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Biomedical subjects

H Becher

Publications and source records attributed to H Becher.

At least 73 records · Page 4Linked to original sources
PubMed1998

Using gene carrier probability to select high risk families for identifying germline mutations in breast cancer susceptibility genes.

Germline mutations in highly penetrant autosomal dominant genes explain about 5% of all breast cancer, and heritable mutations in the BRCA1 breast and ovarian cancer susceptibility gene account for 2-3% of breast cancer in the general population. Nevertheless, the presence of such mutations is highly predictive of disease development. Since screening for mutations is still technically laborious, we investigated whether the prior probability of being a carrier of a dominant breast cancer susceptibility gene in the youngest affected family member could be used to identify families in which the probability of finding a mutation is sufficiently high. Sixty German families with three or more cases of breast/ovarian cancer with at least two cases diagnosed under the age of 60 were screened for mutations by SSCP/CSGE and subsequent direct sequencing. Thirteen germline truncating/splicing mutations in BRCA1 were found in 33% (6/18) of the breast-ovarian cancer families and in 17% (7/42) of breast cancer only families. All the families showing mutations in BRCA1 had carrier probabilities of 0.65 or higher. In families with prior carrier probabilities above 0.6, the proportion detected was 0.46 in breast-ovarian cancer families and 0.26 in breast cancer only families. The average age at diagnosis of breast or ovarian cancer in families with BRCA1 mutations was 41.9 years and significantly lower than in families without mutations (p < 0.05). Mutation carriers and obligate carriers were also found to have cancers at other sites. The probability of being a susceptibility gene carrier, taking into account the complete pedigree information, allows uniform characterisation of all types of families for identifying those in which mutation analysis for BRCA1/2 is warranted. However, prior probabilities calculated using this method can be reduced when the correlation between genotype and phenotype is imperfect. A larger series of families needs to be investigated in this fashion to provide better estimates of the detection rate for different ranges of carrier probabilities.

Adult↗
PubMed1998

High-resolution emboli detection and differentiation by characteristic postembolic spectral patterns.

BACKGROUND AND PURPOSE: High-intensity transient signals (HITS) detected by transcranial Doppler ultrasonography correspond to microemboli in intracranial arteries. The purpose of this study was to develop new diagnostic criteria for the differentiation of these microembolic signals from artifact, based on a high-resolution analysis of Doppler power spectra in an in vitro model. METHODS: Two hundred seventy-six formed emboli, consisting of different biological and nonbiological materials and as air bubbles, were injected into a flow phantom with artificial blood vessels and perfused in a steady or a pulsatile way. Embolic passage was assessed with a modified 2.5-MHz pulsed Duplex machine and a commercial 2-MHz Doppler system. Embolic HITS were analyzed using internationally accepted criteria for the audiovisual characteristics of HITS. Doppler spectra changes associated with HITS were evaluated by means of a specially developed high-resolution analysis of Doppler raw data. RESULTS: Seventy-seven percent of all embolic events could be identified using conventional audiovisual criteria for embolic HITS. Analysis of Doppler spectra showed that all injected emboli generated high-amplitude signals with a minimum of at least 3 dB above background level. In addition, using high-resolution processing, specific changes in Doppler spectral patterns could be identified after all embolic HITS caused by solid particles. These postembolic spectral patterns were always characterized by a Doppler frequency shift decreasing in time and resembling the letter lambda (lambda). Duration and appearance of the postembolic spectral patterns were mainly influenced by the size and velocity of the embolus. Similar phenomena could not be found in case of embolism by either small air bubbles or in case of provoked artifact registration. Using a commercial Doppler system specific, we documented postembolic spectral patterns in 47% of injected emboli. CONCLUSIONS: In this study, highly specific changes in Doppler spectral patterns associated with microembolic HITS could be characterized, resulting in further criteria for the differentiation between microembolic signals and artifact in Doppler emboli detection. The sensitivity of the detection of these signals can be increased by high-resolution analysis of raw Doppler data.

