Relationship between acute physiologic derangement and risk of death

Initial evidence from 481 acutely ill patients with 12 major life-threatening diseases suggests a consistent relationship between the magnitude of physiologic derangement and the patient's risk of death. These results were found in postoperative and nonoperative diseases, including gastrointestinal bleeding, intracranial bleeding, pneumonia, congestive heart failure, trauma and hemorrhagic shock. There appear to be substantial differences in the inherent risk of these diseases, but within each diagnosis, the impact of incremental increases in physiologic derangement on mortality appears to be similar. The existence of a uniform relationship in a variety of diagnoses could have important implications for the researcher and clinician wishing to evaluate outcome from intense medical care. It would allow more reproducible and precise stratification of patients by risk of death prior to therapy, thereby improving our understanding of the efficacy of new and existing treatments.     

Synthesis and antinociceptive activity of 2- and 3-methyl derivatives of 4-(pyridyl) isosteres of meperidine.

The respective cis- and trans-[3-Me,4-(pyridyl)] diastereoisomers of 4-(2-pyridyl)- (8a and 8b), 4-(3-pyridyl)- (8d and 8e) and 4-(4-pyridyl)-1,3-dimethyl-4-ethoxycarbonylpiperidines (8h and 8i) were synthesized for evaluation as 3-methyl substituted isosteres of meperidine. Alkylation of ethyl 2-, 3- or 4-pyridylacetate (7) with N-(2-chloroethyl)-N-(2-chloropropyl)methylamine (6) afforded the respective 3-methyl substituted compounds 8a and 8b, 8d and 8e or 8h and 8i, together with the corresponding 2-methyl substituted compounds 8c (only the trans-isomer was obtained), 8f and 8g, or 8j and 8k. Antinociceptive test results, acquired using the 4% sodium chloride assay in rats, indicated that a cis-3-methyl substituent usually enhanced antinociceptive potency slightly, whereas a trans-3-methyl substituent lowered activity 3-4 fold relative to the parent 3-unsubstituted compounds 3b-d, at a dose of 2 mg/kg sc. A trans-2-methyl substituent (8g and 8k), like a cis-methyl substituent (8a, 8d and 8h), also maintained or provided a small increase in antinociceptive activity. Trans-1,2-Dimethyl-4-ethoxycarbonyl-4-(3-pyridyl)piperidine (8g) and cis-1,3-dimethyl-4-ethoxycarbonyl-4-(4-pyridyl)piperidine (8h) were the most active antinociceptives producing a 66% inhibition of writhing at a dose of 2 mg/kg sc, relative to the reference drug meperidine (ED50 = 0.6 mg/kg sc).     

Initial development of a system-wide maternal-fetal outcomes assessment program

OBJECTIVE: This study was undertaken to develop a comprehensive risk-assessment approach capable of evaluating maternal and fetal outcomes. STUDY DESIGN: Data from 10,984 women and 11,066 infants delivered at 79 military treatment facilities in the United States from 1995 to 1997 were used to develop two individual but complementary risk-adjustment models for maternal and, separately, fetal outcomes. A range of maternal and delivery-related risk variables and clinically important outcomes were identified by expert opinion and selected and weighted with ordinal logistic regression analysis. Receiver operating characteristic curves for the maternal and fetal models were determined. Variation across the facilities in risk-adjusted performance was also evaluated. RESULTS: Risk factors and poor outcomes were rare for both mothers and infants, with 96.9% of infants and 97.7% of mothers having good or excellent outcomes (0.7% mortality and 0.01% mortality, respectively). Despite the low frequency of poor outcomes both models performed well, with receiver operating characteristic curves of 0.75 for maternal outcomes and 0.78 for infant outcomes. When the models were applied to the military treatment facilities, there were significant differences among facilities in risk-adjusted outcomes. Twenty-four of the facilities in the study (30%) had outcomes odds ratios that were significantly >1 or significantly <1 (P <.05). There did not appear to be any relationship between the performance of a military treatment facility for maternal outcome and that for infant outcome. CONCLUSION: Complementary risk models for maternal and infant outcomes were developed that had satisfactory discriminatory power across a variety of facilities within a large health system. With further development and refinement this approach holds promise of being able to detect variations in risk-adjusted performance that could be used to identify best practices. The results might also be used to help coordinate and improve the quality of care for the entire conception-to-delivery process.     

Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2

Here we describe 2 mutations in growth and differentiation factor 5 (GDF5) that alter receptor-binding affinities. They cause brachydactyly type A2 (L441P) and symphalangism (R438L), conditions previously associated with mutations in the GDF5 receptor bone morphogenetic protein receptor type 1b (BMPR1B) and the BMP antagonist NOGGIN, respectively. We expressed the mutant proteins in limb bud micromass culture and treated ATDC5 and C2C12 cells with recombinant GDF5. Our results indicated that the L441P mutant is almost inactive. The R438L mutant, in contrast, showed increased biological activity when compared with WT GDF5. Biosensor interaction analyses revealed loss of binding to BMPR1A and BMPR1B ectodomains for the L441P mutant, whereas the R438L mutant showed normal binding to BMPR1B but increased binding to BMPR1A, the receptor normally activated by BMP2. The binding to NOGGIN was normal for both mutants. Thus, the brachydactyly type A2 phenotype (L441P) is caused by inhibition of the ligand-receptor interaction, whereas the symphalangism phenotype (R438L) is caused by a loss of receptor-binding specificity, resulting in a gain of function by the acquisition of BMP2-like properties. The presented experiments have identified some of the main determinants of GDF5 receptor-binding specificity in vivo and open new prospects for generating antagonists and superagonists of GDF5.     

Novel nonsteroidal antiinflammatory drugs possessing a nitric oxide donor diazen-1-ium-1,2-diolate moiety: design, synthesis, biological evaluation, and nitric oxide release studies

A novel group of hybrid nitric oxide-releasing nonsteroidal antiinflammatory drugs ((*)NO-NSAIDs) possessing a 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (11, 13, 15) or 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (12, 14, 16) moiety attached via a one-carbon methylene spacer to the carboxylic acid group of the traditional NSAIDs aspirin, ibuprofen, and indomethacin were synthesized. Although none of these ester prodrugs (11-16) exhibited in vitro cyclooxygenase (COX) inhibitory activity against the COX-1 and COX-2 isozymes (IC(50) > 100 microM), all of the compounds (11-16) significantly decreased carrageenan-induced rat paw edema. In this regard, the ester prodrugs 11-16 showed equipotent antiinflammatory activities in vivo to that of the parent drugs aspirin, ibuprofen, and indomethacin. All of the compounds released nitric oxide upon incubation with either phosphate buffer solution at pH 7.4 (14-16% range) or porcine liver esterase (16-19% range), but the percentage of (*)NO released was up to sixfold higher (93%) when these ester prodrugs were incubated with guinea pig serum. These incubation studies suggest that both (*)NO and the parent NSAID would be released upon in vivo cleavage by nonspecific serum esterases. The simultaneous release of aspirin and nitric oxide from the (*)NO-aspirin prodrugs constitutes a potentially beneficial property for the prophylactic prevention of thrombus formation and adverse cardiovascular events such as stroke and myocardial infarction. The data acquired in an in vivo ulcer index (UI) assay showed that for this group of ester prodrugs, particularly the (*)NO-aspirins (11, 12) and (*)NO-ibuprofens (13, 14), no lesions were observed (UI = 0) when compared to the parent drugs aspirin (UI = 57, 250 mg/kg po dose), ibuprofen (UI = 45, 250 mg/kg po dose), or indomethacin (UI = 34, 30 mg/kg po dose) at equivalent doses. Accordingly, these hybrid (*)NO-NSAID prodrugs possessing a diazen-1-ium-1,2-diolate moiety, represent a new approach for the rational design of antiinflammatory drugs with reduced gastric ulcerogenicity.     

Severity of illness and the relationship between intensive care and survival.

Currently about 15 per cent of hospital costs are attributed to intensive care. Research using statistical models has not adequately demonstrated that therapy in intensive care units (ICUs) is associated with reductions in the probability of death. In a study of 613 consecutive admissions to a multidisciplinary ICU, we reevaluate the relationship between ICU care and survival using a new acute physiology scoring system to control for the severity of illness of the patient population. When our severity of illness index was employed, we found a statistically significant and nonlinear relationship between the use of intensive medical care and the probability of survival. This statistical relationship produced a U-shaped curve with three distinct segments. The first segment exhibited an overall decrease in the probability of death with increasing therapy (275 admissions); the second segment, a fairly stable survival rate (281 admissions). Only in the third segment, where there were 57 admissions, did we find an overall increase in the probability of death as utilization of therapy increased. These findings suggest that quantitative measurement of severity of illness, when used in clinical studies, could produce improved insights into the relationship between therapy and health outcomes.     

Radiocesium-137 movement in a southern coastal plain ecosystem

The movement of radiocesium (137Cs) in an open ecosystem under natural conditions was investigated at the Louisiana State University Radioecology Field Laboratory. Approximately 80 mCi of 137Cs were transferred to an experimental plot in September 1979. Observations over a six-month period beginning February 1981 indicated that the 137Cs content of plants growing naturally in the plot was low (0.98 Bq/g of plant tissue, dry wt). The vertical mobility of 137Cs to more than 10 cm was also found to be low (up to 1.32 Bq/g of soil, dry wt). The horizontal migration of 137Cs along water drainage directions from the plot was limited to the area of a small ditch that surrounds the experimental plot. No 137Cs above background was found in the fields beyond the 10 m X 10 m plot boundary. The overall results demonstrated that greater than 99.9% of the 137Cs remained within the top 10 cm of the soil profile of the experimental plot under natural field conditions.