The first precise molecular structure of a monomeric transition metal cyanide, copper(I) cyanide.

Copper(I) cyanide is an important reagent in organic, organometallic, and supramolecular chemistry because of both the copper center and the versatile cyanide ligand. Solid-phase CuCN and many of its derivatives show oligomeric or polymeric structures, a trait shared by other metal cyanides. Often, it is difficult to specify the orientation of the cyano ligand in an X-ray structure. Here the first preparation and precise structure of a monomeric transition metal cyanide is reported. Gas-phase reaction between copper vapor and cyanogen (NCCN) clearly gives CuCN (not CuNC). The precise structure of CuCN so produced is determined by millimeter/submillimeter-wave spectroscopy. Because of the highly efficient synthesis and the presence of significant amounts of two copper isotopes, such strong signals were seen that natural-abundance materials allowed observation of transitions for the four isotopomers (63)Cu(12)C(14)N, (65)Cu(12)C(14)N, (63)Cu(13)C(14)N, and (63)Cu(12)C(15)N and the determination of r(o), r(s), and r(m)((2)) structures. All data unequivocally show a linear geometry and that the carbon of cyanide is bound to copper with a Cu-C distance of 1.82962(4) A in the r(m)((2)) structure, which is likely to be closest to the equilibrium geometry.

Check-off logs for routine equipment maintenance.

The regulatory requirement for appropriate routine instrument maintenance documentation is approached by laboratories in numerous ways. Standard operating procedures (SOPs) may refer to maintenance listed in instrument manuals, may indicate "periodic" performance of an action, or may indicate specific tasks to be performed at certain frequencies. The Quality Assurance Unit (QAU) task of assuring the performance of these indicated maintenance tasks can be extremely laborious if these records are merged with other analysis records. Further, the lack of written maintenance schedules often leads to omission of infrequently performed tasks. We recommend creation of routine maintenance check-off logs for instruments with tasks grouped by frequency of expected performance. Usage of such logs should result in better laboratory compliance with SOPs and the compliance can be readily monitored by QAU or by regulatory agencies.

Quality auditing of chromatographic data.

We have developed a method for consistent, in-depth audit of the integrity of chromatographic records. The approach includes definition of the analyte, the method of analyte sample preparation and analysis, and the analyte concentration range. Acceptance criteria (if any) defined in the protocol or method are compared to the data. Run parameters are compared to those specified in the methodology. Certification of the standard is verified and the limit of quantitation for each run is identified and compared to data. Reasons for data discard and/or reassay are examined. If calculation software is not validated, representative calculations are recomputed and chromatograms are examined for attributability. These parameters are examined in addition to other Good Laboratory practice considerations such as sample identity, sample integrity, and transcription accuracy.

Early childhood surveillance of developmental disorders by a birth defects surveillance system: methods, prevalence comparisons, and mortality patterns.

The prevalence of developmental disabilities in early childhood is not well documented. An established birth defects registry extended surveillance to identify cases of developmental disorders in early childhood by adding all known sources of diagnosis and service to case-finding methods. Residents of a northwest Arkansas region born during 1985 to 1987 and diagnosed with either a birth defect or a developmental disorder by the 4th birthday comprised the studied cohort. Case records were linked with death certificates to examine the influence of mortality on prevalence ratios. Prevalence ratios estimated were 64.5/1000 resident live births (60.9/1000 among survivors to age 4 years) for either birth defect or developmental disorder, 33.4/1000 for developmental disorder, 37.0/1000 for birth defect, and 9.5/1000 for both developmental disorder and birth defect. Prevalence ratios of specific developmental disorders and the role of mortality in decreasing population prevalence are reported. The most common diagnostic categories in this age group were developmental delay, seizures, and failure to thrive. Overlap of birth defect categories with a diagnosed developmental disability was examined; 68.8% of children diagnosed with neural tube defects and 45.5% of those with chromosomal abnormalities who survived to age 4 years had clinically diagnosed developmental disorders. An anticipated high degree of overlap (77%) for other central nervous system defects was found. For other birth defect categories, developmental disorder diagnosis was present in 20 to 30% of the study group. Death before age 4 years occurred most often when the diagnosis was newborn seizures (17.1%) or "conditions of the brain" (13.6%); the mortality rate was 6 to 8% for epilepsy or seizure disorders, mental retardation, and vision loss. The large number of developmental diagnoses among this cohort indicates that surveillance of these disorders in early childhood, even with tentative diagnoses, is feasible. Data obtained indicate that many birth defects are associated with developmental disorders; potentially, this association can contribute to earlier identification of developmental disorders in childhood.

