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Biomedical subjects

M Welch

Publications and source records attributed to M Welch.

At least 19 recordsLinked to original sources
PubMed2000

Capsaicin-stimulated release of substance P from cultured dorsal root ganglion neurons: involvement of two distinct mechanisms.

Capsaicin, the pungent component of "hot" chili peppers, selectively activates a distinct population of primary sensory neurons responsive to noxious stimuli. Many of these fibres express neuropeptides including the tachykinin, substance P. Using cultured dorsal root ganglion neurons, we found that capsaicin (10 microM) stimulated a 2-fold increase in release of substance P in the absence of extracellular Ca(2+). Elevated potassium (75 mM) was unable to induce release under these conditions. The introduction of Ca(2+) enhanced capsaicin-induced release and brought about a robust response to potassium. Preincubation of cells with botulinum neurotoxin A (100 nM) completely blocked potassium-induced release but the capsaicin response, in the absence of Ca(2+), was unaffected. However, toxin treatment dramatically reduced capsaicin-stimulated release in the presence of Ca(2+). It is concluded that capsaicin induces release of substance P from dorsal root ganglion neurons via two mechanisms, one requiring extracellular Ca(2+) and the intact synaptosomal-associated protein 25 kDa (SNAP-25), and the other independent of extracellular Ca(2+) and not involving SNAP-25.

Animals↗
PubMed2000

N-acyl homoserine lactone binding to the CarR receptor determines quorum-sensing specificity in Erwinia.

Quorum sensing via an N-acyl homoserine lactone (HSL) pheromone controls the biosynthesis of a carbapenem antibiotic in Erwinia carotovora. Transcription of the carbapenem biosynthetic genes is dependent on the LuxR-type activator protein, CarR. Equilibrium binding of a range of HSL molecules, which are thought to activate CarR to bind to its DNA target sequence, was examined using fluorescence quenching, DNA bandshift analysis, limited proteolysis and reporter gene assays. CarR bound the most physiologically relevant ligand, N-(3-oxohexanoyl)-L-homoserine lactone, with a stoichiometry of two molecules of ligand per dimer of protein and a dissociation constant of 1.8 microM, in good agreement with the concentration of HSL required to activate carbapenem production in vivo. In the presence of HSL, CarR formed a very high molecular weight complex with its target DNA, indicating that the ligand causes the protein to multimerize. Chemical cross-linking analysis supported this interpretation. Our data show that the ability of a given HSL to facilitate CarR binding to its target DNA sequence is directly proportional to the affinity of the HSL for the protein.

Bacterial Proteins↗
PubMed2000

Longitudinal growth in infants and young children treated with budesonide inhalation suspension for persistent asthma.

BACKGROUND: Results of recent growth studies suggest that inhaled glucocorticosteroids may affect growth in children. OBJECTIVE: Three 52-week, open-label extension studies (studies A, B, and C) were conducted to compare the effects of budesonide inhalation suspension (BIS) with conventional asthma therapy (CAT) on long-term safety, including intermediate-term growth, in 3 different pediatric asthma populations. METHODS: Pediatric asthma patients (ages 6 months to 8 years) from 3 multicenter, randomized, 12-week, double-blind, placebo-controlled studies were eligible to enroll in the 52-week, open-label extension studies. The extension studies were multicenter, randomized, open-label, active-controlled, parallel-group studies performed at 26 centers in the United States. Subjects in each extension study were randomized in a 2:1 ratio to receive either BIS or CAT. BIS was initially administered at a dose of 0.5 mg once (studies A and C) or twice daily (study B), with attempts made at each clinical visit to gradually reduce the dose to the minimum effective dose that maintains asthma control, as judged by the investigator. CAT consisted of any available therapy for asthma, including inhaled glucocorticosteroids in studies B and C only. Height SD scores, growth velocity, and skeletal age (only in studies B and C) were examined. RESULTS: In total, 670 subjects were randomized; 223 subjects received CAT and 447 received BIS. Mean ages at entry were 63.0 months and 60.9 months in CAT and BIS groups, respectively. Median total daily doses of BIS ranged from 0.5 to 1. 0 mg and the mean duration of treatment exposure was 304 +/- 119 days and 342 +/- 83 days in CAT and BIS groups, respectively. Changes in height SD scores differed significantly between the BIS and CAT groups in study A (-0.19, P =.003), and there was a small, statistically significant decrease in growth velocity (-0.8 cm/y, P =.002) in the BIS-treated group compared with the CAT group. No significant differences were observed between BIS and CAT groups in the changes in height SD scores or in growth velocities in studies B (+0.10 and +0.7 cm/y, respectively) and C (+0.12 and +0.8 cm/y, respectively). No differences in skeletal age were observed between BIS and CAT groups in studies B and C. CONCLUSION: There was a small, statistically significant decrease in growth velocity in the BIS-treated group compared with the CAT group in the study (study A) where inhaled glucocorticosteroid use was prohibited before entry and in the CAT group during the study. In the studies (B and C) where inhaled glucocorticosteroids were allowed in the CAT group, no differences were observed in height SD scores or growth velocity. The clinical relevance of these effects, including impact on final adult height, remain to be determined in prospectively planned studies that assess growth in children.

