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PubMed2003

Screening for congenital adrenal hyperplasia: adjustment of 17-hydroxyprogesterone cut-off values to both age and birth weight markedly improves the predictive value.

Newborn screening procedures for congenital adrenal hyperplasia (CAH) are still suboptimal because of low specificity, particularly in premature infants. This study evaluated a multitiered strategy for reporting abnormal 17-hydroxyprogesterone screening values that simultaneously takes into account not only birth weight but also age at sampling. A cautious three-tiered cut-off scheme was used during the initial 24 months of CAH screening in Bavaria. Data were then reanalyzed using five birth weight classes to reflect more precisely the markedly higher values in low-birth-weight newborns. Because 17-hydroxyprogesterone values apparently decline with increasing age, these classes were then further subdivided into a total of 21 groups according to the age at sampling. Based on this reanalysis, we defined new multitiered cut-off levels and used them for the next 18 months. A total of 538466 newborns were screened from January 1999 to June 2002; 51 CAH cases were detected. Application of the new threshold values resulted in a 35% reduction of the total recall rate (from 1.13% to 0.74%) and an increase in the positive predictive value from 0.84% to 1.29% without reducing diagnostic sensitivity. This improvement of CAH screening can be achieved by simply using request forms that ask for both age and birth weight at the time of sampling.

17-alpha-Hydroxyprogesterone↗
PubMed1991

Uterine estrogen receptor in vivo: phosphorylation of nuclear specific forms on serine residues.

We have characterized further the heterogeneous nuclear-specific doublet forms of the mouse uterine estrogen receptor (ER). Estrogen treatment produced the multiple nuclear ER forms of 65 and 66.5 kDa, which were isolated and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Soluble ER preparations exhibited only a single 65-kDa form. Isolation of the individual nuclear ER forms and reanalysis demonstrated that formation of the multiple bands was not due to artifacts of nuclear sample preparation or the presence of contaminating proteins. Analysis of individual uterine cell types (epithelial and stromal/myometrium) indicated that both ER forms were present in both cell fractions. Fractionation of nuclear components with low salt showed that both ER forms were found in the salt-resistant fraction. Extraction of nuclei with high salt (0.6 M KCl) solubilized both ER forms. Phosphorylation was studied as a protein modification to account for the multiple forms. Incorporation of 32P into uterine protein both in vivo and in intact tissue incubation indicated 32P labeling of uterine nuclear ER after hormone treatment. Both nuclear ER forms are labeled, although the 66.5-kDa form appears to be more heavily labeled. Phosphoamino acid analysis of the immunopurified 32P-labeled ER from intact uterine tissue indicated phosphoserine as the only phospholabeled residue. These data suggest that phosphorylation is associated with the physiological functioning of the ER in response to hormone and produces the heterogeneous ER forms in the nucleus.

Animals↗
PubMed2002

Diagnostic criteria for respiratory chain disorders in adults and children.

BACKGROUND: Respiratory chain (RC) disorders are clinically, biochemically, and molecularly heterogeneous. The lack of standardized diagnostic criteria poses difficulties in evaluating diagnostic methodologies. OBJECTIVE: To assess proposed adult RC diagnostic criteria that classify patients into "definite," "probable," or "possible" categories. METHODS: The authors applied the adult RC diagnostic criteria retrospectively to 146 consecutive children referred for investigation of a suspected RC disorder. Data were collected from hospital, genetics, and laboratory records, and the diagnoses predicted by the adult criteria were compared with the previously assigned assessments. RESULTS: The authors identified three major difficulties in applying the adult criteria:lack of pediatric-specific criteria; difficulty in segregating continuous data into circumscribed major and minor criteria; and lack of additivity of clinical features or enzyme tests. They therefore modified the adult criteria to allow for pediatric clinical and histologic features and for more sensitive coding of RC enzyme and functional studies. Reanalysis of the patients' data resulted in congruence between the diagnostic certainty previously assigned by the authors' center and that defined by the new general RC diagnostic criteria in 99% of patients. CONCLUSIONS: These general diagnostic criteria appear to improve the sensitivity of the adult criteria. They need further assessment in prospective clinical and epidemiologic studies.

