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Biomedical subjects

B Smith

Publications and source records attributed to B Smith.

At least 163 records · Page 9Linked to original sources
PubMed1997

Asthma prevalence, morbidity and management practices in South Australia, 1992-1995.

BACKGROUND: The Spring South Australian Health Omnibus Survey (SSAHOS) has been used to monitor trends in asthma prevalence, asthma morbidity and asthma management practices between 1992 and 1995. AIMS: To determine if self-reported asthma prevalence and availability of asthma action plans were increasing. To identify deficiencies in asthma management and opportunities for intervention. METHODS: Representative population survey by trained interviewers using a multistage, systematic, clustered area sample of 4200 households in South Australia where people aged 15 years or more are living. RESULTS: Over 3000 interviews were conducted each year. Between 1992 and 1995 the self-reported prevalence of asthma in those aged 15 years or more increased significantly from 15.7% to 20.3% (p < 0.0005), and the prevalence of current asthma increased from 9.3% to 11.4% (p < 0.05). The self-reported availability of individual asthma action plans increased from 21.9% in 1992 to 42.2% in 1995 (p < 0.0005). In 1992, 21% had a nebuliser at home, and 10.5% had a peak flow meter. In 1993, 61.4% were using preventive medications, and 35% thought bronchodilators were 'preventer' medications. In 1994 and 1995, between 12.5% and 15.6% had nocturnal awakening weekly or more often, and 31.4% had morning asthma symptoms weekly or more often. Between 20.1% and 20.8% had lost days from usual activities during the last year. Those on incomes below $20,000 had more symptoms, had more admissions to hospital, and required more medication than those on higher incomes. CONCLUSIONS: Self-reported asthma prevalence has increased. There remains a gap between current asthma management and that recommended by the National Asthma Campaign.

Adolescent↗
PubMed1997

How general practitioners manage acute asthma attacks.

BACKGROUND: The management of asthma attacks by general practitioners in 1992/93 was compared with 1991/92 in relation to recommended guidelines. METHODS: The findings from a postal survey of 299 UK general practitioners who managed 2332 patients with an asthma attack in 1992/93 were compared with those from 218 practitioners who managed 1805 attacks in 1991/92. Management by a subgroup of practitioners from a special interest group was analysed separately. RESULTS: In 1992/93 2031 (87%) of attacks were managed entirely by general practitioners, 251 (11%) were referred for admission to hospital, and 50 (2%) were managed by an accident and emergency department. There was no change in the pattern of management relative to 1991/92. Compared with recommended guidelines there was underuse of systemic steroids and nebulised bronchodilators. Between 1991/92 and 1992/93 use of systemic steroids in acute attacks increased from 56% to 71%, nebulised bronchodilators from 31% to 32%, and an increase in prophylactic medication after an acute attack from 41% to 49%. Contrary to guidelines, antibiotic use increased from 32% to 40% of attacks. Practitioners from a special interest asthma group gave more of their patients systemic steroids and nebulised bronchodilators both in 1991/92 and 1992/93. CONCLUSIONS: Some aspects of the management of asthma attacks by general practitioners has changed in line with guidelines, but there is still a large gap between actual and recommended management.

Acute Disease↗
PubMed1997

Does creatinine adjustment of urinary pregnanediol glucuronide reduce or introduce measurement error?

Correlation between urinary pregnanediol and serum progesterone measurements and the influence of age, race, smoking and urinary creatinine adjustment was determined during the luteal phase of the menstrual cycle in 175 volunteers. A decline in serum progesterone was observed with increasing age. Mean baseline urinary creatinine declined with increasing age in non-smokers and was not affected by race or baseline weight. An excellent correlation between urinary pregnanediol glucuronide and serum progesterone levels existed except when urinary pregnanediol concentrations were adjusted using creatinine measurements in older individuals. Adjustment of urinary pregnanediol glucuronide concentration using creatinine measurement is therefore discouraged.

Adult↗
PubMed1997

Effects of anesthesia of the palmar digital nerves on kinematic gait analysis in horses with and without navicular disease.

