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Biomedical subjects

R Welch

Publications and source records attributed to R Welch.

At least 19 recordsLinked to original sources
PubMed2006

SCOTROC 2B: feasibility of carboplatin followed by docetaxel or docetaxel-irinotecan as first-line therapy for ovarian cancer.

The feasibility of combination irinotecan, carboplatin and docetaxel chemotherapy as first-line treatment for advanced epithelial ovarian carcinoma was assessed. One hundred patients were randomised to receive four 3-weekly cycles of carboplatin (area under the curve (AUC) 7) followed by four 3-weekly cycles of docetaxel 100 mg m(-2) (arm A, n=51) or docetaxel 60 mg m(-2) with irinotecan 200 mg m(-2) (arm B, n=49). Neither arm met the formal feasibility criterion of an eight-cycle treatment completion rate that was statistically greater than 60% (arm A 71% (90% confidence interval (CI) 58-81%; P=0.079; arm B 67% (90% CI 55-78%; P=0.184)). Median-dose intensities were >85% of planned dose for all agents. In arms A and B, 15.6 and 12.2% of patients, respectively, withdrew owing to treatment-related toxicity. Grade 3-4 sensory neurotoxicity was more common in arm A (1.9 vs 0%) and grade 3-4 diarrhoea was more common in arm B (0.6 vs 3.5%). Of patients with radiologically evaluable disease at baseline, 50 and 48% responded to therapy in arms A and B, respectively; at median 17.1 months' follow-up, median progression-free survival was 17.1 and 15.9 months, respectively. Although both arms just failed to meet the formal statistical feasibility criteria, the observed completion rates of around 70% were reasonable. The addition of irinotecan to first-line carboplatin and docetaxel chemotherapy was generally well tolerated although associated with increased gastrointestinal toxicity. Further exploratory studies of topoisomerase-I inhibitors in this setting may be warranted.

Adult↗
PubMed2006

Vascular endothelial growth factor gene haplotypes in Kawasaki disease.

OBJECTIVE: To investigate whether common genetic variants in the vascular endothelial growth factor (VEGF) gene are associated with Kawasaki disease (KD) and the subsequent development of coronary artery lesions. METHODS: Common genetic variants in the VEGF gene were analyzed in an association study in a Dutch cohort of 170 KD patients and 300 healthy Dutch Caucasian controls. Genotyping was done with 5'-nuclease TaqMan assays and 3'-hybridization-triggered fluorescence minor groove binder Eclipse assays. RESULTS: An association with susceptibility to KD was observed with 2 of the 6 single-nucleotide polymorphisms analyzed in VEGF: -2594 A>C (rs699947) and the 236 bp 3' of STP C>T (rs3025039). Also for an 18-bp deletion in the promoter of VEGF a significant difference in the genotype and allele frequencies was observed between the KD patients and the controls. The haplotype CGCC (based on rs699947, rs2010963, rs25648, and rs3025039) was significantly associated with the development of KD (hap score 3.8; P = 0.0002). VEGF plasma levels were significantly higher in patients with the early phase of KD than in the healthy controls, and there was a trend toward higher VEGF plasma levels in KD patients with the -2594 CC and 236 bp 3' of STP CC genotypes. CONCLUSION: Our results suggest that polymorphisms of the VEGF gene may play a role in the pathogenesis of KD.

Adolescent↗
PubMed2005

High dose chemotherapy and autologous stem cell transplantation as adjuvant therapy for primary breast cancer patients with four or more lymph nodes involved: long-term results of an international randomised trial.

BACKGROUND: The purpose of this study was to assess whether a short course of anthracycline containing chemotherapy followed by high dose therapy with autologous stem-cell support improves disease-free and overall survival as compared with conventional, anthracycline containing chemotherapy, in patients with primary breast cancer and four or more histologically involved lymph nodes. PATIENTS AND METHODS: Two hundred and eighty one patients entered into a randomised clinical trial were allocated to receive standard, conventional treatment (5-fluorouracil, epirubicin and cyclophosphamide-FEC for six cycles) or FEC for three cycles followed by high dose therapy consisting of cyclophosphamide, thiotepa and carboplatin and stem cell rescue (HDT). To be eligible, patients had to be free of overt metastatic disease and be < or =60 years of age. Analyses were according to intention to treat. RESULTS: At a median follow up of 68 months, 118 patients have experienced a relapse or death from breast cancer (62 in the FEC followed by HDT arm and 56 in the conventional FEC arm) and a total of 100 patients have died (54 in the FEC followed by HDT arm and 46 in the conventional FEC arm). No significant difference was observed in relapse-free survival [hazard ratio 1.06, 95% CI 0.74-1.52, p = 0.76] or overall survival [hazard ratio 1.18, 95% CI 0.80-1.75, p = 0.40]. Five patients died from treatment related causes, three as a consequence of HDT and two in the conventional FEC arm. CONCLUSIONS: At the present time, no benefit has been observed from replacing three cycles of conventional chemotherapy with the HDT regimen described here. Patients should continue to receive conventional chemotherapy as adjuvant therapy for breast cancer.