Deaths associated with renal agenesis: a population-based study of birth prevalence, case ascertainment, and etiologic heterogeneity.

We report on deaths associated with renal agenesis among 211,704 consecutive births. Sources included birth and death certificates and an active birth defects surveillance system. Medical review and classification of cases were performed for 1985-1990 events. Sixty-one cases of renal agenesis were identified, and review of records was possible for 59 of the 61 cases. Of these 59 cases, 36 (61%) were confirmed, 5 (8%) were questionable, and 18 (31%) were incorrectly coded. The prevalence of confirmed cases is thus estimated at 17/100,000 births (14.2/100,000 births, excluding elective terminations and fetal deaths). Records incorrectly coded were most often those with multicystic dysplasia. Approximately one-third of cases was found by the birth defects surveillance system alone, confirming the utility of this data source for prevalence estimates. Isolated renal agenesis accounted for 44% of confirmed cases; other diagnoses included VATER association (19%), unrecognized multiple malformation syndromes (17%), exstrophy of the cloaca sequence (14%), and chromosome disorders (6%). Based on these data, prevalence rates for ICD code 753.0 and death include overascertainment of cases from erroneous coding of multicystic dysplasia and underascertainment of cases with unilateral renal agenesis associated with other malformations. Population-based ascertainment of cases by active surveillance methods and rigorous diagnostic coding standards are required to improve the accuracy of these rates. Targeted investigations of distinct subclassifications will be necessary to identify specific etiologic factors.

Alpha-tocopherol protects against a reduction in adenosylcobalamin in oxidatively stressed human cells.

Excretion of methylmalonic acid by vitamin E-deficient patients and decreased labeling of adenosylcobalamin (AdoCbl) from cyanocobalamin in vitamin E-deficient rats suggest an interaction of vitamins E and B-12. We studied this interaction in two human cell culture systems: foreskin fibroblasts and a hepatoma cell line (HepG2). We measured radiolabeling of AdoCbl and methylcobalamin from [57Co]hydroxycobalamin for 6 d in the presence and absence of linoleate (an oxidative stressor) and alpha-tocopherol. In both cell types, labeling of AdoCbl was lower in the presence of linoleate unless alpha-tocopherol was present. The decrease was accentuated by peroxidized linoleic acid; AdoCbl synthetic rate was inversely associated with thiobarbituric acid-reactive compound concentration. Subcellular partitioning of labeled cobalamin revealed less in mitochondria in the linoleate-stressed cells that were not treated with alpha-tocopherol. We conclude that lipoperoxidation reduces mitochondrial AdoCbl formation and that alpha-tocopherol exerts a protective effect in oxidatively stressed cells. We suggest that this subcellular deficiency in AdoCbl may be one mechanism by which vitamin E deficiency leads to neurologic injury. The mechanism seems primarily to involve an alteration in intracellular cobalamin distribution with perhaps a minor effect upon enzymes of AdoCbl synthesis.

Small area pesticides data: multiplicity and variability of pesticide usage on southern row crops.

Epidemiologic studies of possible effects of agricultural environments upon human health suffer from lack of reliable pesticides usage data. The Arkansas Reproductive Health Monitoring System has developed a method for estimating specific pesticides usage annually for sub-county regions, including amounts, application method, and months. This method is applied to 39 regions of 8 central Arkansas counties for 1980-82. The hugh variability of pesticides usage on individual crops demonstrates the inaccuracy likely if general survey estimates are employed. Annual usage of pesticides in a single sub-county region of 53,000 hectares (130,880 land acres) was greater than 1/2 million pounds (248,670 kg) of 60 pesticides, 40 of which were applied during a four month period. The multiplicity and variability of pesticides usage indicate the need for locally developed pesticides data for epidemiologic studies and for combined studies across regions with widely differing agricultural practices.

