Effect modification by delta-aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase gene polymorphisms on associations between patella lead and renal function in lead workers

Genetic polymorphisms that affect lead toxicokinetics or toxicodynamics may be important modifiers of risk for adverse outcomes in lead-exposed populations. We recently reported associations between higher patella lead, which is hypothesized to represent a lead pool that is both bioavailable and cumulative, and adverse renal outcomes in current and former Korean lead workers. In the present study, we assessed effect modification by polymorphisms in the genes encoding for delta-aminolevulinic acid dehydratase (ALAD), the vitamin D receptor (VDR), and endothelial nitric oxide synthase on those associations. Similar analyses were conducted with three other lead biomarkers. Renal function was assessed via blood urea nitrogen, serum creatinine, measured and calculated creatinine clearances, urinary N-acetyl-beta-D-glucosaminidase, and retinol-binding protein. Mean (SD) blood, patella, tibia, and dimercaptosuccinic acid-chelatable lead values were 30.9 (16.7) microg/dl, 75.1 (101.1)and 33.6 (43.4) microg Pb/g bone mineral, and 0.63 (0.75) microg Pb/mg creatinine, respectively, in 647 lead workers. Little evidence of effect modification by genotype on associations between patella lead and renal outcomes was observed. The VDR polymorphism did modify associations between the other lead biomarkers and the serum creatinine and calculated creatinine clearance. Higher lead dose was associated with worse renal function in participants with the variant B allele. Models in two groups, dichotomized by median age, showed that this effect was present in the younger half of the population. Limited evidence of effect modification by ALAD genotype was observed; higher blood lead levels were associated with higher calculated creatinine clearance among participants with the ALAD(1-2) genotype. In conclusion, VDR and/or ALAD genotypes modified associations between all the lead biomarkers, except patella lead, and the renal outcomes.     

Polymorphisms in the human monomethylarsonic acid (MMA V) reductase/hGSTO1 gene and changes in urinary arsenic profiles

Large interindividual variability in urinary arsenic profiles, following chronic inorganic arsenic exposure, is well-known in humans. To understand this variability, we studied the relationship between polymorphisms in the gene for human monomethylarsonic acid (MMA(V)) reductase/hGSTO1 and the urinary arsenic profiles of individuals chronically exposed to arsenic in their drinking water. To ensure that we did not overlook rare polymorphisms, not included in the public databases, we amplified and sequenced all six exons of the gene and their flanking regions, using DNA isolated from peripheral blood samples of 75 subjects, living in the vicinity of Torreon, Mexico. Four groups, based on the levels of arsenic (9-100 microg/L) in their drinking water, were studied. We identified six novel polymorphisms and two reported previously. The novel polymorphisms were a three base pair deletion (delGGC) in the first intron; a G > C transversion, leading to a serine-to-cysteine substitution at amino acid 86; a G > T transversion and a A > T transversion in intron 5; a G > A transition resulting in glutamate-to-lysine substitution in amino acid 208; and a C > T transition producing an alanine-to-valine substitution in amino acid 236. Two subjects displayed significant differences in patterns of urinary arsenic; they had increased levels of urinary inorganic arsenic and reduced levels of methylated urinary arsenic species as compared to the rest of the study population. These two subjects had the same unique polymorphisms in hGSTO1 in that they were heterozygous for E155del and Glu208Lys. The identified SNPs may be one of the reasons for the large interindividual variability in the response of humans to chronic inorganic arsenic exposure. The findings suggest the need for further studies to identify unambiguously specific polymorphisms that may account for interindividual variability in the human response to chronic inorganic arsenic exposure.     

F-18]-fluorodeoxyglucose positron emission tomography for targeting radiation dose escalation for patients with glioblastoma multiforme: clinical outcomes and patterns of failure

PURPOSE: [F-18]-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging for brain tumors has been shown to identify areas of active disease. Radiation dose escalation in the treatment of glioblastoma multiforme may lead to improved disease control. Based on these premises, we initiated a prospective study of FDG-PET for the treatment planning of radiation dose escalation for the treatment of glioblastoma multiforme. METHODS AND MATERIALS: Forty patients were enrolled. Patients were treated with standard conformal fractionated radiotherapy with volumes defined by MRI imaging. When patients reached a dose of 45-50.4 Gy, they underwent FDG-PET imaging for boost target delineation, for an additional 20 Gy (2 Gy per fraction) to a total dose of 79.4 Gy (n = 30). RESULTS: The estimated 1-year and 2-year overall survival (OS) for the entire group was 70% and 17%, respectively, with a median overall survival of 70 weeks. The estimated 1-year and 2-year progression-free survival (PFS) was 18% and 3%, respectively, with a median of 24 weeks. No significant improvements in OS or PFS were observed for the study group in comparison to institutional historical controls. CONCLUSIONS: Radiation dose escalation to 79.4 Gy based on FDG-PET imaging demonstrated no improvement in OS or PFS. This study establishes the feasibility of integrating PET metabolic imaging into radiotherapy treatment planning.     

