Biomedical subjects

M W Smith

Publications and source records attributed to M W Smith.

At least 19 recordsLinked to original sources

PubMed2006

Three single-nucleotide polymorphisms in LPA account for most of the increase in lipoprotein(a) level elevation in African Americans compared with European Americans.

BACKGROUND: The extent which universally common or population-specific alleles can explain between-population variations in phenotypes is unknown. The heritable coronary heart disease risk factor lipoprotein(a) (Lp(a)) level provides a useful case study of between-population variation, as the aetiology of twofold higher Lp(a) levels in African populations compared with non-African populations is unknown. OBJECTIVE: To evaluate the association between LPA sequence variations and Lp(a) in European Americans and African Americans and to determine the extent to which LPA sequence variations can account for between-population variations in Lp(a). METHODS: Serum Lp(a) and isoform measurements were examined in 534 European Americans and 249 African Americans from the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease Study. In addition, 12 LPA variants were genotyped, including 8 previously reported LPA variants with a frequency of >2% in European Americans or African Americans, and four new variants. RESULTS: Isoform-adjusted Lp(a) level was 2.23-fold higher among African Americans. Three single-nucleotide polymorphisms (SNPs) were independently associated with Lp(a) level (p<0.02 in both populations). The Lp(a)-increasing SNP (G-21A, which increases promoter activity) was more common in African Americans, whereas the Lp(a)-lowering SNPs (T3888P and G+1/inKIV-8A, which inhibit Lp(a) assembly) were more common in European Americans, but all had a frequency of <20% in one or both populations. Together, they reduced the isoform-adjusted African American Lp(a) increase from 2.23 to 1.37-fold(a 60% reduction) and the between-population Lp(a) variance from 5.5% to 0.5%. CONCLUSIONS: Multiple low-prevalence alleles in LPA can account for the large between-population difference in serum Lp(a) levels between European Americans and African Americans.

Adolescent↗

PubMed2006

A nucleic acid sequence-based amplification assay for real-time detection of norovirus genogroup II.

AIMS: To use molecular beacon based nucleic acid sequence-based amplification (NASBA) to develop a rapid, sensitive, specific detection method for norovirus (NV) genogroupII (GII). METHODS AND RESULTS: A method to detect NV GII from environmental samples using real-time NASBA was developed. This method was routinely sensitive to 100 copies of target RNA and intermittent amplification occurred with as few as 10 copies. Quantitative estimates of viral load were possible over at least four orders of magnitude. CONCLUSIONS: The NASBA method described here is a reliable and sensitive assay for the detection of NV. This method has the potential to be linked to a handheld NASBA device that would make this real-time assay a portable and inexpensive alternative to bench-top, lab-based assays. SIGNIFICANCE AND IMPACT OF THE STUDY: The development of the real-time NASBA assay described here has resulted in a simple, rapid (<1 h), convenient testing format for NV. To our knowledge, this is the first example of a molecular beacon based NASBA assay for NV.

Base Sequence↗

PubMed2005

Comprehensive analysis of CDKN2A (p16INK4A/p14ARF) and CDKN2B genes in 53 melanoma index cases considered to be at heightened risk of melanoma.

OBJECTIVE: Comprehensive analysis of the 9p21 locus including the CDKN2A, ARF, and CDKN2B genes in 53 individuals from melanoma index cases considered to be at heightened risk of melanoma. METHODS AND RESULTS: Using a combination of DNA sequencing, gene copy number by real time quantitative PCR, linkage analysis, and transcript analysis in haploid somatic cell hybrids, we found no evidence for germline alteration in either coding or non-coding domains of CDKN2A and CDKN2B. However, we identified a p14ARF exon 1beta missense germline mutation (G16D) in a melanoma-neural system tumour syndrome (CMM+NST) family and a 8474 bp germline deletion from 196 bp upstream of p14ARF exon 1beta initiation codon to 11233 bp upstream of exon 1alpha of p16(INK4A) in a family with five melanoma cases. For three out of 10 families with at least three melanoma cases, the disease gene was unlinked to the 9p21 region, while linkage analysis was not fully conclusive for seven families. CONCLUSIONS: These data reinforce the hypothesis that ARF is a melanoma susceptibility gene and suggest that germline deletions specifically affecting p14ARF may not be solely responsible for NST susceptibility. Predisposition to CMM+NST could either be due to complete disruption of the CDKN2A locus or be the result of more complex genetic inheritance. In addition, the absence of any genetic alteration in 50 melanoma prone families or patients suggests the presence of additional tumour suppressor genes possibly in the 9p21 region, and on other chromosomes.

