Biomedical subjects

W M Brown

Publications and source records attributed to W M Brown.

At least 19 recordsLinked to original sources

PubMed2005

Correlation of proband and sibling stroke latency: the SWISS Study.

The authors found a correlation between the age at which probands experience an incident stroke and the age at which their siblings experience an incident stroke (r = 0.68; p < 0.0001). Proband-sibling incident stroke latency correlations were observed in analyses restricted to siblings concordant for smoking (r = 0.68; p < 0.0001), diabetes (r = 0.73; p < 0.0001), and hypertension (r = 0.63; p < 0.0001). In the authors' cohort of affected sibling pairs, inherited factors were important determinants of incident ischemic stroke latency.

Adult↗

PubMed2004

Sniffing human sex-steroid derived compounds modulates mood, memory and autonomic nervous system function in specific behavioral contexts.

We asked whether the effects of exposure to two human sex-steroid derived compounds were context dependent. The effects of sniffing 4,16-androstadien-3-one (AND) and 1,3,5(10),16-estratetraen-3-ol (EST) on mood, memory, and autonomic nervous system responses were explored in 72 participants. Subjects were tested with AND, EST, or a Control compound within four mood contexts: neutral, sexually aroused, sad and happy. These moods were successfully induced using selected film segments (P < 0.0001). During the neutral context, none of the compounds affected mood or autonomic nervous system function. However, compound effects were significantly increased within arousing contexts. During the sexually arousing context, both compounds increased sexual arousal (P < 0.029). During the sad context, AND maintained positive mood in women (P< 0.050) and increased negative mood in men (P < 0.031). Memory for events during the sad context was impaired by AND in women (P < 0.047) but not in men. Finally, effects of AND on physiology were observed during the sexually arousing context whereby AND increased skin temperature in both sexes (P < 0.022) but reduced abdominal respiration rate in men only (P < 0.034). These results suggest that sex-steroidal compounds modulate mood, memory and autonomic nervous system responses and increase their significance within specific behavioral contexts. These findings lend support to a specific role for these compounds in chemical communication between humans.

Adolescent↗

PubMed2004

Hereditary prostate cancer in African American families: linkage analysis using markers that map to five candidate susceptibility loci.

African American men have the highest incidence of prostate cancer in the world. Despite this statistic, linkage studies designed to localise prostate cancer susceptibility alleles have included primarily men of Caucasian descent. In this report, we performed a linkage analysis using 33 African American prostate cancer families from two independent research groups. In total, 126 individuals (including 89 men with prostate cancer) were genotyped using markers that map to five prostate cancer susceptibility loci, namely HPC1 at 1q24-25, PCAP at 1q42.2-43, CAPB at 1p36, HPC20 on chromosome 20, and HPCX at Xq27-28. Multipoint mode-of-inheritance-free linkage analyses were performed using the GENEHUNTER software. Some evidence of prostate cancer was detected to HPC1 using all families with a maximum NPL Z score of 1.12 near marker D1S413 (P=0.13). Increased evidence of linkage was observed in the 24 families with prostate cancer diagnosis prior to age 65 years and in the 20 families with male-to-male transmission. Some evidence of prostate cancer linkage was also detected at markers mapping to PCAP, HPC20, and HPCX. Continued collection and analysis of African American prostate cancer families will lead to an improved understanding of inherited susceptibility in this high-risk group.

Black or African American↗

PubMed2004

NMR solution structure of a potent cyclic nonapeptide inhibitor of ICAM-1-mediated leukocyte adhesion produced by homologous amino acid substitution.

