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A strategy is described for designing high-affinity ligands using information derived from the NMR-based screening of fragments. The method involves the fragmentation of an existing lead molecule, identification of suitable replacements for the fragments, and incorporation of the newly identified fragments into the original scaffold. Using this technique, novel substituents were rapidly identified and incorporated into lead inhibitors of adenosine kinase that exhibited potent in vitro and in vivo activities. This approach is a valuable strategy for modifying existing leads to improve their potency, bioavailability, or toxicity profile and thus represents a useful technique for lead optimization.
CleanGene is a software program that helps determine the identifiability of sequenced DNA, independent of any explicit demographics or identifiers maintained with the DNA. The program computes the likelihood that the release of DNA database entries could be related to specific individuals that are the subjects of the data. The engine within CleanGene relies on publicly available health care data and on knowledge of particular diseases to help relate identified individuals to DNA entries. Over 20 diseases, ranging over ataxias, blood diseases, and sex-linked mutations are accounted for, with 98-100% of individuals found identifiable. We assume the genetic material is released in a linear sequencing format from an individual's genome. CleanGene and its related experiments are useful tools for any institution seeking to provide anonymous genetic material for research purposes.
A program, DipoCoup, is presented that allows to search the protein data bank for proteins which have a three dimensional fold that is at least partially homologous to a protein under investigation. The three dimensional homology search uses secondary structure alignment based on chemical shifts and dipolar couplings or pseudocontact shifts for the three dimensional orientation of secondary structure elements. Moreover, the program offers additional tools for handling and analyzing dipolar couplings.
A statistical analysis of NMR-derived binding data on 11 protein targets was performed to identify molecular motifs that are preferred for protein binding. The analysis indicates that compounds which contain a biphenyl substructure preferentially bind to a wide range of proteins and that high levels of specificity (>250-fold) can be achieved even for these small molecules. These results suggest that high-throughput screening libraries that are enriched with biphenyl-containing compounds can be expected to have increased chances of yielding high-affinity ligands for proteins, and they suggest that the biphenyl can be utilized as a template for the discovery and design of therapeutics with high affinity and specificity for a broad range of protein targets.
A number of studies have suggested that type of dialysis membrane is associated with differences in long-term outcome of patients undergoing hemodialysis, both in terms of morbidity and mortality. The purpose of this study was to determine the relationship of membrane type and specific causes of death. Data from the United States Renal Data System Case Mix Adequacy Study, a national random sample of hemodialysis patients who were alive on December 31, 1990, were used. Our study was limited to patients in this data set who were undergoing dialysis for at least 1 year (n = 4,055). For the main analytic models, membrane type was classified into two categories: unmodified cellulose or MC/SYN (which combines modified cellulose [MC] and synthetic membranes [SYN]). The relationships of membrane type and major causes of mortality were analyzed using Cox proportional hazards models, which adjusted for multiple (21) covariates, including demographics, comorbidity, Kt/V, and other parameters. Patients were censored at transplantation or 60 days after a switch to peritoneal dialysis. Compared with patients dialyzed with unmodified cellulose membranes, the adjusted relative mortality risk (RR) from infection was 31% lower (RR = 0.69; P = 0.03) and from coronary artery disease was 26% lower (RR = 0.74; P = 0.07) for patients dialyzed with MC/SYN membranes. No statistically significant difference (all P > 0.1) was found in mortality risk from cerebrovascular disease (RR = 1.08), other cardiac causes (RR = 0.86), malignancy (RR = 0.90), or other known causes (RR = 0.82) between patients dialyzed with MC/SYN compared with unmodified cellulose membranes. These results offer support to reported experimental and observational clinical studies that have found that unmodified cellulose membranes may increase the risk for both infection and atherogenesis. Further studies are necessary to evaluate the possibility of confounding factors, compare more specific membrane types, and determine the pathophysiology linking membrane type to cause-specific mortality.
BACKGROUND - To evaluate the role of in utero exposure to metronidazole (a carcinogen in some animal models) and the risk of subsequent cancer, the authors conducted a retrospective cohort study of childhood cancer.
METHODS - The cohort included 328,846 children younger than 5 years born to women enrolled in Tennessee Medicaid at any time between the last menstrual period (LMP) and the date of delivery. The cohort was identified by linking files of Tennessee Medicaid mothers ages 15-44 years and children and the children's birth and death certificates for the period January 1, 1975 through December 31, 1992. Exposure data were obtained from Medicaid pharmacy records and exposure was defined as filling a metronidazole prescription that had at least a day's supply between the 30 days prior to the LMP and the date of delivery. Study cases were cohort children diagnosed with a first primary cancer before age 5 years, identified by linking the cohort with a statewide childhood cancer database for the study period.
