Completing the picture for the smallest eigenvalue of real Wishart matrices.

Rectangular real N×(N+ν) matrices W with a Gaussian distribution appear very frequently in data analysis, condensed matter physics, and quantum field theory. A central question concerns the correlations encoded in the spectral statistics of WW^{T}. The extreme eigenvalues of WW^{T} are of particular interest. We explicitly compute the distribution and the gap probability of the smallest nonzero eigenvalue in this ensemble, both for arbitrary fixed N and ν, and in the universal large N limit with ν fixed. We uncover an integrable Pfaffian structure valid for all even values of ν≥0. This extends previous results for odd ν at infinite N and recursive results for finite N and for all ν. Our mathematical results include the computation of expectation values of half-integer powers of characteristic polynomials.

Burnout syndrome in seafarers in the merchant marine service.

PURPOSE: As seafarers face a wide range of psychosocial stressors on board, they may be endangered to develop burnout syndrome. This study aims to investigate respective indicators. METHODS: In a cross-sectional study, 251 seafarers were asked about demographic data and job-related stressors. Particularly, the subscale emotional exhaustion (EE) of the Maslach Burnout Inventory and the Epworth Sleepiness Scale were used to assess the respective risks of job-related burnout and daytime sleepiness among seafarers. The statistical analysis was carried out using multiple logistic regression. RESULTS: Within the whole study group, the EE score was elevated in 10.8 %. A higher EE score was found in 10.7 % of officers, in 4.5 % of lower crew ranks and in 25.0 % of the galley staff (p = 0.05). Furthermore, long working days were associated with an elevated EE score [OR 3.83 (CI 1.46-10.03)]. Emotional exhaustion was associated with a subjective perception of enough sleep on board [OR 3.33 (CI 1.17-9.46)], lack of care taken by the shipboard superiors and/or the shipping company [OR 1.19 (CI 1.04-1.36)], with high responsibility for work organisation of those involved in leadership [OR 1.46 (CI 1.20-1.78)] and with social problems due to the long periods of separation from their families [OR 1.19 (CI 1.02-1.39)], taking into account relevant demographic parameters. CONCLUSIONS: Compared with the majority of on-shore occupations, the burnout risk in seafaring seems to be moderate. To reduce the EE among seafarers, it is recommended to extend the sleeping time, to avoid long working hours, to improve the superiors' communication and leadership skills, to diminish the superiors' stress load caused by organisational duties and to support low-price telecommunication possibilities at home.

Genomic chondrocyte culture profiling by array-CGH, interphase-FISH and RT-PCR.

OBJECTIVE: In vitro expansion is an important step to acquire sufficient cells in human tissue engineering technologies. The high number of chondrocytes needed for human articular cartilage implants requires in vitro expansion of the primary cells, bearing a theoretical risk of in vitro induced changes in the genomes. To gain more insights into this situation, model cultures were prepared and analyzed. DESIGN: 25 chondrocyte cell DNA samples from nine donors were analyzed by array comparative genomic hybridization (aCGH) on whole genome level and 28 chondrocyte cell samples from 16 individuals were analyzed by fluorescence in situ hybridization (FISH) on single cell level. The expanded cells were further characterized upon the chondrocytic mRNA phenotype by reverse-transciptase polymerase chain reaction (RT-PCR). RESULTS: The molecular karyotyping results revealed autosomal stability, but all male samples analyzed by aCGH displayed a variable loss of the Y-chromosome. These data were confirmed by FISH-experiments and suggest an age dependant effect toward the loss of the Y-chromosome in cultured chondrocytes. RT-PCR data for the mRNAs from collagen types I, II, and aggrecan and the pro-inflammatory cytokine interleukin-1ß (IL-1ß) did not reveal any correlation of transcriptional activity in cultures with Y-chromosome losses, nor were there statistically significant differences between cells from female and male donors. CONCLUSIONS: While cells of male origin may suffer from an age-related loss of the Y-chromosome, there was no indication of a functional impairment. The data suggest some caution toward applying proliferative steps when considering chondrocytes from elderly male patients for tissue engineering approaches.

Dystocia and fetotomy associated with cerebral aplasia in a greater one-horned rhinoceros (Rhinoceros unicornis).