We have previously described a disulfide-linked cyclic nonapeptide (inhibitory peptide-01, IP01), with the sequence CLLRMRSIC, which binds to intercellular adhesion molecule-1 (ICAM-1), and blocks binding to its counter-structure, the integrin alphaLbeta2 (leukocyte functional antigen-1, LFA-1) (Sillerud et al., J. Peptide Res. 62, 2003: 97). We now report the optimization of this peptide by means of single homologous amino acid substitutions to yield a new peptide (IP02-K6; CLLRMKSAC) which shows an approximately sixfold improvement in inhibitory activity of multivalent leukocyte binding (inhibition constant for 50% inhibition, IC50 = 90 microm) compared with IP01 (IC50 = 580 microm). This improvement in activity gives IP02-K6 potent in vivo activity in a murine model of ischemia reperfusion injury (Merchant et al., Am. J. Physiol. Heart Circ. 284, 2003: H1260). In order to determine the structural features relevant to ICAM-1-binding, we have determined the structure of IP02-K6 using proton nuclear magnetic resonance (NMR) spectroscopy and restrained molecular modeling. In our previously reported study of solution models of IP01, we observed three interconverting conformations during low-temperature molecular dynamics simulation. In the present study, we find a single conformation of IP02-K6 similar to one of the previously found conformations of IP01 (family C). In particular, an R4-S7 beta-turn is present in similar proportions in both conformation C of IP01 and in IP02-K6; this motif is important in binding to ICAM-1 because this turn enables the IP02-K6 backbone to drape over proline-36 on ICAM-1. The NMR-derived solution model of IP02-K6 was found to dock at the alphaLbeta2-binding site on ICAM-1 with no changes in peptide backbone conformation. This docking model displaced five of the 15 alphaLbeta2 residues at the ICAM-1-binding site and provided a rationale for understanding the quantitative relationship between IP02-K6 structure and biologic activity.

Amino Acid Motifs↗

PubMed2003

Sex-steroid derived compounds induce sex-specific effects on autonomic nervous system function in humans.

The physiological and psychological effects of 2 human sex-steroid derived compounds, 4.16-androstadien-3-one (AND) and l,3,5(10),16-estratetraen-3-ol(EST) were measured in 24 subjects who participated in a within-subjects, double-blind experiment. A dissociation was evident in the physiological effects of AND, in that it increased physiological arousal in women but decreased it in men. EST did not significantly affect physiological arousal in women or men. Neither compound significantly affected mood. AND is an androgen derivative that is the most prevalent androstene in human male sweat, male axillary hair, and on the male axillary skin surface. The authors argue that AND's opposite effects on physiology in men and women further implicate this compound in chemical communication between humans.

Adult↗

PubMed2001

The scented brain: pheromonal responses in humans.

Using PET, Savic et al., in this issue of Neuron, found a sexually dimorphic neural response to two putative human pheromones. The specific regions activated combined with the pronounced sex difference depict a pheromonal-type brain response in humans. Here, we preview this finding and suggest that human pheromones exist.

Brain↗

PubMed2001

Genetic linkage and transmission disequilibrium of marker haplotypes at chromosome 1q41 in human systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies to a wide range of self-antigens. Recent genome screens have implicated numerous chromosomal regions as potential SLE susceptibility loci. Among these, the 1q41 locus is of particular interest, because evidence for linkage has been found in several independent SLE family collections. Additionally, the 1q41 locus appears to be syntenic with a susceptibility interval identified in the NZM2410 mouse model for SLE. Here, we report the results of genotyping of 11 microsatellite markers within the 1q41 region in 210 SLE sibpair and 122 SLE trio families. These data confirm the modest evidence for linkage at 1q41 in our family collection (LOD = 1.21 at marker D1S2616). Evidence for significant linkage disequilibrium in this interval was also found. Multiple markers in the region exhibit transmission disequilibrium, with the peak single marker multiallelic linkage disequilibrium noted at D1S490 (pedigree disequilibrium test [PDT] global P value = 0.0091). Two- and three-marker haplotypes from the 1q41 region similarly showed strong transmission distortion in the collection of 332 SLE families. The finding of linkage together with significant transmission disequilibrium provides strong evidence for a susceptibility locus at 1q41 in human SLE.

Chromosomes, Human, Pair 1↗

PubMed2001

Statistical issues in analyzing 24-hour dietary recall and 24-hour urine collection data for sodium and potassium intakes.

Dietary recalls and urine assays provide different metrics for assessing sodium and potassium intakes. Means, variances, and correlations of data obtained from these two modes of measurement differ. Pooling of these data is not straightforward, and results from studies employing the different modes may not be comparable. To explore differences between these metrics, the authors used data from the Trial of Nonpharmacologic Intervention in the Elderly (TONE), which included repeated standardized 24-hour dietary recalls and 24-hour urine collections administered over 3 years of follow-up, to estimate sodium and potassium intakes. The authors examined data from 341 control participants assigned to usual care that were collected between August 1992 and December 1995. Dietary recalls yielded estimates of sodium intake that averaged 22% less than those from urine assays and estimates of potassium intake that averaged 16% greater than those from urine assays. Sodium intake estimates were less repeatable (r = 0.22 for diet; r = 0.30 for urine) than potassium intake estimates (r = 0.49 for diet; r = 0.50 for urine), making relations with outcomes more difficult to characterize. Overall, the performance of the two measurement modes was fairly similar across demographic subgroups. Errors in separate estimations of long term sodium and potassium intakes using short term data were strongly correlated, more strongly than the underlying long term intakes of these electrolytes. Because of the correlated measurement error, estimated regression coefficients for linear models including both electrolytes as predictors may be confounded such that the separate relations between these nutrients and outcomes such as blood pressure cannot be reliably estimated by common analytical strategies.

