Arsenic toxicology: translating between experimental models and human pathology

Background: Chronic arsenic exposure is a worldwide health problem. How arsenic exposure promotes a variety of diseases is poorly understood, and specific relationships between experimental and human exposures are not established. We propose phenotypic anchoring as a means to unify experimental observations and disease outcomes.Objectives: We examined the use of phenotypic anchors to translate experimental data to human pathology and investigated research needs for which phenotypic anchors need to be developed.Methods: During a workshop, we discussed experimental systems investigating arsenic dose/exposure and phenotypic expression relationships and human disease responses to chronic arsenic exposure and identified knowledge gaps. In a literature review, we identified areas where data exist to support phenotypic anchoring of experimental results to pathologies from specific human exposures.Discussion: Disease outcome is likely dependent on cell-type–specific responses and interaction with individual genetics, other toxicants, and infectious agents. Potential phenotypic anchors include target tissue dosimetry, gene expression and epigenetic profiles, and tissue biomarkers.Conclusions: Translation to human populations requires more extensive profiling of human samples along with high-quality dosimetry. Anchoring results by gene expression and epigenetic profiling has great promise for data unification. Genetic predisposition of individuals affects disease outcome. Interactions with infectious agents, particularly viruses, may explain some species-specific differences between human pathologies and experimental animal pathologies. Invertebrate systems amenable to genetic manipulation offer potential for elaborating impacts of specific biochemical pathways. Anchoring experimental results to specific human exposures will accelerate understanding
of mechanisms of arsenic-induced human disease.     

Diagnosis and treatment of neonatal diabetes: a United States experience

Background/objective: Mutations in KCNJ11, ABCC8, or INS are the cause of permanent neonatal diabetes mellitus in about 50% of patients diagnosed with diabetes before 6 months of age and in a small fraction of those diagnosed between 6 and 12 months. The aim of this study was to identify the genetic cause of diabetes in 77 consecutive patients referred to the University of Chicago with diabetes diagnosed before 1 yr of age. Methods: We used Oragene? DNA Self‐Collection kit to obtain a saliva sample for DNA. We sequenced the protein‐coding regions of KCNJ11, ABCC8, and INS using standard methods. Results: We enrolled 32 patients diagnosed with diabetes before 6 months of age and 45 patients diagnosed between 6 and 12 months. We identified a mutation in KCNJ11 in 14 patients from 12 families and in INS in 7 patients from 4 families. Three of the patients with an INS mutation were diagnosed with diabetes between 6 and 12 months of age. Finally, we found that two patients had an abnormality of chromosome 6q24 associated with transient neonatal diabetes mellitus. Conclusions: We were able to establish a genetic cause of diabetes in 63% of patients diagnosed with diabetes before 6 months of age and in 7% of patients diagnosed between 6 and 12 months. Genetic testing, which is critical for guiding appropriate management, should be considered in patients diagnosed with diabetes before 1 yr of age, especially if they are autoantibody negative, although the presence of autoantibodies does not rule out a monogenic cause.     

The role of the orthopedist in injury prevention

Injury is an endemic disease process that is a leading cause of death and the leading cause of disability in the United States today. Among physicians, the orthopedic surgeon is most likely to be consulted by injured patients. Traditionally, orthopedists have played an important role in injury prevention as exemplified by the field of sports medicine. Three mechanisms have been demonstrated to be effective means of controlling the injury problem: (1) persuading persons at risk of injury to alter their behavior; (2) requiring individual behavior changes by law or administrative rule; and (3) providing automatic protection by product and environmental design. Specific strategies for implementing injury-prevention programs by the orthopedic surgeon are physician education, patient education, and public education.     

Efficacy of thermal treatment and copper-silver ionization for controlling Legionella pneumophila in high-volume hot water plumbing systems in hospitals

Background: Thermal treatment and copper-silver ionization are often used for controlling Legionella pneumophila in high-volume hospital plumbing systems, although the comparative efficacies of these measures in high-volume systems are unknown.Methods: Thermal treatment of a hot water circuit was accomplished by flushing hot water (>60° C) through distal fixtures for 10 minutes. Copper-silver ionization was conducted in three circuits by installing units into return lines immediately upstream from hot water tanks. Recovery rates of L. pneumophila were monitored by culturing swab samples from faucets. Concentrations of copper and silver in water samples were determined by atomic absorption spectrophotometry.Results: Four heat-flush treatments failed to provide long-term control of L. pneumophila. In contrast, ionization treatment reduced the rate of recovery of L. pneumophila from 108 faucets from 72% to 2% within 1 month and maintained effective control for at least 22 months. Only three samples (1.9%) of hot water from faucets exceeded Environmental Protection Agency standards for silver, and none exceeded the standards for copper. Of 24 samples obtained from hot water tanks, 42% and 50% exceeded the silver and copper standards, respectively.Conclusions: Copper-silver ionization effectively controls L. pneumophila in high-volume plumbing systems and is superior to thermal treatment; however, high concentrations of copper and silver can accumulate at the bottom of hot water tanks.