Adult↗
PubMed1984

Interpretation of serum phenytoin concentrations in uremia is assay-dependent.

A 25-year-old man with sickle cell disease and chronic renal insufficiency had tonic-clonic seizures treated with phenytoin. Serum phenytoin concentrations, total and free, measured by two homogeneous enzyme immunoassays (EMIT, CAC) were reported to be within the therapeutic range, yet the patient experienced seizures. Values on discharge exceeded the therapeutic range but were not associated with signs or symptoms of toxicity. Reanalysis of serum samples by a more specific, high performance liquid chromatographic (HPLC) method revealed the previous values were spurious, apparently due to phenytoin metabolite cross-reactivity. Values by fluorescence polarization immunoassay (TDX) correlated well with those by HPLC, as well as with the patient's clinical course.

Adult↗
PubMed1992

Cognitive planning deficit in patients with cerebellar atrophy.

We compared the performance of 12 patients with cerebellar atrophy (CA) and 12 normal controls matched for age and education on the Tower of Hanoi, a nine-problem task that requires cognitive planning. CA patients performed significantly worse than controls on this task despite no difference in planning and between-move pause times. A reanalysis of the data using just the subgroup of patients with pure cerebellar cortical atrophy (CCA) (N = 9) replicated the above results and also showed that CCA patients had significantly increased planning times compared with controls. Neither age, sex, education level, severity of dementia, word fluency, response time, memory, nor visuomotor procedural learning predicted CA or CCA performance. This deficit in cognitive planning suggests a functional link between the cerebellum, basal ganglia, and the frontal lobe concerning specific cognitive processes. However, the exact role of the cerebellum in cognitive planning remains undetermined.

Adult↗
PubMed2005

Field metabolic rate and body size.

The field metabolic rates (FMRs) of 229 species of terrestrial vertebrates, all measured using the doubly labeled water method in free-living individuals, were evaluated. Daily rates of energy expenditure were as low as 0.23 kJ per day in a small reptile (gecko), to as high as 52 500 kJ per day in a marine mammal (seal). This is a range of nearly six orders of magnitude. More than 70% of the variation in log-transformed data is due to variation in body size (expressed as body mass). Much of the remaining variation is accounted for by thermal physiology, with the endothermic mammals and birds having FMRs that are about 12 and 20 times higher, respectively, than FMRs of equivalent-sized, but ectothermic, reptiles. Variation in log(body mass) within each of these three taxonomic classes accounts for over 94% of the variation in log(FMR), and results from nonlinear regression analyses using untransformed data support this conclusion. However, the range of residual variation in mass-adjusted FMR within classes is still more than sixfold (ratio of highest over lowest). Some of this variation is associated with affiliations with lower taxonomic levels (Infraclass: eutherian vs metatherian mammals; Family: passerine, procellariform and galliform birds vs other birds), some is associated with habitat (especially desert vs nondesert), and some with differences in basic diet preference and foraging mode and season. The scaling slopes for FMR often differ from BMR slopes for the same Class of animals, and most differ from the theoretical slope of 0.75. Differences among slopes and intercepts that were detected using conventional regression analyses were largely confirmed upon reanalysis using Independent Contrasts Analysis to adjust for phylogenetic biases.

Animals↗
PubMed2006

A critical understanding of the fractal model of metabolic scaling.

The exponent of the scaling of metabolic rate with body mass has been the subject of debate for more than a century. The argument is at two levels, one concerning questions of empirical support for the exponent and the other, how to derive it theoretically. At this second level, the exponent is usually treated as the outcome of an underlying physical burden and approached as the search for a natural law emerging within energetic and geometric constraints. Recently, a model relying on fractal geometry was proposed as a general explanation for the phenomenon. In the present study, a reanalysis of the fractal model is performed to verify its validity. All the conditions that allow for the connection between the geometric proposition and the allometric exponent are evaluated, as well as the energy loss minimization procedure put forward in the model. It is demonstrated that the minimization procedure is mathematically incorrect and ill-posed. Also, it is shown that none of the connecting conditions are fulfilled. Therefore, it is concluded that the fractal model lacks self-consistency and correct statement: it relies on strong assumptions of homogeneity in morpho-physiological features among organisms instead of demonstrating them, as claimed by its authors. It is proposed that empiricists and theoreticians should rather evaluate the frameworks for addressing metabolic scaling phenomena.

