotide repeat expansion causing spinocerebellar ataxia. The (CAG)n repeat length is inversely correlated with the age at onset. In 11 parental transmissions of the expanded allele no repeat instability has been observed. Repeat instability was also not found for the normal allele investigating 431 meioses in the CEPH families. Analyzing 248 apparently healthy octogenerians revealed one allele of 18 repeats which is the longest normal CAG repeat in the CACNL1A4 gene reported. The SCA6 mutation causes the disease in approximately 10% of autosomal dominant SCA in Germany. Most importantly, the trinucleotide expansion was observed in four ataxia patients without obvious family history of the disease which necessitates a search for the SCA6 (CAG)n expansion even in sporadic patients.      

紫草辅助米非司酮抗早孕对生殖激素的影响

为了探讨紫草辅助米非司酮抗早孕时对早孕妇女血中生殖激素的影响 ,88例早孕妇女随机分成服用米非司酮、紫草、米非司酮加紫草组和空白对照组 ,比较用药前后血人绒毛膜促性腺激素β亚单位 (β-h CG)、卵泡刺激素 ( F SH)、黄体生成素 ( L H)、雌二醇 ( E2 )、孕酮 ( P)和睾酮 ( T)的变化。结果 :单用米非司酮或紫草均对 β-h CG有一定的抑制作用 ,二者合用抑制作用更加明显 ;单用紫草对血中 FSH、 L H有较明显的抑制作用 ,对 E2 、P及 T无明显影响。认为紫草对绒毛功能有一定的影响 ,与米非司酮合用影响更明显 ;紫草对垂体生殖激素有明显的抑制作用。但是否与紫草能提高药物流产效果有关 ,尚需进一步研究。     

Cumulative risk of developing polyps or malignancy at the ileal pouch-anal anastomosis in patients with familial adenomatous polyposis

Restorative proctocolectomy with an ileal pouch-anal anastomosis is performed in an increasing number of patients with familial adenomatous polyposis (FAP). Two techniques are currently used to construct an ileal pouch-anal anastomosis: (1) a double-stapled anastomosis between the pouch and the anal canal and (2) mucosectomy with a hand-sewn iteoanal anastomosis at the dentate line. Although this procedure is thought to abolish the risk of colorectal adenoma, an increasing number of case reports have been published concerning the development of adenoma at the anastomotic site. The purpose of this study was to evaluate the overall cumulative risk of developing adenomatous polyps after ileal pouch-anal anastomosis and to compare the cumulative risk after either anastomotic technique. A total of 126 consecutive FAP patients undergoing a restorative proctocolectomy were identified from polyposis registries in The Netherlands, Denmark, Italy, Germany, and New York. Life-table analysis was used to calculate the cumulative risk of developing polyps in 97 patients with at least 1 year of endoscopic follow-up (median 66 months, range 12 to 188 months). A double-stapled anastomosis was used in 35 patients, whereas in 62 patients a handsewn anastomosis with a mucosectomy was performed. In 13 patients polyps developed at the anastomotic site, four with severe and four with moderate dysplasia. None of the patients developed a carcinoma at the anastomotic site. The cumulative risk of developing a polyp at the anastomotic site was 8% (95% confidence interval 2% to 14%) at 3.5 years and 18% (95% confidence interval 8% to 28%) at 7 years, respectively. The risk of developing a polyp at the anastomotic site within 7 years was 31 % for patients with a double-stapled vs. 10% for patients with a hand-sewn anastomosis with mucosectomy (P = 0.03 [log-rank test]). Because FAP patients undergoing a restorative proctocolectomy with either a double-stapled or hand-sewn anastomosis have a substantial risk of developing adenomatous polyps at the anastomotic site, lifelong endoscopic surveillance is mandatory in both groups. Presented at the Thirty-Ninth Annual Meeting of The Society for Surgery of the Alimentary Tract, New Orleans, La., May 17–20, 1998.     

Effect of nutritional route on colonic anastomotic healing in the rat

Although early enteral feeding has been shown to benefit cutaneous healing when compared to parenteral feeding, the effect of the route of nutritional support in gastrointestinal anastomotic healing has not been defined. The aim of the present study was to determine whether the route of nutritional support influences colonic anastomotic healing. Twenty male Sprague-Dawley rats weighing 270 to 290 grams underwent identical surgical manipulation consisting of central venous catheterization, gastrostomy insertion, and distal colonic anastomosis (single-layer, inverted). Identical nutrient infusates composed of 4.25% amino acids, 25% dextrose, and vitamins were administered, with half the animals receiving the infusions via the gastrostomy and the other half via the venous catheter. Animals were killed 5 days after surgery. There were no differences in nutritional parameters between the parenterally and enterally fed groups. Colonic anastomotic bursting pressure was significantly higher in the enterally fed group (180 ±6 vs. 150±11 mm Hg; P<0.01). The measured insoluble collagen and total protein content in anastootic tissue were enhanced in the enterally supported group. The fraction of soluble (newly synthesized) collagen did not differ between the two groups. The data demonstrate that the route of nutrient administration influences colonic anastomotic healing. The preservation of colonic structural collagen in the enteral group may improve the ability of the gut to hold sutures and thus enhance anastomotic healing. Presented at the Thirty-Ninth Annual Meeting of The Society for Surgery of the Alimentary Tract, New Orleans, La., May 17–20, 1998.     