The captive greater one-horned rhinoceros population consists of 176 animals. Since 1971, a total of 226 calves were born into this captive population. However, 24% of the offspring born were either stillborn or did not survive the first 3 months. The causes for this high rate of stillbirth and neonate mortality have not yet been documented. Here, we report on the veterinary management of a dystocia and foetotomy resulting from a malpositioned greater one-horned rhinoceros foetus. The dead foetus presented with a forelimb flexed at the shoulder joint, with all other joints extended. The foetus was dissected into five parts and extracted during two anaesthesias on two consecutive days. The dam recovered fully and came into oestrous 31 days after surgery. Post-mortem and CT examination of the malformed foetal head revealed cranioschisis with cerebral aplasia and cerebellar hypoplasia. The cerebral aplasia presented here and in other recent cases suggests that neural tube defects and cranial malformations may be associated with more captive rhinoceros stillbirths than previously considered. Epidemiologic studies of these phenomena and possible nutritional deficiencies or hereditary defects are warranted.

The impact of first trimester screening and early fetal anomaly scan on invasive testing rates in women with advanced maternal age.

PURPOSE: To evaluate the acceptance of noninvasive screening for trisomy 13, 18, 21 and the impact on invasive testing rates in women at an age≥35 years. MATERIALS AND METHODS: In a retrospective analysis from 2003-2006 including 13 268 women≥35 years old with singleton pregnancies and 3133 invasive procedures, we evaluated the prenatal detection rate of aneuploidies in two cohorts. Group 1: advanced maternal age as sole indication, group 2: additional abnormalities and/or suspicious maternal serum parameters. In an additional analysis from 1998-2006 including 31,076 patients≥35 years, we investigated the shift in time of sonography at 11+0-13+6, 14+0-17+6 and 18+0-22+6 gestational weeks (gw). RESULTS: Among 13,268 women, 3133 invasive tests were performed with a significant decrease over time (-17%). 9% of women chose invasive testing after a normal ultrasound (group 1, n=1,267) and 14% in the case of additional markers (group 2, n=1,866). 102 cases of aneuploidy were disclosed. The proportion of detected aneuploidies was 0.86% in group 1 and 4.9% in group 2. No change in the overall detection rate (90-93%) was observed. The number of patients≥40 years increased significantly (+2.8%). There was an increase in examinations at 11+0-13+6 gw (+8%), a decrease at 14+0-17+6 gw (-10.3%) and no significant change at 18+0-22+6 gw over time. CONCLUSION: Increasing numbers of women≥35 years of age rely on the individually adjusted risk figure to make a decision about invasive testing. The application of these selective procedures can reduce the rates of invasive testing with fewer losses of normal fetuses and led to an earlier diagnosis of aneuploidies.

A mixture model of nuchal translucency thickness in screening for chromosomal defects: validation of a single operator dataset.

OBJECTIVE: (1) To validate the mixture model in a single operator dataset and (2) to compare the detection rates for fetal chromosomal defects obtained from the mixture model with those obtained from either the delta nuchal translucency (NT) or log multiple of the median (MoM) approach. METHODS: Database query, viable singletons [crown-rump length (CRL) 45-84 mm corresponding to 11-13(+6) weeks], December 1997 to November 2006, examined by Adam Gasiorek-Wiens, the statistical mixture model was applied. RESULTS: Seventy-four of 4171 were lost to follow-up (1.8%), 4097 singleton pregnancies included trisomy 21 (n = 34, 0.8%), trisomy 18 (n = 20, 0.5%), trisomy 13 (n = 8, 0.2%), Turner syndrome (n = 9, 0.2%) and other chromosomal abnormalities (n = 14, 0.3%). The main findings are that (1) the log-transformed NT measurements follow a mixture of two Gaussian distributions and (2) the criteria to apply either the delta-NT or log MoM models are not met. In the normal group, the majority of NT measurements were dependent on the CRL, a small group showed a median independent of the CRL. In the abnormal group it was the opposite. For a 5% false-positive rate (FPR), the trisomy 21 detection rate was 83%. CONCLUSIONS: The use of the mixture model in a single operator dataset produces results compatible with the original study. The mixture model has thus been validated.

First-trimester prenatal diagnosis of Okihiro syndrome.