Bone lead levels and blood pressure endpoints: a meta-analysis

BACKGROUND: Previous reviews have shown increases in blood pressure and hypertension associated with increases in lead levels in blood. We performed a meta-analysis of the association of bone lead levels with systolic blood pressure, diastolic blood pressure, and hypertension using published data. METHODS: We searched Medline, Embase, and Toxline for epidemiologic studies on bone lead levels and blood pressure endpoints. We used inverse-variance weighted random-effects models to summarize the association of tibia or patella lead levels with blood pressure endpoints. RESULTS: We summarized data from 3 prospective studies and 5 cross-sectional studies. All studies measured lead levels in tibia bone and 3 studies measured lead levels in patella. For a 10 microg/g increase in tibia lead, the cross-sectional summary increases in blood pressure were 0.26 mm Hg for systolic (95% confidence interval = 0.02 to 0.50) and 0.02 mm Hg for diastolic (-0.15 to 0.19). The summary odds ratio for hypertension was 1.04 (1.01 to 1.07). For a 10 microg/g increase in patella lead, the summary odds ratio for hypertension was 1.04 (0.96 to 1.12). CONCLUSION: Systolic blood pressure and hypertension risk were associated with lead levels in tibia bone, but the magnitude of the summary estimates was small. These summary estimates, however, were based on published data and we could not evaluate nonlinear dose-response relationships, the relative contribution of bone and blood lead levels, or the influence of differences in study populations. A more detailed characterization of the association of bone lead levels and blood pressure endpoints would require a pooled analysis of individual participant data from existing studies.     

Characterization of the striatal dopamine receptor supersensitivity produced by estrogen treatment of male rats

Estrogen treatment of male rats produced an increase in the number of striatal dopamine receptors, without altering their affinity. This effect only occurs in vivo and has a slow onset. Only the β-diastereomer of 17-estradiol was active. Other striatal receptors appeared to be unchanged as was the presynaptic uptake of dopamine. Hypophysectomy completely blocked the response to estrogen as measured on striatal dopamine receptors and on stereotypy, a behavior associated with striatal dopamine receptor stimulation. These results are relevant to the clinical observations of chorea associated with the use of oral contraceptives or with pregnancy.     

Vaginal allodynia as the presentation of a thalamic tumor

Central pain syndromes associated with damage to the thalamic sensory relay nuclei have been described predominantly in the stroke literature; however, pain syndromes associated with thalamic neoplasms are much less common. We describe a woman with dyspareunia secondary to vaginal allodynia as the presenting sign of a left thalamic juvenile pilocytic astrocytoma. Subsequent to an uneventful stereotactic biopsy, her vaginal allodynia progressed to hemi-body allodynia. We believe that this is the first reported case of isolated vaginal allodynia associated with a thalamic neoplasm or any other structural pathology of the central nervous system.     

Disseminated intravascular coagulation associated with toxic epidermal necrolysis (Lyell''s syndrome)

Evidence of disseminated intravascular coagulation was recorded in eight patients with toxic epidermal necrolysis (TEN)--Lyell's syndrome. Patients were treated with low doses of heparin in combination with the usual treatment of TEN, i.e. maintenance of fluid and electrolyte balance, systemic corticosteroids, antibiotics and aseptic dressings, in the Intensive Care Unit environment. It is suggested that the alteration of haemostasis and inter-related biological systems, such as activation of components of complement, kinins and immunoglobulins, may affect the outcome of TEN.     

MOTOR RESTLESSNESS

Motor restlessness, characterised by an irresistible urge to move about, can be a manifestation of many underlying disorders. Unfortunately, it is often poorly recognised and underdiagnosed in clinical practice, possibly because patients do not seek medical attention, or their complaints were thought to be secondary to anxiety. While the two major conditions to consider are restless legs syndrome and neuroleptic-induced akathisia, there are many other differential diagnoses. We provide a concise review of the clinical features and diagnostic pitfalls of these conditions. A proper detailed clinical history and examination can often help clinch the diagnosis, as most of these conditions have their unique clinical features.