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Biomedical subjects

Daniel Smith

Publications and source records attributed to Daniel Smith.

At least 19 recordsLinked to original sources
PubMed2006

Exploration of the diketoacid integrase inhibitor chemotype leading to the discovery of the anilide-ketoacids chemotype.

Integrase is one of three enzymes expressed by HIV and represents a validated target for therapy. A previous study of the diketoacid-based chemotype suggested that there are two aryl-binding domains on integrase. In this study, modifications to the indole-based diketoacid chemotype are explored. It is demonstrated that the indole group can be replaced with secondary but not tertiary (e.g., N-methyl) aniline-based amides without sacrificing in vitro inhibitory activity. The difference in activity between the secondary and tertiary amides is most likely due to the opposite conformational preferences of the amide bonds, s-trans for the secondary-amide and s-cis for the tertiary-amide. However, it was found that the conformational preference of the tertiary amide can be reversed by incorporating the amide nitrogen atom into an indoline heterocycle, resulting in very potent integrase inhibitors.

Amides↗
PubMed2006

Arsine toxicity treated with red blood cell and plasma exchanges.

BACKGROUND: Acute toxicity due to inhalation of arsine gas (AsH(3)) has no known antidote. Exchange transfusion may be beneficial, and dialysis is often required because arsine may cause acute intravascular hemolysis and renal failure. A patient with arsine toxicity has recently been treated by both red blood cell exchange (RBC-E) and plasma exchange (PE) therapy and our experience is reported. CASE REPORT: A 46-year-old man was accidentally and unknowingly exposed to arsine gas while observing an industrial procedure. Within 6 hours he developed fatigue, nausea, vomiting, and tingling in his extremities and voided dark urine. He quickly developed renal failure secondary to acute arsine toxicity (arsenic level, 1250 microg/L). Laboratory findings were a hematocrit level of 24 percent; blood urea nitrogen and creatinine, 84 and 5.5 mg per dL, respectively; bilirubin, 9.1 mg per dL; indirect bilirubin, 6.8 mg per dL; haptoglobin, less than 6 (normal, 30-200); and lactic dehydrogenase, 10,413 units per L (normal, 265-580). An emergent 1-vol RBC-E transfusion by continuous-flow method revealed dramatic black, grossly hemolyzed plasma. After two additional RBC-E and two PE and daily hemodialysis, he completely recovered over the course of 1 month. CONCLUSION: Patients with arsine toxicity resulting in intravascular hemolysis should receive RBC-E as soon as possible. In addition, PE may be beneficial in removing the components of RBC lysis and further reducing arsenic levels.

Acute Kidney Injury↗
PubMed2006

Contribution of ethylamine degrading bacteria to atrazine degradation in soils.

Bacterial communities that cooperatively degrade atrazine commonly consist of diverse species in which the genes for atrazine dechlorination and dealkylation are variously distributed among different species. Normally, the first step in degradation of atrazine involves dechlorination mediated by atzA, followed by stepwise dealkylation to yield either N-ethylammelide or N-isopropylammelide. As the liberated alkylamine moieties are constituents of many organic molecules other than atrazine, it is possible that a large number of alkylamine-degrading bacteria other than those previously described might contribute to this key step in atrazine degradation. To examine this hypothesis, we isolated 82 bacterial strains from soil by plating soil water extracts on agar media with ethylamine as a sole carbon source. Among the relatively large number of isolates, only 3 were able to degrade N-ethylammelide, and in each case were shown to carry the atzB gene and atzC genes. The isolates, identified as Rhizobium leguminosarum, Flavobacterium sp., and Arthrobacter sp., were all readily substituted into an atrazine-degrading consortium to carry out N-ethylammelide degradation. The distribution of these genes among many different species in the soil microbial population suggests that these genes are highly mobile and over time may lead to generation of various atrazine-degrading consortia.

