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Aprotinin (Trasylol) is used to control bleeding during coronary-artery bypass grafting (CABG), but in this observational study, there was an increased risk of in-hospital death when this drug was used, as compared with when aminocaproic acid was used. These data concur with those of Shaw et al. in this issue of the Journal and, in conjunction with those from previous studies, call into question the safety of aprotinin use in patients undergoing CABG. Aprotinin (Trasylol) is used to control bleeding during coronary-artery bypass grafting. In this observational study, there was an increased risk of in-hospital death when this drug was used, as compared with when aminocaproic acid was used. The administration of aprotinin (Trasylol, Bayer HealthCare) during cardiac surgery reduces blood loss and preserves platelet function. 1 , 2 A recent international study of over 4000 patients undergoing coronary-artery bypass grafting (CABG) showed a 59% increase in the risk of in-hospital death (relative risk, 1.59; 95% confidence interval [CI], 0.76 to 3.34) in aprotinin recipients as compared with nonrecipients 3 and a higher 5-year mortality among aprotinin recipients (relative risk, 1.48; 95% CI, 1.13 to 1.93). 4 A meta-analysis of trials and a single-center observational study showed less worrisome results, though both lacked the statistical power of the earlier studies. 5 , 6 Most recently, . . .

Hydroxycinnamoyltransferase (HCT) from sorghum (Sorghum bicolor) participates in an early step of the phenylpropanoid pathway, exchanging coenzyme A (CoA) esterified to p-coumaric acid with shikimic or quinic acid as intermediates in the biosynthesis of the monolignols coniferyl alcohol and sinapyl alcohol. In order to elucidate the mode of action of this enzyme, we have determined the crystal structures of SbHCT in its apo-form and ternary complex with shikimate and p-coumaroyl-CoA, which was converted to its product during crystal soaking. The structure revealed the roles of threonine-36, serine-38, tyrosine-40, histidine-162, arginine-371, and threonine-384 in catalysis and specificity. Based on the exact chemistry of p-coumaroyl-CoA and shikimic acid in the active site and an analysis of kinetic and thermodynamic data of the wild type and mutants, we propose a role for histidine-162 and threonine-36 in the catalytic mechanism of HCT. Considering the calorimetric data, substrate binding of SbHCT should occur sequentially, with p-coumaroyl-CoA binding prior to the acyl acceptor molecule. While some HCTs can use both shikimate and quinate as an acyl acceptor, SbHCT displays low activity toward quinate. Comparison of the structure of sorghum HCT with the HCT involved in chlorogenic acid synthesis in coffee (Coffea canephora) revealed many shared features. Taken together, these observations explain how CoA-dependent transferases with similar structural features can participate in different biochemical pathways across species.

It is widely accepted that the use of folic acid by pregnant women reduces their risk of having an infant with a neural-tube defect. Although observational studies had identified reductions in risk with the use of multivitamins that contain folic acid, it was two intervention studies of folic acid alone that documented the specific effect of folic acid. 1 , 2 Periconceptional supplementation with multivitamins containing folic acid may also reduce the risk of congenital malformations other than neural-tube defects, such as cardiovascular defects, 3 – 6 oral clefts, 6 – 9 urinary tract defects, 4 , 6 , 9 – 11 and limb-reduction defects. 3 , 4 , 9 However, it is . . .

In November 2000, alosetron HCl (Lotronex), a treatment for irritable bowel syndrome (IBS), was removed from the U.S. market in part because of the occurrence of colon ischemia in treated patients. Since the relation between colon ischemia and IBS is poorly understood, we evaluated the incidence of colon ischemia among people with and without IBS. Using medical claims data from a large health care organization in the United States, we identified 87,449 people with an IBS diagnosis between January 1995 and December 1999. We calculated age- and sex-specific incidence rates in the general population and in IBS patients. There were 740 cases of colon ischemia during 8.5 million person-years of observation in 5.4 million persons. The crude incidence rate was 42.8 cases per 100,000 person-years for IBS patients. By comparison, the incidence rate was 7.2 per 100,000 person-years in the general population. After adjustment for age, sex, and calendar year, the incidence of colon ischemia in people with IBS was 3.4 times higher than in persons without (95% CI 2.6-4.5). Rates of colon ischemia among patients carrying a diagnosis of IBS are substantially higher than in the general population. Colon ischemia, though unusual in IBS patients, may nonetheless constitute a distinct part of the IBS natural history. Alternatively, it may be a consequence of therapy, or a manifestation of other bowel pathology that is sometimes confused with IBS.

Cinnamoyl-coenzyme A reductase (CCR) catalyzes the reduction of hydroxycinnamoyl-coenzyme A (CoA) esters using NADPH to produce hydroxycinnamyl aldehyde precursors in lignin synthesis. The catalytic mechanism and substrate specificity of cinnamoyl-CoA reductases from sorghum (Sorghum bicolor), a strategic plant for bioenergy production, were deduced from crystal structures, site-directed mutagenesis, and kinetic and thermodynamic analyses. Although SbCCR1 displayed higher affinity for caffeoyl-CoA or p-coumaroyl-CoA than for feruloyl-CoA, the enzyme showed significantly higher activity for the latter substrate. Through molecular docking and comparisons between the crystal structures of the Vitis vinifera dihydroflavonol reductase and SbCCR1, residues threonine-154 and tyrosine-310 were pinpointed as being involved in binding CoA-conjugated phenylpropanoids. Threonine-154 of SbCCR1 and other CCRs likely confers strong substrate specificity for feruloyl-CoA over other cinnamoyl-CoA thioesters, and the T154Y mutation in SbCCR1 led to broader substrate specificity and faster turnover. Through data mining using our structural and biochemical information, four additional putative CCR genes were discovered from sorghum genomic data. One of these, SbCCR2, displayed greater activity toward p-coumaroyl-CoA than did SbCCR1, which could imply a role in the synthesis of defense-related lignin. Taken together, these findings provide knowledge about critical residues and substrate preference among CCRs and provide, to our knowledge, the first three-dimensional structure information for a CCR from a monocot species.