Animals↗
PubMed1998

Recent bacterial and viral infection is a risk factor for cerebrovascular ischemia: clinical and biochemical studies.

We performed a case-control study to investigate the role of recent infection as stroke risk factor and to identify pathogenetic pathways linking infection and stroke. We examined 166 consecutive patients with acute cerebrovascular ischemia and 166 patients hospitalized for nonvascular and noninflammatory neurologic diseases. Control subjects were individually matched to patients for sex, age, and season of admission. We assessed special biochemical parameters in subgroups of stroke patients with and without recent infection (n = 21) who were similar with respect to demographic and clinical parameters. Infection within the preceding week was a risk factor for cerebrovascular ischemia in univariate (odds ratio [OR] 3.1; 95% confidence interval (CI), 1.57 to 6.1) and age-adjusted multiple logistic regression analysis (OR 2.9; 95% CI, 1.31 to 6.4). The OR of recent infection and age were inversely related. Both bacterial and viral infection contributed to increased risk. Infection elevated the risk for cardioembolism and tended to increase the risk for arterioarterial embolism. Stroke patients with and without preceding infection were not different with respect to factor VII and factor VIII activity, fibrin monomer, fibrin D-dimer, von Willebrand factor, C4b-binding protein, protein S, anticardiolipin antibodies, interleukin-1 receptor antagonist, soluble tumor necrosis factor-alpha receptor, interleukin-6, interleukin-8, and neopterin. In conclusion, recent infection is an independent risk factor for acute cerebrovascular ischemia. Its role appears to be more important in younger age groups. The pathogenetic linkage between infection and stroke is still insufficiently understood.

Adult↗
PubMed1998

Exposure to dioxin and nonneoplastic mortality in the expanded IARC international cohort study of phenoxy herbicide and chlorophenol production workers and sprayers.

The authors studied noncancer mortality among phenoxyacid herbicide and chlorophenol production workers and sprayers included in an international study comprising 36 cohorts from 12 countries followed from 1939 to 1992. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin or higher chlorinated dioxins (TCDD/HCD) was discerned from job records and company questionnaires with validation by biologic and environmental measures. Standard mortality ratio analyses suggested a moderate healthy worker effect for all circulatory diseases, especially ischemic heart disease, among both those exposed and those not exposed to TCDD/HCD. In Poisson regression analyses, exposure to TCDD/HCD was not associated with increased mortality from cerebrovascular disease. However, an increased risk for circulatory disease, especially ischemic heart disease (rate ratio [RR] 1.67, 95% confidence interval [Cl] 1.23-2.26) and possibly diabetes (RR 2.25, 95% Cl 0.53-9.50), was present among TCDD/HCD-exposed workers. Risks tended to be higher 10 to 19 years after first exposure and for those exposed for a duration of 10 to 19 years. Mortality from suicide was comparable to that for the general population for all workers exposed to herbicides or chlorophenols and was associated with short latency and duration of exposure. More refined investigations of the ischemic heart disease and TCDD/HCD exposure association are warranted.

Adult↗
PubMed1998

Estimation of the cumulated exposure to polychlorinated dibenzo-p-dioxins/furans and standardized mortality ratio analysis of cancer mortality by dose in an occupationally exposed cohort.