Amidohydrolases↗
PubMed2006

Diagnosis and treatment of peripheral arterial disease compared with other atherosclerotic vascular diseases in a university primary care clinic.

BACKGROUND: Despite the fact that peripheral arterial disease (PAD) significantly increases the risk of cardiovascular mortality, it is significantly underdiagnosed and undertreated. The purpose of this study was to evaluate the practice at a northeast Tennessee university primary care clinic regarding the diagnosis and treatment of PAD. METHODS: A retrospective medical record survey was conducted to evaluate practice patterns in diagnosing and treating PAD in a university primary care clinic. A clinic population of 711 patients was selected using International Classification of Diseases-9 codes for coronary artery disease (CAD), cerebovascular disease (CVD), and/or PAD. A sample of 180 patients (25.3%) was randomly selected using a systematic statistical method. Of these, 125 patients met the diagnostic criteria for CAD, CVD, and/or PAD. The study covered a 3-year period, from July 2001 until June 2004. Demographic and other data, including the use of antiplatelet therapy, were collected. RESULTS: One hundred ten patients met all of the inclusion and exclusion criteria. Thirty-nine percent were males, and 61% were females. Overall, 79% had CAD, 53% had CVD, and 25% had PAD. Almost half of the patients had some combination of these. Only about 2% had PAD only compared with 36% with CAD only and 17% with CVD only. Although the prevalence of CAD and CVD (among other atherosclerotic vascular diseases) in our clinic was comparable to national figures, the prevalence of PAD was significantly lower (p = .004). The overall use of any antiplatelet agent was 84.2% for patients with only CAD and 80% for only CVD. There was not an adequate number of patients with only PAD to evaluate the use of antiplatelet therapy in this group. CONCLUSION: The low prevalence of PAD only (most PAD patients had coexisting CAD and CVD) indicates that PAD is underdiagnosed at our clinic. There was suboptimal use of aspirin and other antiplatelet drugs among patients with atherosclerotic vascular disease.

Adult↗
PubMed2005

Assembly of cytochrome-c oxidase in the absence of assembly protein Surf1p leads to loss of the active site heme.

Surf1p is a protein of the inner membrane of mitochondria that functions in the assembly of cytochrome-c oxidase. The specifics of the role of Surf1p have remained unresolved. Numerous mutations in human Surf1p lead to severe mitochondrial disease. A homolog of human Surf1p is encoded by the genome of the alpha-proteobacterium Rhodobacter sphaeroides, which synthesizes a mitochondrial-like aa(3)-type cytochrome-c oxidase. The gene for Surf1p was deleted from the genome of R. sphaeroides. The resulting aa(3)-type oxidase was purified and analyzed by biochemical methods plus optical and EPR spectroscopy. The oxidase that assembled in the absence of Surf1p was composed of three subpopulations with structurally distinct heme a(3)-Cu active sites. 50% of the oxidase lacked heme a(3), 10-15% contained heme a(3) but lacked Cu(BB), and 35-40% had a normal heme a(3) -Cu(B) active site with normal activity. Cu(A) assembly was unaffected. All of the oxidase contained low-spin heme a, but the environment of the heme a center was slightly altered in the 50% of the enzyme that lacked heme a(3). Introduction of a normal copy of the gene for Surf1p on an exogenous plasmid resulted in a single population of normally assembled, highly active enzyme. The data indicate that Surf1p plays a role in facilitating the insertion of heme a(3) into the active site of cytochrome-c oxidase. The results suggest that maturation of the heme a(3)-Cu(B) center is a step that limits the association of subunits I and II in the assembly of mitochondrial cytochrome oxidase.

Binding Sites↗
PubMed2005

Cooperative catabolic pathways within an atrazine-degrading enrichment culture isolated from soil.