Aged↗

PubMed2001

Metabolism of the 2-oxoaldehyde methylglyoxal by aldose reductase and by glyoxalase-I: roles for glutathione in both enzymes and implications for diabetic complications.

Numerous physiological aldehydes besides glucose are substrates of aldose reductase, the first enzyme of the polyol pathway which has been implicated in the etiology of diabetic complications. The 2-oxoaldehyde methylglyoxal is a preferred substrate of aldose reductase but is also the main physiological substrate of the glutathione-dependent glyoxalase system. Aldose reductase catalyzes the reduction of methylglyoxal efficiently (k(cat)=142 min(-1) and k(cat)/K(m)=1.8x10(7) M(-1) min(-1)). In the presence of physiological concentrations of glutathione, methylglyoxal is significantly converted into the hemithioacetal, which is the actual substrate of glyoxalase-I. However, in the presence of glutathione, the efficiency of reduction of methylglyoxal, catalyzed by aldose reductase, also increases. In addition, the site of reduction switches from the aldehyde to the ketone carbonyl. Thus, glutathione converts aldose reductase from an aldehyde reductase to a ketone reductase with methylglyoxal as substrate. The relative importance of aldose reductase and glyoxalase-I in the metabolic disposal of methylglyoxal is highly dependent upon the concentration of glutathione, owing to the non-catalytic pre-enzymatic reaction between methylglyoxal and glutathione.

Aldehyde Reductase↗

PubMed2001

Nonparametric linkage regression. II: Identification of influential pedigrees in tests for linkage.

We applied case-deletion-based diagnostics to the combined Caucasian genome scan data for asthma and IgE from the Collaborative Study on the Genetics of Asthma (CSGA) and German family studies in order to identify influential pedigrees in tests for linkage. These methods identified 12 pedigrees whose data appear not to fit the asthma linkage model and for whom alternative genetic and nongenetic explanations can be explored. The methods also identified four pedigrees for chromosome 1 and two pedigrees for chromosome 2 that provide strong evidence for linkage at their respective loci. Similarly, these methods helped identify four pedigrees that strongly influenced the linkage tests for IgE. From these data, we can construct an enriched subset of pedigrees to be used in further analysis for mapping region-specific putative trait predisposing loci.

Adult↗

PubMed2001

Nonparametric linkage regression. I: Combined Caucasian CSGA and German genome scans for asthma.

In this paper we applied the nonparametric linkage (NPL) regression approach to the combined Caucasian genome scan data from the Collaborative Study on the Genetics of Asthma (CSGA) and German family studies to search for regions of the genome that exhibit evidence for linkage to putative asthma-predisposing genes. The multipoint single-locus model identified three regions of the genome with LOD scores of approximately two or greater. These regions were on 6p near D6S291 (LOD = 2.78), 2p near D2S2298 (LOD = 2.11), and 1p near D1S1597 (LOD = 1.92). Modeling multiple loci together and testing for interactions among loci yielded stronger evidence for linkage in these regions. We observed a potential epistatic interaction between 2p and 14p (p = 0.0003) and conditional LOD scores of 2.75 on 1p, 3.89 on 6p, 1.64 on 7p, and 1.64 on 15q.

Adult↗

PubMed2001

In vivo hemodynamic, histologic, and antimineralization characteristics of the Mosaic bioprosthesis.