Cell Line, Tumor↗

PubMed2005

Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance.

Hepatitis C virus (HCV) is an infectious blood-borne pathogen that usually persists as a chronic infection. However, approximately 15% of the time, patients can clear the virus, indicating that host differences could be critical in determining the course of HCV infection. The inflammatory response is crucial to resolving or failing to resolve an acute HCV infection. Some previous reports have implicated interleukin 10 (IL10) polymorphisms with successful anti-HCV therapy and natural viral clearance. We tested 54 single nucleotide polymorphisms (SNPs) in the IL10 region (+/-300 kb and 24 within the IL10 gene itself), which contains 13 genes including the IL10 immunomodulatory paralogs IL19, IL20, and IL24, for association with HCV clearance vs persistence. SNPs from two haplotype block regions, one at IL10 and the other from IL19/IL20, were associated with HCV clearance in African Americans (91 clearance cases and 183 chronically infected matched controls; P=0.05-0.002) while with expectation-maximization algorithm-reconstructed haplotypes, these associations remained (P=0.05-0.002). However, no significant associations were detected in European Americans (108 clearance and 245 chronic). Our results indicate that variants of the immunomodulatory IL10 and IL19/IL20 genes may be involved in natural clearance of HCV in the African-American population.

Black or African American↗

PubMed2004

Fraction of cases of acquired immunodeficiency syndrome prevented by the interactions of identified restriction gene variants.

Previous research has demonstrated isolated effects of host genetic factors on the progression of human immunodeficiency virus type 1 (HIV-1) infection. In this paper, the authors present a novel use of multivariable methods for estimating the prevented fraction of acquired immunodeficiency syndrome (AIDS) cases attributable to six restriction genes after accounting for their epidemiologic interactions. The methods presented will never yield a prevented fraction above 1. The study population consisted of a well-characterized cohort of 525 US men with HIV-1 seroconversion documented during follow-up (1984-1996). On the basis of a regression tree approach using a Cox proportional hazards model for times to clinical AIDS, the combinations of genes associated with the greatest protection, relative to the lack of a protective genotype, consisted of: 1) C-C chemokine receptor 5 (CCR5)-Delta 32 and C-C chemokine receptor 2 (CCR2)-64I (relative hazard = 0.44); 2) interleukin 10 (IL10)-+/+ in combination with CCR5-Delta 32 or CCR2-64I (relative hazard = 0.45); and 3) IL10-+/+ in combination with stromal-derived factor (SDF1)-3 'A and CCR5 promoter P1/approximately P1 (relative hazard = 0.37). Overall, 30% of potential AIDS cases were prevented by the observed combinations of restriction genes (95% confidence interval: 7, 47). However, the combined effect was confined to the first 4 years following HIV-1 seroconversion. Additional research is needed to identify AIDS restriction genes with stronger and long-lasting protection to better characterize the genetic epidemiology of HIV-1.

Acquired Immunodeficiency Syndrome↗

PubMed2004

Evaluating association and transmission of eight inflammatory genes with Viliuisk encephalomyelitis susceptibility.

Since the discovery of Viliuisk encephalomyelitis (VE) in 1887, scientists have tried to understand the natural history and aetiology of this endemic neurological disorder among the native Sakha population of Central Siberia. Familial aggregation and segregation analysis suggested a genetic influence on VE incidence. However, recent studies have implicated an unknown virus, possibly from the alpha herpesvirus family, as a possible cause for this disease. As VE is a neurological disease characterized by the inflammatory reactions systematically observed in the spinocerebellar fluid and in the brain tissue of deceased patients, we examined 17 single nucleotide polymorphisms (SNPs) across seven inflammation-related candidate gene regions, including chemokine receptors type 2 and 5 (CCR2/CCR5), interferon-gamma (IFN-gamma), interleukin-4 (IL-4), IL-6, IL-10, stromal cell-derived factor (SDF) and chemokine regulated upon activation, normal T-cell expressed and presumably secreted (RANTES). Our main objective was to analyse the degree of genetic association between VE and candidate genes that have been previously implicated in other inflammatory diseases. Samples were collected from 83 affected families comprising 88 verified VE cases, 156 family members, and an additional 69 unrelated, unaffected inhabitants of the same geographical area. This collection included substantially all of the cases that are currently on the VE Registry. The experimental design included both case-control and transmission/disequilibrium test (TDT)-based familial association analyses. None of 17 SNPs analysed was significantly associated with VE occurrence. Exclusion of these eight genes based on the lack of association has important implications for identifying the disease agent, as well as prescribing therapy and understanding Viliuisk encephalomyelitis.