Atrazine degradation previously has been shown to be carried out by individual bacterial species or by relatively simple consortia that have been isolated using enrichment cultures. Here, the degradative pathway for atrazine was examined for a complex 8-membered enrichment culture. The species composition of the culture was determined by PCR-DGGE. The bacterial species included Agrobacterium tumefaciens, Caulobacter crescentus, Pseudomonas putida, Sphingomonas yaniokuyae, Nocardia sp., Rhizobium sp., Flavobacterium oryzihabitans, and Variovorax paradoxus. All of the isolates were screened for the presence of known genes that function for atrazine degradation including atzA,-B,-C,-D,-E,-F and trzD,-N. Dechlorination of atrazine, which was obligatory for complete mineralization, was carried out exclusively by Nocardia sp., which contained the trzN gene. Following dechlorination, the resulting product, hydroxyatrazine was further degraded via two separate pathways. In one pathway Nocardia converted hydroxyatrazine to N-ethylammelide via an unidentified gene product. In the second pathway, hydroxyatrazine generated by Nocardia sp. was hydrolyzed to N-isopropylammelide by Rhizobium sp., which contained the atzB gene. Each member of the enrichment culture contained atzC, which is responsible for ring cleavage, but none of the isolates carried the atzD,-E, or -F genes. Each member further contained either trzD or exhibited urease activity. The enrichment culture was destabilized by loss of Nocardia sp. when grown on ethylamine, ethylammelide, and cyanuric acid, after which the consortium was no longer able to degrade atrazine. The analysis of this enrichment culture highlights the broad level bacterial community interactions that may be involved in atrazine degradation in nature.

Atrazine↗
PubMed2005

ASRP: the Arabidopsis Small RNA Project Database.

Eukaryotes produce functionally diverse classes of small RNAs (20-25 nt). These include microRNAs (miRNAs), which act as regulatory factors during growth and development, and short-interfering RNAs (siRNAs), which function in several epigenetic and post-transcriptional silencing systems. The Arabidopsis Small RNA Project (ASRP) seeks to characterize and functionally analyze the major classes of endogenous small RNAs in plants. The ASRP database provides a repository for sequences of small RNAs cloned from various Arabidopsis genotypes and tissues. Version 3.0 of the database contains 1920 unique sequences, with tools to assist in miRNA and siRNA identification and analysis. The comprehensive database is publicly available through a web interface at http://asrp.cgrb.oregonstate.edu.

Arabidopsis↗
PubMed2005

Regional variations in breast cancer incidence among California women, 1988-1997.

BACKGROUND: Internationally, California has some of the highest breast cancer rates; these rates also show substantial regional variations within the state. This study describes geographic breast cancer incidence patterns within California and evaluates the degree to which socioeconomic status (SES) and urbanization explain the regional variability. METHODS: Invasive breast cancer cases in women > or =20 year of age were identified from the California Cancer Registry, for 1988-1997, then assigned to one of three regions (San Francisco Bay Area, Southern Coastal Area and the rest of California), based on residence at diagnosis. Neighborhood SES and urbanization were derived from U.S. Census data. Rate ratios (RR) and 95% confidence intervals (CI) were computed using Poisson regression. Analyses were conducted for all invasive breast cancer cases (n=176,302) and by selected histologic subtypes: ductal (n=121,619); lobular (n=13,410); mixed ductal and lobular (n=9744). RESULTS: Compared to block groups with the lowest quartile of SES, rates were highest in block groups with high SES. Rates also were higher in suburban and city areas than in small town/rural areas. Compared to the rest of California, age- and race-adjusted rates for all breast cancer were approximately 20% higher in the San Francisco Bay Area and 10% higher in the Southern Coastal Area. After adjusting for SES and urbanization the rate ratios were reduced to near unity (RR=1.06, 95% CI: 1.03-1.09 for San Francisco Bay Area; RR=1.02, 95% CI: 0.99-1.04 for Southern Coastal Area). Rates ratios for ductal carcinomas mirrored those for all cases. For lobular cases, rate ratios remained elevated after adjustment for age, race/ethnicity, neighborhood SES and urbanization (RR=1.18, 95% CI: 1.11-1.27 for San Francisco Bay Area; RR=1.10, 95% CI: 1.04-1.17 for Southern Coastal Area). For the subset of cases with mixed ductal and lobular histologies, the rate ratio for the San Francisco Bay Area was no longer elevated after adjusting for age, race/ethnicity, SES and urbanization (RR=0.92, 95% CI: 0.84-1.01); the adjusted rate ratio for the Southern Coastal Area, however, remained elevated (RR=1.22, 95% CI: 1.12-1.32). CONCLUSIONS: Regional differences in neighborhood SES and urbanization appear to largely explain regional rate differences in California for all breast cancers and ductal carcinomas but do not fully explain geographic patterns of breast cancer with a lobular component.

