Distinguishing the associations between daily mortality and hospital admissions and nitrogen dioxide from those of particulate matter: a systematic review and meta-analysis.

OBJECTIVES: To quantitatively assess time-series studies of daily nitrogen dioxide (NO2) and mortality and hospital admissions which also controlled for particulate matter (PM) to determine whether or to what extent the NO2 associations are independent of PM. DESIGN: A systematic review and meta-analysis. METHODS: Time-series studies-published in peer-reviewed journals worldwide, up to May 2011-that reported both single-pollutant and two-pollutant model estimates for NO2 and PM were ascertained from bibliographic databases (PubMed, EMBASE and Web of Science) and reviews. Random-effects summary estimates were calculated globally and stratified by different geographical regions, and effect modification was investigated. OUTCOME MEASURES: Mortality and hospital admissions for various cardiovascular or respiratory diseases in different age groups in the general population. RESULTS: 60 eligible studies were identified, and meta-analysis was conducted on 23 outcomes. Two-pollutant model study estimates generally showed that the NO2 associations were independent of PM mass. For all-cause mortality, a 10 µg/m(3) increase in 24-hour NO2 was associated with a 0.78% (95% CI 0.47% to 1.09%) increase in the risk of death, which reduced to 0.60% (0.33% to 0.87%) after control for PM. Heterogeneity between geographical region-specific estimates was removed by control for PM (I(2) from 66.9% to 0%). Estimates of PM and daily mortality assembled from the same studies were greatly attenuated after control for NO2: from 0.51% (0.29% to 0.74%) to 0.18% (-0.11% to 0.47%) per 10 µg/m(3) PM10 and 0.74% (0.34% to 1.14%) to 0.54% (-0.25% to 1.34%) for PM2.5. CONCLUSIONS: The association between short-term exposure to NO2 and adverse health outcomes is largely independent of PM mass. Further studies should attempt to investigate whether this is a generic PM effect or whether it is modified by the source and physicochemical characteristics of PM. This finding strengthens the argument for NO2 having a causal role in health effects.

Air pollution: The last 35 years.

Perceptions of the effects on health of air pollutants have changed dramatically over the past thirty five years. It is now clear that current, historically low, concentrations of air pollutants have significant effects on health and that these effects bear most heavily on deaths and illness caused by cardiovascular diseases. Epidemiological studies have provided the evidence for these conclusions; toxicological studies have provided explanations, not yet complete, for these effects. Most emphasis has been placed on the effects of airborne particles and the evidence for their effects is convincing. Less attention has been paid to the effects of gaseous air pollutants: it may be that their effects have been, and are, under-estimated. Recent work has allowed the effects on health of air pollutants to be quantified at both a national and global scale. This work has led to the realization that the effects are large and that air pollutants continue to pose an important threat to health.

Neurotranmission systems as targets for toxicants: a review.

Neurotransmitters are chemicals that transmit impulses from one nerve to another or from nerves to effector organs. Numerous neurotransmitters have been described in mammals, amongst them acetylcholine, amino acids, amines, peptides and gases. Toxicants may interact with various parts of neurotransmission systems, including synthetic and degradative enzymes, presynaptic vesicles and the specialized receptors that characterize neurotransmission systems. Important toxicants acting on the cholinergic system include the anticholinesterases (organophosphates and carbamates) and substances that act on receptors such as nicotine and the neonicotinoid insecticides, including imidacloprid. An important substance acting on the glutamatergic system is domoic acid, responsible for amnesic shellfish poisoning. 4-Aminobutyric acid (GABA) and glycine are inhibitory neurotransmitters and their antagonists, fipronil (an insecticide) and strychnine respectively, are excitatory. Abnormalities of dopamine neurotransmission occur in Parkinson's disease, and a number of substances that interfere with this system produce Parkinsonian symptoms and clinical signs, including notably 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which is the precursor of 1-methyl-4-phenylpyridinium. Fewer substances are known that interfere with adrenergic, histaminergic or seroninergic neurotransmission, but there are some examples. Among peptide neurotransmission systems, agonists of opioids are the only well-known toxic compounds.

Diffuse centromere and chromosome polymorphism in haplogyne spiders of the families Dysderidae and Segestriidae.

The karyotypes of several individuals of Dysdera crocata C.L. Koch 1838 (Dysderidae), Ariadna boesenbergi Keyserling 1877, and Segestria ruficeps Guérin 1832 (Segestridae) are described. Diffuse centromeres were observed in the 3 species. D. crocata and A. boesenbergi exhibit chromosome number polymorphism, with the presence of trivalent chromosomes in the first metaphase in some individuals. They also show testicular cysts with polyploid spermatogonia and spermatocytes. The haploid chromosome number for these 2 species varies between n = 3 + X and n = 6 + X. The first meiotic division in D. crocata is equational while the second meiotic division is reductional for trivalents and the X chromosome. The first meiotic division in A. boesenbergi is equational for trivalents, and reductional for the X, while the second division is reductional for hemi-trivalents and equational for the X. In S. ruficeps the haploid chromosome number is n = 6 + X(1)X(2), and the first division is reductional for the Xs. The evolution of karyotypes within haplogyne spiders is discussed in relation to the origin of diffuse centromeres.