For a cohort of 1189 male German former herbicide and insecticide workers with exposure to polychlorinated dibenzo-p-dioxins and -furans (PCDD/F), we report an extended standardized mortality ratio (SMR) analysis based on a new quantitative exposure index. This index characterizes the cumulative lifetime exposure by integrating the estimated concentration of PCDD/F at every point in time (area under the curve). Production department-specific dose rates were derived from blood levels and working histories of 275 workers by applying a first-order kinetic model. These dose rates were used to estimate exposure levels for all cohort members. Total mortality was elevated in the cohort; 413 deaths yielded an SMR of 1.15 (95% confidence interval [Cl] 1.05, 1.27) compared to the mortality of the population of Germany. Overall cancer mortality (n = 124) was significantly increased (SMR = 1.41, 95% Cl 1.17, 1.68). Various cancer sites showed significantly increased SMRs. The exposure index was used for an SMR analysis of total cancer mortality by dose. For 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) a significant trend (p = 0.01) for the SMRs with increasing cumulative PCDD/F exposure was observed. The SMR in the first exposure quartile (0-125.2 ng/kg x years) was 1.24 (95% Cl 0.82, 1.79), increasing to 1.73 (95% Cl 1.21, 2.40) in the last quartile (> or = 2503.0 ng/kg x years). For all congeners combined as toxic equivalencies (TEQ) using international toxic equivalency factors, a significant increase in cancer mortality was observed in the second quartile (360.9-1614.4 ng/kg x years, SMR 1.64; 95% Cl 1.13, 2.29) and the fourth quartile (> or = 5217.7 ng/kg x years TEQ, SMR 1.64, 95% Cl 1.13, 2.29). The trend test was not significant. The results justify the use of this cohort for a quantitative risk assessment for TCDD and to a lesser extent for TEQ.

Adult↗
PubMed1998

Quantitative cancer risk assessment for dioxins using an occupational cohort.

We consider a cohort of 1189 male German factory workers (production period 1952-1984) who produced phenoxy herbicides and were exposed to dioxins. Follow-up until the end of 1992 yielded a significantly increased standardized mortality ratio (SMR) for total cancer (SMR 141; 95% confidence interval 117-168). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) concentrations up to 2252 ng/kg body fat were measured in 275 cohort members. Other higher chlorinated dioxins and furans also occurred in high concentrations. For quantitative analysis, the integrated TCDD concentration over time was used as an exposure variable, which was calculated using results from half-life estimation for TCDD and workplace history data. The other congeners were expressed as toxic equivalency (TEQ) and compared to TCDD using international toxic equivalency factors. Poisson and Cox regressions were used to investigate dose-response relationships. Various covariables (e.g., exposure to beta-hexachlorocyclohexane, employment characteristics) were considered. In all analyses, TCDD and TEQ exposures were related to total cancer mortality. The power model yielded a relative risk (RR) function RR(x) = (1 + 0.17x)0.326 for TCDD (in microgram/kilogram blood fat x years)--only a slightly better fit than a linear RR function--and RR(x) = (1 + 0.023x)0.795 for TEQ. Investigations on latency did not show strong effects. Different methods were applied to investigate the robustness of the results and yielded almost identical results. The results were used for unit risk estimation. Taking into account different sources of variation, an interval of 10(-3) to 10(-2) for the additional lifetime cancer risk under a daily intake of 1 pg TCDD/kg body weight/day was estimated from the dose-response models considered. Uncertainties regarding the dose-response function remain. These data did not indicate the existence of a threshold value; however, such a value cannot be excluded with any certainty.

Adult↗
PubMed1998

Blood lipid concentrations of dioxins and furans in a sample of BASF employees included in the IARC registry of workers exposed to phenoxy acid herbicides and/or chlorophenols.

Depending on process conditions, polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) may be generated as low-level byproducts of chlorophenol and chlorophenoxy herbicides manufacture. A stratified random sample of 20 active employees from a cohort of phenoxy herbicide workers was selected in 1995 for determining PCDD and PCDF congeners in blood lipids to assess the extent of past PCDD and PCDF exposure in this cohort and whether that exposure might explain site-specific cancer findings in the total cohort. This cohort is included in the IARC International Registry of Persons Exposed to Phenoxyacid Herbicides and Their Contaminants. For the 19 persons who participated, median PCDD and PCDF concentrations were comparable to background concentrations in the general population. Median levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin, the sum of hexachlorodibenzo-p-dioxin, pentachlorodibenzofurans, and two dioxin toxicity equivalents values were statistically higher in 7 employees assigned to synthesis operations than for 12 employees assigned to other operations. However, the PCDD and PCDF concentrations were low relative to those seen in other dioxin-exposed cohorts. We conclude that PCDD and PCDF exposures of cohort members are unlikely to explain the elevated standardized mortality ratios observed in this cohort for several cancer sites.

