Should Level I trauma centers be rated NC-17?

BACKGROUND: Previous studies have reached contradictory conclusions regarding where injured children are best treated. Our hypothesis was that no differences in survival outcome exist among trauma centers caring for pediatric patients. METHODS: For 16,108 injured children, we created a dependant variable, As-Ps (actual survival--predicted survival), which represents variation from TRISS-predicted outcome for each individual. We then used that variable to compare trauma centers' survival results overall and results for liver, spleen, and head injuries, statistically adjusting for age and injury severity. RESULTS: When adjusted for age and injury severity, centers with added qualifications in pediatrics and Level I centers had improved survival performance overall and in the subcategory of head injured children. No differences existed in other organ-specific injury categories. CONCLUSION: The improved unexpected outcome results at Level I centers and centers with Added Qualifications in Pediatrics suggest that a team of qualified professionals working in an institution willing to commit the required resources can sufficiently offer injured children the survival advantage expected of a trauma center.

Potent and specific inhibitors of trypanothione reductase from Trypanosoma cruzi: bis(2-aminodiphenylsulfides) for fluorescent labeling studies.

In order to optimise the activity of bis(2-aminodiphenylsulfides) upon trypanothione reductase (TR) from Trypanosoma cruzi, a new series of bis(2-aminodiphenylsulfides) possessing three side chains was synthesized. Various moieties were introduced at the end of the third side chain, including acridinyl or biotinyl moieties for fluorescent labeling studies. TR inhibition was improved: the most potent inhibitor (IC50 = 200 nM) was selective towards TR versus human glutathione reductase and corresponded to a single myristyl group. Compounds were also tested in vitro upon Trypanosoma cruzi and Leishmania infantum amastigotes, upon-Trapanosoma brucei trypomastigotes, and for their cytotoxicity upon human MRC-5 cells. In the presence of serum, acridine derivative was no longer detectable in mass spectrometry and its antitrypanosomal activity no longer observed. This transformation might explain the absence of correlation between the potent TR inhibition and the in vitro and in vivo antiparasitic activity with both of the first generation of 2-aminodiphenylsulfides.

2- and 3-substituted 1,4-naphthoquinone derivatives as subversive substrates of trypanothione reductase and lipoamide dehydrogenase from Trypanosoma cruzi: synthesis and correlation between redox cycling activities and in vitro cytotoxicity.

Trypanothione reductase (TR) is both a valid and an attractive target for the design of new trypanocidal drugs. Starting from menadione, plumbagin, and juglone, three distinct series of 1,4-naphthoquinones (NQ) were synthesized as potential inhibitors of TR from Trypanosoma cruzi (TcTR). The three parent molecules were functionalized at carbons 2 and/or 3 by various polyamine chains. Optimization of TcTR inhibition and TcTR specificity versus human disulfide reductases was achieved with the 3,3'-[polyaminobis(carbonylalkyl)]bis(1,4-NQ) series 19-20, in which an optimum chain length was determined for inhibition of the trypanothione disulfide reduction. The most active derivatives against trypanosomes in cultures were also studied as subversive substrates of TcTR and lipoamide dehydrogenase (TcLipDH). The activities were measured by following NAD(P)H oxidation as well as coupling the reactions to the reduction of cytochrome c which permits the detection of one-electron transfer. For TcTR, 20(4-c) proved to be a potent subversive substrate and an effective uncompetitive inhibitor versus trypanothione disulfide and NADPH. Molecular modeling studies based on the known X-ray structures of TcTR and hGR were conducted in order to compare the structural features, dimensions, and accessibility of the cavity at the dimer interface of TcTR with that of hGR, as one of the putative NQ binding sites. TcLipDH reduced the plumbagin derivatives by an order of magnitude faster than the corresponding menadione derivatives. Such differences were not observed with the pig heart enzyme. The most efficient and specific subversive substrates of TcTR and TcLipDH exhibited potent antitrypanosomal activity in in vitro T. brucei and T. cruzi cultures. The results obtained here confirm that reduction of NQs by parasitic flavoenzymes is a promising strategy for the development of new trypanocidal drugs.

