Prognostic impact of BRCA1 pathogenic and BRCA1/BRCA2 unclassified variant mutations in patients with ovarian carcinoma

BACKGROUND: The clinical relevance of BRCA1/2 alterations in ovarian carcinoma patients is debatable. Our aim was to determine factors influencing the risk of recurrence and death in ovarian carcinoma patients with BRCA pathogenic and unclassified variant mutations. METHODS: A consecutive series of 205 women with primary ovarian carcinoma were screened for mutations in BRCA1 and BRCA2 genes using a conformational sensitive gel electrophoresis and direct sequencing. Data regarding medical and familial history were collected using questionnaires. Clinical and pathologic data were extracted from medical records. RESULTS: Unclassified variant mutations in BRCA1 or BRCA2 genes were found in 16 (8%) patients, and BRCA1 pathogenic mutations were found in 18 (9%) patients. No pathogenic mutation was found in BRCA2 gene. Multivariate analysis showed that BRCA1 pathogenic mutation was an independent predictor of reduced risk of relapse and death (Hazard ratios [HR] 0.52 [confidence interval {CI} 0.28-0.98] and 0.38 [CI 0.10-0.96], respectively). Unclassified variant mutation did not affect recurrence and survival (HR 0.84 [CI 0.43-1.66] and 0.94 [CI 0.48-1.82], respectively). Other factors associated with reduced risk of relapse and death were complete pathologic remission at second-look laparotomy and family history of breast and ovarian carcinoma, respectively. Recurrence and death outcomes among unclassified variant mutation carriers did not differ significantly from those in sporadic cases. CONCLUSIONS: Patients with BRCA1 pathogenic mutation seem to have reduced risk of recurrence and death. These results should be interpreted with caution as they may be influenced by more intensive treatment, better response to cisplatin, and younger age of mutation carriers. Clinical relevance of BRCA1/2 unclassified variant mutations warrants further studies.     

Die unterlassene Hilfeleistung gemäß § 323c StGB

Zusammenfassung  Gemäß § 323c StGB wird mit Freiheitsstrafe bis zu einem Jahr oder mit Geldstrafe bestraft, wer bei Unglücksfällen nicht Hilfe leistet, obwohl dies erforderlich und zumutbar ist. Diese Nothilfepflicht besteht zwar nicht nur für den Arzt, sondern für jedermann. Jedoch sind Ärzte in der Notfall- und Rettungsmedizin durch ihre Fachkenntnis besonders gefordert und öfters dem Vorwurf der unterlassenen Hilfeleistung ausgesetzt. Der vorliegende Beitrag beschreibt die Voraussetzungen, die für diesen Tatbestand nach § 323c StGB erfüllt sein müssen. Diese sollten dem Arzt bekannt sein, um sich gegen unberechtigte Vorwürfe zu wappnen. Eine sorgfältige Dokumentation von Einsatzumständen ist dabei von entscheidender Bedeutung, um strafrechtliche Konsequenzen abzuwehren.     

Genetic background determines the size and structure of the endocrine pancreas

Key parameters of the endocrine pancreas, such as islet number, islet mass, beta-cell mass, and alpha-cell mass, were studied in different strains of inbred mice to investigate the impact of genetic background on the size and structure of the endocrine pancreas. Six mice from each of seven different strains of inbred mice were included in the study. For all parameters investigated, there was a pronounced interstrain variation. ANCOVA showed that only mouse strain was statistically significant as an explanatory parameter for the number of islets. Mouse strain, body weight, and pancreas mass reached statistical significance as explanatory parameters for the islet mass, with mouse strain as the most significant predictor. These data show that genetic background is the most important predictor of both the number of islets and total islet volume. We also conclude that inbred mice could be a valuable resource to identify the genes responsible for the size and structure of the endocrine pancreas.     

Growth and functional maturation of beta-cells in implants of endocrine cells purified from prenatal porcine pancreas

The development of islet cell transplantation as a cure for diabetes is limited by the shortage of human donor organs. Moreover, currently used grafts exhibit a marginal beta-cell mass with an apparently low capacity for beta-cell renewal and growth. Although duct-associated nonendocrine cells have often been suggested as a potential source for beta-cell production, recent work in mice has demonstrated the role of beta-cells in postnatal growth of the pancreatic beta-cell mass. The present study investigated whether the beta-cell mass can grow in implants that are virtually devoid of nonendocrine cells. Endocrine islet cells were purified from prenatal porcine pancreases (gestation >110 days) and implanted under the kidney capsule of nude mice. beta-Cells initially presented with signs of immaturity: small size, low insulin content, undetectable C-peptide release, and an inability to correct hyperglycemia. They exhibited a proliferative activity that was highest during posttransplant week 1 (2.6 and 5% bromodeoxyuridine [BrdU]-positive beta-cells 4 and 72 h posttransplant) and then decreased over 20 weeks to rates measured in the pancreas (0.2% BrdU-positive cells). beta-Cell proliferation in implants first compensated for beta-cell loss during posttransplant week 1 and then increased the beta-cell number fourfold between posttransplant weeks 1 and 20. Rates of alpha-cell proliferation were only shortly and moderately increased, which explained the shift in cellular composition of the implant (beta-cell 40 vs. 90% and alpha-cell 40 vs. 7% at the start and posttransplant week 20, respectively). beta-Cells progressively matured during the 20 weeks after transplantation, with a twofold increase in cell volume, a sixfold increase in cellular insulin content, plasma C-peptide levels of 1-2 ng/ml, and an ability to correct diabetes. They became structurally organized as homogenous clusters with their secretory vesicles polarized toward fenestrated capillaries. We concluded that the immature beta-cell phenotype provides grafts with a marked potential for beta-cell growth and differentiation and hence may have a potential role in curing diabetes. Cells with this phenotype can be isolated from prenatal organs; their presence in postnatal organs needs to be investigated.     