Case-Control Studies↗

PubMed2004

Prospective risk of cancer in CDKN2A germline mutation carriers.

BACKGROUND: The CDKN2A gene is the major known high-risk melanoma susceptibility gene. Susceptibility to other cancers has also been suggested. However, most studies examining the risks of other cancers classified individuals according to the family's CDKN2A mutation rather than determining individual mutation status. For non-population-based studies, risks could also be biased because of cancer occurrence prior to family ascertainment. METHODS: We examined the risk of non-melanoma cancer in 117 mutation-positive and 136 mutation-negative members from 15 families that had at least two first degree relatives with melanoma and CDKN2A mutations restricting the analysis to the period after the families were ascertained (that is, the prospective period) and using individual mutation data. The families have been followed prospectively for 4-26 years starting in the 1970s. RESULTS: Overall, there was no significant association for mutation-negative subjects (Obs/Exp = 0.3, 95% confidence interval (CI) 0.0 to 1.2) although this group had only two observed cancers. In contrast, mutation-positive subjects had a significantly increased risk for all cancers combined (Obs/Exp = 12/5.5 = 2.2, 95% CI 1.1 to 3.8) primarily because of digestive system tumours, particularly pancreatic cancer. No other organ systems or individual tumour sites showed significantly increased risks. CONCLUSIONS: Differences in CDKN2A-non-melanoma cancer associations across studies may result from variation in genetic backgrounds, insufficient follow up, misclassification of mutation carriers, or the presence of other genetic and/or environmental risk factors in both CDKN2A mutation carriers and non-carriers. Larger sample sizes, prospective follow up, and individual mutation data will be required to understand these differences.

Cyclin-Dependent Kinase Inhibitor p16↗

PubMed2002

Range of motion after arthroplasty for the stiff osteoarthritic knee.

In 28 of 1656 total knee arthroplasties (TKAs) (1.7%) performed for osteoarthritis at this institution, the preoperative arc of motion was 60 degrees or less (average 47.5 degrees; range, 20-60 degrees). The outcome of 22 of the 28 TKAs (21 patients) is reported at a mean follow-up of 52.9 months (range, 24-144 months). Eighty-two percent of the cases were managed with standard soft-tissue releases and posterior cruciate-retaining implants and 18% with a cruciate-substituting design. The joint score rose from 28.8 to 82.2 and the Knee Society Score from 24.6 to 77 points. The mean postoperative arc of motion improved by 46 degrees-93.5 degrees. At latest follow-up, 68.2% of knees achieved maximal flexion of 90 degrees or more. Manipulation was performed in 22.7%. Complications were minimal. A functionally useful range of motion is possible after total knee arthroplasty in the majority of stiff osteoarthritic knees, often without the need for posterior cruciate substitution.

Arthroplasty, Replacement, Knee↗

PubMed2001

Dopamine D(3) receptor antagonists. 1. Synthesis and structure-activity relationships of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans.