Predicting needs for special education resources for mental retardation from birth defects records.

Planning of service delivery systems for children with special health care needs would be enhanced by knowledge of numbers of cases anticipated in defined geographic areas. A method is described for predicting numbers of children who will likely have mental retardation sufficient to require special education services, based on the birth prevalence of birth defects and clinicians' estimates of the likelihood of mental retardation associated with each specific birth defect. This method is applied to the 1980-82 birth cohort of a 28-county area of south and central Arkansas, and it is compared with special education enrollment data for children ages 6 to 8 in academic year 1988-89. According to this estimate, children with birth defects may account for 32 to 56 percent of the cases of mental retardation among 6- to 8-year-olds reported by the public schools.

Pesticide concentrations in Arkansas breast milk.

During an episode of pesticide dairy product contamination in Arkansas in 1986, breast milk samples from 942 women were analyzed for concentrations of chlorinated pesticides. The pesticides found most frequently in quantifiable concentrations were p,p'-DDE (100%), oxychlordane (84%), trans-nonachlor (77%), heptachlor epoxide (74%) and beta-HCH, an isomer of lindane (27%). The pesticides present in highest mean concentrations of all samples analyzed (reported as ppm in milk fat) were p,p'-DDE (0.952 ppm), trans-nonachlor (0.062 ppm), oxychlordane (0.051 ppm), heptachlor epoxide (0.045 ppm), p,p'-DDT (0.039 ppm), and beta-HCH (0.032 ppm). These concentrations are lower than previous reports from similar regions of the US. However, continued persistence in human breast milk is of concern due to potential adverse health effects from these chemicals.

Biomarkers of pesticide exposure.

Incorporation of biomarkers in studies of occupational exposure hazards is now recognized as a highly useful adjunct to the surrogate measures employed in the past, for example, time worked, ambient air data, interview responses. Application to studies of workers potentially exposed to pesticides has barely begun and provides many challenges to chemist/epidemiologist teams. This review indicates several excellent studies employing multiple-exposure measures to document the validity of specific biomarkers for particular exposure situations. In general, exposure reflected by urinary assays of specific pesticides is a low percentage of that indicated by dermal or breathing zone measures. Markers for many of the pesticides in current usage have yet to be developed and validated, and information on population variability is generally lacking for existing markers. The challenge provided by the complexity of multiple, and often unknown, exposures to individuals in pesticide environments has begun to be addressed employing cytogenetic or urinary measures that attempt to integrate these complex exposures. The lack of data regarding sensitivity and specificity of biomarkers, especially in complex exposure situations, is a major problem that perhaps will best be addressed by studies combining nonspecific measures with specific ones, utilizing stored sample banks created for that purpose. Expanding the repertoire of available biomarkers of pesticide exposure and employing multiple ones in well-designed study protocols will provide critical tools in the evaluation of pesticide safety and design of appropriate measures to minimize adverse exposures. Ironically, one of the problems that biological markers of exposure can help overcome, reliance on poorly measured ambient exposure data, hampers the evaluation of the markers themselves. Therefore, the combination of in vitro, animal, and human data will give the best picture of a marker's performance. (Wilcosky 1990).

The potential of exposure biomarkers in epidemiologic studies of reproductive health.