Body Mass Index↗
PubMed2007

Analyzing the effect of wind on flight: pitfalls and solutions.

How flying organisms alter their air speed in response to wind is important in theories of flight energetics. Numerous studies have investigated the relationship between air and wind as a function of ground speed and air speed. This study shows that this approach can lead to erroneous results, due to spurious correlations. An alternative way to analyze air speed is proposed that overcomes the problems of one-dimensional linear models. The new model is non-linear and has two explanatory variables. Using two synthetic data sets with known properties and a data set with real observations of migratory bird tracks and wind observations, we illustrate the weaknesses of the conventional analysis as well as the strengths of the newly proposed model. This leads to the conclusion that for many studies a reanalysis of the effect of wind on air speed is desirable.

Animals↗
PubMed2005

An analysis of thyroid function diagnosis using Bayesian-type and SOM-type neural networks.

Thyroid function diagnosis is an important classification problem, and we made reanalysis of the human thyroid data, which had been analyzed by the multivariate analysis, by the two notable neural networks. One is the self-organizing map approach which clusters the patients and displays visually a characteristic of the distribution according to laboratory tests. We found that self-organizing map (SOM) consists of three well separated clusters corresponding to hyperthyroid, hypothyroid and normal, and more detailed information for patients is obtained from the position in the map. Besides, the missing value SOM which we had introduced to investigate QSAR problem turned out to be also useful in treating such classification problem. We estimated the classification rates of thyroid disease using Bayesian regularized neural network (BRNN) and found that its prediction accuracy is better than multivariate analysis. Automatic relevance determination (ARD) method of BRNN was surely verified to be effective by the direct calculation of classification rates using BRNN without ARD for all possible combinations of laboratory tests.

Bayes Theorem↗
PubMed2003

Why do telemedicine systems fail to normalize as stable models of service delivery?

Two groups independently carried out qualitative studies of the development, implementation and evaluation of telehealth systems and services in the UK. The data collected (in more than 600 discrete data collection episodes) included semistructured interviews, observations and documents. We conducted a conjoint reanalysis of the data. The objective was to identify the conditions which dispose a telehealth service to be successful or to fail. There appear to be four conditions necessary for a telemedicine system to stabilize and then normalize as a means of service delivery. When one or more is absent, failure can be expected. These conditions are often overlooked by local proponents of telemedicine, who seem to rely on demonstrations that the equipment works as the primary criterion of success.

Delivery of Health Care↗
PubMed2005

Hormone replacement therapy and colorectal cancer: an update.

Observational studies and randomized clinical trials that have looked at the effect of hormone replacement therapy (HRT) on the risk of colorectal cancer are reviewed. Nine cohort studies in this area have included a total of over 2700 cases of colorectal cancer. Most of these studies found a relative risk (RR) of around or below unity. Of 15 case-control studies, with a total of over 7300 cases, six reported a 20-40% risk reduction among women who had ever used HRT. With reference to randomized clinical trials, in the Women's Health Initiative (WHI) study, after seven years of follow-up, 45 cases of colorectal cancer were observed in the combined HRT group versus 67 in the placebo group, corresponding to a RR of 0.63. A combined reanalysis of data from both the WHI and the Heart and Estrogen Progestin Replacement Study (HERS) included 56 cases in the combined HRT group and 83 cases in the placebo group (pooled RR = 0.64). However, in the WHI study cancers diagnosed in the HRT group were more advanced and there were more positive lymph nodes. Furthermore, among women in the WHI who had had a hysterectomy, there was no difference at the eight-year follow-up in the incidence of colorectal cancer between those in the estrogen-only arm of the trial (n = 61) and those in the control group (n = 68).

