Acute health effects after exposure to chlorine gas released after a train derailment.

In January 2005, a train derailment on the premises of a textile mill in South Carolina released 42 to 60 tons of chlorine gas in the middle of a small town. Medical records and autopsy reports were reviewed to describe the clinical presentation, hospital course, and pathology observed in persons hospitalized or deceased as a result of chlorine gas exposure. Eight persons died before reaching medical care; of the 71 persons hospitalized for acute health effects as a result of chlorine exposure, 1 died in the hospital. The mean age of the hospitalized persons was 40 years (range, 4 months-76 years); 87% were male. The median duration of hospitalization was 4 days (range, 1-29 days). Twenty-five (35%) persons were admitted to the intensive care unit; the median length of stay was 3 days. Many surviving victims developed significant pulmonary signs and severe airway inflammation; 41 (58%) hospitalized persons met PO2/FiO2 criteria for acute respiratory distress syndrome or acute lung injury. During their hospitalization, 40 (57%) developed abnormal x-ray findings, 74% of those within the first day. Hypoxia on room air and PO2/FiO2 ratio predicted severity of outcome as assessed by the duration of hospitalization and the need for intensive care support. This community release of chlorine gas caused widespread exposure and resulted in significant acute health effects and substantial health care requirements. Pulse oximetry and arterial blood gas analysis provided early indications of outcome severity.

Panel classification of self-reported exposure histories: a useful exposure index after a mass-casualty event.

OBJECTIVE: Although rapid epidemiologic investigations of toxic exposures require estimates of individual exposure levels, objective measures of exposure are often unavailable. We investigated whether self-reported exposure histories, when reviewed and classified by a panel of raters, provided a useful exposure metric. METHODS: A panel reviewed exposure histories as reported by people who experienced a chlorine release. The panelists received no information about health-care requirements or specific health effects. To each exposure case, each panelist assigned one of five possible exposure severity ratings. When assigned ratings were not in initial agreement, the panelists discussed the case and assigned a consensus rating. Percent agreement and kappa statistics assessed agreement among panelists, Kendall's W measured agreement among panelists in their overall ordering of the exposure histories, and Spearman's rho compared the resultant rankings with individual health outcome. RESULTS: In 48% of the cases, the panelists' initial ratings agreed completely. Overall, initial ratings for a given case matched the consensus rating 69% to 89% of the time. Pair-wise comparisons revealed 85% to 95% agreement among panelists, with weighted kappa statistics between 0.69 and 0.83. In their overall ranking of the exposure histories, the panelists reached significant agreement (W = 0.90, p < 0.0001). Disagreement arose most frequently regarding probable chlorine concentration and duration of exposure. This disagreement was most common when panelists differentiated between adjacent categories of intermediate exposure. Panel-assigned exposure ratings significantly correlated with health outcome (Spearman's rho = 0.56; p < 0.0001). CONCLUSION: Epidemiologists and public health practitioners can elicit and review self-reported exposure histories and assign exposure severity ratings that predict medical outcome. When objective markers of exposure are unavailable, panel-assigned exposure ratings may be useful for rapid epidemiologic investigations.

Rapid assessment of exposure to chlorine released from a train derailment and resulting health impact.

OBJECTIVES: After a train derailment released approximately 60 tons of chlorine from a ruptured tanker car, a multiagency team performed a rapid assessment of the health impact to determine morbidity caused by the chlorine and evaluate the effect of this mass-casualty event on health-care facilities. METHODS: A case was defined as death or illness related to chlorine exposure. Investigators gathered information on exposure, treatment received, and outcome through patient questionnaires and medical record review. An exposure severity rating was assigned to each patient based on description of exposure, distance from derailment, and duration of exposure. A case involving death or hospitalization > or = 3 nights was classified as a severe medical outcome. Logistic regression was used to examine factors associated with severe medical outcomes. RESULTS: Nine people died, 72 were hospitalized in nine hospitals, and 525 were examined as outpatients. Fifty-one people (8%) had a severe medical outcome. Of 263 emergency department visits within 24 hours of the incident, 146 (56%) were in Augusta, Georgia; at least 95 patients arrived at facilities in privately owned vehicles. Patients with moderate-to-extreme exposure were more likely to experience a severe medical outcome (relative risk: 15.2; 95% confidence interval 4.8, 47.8) than those with a lower rating. CONCLUSIONS: The rapid investigation revealed significant morbidity and mortality associated with an accidental release of chlorine gas. Key findings that should be addressed during facility, community, state, and regional mass-casualty planning include self-transport of symptomatic people for medical care and impact on health-care facilities over a wide geographic area.

