Evaluation and updates to the Leggett model for pharmacokinetic modeling of exposure to lead in the workplace - Part II adjustments to the adult exposure model, confirmation of Leggett+, and modeling of workplace exposure.

California's Office of Environmental Health Hazard Assessment has updated the comprehensive age-specific model of lead metabolism in humans published by Richard W. Leggett in 1993. The updated model, called Leggett+, was introduced in a peer-reviewed report in 2013. The Leggett + model simulates the relationship between blood lead and exposure in the workplace. Leggett + includes a workplace exposure model comprising respiratory tract intake (workplace lead inhaled by a worker) and uptake (lead absorbed into the blood from the respiratory tract plus uptake from ambient air and diet). The latter is calculated as intake times an inhalation transfer coefficient plus background uptake. An adjusted adult systemic model describes the metabolism of the absorbed lead. This paper provides details about the workplace exposure and uptake elements of Leggett+, an updated approach to calibrating an inhalation transfer coefficient, confirmation of the model's performance in predicting blood lead levels from workplace studies, and predictions of blood lead levels from simulated exposures to workplace airborne lead over a working lifetime. Blood lead relative to airborne lead concentrations in a standard workplace scenario predicted by Leggett + was similar to corresponding relationships from four published workplace studies. Leggett + predictions displayed a good fit to regression equations when other key factors were considered such as pre-employment blood lead and ongoing background intake of lead, workplace air concentration, lead aerosol characteristics, and worker activity levels. The comprehensive Leggett + model can simulate plausible workplace air-blood lead relationships from a broad range of worker exposures. The inhalation transfer coefficient of 0.30, derived from empirical data described in the 2013 report has been reexamined. The original estimate continues to represent a plausible mid-point for a coefficient derived from an expanded range of theoretical particle size distributions deposited in the upper and lower regions of the respiratory tract considering intake during sedentary and outdoor activity breathing scenarios. This coefficient is slightly lower than the value of 0.35 estimated for unknown forms of lead by Leggett in 1993.

Evaluation and updates to the Leggett model for pharmacokinetic modeling of exposure to lead in the workplace - Part I adjustments to the adult systemic model.

California's Division of Occupational Safety and Health has initiated a process to update its standards for exposure to lead in workplaces. In support of this effort, the state's Office of Environmental Health Hazard Assessment evaluated the age-specific, bio-kinetic model of lead metabolism in humans, originally published by R.W. Leggett in 1993. This model was ultimately chosen for its physiologic realism and practicality in characterizing the relationship between air lead concentrations and blood lead levels in chronically exposed worker and its practicality in making necessary adjustments. Leggett's original model systematically under-predicts bone and blood levels in workers such that several adjustments to the parameters are needed to improve predictions for occupational exposure scenarios. The aim of this work is to incorporate new information about the bio-kinetics of lead in workers and to adjust the Leggett model to improve its predictions.The Leggett model was evaluated by comparing its predictions with information on lead concentrations in bone, blood, and urine from workers and other chronically exposed adults. Key model parameters were identified based upon a review of the relevant exposure assessment and modeling literature. Adjustments to the model parameters were made based on empirical evidence. They included reducing the level of lead in blood (BLL) where the rate of decrease in red blood cell binding begins and ends, lead accumulation rate in cortical bone, the rate of lead elimination in trabecular bone, and rate of lead transferred from diffusible plasma to urine. Regression methods and visual inspection of plotted data were used to assess the effect of adjustments on model predictions. When compared with the original, the adjusted Leggett model more accurately predicted lead concentrations observed in active and retired workers. Also, the adjusted Leggett model required less lead uptake to reach the same BLLs for BLLs less than 25 µg/dL and more time for BLLs to decline than the original Leggett model. These findings are important for defining an adequately protective occupational standard for lead exposure.

Using the modern Silverhawk™ atherectomy catheter to characterize biliary structures that appear malignant: review of initial experience.