Trypanothione reductase inhibition/trypanocidal activity relationships in a 1,4-bis(3-aminopropyl)piperazine series.

A series of symmetrically substituted 1,4-bis(3-aminopropyl)piperazines was synthesized and tested towards trypanothione reductase and for its in vitro trypanocidal potency. The most trypanocidal amongst them was found to be totally inactive towards the enzyme and thus constitutes a lead structure for the identification of new potential Trypanosoma cruzi target(s).

Comparison of measures of physiologic stress during treadmill exercise in a patient with 20% lower extremity burn injuries and healthy matched and nonmatched individuals.

Patients with burn injuries are referred for rehabilitation within days after the injuries to encourage early ambulation and functional training. Many of these patients are hypermetabolic at rest. Metabolic demands of activity are added to the already hypermetabolic state and elevate total energy requirements and some physiologic measures. Reports on the physiologic stress imposed by therapeutic activities for patients with burn injuries are limited to low levels of metabolic demand (< or =2 metabolic equivalents [METS]). The degree of stress imposed by functional activities such as ambulation (3 METS) and stair climbing (5 METS) is not known for adults with burn injuries. The purpose of this study was to report the clinical measures of myocardial and physiologic stress in a patient with 20% lower extremity total body surface area burns during an exercise challenge equivalent to stair climbing. Physiologic measures were assessed before and during a treadmill activity (5 METS) for a 40-year-old obese man 3 weeks after he had lower extremity burn injuries. These measures were compared with mean values for 62 healthy counterparts and 6 healthy subjects matched for age, gender, and fitness level. Heart rate, systolic blood pressure, rate pressure product, and the rating of perceived exertion for the patient with burn injuries were higher at baseline and during exercise than the mean values for the 62 healthy individuals and the 6 matched subjects. The steady state exercise values for heart rate, systolic blood pressure, rate pressure product, and rating of perceived exertion at 6 minutes were 189 beats per minute, 190 mm Hg, 3591, and 17, respectively, for the patient with burn injuries and were 111.3 beats per minute, 149 mm Hg, 1680, and 11.7, respectively, for the 6 matched subjects. Ventilation during exercise also increased for the patient with burn injuries more than for the matched subjects (3/4 vs 1/4). Pain experienced by the patient with burn injuries decreased with activity (9.8 vs 7.3 on a 15-cm scale). Treadmill walking produced near maximal responses for most physiologic measures for this patient who was hypermetabolic at rest. We provided normative data to assist therapists who work with patients with similar burn injuries.

Synthesis of polyamine derivatives for the preparation of affinity chromatography columns for the search of new Trypanosoma cruzi targets.

The most potent trypanocidal compound of a series of symmetrically substituted 1,4-bis(3-aminopropylpiperazines) which displayed an IC50 value of 5 microM on Trypanosoma cruzi trypomastigotes, was inactive on trypanothione reductase. Two derivatives 6 and 12 of this compound, one symmetrical and one dissymmetrical, were synthesized via a reductive amination reaction, to prepare affinity chromatography columns, which allowed us to isolate three parasitic proteins. Among these, the major ligand 6- and 12-binding protein having an apparent molecular weight of 52 kDa has been identified as the thiol-disulfide oxido-reductase Tc52, previously characterized in Trypanosoma cruzi.

Synthesis of 5,5'-dithiobis(2-nitrobenzamides) as alternative substrates for trypanothione reductase and thioredoxin reductase: a microtiter colorimetric assay for inhibitor screening.