Administration, Inhalation↗
PubMed1999

Enzymatic syntheses of 6-(4H-selenolo[3,2-b]pyrrolyl)-L-alanine, 4-(6H-selenolo[2,3-b]pyrrolyl)-L-alanine, and 6-(4H-furo[3,2-b]pyrrolyl-L-alanine.

6-(4H-Selenolo[3,2-b]pyrrolyl)-L-alanine 1, 4-(6H-selenolo[2,3-b]pyrrolyl)-L-alanine 2, and 6-(4H-furo[3,2-b]pyrrolyl)-L-alanine 3 have been synthesized via reactions of selenolo[3,2-b]pyrrole, selenolo[2,3-b]pyrrole, and furo[3,2-b]pyrrole, respectively, with L-serine. The reactions are catalyzed by Salmonella typhimurium tryptophan synthase.

Alanine↗
PubMed1999

DNA shuffling of subgenomic sequences of subtilisin.

DNA family shuffling of 26 protease genes was used to create a library of chimeric proteases that was screened for four distinct enzymatic properties. Multiple clones were identified that were significantly improved over any of the parental enzymes for each individual property. Family shuffling, also known as molecular breeding, efficiently created all of the combinations of parental properties, producing a great diversity of property combinations in the progeny enzymes. Thus, molecular breeding, like classical breeding, is a powerful tool for recombining existing diversity to tailor biological systems for multiple functional parameters.

Enzyme Stability↗
PubMed1999

Vascular surgical society of great britain and ireland: randomized double-blind study of dopexamine versus placebo in aortic surgery

BACKGROUND: Mechanisms involved in the development of colon- ic ischaemia are not fully understood and there are conflicting reports regarding predisposing factors. The aim of this study was to evaluate the effect of dopexamine hydrochloride on the incidence of colonic ischaemia following aortic surgery and to correlate immunohistochemical markers of inflammatory activation in its pathogenesis. METHODS: Thirty patients, of mean age 65 (range 46-84) years, undergoing elective infrarenal aortic surgery were randomized to receive a perioperative infusion of either dopexamine 2 &mgr;g kg-1 min-1 (n = 12) or 0.9 per cent saline placebo (n = 18). All patients underwent colonoscopy and biopsy following induction of anaesthesia and at 1 week after operation. Sections were stained with haematoxylin and eosin, and for mast cell tryptase (MCT), myeloperoxidase (MPO) and both the inducible (iNOS) and endothelial (eNOS) isoforms of nitric oxide synthase. Sections were analysed blindly and independently by two histopathologists. Patient and operative data were collected and stored separately. RESULTS: Colonic ischaemia was noted in nine patients based on microscopic findings. Endoscopy alone had a sensitivity of 56 per cent. There was a significantly lower incidence of colonic ischaemia in patients receiving dopexamine compared with placebo (P < 0.05). One death resulted from colonic infarction in the placebo group 11 days after operation. There was increased MPO and MCT expression in patients with histological evidence of ischaemia (P < 0.05); iNOS staining within the vascular (P = 0.001) and lamina propria (P < 0.05) components of the mucosa was also significantly greater. No association was found with eNOS. CONCLUSION: Perioperative dopexamine infusion confers a degree of protection to colonic mucosa following aortic surgery, possibly through an anti-inflammatory effect.

Journal Article↗
PubMed1999

Variations of the pursestring suture in skin cancer reconstruction.