Carcinoma↗
PubMed2003

No evidence of dioxin cancer threshold.

The U.S. Environmental Protection Agency (EPA) has developed an estimate of the human cancer risk from dioxin, using the standard low-dose linear extrapolation approach. This estimate has been controversial because of concern that it may overestimate the cancer risk. An alternative approach has been published and was presented to the U.S. EPA Science Advisory Board's Dioxin Review Panel in November 2000. That approach suggests that dioxin is a threshold carcinogen and that the threshold is an order of magnitude above the exposure levels of the general population. We have reexamined the threshold analysis and found that the data have been incorrectly weighted by cohort size. In our reanalysis, without the incorrect weighting, the threshold effect disappears.

Carcinogens↗
PubMed2003

An assessment of the cord blood:maternal blood methylmercury ratio: implications for risk assessment.

In the current U.S. Environmental Protection Agency reference dose (RfD) for methylmercury, the one-compartment pharmacokinetic model is used to convert fetal cord blood mercury (Hg) concentration to a maternal intake dose. This requires a ratio relating cord blood Hg concentration to maternal blood Hg concentration. No formal analysis of either the central tendency or variability of this ratio has been done. This variability contributes to the overall variability in the dose estimate. A ratio of 1.0 is implicitly used in the model, but an uncertainty factor adjustment is applied to the central tendency estimate of dose to address variability in that estimate. Thus, incorporation of the cord:maternal ratio and its variability into the estimate of intake dose could result in a significant change in the value of the RfD. We analyzed studies providing data on the cord:maternal blood Hg ratio and conducted a Monte Carlo-based meta-analysis of 10 studies meeting all inclusion criteria to generate a comprehensive estimate of the central tendency and variability of the ratio. This analysis results in a recommended central tendency estimate of 1.7, a coefficient of variation of 0.56, and a 95th percentile of 3.4. By analogy to the impact of the similar hair:blood Hg ratio on the overall variability in the dose estimate, incorporation of the cord:maternal ratio may support a 3-fold uncertainty factor adjustment to the central tendency estimate of dose to account for pharmacokinetic variability. Whether the information generated in this analysis is sufficient to warrant a revision to the RfD will depend on the outcome of a comprehensive reanalysis of the entire one-compartment model. We are currently engaged in such an analysis.

Adult↗
PubMed2004

Natural variability and the influence of concurrent control values on the detection and interpretation of low-dose or weak endocrine toxicities.

While defining the no effect level for the 5 alpha-reductase inhibitor finasteride in the Hershberger assay, we encountered an inverted-U low-dose trophic effect on the prostate gland of the rat. Two attempts to confirm this observation were unsuccessful, and we concluded that the positive effect initially observed was associated with normal biologic variability. During the same period we attempted, unsuccessfully, to repeat our own observation of weak uterotrophic activity in the rat for the sunscreen 3-(4-methylbenzylidene)camphor (4MBC). Further evaluation led us to conclude that 4MBC is uterotrophic only when the control uterine weights are at the low end of their normally encountered range. This led us to reevaluate our earlier mouse uterotrophic assay data for bisphenol A (BPA). Originally we had concluded that BPA gave irreproducible evidence of weak uterotrophic activity, but upon ordering the eight experiments we had conducted, according to decreasing control uterine weight, we confirmed reproducible weak uterotrophic activity for BPA when the control uteri were at the low end of their normal range. In this article, we describe these observations, together with a reanalysis of the data associated with several reported instances of weak or low-dose endocrine effects that have proven difficult to confirm in independent laboratories. These include the activity of BPA on the CF1 mouse prostate; the activities of BPA, octylphenol, and nonylphenol on the rat testis; and the effect of polycarbonate caging on control mouse uterine weight. In all of these cases, variability among controls provides a major obstacle to data interpretation and confirmation. Our recommendations on experimental design are also presented, with a view to ending the current impasse on the reality, or otherwise, of low-dose or weak endocrine toxicities.

Animals↗
PubMed1990

An update on mortality among workers at a 1,3-butadiene facility--preliminary results.