A case of Okihiro syndrome (OS) detected by 2- and confirmed by 3-dimensional ultrasound at 13+2 gestational weeks is reported. While the pregnant woman affected by the OS presented with limb anomalies, the fetus showed severe thoracoabdominal and skeletal anomalies. Termination of pregnancy was performed at 14+1 gestational weeks and confirmed the sonographically detected symptoms. The diagnosis was confirmed by autoptic, radiologic and molecular genetic analysis. To our knowledge, this is the first case of prenatal diagnosis of OS.

10p11.2 to 10q11.2 is a yet unreported region leading to unbalanced chromosomal abnormalities without phenotypic consequences.

Directly transmitted unbalanced chromosomal abnormalities (UBCA) or euchromatic variants (EV) were recently reported for >50 euchromatic regions of almost all human autosomes. UBCA and EV are comprised of a few megabases of DNA, and carriers are in many cases clinically healthy. Here we report on partial trisomies of chromosome 10 within the pericentromeric region which were detected by standard G banding. Those were referred for further delineation of the size of these duplicated regions for molecular cytogenetics and/or array-CGH. Partial trisomies of chromosome 10 in the pericentromeric region were identified prenatally in seven cases. A maximum of three copies of the region from 10p12.1 to 10q11.22 was observed in all cases without apparent clinical abnormalities. The imbalances were either caused by a direct duplication in one familial case or by de novo small supernumerary marker chromosomes (sSMC). Thus, we report a yet unrecognized chromosomal region subject to UBCA detected in seven unrelated cases. To the best of our knowledge, this is the first report of a UBCA in the pericentromeric region of chromosome 10 that is not correlated with any clinical consequences.

Forty-eight new cases with infertility due to balanced chromosomal rearrangements: detailed molecular cytogenetic analysis of the 90 involved breakpoints.

A molecular cytogenetic study was performed on 48 infertile patients who were identified as carriers of balanced translocations (40 cases), inversions (6 cases) or insertions (2 cases) by means of banding cytogenetics. Cases with a Robertsonian translocation or pericentric inversion 2 or 9 were not included. In summary, 100 break-events occurred in these patients, and 90 different chromosomal regions were involved. Thus, this study confirmed the presence of abnormal karyotypes in a subgroup of patients seeking infertility treatment. Breaks were demonstrated to appear preferentially in GTG-light bands in these patients. Furthermore, the observed breakpoints were associated with genomic regions prone to instability due to the presence of segmental duplications. Nonetheless, further detailed molecular analysis will be necessary in the future to characterize the mechanisms and genetic basis for this phenomenon.

Interphase M-FISH applications using commercial probes in prenatal and PGD diagnostics.

Early, rapid and reliable diagnosis is of first priority in prenatal medicine. The combination of specific sonographic markers (e.g. nuchal translucency) and biochemical parameters in maternal serum (e.g. free beta-human chorionic gonadotropin, pregnancy-associated plasma protein A), has already dramatically improved the sensitivity of non-invasive first trimester risk screening in pregnancy. In invasive prenatal diagnosis, in addition to well-established chorionic villi short-term culture, interphase multi-colour-fluorescence in situ hybridisation (M-FISH) on uncultured amnion cells has become a reliable tool for the rapid detection of fetal aneuploidies. Interphase M-FISH applications have enabled the diagnosis of selected chromosomal abnormalities in single cells and, therefore, have also become an important diagnostic tool for preimplantation diagnosis (PGD). The development of commercially available probe sets, in particular, has led to a broad use of interphase M-FISH in prenatal and PGD diagnosis.

Characterization of cell cycle checkpoint responses after ionizing radiation in Nijmegen breakage syndrome cells.

Nijmegen breakage syndrome (NBS), which in the past also has been classified as a variant of ataxia telangiectasia (AT), is characterized by cancer proneness and extreme sensitivity to ionizing radiation. We investigated the DNA damage responses of four independent primary NBS fibroblast cell lines. Following a low dose of ionizing radiation, p53 is mostly induced with slower kinetics and shows more transient induction in NBS fibroblasts. Nonetheless, this damage-induced protein appears biologically functional: unsynchronized and synchronized NBS cells show a G1 arrest after ionizing radiation as determined by bivariate flow cytometry. Neither an AT cell line nor a NBS cell line transformed with human papillomavirus genes E6 and E7 shows a G1 arrest. Furthermore, NBS cells show a normal G2 block, unlike that shown for AT cells. These data provide a cellular distinction between NBS and AT, thereby clearly separating the NBS from the AT syndrome.

