Benzocaine-associated methemoglobinemia following bronchoscopy in a healthy research participant

Benzocaine (ethyl aminobenzoate) is a local anesthetic commonly used to achieve topical anesthesia of the skin and mucous membranes prior to endoscopic procedures. Methemoglobinemia, a condition in which hemoglobin cannot bind and deliver oxygen normally, has been associated with benzocaine use in various patient populations. This is the first report of benzocaine-associated methemoglobinemia occurring in a healthy research participant. The research participant developed a methemoglobin level of 27% and marked cyanosis. No adverse sequelae other than cyanosis were identified. This report extends the population in which benzocaine-associated methemoglobinemia has been described. Additionally, this report supports the observation that methemoglobin levels approaching 30% may be tolerated in otherwise healthy individuals, producing few clinically important effects. Finally, this case also indicates that, in obtaining informed consent for a procedure in which benzocaine will be administered, patients and research participants should be specifically informed of the risk of benzocaine-induced methemoglobinemia. This information is especially important in those settings in which the manufacturer-recommended dose of benzocaine may either intentionally or inadvertently be exceeded.     

Gross, histological and immunohistochemical features of mucormycosis in the platypus

Nine male and five female adult free-living platypuses, obtained in a prospective capture-release study from northern Tasmania, exhibited gross features of cutaneous mycosis caused by Mucor amphibiorum. The lesions were present on the hind limbs (six cases), front limbs (four), tail (five), dorsal trunk (three) and ventral trunk (one). They varied in size, and ranged from raised red nodules or plaques, which sometimes exuded purulent material, to ulcerated lesions with central cavitation, red exuding centres and raised epidermal margins. Older lesions were covered either partly or fully by thickened and irregular epidermis. Histological examination of skin biopsies revealed discrete, poorly encapsulated granulomas, or more commonly a diffuse granulomatous or pyogranulomatous inflammation. Inflammatory cells consisted of neutrophils or eosinophils, sparse plasma cells and lymphocytes, many macrophages and occasional multinucleated giant cells. Fibrovascular tissue was diffusely and irregularly scattered in the granulomatous regions. Sphaerules characteristic of M. amphibiorum infection were observed in all lesions. The cutaneous distribution of the lesions and the natural history of the platypus indicated that entry of M. amphibiorum may have been via superficial skin wounds. T cells were the predominant infiltrating lymphoid cells in the diffuse lesions, indicating the importance of the cell-mediated response to infection.     

Zinc nutriture in type I diabetes mellitus: relationship to growth measures and metabolic control

Zinc concentrations in plasma, hair, and urine from children and young adults with insulin-requiring or Type I diabetes mellitus were significantly correlated with height, weight, and age, as well as with indices of metabolic control, i.e., fasting serum glucose, percent glycosylated hemoglobin (HbA1), and 24-h urine glucose and insulin excretion. Urinary zinc excretion was greater in subjects than in controls (p less than 0.0001) and significantly correlated with urine glucose (p less than 0.004, r = 0.35) and volume (p less than 0.0007, r = 0.40). Urinary zinc and volume were not correlated in controls. Hyperzincuria in the subjects was not secondary to hyperinsulinuria, although zinc and insulin excretion were significantly correlated in controls (p less than 0.03, r = 0.63). Zinc in insulin preparations could not explain the excessive zinc excretion. Mean fasting plasma zinc was significantly higher than in controls, and positively correlated with height for age, while being inversely correlated with age, duration of diabetes, HbA1, urine volume, and glucose excretion. Both the mean and range of hair zinc concentration in the subjects were not different from controls. Male subjects with diabetes had a significantly lower hair concentration when compared with female subjects with diabetes (p less than 0.0009). Zinc homeostasis appears to be altered as a consequence of glucose intolerance in diabetes. Continued urinary zinc losses over time may result in a zinc deficiency state not demonstrable by altered zinc concentrations in plasma and hair.     

Dominant negative mutants of filamin A block cell surface expression of the D2 dopamine receptor

Protein interaction screens have revealed an interaction between the D2 dopamine receptor and the actin cross-linking protein filamin A. However, the physiological significance of this interaction has not been explained. To better understand the role of filamin A in D2 receptor-mediated signaling, we examined the effect of disrupting filamin A/D2 receptor interaction. Overexpression of a truncated form of filamin A (repeat units 18-19 containing the D2, but not the actin, binding domain) caused a marked reduction in both the number and half-life of cell surface D2 receptors. These results suggest that disruption of the linkage between D2 receptors and the actin cytoskeleton destabilizes plasma membrane-associated D2 receptors. Several missense mutations within repeat unit 19 of filamin A were identified that abrogate filamin A/D2 receptor interaction. Introduction of mutant and wild-type filamin A into filamin A-deficient M2 cells demonstrated that wild-type filamin A, but not the filamin A-binding mutants, was able to promote cell-surface expression of D2 receptors. Together, these studies provide evidence that filamin A/D2 receptor interaction is required for the proper targeting or stabilization of D2 dopamine receptors at the plasma membrane.     