Adult↗
PubMed2004

Successful patching of iatrogenic rupture of the fetal membranes.

Rupture of the fetal membranes is a common, but potentially serious complication of invasive fetal procedures. Quintero described a technique to seal the fetal membrane defect by means of a bloodpatch, usually called 'amniopatch' in this application. The successful use in two consecutive patients with ruptured membranes after a fetoscopic intervention at respectively 17 and 22 weeks' gestational age is described, together with a literature review of published experience.

Adult↗
PubMed2003

Candidate genes for anorexia nervosa in the 1p33-36 linkage region: serotonin 1D and delta opioid receptor loci exhibit significant association to anorexia nervosa.

Serotonergic and opioidergic neurotransmitter system alterations have been observed in people with eating disorders; the genes for the serotonin 1D receptor (HTR1D) and the opioid delta receptor (OPRD1) are found on chr1p36.3-34.3, a region identified by our group in a linkage analysis of anorexia nervosa (AN). These candidate genes were evaluated for sequence variation and for linkage and association of this sequence variation to AN in family and case : control data sets. Resequencing of the HTR1D locus and a portion of the OPRD1 locus identified novel SNPs and confirmed existing SNPs. Genotype assay development and genotyping of nine SNPs (four at HTR1D and five at OPRD1) was performed on 191 unrelated individuals fulfilling DSM-IV criteria (w/o amenorrhea criterion) for AN, 442 relatives of AN probands and 98 psychiatrically screened controls. Linkage analysis of these candidate gene SNPs with 33 microsatellite markers in families including relative pairs concordantly affected with restricting AN (N=37) substantially increased the evidence for linkage of this region to restricting AN to an NPL score of 3.91. Statistically significant genotypic, allelic, and haplotypic association to AN in the case : control design was observed at HTR1D and OPRD1 with effect sizes for individual SNPs of 2.63 (95% CI=1.21-5.75) for HTR1D and 1.61 (95% CI=1.11-2.44) for OPRD1. Using genotype data on parents and AN probands, three SNPs at HTR1D were found to exhibit significant transmission disequilibrium (P&<0.05). The combined statistical genetic evidence suggests that HTR1D and OPRD1 or linked genes may be involved in the etiology of AN.

Anorexia Nervosa↗
PubMed2003

Candidate gene analysis of the Price Foundation anorexia nervosa affected relative pair dataset.

The eating disorders are severe psychiatric illnesses with significant morbidity and mortality that exhibit statistically significant familial risk and heritability, providing support for a molecular genetic approach toward defining etiological factors. An emerging candidate gene literature has concentrated on serotinergic and dopaminergic candidates. With the financial support of the Price Foundation, a group of investigators initiated an international multi-center collaboration (Price Foundation Collaborative Group) in 1995 to study the genetics of anorexia and bulimia nervosa by collecting and analyzing phenotypes and genotypes of individuals and their relatives affected with eating disorders. The first sample of families collected by this collaborative group, known as the Price Foundation Anorexia Nervosa Affected Relative Pair (AN-ARP) dataset, was ascertained on an proband affected with Anorexia Nervosa (AN), with relative pairs affected with the eating disorders AN, Bulimia Nervosa or Eating Disorders Not Otherwise Specified [1]. Biognosis U.S., Inc. was founded to identify and characterize candidate susceptibility genes for anorexia and bulimia nervosa phenotypes in the Price Foundation eating disorder datasets. During 2000-2001, Biognosis U.S., Inc. developed and implemented a research program with a focus on the analysis of candidate genes nominated by neurochemical characteristics of eating disorder patients [2], serotonergic and dopaminergic candidate gene polymorphisms [3], neuroendocrine regulation of appetite [4], and by a positional hypothesis from a linkage analysis of the AN-ARP dataset [5]. This report reviews the anorexia nervosa candidate gene literature through 2001, the candidate gene research program implemented at Biognosis U.S., Inc. and selected candidate gene findings in the AN-ARP dataset derived from that research program.