To further the development and application of exposure markers in field investigations in reproductive epidemiology, we have synthesized recent examinations of the issues surrounding exposure measurements in reproductive epidemiology. The specific goals of this paper are to define exposure biomarkers and explore their potential uses, particularly as screening tools. The tests for glucaric acid, thioethers, mutagenicity, and porphyrin patterns meet the general criteria for useful exposure screens. For certain xenobiotic agents, these tests accurately differentiate exposure levels, as demonstrated in occupational and environmental epidemiologic studies. As urinary screens, they are noninvasive and applicable on a large scale with current laboratory techniques. For short-term exposure, glucaric acid, thioethers, and mutagenicity tests are useful. Porphyrin patterns may measure cumulative effects as well as current exposure levels. The usefulness of these tests in epidemiologic studies of environmental effects on reproductive health has yet to be studied. To do so, the battery must be standardized for pregnant women, and test results must be correlated with measured adverse reproductive outcomes, such as gestational length and birthweight. This correlation is particularly important because maternal exposure rather than fetal exposure is being measured. The extent to which xenobiotic chemicals cross the placental barrier may vary greatly depending on the type of exposures, timing in pregnancy, and maternal detoxification capability. Without better exposure measures, epidemiologic studies of reproductive health probably will not successfully identify xenobiotic fetotoxic agents in the environment. However, with an adequate battery of nonspecific exposure biomarkers, prospective studies of environmental effects on pregnancy outcomes might be possible.(ABSTRACT TRUNCATED AT 250 WORDS)

The use of serum electrolyte concentrations determined by automated analyzers to indirectly quantitate serum bromide concentration.

Bromide is not often prescribed today as antiepileptic therapy. One reason is that serum bromide concentrations are not routinely performed in hospital laboratories, making clinical decisions difficult. Because of bromide ion interference with the electrodes of commonly used automated electrolyte analyzers, factitious "hyperchloremia" (and in some cases, "hyperbicarbonatemia"), are produced. These values, and the resulting calculated anion gap, correlate well with the measured serum bromide concentration. The correlation permits results from routine automated electrolyte analyzers to be used to indirectly determine serum bromide concentration.

Adverse effects of trimethoprim-sulfamethoxazole in a child with dihydropteridine reductase deficiency.

A child with dihydropteridine reductase (DHPR) deficiency developed signs of dopamine insufficiency after being given trimethoprim-sulfamethoxazole (TMP-SMX). She recovered function after the antibiotic was stopped, which suggests that it adversely influenced dopamine metabolism in the CNS. The authors speculate that TMP, a dihydrofolate reductase inhibitor, was the major cause of the patient's deterioration, and suggest that it and other dihydrofolate inhibitors, notably methotrexate, are contra-indicated for patients with DHPR deficiency.

Telencephalic dysgenesis associated with presumptive maternal carbon monoxide intoxication in the first trimester of pregnancy.

We report the association of telencephalic dysgeneses (expected to occur around week 6 of gestation) with presumptive maternal carbon monoxide intoxication. This case supports the hypothesis that carbon monoxide intoxication at critical periods of human brain development may lead not only to decreased brain size and hypoxic-ischemic lesions, but also to dysgeneses.

Progressive intracranial calcification in dihydropteridine reductase deficiency prior to folinic acid therapy.

Hyperphenylalaninemia in infants and children may be caused by a deficiency of dihydropteridine reductase (DHPR). Recommended therapy includes folinic acid as a source of tetrahydrofolate, a phenylalanine-restricted diet, and both dopamine and serotonin precursors. We report a child with progressive basal ganglia and other subcortical calcifications prior to the use of folinic acid. Six other reported cases of DHPR deficiency demonstrated similar calcifications prior to folinic acid therapy. Since this pattern of calcification also resembles that seen in CNS folate deficiency caused by both congenital folate deficiency and that which is methotrexate-induced, we propose that intracranial calcification in DHPR deficiency is caused by inadequate CNS tetrahydrofolate and may be prevented by the use of folinic acid. Our patient achieved excellent seizure control following the use of folinic acid, suggesting either a direct or indirect anticonvulsant effect of this compound in patients with DHPR deficiency.

Biomarkers of xenobiotic exposures.

Direct measurement of xenobiotic (foreign) chemicals is not always feasible as an exposure assessment,--owing to rapid metabolism, sequestration into fatty tissues, or lack of suitable assay methods. Furthermore, suspect exposures often involve complex mixtures of organics. In these circumstances, indirect biomarkers of exposure can be most helpful. This paper reviews four urinary parameters that hold promise as biomarkers of exposure in occupational and environmental settings: glucaric acid (end-product of the glucuronidation pathway), thioethers (end-product of glutathione reaction with electrophilic or alkylating agents), porphyrin pattern (altered with disruption in heme biosynthesis), and the Ames mutagenicity test.