5,6-Dimethoxy-2-(N-dipropyl)-aminoindan (3, PNU-99194A) was found to be a selective dopamine D(3) receptor antagonist with potential antipsychotic properties in animal models. To investigate the effects of nitrogen substitution on structure-activity relationships, a series of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans were synthesized and evaluated in vitro for binding affinity and metabolic stability. The results indicate that substitution at the amine nitrogen of the 2-aminoindans is fairly limited to the di-N-propyl group in order to achieve selective D(3) antagonists. Thus, combinations of various alkyl groups were generally inactive at the D(3) receptor. Although substitution with an N-alkylaryl or N-alkylheteroaryl group yields compounds with potent D(3) binding affinity, the D(2) affinity is also enhanced, resulting in a less than 4-fold preference for the D(3) receptor site, and no improvements in metabolic stability were noted. A large-scale synthesis of the D(3) antagonist 3 has been developed that has proven to be reproducible with few purification steps. The improvements include the use of 3,4-dimethoxybenzaldehyde as a low-cost starting material to provide the desired 5,6-dimethoxy-1-indanone 5c in good overall yield (65%) and the formation of a soluble silyl oxime 17 that was reduced efficiently with BH(3).Me(2)S. The resulting amino alcohol was alkylated and then deoxygenated using a Lewis acid and Et(3)SiH to give the desired product 3 in good overall yield of ( approximately 65%) from the indanone 5c.

Animals↗

PubMed2001

Psychosocial predictors of hypertension in men and women.

BACKGROUND: Psychosocial stressors have been shown to predict hypertension in several cohort studies; patterns of importance, sex differences, and interactions with standard risk factors have not been fully characterized. METHODS: Among 2357 adults in a population sample of Alameda County, California, free of hypertension in 1974, 637 reported in 1994 having ever used antihypertensive medication (27.9% of the men and 26.3% of the women). The effects of baseline psychosocial, behavioral, and sociodemographic factors on the incidence of treated hypertension were examined using multiple logistic regression. RESULTS: Low education, African American race, low occupational prestige, worry about job stability, feeling less than very good at one's job, social alienation, and depressive symptoms each had significant (P<.05) age-adjusted associations with incident hypertension. Associations were weakened by adjustment for body mass index, alcohol consumption, smoking status, and leisure time physical activity, especially the associations of anomy and depression, which persisted in women but not in men. In multivariate models, job insecurity (odds ratio, 1.6), unemployment (odds ratio, 2.7), and low self-reported job performance (odds ratio, 2.1) remained independent predictors of hypertension in men, whereas low-status work (odds ratio, 1.3) was an independent predictor of hypertension in women. CONCLUSIONS: In the general population, low occupational status and performance and the threat or reality of unemployment increase the likelihood of developing hypertension, especially among men, independent of demographic and behavioral risk factors. Psychological distress and social alienation may also increase hypertension incidence, especially in women, chiefly through an association with health risk behaviors.

Adult↗

PubMed2001

Body mass index as a predictor of outcome in total knee replacement.

The clinical and radiographic outcomes of 326 total knee replacements (TKR) in 285 osteoarthritic patients with body mass index (BMI) greater than 30 kg/m2 were compared with the results of a matched group of 425 TKR in 371 patients with BMI less than 30 kg/m2. At an average follow-up of 75.9 (48-144) months the Knee Society score (KSS) in the obese patients had increased by 41.9 points, and the joint score by 43.7. In the non-obese group the KSS rose by 40.2 points and the joint score by 42.6 points. Although patients with BMI greater than 40 kg/m2 achieved a lower final KSS the 'absolute improvement' appeared to be independent of BMI. Of the obese patient group 4.9% underwent a revision of their TKR, compared with 3.1% of the non-obese group. Although linear osteolysis (radiolucency) rates were comparable, focal osteolysis rates were 5 times those of control subjects when the BMI exceeded 40 kg/m2. Ten-year survivorship figures were similar for both obese and non-obese patients.

Adult↗

PubMed2001

Cementless cup fixation in total hip arthroplasty after 5-8 years.

A series of 199 total hip arthroplasties was performed using a porous-coated, hemispherical press-fit acetabular cup. At a mean follow-up of 91.5 months 158 cups were available for clinical and radiological review. The mean age of the patients at the time of the index arthroplasty was 62.5 years. The mean Harris Hip score at final follow-up was 87.3. No shells were revised although eccentric polyethylene wear prompted liner replacement in two cases. Osteolysis was noted in six cases but predominantly in relation to the femoral stem. Focal pelvic osteolytic lesions were rare. All the cups were classified as stable on radiography.

Adult↗

PubMed2001

Culture and psychopharmacology.

