Protonation state of F420H2 in the prodrug-activating deazaflavin dependent nitroreductase (Ddn) from Mycobacterium tuberculosis.

The protonation state of the deazaflavin dependent nitroreductase (Ddn) enzyme bound cofactor F420 was investigated using UV-visible spectroscopy and computational simulations. The reduced cofactor F420H2 was determined to be present in its deprotonated state in the holoenzyme form. The mechanistic implications of these findings are discussed.

Entropy-Driven Selectivity for Chain Scission: Where Macromolecules Cleave.

We show that, all other conditions being equal, bond cleavage in the middle of molecules is entropically much more favored than bond cleavage at the end. Multiple experimental and theoretical approaches have been used to study the selectivity for bond cleavage or dissociation in the middle versus the end of both covalent and supramolecular adducts and the extensive implications for other fields of chemistry including, e.g., chain transfer, polymer degradation, and control agent addition are discussed. The observed effects, which are a consequence of the underlying entropic factors, were predicted on the basis of simple theoretical models and demonstrated via high-temperature (HT) NMR spectroscopy of self-assembled supramolecular diblock systems as well as temperature-dependent size-exclusion chromatography (TD SEC) of covalently bonded Diels-Alder step-growth polymers.

Using risk for advanced proximal colonic neoplasia to tailor endoscopic screening for colorectal cancer.

BACKGROUND: Colonoscopic screening for colorectal cancer has been suggested because sigmoidoscopy misses nearly half of persons with advanced proximal neoplasia. OBJECTIVE: To create a clinical index to stratify risk for advanced proximal neoplasia and to identify a subgroup with very low risk in which screening sigmoidoscopy alone might suffice. DESIGN: Cross-sectional study. SETTING: A company-based program of screening colonoscopy for colorectal cancer. PATIENTS: Consecutive persons 50 years of age or older undergoing first-time screening colonoscopy between September 1995 and June 2001. MEASUREMENTS: A clinical index with 3 variables was created from information on the first 1994 persons. Points were assigned to categories of age, sex, and distal findings. Risk for advanced proximal neoplasia (defined as an adenoma 1 cm or larger or one with villous histology, severe dysplasia, or cancer) was measured for each score. The index was tested on the next 1031 persons from the same screening program. RESULTS: Of 1994 persons, 67 (3.4%) had advanced proximal neoplasia. A low-risk subgroup comprising 37% of the cohort had scores of 0 or 1 and a risk of 0.68% (95% CI, 0.22% to 1.57%). Among the validation group of 1031 persons, risk for advanced proximal neoplasia in the low-risk subgroup (comprising 47% of the cohort) was 0.4% (upper confidence limit of 1.49%). Application of this index detected 92% of persons with advanced proximal neoplasms and, if applied following screening sigmoidoscopy, could reduce the need for colonoscopy by 40%. The marginal benefit of colonoscopy among low-risk persons was small: To detect 7 additional persons with advanced proximal neoplasia, 1217 additional colonoscopies would be required. CONCLUSIONS: This clinical index stratifies the risk for advanced proximal neoplasia and identifies a subgroup at very low risk. If it is validated in other cohorts or groups, the index could be used to tailor endoscopic screening for colorectal cancer.

The covariance between relatives conditional on genetic markers.

The development of molecular genotyping techniques makes it possible to analyze quantitative traits on the basis of individual loci. With marker information, the classical theory of estimating the genetic covariance between relatives can be reformulated to improve the accuracy of estimation. In this study, an algorithm was derived for computing the conditional covariance between relatives given genetic markers. Procedures for calculating the conditional relationship coefficients for additive, dominance, additive by additive, additive by dominance, dominance by additive and dominance by dominance effects were developed. The relationship coefficients were computed based on conditional QTL allelic transmission probabilities, which were inferred from the marker allelic transmission probabilities. An example data set with pedigree and linked markers was used to demonstrate the methods developed. Although this study dealt with two QTLs coupled with linked markers, the same principle can be readily extended to the situation of multiple QTL. The treatment of missing marker information and unknown linkage phase between markers for calculating the covariance between relatives was discussed.

Results of screening colonoscopy among persons 40 to 49 years of age.

BACKGROUND: The prevalence of colorectal lesions in persons 40 to 49 years of age, as identified on colonoscopy, has not been determined. METHODS: We reviewed the procedure and pathology reports for 906 consecutive persons 40 to 49 years of age who voluntarily participated in an employer-based screening-colonoscopy program. The histologic features of lesions that were identified and removed on endoscopy were categorized according to those of the most advanced lesion removed proximally (up to the junction of the splenic flexure and the descending colon) and the most advanced lesion removed distally. An advanced lesion was defined as an adenoma at least 1 cm in diameter, a polyp with villous histologic features or severe dysplasia, or a cancer. RESULTS: Among those who underwent colonoscopic screening, 78.9 percent had no detected lesions, 10.0 percent had hyperplastic polyps, 8.7 percent had tubular adenomas, and 3.5 percent had advanced neoplasms, none of which were cancerous (95 percent confidence interval for cancer, 0 to 0.4 percent). Eighteen of 33 advanced neoplasms (55 percent) were located distally and were potentially within reach of a sigmoidoscope. If these results are applicable to the general population, at least 250 persons, and perhaps 1000 or more, would need to be screened to detect one cancer in this age group. CONCLUSIONS: Colonoscopic detection of colorectal cancer is uncommon in asymptomatic persons 40 to 49 years of age. The noncancerous lesions are equally distributed proximally and distally. The low yield of screening colonoscopy in this age group is consistent with current recommendations about the age at which to begin screening in persons at average risk.