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Biomedical subjects

C J Smith

Publications and source records attributed to C J Smith.

At least 19 recordsLinked to original sources
PubMed1999

Mutant yields and mutational spectra of the heterocyclic amines MeIQ and PhIP at the S1 locus of human-hamster AL cells with activation by chick embryo liver (CELC) co-cultures.

Cooking meat and fish at high temperature creates heterocyclic amines (HA) including 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Several HA are mutagens in the Ames' S9/Salmonella assay. While PhIP is a substantial Ames' test mutagen, it is 1000-fold less active than the extraordinarily potent MeIQ. In contrast, MeIQ is significantly less mutagenic than PhIP in several mammalian cell assays, especially in repair-deficient Chinese hamster ovary (CHO) cells. HA are suspect human carcinogens on the basis of (i) epidemiological evidence, (ii) induction of tumors in rodents and monkeys, (iii) DNA adduct formation and (iv) mutagenic capacity. In this study, MeIQ and PhIP were significant mutagens at the S1 locus of co-cultivated human/hamster hybrid AL cells following metabolic activation by beta-napthoflavone (betaNF)-induced chick embryonic liver cultures (CELC). MeIQ was more mutagenic than PhIP in the CELC+AL cell assay. The mutant response curves increase with dose and then plateau (PhIP), or decrease (MeIQ). The inflections in these response curves coincide with dose-dependent decreases in cytochrome CYP1A1 activity. Molecular analysis of S1- mutants indicates that a substantial fraction, >65%, of the mutations induced by PhIP are deletions of 4.2 to 133 (Mbp); half are larger than 21 Mbp. Mutations induced by MeIQ were smaller, most (56%) being less than 5.7 Mbp. When appropriate metabolic activation is combined with a target locus, which can detect both small and large chromosomal mutations, both MeIQ and PhIP are significant mutagens and clastogens in repair proficient mammalian cells.

Animals↗
PubMed1999

Outcome of primary radiocephalic fistula for haemodialysis.

BACKGROUND: Patient characteristics may help select the most appropriate type of permanent vascular access for haemodialysis. The aim of this study was to assess the influence of patient-related variables on the outcome of radiocephalic fistulas. METHODS: Over 3 years 107 consecutive patients underwent formation of a radiocephalic fistula for permanent haemodialysis access. Patients receiving prosthetic, ulnar, brachial or secondary fistulas were excluded. Patients were followed prospectively until access failure, transplantation or death, or for a minimum of 6 months (median follow-up 24 months). RESULTS: Primary patency was 69 per cent at 12 months and 56 per cent at 24 months. Endovascular and surgical intervention led to limited improvement in secondary patency to 63 per cent at 24 months. Regression analysis showed that fistula failure was more common in women (P = 0.02), diabetics (P = 0.03) and young patients (P = 0.02). By life-table analysis, primary and secondary patency were significantly better (P = 0.01) for men and non-diabetics, while the outcome was similar for all age groups. CONCLUSION: One-third of radiocephalic fistulas fail irreversibly within 2 years. Failure is more likely in women and diabetic patients.

Aged↗
PubMed1999

Identifying families with likely genetic protective factors against Alzheimer disease.

Elderly individuals who lived beyond the age of 90 years without dementia were hypothesized to have increased concentrations of genetic protective factors against Alzheimer disease (AD), conferring a reduced liability for this disease relative to less-aged nondemented elderly. However, testing this hypothesis is complicated by having to distinguish such a group from those who may lack genetic risk factors for AD, have had protective environmental exposures, or have escaped dementia for other reasons. Probands carrying genetic protective factors, however, should have relatives with lower illness rates not only for earlier-onset disease, when genetic risk factors are a strong contributing factor to the incidence of AD, but also for later-onset disease, when the role of these factors appears to be markedly diminished. AD dementia was assessed through family informants in 6,660 first-degree relatives of 1,049 nondemented probands aged 60-102 years. The probands were grouped by age (60-74, 75-89, and 90-102 years), and the cumulative survival from AD and 10-year-age-interval hazard rates of AD were calculated in their first-degree relatives. Cumulative survival from AD was significantly greater in the relatives of the oldest proband group (aged 90-102 years) than it was in the two younger groups. In addition, the reduction in the rate of illness for this group was relatively constant across the entire late life span. The results suggest that genetic factors conferring a lifelong reduced liability of AD may be more highly concentrated among nondemented probands aged >/=90 years and their relatives. Efforts to identify protective allele-bearing genes that are associated with very late-onset AD should target the families of nonagenarians and centenarians.

