Rates of, and the factors affecting, cycle helmet use among secondary schoolchildren in East Sussex and Kent

Objectives—To assess the level of cycle helmet wearing among young people in two counties in the South East of England in 1994, and to identify the factors associated with helmet wearing.     

A missense mutation in the BRCA2 gene in three siblings with ovarian cancer.

Inherited susceptibility to ovarian cancer has been associated with germline defects at several loci. The major known ovarian cancer susceptibility gene is BRCA1 on chromosome 17q, which confers a risk of approximately 60% by the age of 70 years. Truncating mutations in BRCA2 on chromosome 13q also predispose to ovarian cancer, although they confer a lower risk than mutations in BRCA1. We have studied the molecular basis of ovarian cancer predisposition in a Finnish family with three affected sisters. Analysis of polymorphic markers provided evidence against linkage to BRCA1, but the sibship was consistent with linkage to BRCA2. Conformation-sensitive gel electrophoresis was used to screen the entire coding sequence of BRCA2. A G to A transition at nucleotide 8702 was observed, which is predicted to convert glycine 2901 to aspartate in the encoded protein. This sequence variant was not detected in 220 cancer-free Finnish control individuals, or in several hundred cancer families of many nationalities previously screened for BRCA2 mutations. Taken together with the fact that this amino acid residue and the surrounding region of BRCA2 is identical in mouse and chicken, the data suggest that this alteration is a disease-causing BRCA2 missense mutation. Previously published data indicate that the risks of breast and ovarian cancer conferred by BRCA2-truncating mutations varies with the position of the mutation in the gene. The missense mutation reported here suggests that the BRCA2 domain including and surrounding glycine 2901 may be more important in preventing neoplastic transformation in ovarian epithelium than in breast epithelium.     

Maternal mortality: a twenty-year survey at the King Faisal University Hospital, Al-Khobar, Eastern Saudi Arabia.

This was an institutional study of all maternal deaths that occurred among 56422 total births at the King Faisal University Hospital, Al-Khobar, Saudi Arabia, between 1983 and 2002. The underlying cause of each maternal death and potentially avoidable factors were analysed. There were 16 maternal deaths in the hospital during the study period, giving a maternal mortality rate of 28.4/100,000 births. The leading cause of death was haemorrhage in seven (43.75%) patients, followed by pulmonary embolism in four (25%) and general anaesthesia in two (12.5%) mothers. The risk factors noted were maternal age 35 years and parity 5 coupled with iron deficiency anaemia. The main avoidable factors were failure of the patients to seek timely medical care and to follow medical advice. More than half the number of direct obstetrical causes of death was thought to be preventable. A rapidly changing attitude of women towards childbirth is occurring through progressively increasing female education and community health programmes in the region. Further reduction of maternal mortality rates in the community is envisaged through greater patient acceptance of medical advice, family spacing and proficient obstetric services.     

Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes.

PURPOSE: This article summarizes data submitted to the U.S. Food and Drug Administration for marketing approval of azacitidine as injectable suspension (Vidaza, Pharmion Corporation, Boulder, CO) for treatment of patients with myelodysplastic syndrome. EXPERIMENTAL DESIGN: In one phase 3 controlled trial, 191 study subjects were randomized to treatment with azacitidine or to observation; an additional 120 patients were treated with azacitidine in two phase 2 single arm studies. The primary efficacy end point was the overall response rate, defined as complete or partial normalization of peripheral blood counts and bone marrow blast percentages for at least 4 weeks. RESULTS: In the controlled trial, the overall response rate was 15.7% in the azacitidine treatment group; there were no responders in the observation group (P < 0.0001). Response rates were similar in the two single arm studies. During response patients stopped being red cell or platelet transfusion dependent. Median duration of responses was at least 9 months. An additional 19% of azacitidine-treated patients had less than partial responses, most becoming transfusion independent. The most common adverse events attributed to azacitidine were gastrointestinal, hematologic, local (injection site), and constitutional. There were no azacitidine-related deaths. CONCLUSIONS: On May 19, 2004 the U.S. Food and Drug Administration approved azacitidine as injectable suspension for treatment of patients with the following myelodysplastic syndrome subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia. Full prescribing information is available at http://www.fda.gov/cder/foi/label/2004/050794lbl.pdf. Azacitidine is the first agent approved for treatment of myelodysplastic syndrome.     

Prognostic Value of PCNA and Mutant p53 Expression in Laryngeal Squamous Cell Carcinoma

The objective of this study was to investigate the prognostic significance of p53, and proliferative cell nuclear antigen (PCNA) in laryngeal squamous cell carcinoma (LSCC). Sixty pathologic specimens from the patients with LSCC were examined for the expression of the p53 and PCNA, with complete follow-up data. Sixty-three percent of the cases displayed nuclear p53 overexpression. There was a correlation between p53 overexpression and histological grades (p = 0.03), and localization site (p = 0.05). Median of PCNA index was 42.2 (range 5.9 to 85.2). There was no difference between the p53 overexpression group and the normal group in proliferative activity determined by PCNA (p = 0.73). In univariate analyses, localization site, grade, stage, invasion pattern, lymph node status, were significant factors in estimating disease free survival (DFS). Grade was the most important factor affecting recurrence (p = 0.002). In multivariate analyses, grade was the only significant predictor for DFS (p = 0.001). Grade (p = 0.001) and invasion pattern (p = 0.03) were found to be significant predictors of overall survival. In conclusion, the histological grade was the most reliable important prognostic factor. Further studies are necessary to facilitate understanding of the mechanisms of laryngeal carcinogenesis.     

HLA-G upregulation in pre-malignant and malignant lesions of the gastrointestinal tract

HLA-G belongs to the nonclassical MHC class Ib group of molecules and has been implicated in mediating immune-responsiveness in various cancerous and non-cancerous cell types. We have examined HLA-G expression in a number of human gastrointestinal malignancies, including pancreatic ductal adenocarcinoma, ampullary cancer, biliary cancer, and colorectal cancer by immunolabeling analysis. We used indices of <5% (negative), 6–25%, 26–50%, 51–75%, and >75% (diffuse) to subclassify lesions based on percentage of positive cell labeling. Across all cancer subtypes, 52–79% of lesions demonstrated expression of HLA-G, with up to 33% of lesions demonstrating diffuse (>75%) expression. In addition, we utilized the neoplastic progression model of colorectal cancer to evaluate HLA-G protein expression in normal colon, tubulovillous adenomas, invasive cancer, and liver metastases arising from colorectal cancer. Focal HLA-G expression was detected in regions of normal colon adjacent to sites of adenomatous and cancerous lesions, as well as in all stages of cancer progression. Overall, the percentage of diffusely (>75%) labeled lesions appeared increased in preneoplastic and neoplastic conditions, as compared to normal colon. Specifically, tubulovillous adnenomas demonstrated pronounced diffuse labeling in 58% of lesions examined. No correlation with HLA-G expression and CD4+ or CD8+ T cells was identified. We propose that HLA-G expression is upregulated in a large percentage of gastrointestinal lesions and may serve to mediate immuneresponsiveness in certain instances.