Animals↗
PubMed2002

Re-colonisation and recovery of populations of dogwhelks Nucella lapillus (L.) on shores formerly subject to severe TBT contamination.

Dogwhelks Nucella lapillus became locally extinct on some shores adjacent to areas of high shipping/boating activity during the period of high tributyltin (TBT) contamination in the 1980s and early 1990s. However, the species has now re-colonised sites at which extinction occurred on the Isle of Cumbrae, the northeast coast of England, the Shetland Isles and southwest England. There have also been substantial declines in the severity of imposex on adjacent shores where the species has persisted during this period. Re-colonisation and recovery can be attributed to two measures: regulations prohibiting the use of TBT-based paints on vessels < 25 m in length and the development of slow-releasing, self-polishing copolymer paints. Nevertheless, the International Maritime Organisation has now imposed a total ban on the use of TBT-based paints as antifoulants. This is almost certain to result in the use of paints containing alternative biocides and there is widespread concern that there is relatively little information on which to assess their likely environmental impacts. They could cause substantial environmental damage.

Animals↗
PubMed2001

Cell behavior in traveling wave patterns of myxobacteria.

Cells in the early stages of starvation-induced fruiting body development migrate in a highly organized periodic pattern of equispaced accumulations that move as traveling waves. Two sets of waves are observed moving in opposite directions with the same wavelength and speed. To learn how the behavior of individual cells contributes to the wave pattern, fluorescent cells were tracked within a rippling population. These cells exhibit at least three types of organized behavior. First, most cell movement occurs along the same axis as the rippling movement. Second, there is a high degree of cell alignment parallel to the direction of rippling, as indicated by the biased movement. Third, by controlling the reversal frequency, cell movement becomes periodic in a rippling field. The periodicity of individual cells matches the period of macroscopic rippling. This last behavior is unique to a rippling population and, on the basis of Myxococcus xanthus genetic data, we conclude that this periodicity is linked to the C signal, a nondiffusible cell contact-mediated signaling molecule. When two cells moving in opposite directions meet end to end, they transmit the C signal to each other and in response reverse their gliding direction. This model of traveling waves represents a new mode of biological pattern formation that depends on cell-contact interactions rather than reaction diffusion.

Chemotaxis↗
PubMed2001

An amino acid triplet in the NH2 terminus of rat ROMK1 determines interaction with SUR2B.

ATP-regulated (K(ATP)) channels are formed by an inward rectifier pore-forming subunit (Kir) and a sulfonylurea (glibenclamide)-binding protein, a member of the ATP binding cassette family (sulfonylurea receptor (SUR) or cystic fibrosis transmembrane conductance regulator). The latter is required to confer glibenclamide sensitivity to K(ATP) channels. In the mammalian kidney ROMK1-3 are components of K(ATP) channels that mediate K(+) secretion into urine. ROMK1 and ROMK3 splice variants share the core polypeptide of ROMK2 but also have distinct NH(2)-terminal extensions of 19 and 26 amino acids, respectively. The SUR2B is also expressed in rat kidney tubules and may combine with Kir.1 to form renal K(ATP) channels. Our previous studies showed that co-expression of ROMK2, but not ROMK1 or ROMK3, with rat SUR2B in oocytes generated glibenclamide-sensitive K(+) currents. These data suggest that the NH(2)-terminal extensions in both ROMK1 and ROMK3 block ROMK-SUR2B interaction. Seven amino acids in the NH(2)-terminal extensions of ROMK1 and ROMK3 are identical (amino acids 13-19 in ROMK1 and 20-26 in ROMK3) and may determine ROMK-SUR2B interaction. We constructed a series of hemagglutinin-tagged ROMK1 NH(2)-terminal deletion and substitution mutants and examined glibenclamide-sensitive K(+) currents in oocytes when co-expressed with SUR2B. These studies identified an amino acid triplet "IRA" within the conserved segment in the NH(2) terminus of ROMK1 and ROMK3 that blocks the ability of SUR2B to confer glibenclamide sensitivity to the expressed K(+) currents. The position of this triplet in the ROMK1 NH(2)-terminal extension is also important for the ROMK-SUR2B interactions. In vitro co-translation and immunoprecipitation studies with hemagglutinin-tagged ROMK mutants and SUR2B indicted that direct interaction between these two proteins is required for glibenclamide sensitivity of induced K(+) currents in oocytes. These results suggest that the IRA triplet in the NH(2)-terminal extensions of both ROMK1 and ROMK3 plays a key role in subunit assembly of the renal secretary K(ATP) channel.