To illustrate that matching on provider may exacerbate, not remove, bias. The degree of confounding bias depends in part on the proportions of treatment variation that can be ascribed to confounders and to instruments, respectively. This commentary raises the specific example of bias by matching on hospital induced in a study of coronary artery bypass graft surgery patients and illustrates the effect of matching on provider in a constructed example. Matching on provider removes a “benign” source of treatment variability, leaving unmeasured confounders as potentially the most important determinants of treatment. Researchers need to articulate the presumed source of pseudorandom variation in observational studies and need to take care not to reduce their effect through unnecessary control.

Caffeoyl-coenzyme A 3-O-methyltransferase (CCoAOMT) is an S-adenosyl methionine (SAM)-dependent O-methyltransferase responsible for methylation of the meta-hydroxyl group of caffeoyl-coenzyme A (CoA) on the pathway to monolignols, with their ring methoxylation status characteristic of guaiacyl or syringyl units in lignin. In order to better understand the unique class of type 2 O-methyltransferases from monocots, we have characterized CCoAOMT from sorghum (Sorghum bicolor; SbCCoAOMT), including the SAM binary complex crystal structure and steady-state enzyme kinetics. Key amino acid residues were validated with site-directed mutagenesis. Isothermal titration calorimetry data indicated a sequential binding mechanism for SbCCoAOMT, wherein SAM binds prior to caffeoyl-CoA, and the enzyme showed allosteric behavior with respect to it. 5-Hydroxyferuloyl-CoA was not a substrate for SbCCoAOMT. We propose a catalytic mechanism in which lysine-180 acts as a catalytic base and deprotonates the reactive hydroxyl group of caffeoyl-CoA. This deprotonation is facilitated by the coordination of the reactive hydroxyl group by Ca²⁺ in the active site, lowering the pKₐ of the 3ʹ-OH group. Collectively, these data give a new perspective on the catalytic mechanism of CCoAOMTs and provide a basis for the functional diversity exhibited by type 2 plant OMTs that contain a unique insertion loop (residues 208–231) conferring affinity for phenylpropanoid-CoA thioesters. The structural model of SbCCoAOMT can serve as the basis for protein engineering approaches to enhance the nutritional, agronomic, and industrially relevant properties of sorghum.

Cinnamyl alcohol dehydrogenase (CAD) catalyzes the final step in monolignol biosynthesis, reducing sinapaldehyde, coniferaldehyde, and p-coumaraldehyde to their corresponding alcohols in an NADPH-dependent manner. Because of its terminal location in monolignol biosynthesis, the variation in substrate specificity and activity of CAD can result in significant changes in overall composition and amount of lignin. Our in-depth characterization of two major CAD isoforms, SbCAD2 (Brown midrib 6 [bmr6]) and SbCAD4, in lignifying tissues of sorghum (Sorghum bicolor), a strategic plant for generating renewable chemicals and fuels, indicates their similarity in both structure and activity to Arabidopsis (Arabidopsis thaliana) CAD5 and Populus tremuloides sinapyl alcohol dehydrogenase, respectively. This first crystal structure of a monocot CAD combined with enzyme kinetic data and a catalytic model supported by site-directed mutagenesis allows full comparison with dicot CADs and elucidates the potential signature sequence for their substrate specificity and activity. The L119W/G301F-SbCAD4 double mutant displayed its substrate preference in the order coniferaldehyde > p-coumaraldehyde > sinapaldehyde, with higher catalytic efficiency than that of both wild-type SbCAD4 and SbCAD2. As SbCAD4 is the only major CAD isoform in bmr6 mutants, replacing SbCAD4 with L119W/G301F-SbCAD4 in bmr6 plants could produce a phenotype that is more amenable to biomass processing.

Background: In observational research, propensity score techniques can be used to account for baseline differences between compared therapies. Although propensity scores are used increasingly often, their limitations in settings without complete data may not be recognized. Objectives: We sought to evaluate the ability of propensity score matching to mitigate confounding by indication in an observational study of the effect of statin therapy on acute myocardial infarction (AMI). Matching was performed at random, and with propensity scores that incorporated a reduced or expanded set of variables. Research Design/Subjects: This was a propensity score matched cohort study using members of a health insurer database. Measures: Exposure to statin therapy was assessed at the beginning of follow-up with all cohort members being statin initiators or noninitiators, and the outcome of AMI was identified on the basis of claims codes. Results: Matching on the basis of the propensity score provided results that are similar in magnitude to randomized clinical trials, suggesting that confounding was mitigated. However, matching on a propensity score created on a reduced set of variables yielded a result that suggested no effect of statin therapy, and demonstrated substantial imbalance on some variables that were not part of the propensity score. Conclusions: Propensity score matching can balance with respect to variables not explicitly included in the score, but external data are required to evaluate this.

According to the World Health Organization, more than 2 billion people in the world have serologic markers of hepatitis B infection, including 350 million chronic carriers of the virus, 1 of whom about 65 million will die from liver disease caused by the infection. 1 A vaccine against hepatitis B became available in 1982, and more than 1 billion doses have been administered, with documented reductions in the rate of childhood liver cancer. 1 This vaccine, considered one of the least reactogenic, has an excellent safety profile 2 – 4 and is part of routine immunization programs in many countries. Nevertheless, several cases of multiple . . .