Adult↗
PubMed1997

[Effect of diagnostic imaging on pre-mortem diagnostic reliability].

BACKGROUND: Between 1972 and 1984 the diagnostic arsenal has much changed due to wide application of endoscopy, sonography and computed tomography. PATIENTS AND METHOD: Using the data from patients undergoing autopsy in the years 1972, 1977, 1981, and 1984, it was assessed how many of the diagnostic techniques had been used and to what extent the premortal diagnosis of abnormalities found at autopsy improved during this period. RESULT: While the number of autopsies declined from 113 in 1977 to 66 in 1984, the number of diagnostic techniques used increased continuously (94, 107, 118, and 140, amounting to 0.83, 1.34, 1.76 and 2.12 per patient). The premortal detection of abdominal abnormalities increased globally from 16.8 to 32.5%. This increase was largely due to better diagnosis of liver and gallbladder abnormalities which were in most cases of little relevance. CONCLUSION: Thus, the massive increase of the application of technical diagnostic tools leads only to a limited premortal diagnostic gain while costs are significant.

Abdomen↗
PubMed1997

Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins. An expanded and updated international cohort study.

The authors examined cancer mortality in a historical cohort study of 21,863 male and female workers in 36 cohorts exposed to phenoxy herbicides, chlorophenols, and dioxins in 12 countries. Subjects in this updated and expanded multinational study coordinated by the International Agency for Research on Cancer were followed from 1939 to 1992. Exposure was reconstructed using job records, company exposure questionnaires, and serum and adipose tissue dioxin levels. Among workers exposed to phenoxy herbicides contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or higher chlorinated dioxins, mortality from soft-tissue sarcoma (6 deaths; standardized mortality ratio (SMR) = 2.03, 95% confidence interval (CI) 0.75-4.43) was higher than expected from national mortality rates. Mortality from all malignant neoplasms (710 deaths; SMR = 1.12, 95% CI 1.04-1.21), non-Hodgkin's lymphoma (24 deaths; SMR = 1.39, 95% CI 0.89-2.06), and lung cancer (225 deaths; SMR = 1.12, 95% CI 0.98-1.28) was slightly elevated. Risks for all neoplasms, for sarcomas, and for lymphomas increased with time since first exposure. In workers exposed to phenoxy herbicides with minimal or no contamination by TCDD and higher chlorinated dioxins, mortality from all neoplasms (398 deaths; SMR = 0.96, 95% CI 0.87-1.06), non-Hodgkin's lymphoma (9 deaths; SMR = 1.00), and lung cancer (148 deaths; SMR = 1.03) was similar to that expected, and mortality from soft-tissue sarcoma was slightly elevated (2 deaths; SMR = 1.35). In a Poisson regression analysis, workers exposed to TCDD or higher chlorinated dioxins had an increased risk for all neoplasms (rate ratio = 1.29, 95% CI 0.94-1.76) compared with workers from the same cohort exposed to phenoxy herbicides and chlorophenols but with minimal or no exposure to TCDD and higher chlorinated dioxins. These findings indicate that exposure to herbicides contaminated with TCDD and higher chlorinated dioxins may be associated with a small increase in overall cancer risk and in risk for specific cancers.

Australia↗
PubMed1997

Improved odds ratio estimation by post hoc stratification of case-control data.

We propose a logistic regression analysis of unmatched or frequency matched case-control studies with conditional maximum likelihood estimation through post hoc stratification. In this model fewer parameters have to be estimated. With a simulation study we show that parameter estimates have smaller variance and are less biased. Also, the residual confounding effect was quantified. A more refined post hoc stratification reduces computing time, but to the cost of a larger bias and a loss in efficiency. The model was also applied to data of unmatched case-control studies on laryngeal cancer, oesophageal cancer and lung cancer.

Case-Control Studies↗
PubMed1997

Modifying effect of reproductive risk factors on the age at onset of breast cancer for German BRCA1 mutation carriers.