BACKGROUND: The pursestring suture (PSS) utilizes a circumferentially placed intradermal suture to decrease the size of a defect. Its primary application in dermatologic surgery has been to allow placement of a smaller full-thickness skin graft and to enhance secondary intention wound healing. OBJECTIVE: To present our experience with 3 variations of the PSS. METHODS: The oval defects resulting after surgical excision of cutaneous malignancies were managed with 3 variations of the traditional pursestring technique. These variations included (1) complete closure of the PSS-reduced defect by the placement of traditional interrupted sutures; (2) PSS with the Burow's triangle graft; (3) use of a PSS only part way around an oval defect to avoid distortion of a nearby free margin. RESULTS: In the 7 years of performing these variations of the PSS technique, we have consistently achieved favorable results. CONCLUSION: We report 3 simple-to-use variations of the PSS technique that have been extremely useful in the management of cutaneous malignancies.

Facial Neoplasms↗
PubMed1999

Studies of human immunodeficiency virus type 1 mucosal viral shedding and transmission in Kenya.

If human immunodeficiency virus type 1 (HIV-1) vaccines are to be highly effective, it is essential to understand the virologic factors that contribute to HIV-1 transmission. It is likely that transmission is determined, in part, by the genotype or phenotype (or both) of infectious virus present in the index case, which in turn will influence the quantity of virus that may be exchanged during sexual contact. Transmission may also depend on the fitness of the virus for replication in the exposed individual, which may be influenced by whether a virus encounters a target cell that is susceptible to infection by that specific variant. Of interest, our data suggest that the complexity of the virus that is transmitted may be different in female and male sexual exposures.

Adult↗
PubMed1999

A controlled trial of chlorofluorocarbon-free triamcinolone acetonide inhalation aerosol in the treatment of adult patients with persistent asthma. Azmacort HFA Study Group.

STUDY OBJECTIVE: To compare the dose response, efficacy, and safety of inhaled triamcinolone acetonide (TAA) with a hydrofluoroalkane (HFA) propellant (75 microg/puff), TAA with a chlorofluorocarbon propellant (dichlorodifluoromethane [P-12]; 75 microg/puff), and placebo in adult patients with persistent asthma. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, parallel-group study of 514 adult patients with persistent asthma. INTERVENTIONS AND MEASUREMENTS: Patients received 8 weeks of treatment with 150, 300, or 600 microg/d of TAA HFA, the same doses of TAA P-12, or placebo following a 5- to 21-day baseline period. Efficacy was assessed by spirometry, and by daily recordings of albuterol use, peak expiratory flow (PEF), asthma symptom ratings, and nighttime awakenings throughout the study. RESULTS: Linear trend analysis showed that both formulations of TAA at all doses produced statistically significant improvements compared with placebo in spirometry, asthma symptom scores, albuterol use, and PEF. Significant improvement was seen as early as 24 h for morning PEF and as early as 1 week for FEV(1) (TAA HFA, 600 microg/d; TAA P-12, 300 and 600 microg/d) and albuterol use (all doses of both formulations). The P-12 and HFA formulations had comparable efficacy. A dose response showing greater improvement with higher doses was evident for the majority of parameters for both formulations. The incidences of adverse events were similar across all treatment groups with no dose-related trends. CONCLUSION: HFA and P-12 formulations of TAA inhalation aerosol were therapeutically equivalent and showed comparable safety and dose-related efficacy in the treatment of patients with persistent asthma.

Administration, Inhalation↗
PubMed1999

A multiple-dosing, placebo-controlled study of budesonide inhalation suspension given once or twice daily for treatment of persistent asthma in young children and infants.