Aged↗
PubMed1998

Pharmacological analysis of cyclooxygenase-1 in inflammation.

The enzymes cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. These lipid mediators play important roles in inflammation and pain and in normal physiological functions. While there are abundant data indicating that the inducible isoform, COX-2, is important in inflammation and pain, the constitutively expressed isoform, COX-1, has also been suggested to play a role in inflammatory processes. To address the latter question pharmacologically, we used a highly selective COX-1 inhibitor, SC-560 (COX-1 IC50 = 0.009 microM; COX-2 IC50 = 6.3 microM). SC-560 inhibited COX-1-derived platelet thromboxane B2, gastric PGE2, and dermal PGE2 production, indicating that it was orally active, but did not inhibit COX-2-derived PGs in the lipopolysaccharide-induced rat air pouch. Therapeutic or prophylactic administration of SC-560 in the rat carrageenan footpad model did not affect acute inflammation or hyperalgesia at doses that markedly inhibited in vivo COX-1 activity. By contrast, celecoxib, a selective COX-2 inhibitor, was anti-inflammatory and analgesic in this model. Paradoxically, both SC-560 and celecoxib reduced paw PGs to equivalent levels. Increased levels of PGs were found in the cerebrospinal fluid after carrageenan injection and were markedly reduced by celecoxib, but were not affected by SC-560. These results suggest that, in addition to the role of peripherally produced PGs, there is a critical, centrally mediated neurological component to inflammatory pain that is mediated at least in part by COX-2.

Animals↗
PubMed1998

Clathrin coats at 21 A resolution: a cellular assembly designed to recycle multiple membrane receptors.

We present a map at 21 A resolution of clathrin assembled into cages with the endocytic adaptor complex, AP-2. The map was obtained by cryo-electron microscopy and single-particle reconstruction. It reveals details of the packing of entire clathrin molecules as they interact to form a cage with two nested polyhedral layers. The proximal domains of each triskelion leg depart from a cage vertex in a skewed orientation, forming a slightly twisted bundle with three other leg domains. Thus, each triskelion contributes to two connecting edges of the polyhedral cage. The clathrin heavy chains continue inwards under the vertices with local 3-fold symmetry, the terminal domains contributing to 'hook-like' features which form an intermediate network making possible contacts with the surface presented by the inner adaptor shell. A node of density projecting inwards from the vertex may correspond to the C-termini of clathrin heavy chains which form a protrusion on free triskelions at the vertex. The inter-subunit interactions visible in this map provide a structural basis for considering the assembly of clathrin coats on a membrane and show the contacts which will need to be disrupted during disassembly.

Adaptor Protein Complex alpha Subunits↗
PubMed1998

Separation of polycyclic aromatic hydrocarbon metabolites by gamma-cyclodextrin-modified micellar electrokinetic chromatography with laser-induced fluorescence detection.

Using a modified micellar buffer consisting of gamma-cyclodextrin (gamma-CD) and sodium dodecyl sulfate (SDS), we have obtained separations of hydroxy-polycyclic aromatic hydrocarbons (hydroxyPAHs). These compounds are oxidative products of mammalian PAH metabolism. The analytes were detected with a commercial laser-induced fluorescence (LIF) detector. A number of hydroxyPAH isomers could be separated by changes in gamma-CD concentration. Baseline resolution of 12 hydroxyPAHs was obtained using 30 mM borate, 60 mM SDS and 40 mM gamma-CD. The particular site substitution of the hydroxy group can produce changes in the hydroxyPAH fluorescence spectrum, and the effect of optical filter selection was studied for the LIF detection. The mass detection limits were in the (0.08-0.5) x 10(-15) mol range. To our knowledge, this is the first report of the separation of metabolic products of PAHs (and several positional isomers) using gamma-CD and micellar electrokinetic chromatography.

Chromatography, Liquid↗
PubMed1998

Lateral ventricular enlargement in schizophrenic probands and their siblings with schizophrenia-related disorders.