Steady-state kinetics of the hypoxanthine phosphoribosyltransferase from Trypanosoma cruzi.

The kinetic mechanism for the reaction catalyzed by the hypoxanthine phosphoribosyltransferase (HPRT) from Trypanosoma cruzi was analyzed to determine the feasibility of designing a parasite-specific mechanism-based inhibitor of this enzyme. The results show that the HPRT from T. cruzi follows an essentially ordered bi-bi reaction, and like its human counterpart also likely forms a dead end complex with purine substrates and the product pyrophosphate. Computational fitting of the kinetics data to multiple initial velocity equations gave results that are consistent with the dead end complex arising when the hypoxanthine- or guanine-bound form of the enzyme binds pyrophosphate rather than the phosphoribosylpyrophosphate substrate of the productive forward reaction. Limited proteolytic digestion was employed to provide additional support for formation of the dead end complex and to estimate the K(d) values for substrates of both the forward and reverse reactions. Due to similarities with the kinetic mechanism of the human HPRT, the results reported here for the HPRT from T. cruzi indicate that the design of a mechanism-based inhibitor of the trypanosomal HPRT, that would not also inhibit the human enzyme, may be difficult. However, the results also show that a potent selective inhibitor of the trypanosomal HPRT might be achieved via the design of a bi-substrate type inhibitor that incorporates analogs of moieties for a purine base and pyrophosphate.

Interactions at the dimer interface influence the relative efficiencies for purine nucleotide synthesis and pyrophosphorolysis in a phosphoribosyltransferase.

Enzymes that salvage 6-oxopurines, including hypoxanthine phosphoribosyltransferases (HPRTs), are potential targets for drugs in the treatment of diseases caused by protozoan parasites. For this reason, a number of high-resolution X-ray crystal structures of the HPRTs from protozoa have been reported. Although these structures did not reveal why HPRTs need to form dimers for catalysis, they revealed the existence of potentially relevant interactions involving residues in a loop of amino acid residues adjacent to the dimer interface, but the contributions of these interactions to catalysis remained poorly understood. The loop, referred to as active-site loop I, contains an unusual non-proline cis-peptide and is composed of residues that are structurally analogous with Leu67, Lys68, and Gly69 in the human HPRT. Functional analyses of site-directed mutations (K68D, K68E, K68N, K68P, and K68R) in the HPRT from Trypanosoma cruzi, etiologic agent of Chagas' disease, show that the side-chain at position 68 can differentially influence the K(m) values for all four substrates as well as the k(cat) values for both IMP formation and pyrophosphorolysis. Also, the results for the K68P mutant are inconsistent with a cis-trans peptide isomerization-assisted catalytic mechanism. These data, together with the results of structural studies of the K68R mutant, reveal that the side-chain of residue 68 does not participate directly in reaction chemistry, but it strongly influences the relative efficiencies for IMP formation and pyrophosphorolysis, and the prevalence of lysine at position 68 in the HPRT of the majority of eukaryotes is consistent with there being a biological role for nucleotide pyrophosphorolysis.

Role of the long slender to short stumpy transition in the life cycle of the african trypanosomes.

It is shown using mouse models that the African trypanosomes exert a significant drain upon their host's carbohydrate (energy) resources; and that the higher the parasitemia, the greater the energy demand. It is, therefore, hypothesized that the long slender (LS) to short stumpy (SS) transition evolved, in part, to help control the parasitemia and to increase host survival time. It is also suggested that the SS population is heterogeneous. One part of the population is tsetse infective, while a second older SS population is undergoing apoptotic-like events, which leads to their cell death and their stimulation of the host's immune response. This immune stimulation by the old dying SS forms would eliminate the major LS and SS variant antigen population, and produce the chronic relapsing infection. It is concluded that the SS stages during the apoptosis-like process are acting altruistically. They give their lives to insure the long-term survival of the host, and to insure renewed growth of the minor LS variants and new infective SS forms. This process is predicted to increase the probability for the successful transmission of the trypanosomes to a new host.

The purine transferase from Trypanosoma cruzi as a potential target for bisphosphonate-based chemotherapeutic compounds.

We identified and tested bisphosphonates as inhibitors of a protozoan molecular target. Computational modeling studies demonstrated that these compounds are mimics of the natural substrate of the enzyme. The most potent bisphosphonates in vitro are pamidronate and risedronate, which inhibit the purine transferase from Trypanosoma cruzi in the micromolar range.