BACKGROUND: Diagnosis of a biliary stricture often hinges on cytological interpretation. In the absence of accompanying stroma, these results can often be equivocal. In theory, advanced shave biopsy techniques would allow for the preservation of tissue architecture and a more accurate definition of biliary pathology. OBJECTIVES: We sought to determine the initial diagnostic utility of the modern Silverhawk™ atherectomy (SA) catheter in the evaluation of biliary strictures that appear to be malignant. METHODS: A total of 141 patients with biliary pathology were identified during a retrospective review of medical records for the years 2006-2011. The SA catheter was employed 12 times in seven patients for whom a tissue diagnosis was otherwise lacking. RESULTS: Neoplasia was definitively excluded in seven specimens from four patients. These four individuals were followed for 1-5 years to exclude the development of cholangiocarcinoma (CC). Samples were positive for CC in three patients, one of whom became eligible for neoadjuvant therapy and orthotopic liver transplantation. CONCLUSIONS: The SA catheter appears to be a useful adjunct in diagnosing patients with biliary pathology. The existence of this technique, predicated on tissue architecture, may impact therapy, allow more timely diagnosis, and exclude cases of equivocal cytology. Although the initial results of SA use are promising, more experience is required to effectively determine its clinical accuracy.

Superoxide dismutase A antigens derived from molecular analysis of sarcoidosis granulomas elicit systemic Th-1 immune responses.

BACKGROUND: Sarcoidosis is an idiopathic granulomatous disease with pathologic and immunologic features similar to tuberculosis. Routine histologic staining and culture fail to identify infectious agents. An alternative means for investigating a role of infectious agents in human pathogenesis involves molecular analysis of pathologic tissues for microbial nucleic acids, as well as recognition of microbial antigens by the host immune system. Molecular analysis for superoxide dismutase A (sodA) allows speciation of mycobacteria. SodA is an abundantly secreted virulence factor that generates cellular immune responses in infected hosts. The purpose of this study is to investigate if target antigens of the sarcoidosis immune response can be identified by molecular analysis of sarcoidosis granulomas. METHODS: We detected sodA amplicons in 12 of 17 sarcoidosis specimens, compared to 2 of 16 controls (p = 0.001, two-tailed Fisher's exact test), and 3 of 3 tuberculosis specimens (p = 0.54). Analysis of the amplicons revealed sequences identical to M. tuberculosis (MTB) complex, as well as sequences which were genetically divergent. Using peripheral blood mononuclear cells (PBMC) from 12 of the 17 sarcoidosis subjects, we performed enzyme-linked immunospot assay (ELISPOT) to assess for immune recognition of MTB sodA peptides, along with PBMC from 26 PPD- healthy volunteers, and 11 latent tuberculosis subjects. RESULTS: Six of 12 sarcoidosis subjects recognized the sodA peptides, compared to one of 26 PPD- controls (p = 0.002), and 6/11 PPD+ subjects (p = .68). Overall, 10 of the 12 sarcoidosis subjects from whom we obtained PBMC and archival tissue possessed molecular or immunologic evidence for sodA. CONCLUSION: Dual molecular and immunologic analysis increases the ability to find infectious antigens. The detection of Th-1 immune responses to sodA peptides derived from molecular analysis of sarcoidosis granulomas reveals that these are among the target antigens contributing to sarcoidosis granulomatous inflammation.

Management of Primary Hyperparathyroidism: Can We Do Better?

The failure to follow national guidelines in management of various diseases has been previously established. We sought to quantify primary care providers' familiarity with primary hyperparathyroidism as it affects adherence to the 2009 National Institute of Health (NIH) consensus recommendations in treatment of primary hyperparathyroidism. A large primary care group was surveyed to determine their familiarity with the 2009 NIH consensus recommendations for management of primary hyperparathyroidism (PHPT). Retrospective review of the group's records (2009-2011) was performed to verify compliance. Survey responders included 109 clinicians, 31 per cent were familiar with all criteria for surgical intervention in asymptomatic patients and 34 per cent correctly identified appropriate surveillance testing for patients undergoing observation. Chart review identified 124 patients with PHPT. Of the patients who met NIH criteria, 34 per cent had a parathyroidectomy. Younger age, higher intact parathyroid hormone, hypercalciuria, and history of nephrolithiasis were associated with surgery in multivariable analysis. Of the observed patients, 16 per cent had appropriate surveillance studies. In conclusion, this study confirms suboptimal adherence with consensus recommendations in management of PHPT. A minority of clinicians demonstrated solid familiarity with management strategies, paralleling their treatment approach. Educational efforts may improve adherence with upcoming national recommendations.

Multicenter Prospective Clinical Series Evaluating Radiofrequency Ablation in the Treatment of Painful Spine Metastases.