BACKGROUND: To investigate possible genetic determinants of ventricular enlargement in schizophrenia, we compared lateral ventricle/brain ratios (VBRs) in schizophrenic patients with their own siblings, some with and some without other schizophrenia-related disorders [e.g., schizotypal personality disorder (SPD)], as well as with a group of unrelated normal controls. METHODS: VBRs, measured by computed tomography, were compared in both groupwise and within-sibship analyses, the latter method providing a measure of control over familial/genetic factors related to VBR, but unrelated to schizophrenia. RESULTS: The VBRs were significantly different across the groups, but the only significant pairwise group comparison was between the schizophrenia and no-SRD family member groups. In the within-sibship analyses, however, the VBRs of those with SPD and schizophrenia were similar, and both groups had significantly larger VBRs than their own siblings without SRD. In addition, siblings with a negative family history for SRD had larger VBRs than family history positive siblings. CONCLUSIONS: The results suggest that specific schizophrenia-related genetic factors may help determine ventricular enlargement in familial schizophrenia. The larger VBRs in family history negative siblings might be attributable to genetic factors not specifically associated with schizophrenia, but which nevertheless increase its susceptibility.

Adult↗
PubMed1998

Downregulation of right ventricular phosphodiesterase PDE-3A mRNA and protein before the development of canine heart failure.

Phosphodiesterase III (PDE-3) inhibitors are inotropes used to treat congestive heart failure (HF). Previous studies showed PDE-3A mRNA levels were reduced in the left ventricle (LV) in dogs subjected to pacing-induced HF. The present study evaluated a time-course for RV-specific changes in PDE-3A mRNAs and proteins after pacing for 3 wk (n = 4) or in HF (4-5 wk; n = 4-6). Total RNA from LV/RV tissues was isolated for Northern analyses; cytosolic and microsomal proteins were prepared for PDE-3A immunoblots. PDE-3A mRNAs (7-8 and 10 kb) were normalized against glyceraldehyde-3-phosphodehydrogenase (GAPDH) or ribosomal 18s with similar results. PDE-3A/GAPDH ratios in 3 wk were unchanged in LV, but significantly (p < 0.05) reduced by 48% in RV vs unpaced controls (n = 8). In contrast, PDE-3A (7-8 kb)/GAPDH ratios were significantly reduced in HF by 50-59% in both ventricles. Consistent with mRNA levels, significant reductions in microsomal 135 kDa (93-96%) and cytosolic 120 kDa PDE-3A (57-69%) were seen in both ventricles in HF or in the RV at 3 wk; an LV-specific reduction (50%) in cytosolic 80 kDa PDE-3A in HF was also detected. In summary, RV-specific downregulation of PDE-3A mRNA/protein(s) at 3 wk suggests that hemodynamic rather than humoral mechanisms are responsible, and provides a molecular basis for the limited efficacy of milrinone in the progression of HF.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1998

The necessary role of the autopsy in cardiovascular epidemiology.

The autopsy rate in the United States today is remarkably low, with proportionally fewer autopsies for natural causes of death. Consequently, most cardiovascular epidemiology studies do not use autopsy data and rely on death certificates, medical records, questionnaires, and family interviews as sources of mortality information. These practices introduce a high degree of variability and uncertainty regarding cause of death. This review illustrates the necessity for increased use of autopsies in cardiovascular epidemiology by critically evaluating other measures of cardiovascular disease (CVD) incidence. We evaluated the literature regarding CVD as cause of death and conducted discussions with cardiologists, pathologists, and epidemiologists. No attempt was made for meta-analysis. This review shows the limited reliability of death certificates, medical records, and interviews as sources of mortality statistics. In addition, the autopsy's role in clearly indicating the presence of CVD is illustrated. The autopsy used in conjunction with medical records is the only reliable means for establishing cause of death from CVD. There is an urgent need to reassess the current dependence of statistical mortality data on death certificates and other inadequate sources of CVD incidence. Death certificates, in general, are inadequately monitored for quality control and appropriate administrative oversight. With an increase in the number of hospitals performing no autopsies to investigate cause of death, a uniform national autopsy database is needed.

Autopsy↗
PubMed1998

Dietary calcium and blood pressure in a Native American population.