Female carriers of mutations in the BRCA1 gene on chromosome 17q have a very high risk of developing breast and/or ovarian cancer during their lifetime. There is, however, little knowledge of to what extent non-genetic risk factors, such as age at menarche, age at first birth, and body mass index, alter the age at onset of disease. We identified individuals showing a high probability of linkage to BRCA1 and examined the effect of other known risk factors on disease risk. A total of 43 families with at least three breast or ovarian cancer cases, including two affected before 60 years of age, were studied for linkage to the susceptibility locus BRCA1. Blood samples from relevant family members were used to genotype for at least three chromosome 17q polymorphic markers. Information on reproductive history, hormone use and lifestyle factors was collected from female members using a self-administered questionnaire. Diagnoses of breast and ovarian cancer were verified through pathology reports and paraffin blocks were obtained when available. Multipoint LOD (logarithm of the odds) scores were calculated and individuals from 10 families with a posteriori probability for linkage greater than 0.90 were used for further analysis. Forty-six BRCA1 carriers were identified by the disease haplotype; 30 were affected with breast cancer and 5 with ovarian cancer. Proportional- hazards analysis of age at onset of breast cancer yielded increased relative risks of 1.74 for early age at menarche (< 14 years), 1.58 for late age at first birth (> or = 25 years) or nulliparity, and 2.78 for recent year of birth (> or = 1940); however, none of the risk estimates was statistically significant. When both breast and ovarian cancer were considered as disease endpoints, the birth cohort effect was stronger and age at first birth showed no effect. Our data provide some evidence that reproductive risk factors for breast cancer have an effect on age at onset for BRCA1 carriers. However, considering that our analyses were based on limited numbers, these results warrant further clarification.

Adult↗
PubMed1997

[Enhancement of Doppler signals in aortic and mitral valve diseases].

Ultrasound contrast media increase backscatter from blood, thus improving the signal-to-noise ratio. Potential clinical applications of intravenous ultrasound contrast are reviewed. Contrast enhancement of continuous wave Doppler is indicated when the native recordings are noisy and no complete envelope of the Doppler spectrum is obtained. In aortic stenosis several investigations showed good agreement between the gradient calculated from Doppler measurements and the results of cardiac catheterization. In mitral insufficiency maximum area of the regurgitant jet is a widely used parameter for estimation of the severity of the regurgitation. However, assessment of the maximum jet area may not be possible because of poor acoustic windows. Contrast enhancement provides complete display of the regurgitant jet in most of the patients. The diagnostic confidence of the Doppler investigation is further improved by the recording of the pulmonary venous flow, which can be recorded in most of the patients following contrast injection. Therefore contrast enhanced transthoracic Doppler is an alternative to transesophageal Doppler investigation in patients with poor transthoracic windows.

Aortic Valve Stenosis↗
PubMed1997

Elimination of beta-hexachlorocyclohexane in occupationally exposed persons.

The elimination of beta-hexachlorocyclohexane (beta-HCH) in humans was investigated in a group of 40 former workers of a lindane-producing plant by analyzing at least 2 blood specimens (3 specimens in 3 workers) from different time points. Assuming a first-order kinetic model for excretion, the median half-life of beta-HCH is 7.2 yr calculated by concentrations in whole blood and 7.6 yr calculated by concentrations in extractable lipids. In univariate analyses an influence of age, percent body fat, and liver disease (additionally in whole blood an influence of contents of extractable lipids) on clearance was observed. All factors show a positive correlation with half-life. According to a multiple regression model, influence of percent body fat calculated according to Deurenberg et al. (1991) is an important covariate in the description of the variations of the clearance rate (calculated on the basis of extractable lipids) of beta-HCH. The data support the assumption of first-order kinetics.

Adipose Tissue↗
PubMed1997

Familial aggregation of oesophageal cancer in a high incidence area in China.