Prenatal diagnosis in Germany.

Prenatal diagnosis (PND) in Germany is well established. A wide spectrum of sonographic, cytogenetic, molecular and biochemical investigations can be chosen by pregnant women. While sonographic examinations are offered to all pregnant women, the methods requiring invasive procedures are performed predominantly when there is a higher risk than in the general population. However, PND is also performed on request by the mother in the absence of an increased risk. Pretest genetic counselling is recommended before invasive techniques. PND is performed in public as well as in private settings. Guidelines are in effect for specialisation of gynaecologists and human geneticists. Quality assessment for cytogenetic and molecular laboratories is performed on a voluntary basis. Since October 1995, termination of pregnancies is regulated by a new law.

Localisation of a Fanconi anaemia gene to chromosome 9p.

Using homozygosity mapping in a large consanguineous family, we have localised to chromosome 9p a further gene for the autosomal recessive, genetically heterogeneous disease Fanconi anaemia (FA). This is the fourth of at least eight FA genes to be localised to a discrete chromosomal region. Previously localised genes are FAA, FAC and FAD. By analysis of assigned families we show that the gene localised to chromosome 9p is FAF, FAG or FAH, or a new FA gene, and refine the localisation to the 21 cM region between markers D9S1678 and D9S175.

Increased genetic risk of hypertension in glomerulonephritis?

The present study was carried out to test the hypothesis that the familial risk of hypertension is elevated in individuals with glomerulonephritis. Sixty-three parents of 39 consecutive patients below the age of 50 years who were admitted with biopsy-confirmed primary glomerulonephritis (excluding familial glomerulonephritis) were examined. Of these parents, 57% had blood pressure greater than or equal to 160/95 mmHg and/or were taking antihypertensive medication (81% of hypertensives). In 138 parents of 87 controls (age- and sex-matched patients admitted to a surgical ward for trauma), hypertension was found in 32.6% (of whom 73% were on antihypertensive medication). Age, sex ratio and body mass index were comparable in both groups of parents. A similar proportion of parents of patients with glomerulonephritis (27%) and parents of controls (25%) had already died. There was no evidence of excess cardiovascular or renal mortality in either group of parents. Urinary abnormalities were found in a similar proportion of the parents of patients with glomerulonephritis (5%) and controls (8%). Although the effects of a shared environment are not formally excluded, the data are consistent with a possible increased genetic risk of hypertension in patients with primary chronic glomerulonephritis.

Effects of theophylline withdrawal in severe chronic obstructive pulmonary disease.

To determine the value of theophylline in the maintenance therapy of patients with severe chronic obstructive pulmonary disease (COPD), we conducted a trial of theophylline therapy withdrawal in 38 clinically stable patients with severe COPD (FEV1 < 60 percent) predicted. Symptoms, lung function, blood gases, and 6-min walking distance were assessed on days 1 and 2. Quality of life and overall dyspnea were scored using four different clinical rating scales. Theophylline therapy was continued in 20 patients and replaced by placebo from day 3 on in the remainder; measurements were repeated on days 5 and 6. Withdrawal of theophylline therapy resulted in significant (p < 0.05) deterioration in lung function, exercise performance, and two indices of overall dyspnea, and a significant increase in scoring of symptoms and auscultation findings. Individual analysis revealed a clinically relevant deterioration in 72 percent of patients from whom theophylline therapy was withdrawn, while only 15 percent of patients receiving theophylline exhibited deterioration. No major side effects were observed. Our data show that about half of the patients with severe COPD can be considered as theophylline responders. The response of these patients to withdrawal of theophylline therapy suggests that the clinical effectiveness of this drug cannot be explained exclusively by bronchodilation. Due to the inherent difficulties in predicting response to theophylline, its effectiveness in patients with severe COPD should be determined individually, including assessment of exercise performance and ratings of dyspnea.

Partial trisomy 1q, an uncommon chromosomal aberration in erythroleukemia.