OBJECTIVE: To assess the relationship between dietary calcium and blood pressure. METHODS: Cross-sectional study of 404 adult Pima Indians of Arizona. Dietary variables were assessed by the 24-hour recall. Hypertension (HTN) was defined as systolic blood pressure (SBP) > or = mmHg or diastolic blood pressure (DBP) > or = 90 mmHg or drug treatment. RESULTS: Controlled for age and sex, dietary calcium intake was higher in subjects with HTN than in those without (p < 0.01), and higher dietary calcium was associated with a higher prevalence of HTN (odds ratio comparing highest with lowest tertile group of calcium = 2.6, 95% CI 1.4-4.8). Age-sex-adjusted men DBP in low, middle and high tertiles of calcium was 74, 76, and 79 mmHg, respectively (p < 0.001). SBP was not significantly different in the three tertiles (p = 0.07). Multiple regression analyses that controlled for age, sex, body mass index, sodium, potassium and alcohol also suggested a positive association between DBP and dietary calcium (p < 0.01), an association which was stronger at higher glucose concentrations (p < 0.01 for the calcium-glucose interaction). CONCLUSION: In Pima Indians, a population with a high incidence of diabetes, the inverse association between dietary calcium and blood pressure reported in other populations was not found.

Adolescent↗
PubMed1998

The transfer origin for Bacteroides mobilizable transposon Tn4555 is related to a plasmid family from gram-positive bacteria.

Conjugal transfer of Bacteroides mobilizable transposon Tn4555 was examined with an Escherichia coli-based assay system. It was shown that mobilization required the cis-acting oriT(Tn) region and that the Tn4555 mobA(Tn) gene and RK231 must be present in trans. With alkaline agarose gel electrophoresis and filter blot hybridizations, it was shown that at oriT(Tn) there was a site- and strand-specific cleavage event that was dependent on mobA(Tn). The 5' end of this cleavage site was mapped by primer extension, and the nucleotide sequence surrounding the site had homology to a family of oriT nick sites found in mobilizable plasmids of gram-positive bacteria. Removal of the nick site by deletion of 18 bp surrounding the site resulted in a significant loss of transfer activity.

Bacteroides↗
PubMed1998

Characterization of a peroxide-resistant mutant of the anaerobic Bacterium bacteroides fragilis.

A Bacteroides fragilis mutant resistant to hydrogen peroxide and alkyl peroxide was isolated by enrichment in increasing concentrations of hydrogen peroxide. The mutant strain was constitutively resistant to 100 mM H2O2 and 5 mM cumene hydroperoxide (15-min exposure). In contrast, the parent strain was protected against <10 mM H2O2 when the peroxide response was induced with a sublethal concentration of H2O2, and no protection was observed in untreated cells. In addition, catalase activity in the mutant strain was not repressed in anaerobic cultures as reported previously for the parent strain. Comparison of the protein profile of crude extracts of the B. fragilis strains revealed that at least three oxidative stress-induced proteins in the parent strain were constitutively expressed in the mutant as detected by nondenaturing polyacrylamide gel electrophoresis. N-terminal amino acid sequence of these overexpressed proteins confirmed the presence of a deregulated catalase (KatB), an alkyl hydroperoxidase reductase subunit C (AhpC), and a Dps/PexB homologue. Northern blot analysis and katB::cat transcriptional fusion studies revealed that in the mutant, katB was deregulated compared to the parent and that katB was controlled by a trans-acting regulatory mechanism. Moreover, constitutive expression of KatB and of the AhpC and Dps homologues in the H2O2-resistant mutant suggests that these proteins may share a common oxidative stress transcriptional regulator and may be involved in B. fragilis peroxide resistance.

Amino Acid Sequence↗
PubMed1998

A repeatable method for determination of carboxyhemoglobin levels in smokers.

Fourteen male smokers participated in ten afternoon test sessions to determine the daily variation in expired breath carbon monoxide (CO), and whole blood percent carboxyhemoglobin (%COHb), hemoglobin and hematocrit levels. Each individual's test session was conducted at approximately the same time of day to estimate CO-related measures under relatively stable conditions. Subjects smoked ad libitum prior to testing. The 'usual brand' cigarette was smoked during the first measurement week (sessions 1-5 held on Monday through Friday) and a research cigarette prototype which primarily heats rather than burns tobacco (TOB-HT) was smoked by 12 of the 14 subjects for 3 weeks prior to and during the second measurement week (sessions 6-9 held on Tuesday through Friday). Following the last 'usual brand' measurement session, subjects completed 21 days of ad libitum smoking of the TOB-HT cigarette before starting sessions 6-9 to allow acclimation to the TOB-HT research cigarette. Following session 9, 11 of the 14 subjects continued to smoke the TOB-HT cigarette for an additional 3 weeks and then participated in an additional test session (session 10). The data indicate that daily measurements of afternoon %COHb and expired breath CO values for an individual are reproducible when using this protocol. Carboxyhemoglobin and expired breath CO levels were elevated by 24.4 and 30.6%, respectively, after switching to the TOB-HT cigarette. This increase was not due to an increase in the number of cigarettes consumed since the subjects smoked an average of 21 cigarettes prior to the measurement session when smoking either their 'usual brand' or the TOB-HT cigarette.