In this brief review the authors strive to provide a broad overview of various factors that impinge on psychopharmacotherapeutic practices. The literature revealed an impressive progress in research focusing on the delineation of the biologic mechanisms responsible for cross-ethnic variations in psychotropic metabolism and effects. With the field progressing at an accelerating pace, there is little doubt that in the coming decade clinicians will be provided with a detailed map showing the prevalence and distribution of genetic polymorphisms of most, if not all, of the drug-metabolizing enzymes, and clinicians also will have an overall picture on what these polymorphisms mean clinically. At the same time, clinicians should also start to have a good grasp on the meaning of the variations of the genes that encode therapeutic targets of psychotropics (e.g., neurotransmitter transporters and receptors). Such genetic fingerprinting, which will soon become a clinical reality, will provide tremendous help in ensuring that pharmacotherapies are increasingly more individually tailored, taking into consideration each patients genetic makeups that vary substantially across ethnic groups. As exciting as these new developments will be, they are dwarfed by the challenges ahead on the cultural side of the equation. Issues that are still awaiting further clarification include the following: How do we assess patients' beliefs and expectations related to psychotropic treatment? How do we minimize the communication gaps between patients and clinicians who are often from divergent sociocultural backgrounds? To what extent, and in what ways, do cultural (environmental) factors interact with biologic factors, and what might be the most efficient way to systematically assess such interactions? Data that have emerged in the past several decades clearly indicate the importance of culture and ethnicity in influencing patients' psychopharmacological response. It is expected that continuing progress in the near future will bring a better understanding on the way these cultural and biologic processes, separately and in interaction with each other, mediate treatment responses. Such knowledge will be crucial for the optimal pharmacotherapeutic care of for the majority of patients who will increasingly be of diverse ethnic and cultural backgrounds and will represent a significant contribution to the field of psychopharmacology as a whole.

Cross-Cultural Comparison↗

PubMed2001

Polymorphisms in inflammatory cytokines and Fcgamma receptors in childhood chronic immune thrombocytopenic purpura: a pilot study.

Inflammatory cytokines and low-affinity Fcgamma receptor (FcgammaR) polymorphisms were investigated in 37 children with chronic immune thrombocytopenic purpura (cITP) and 218 controls. Genotype analysis included common variants in the regulatory regions of cytokines, TNF, LTA, IL1RN, IL1A, IL1B, IL4, IL6 and IL10, and structural variants of the low affinity FcgammaRs, FCGR2A, FCGR3A and FCGR3B. Associations were observed for TNF (P = 0.0032), LTA (P = 0.019), FCGR3A (P = 0.038) and FCGR3B (P = 0.0034). Two combinations of genotypes (TNF and FCGR3A; P = 0.0003, and LTA and FCGR3B; P = 0.011) were significantly associated with cITP. These results provide preliminary evidence that variant genotypes of FcgammaRs and cytokines contribute to cITP pathogenesis.

Case-Control Studies↗

PubMed2001

Markers for mapping by admixture linkage disequilibrium in African American and Hispanic populations.

Population linkage disequilibrium occurs as a consequence of mutation, selection, genetic drift, and population substructure produced by admixture of genetically distinct ethnic populations. African American and Hispanic ethnic groups have a history of significant gene flow among parent groups, which can be of value in affecting genome scans for disease-gene discovery in the case-control and transmission/disequilibrium test designs. Disease-gene discovery using mapping by admixture linkage disequilibrium (MALD) requires a map of polymorphic markers that differentiate between the founding populations, along with differences in disease-gene allele frequencies. We describe markers appropriate for MALD mapping by assessing allele frequencies of 744 short tandem repeats (STRs) in African Americans, Hispanics, European Americans, and Asians, by choosing STR markers that have large differences in composite delta, log-likelihood ratios, and/or I*(2) for MALD. Additional markers can be added to this MALD map by utilization of the rapidly growing single-nucleotide-polymorphism databases and the literature, to achieve a 3-10-cM scanning scale. The map will be useful for studies of diseases, including prostate and breast cancer, diabetes, hypertension, and end-stage renal disease, that have large differences in incidence between the founding populations of either Hispanics or African Americans.

Black or African American↗

PubMed2001

Subcellular localization and targeting of glucocorticoid receptor protein fusions expressed in transgenic Arabidopsis thaliana.