Adult↗
PubMed2005

Adipose levels of dioxins and risk of breast cancer.

OBJECTIVE: Our objective was to evaluate the breast cancer risk associated with body burden levels of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). METHODS: We conducted a hospital-based case-control study among 79 women diagnosed with invasive breast cancer and 52 controls diagnosed with benign breast conditions. We collected breast adipose tissue and analyzed it for all 17 2,3,7,8-substitituted PCDD/PCDFs. We used unconditional logistic regression to calculate age- and race-adjusted exposure-specific odds ratios (ORs) and 95% confidence intervals (CI) for each individual PCDD/PCDF congener as well as for the summary measures (I-TEQ, Adj-TEQ). RESULTS: Dioxin levels were consistent with reports from other small, contemporary studies of body burdens in the U.S. None of the odds ratios for any of the congeners or summary measures differed significantly from one. Especially for the PCDF congeners, point estimates tended to be below one. One notable exception was octachlorodibenzo-p-dioxin (OCDD), for which the odds ratio for the second and third tertiles appeared modestly elevated (OR = 1.22, 95% CI: 0.47:3.16 and OR = 1.62, 95% CI: 0.64:4.12, respectively), though the test for trend was not significant (p = 0.36). CONCLUSION: Breast cancer risk was not associated with adipose levels of PCDD/PCDFs. More study is suggested among women of color who may have higher body burden levels of these compounds.

Adipose Tissue↗
PubMed2005

Saccade-contingent spatial and temporal errors are absent for saccadic head movements.

Psychophysical studies extending over a thirty-year period have repeatedly demonstrated that visual stimuli presented close to the onset of a saccadic eye movement are mislocalised both spatially and temporally. When post-saccadic visual references are available, this spatial distortion is best characterised by a compression of visual space toward the target of the saccadic eye movement. An important but unresolved issue, concerns the specificity of saccade-dependent visual mislocalisation phenomena. We investigated this by examining whether saccade-dependent spatial and temporal mislocalisation are observed in an individual (A.I.) who cannot make any form of eye movement (opthalamoplegia), but compensates when reading or scanning visual scenes by making saccadic head movements. We demonstrate that saccade-dependent spatial and temporal mislocalisation are absent in subject A.I. and suggest that spatiotemporal mislocalisation may be specific to rapid forms of movement, such as ocular saccades, that necessitate predictive re-mapping to maintain space constancy.

Adult↗
PubMed2005

Trends in the sex ratio of California births, 1960-1996.

STUDY OBJECTIVE: The male sex ratio at birth (or the proportion of male births in a population) has been suggested as a sentinel environmental health indicator. Usually around 51%, the proportion may be dramatically decreased in offspring of persons with chemical exposures. Recent publications from the USA and elsewhere have noted a small but apparently declining male birth proportion, suggesting the effect of some environmental exposures. This paper sought to examine these trends more closely in California's large and diverse population. DESIGN: Using computerised birth certificate data, time trends were examined by multivariate linear and spline regression, controlling for demographic factors. SETTING: California. PARTICIPANTS: About 15 million births from 1960 to 1996. MAIN RESULTS: In the raw data, the male birth proportion is indeed declining. However, during this period, there were also shifts in demographics that influence the sex ratio. Controlling for birth order, parents' age, and race/ethnicity, different trends emerged. White births (which account for over 80%) continued to show a statistically significant decline, while other racial groups showed non-statistically significant declines (Japanese, Native American, other), little or no change (black), or an increase (Chinese). Finally, when the white births were divided into Hispanic and non-Hispanic (possible since 1982), it was found that both white subgroups suggest an increase in male births. CONCLUSION: This analysis shows that the decline in male births in California is largely attributable to changes in demographics.