Adult↗
PubMed1997

Development of decompensated dilated cardiomyopathy is associated with decreased gene expression and activity of the milrinone-sensitive cAMP phosphodiesterase PDE3A.

BACKGROUND: Phosphodiesterase III (PDE3) inhibitors are inotropic agents used to treat congestive heart failure (CHF) and are less effective in patients with severe CHF. Little is known about relative changes in PDE3 activity or gene expression during the evolution of cardiomyopathy. METHODS AND RESULTS: In the present study, we evaluated temporal changes in PDE3A gene expression before and after pacing-induced CHF in nine mongrel dogs. Three weeks of left ventricular (LV) pacing produced LV end-diastolic pressures of 15+/-1.7 mm Hg, whereas overt CHF at 4 to 5 weeks was associated with LV end-diastolic pressures of 24+/-1.7 mm Hg; prepacing values were 6.6+/-0.6 mm Hg. Total RNA isolated from LV tissues was analyzed on Northern blots; 10 unpaced normal hearts served as tissue controls. Signals for PDE3A mRNAs (7, 8, and 10 kb) or PDE4D (7.6 kb) were normalized against glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or ribosomal 18S RNA. Before the onset of CHF, PDE3A/GAPDH ratios were not different between the control and 3-week paced groups. In contrast, all PDE3A/GAPDH ratios were selectively reduced by 52%, and PDE3A/18S was reduced by 70% (P<.05) in CHF; PDE4D/GAPDH (or 18S) was unchanged. LV tissues from four control and four CHF dogs were also processed to isolate cytosolic and microsomal membrane protein for cAMP PDE3 activity assays. CHF was associated with a significant 54% reduction (P<.05) in microsomal but not cytosolic PDE3 activity. CONCLUSIONS: Selective downregulation of PDE3A may account in part for the ineffectiveness of milrinone in the treatment of severe CHF.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1997

QSAR treatment of multiple toxicities: the mutagenicity and cytotoxicity of quinolines.

A series of 15 quinoline congeners were assayed for mutagenicity and cytotoxicity in the Ames test using strain TA100 bacteria. Statistical analysis of the data allowed simultaneous determination of the mutagenicity and cytotoxicity of each quinoline. These data were used to develop three quantitative structure-activity relationships (QSAR). In all three QSAR, the strength of the relationship between hydrophobicity (as measured by log P) and biological activity was similar as h was near 1 in all three cases. For the mutagenicity of these quinolines, both hydrophobic and steric interactions appear to be important. In contrast, the cytotoxicity is mainly affected by increasing hydrophobicity and by the addition of electron withdrawing substituents to the quinoline ring. Comparison to other QSAR from our laboratory and others lends support to these findings. Both simultaneous consideration of different biological activities and the comparison of newly developed QSAR with previous data for the purpose of lateral validation should be encouraged in future QSAR studies.

Models, Statistical↗
PubMed1997

Validity of the family history method for identifying schizophrenia-related disorders.

We examined the family history method's validity for identifying schizophrenia related disorders (SRD) by comparing family history and family study derived diagnoses. First degree relatives (n = 284) of 48 psychiatrically disordered probands, predominantly with schizophrenia, were diagnosed using the Family History RDC (FH-RDC) which include three psychotic schizophrenia related disorders (P-SRD): schizophrenia, chronic SAD and chronic unspecified functional psychosis (CUFP). Supplementary criteria for schizophrenia related personality disorders (SRP), derived to identify schizotypal and paranoid personality disorders (PD), were also assessed. About two thirds of these relatives (n = 196; 69.0%) were independently diagnosed by RDC and DSM-III-R on both axis I and axis II in a family study. The specificity was 1.0 (178/178) and the sensitivity of the family history derived diagnosis for P-SRD was 0.72 (13/18). Sensitivity for P-SRD was improved, however, by inclusion of SRP which captured three of the five false negative relatives. The sensitivity of SRP for schizotypal or paranoid PD was 0.39 (15/38) and the specificity was 0.92 (127/138). The FH-RDC have moderately good sensitivity and excellent specificity for the psychotic schizophrenia related disorders. While family history criteria for SRP are not a good proxy for schizotypal or paranoid PD, they can enhance the family history method's sensitivity for SRD.

Adult↗