RATIONALE: Topical antiinflammatory medications such as inhaled corticosteroids are recommended for therapy of asthma, but no formulation suitable for administration to infants and young children is available in the United States. METHODS: This was a 12-week, multicenter, double-blind, randomized, parallel-group study comparing the efficacy and safety of four dosing regimens of bude-sonide inhalation suspension (BIS) or placebo in 480 asthmatic infants and children (64% boys), ages 6 months to 8 years, with moderate persistent asthma. Approximately 30% of children were previously on inhaled corticosteroids that were discontinued before the study. Active treatments were comprised of BIS 0.25 mg once daily (QD), 0.25 mg twice a day (BID), 0.5 mg BID, or 1.0 mg QD. Efficacy was assessed by twice daily recording at home of asthma symptom scores and use of rescue medication, and discontinuation from the study because of worsening asthma and/or a requirement for systemic steroids. Peak flow measurements were recorded twice daily on diary and spirometry was recorded at clinic visits for those children able to perform these tests. Safety was assessed by reported adverse events and by cortisol testing (adrenocorticotropic hormone stimulation) in a subset of patients. RESULTS: Patients enrolled had an average duration of asthma of 34 months; the mean asthma symptom score was approximately 1.3 (scale of 0-3). All dosing regimens with BIS produced statistically significant improvement in various clinical efficacy measures for asthma control compared with placebo. The lowest dose used, 0.25 mg QD, was efficacious but with fewer efficacy parameters than seen with the other doses administered. Separation between active treatment and placebo in daytime and nighttime symptom scores were observed by week 2 of treatment for all BIS treatment regimens. A significant increase in peak flow measurement was observed in most active treatment groups compared with placebo in the subset of children able to do pulmonary function testing. All treatment groups showed numerical improvement in forced expiratory volume in 1 second but only the 0.5-mg BID dose was significantly different from placebo. Adverse events for the entire group and response to adrenocorticotropic hormone in a subgroup of children who underwent cortisol testing before and at the end of the treatment period were no different in budesonide-treated patients in comparison to placebo. CONCLUSION: Results of this study demonstrate that BIS is effective and safe for infants and young children with moderate persistent asthma in a multiple dose range, and that QD dosing is an important option to be considered by the prescribing physician.

Administration, Inhalation↗
PubMed1999

Web-based teledermatology consult system: preliminary results from the first 100 cases.

The TRICARE Region 1 Teledermatology Consortium has developed a secure web-based "store and forward" consult system designed to allow medical treatment facilities throughout the region to submit dermatology consults. Realizing that there is very little objective data on teledermatology, we have begun to evaluate our system through the integration of questionnaires for patients, referring physicians, and consultants in addition to telephonic patient follow up. We report the preliminary data from the first 100 cases received in the first two months since partly deploying the web based teledermatology consult system in the Tricare Region I (Northeast United States). We primarily address system effectiveness (percentage of cases that required follow up to dermatology and/or primary care physicians, adequacy of evaluating pigmented lesions) diagnostic agreement, acceptance, effect on access to care, and educational value to the primary care physicians.

Attitude of Health Personnel↗
PubMed1998

Pretreatment with intralesional hyaluronidase prior to excision of dermatofibrosarcoma protuberans.

Dermatofibrosarcoma protuberans (DFSPs) are an uncommon malignancy that commonly recur, but rarely metastasize. The origin of DFSPs is controversial; however, they stain with the progenitor marker CD34. DFSPs usually show increased stromal mucin, mainly hyaluronic acid (HA). HA increases cellular proliferation, delays differentiation and increases cellular motion. We evaluated the pretreatment of DFSPs with intralesional injections of hyaluronidase (HD) prior to the surgical excision. Five of nine cases of DFSPs were pretreated with HD. In HD-pretreated cases the margins for excision of the residual tumor were reduced. HD pretreatment also decreased CD34 staining and increased polarizable collagen in the residual tumor.

Adult↗
PubMed1998

Prevalence of sensitization to aeroallergens in California patients with respiratory allergy. Allergy Skin Test Project Team.

BACKGROUND: The number of allergy skin tests required to evaluate patients with respiratory allergy has recently been challenged by the managed care community. OBJECTIVES: The purpose of this study was to determine which aeroallergens are prevalent in patients with respiratory allergy (allergic rhinitis and bronchial asthma) in California. METHODS: Utilizing aeroallergens thought to be relevant from recent aerobiologic and botanic data, 141 allergic and 17 asymptomatic control subjects were tested for the prevalence of 103 allergens. A standardized prick puncture technique and standardized interpretation of wheal/flare responses were utilized using the same lot of allergen for 13 allergy practices distributed throughout California. Frequency curves based on prevalence were established to determine the number of tests required to give up to 90% of positive responses for tree, weed and grass pollen, mold spores, and miscellaneous allergens which included house dust mite, cat, dog, and cockroach allergens. RESULTS: Positive responses in allergic subjects for grasses ranged from 46% to 54%, for weeds 19% to 37%, and for trees 10% to 42%. For molds the range was from 11% to 22%. The response rate for Dermatophagoides pteronyssinus was 53%, for Dermatophagoides farinae 42%, for cat pelt 39% and cat hair 37%, for cockroach 23% and dog dander 19%. Asymptomatic control subjects responded to only 4% of all allergens tested. Ninety percent of all positive tests required three miscellaneous allergens (house dust mite, cat, and cockroach), 9 molds, 2 grasses, 16 weeds, and 27 trees for a total of 57 allergens (56% of total tested). There was no clear relationship between locale and specific allergen response, probably related to the limited number of subjects tested and variability within the same geographic region. Several seldom tested tree and weed allergens showed a higher prevalence rate than several commonly tested for allergens. CONCLUSIONS: This preliminary study suggests that approximately 57 aeroalleroens might be adequate to detect 90% of all positive responses in patients with respiratory allergy in California. This study was limited by subject number and variability between study sites. It is hoped a standardized model can be developed from this pilot study to definitively determine which aeroallergens are relevant in the United States.