Gas chromatographic-mass spectrometric differentiation of atenolol, metoprolol, propranolol, and an interfering metabolite product of metoprolol

Over a 10-year period, 1993-2002, Federal Aviation Administration identified 50 pilot fatalities involving atenolol, metoprolol, and propranolol, which is consistent with the fact that these drugs have been in the lists of the top 200 drugs prescribed in the U.S. In a few of the 50 pilot fatality cases, initial analysis suggested the presence of atenolol and metoprolol. However, there was no medical history with these cases supporting the use of both drugs. Therefore, atenolol, metoprolol, and/or propranolol, with their possible metabolite(s), were re-extracted from the selected case specimens, derivatized with pentafluoropropionic anhydride (PFPA), and analyzed by gas chromatography-mass spectrometry (GC-MS). The MS spectra of these three antihypertensives and a metoprolol metabolite are nearly identical. All of the PFPA derivatives had baseline GC separation, with the exception of a metoprolol metabolite product, which co-eluted with atenolol. There were four primary mass fragments (m/z 408, 366, 202, and 176) found with all of the PFPA-beta-blockers and with the interfering metabolite product. However, atenolol has three unique fragments (m/z 244, 172, and 132), metoprolol has two unique fragments (m/z 559 and 107), propranolol has four unique fragments (m/z 551, 183, 144, and 127), and the metoprolol metabolite product has two unique fragments (m/z 557 and 149). These distinctive fragments were further validated by using a computer program that predicts logical mass fragments and performing GC-MS of deuterated PFPA-atenolol and PFPA-propranolol and of the PFPA-alpha-hydroxy metabolite of metoprolol. By using the unique mass fragments, none of the pilot fatality cases were found to contain more than one beta-blocker. Therefore, these mass ions can be used for differentiating and simultaneously analyzing these structurally similar beta-blockers in biological samples.     

Low-level environmental lead exposure and children's intellectual function: an international pooled analysis

Lead is a confirmed neurotoxin, but questions remain about lead-associated intellectual deficits at blood lead levels < 10 microg/dL and whether lower exposures are, for a given change in exposure, associated with greater deficits. The objective of this study was to examine the association of intelligence test scores and blood lead concentration, especially for children who had maximal measured blood lead levels < 10 microg/dL. We examined data collected from 1,333 children who participated in seven international population-based longitudinal cohort studies, followed from birth or infancy until 5-10 years of age. The full-scale IQ score was the primary outcome measure. The geometric mean blood lead concentration of the children peaked at 17.8 microg/dL and declined to 9.4 microg/dL by 5-7 years of age; 244 (18%) children had a maximal blood lead concentration < 10 microg/dL, and 103 (8%) had a maximal blood lead concentration < 7.5 microg/dL. After adjustment for covariates, we found an inverse relationship between blood lead concentration and IQ score. Using a log-linear model, we found a 6.9 IQ point decrement [95% confidence interval (CI), 4.2-9.4] associated with an increase in concurrent blood lead levels from 2.4 to 30 microg/dL. The estimated IQ point decrements associated with an increase in blood lead from 2.4 to 10 microg/dL, 10 to 20 microg/dL, and 20 to 30 microg/dL were 3.9 (95% CI, 2.4-5.3), 1.9 (95% CI, 1.2-2.6), and 1.1 (95% CI, 0.7-1.5), respectively. For a given increase in blood lead, the lead-associated intellectual decrement for children with a maximal blood lead level < 7.5 microg/dL was significantly greater than that observed for those with a maximal blood lead level > or = 7.5 microg/dL (p = 0.015). We conclude that environmental lead exposure in children who have maximal blood lead levels < 7.5 microg/dL is associated with intellectual deficits.     

Principles and practices of neurodevelopmental assessment in children: lessons learned from the Centers for Children's Environmental Health and Disease Prevention Research

Principles and practices of pediatric neurotoxicology are reviewed here with the purpose of guiding the design and execution of the planned National Children's Study. The developing human central nervous system is the target organ most vulnerable to environmental chemicals. An investigation of the effects of environmental exposures on child development is a complex endeavor that requires consideration of numerous critical factors pertinent to a study's concept, design, and execution. These include the timing of neurodevelopmental assessment, matters of biologic plausibility, site, child and population factors, data quality assurance and control, the selection of appropriate domains and measures of neurobehavior, and data safety and monitoring. Here we summarize instruments for the assessment of the neonate, infant, and child that are being employed in the Centers for Children's Environmental Health and Disease Prevention Research, sponsored by the National Institute of Environmental Health Sciences and the U.S. Environmental Protection Agency, discuss neural and neurobiologic measures of development, and consider the promises of gene-environment studies. The vulnerability of the human central nervous system to environmental chemicals has been well established, but the contribution these exposures may make to problems such as attention deficit disorder, conduct problems, pervasive developmental disorder, or autism spectrum disorder remain uncertain. Large-scale studies such as the National Children's Study may provide some important clues. The human neurodevelopmental phenotype will be most clearly represented in models that include environmental chemical exposures, the social milieu, and complex human genetic characteristics that we are just beginning to understand.