BACKGROUND: Performance of bioprosthetic valves is limited by tissue degeneration due to calcification with reduced performance and longevity. The Mosaic bioprosthetic valve (Medtronic Heart Valves, Inc, Minneapolis, MN) combines zero pressure fixation, antimineralization properties of alpha-amino oleic acid (AOA), and a proven stent design. We tested the hypothesis that AOA treatment of Mosaic valves improves hemodynamics, antimineralization properties, and survival in a chronic ovine model. METHODS: Mitral valves were implanted in juvenile sheep with Mosaic valves with AOA treatment (n = 8) or without AOA treatment (non-AOA, n = 8), or Hancock I (HAN, n = 4) tissue valves, and explanted at 20 postoperative weeks. RESULTS: Survival was equivalent in AOA and non-AOA (140 +/- 0.4 and 129 +/- 30 days), but was significantly less in HAN (82 +/- 35). Leaflet calcium (microgCa/mg tissue) was less in AOA (9.6 +/- 13.9; p < 0.05 versus non-AOA and HAN) than non-AOA (96.3 +/- 63.8) and HAN (130.8 +/- 43.2). Explant valve orifice area (cm2) was significantly preserved in the AOA group compared with the non-AOA group (1.5 +/- 0.7 vs 0.8 +/- 0.3; p < 0.05 versus non-AOA and HAN). CONCLUSIONS: We conclude that AOA treatment of Mosaic valves reduces leaflet calcification and valve gradient in juvenile sheep, and that the Mosaic design and fixation features may offer survival advantages that must be confirmed in extended trials.

Animals↗

PubMed2001

Clinical outcomes, angiographic patency, and resource utilization in 200 consecutive off-pump coronary bypass patients.

BACKGROUND: This retrospective study compared clinical outcomes and resource utilization in patients having off-pump coronary artery bypass grafting (OPCAB) versus conventional coronary artery bypass grafting (CABG). Angiographic patency was documented in the OPCAB group. METHODS: From April 1997 through November 1999, OPCAB was performed in 200 consecutive patients, and the results were compared with those in a contemporaneous matched control group of 1,000 patients undergoing CABG. Patients were matched according to age, sex, preexisting disease (renal failure, diabetes, pulmonary disease, stroke, hypertension, peripheral vascular disease, previous myocardial infarction, and primary or redo status. Follow-up in the OPCAB patients was 93% and averaged 13.4 months. RESULTS: Hospital death (1.0%), postoperative stroke (1.5%), myocardial infarction (1.0%), and re-entry for bleeding (1.5%) occurred infrequently in the OPCAB group. There were reductions in the rates of transfusion (33.0% versus 70.0%; p < 0.001) and deep sternal wound infection (0% versus 2.2%; p = 0.067) in the OPCAB group compared with the CABG group. Angiographic assessment of 421 grafted arteries was performed in 167 OPCAB patients (83.5%) prior to hospital discharge. All but five were patent (98.8%) (93.3% FitzGibbon A, 5.5% FitzGibbon B, 1.2% FitzGibbon O). All 163 internal mammary artery grafts were patent. Off-pump coronary artery bypass grafting reduced postoperative hospital stay from 5.7 +/- 5.3 days in the CABG group to 3.9 +/- 2.6 days (p < 0.001), with a decrease in hospital cost of 15.0% (p < 0.001). CONCLUSIONS: Off-pump coronary artery bypass grafting reduces hospital cost, postoperative length of stay, and morbidity compared with CABG on cardiopulmonary bypass. Off-pump coronary bypass grafting is safe, cost effective, and associated with excellent graft patency and clinical outcomes.

Aged↗

PubMed2001

Trichinella spiralis mtDNA: a nematode mitochondrial genome that encodes a putative ATP8 and normally structured tRNAS and has a gene arrangement relatable to those of coelomate metazoans.

The complete mitochondrial DNA (mtDNA) of the nematode Trichinella spiralis has been amplified in four overlapping fragments and 16,656 bp of its sequence has been determined. This sequence contains the 37 genes typical of metazoan mtDNAs, including a putative atp8, which is absent from all other nematode mtDNAs examined. The genes are transcribed from both mtDNA strands and have an arrangement relatable to those of coelomate metazoans, but not to those of secernentean nematodes. All protein genes appear to initiate with ATN codons, typical for metazoans. Neither TTG nor GTT start codons, inferred for several genes of other nematodes, were found. The 22 T. spiralis tRNA genes fall into three categories: (i) those with the potential to form conventional "cloverleaf" secondary structures, (ii) those with TPsiC arm + variable arm replacement loops, and (iii) those with DHU-arm replacement loops. Mt-tRNA(R) has a 5'-UCG-3' anticodon, as in most other metazoans, instead of the very unusual 5'-ACG-3' present in the secernentean nematodes. The sequence also contains a large repeat region that is polymorphic in size at the population and/or individual level.