RESULTS - Cohort members contributed 1,172,696 person-years of follow-up for analysis, with children exposed (8.1%) and not exposed (91.9%) in utero to metronidazole contributing 79,716 and 1,092,980 person-years, respectively. Of 952 children younger than 5 years in the statewide cancer database, 175 met study eligibility criteria. Of these, 42 had leukemia, 30 had central nervous system (CNS) tumors, 28 had neuroblastoma, and 75 had other cancers. Using Poisson regression modeling, children exposed to metronidazole in utero had no significant increase in adjusted relative risk (RR) for all cancers (RR: 0.81; 95% confidence interval [95% CI], 0.41-1.59), leukemia (no exposed case), CNS tumors (RR: 1.23; 95% CI, 0.29-5.21), neuroblastomas (RR: 2.60; 95% CI, 0.89-7.59), and other cancers (RR: 0.57; 95% CI, 0.18-1.82).
CONCLUSIONS - The authors conclude that although there was no increase in risk for all cancers associated with in utero exposure to metronidazole, the observed increased risk for neuroblastomas, although not significant, requires further evaluation.
BACKGROUND - Hospital databases contain vital demographic patient information, which is increasingly being used as a basis to dictate care. It is hypothesized that the validity of data administratively generated from such sources is suboptimal, especially for rare subspecialties. The authors examined three databases to determine their concordance in an academic orthopaedic oncology subspecialty practice.
METHODS - A 2-year retrospective review was performed on three databases searching for seven fundamental variables: additions/deletions; identification number; birthdate; procedure date; admit/discharge date; procedure code; and diagnostic code. Two university-maintained hospital databases (medical records and physician billing) were compared to the surgeon's personal handwritten daily log, which served as the "gold standard."
RESULTS - All seven variables were in agreement with the physician's log in only 60% of the medical records and 61% of the physician billing patient entries (n = 564). On more detailed statistical analysis using chi(2), cross tabulations, and the K statistic for interobserver agreement, it was determined that poor concordance exists among the databases.
CONCLUSION - Surgeons delivering quartenary care should maintain his or her own database because the hospital's information often differs on one or more important variables. Further investigation into the accuracy of hospital databases regarding commonly practiced medical disciplines appears warranted.
The degree of chemical shift similarity for homologous proteins has been determined from a chemical shift database of over 50 proteins representing a variety of families and folds, and spanning a wide range of sequence homologies. After sequence alignment, the similarity of the secondary chemical shifts of C alpha protons was examined as a function of amino acid sequence identity for 37 pairs of structurally homologous proteins. A correlation between sequence identity and secondary chemical shift rmsd was observed. Important insights are provided by examining the sequence identity of homologous proteins versus percentage of secondary chemical shifts that fall within 0.1 and 0.3 ppm thresholds. These results begin to establish practical guidelines for the extent of chemical shift similarity to expect among structurally homologous proteins.
Administrative policies and programs play an important and growing role as determinants of the use of medical care. Although some policies and programs may be harmful or ineffectual, randomized, controlled trials or prospective evaluations are rarely done for political or logistic reasons. Most evaluations are retrospective and often use administrative databases. Major problems with such evaluations include poor data quality, lack of concurrent controls, inability to ascertain important study outcomes, and incomplete data on case mix. This article uses published evaluations to illustrate these problems and suggests strategies that can minimize their impact. Such strategies include thorough assessment of data quality, interrupted time-series or policy gradient analysis, restriction of studies to those clinical outcomes that reliably result in medical care, and use of data on medical encounters as surrogates for determining case mix. However, even when these strategies are used, adequate evaluation of the effects of many policies and programs may continue to be impossible. Prospective evaluations need to be used more frequently to ensure that changes are held to the same standard used for other therapeutic interventions.
To understand mechanisms of DNA methylation in Helicobacter pylori, a human pathogen associated with peptic ulcer disease and gastric adenocarcinoma, we cloned a putative DNA methyltransferase gene, hpyIM. This gene contains a 990-bp open reading frame encoding a 329-amino-acid protein, M.HpyI. Sequence analysis revealed that M.HpyI was closely related to CATG-recognizing adenine DNA methyltransferases, including M.NlaIII in N. lactamica. hpyIM was present in all H. pylori strains tested. DNA from wild-type H. pylori strains was resistant to digestion by SphI and NlaIII, which recognize DNA at sites containing CATG, whereas their isogenic hpyIM mutants were susceptible, indicating lack of modification. Overexpression of hpyIM in Escherichia coli rendered DNA from these cells resistant to NlaIII digestion, confirming the role of hpyIM in modifying CATG sites. We conclude that hpyIM encodes a DNA methyltransferase, M.HpyI, that is well conserved among diverse H. pylori strains and that modifies H. pylori genomes at CATG sites.