Exogenous surfactant reduces ventilator-induced decompartmentalization of tumor necrosis factor alpha in absence of positive end-expiratory pressure

OBJECTIVE: To determine the effect of pretreatment with exogenous surfactant on ventilator-induced decompartmentalization of TNF-alpha. DESIGN AND SETTING: Prospective, randomized, animal study in the experimental laboratory of a university. SUBJECTS AND INTERVENTIONS: Male Sprague-Dawley rats (n=102) received lipopolysaccharide either intratracheally or intraperitoneally to stimulate TNF-alpha production; one-half of the animals were pretreated with surfactant. Animals were ventilated for 20 min with a peak inspiratory pressure/positive end-expiratory pressure (PEEP) ratio of either 45/0 or 45/10 (frequency 30 bpm, I/E ratio 1:2, FIO(2)=1). MEASUREMENTS AND RESULTS: Blood gas tension and arterial pressures were recorded 1, 10, and 20 min after the start of mechanical ventilation. After the animals were killed pressure-volume curves were recorded, and bronchoalveolar lavage was performed for assessment of protein content and the small/large surfactant aggregate ratio. TNF-alpha was determined in serum and bronchoalveolar lavage. Pretreatment with surfactant decreased decompartmentalization of TNF-alpha during 45/0 ventilation. Addition of a PEEP level of 10 cm H(2)O reduced decompartmentalization even further. In addition, surfactant prevented deterioration in oxygenation and decreased accumulation of protein in the bronchoalveolar lavage in the zero-PEEP group. CONCLUSIONS: An excess of active surfactant decreases transfer of cytokines across the alveolar-capillary membrane similar to PEEP. The combination of PEEP and surfactant reduces decompartmentalization of TNF-alpha even further.     

Elevated Blood Lead Levels Among Fire Assay Workers and Their Children in Alaska, 2010–2011

In October 2010, an employee at Facility A in Alaska that performs fire assay analysis, an industrial technique that uses lead-containing flux to obtain metals from pulverized rocks, was reported to the Alaska Section of Epidemiology (SOE) with an elevated blood lead level (BLL) ≥10 micrograms per deciliter (μg/dL). The SOE initiated an investigation; investigators interviewed employees, offered blood lead screening to employees and their families, and observed a visit to the industrial facility by the Alaska Occupational Safety and Health Section (AKOSH). Among the 15 employees with known work responsibilities, 12 had an elevated BLL at least once from October 2010 through February 2011. Of these 12 employees, 10 reported working in the fire assay room. Four children of employees had BLLs ≥5 μg/dL. Employees working in Facility A''s fire assay room were likely exposed to lead at work and could have brought lead home. AKOSH inspectors reported that they could not share their consultative report with SOE investigators because of the confidentiality requirements of a federal regulation, which hampered Alaska SOE investigators from fully characterizing the lead exposure standards.Occupational lead exposure continues to threaten workers'' health.^1–3 In the United States, the Occupational Safety and Health Administration (OSHA) prescribes standards for permissible exposure limits for lead in the workplace and specifies that a blood lead level (BLL) of 40 micrograms per deciliter (μg/dL) triggers more frequent (i.e., every two months rather than every six months) blood lead testing. OSHA standards require that workers with a BLL ≥60 μg/dL, or an average BLL for the last three tests or all tests during the previous six months (whichever is longer) of ≥50 μg/dL, be removed from the lead exposure area, unless the most recent test indicated a BLL ≤40 μg/dL.⁴ However, research has increased concern regarding lead toxicity at lower doses and has supported a reevaluation of the level at which BLLs can be considered safe.⁵ The National Institute for Occupational Safety and Health (NIOSH) defines an elevated BLL in an adult as ≥10 μg/dL.⁶ In addition to adverse impacts on the health of the workers themselves, children of lead-exposed workers have disproportionately higher BLLs when compared with other children.^7–9Elevated BLLs among adults are associated with muscle and joint pain, reproductive problems, and neurologic symptoms, including memory loss.¹⁰ Negative health effects have been observed among adults with only modestly elevated BLLs,^11–13 with increased odds of an ill effect occurring at levels as low as 1.6–2.4 μg/dL.¹¹ Among children, elevated BLLs can result in devastating health effects, including brain and nervous system damage, slow growth, and hearing problems.¹⁰ Research indicates that there is no safe level of lead among children.¹⁴ Despite considerable data on the deleterious health effects of lead regarding both children and adults, harmful occupational exposures that are inadequately controlled continue to put workers and their families at risk. A BLL of ≥5 μg/dL is the reference level that the Advisory Committee on Childhood Lead Poisoning Prevention has recommended to identify children with elevated BLLs.¹⁴ Elevated BLLs ≥10 μg/dL for children and adults are reportable in Alaska under Alaska Administrative Code 27.014.¹⁵     

Adoption of pharmacogenomic testing by US physicians: results of a nationwide survey

To develop a benchmark measure of US physicians' level of knowledge and extent of use of pharmacogenomic testing, we conducted an anonymous, cross-sectional, fax-based, national survey. Of 397,832 physicians receiving the survey questionnaire, 10,303 (3%) completed and returned it; the respondents were representative of the overall US physician population. The factors associated with the decision to test were evaluated using χ(2) and multivariate logistic regression. Overall, 97.6% of responding physicians agreed that genetic variations may influence drug response, but only 10.3% felt adequately informed about pharmacogenomic testing. Only 12.9% of physicians had ordered a test in the previous 6 months, and 26.4% anticipated ordering a test in the next 6 months. Early and future adopters of testing were more likely to have received training in pharmacogenomics, but only 29.0% of physicians overall had received any education in the field. Our findings highlight the need for more effective physician education on the clinical value, availability, and interpretation of pharmacogenomic tests.     

Dual architectural roles of HU: formation of flexible hinges and rigid filaments

The nucleoid-associated protein HU is one of the most abundant proteins in Escherichia coli and has been suggested to play an important role in bacterial nucleoid organization and regulation. Although the regulatory aspects of HU have been firmly established, much less is understood about the role of HU in shaping the bacterial nucleoid. In both functions (local) modulation of DNA architecture seems an essential feature, but information on the mechanical properties of this type of sequence-independent nucleoprotein complex is scarce. In this study we used magnetic tweezers and atomic force microscopy to quantify HU-induced DNA bending and condensation. Both techniques revealed that HU can have two opposing mechanical effects depending on the protein concentration. At concentrations <100 nM, individual HU dimers induce very flexible bends in DNA that are responsible for DNA compaction up to 50%. At higher HU concentrations, a rigid nucleoprotein filament is formed in which HU appears to arrange helically around the DNA without inducing significant condensation.