BACKGROUND: Radiofrequency ablation (RFA) of vertebral body metastases (VBM) has been reported as safe and effective in retrospective studies. This single-arm prospective multicenter clinical study evaluates RFA in the treatment of painful VBM. METHODS: Fifty patients with VBM were prospectively enrolled during a 13-month period at eight US centers under an IRB-approved study. Percutaneous RFA was performed under imaging guidance with cement augmentation at the discretion of the operator. Pain, disability and quality of life were evaluated at baseline, prior to discharge, days 3, 7, 30 and 90 using the Numerical Pain Rating Scale, Oswestry Disability Index (ODI), the Functional Assessment of Cancer Therapy-General 7 (FACT-G7) and Functional Assessment of Cancer Therapy Quality-of-Life Measurement in Patients with Bone Pain (FACT-BP). Adverse events were monitored throughout this time interval. RESULTS: Twenty-six male and 24 female patients (mean age 61.0) underwent 69 treatments (30 thoracic and 39 lumbar). Cement augmentation was performed in 96 % of reported levels. Significant improvement in mean scores for pain, disability and cancer-specific health-related quality of life from baseline to all time intervals was seen. NRPS improved from 5.9 to 2.1 (p < 0.0001). ODI improved from 52.9 to 37.0 (p < 0.08). FACT-G7 improved form 10.9 to 16.2 (p = 0.0001). FACT-BP improved from 22.6 to 38.9 (p < 0.001). No complications related to the procedure were reported. CONCLUSION: RFA with cement augmentation safely and effectively reduces pain and disability rapidly, while increasing quality of life in patients suffering from vertebral body metastases.

Treatment strategies for primary hyperparathyroidism: what is the cost?

Primary hyperparathyroidism (HPT) contributes to the onset of many chronic conditions. Although parathyroidectomy is the only definitive treatment, observation remains a valid option. Over a 3-year span, a major health plan was queried for HPT and benign parathyroid neoplasm. Patients with secondary and tertiary HPT, Stage III to V kidney disease, and prior renal transplant were excluded. Patients were divided into: observation (Group 1), parathyroidectomy during the study period (Group 2), and parathyroidectomy before the study group (Group 3), and were compared with a control group of 27,092 adult members without HPT using analysis of variance. The 3-year mean total allowed expenditure for Group One (n = 559), Group Two (n = 93), and Group Three (n = 48) were $21,267, $37,043, and $14,702, respectively. Groups One and Two had significantly higher use than the nonparathyroid group (P < 0.0001), whereas that of Group Three was comparable. Group Two had the highest cost, whereas Group Three had a significantly lower cost than Group One (P 0.0001). Primary hyperparathyroidism is associated with a higher use of healthcare resources. Patients observed incurred a higher allowed expenditure than those with prior parathyroidectomy. Surgical treatment may represent a cost-effective strategy for treatment of hyperparathyroidism, although more comprehensive studies are needed to confirm these findings.

Evaluation of gastropexy and stoma tract maturation using a novel introducer kit for percutaneous gastrostomy in a porcine model.

BACKGROUND: Fluoroscopic placement of percutaneous gastrostomy (PG) requires the use of T-bar fasteners to affix the stomach to the anterior abdominal wall; the effect of T-fasteners on stoma tract maturation is unknown. The authors studied PG stoma tract maturation, comparing PG + gastropexy with standard percutaneous endoscopic gastrostomy (PEG). METHODS: Sixteen pigs underwent PG placement using a novel introducer kit. Three absorbable suture T-fasteners were placed around the stoma site, and PG was placed using the Russell method. A standard PEG was then placed using the Ponsky pull method, allowing each animal to serve as its own control. Gross and histopathological integrity of stoma tract formation was assessed at 1-3 weeks. RESULTS: At sacrifice, all PGs were intact with no evidence of infection, disruption, or significant leakage. Stoma tracts of all test and control sites were robust and histologically mature at all time points. Stoma tract diameters were also similar between test and control PGs (mean ± SEM: control 13.1 ± 0.7 mm, test 12.1 ± 0.4 mm; P = .2, n = 15). Histopathological evaluation demonstrated a generally comparable tissue response between test and control PGs, with slight decreases in fibrosis noted in test compared to control sites (P = .02, n = 15). CONCLUSIONS: Stoma tract maturation of PG with gastropexy provides similar results to standard PEG. Stoma tracts were mature at 1 week regardless of placement method. Placement and performance of PG using the new introducer kit with novel T-fasteners and absorbable suture yields effective gastric anchoring and has similar ease of use as standard PEG placement.

A blood lead benchmark for assessing risks from childhood lead exposure.