Adenosine Triphosphatases↗

PubMed2001

Complete sequence of the mitochondrial genome of the tapeworm Hymenolepis diminuta: gene arrangements indicate that Platyhelminths are Eutrochozoans.

Using "long-PCR," we amplified in overlapping fragments the complete mitochondrial genome of the tapeworm Hymenolepis diminuta (Platyhelminthes: Cestoda) and determined its 13,900-nt sequence. The gene content is the same as that typically found for animal mitochondrial DNA (mtDNA) except that atp8 appears to be lacking, a condition found previously for several other animals. Despite the small size of this mtDNA, there are two large noncoding regions, one of which contains 13 repeats of a 31-nt sequence and a potential stem-loop structure of 25 bp with an 11-member loop. Large potential secondary structures were identified also for the noncoding regions of two other cestode mtDNAS: Comparison of the mitochondrial gene arrangement of H. diminuta with those previously published supports a phylogenetic position of flatworms as members of the Eutrochozoa, rather than placing them basal to either a clade of protostomes or a clade of coelomates.

Animals↗

PubMed2001

The complete mitochondrial genome of the articulate brachiopod Terebratalia transversa.

We sequenced the complete mitochondrial DNA (mtDNA) of the articulate brachiopod Terebratalia transversa. The circular genome is 14,291 bp in size, relatively small compared with other published metazoan mtDNAs. The 37 genes commonly found in animal mtDNA are present; the size decrease is due to the truncation of several tRNA, rRNA, and protein genes, to some nucleotide overlaps, and to a paucity of noncoding nucleotides. Although the gene arrangement differs radically from those reported for other metazoans, some gene junctions are shared with two other articulate brachiopods, Laqueus rubellus and Terebratulina retusa. All genes in the T. transversa mtDNA, unlike those in most metazoan mtDNAs reported, are encoded by the same strand. The A+T content (59.1%) is low for a metazoan mtDNA, and there is a high propensity for homopolymer runs and a strong base-compositional strand bias. The coding strand is quite G+T-rich, a skew that is shared by the confamilial (laqueid) species L. rubellus but is the opposite of that found in T. retusa, a cancellothyridid. These compositional skews are strongly reflected in the codon usage patterns and the amino acid compositions of the mitochondrial proteins, with markedly different usages being observed between T. retusa and the two laqueids. This observation, plus the similarity of the laqueid noncoding regions to the reverse complement of the noncoding region of the cancellothyridid, suggests that an inversion that resulted in a reversal in the direction of first-strand replication has occurred in one of the two lineages. In addition to the presence of one noncoding region in T. transversa that is comparable with those in the other brachiopod mtDNAs, there are two others with the potential to form secondary structures; one or both of these may be involved in the process of transcript cleavage.

Amino Acid Sequence↗

PubMed2001

Barley yellow rust in North America.

Yellow rust of barley is an invasive disease that was found in the past 10 years in North America. The causal agent, Puccinia striiformis f. sp. hordei, was introduced into Colombia, South America, from Europe in 1975. It spread to all major barley-producing areas in South America by 1982. In 1988 it was found in Mexico and in 1991 in Texas. Since then it has been found in all major barley-producing areas of the American West. Originally described as race (R) 24, barley yellow rust in North America is now known to be a very heterogeneous population. Resistance has been identified, evaluated, and is being introduced into commercial malting and other barley cultivars. Cultural and chemical controls are effective and available. An integrated approach using general field resistance and other tactics is described for sustainable management of barley yellow rust.

Agriculture↗

PubMed2001

Taltirelin (Tanabe Seiyaku).

Taltirelin (TA-0910), a synthetic thyrotropin-releasing hormone (TRH) analog, has been developed by Tanabe Seiyaku for the treatment of neurodegenerative diseases [154099], [263997]. An NDA was filed in Japan in April 1999 for the treatment of spinocerebellar degeneration (SCD) [296442] and was approved in July 2000 [391719]; the drug was launched in Japan in September 2000 [382555], [383484]. It is the first orally administered drug for this indication [382555]. In September 2001, UBS Warburg (Japan) stated that total sales of taltirelin in 2000 were Yen 3.5 bn, and estimated that sales in 2001 would reach Yen 7.6 bn, rising to Yen 8.6 bn by 2005 [433991]. Also in this month, Morgan Stanley predicted that there would be sales of Yen 8 bn in 2001, rising to Yen 10 bn in 2002 [422782].

Journal Article↗