This is a cohort study of 2582 male workers employed at least 6 months between 1943 and 1979 at a 1,3-butadiene manufacturing facility. An earlier report on mortality through 1979 found a statistically significant deficit for all causes of death and lower than expected mortality for most of the leading causes of death. However, there was a statistically significant excess of deaths from lymphosarcoma. This report is a preliminary update of cohort information through 1985 and also a reanalysis of mortality. The all-causes standardized mortality ratio is 84 and that for all cancers is 80. These are statistically significant deficits; significant deficits were also seen for all cancer of the digestive system and all external causes of death. One additional death from lymphosarcoma was observed during the extended follow-up period giving a statistically significant standardized mortality ratio (SMR) of 229. The increase was concentrated in those employed less than 10 years and in those first employed before 1946. No increase was seen overall for leukemia (SMR = 102).

Butadienes↗
PubMed1995

Environmental and dietary estrogens and human health: is there a problem?

It has been hypothesized that organochlorine pesticides and other environmental and dietary estrogens may be associated with the increased incidence of breast cancer in women and decreased sperm concentrations and reproductive problems in men. However, elevation of organochlorine compounds such as dichlorodipehenyldichloroethylene (DDE) and polychlorinated biphenyls (PCBs) in breast cancer patients is not consistently observed. Reanalysis of the data showing that male sperm counts decreased by over 40% during 1940 to 1990 indicated that inadequate statistical methods were used and that the data did not support a significant decline in sperm count. Humans are exposed to both natural and industrial chemicals which exhibit estrogenic and antiestrogenic activities. For example, bioflavonoids, which are widely distributed in foods, and several industrial compounds, including organochlorine pesticides and various phenolic chemicals, exhibit estrogenic activity. Humans are also exposed to chemicals which inhibit estrogen-induced responses such as the aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin and related chlorinated aromatics, polynuclear aromatic hydrocarbon combustion products, and indole-3-carbinol, which is found in cruciferous vegetables. Many of the weak estrogenic compounds, including bioflavonoids, are also antiestrogenic at some concentrations. A mass balance of dietary levels of industrial and natural estrogens, coupled with their estimated estrogenic potencies, indicates that the dietary contribution of estrogenic industrial compounds is 0.0000025% of the daily intake of estrogenic flavonoids in the diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Neoplasms↗
PubMed1996

Leukemia risk associated with benzene exposure in the Pliofilm cohort.

A reanalysis of the Pliofilm cohort was conducted incorporating six additional years of follow-up information gathered by the National Institute of Occupational Safety and Health (NIOSH) and a new set of exposure estimates developed recently. The distribution of individual worker exposures calculated with the Paustenbach exposure estimates was compared to those derived using two earlier sets of job-, plant-, and year-specific exposure estimates. A traditional standardized mortality ratio analysis and the Cox proportional hazards model were used to investigate the impact of these exposure estimates and the NIOSH updated information on evaluation of benzene's leukemogenicity. There were no additional cases of multiple myeloma or any indication of increased incidences of solid tumors. The data added in the update did not greatly modify the estimated relative risk of all leukemias associated with benzene exposure but confirmed previous findings that occupational exposure only to very high concentrations had leukemogenic potential. Leukemia has not been observed in anyone who began employment in Pliofilm production after 1950. Neither the Paustenbach nor the Crump exposures gave dose-response estimates as steep as that resulting from the Rinsky exposures.

Benzene↗
PubMed2001

A readability analysis of Australian stroke information.

The aims of this study were to document the readability of a stroke education brochure and to illustrate how the readability of this document might be improved. Readability analyses using three different formulas were conducted on a stroke education brochure from the Australian National Stroke Foundation. Consistent with previous studies of the readability of written health information, results indicated that the overall level of difficulty of the material was too complex for the average member of the public to read and understand. Revision of a randomly selected section of text using established guidelines for writing patient information, and subsequent reanalysis of this section, showed that simple revisions of health literature can dramatically improve readability. Given the importance of effective communication of preventative information about stroke, we present these results as a model of how future revisions of difficult to read stroke-related literature might be conducted to improve public education.

Journal Article↗