Lead exposure is an insidious problem, causing subtle effects in children at low exposure levels where clinical signs are not apparent. Although a target blood lead concentration (Pb(B)) of ten micrograms per deciliter (10 microg/dL) has been used as the basis for environmental decision-making in California for nearly two decades, recent epidemiologic evidence suggests a relationship between cognitive deficits and Pb(B) at concentrations < 10 microg/dL. Based on a published meta-analysis of children's IQ scores and their blood lead concentrations, we developed a new blood lead benchmark: an incremental increase in blood lead concentration (DeltaPb(B)) of 1 microg/dL, an increase that we estimate could decrease the IQ score in an average school child in California by up to one point. Although there is no evidence to date for a threshold for the neurobehavioral effects of lead, a one-point IQ decrement was chosen to represent a de minimus change. To safeguard the intellectual potential of all children, additional efforts to reduce or eliminate multiple-source exposures to lead are warranted.

Multiple sequence variants in hereditary hemorrhagic telangiectasia cases: illustration of complexity in molecular diagnostic interpretation.

Hereditary hemorrhagic telangiectasia is an autosomal dominant disease caused by mutations in the ACVRL1 and ENG genes characterized by arterio-venous malformations and telangiectases. Over 700 mutations have been described in these two genes, and missense mutations are common. We describe 10 cases in which more than one potentially pathogenic mutation was identified. We report that 8 novel missense mutations, as well as previously reported pathogenic missense mutations, were seen in combination with a second mutation, which raises questions with regards to their respective pathogenicity. Our data and discussion indicate the challenges of classifying missense mutations as pathogenic or benign and the value of co-segregation studies, as well as suggest that there may be hereditary hemorrhagic telangiectasia gene mutations that have only mild phenotypic effects. We present evidence to suggest that four missense mutations (ENG p.G331S, ENG p.L8P, ENG p.P452L and ACVRL1 p.C344R) are pathogenic, two novel mutations (ACVRL1 p.A311T and ENG p.S576G) are neutral, and two previously reported disease-causing mutations are benign or have suspected benign variants (ACVRL1 p.A482V and ENG p.V504M). We conclude that for the purpose of establishing a causative hereditary hemorrhagic telangiectasia mutation in a family proband, all exons and intron/exon borders of both genes should be sequenced and deletion/duplication analysis should be performed unless a mutation that is well-proven to be pathogenic is identified.

Mycobacterium tuberculosis Antigen 85A induces Th-1 immune responses in systemic sarcoidosis.

Sarcoidosis is a granulomatous disease of unknown etiology, characterized by a Th-1 immunophenotype. Although humoral immune responses by sarcoidosis subjects to mycobacterial proteins have been detected, mycobacterial antigens capable of inducing cellular immune responses in sarcoidosis subjects have not been reported. We used the enzyme-linked immunospot assay to assess for recognition of the Mycobacterium tuberculosis mycolyl transferase, Antigen 85A, by peripheral blood mononuclear cells from 25 sarcoidosis subjects, 22 PPD- (purified protein derivative) healthy volunteers, and 16 PPD+ healthy subjects. Reactivity to Ag85A whole protein was observed in 15 of 25 sarcoidosis subjects compared to 2 of 22 PPD- subjects (p=0.0006, Fisher's exact test) and to 14 of 16 PPD+ subjects (p=0.084, Fisher's exact test). Monoclonal antibody against HLA-DR inhibited recognition. In addition to immune recognition of Ag85A whole protein, peptide-mapping studies identified four immunogenic Ag85A peptides, which induced Th-1 immune responses in individual sarcoidosis subjects, suggesting that multiple epitopes from a mycobacterial protein may have a role in sarcoidosis immunopathogenesis.

Portable X-ray fluorescence in the characterisation of arsenic contamination associated with industrial buildings at a heritage arsenic works site near Redruth, Cornwall, UK.

An investigation using in situ analysis by portable X-ray fluorescence (PXRF) has shown that contamination present on industrial buildings at a heritage arsenic works site near Redruth, Cornwall, UK results from the absorption of arsenic by porous and semi-porous building materials that were in contact with arsenic-rich flue gases. Results from a preliminary survey indicate that arsenic remains locked in these materials and is being gradually leached out by weathering processes. This weathering causes general contamination of the adjacent building surfaces averaging 1845 microg g(-1) arsenic, presumably caused by evaporation of leach solutions in contact with air at the surface of the building materials. More extensive crystalline deposits were found under arches protected from dissolution and further dispersion by rain water. These deposits appeared to comprise calcium sulfate (gypsum), associated with on average between 1.2 and 6.8% m/m As. In situ PXRF proved to be highly effective in locating sources of contamination at the site and in providing data that allowed a hypotheses for the origin of this contamination to be formulated and tested in the field.