ATP-Binding Cassette Transporters↗
PubMed2001

Expression of aromatase in the human growth plate.

Aromatase catalyzes the synthesis of estrogen from its androgen precursors. Estrogen is known to be important in regulating long bone growth and epiphyseal plate closure. To assess whether there may be growth plate-specific production of estrogen, we performed reverse transcriptase polymerase chain reaction (RT-PCR) to determine whether aromatase transcripts are present in the human growth plate. Immunohistochemistry was also employed to identify the specific sites of expression. Growth plates were obtained from an adolescent male and female undergoing ephysectomy to counter premature growth plate closure in the opposite leg. Aromatase transcripts were detected in RNA preparations from both growth plates. The aromatase protein was mainly expressed in the zone of maturation and the hypertrophic zone, with greatest expression in the latter. Since estrogen receptors are known to be expressed in chondrocytes, this data is consistent with a role for local estrogen production in the autocrine/paracrine control of long bone growth and growth plate maturation.

Adolescent↗
PubMed2001

Volunteers assess marine biodiversity.

Much less is known about marine biodiversity than that of terrestrial and freshwater environments. There is surprisingly little information about even the most common of organisms that live on the seashore. Science has limited resources to study them and volunteers can therefore make significant contributions. This article considers the value of a project in which volunteers are mapping the distribution and abundance of littoral animals and plants of the Northumberland coast.

Animals↗
PubMed2000

Rat homolog of sulfonylurea receptor 2B determines glibenclamide sensitivity of ROMK2 in Xenopus laevis oocyte.

Recent studies showed that coexpression of Kir6.1 or Kir6.2 with the sulfonylurea receptor (SUR1, SUR2A, or SUR2B) reconstituted an inwardly rectifying, ATP-sensitive K(+) channel that was inhibited by glibenclamide (2, 15-17). Here we report the isolation of a rat homolog of mouse SUR2B (denoted rSUR2B) from a rat kidney cDNA library. The rSUR2B sequence contains a 4,635-bp open reading frame that encodes a 1,545-amino acid polypeptide, showing 67% shared identity with SUR1 (a pancreatic beta-cell isoform) and 98% with both SUR2A (a brain isoform) and SUR2B (a vascular smooth muscle isoform). Consistent with the predicted structures of other members of the ATP-binding cassette (ABC) superfamily, the sequence of rSUR2B contains 17 putative membrane-spanning segments. Also, predicted Walker A and B consensus binding motifs, present in other ABC members, are conserved in the rSUR2B sequence. RT-PCR revealed that rSUR2B is widely expressed in various rat tissues including brain, colon, heart, kidney, liver, skeletal muscle, and spleen. The intrarenal distribution of the rSUR2B transcript was investigated using RT-PCR and Southern blot of microdissected tubules. The rSUR2B transcript was detected in proximal tubule, cortical thick ascending limb, distal collecting tubule, cortical collecting duct, and outer medullary collecting duct, but not medullary thick ascending limb. This distal distribution overlaps with that of ROMK. Coexpression of rSUR2B with ROMK2 cRNA (in 1:10 ratio) in Xenopus laevis oocytes resulted in whole cell Ba(2+)-sensitive K(+) currents that were inhibited by glibenclamide (50% inhibition with 0.2 mM glibenclamide). In contrast, rSUR2B did not confer significant glibenclamide sensitivity to oocytes coinjected with ROMK1 or ROMK3. The interaction between ROMK2 and rSUR2B was further studied by coimmunoprecipitation of in vitro translated rSUR2B and ROMK2. In agreement with the functional data, the rSUR2B protein was coimmunoprecipitated with ROMK2 in the ROMK2-rSUR2B cotranslated samples. Our data demonstrate that ROMK2, but not ROMK1 and ROMK3, can interact with rSUR2B to confer a sulfonylurea-sensitive K(+) channel, implicating SUR proteins in forming and regulating renal ATP-sensitive K(+) channels. The ROMK isoform specificity of glibenclamide effects suggests that the NH(2) terminus of the ROMK protein mediates rSUR2B-ROMK2 interactions.

ATP-Binding Cassette Transporters↗
PubMed2000

Antipsychotic agents and QT changes.