An animal system of inducible activation of protein fusions with the binding domain of glucocorticoid receptor (BDGR) was tested in Arabidopsis thaliana by monitoring dexamethasone (DEX)-induced nuclear targeting of reporter constructs. Two constructs containing green fluorescent protein (GFP), human homeobox protein Hanf-1 and Xenopus laevis BDGR were used, GFP/Hanf-1/BDGR and GFP/BDGR. The control construct contained GFP alone. In the absence of DEX both fusion proteins were uniformly distributed in the cytoplasm of root cells, but showed strong association with plastids in plant aerial parts. DEX treatment of roots prompted a strong and reversible nuclear accumulation of GFP/Hanf-1/BDGR, but not GFP/BDGR. Thus, in roots, the specific nuclear translocation of GFP/Hanf-1/BDGR was driven by Hanf-1 and tightly regulated by BDGR. However, in plant aerial parts treated with DEX, nuclear translocation of GFP/Hanf-1/BDGR was observed only in a few cases, and most part of the fusion protein was incorrectly and irreversibly targeted to plastids. Protease X digestion of isolated chloroplasts showed that BDGR fusion proteins were translocated into the chloroplast envelope and bound to envelope membranes, probably due to association with the chloroplast import apparatus. Thus, for efficient use of the glucocorticoid-inducible system in plants, it will be necessary to modify BDGR structure to prevent incorrect targeting of fusion proteins.

Animals↗

PubMed2001

Physician incentives and the timing of cesarean sections: evidence from California.

OBJECTIVES: The timing of cesarean sections is studied to examine how physician convenience and financial incentives play a role in the decision to perform a cesarean section. METHODS: Using birth certificate and hospital financial data from California, the likelihood of cesarean sections being performed at particular times of day was examined, controlling for maternal characteristics and the mother's insurance coverage. Two diagnoses associated with cesarean sections are examined separately: fetal distress and prolonged/dysfunctional labor. The hypotheses are that cesarean sections performed for physician convenience are more likely to occur in the evening hours and that type of insurance will affect the incentive to perform cesarean sections to obtain leisure. RESULTS: The probability of cesarean sections for patients insured by a group-model HMO is more stable during the course of a day than that for patients insured by all other insurance plans. Group-model HMO patients with previous cesarean sections are less likely to have cesarean sections in the evening hours and are less likely to be diagnosed with fetal distress or prolonged/dysfunctional labor. CONCLUSIONS: The differences in cesarean sections and diagnosis rates between group-model HMO patients and other patients could arise from several mechanisms: group-model HMOs provide consistent financial incentives to their staff, they may be better able to guide physician practice, and they might provide staff support to physicians so there is less leisure-based incentive to perform cesarean sections. In contrast, nongroup-model HMOs do not appear to reduce the incentive of physicians to maximize leisure relative to traditional insurance.

California↗

PubMed2001

Saturation mutagenesis of 5S rRNA in Saccharomyces cerevisiae.

rRNAs are the central players in the reactions catalyzed by ribosomes, and the individual rRNAs are actively involved in different ribosome functions. Our previous demonstration that yeast 5S rRNA mutants (called mof9) can impact translational reading frame maintenance showed an unexpected function for this ubiquitous biomolecule. At the time, however, the highly repetitive nature of the genes encoding rRNAs precluded more detailed genetic and molecular analyses. A new genetic system allows all 5S rRNAs in the cell to be transcribed from a small, easily manipulated plasmid. The system is also amenable for the study of the other rRNAs, and provides an ideal genetic platform for detailed structural and functional studies. Saturation mutagenesis reveals regions of 5S rRNA that are required for cell viability, translational accuracy, and virus propagation. Unexpectedly, very few lethal alleles were identified, demonstrating the resilience of this molecule. Superimposition of genetic phenotypes on a physical map of 5S rRNA reveals the existence of phenotypic clusters of mutants, suggesting that specific regions of 5S rRNA are important for specific functions. Mapping these mutants onto the Haloarcula marismortui large subunit reveals that these clusters occur at important points of physical interaction between 5S rRNA and the different functional centers of the ribosome. Our analyses lead us to propose that one of the major functions of 5S rRNA may be to enhance translational fidelity by acting as a physical transducer of information between all of the different functional centers of the ribosome.

Alleles↗