BACKGROUND: The high incidence of oesophageal cancer in northern China is attributed predominantly to environmental factors. The role of genetic factors has not been extensively studied. METHODS: Our aim was to study familial aggregation of oesophageal cancer in pedigrees from a defined population base in a high incidence area in China and to quantify the risk associated with different first degree relatives using different analytical approaches. Detailed data on family members of three successive generations and the occurrence of oesophageal and other cancers in family members were collected from a population-based series of 244 oesophageal cancer cases which occurred between 1987 and mid-1992 in Huixian County, Henan. RESULTS: Compared to expected rates, the standardized mortality ratio (SMR) of oesophageal cancer among first degree relatives of oesophageal cancer patients was 2.4 (2.2 in male and 2.7 in female relatives). The corresponding SMR for first and second degree relatives were 1.6 and 2.2. The null hypothesis of 'no familial aggregation' was rejected using Tarone's one-sided score test for binomial distributions indicating some evidence for clustering within families. To account for variance due to between-pairs correlation and family and/or individual specific variables, we fitted a series of regression models using a Generalized Estimation Equations (GEE) approach. The pairwise odds ratios were 2.3 for parent-parent, 1.9 for sib-parent and 1.1 for sib-sib, adjusted for sex, age and sex of index case. DISCUSSION: The existence of familial aggregation of oesophageal cancer in the study population was confirmed using different analyses and a two- to threefold increased risk was found for first degree relatives. The clear association of disease between parent and sib provides some indication of a genetic component. The pairwise association between parents but not between sibs suggests that environmental factors have a stronger action after childhood.

Aged↗
PubMed1997

Association between acute cerebrovascular ischemia and chronic and recurrent infection.

BACKGROUND AND PURPOSE: We performed a case-control study to investigate whether chronic or recurrent respiratory, ear-nose-throat (ENT), and dental infections are risk factors for cerebrovascular ischemia. METHODS: Using a standardized questionnaire we investigated past infectious diseases in 166 consecutive patients with acute cerebrovascular ischemia and in 166 age- and sex-matched nonstroke neurological patient controls. In subgroups, we performed standardized ENT (69 patients, 66 control subjects) and dental examinations including orthopantomography (66 patients, 60 control subjects). Dental status was determined by a total dental index (TDI) that reflects caries, periapical lesions, periodontitis, and other dental lesions and by an orthopantomography index (OPGI) that was assessed blinded. RESULTS: Frequent (> or = 2 episodes in each of the 2 preceding years) or chronic bronchitis was associated with cerebrovascular ischemia in age-adjusted multiple logistic regression analysis (odds ratio, OR, 2.2; 95% confidence interval, CI, 1.04 to 4.6). Groups were not different in ENT examination. Patients tended to have a worse dental status (TDI: P = .070; OPGI: P = .062) and had more severe periodontitis (P = .047) and periapical lesions (P = .027) than control subjects. In age-adjusted multiple logistic regression analysis with social status and established vascular risk factors, poor dental status (TDI) was independently associated with cerebrovascular ischemia (OR, 2.6; 95% CI, 1.18 to 5.7). CONCLUSION: Recurrent or chronic bronchial infection and poor dental status, mainly resulting from chronic dental infection, may be associated with an increased risk for cerebrovascular ischemia.

Acute Disease↗
PubMed1997

Estimating the generalized impact fraction from case-control data.

The generalized impact fraction (also called the generalized attributable fraction) was introduced by Walter (1980, American Journal of Epidemiology 112, 409-416) and Morgenstern and Bursic (1982, Journal of Community Health 7, 292-309) as a measure that generalizes the population attributable fraction (attributable risk). It is defined as the fractional reduction of a disease resulting from changing the current distribution of a risk factor to some modified distribution. We show that the point and variance estimator derived by Greenland and Drescher (1993, Biometrics 49, 865-872) for fixed shift functions can be extended to situations where the shift is a probabilistic function of the actual exposure value. The formulas are applicable for case-control designs where the cases are simply randomly selected and the controls are chosen in one of three ways: simple random sampling, stratified random sampling, and frequency matching.

Alcohol Drinking↗