A 2 years 4 months old boy with erythroleukemia (FAB-M6) and Down's syndrome is described. Chromosome analysis of bone marrow leukemic blasts revealed apart from the trisomy 21 a partial trisomy of the long arm of chromosome 1:1q23-->1qter in all cells and trisomy 8 mosaicism. To the best of our knowledge this is the first time that a partial trisomy of chromosome 1 in association with erythroleukemia has been described. Previous reports of other hematologic malignancies with aberrations of chromosome 1 indicate that the breakpoint 1q23 is nonrandom and that trisomies of chromosome 1 plays a crucial role in the course of development of hematologic malignancies. This could probably also be true for erythroleukemias.

Genetic haplotyping of ataxia-telangiectasia families localizes the major gene to an approximately 850 kb region on chromosome 11q23.1.

The genotyping data given localize the major A-T gene to an approximately 850 kb region. They also localize the group A A-T gene (ATA) to a region that contains the approximately 850 kb region. They are compatible with linking A-TFresno to 11q22-23. NBS-V2 does not link to this region. Four non-linking families contain only single affecteds, suggesting that these may be spontaneous mutations rather than evidence for an A-T gene outside the 11q22-23 region. Finally, two other non-linking families contain recombinant haplotypes that are compatible with a second A-T gene at 11q22-23, slightly distal to the approximately 850 kb region. However, convincing evidence for a second gene is still lacking.

Frequency of trisomy 21 in Germany before and after the Chernobyl accident.

For Berlin (West) the rate of trisomy 21 among newborn and all prenatally diagnosed cases can be almost completely recorded, including the maternal age distribution. During the 9-year-period from 1980 and 1988 the average number of trisomy 21 per month was about 2, following a Poisson distribution. A significant increase (P less than 0.01) was observed in January 1987, exactly 9 months after the Chernobyl accident. In a supraregional study based on greater than 30,000 prenatal diagnoses performed in 1986, no significant effect could be observed. However, the highest rates of trisomy 21 were observed in the more heavily contaminated, southern part of Germany. The majority of these fetuses were conceived during the period of greatest radioactive exposure. The data are discussed with respect to the effect of low-dose radiation around the time of conception on the induction of non-disjunction in man.

Biomonitoring results and cytogenetic markers among harbour workers with potential exposure to river silt aerosols.

BACKGROUND: Workers on dredgers and lighters on rivers are potentially exposed to a variety of substances. AIMS: To determine the internal load of heavy metals and arsenic as well as levels of cytogenetic markers in workers exposed to river silt aerosols. METHODS: One hundred exposed workers were examined up to eight times within three years. Additionally, 100 control workers were studied once. Blood samples were analysed for lead, mercury, and cadmium. Additionally, micronuclei frequency and sister chromatid exchange (SCE) rates were determined. Urinary samples were analysed for cadmium, mercury, nickel, chromium, and arsenic. Information on potential confounders, such as smoking habits and consumption of fish were assessed. RESULTS: Apart from some increased concentrations of mercury in blood (maximum 14.6 microg/l) and arsenic in urine (maximum 356.5 microg/l) all measurements were within reference values. None of the exposure and effect markers were found to be significantly increased in exposed workers compared to non-exposed controls. In multiple linear regression models, mercury levels in blood as well as the concentration of arsenic in urine were strongly related to fish consumption. Cadmium levels in blood as well as urinary cadmium concentrations were strongly related to smoking habits. After adjusting for smoking habits, SCE rates were associated with cadmium levels in blood. CONCLUSION: Increased exposure levels or enhanced levels of cytogenetic markers were not found in workers exposed to river silt aerosols. However, cadmium exposure in blood was related to SCE frequency.

Investigation into the possible genetic effects of diagnostic ultrasound.

The mutagenic effect of DUS (diagnostic ultrasound) was examined using two generators emitting continuous waves and pulsed waves, respectively. Three different test systems for mutagenic activity were employed in this study. 1. The frequency of sister chromatid exchanges (SCEs) was determined in metaphase chromosomes of human lymphocytes and of Chinese hamster ovary (CHO) cells sonicated at different stages of the cell cycle. 2. The induction of DNA single strand breaks was tested in CHO cells treated with continuous wave ultrasound. Following sonication an endonuclease was introduced into the cells converting single strand breaks to chromosomal aberrations scorable in the following metaphase. 3. The influence of DUS on the number of point mutations was evaluated in the Ames test. A tester strain of Salmonella typhimurium indicating base substitutions was sonicated. At the present stage, all results proved to be completely negative and could thus not support the view of any mutagenic activity of diagnostic ultrasound.