利用CRISPR-Cas9系统敲除小鼠黑色素瘤细胞系MATP基因的初步研究

目的利用CRISPR/Cas9系统,敲除小鼠黑色素瘤细胞系的MATP基因,为MATP基因的功能研究奠定基础。方法利用http://crispr.mit.edu/网站,设计针对MATP的特异性引物,并将引物链接到pCAS9/gRNA1载体。将阳性载体转染小鼠黑色素瘤细胞系B16F10,利用无限稀释的方法获得转染后的单克隆细胞株。提取不同细胞株的基因组,通过测序的方法进一步筛选出发生MATP基因切割的细胞株,并利用Western-blot的方法验证MATP的表达情况。结果成功获得了3株MATP基因敲除的细胞株,Western-blot结果表明,该细胞株不表达MATP蛋白。结论利用pCAS9/gRNA1载体,可以实现B16F10细胞系MATP基因的敲除。     

我省长学制医学教育的回顾与思考

我省七年制医学教育开办了近20年,为社会培养了一批深受欢迎、质量较好和具有较高综合素质的高层次医学人才。建立与我省经济发展水平相适应的以五年制为主体、重点发展八年制的医学教育学制体系,是我省高等医学教育发展的必然趋势。     

Predicting a local recurrence after breast-conserving therapy by gene expression profiling

Introduction

To tailor local treatment in breast cancer patients there is a need for predicting ipsilateral recurrences after breast-conserving therapy. After adequate treatment (excision with free margins and radiotherapy), young age and incompletely excised extensive intraductal component are predictors for local recurrence, but many local recurrences can still not be predicted. Here we have used gene expression profiling by microarray analysis to identify gene expression profiles that can help to predict local recurrence in individual patients.

Methods

By using previously established gene expression profiles with proven value in predicting metastasis-free and overall survival (wound-response signature, 70-gene prognosis profile and hypoxia-induced profile) and training towards an optimal prediction of local recurrences in a training series, we establish a classifier for local recurrence after breast-conserving therapy.

Results

Validation of the different gene lists shows that the wound-response signature is able to separate patients with a high (29%) or low (5%) risk of a local recurrence at 10 years (sensitivity 87.5%, specificity 75%). In multivariable analysis the classifier is an independent predictor for local recurrence.

Conclusion

Our findings indicate that gene expression profiling can identify subgroups of patients at increased risk of developing a local recurrence after breast-conserving therapy.     

Genomic patterns resembling BRCA1- and BRCA2-mutated breast cancers predict benefit of intensified carboplatin-based chemotherapy

Introduction

BRCA-mutated breast cancer cells lack the DNA-repair mechanism homologous recombination that is required for error-free DNA double-strand break (DSB) repair. Homologous recombination deficiency (HRD) may cause hypersensitivity to DNA DSB-inducing agents, such as bifunctional alkylating agents and platinum salts. HRD can be caused by BRCA mutations, and by other mechanisms. To identify HRD, studies have focused on triple-negative (TN) breast cancers as these resemble BRCA1-mutated breast cancer closely and might also share this hypersensitivity. However, ways to identify HRD in non-BRCA-mutated, estrogen receptor (ER)-positive breast cancers have remained elusive. The current study provides evidence that genomic patterns resembling BRCA1- or BRCA2-mutated breast cancers can identify breast cancer patients with TN as well as ER-positive, HER2-negative tumors that are sensitive to intensified, DSB-inducing chemotherapy.

Methods

Array comparative genomic hybridization (aCGH) was used to classify breast cancers. Patients with tumors with similar aCGH patterns as BRCA1- and/or BRCA2-mutated breast cancers were defined as having a BRCA-like^CGH status, others as non-BCRA-like^CGH. Stage-III patients (n = 249) had participated in a randomized controlled trial of adjuvant high-dose (HD) cyclophosphamide-thiotepa-carboplatin (CTC) versus 5-fluorouracil-epirubicin-cyclophosphamide (FE₉₀C) chemotherapy.

Results

Among patients with BRCA-like^CGH tumors (81/249, 32%), a significant benefit of HD-CTC compared to FE₉₀C was observed regarding overall survival (adjusted hazard ratio 0.19, 95% CI: 0.08 to 0.48) that was not seen for patients with non-BRCA-like^CGH tumors (adjusted hazard ratio 0.90, 95% CI: 0.53 to 1.54) (P = 0.004). Half of all BRCA-like^CGH tumors were ER-positive.

Conclusions

Distinct aCGH patterns differentiated between HER2-negative patients with a markedly improved outcome after adjuvant treatment with an intensified DNA-DSB-inducing regimen (BRCA-like^CGH patients) and those without benefit (non-BRCA-like^CGH patients).