Bicarbonate transport by the human pancreatic ductal cell line HPAF.

OBJECTIVES: The human pancreatic duct cell line, HPAF, has been shown previously to secrete Cl(-) in response to Ca(2+)-mobilizing stimuli. Our aim was to assess the capacity of HPAF cells to transport and secrete HCO3(-). METHODS: HPAF cells were grown as confluent monolayers on permeable supports. Short-circuit current was measured by voltage clamp. Intracellular pH (pHi) was measured by microfluorometry in cells loaded with 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF). RESULTS: In HCO3(-)-free solutions, ATP-evoked changes in short-circuit current were inhibited by bumetanide, and the recovery of pHi from acid loading was abolished by 5-(N-ethyl-N-isopropyl)-amiloride (EIPA). In the presence of HCO3(-), ATP-evoked secretion was no longer inhibited by bumetanide, and there was a strong EIPA-insensitive recovery from acid loading, which was inhibited by 4,4'-diisothiocyanatodihydrostilbene-2,2'-disulfonate (H2DIDS). ATP, but not forskolin, stimulated HCO3(-) efflux from the cells. CONCLUSIONS: In the absence of HCO3(-), ATP-evoked Cl(-) secretion is driven by a basolateral Na(+)-K(+)-2Cl(-) cotransporter, and pH(i) is regulated by apical and basolateral Na(+)/H(+) exchangers. In the presence of HCO3(-), ATP-evoked secretion is sustained in the absence of Na(+)-K(+)-2Cl(-) cotransporter activity and is probably driven by basolateral Na(+)-HCO3(-) cotransport.

Aggressive vs. conservative phototherapy for infants with extremely low birth weight.

BACKGROUND: It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less). METHODS: We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments. RESULTS: Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 micromol per liter], P<0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P=0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g. CONCLUSIONS: Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials.gov number, NCT00114543.)

Meropenem pharmacokinetics, pharmacodynamics, and Monte Carlo simulation in the neonate.

BACKGROUND: Hospitalized neonates are exposed to antibiotic-resistant bacterial pathogens and develop nosocomial infections. Limited data are available regarding the neonatal pharmacokinetics of meropenem, a broad spectrum carbapenem antibiotic. METHODS: Neonates <2 months of age received a single dose of meropenem at 10 or 20 mg/kg. Meropenem serum concentrations were measured at specified times during the 24 hours postinfusion. Population pharmacokinetics (PPK) were evaluated using NONMEM. Using Monte Carlo simulation (MCS), the probability of pharmacokinetic-pharmacodynamic target attainment was evaluated by computer modeling from predictions extrapolated from PPK data, using "virtual" dosing regimens of 10, 20, and 40 mg/kg administered every 8 or 12 hours against community- and hospital-acquired pathogens. RESULTS: Thirty-seven neonates were enrolled, 22 were born at <36 weeks (range, 23-41 weeks) gestational age. Meropenem clearance was greater in neonates with older chronologic ages and in those born at later gestational ages. Serum creatinine and postconceptional age (PCA) were the best overall predictors of meropenem elimination: CL (L/h/kg) = 0.041 + 0.040/SCr + 0.003 x (PCA-35). MCS demonstrated that in infants during the first 2 weeks of life, a dosage of 20 mg/kg/dose every 8 hours achieved the desired PD target in 95% of preterm neonates and 91% of term neonates against Pseudomonas aeruginosa isolated from patients managed in adult and pediatric intensive care units in the United States. CONCLUSIONS: MCS based on PPK determinations demonstrated that a meropenem dose of 20 mg/kg every 8 hours should provide adequate therapy for most nosocomial Gram-negative pathogens.

Polluted air--outdoors and indoors.

Many air pollutants which are considered important in ambient (outdoor) air are also found, sometimes at higher levels, in indoor air. With demanding standards having been set for many of these pollutants, both in the workplace and ambient air, consideration of the problems posed by indoor pollution is gaining pace. Studies on exposure to pollutants found in the indoor domestic environment are increasing and are contributing to an already significant compilation of datasets. Improvement in monitoring techniques has helped this process. Documented reports of fatalities from carbon monoxide poisonings are still worrying. However, studies on health effects of non-fatal, long term, low dose, indoor exposure to carbon monoxide and other pollutants, are still inconclusive and too infrequently documented. Of particular concern are the levels of air pollutants found in the domestic indoor environment in developing countries, despite simple interventions such as vented stoves having shown their value. Exposure to biomass smoke is still a level that would be considered unacceptable on health grounds in developed countries. As in the occupational environment, steps need to be taken to control the risks from exposure to the harmful constituents of indoor air in the home. However, the difficulty regarding regulation of the domestic indoor environment is its inherent privacy. Monitoring levels of pollutants in the home and ensuring regulations are adhered to, would likely prove difficult, especially when individual behaviour patterns and activities have the greatest influence on pollutant levels in indoor air. To this end, the Department of Health is developing guidance on indoor air pollution to encourage the reduction of pollutant levels in indoor domestic air. The importance of the effects of domestic indoor air on health and its contribution to the health of the worker are increasingly appreciated. Occupational physicians, by training and interest, are well placed to extend their interests into the environmental field and to focus on this important area.