A comparison of two portable dynamometers in the assessment of shoulder and elbow strength

Objectives To compare the practical applicability and measurement properties of a hand-held dynamometer (MicroFET2^®) and a fixed dynamometer (Isobex2.1^®) in determining isometric strength of the shoulder and elbow.Design Muscle strength in four directions (glenohumeral abduction, external rotation and elevation and elbow flexion) was measured using both instruments by two examiners. The assessments were repeated by one of the examiners 3 days later.Setting Leiden University Medical Center.Participants Twenty healthy volunteers.Main outcome measures Time to complete a set of measurements and discomfort were recorded. To determine intra- and inter-observer reliability, intra-class correlation coefficients (ICCs), limits of agreement and smallest detectable difference were computed.Results The time to complete a set of measurements was significantly shorter for the hand-held dynamometer than for the fixed dynamometer in both examiners. The number of subjects reporting discomfort was similar with the two dynamometers. Except for glenohumeral abduction, the forces measured using the hand-held dynamometer were significantly higher than those when using the fixed dynamometer in both examiners. The intra- and inter-observer ICCs for the four directions ranged from 0.82 to 0.98 for both dynamometers. However, the mean differences between replications and the wide limits of agreement suggest substantial bias and variability. For example, for the measurement of shoulder abduction with the fixed dynamometer by one tester (190 N), the results suggest that on 95% of occasions the second tester's measurement would be between 158 and 275 N.Conclusions Although time taken and discomfort should be considered in the selection of dynamometers, due consideration should be given to the significant differences in absolute results. Neither the dynamometers nor the testers can be considered interchangeable. Both the intra- and inter-observer reliability of the two dynamometers were similar, yet both demonstrated systematic bias and variability in the measurements obtained.     

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Blood coagulation tests in children with cyanotic heart defects]

In 57 children with congenital cyanotic heart disease coagulation analyses were performed before operation. The patients with low haematocrit only sometimes exhibited defects of low degree. In patients with haematocrit values of more than 60% were increasingly found complex coagulation disturbances. Many correlations could be proved between the coagulation parameters. Thrombocytopenia, plasmatic defects and hyperfibrinolysis were parallel. The cause of the changes is to be seen in chronic disseminated intravasal coagulation processes. The results of investigations presented confirm the necessity of preoperative coagulation analyses especially in patients with high haematocrit values. Larger disturbances of coagulation may influence the decision between a palliative intervention or immediate causal operation.     

Genetic analysis of a transposable suppressor gene in Saccharomyces cerevisiae.

We have demonstrated in Saccharomyces cerevisiae the transposition of a gene coding for an efficient ochre (UAA) suppressor from a centromere-linked site on chromosome III to two new sites in the yeast genome. One site is on chromosome VI, very close to, if not allelic with, SUP11, one of eight genes coding for a tyrosine-inserting suppressor. The second site is on chromosome III, unlinked to the centromere and distal to the mating type locus. This site is very close to those mapped for the recessive lethal amber suppressors, SUP-RL1 and SUP61.     

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Functional heterogeneity of UDP-glucuronosyltransferase activities in C57BL/6 and DBA/2 mice

Functional heterogeneity of liver microsomal UDP-glucuronosyltransferase activities towards 1-naphthol, 4-methylumbelliferone or 3-hydroxybenzo(a)pyrene (UDP-GT1 activities) and morphine or 4-hydroxybiphenyl (UDP-GT2 activities) was studied in two inbred strains of mice which are genetically responsive (C57BL/6) or non-responsive (DBA/2) to 3-methylcholanthrene-induction of drug metabolizing enzymes. 3-Methylcholanthrene preferentially induced UDP-GT1 activities in C57BL/6 mice. Phenobarbital, however, at low doses (50 mg/kg), selectively induced UDP-GT2 activities. Higher doses of phenobarbital (80 mg/kg) induced both UDP-GT1 and UDP-GT2 activities. In DBA/2 mice 3-methylcholanthrene-induction of UDP-glucuronosyltransferase activities was not detectable whereas enzyme induction by phenobarbital appeared to be unimpaired. UDP-GT1 activities were ubiquitously detectable in mouse tissues whereas appreciable UDP-GT2 activities were only found in liver and small intestinal mucosa. UDP-GT1 (1-naphthol as substrate) was not inhibited by morphine suggesting different active sites for the conjugation of these substrates. The results suggest the presence of at least two functionally different forms of UDP-glucuronosyltransferase in mice. In conjunction with the results of Owens (J. biol. Chem. 252, 2827 (1977)) it is evident that one of these enzyme forms is regulated by the Ah locus.