Adult↗
PubMed1998

Structure of the CheY-binding domain of histidine kinase CheA in complex with CheY.

Bacterial adaptation to the environment is accomplished through the coordinated activation of specific sensory receptors and signal processing proteins. Among the best characterized of these pathways are those which employ the two-component paradigm. In these systems, signal transmission is mediated by Mg(2+)-dependent phospho-relay reactions between histidine auto-kinases and phospho-accepting receiver domains in response-regulator proteins. Although this mechanism of activation is common to all response-regulators, detrimental cross-talk between different two-component pathways within the same cell is minimized through the use of specific recognition domains. Here, we report the crystal structure, at 2.95 A resolution, of the response regulator of bacterial chemotaxis, CheY, bound to the recognition domain from its cognate histidine kinase, CheA. The structure suggests that molecular recognition, in this low affinity complex (KD = 2 microM), may also contribute to the mechanism of CheY activation.

Amino Acid Sequence↗
PubMed1998

Histological study of colonic ischaemia after aortic surgery.

BACKGROUND: Colonic ischaemia is a well documented complication of abdominal aortic reconstruction. In this prospective study patients had routine preoperative and postoperative colonoscopy and biopsy, in order to determine the true incidence and implications. METHODS: Fifty-six patients undergoing elective infrarenal aortic surgery, 28 for aneurysm and 28 for occlusive disease, had colonoscopy and biopsy before and 1 week after operation. RESULTS: Colonic ischaemia was identified histologically in biopsies from 16 (30 per cent) of 53 patients. Almost half the patients had normal macroscopic appearances. Two factors exhibited a statistically significant association with the development of ischaemia: prolonged cross-clamp time (P < 0.05) and postoperative diarrhoea (P< 0.001). Co-morbidity was much higher in patients with colonic ischaemia (P< 0.005). Overall morbidity was significantly greater in the aneurysm group (P < 0.05). CONCLUSION: Colonic ischaemia is common after aortic reconstruction. When suspected, colonoscopy with biopsy is diagnostic.

Aged↗
PubMed1997

A short-range signal restricts cell movement between telencephalic proliferative zones.

During telencephalic development, a boundary develops that restricts cell movement between the dorsal cortical and basal striatal proliferative zones. In this study, the appearance of this boundary and the mechanism by which cell movement is restricted were examined through a number of approaches. The general pattern of neuronal dispersion was examined both with an early neuronal marker and through the focal application of DiI to telencephalic explants. Both methods revealed that, although tangential neuronal dispersion is present throughout much of the telencephalon, it is restricted within the boundary region separating dorsal and ventral telencephalic proliferative zones. To examine the cellular mechanism underlying this boundary restriction, dissociated cells from the striatum were placed within both areas of the boundary, where dispersion is limited, and areas within the cortex, where significant cellular dispersion occurs. Cells placed within the boundary region remain round and extend only thin processes, whereas progenitors placed onto the cortical ventricular zone away from this boundary are able to migrate extensively. This suggests that the boundary inhibits directly the migration of cells. To examine whether the signal inhibiting dispersion within the boundary region acts as a long- or short-range cue, we apposed explants of boundary and nonboundary regions in vitro. Within these explants we found that migration was neither inhibited in nonboundary regions nor induced in boundary regions. This suggests that the boundary between dorsal and ventral telencephalon isolates these respective environments through either a contact-dependent or a short-range diffusible mechanism.

Acridine Orange↗