A randomized, multicenter masked comparison trial of poractant alfa (Curosurf) versus beractant (Survanta) in the treatment of respiratory distress syndrome in preterm infants.

We compared the onset of clinical response and safety of two surfactants, poractant alfa (Curosurf, Chiesi Pharmaceuticals, Parma, Italy) and beractant (Survanta, Ross Laboratories, Columbus, OH), for treatment of respiratory distress syndrome (RDS) in preterm infants weighing 750 to 1750 g at birth and <35 weeks gestation. The study was performed as a 20-center prospective, randomized, masked comparison trial. Preterm infants (n = 293) with RDS were randomized to receive an initial dose of either 100 (n = 96) or 200 (n = 99) mg/kg of poractant alfa or 100 ( n = 98) mg/kg of beractant. All repeat dosing was given at 100 mg/kg. The onset of clinical response after the first dose was studied by comparing changes in the fraction of inspired oxygen (F IO(2)) between 0 and 6 hours measured using the area under the curve (F IO(2) AUC (0-6)); other outcomes were assessed for the entire cohort at 28 days and for infants born at < or = 32 weeks gestation at 36 weeks postconceptional age. We found that the mean F IO(2) AUC (0-6) values for the 100 and 200 mg/kg poractant alfa groups were both significantly lower than the mean F IO(2) AUC (0-6) values for the beractant group ( p < 0.005) but were not different from each other. Other outcomes were not different among the three groups for the entire cohort, but in infants born at < or = 32 weeks gestation, mortality up to 36 weeks postconceptional age was significantly less in the 200 mg/kg poractant alfa group than in either the beractant group (3% versus 11%; p = 0.034) or in the 100 mg/kg poractant alfa group (3% versus 11%; p = 0.046). Need for more than one dose of surfactant was significantly lower in infants treated with an initial dose of 200 mg/kg poractant alfa in comparison to the beractant-treated group ( p < 0.002). Treatment with poractant alfa (200 mg/kg initial dose) resulted in rapid reduction in supplemental oxygen with fewer additional doses of surfactant versus treatment with beractant in infants <35 weeks gestation with RDS, and significantly reduced mortality ( p <0.05) than either beractant or poractant alfa (100 mg/kg dosing) in infants < or =32 weeks gestation with RDS.

In vitro toxicology of respirable Montserrat volcanic ash.

OBJECTIVES: In July 1995 the Soufriere Hills volcano on the island of Montserrat began to erupt. Preliminary reports showed that the ash contained a substantial respirable component and a large percentage of the toxic silica polymorph, cristobalite. In this study the cytotoxicity of three respirable Montserrat volcanic ash (MVA) samples was investigated: M1 from a single explosive event, M2 accumulated ash predominantly derived from pyroclastic flows, and M3 from a single pyroclastic flow. These were compared with the relatively inert dust TiO(2) and the known toxic quartz dust, DQ12. METHODS: Surface area of the particles was measured with the Brunauer, Emmet, and Teller (BET) adsorption method and cristobalite content of MVA was determined by x ray diffraction (XRD). After exposure to particles, the metabolic competence of the epithelial cell line A549 was assessed to determine cytotoxic effects. The ability of the particles to induce sheep blood erythrocyte haemolysis was used to assess surface reactivity. RESULTS: Treatment with either MVA, quartz, or titanium dioxide decreased A549 epithelial cell metabolic competence as measured by ability to reduce 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). On addition of mannitol, the cytotoxic effect was significantly less with M1, quartz, and TiO(2). All MVA samples induced a dose dependent increase in haemolysis, which, although less than the haemolysis induced by quartz, was significantly greater than that induced by TiO(2). Addition of mannitol and superoxide dismutase (SOD) significantly reduced the haemolytic activity only of M1, but not M2 or M3, the samples derived from predominantly pyroclastic flow events. CONCLUSIONS: Neither the cristobalite content nor the surface area of the MVA samples correlated with observed in vitro reactivity. A role for reactive oxygen species could only be shown in the cytotoxicity of M1, which was the only sample derived from a purely explosive event. These results suggest that in general the bioreactivity of MVA samples in vitro is low compared with pure quartz, but that the bioreactivity and mechanisms of biological interaction may vary according to the ash source.

Instabilities of waves in nonlinear disordered media

We develop a self-consistent theory of temporal fluctuations of a speckle pattern resulting from the multiple scattering of a coherent wave in a weakly nonlinear disordered medium. The speckle pattern is shown to become unstable if the nonlinearity exceeds a threshold value. The instability is due to a feedback provided by the multiple scattering and manifests itself in spontaneous fluctuations of the scattered intensity. The development of instability is independent of the sign of nonlinearity.