Adolescent↗
PubMed2004

Patterns of use, dosing, and economic impact of biologic agent use in patients with rheumatoid arthritis: a retrospective cohort study.

BACKGROUND: Variability in dosing and costs of biologics among patients with rheumatoid arthritis (RA) is of interest to healthcare descision-makers. We examined dosing and costs among RA patients newly treated with infliximab or etanercept under conditions of typical clinical practice. METHODS: Integrated pharmacy and medical claims data were obtained from 61 U.S. health plans. RA patients newly treated with infliximab or etanercept between July 1999-June 2002 were selected. A maintenance number of infliximab vials was determined after the "loading period" (2-3 infusions); those with >or= 2 occurrences of an increase in vials or an interval between infusions of <49 days were considered to have had escalated. For etanercept patients, escalation was based on >or= 2 instances of increased average daily dose. Multiple logistic regression analyses were conducted to assess variables associated with dose escalation. RA-related costs at one year post-initiation also were examined; comparisons were made using generalized linear models. RESULTS: A total of 1,548 patients were identified (n = 598 and 950 for infliximab and etanercept respectively). Infliximab recipients were somewhat older (50.5 vs. 46.6 years for etanercept). Nearly 60% of infliximab patients increased their dose at one year, compared to 18% for etanercept. Infliximab patients who escalated dose incurred a 25% increase in mean one-year costs (20,915 dollars vs. 16,713 dollars for no increase; p < 0.0001). Costs among etanercept patients did not substantially differ based on dose escalation (14,482 dollars vs. 13,866 dollars respectively). CONCLUSIONS: Infliximab is associated with higher rates of dose escalation relative to etanercept, which contributes to substantially higher one-year medical costs.

Antibodies, Monoclonal↗
PubMed2004

Tubulin inhibitors. Synthesis and biological activity of HTI-286 analogs with B-segment heterosubstituents.

Modifications of the B-segment of HTI-286 (2) produced a class of analogs incorporating heteroatom-substituents. The structure-activity relationship was studied. Analogs bearing methylsulfide and fluoride groups exhibited potency comparable to that of the parent compound HTI-286 and to paclitaxel in cytotoxicity assays against KB-3-1 cell lines. These analogs were more potent than paclitaxel against P-glycoprotein expressing KB-8-5 and KB-V1 cell lines. Several analogs showed strong inhibition of tubulin polymerization.

Cell Line↗
PubMed2004

Address entry while driving: speech recognition versus a touch-screen keyboard.

A driving simulator experiment was conducted to determine the effects of entering addresses into a navigation system during driving. Participants drove on roads of varying visual demand while entering addresses. Three address entry methods were explored: word-based speech recognition, character-based speech recognition, and typing on a touch-screen keyboard. For each method, vehicle control and task measures, glance timing, and subjective ratings were examined. During driving, word-based speech recognition yielded the shortest total task time (15.3 s), followed by character-based speech recognition (41.0 s) and touch-screen keyboard (86.0 s). The standard deviation of lateral position when performing keyboard entry (0.21 m) was 60% higher than that for all other address entry methods (0.13 m). Degradation of vehicle control associated with address entry using a touch screen suggests that the use of speech recognition is favorable. Speech recognition systems with visual feedback, however, even with excellent accuracy, are not without performance consequences. Applications of this research include the design of in-vehicle navigation systems as well as other systems requiring significant driver input, such as E-mail, the Internet, and text messaging.