Recently, antipsychotic medications of the novel or atypical classes have received increased attention because of concerns with respect to potential lengthening of the QT interval, yet the currently available and commonly prescribed conventional antipsychotics are significantly more cardiotoxic, particularly agents in the butyrophenone and phenothiazine classes. Lengthening of the QT interval can be associated with a fatal paroxysmal ventricular arrhythmia known as torsades de pointes. The specific duration of the QT interval at which the risk of an adverse cardiac event is greatest, is not established. There is not only significant variation in the applied definition of an abnormal interval, but the maximal QT interval in healthy volunteers is greater than the currently accepted standards. The QT interval is influenced by normal physiological and pathologic factors, but the mechanisms remain unclear. Using recombinant technology, haloperidol and sertindole have been demonstrated to be high-affinity antagonists of a human cardiac potassium channel encoded by the human ether-a-go-go-related gene. Pimozide, however, has been shown to act principally through calcium channel antagonism, and chlorpromazine may affect sodium channels. Nevertheless, it is possible that these effects are significant only in the presence of predisposing factors, either genetic or acquired. Despite proven efficacy in clinical trials and subsequent supervised use in Europe, a number of recently developed antipsychotic medications are not available to patients in North America. Yet, conventional antipsychotic medications that would not be approved by current safety standards continue to be widely used.

Animals↗
PubMed1999

Variations in self-reported health by occupational grade in the British Post Office: the Q-health project.

Between 1995 and 1998 a national sample of 58,501 (42,885 males, 15,616 females) Post Office employees (29%) completed and returned a postal questionnaire survey providing information on demographic characteristics, physical and psychological health, health and lifestyles and health screening behaviour. Response rates by occupational grade were as follows: manual (male 69.3%, females 43.6%); clerical (male = 11.8%, female, 42.3%); middle management (males 15.5%, females 10.7%) and senior management (males 3.4%, females 3.3%). A number of differences in health status occurred with occupational grade. Angina, high blood pressure, obesity, smoking, arthritis, disability, GP consultations and abnormal smears were all more prevalent in lower occupational grades. Height, job satisfaction, seat belt use and breast self-examination were also lower in lower status jobs. Some findings were unexpected: GHQ scores indicated better mental health in lower grades, whilst knowledge and frequency of testicular self-examination and attendance for mammograms were higher in lower grades. Self-reports for asthma, diabetes and family history of bowel cancer were also greater in higher grades. These findings are considered in terms of response bias, health selection, the psychosocial work environment, occupational health interventions and the nature, meaning and organization of social position within the Post Office.

Administrative Personnel↗
PubMed1998

Aftereffects and sense of presence in virtual environments: formulation of a research and development agenda.

This report represents a committee summary of the current state of knowledge regarding aftereffects and sense of presence in virtual environments (VEs). The work presented in this article, and the proposed research agenda, are the result of a special session that was set up in the framework of the Seventh International Conference on Human Computer Interaction. Recommendations were made by the committee regarding research needs in aftereffects and sense of presence, and, where possible, priorities were suggested. The research needs were structured in terms of the short, medium, and long term and, if followed, should lead toward the effective use of VE technology. The 2 most critical research issues identified were (a) standardization and use of measurement approaches for aftereffects and (b) identification and prioritization of sensorimotor discordances that drive aftereffects. Identification of aftereffects countermeasures (i.e., techniques to assist users in readily transitioning between the real and virtual worlds), reduction of system response latencies, and improvements in tracking technology were also thought to be of critical importance.

Adaptation, Physiological↗
PubMed1997

Comparison of men and women with binge eating disorder.

OBJECTIVE: This study examined gender differences in individuals with binge eating disorder (BED) on eating-related psychopathology and general psychological functioning. METHOD: Subjects were age-matched men (n = 21) and women (n = 21) with BED who were administered the Eating Disorders Examination (EDE), the Structured Clinical Interview for DSM-III-R (SCID) and SCID II, and who completed the Emotional Eating Scale (EES) and other questionnaires regarding psychological functioning. RESULTS: Men and women did not differ on measures of eating disturbance, shape and weight concerns, interpersonal problems, or self-esteem, but more men than women met criteria for at least one Axis I diagnosis and had a lifetime diagnosis of substance dependence. Women were more likely to report eating in response to negative emotions, particularly anxiety, anger and frustration, and depression. DISCUSSION: Results from our study suggest that while men and women presenting for treatment for BED are very similar, males may have more Axis I psychiatric disturbance and less emotional eating than their female counterparts. These findings are discussed in terms of the role of gender in BED and possible treatment implications are explored.

Adult↗