Trypanothione reductases (TR; EC 1.6.4.8) and thioredoxin reductases (TrxR; EC 1.6.4.5.) are enzymes central to cellular thiol metabolism. Trypanosoma cruzi TR (TcTR) is therefore considered as a potential candidate for drug design against trypanosomiasis. Inhibition of human TrxR (hTrxR) is likely to be beneficial in psoriasis, cancer, and autoimmune diseases, while inhibition of a putative TrxR from Plasmodium falciparum (PfTrxR) might prove effective against malaria. The natural substrates of the first two enzymes are very expensive and difficult to obtain; in the case of PfTrxR, the physiological substrate has not yet been identified. We have therefore synthesized and tested three different 5,5'-dithiobis(2-nitrobenzamides) as alternative substrates of the above enzymes. As with 5, 5'-dithiobis(2-nitrobenzoate) (DTNB), which can be reduced by TRs and TrxRs, the new compounds are converted to their corresponding chromophoric thiolates; however, they have much lower Km values and are therefore less likely to interfere with inhibitor testing. Using the new substrates, a novel enzyme assay has been developed which is identical for all three enzymes, can be performed in a microtiter plate, and is amenable to automation. Thus, the assay provides a versatile and inexpensive tool for kinetic studies and high-throughput inhibitor screening.

An introduction to the biostatistical technique of resampling.

This article will introduce resampling method to burn injury researchers and care givers. With the use of a data set taken from a published burn injury research project, this technique is extensively described and fully illustrated in a stepwise fashion by tables and figures. The recent exponential growth in the use of this method has produced a concurrent need to understand its fundamentals. Researchers, reviewers, and care givers will need to be familiar with resampling to evaluate the published results of various studies. Additionally, as burn research continues to focus on the molecular and cellular aspects of injury and healing, data analysis by resampling might prove to be a useful adjunct to standard biostatistical methods. Many useful links on the Internet (starting at www.statistics.com) can be followed for further readings, software, and tutorials.

A general approach to the synthesis of polyamine linked-monoindolylmaleimides, a new series of trypanothione reductase inhibitors.

A simplified approach to the synthesis of 2-polyamine linked-monoindolylmaleimides has been achieved, leading to a new series of trypanothione reductase inhibitors. The conditions of access to N,2-bis(polyamine)-3-monoindolylmaleimides and N,N'-bis(monoindolylmaleimide) polyamines are described. Measured inhibitory activities towards trypanothione reductase from Tryanosoma cruzi show the importance of both aromatic moieties and polyamine chains for trypanothione reductase recognition.

New spermine and spermidine derivatives as potent inhibitors of Trypanosoma cruzi trypanothione reductase.

Several spermine and spermidine derivatives containing 2-amino diphenylsulfide substituents were prepared and tested for their inhibiting effects on Trypanosoma cruzi trypanothione reductase. IC50 values were assessed between 0.3 and 3 microM. Compound 32 (Ki = 0.4 microM) is the most potent TR inhibitor described so far.

Animal extremists: a cause for concern?

Investigators in various biomedical specialties, as well as hunters, farmers, and fur ranchers, have been victimized by animal rights extremists in the United States, the United Kingdom, and other countries during recent years. Given the extent of animal-based burn research, in which rodents and higher mammals are subjected to burn and smoke trauma, the potential for a liberation attack by an animal rights fringe group must be taken seriously. Suggestions are given to researchers and their institutions to prevent or minimize such an attack.

The publication outcome for the papers presented at the 1990 ABA conference.

This retrospective review of the 1990 ABA orally presented abstracts found an overall publication rate of slightly more than 26%. This included both same-content and related-content publications. When the abstracts were made a subset by theme, a major variance in the publication rates was found. Abstracts that had a psychologic content (72.73%), for example, fared much better than reports of in vitro research (6.9%). This overall rate when compared to publication studies in other clinical areas was found to be quite low. This study further found that there was a great deal of similarity between abstracts that were published and those that were not. The one meaningful predictor of ultimate journal publication was the clarity of the presentation of statistically related information.

Pastoral care in a trauma center.

The pastoral staff of the Mercy Hospital of Pittsburgh, Pennsylvania, is a vital participant in the advanced trauma-care team. The staff of professionally certified chaplains take an active role in ministering to the unique temporal, psychological, and spiritual needs of both patients and patients' families. These professionals serve as hosts, counselors, confidants, and friends to people who have been suddenly thrown into chaos. The pastoral staff at a trauma center also ministers to the emotional and spiritual needs of the various medical and nursing staffs.