Accidents, Traffic↗
PubMed2004

Distribution of persistent, lipid-soluble chemicals in breast and abdominal adipose tissues: lessons learned from a breast cancer study.

OBJECTIVES: We sought to determine differences between concentrations of persistent, lipid-soluble chemical contaminants in breast and abdominal adipose tissues and to explore whether concentrations measured in one tissue could predict concentrations in the other tissue. METHODS: We analyzed surgical specimens and measured concentrations of prevalent dioxins, furans, polychlorinated biphenyls, organochlorine pesticides, and brominated diphenyl ethers to determine their partitioning between breast and abdominal adipose tissues of 21 women. The women constituted a subgroup, undergoing mastectomies with simultaneous breast reconstruction, of a case-control study evaluating links between breast cancer and body burdens of organohalogen contaminants. RESULTS: For every contaminant, differences between concentrations in breast and abdominal adipose tissues did not exceed the analytical error. Results indicated that, with some notable exceptions, measurements in breast and abdominal adipose tissues were correlated and that concentrations of target chemicals in one tissue could be derived from measurements in the other tissue. CONCLUSIONS: This information will allow comparison of results from body burden studies that used different tissues. It may also facilitate future breast cancer studies by allowing selection of controls among patients undergoing surgical procedures other than breast surgery, minimizing concerns about overmatching. We also observed large differences in the lipid content of surgical specimens. These differences underscore the need for lipid adjustment of concentrations to avoid misclassification.

Adipose Tissue↗
PubMed2003

Parental and birth characteristics in relation to testicular cancer risk among males born between 1960 and 1995 in California (United States).

OBJECTIVE: We explored birth and parental risk factors for testicular cancer, examining risk factors for all testicular cancers and by histologic type. METHODS: We linked 1645 testicular cancer cases to live singleton birth certificates, selecting three random controls per case, matched by sex and date of birth. We used conditional multiple logistic regression to assess the mutually adjusted effects of parental and birth characteristics on testicular cancer risk. RESULTS: Sons of Black mothers had a lower risk than those of White mothers (adjusted odds ratio (AOR) = 0.38, 95% confidence interval (CI)=0.12, 1.22). Increasing maternal age was associated with an increased risk in offspring (AOR=1.03 for each year of maternal age, 95% CI=1.01, 1.05). Sons of primiparous and low-multiparous women had increased risks compared to sons of high-multiparous women (AOR=1.22, 95% CI=1.04, 1.44; and AOR=1.31, 95% CI=1.12, 1.54, respectively). Among seminomas, term infants with birth weights of 1500-2499 g had a higher risk compared to term, normal birth weight infants (AOR=2.69, 95% CI=1.40, 5.17; p-value for homogeneity=0.008). CONCLUSIONS: Markers of higher estrogen exposure in the mother (age and parity) are associated with increased testicular cancer risk, and factors associated with fetal growth retardation may be associated with seminoma testicular cancer.

Adolescent↗
PubMed2003

Clostridium perfringens alpha-N-acetylgalactosaminidase blood group A2-degrading activity.

Enzymic modification of type A(2) erythrocyte membranes with Clostridium perfringens alpha-N-acetylgalactosaminidase was investigated. An ELISA demonstrated hydrolysis of type A(2) epitopes under conditions of red-blood-cell collection and storage. The enzyme hydrolysed the terminal N-acetyl-alpha-D-galactosamine from the blood type A(2) antigen, producing H antigen, blood group O, which is universally compatible in the ABO system. The enzyme was active in common red-cell preservative solutions at pH 6.4-7.0, at 4 degrees C, at ionic strengths found in stored red cell units and in the presence of type A plasma. These data imply that the C. perfringens alpha-N-acetylgalactosaminidase might be added directly to packed A(2) red-blood-cell units for enzymic conversion to blood type O. Further studies are warranted.

ABO Blood-Group System↗