OBJECTIVE: To determine the effect of local anesthesia of the palmar digital nerves on forelimb kinematics in Quarter Horses with and without navicular disease. ANIMALS: 12 adult Quarter Horses; 5 clinically normal (sound) and 7 with navicular disease. PROCEDURE: Kinematic measurements were made on adult horses trotting on a treadmill, before and after palmar digital nerve block (PDNB). Twenty-three displacement, joint angle, and temporal gait measurements of the right forelimb and head were made for 5 strides in each horse. Initial (before local anesthesia) right forelimb measurements were obtained after a left forelimb PDNB. Kinematic measurements were compared before and after PDNB of the right forelimb by multiple ANOVA with an alpha = 0.05, adjusted for posthoc comparisons by Bonferroni correction. RESULTS: In sound horses, the only significant change in kinematic measurements after PDNB nerve block was in the maximum extension of the metacarpophalangeal joint at mid-stance, which was decreased by an angle of 2 degrees. In horses with navicular disease, mean maximum extension of the metacarpophalangeal joint during stance phase and maximum flexion of the carpal joint during swing phase were significantly increased after PDNB. Also, total stance phase, cranial stance phase, and break-over durations were significantly shorter. In horses with navicular disease, differences between minimum head heights during stance phase of each forelimb and total vertical head excursion during a complete stride were significantly smaller after PDNB. CONCLUSION: Several kinematic measurements of gait can be used to determine improvement of lameness in horses with navicular disease after PDNB block while trotting on a treadmill.

Analysis of Variance↗
PubMed1997

Does participation in distance learning and audit improve the care of patients with acute asthma attacks? The General Practitioners in Asthma Group.

OBJECTIVE: To test whether general practitioners who completed an audit cycle encompassing a data recording exercise, distance learning programme and personalized feedback changed their management of patients with acute asthma attacks. DESIGN, SETTING AND SUBJECTS: Practice and patient details from two national correspondence surveys of the management of acute asthma attacks in the United Kingdom in 1991-92 and 1992-93 were compared. Main outcome measures were use of nebulised bronchodilators, systemic steroids during an asthma attack, and increased use of prophylactic therapy after attacks. RESULTS: Ninety-one general practitioners completed an audit cycle and reported data on 782 patients with asthma attacks in 1991-92 and 669 in 1992-93. There were no significant changes in practice resources during this time. Management changed in line with recommended guidelines and audit feedback suggestions leading to more use of nebulised bronchodilators [272 (35%) before, 268 (40%) after, Odds Ratio (OR) 0.80, 95% Confidence Intervals (CI) 0.64-0.99], systemic steroids [563 (72%) before, 506 (76%) after, OR 0.83, CI 0.65-1.06], and 'step-up' in preventative therapy [402 (51%) before, 382 (57%) after, OR 0.79, CI 0.64-0.98]. CONCLUSION: General Practitioners who completed an audit cycle showed changes in the management of acute asthma attacks in line with guidelines which may have been caused by participation in distance learning and clinical audit. However, general practitioners motivated to change clinical management may be similarly motivated to take part in audit. Audit may be the catalyst for change rather than the cause of change.

Acute Disease↗
PubMed1996

Essential role of beta-adrenergic receptor kinase 1 in cardiac development and function.

The beta-adrenergic receptor kinase 1 (beta ARK1) is a member of the G protein-coupled receptor kinase (GRK) family that mediates the agonist-dependent phosphorylation and desensitization of G protein-coupled receptors. We have cloned and disrupted the beta ARK1 gene in mice by homologous recombination. No homozygote beta ARK1-/- embryos survive beyond gestational day 15.5. Prior to gestational day 15.5, beta ARK1-/- embryos display pronounced hypoplasia of the ventricular myocardium essentially identical to the "thin myocardium syndrome" observed upon gene inactivation of several transcription factors (RXR alpha, N-myc, TEF-1, WT-1). Lethality in beta ARK1-/- embryos is likely due to heart failure as they exhibit a > 70% decrease in cardiac ejection fraction determined by direct in utero intravital microscopy. These results along with the virtual absence of endogenous GRK activity in beta ARK1-/- embryos demonstrate that beta ARK1 appears to be the predominant GRK in early embryogenesis and that it plays a fundamental role in cardiac development.

Animals↗
PubMed1996

Randomised controlled trial of steroid withdrawal in renal transplant recipients receiving triple immunosuppression.

BACKGROUND: The combination of cyclosporin, azathioprine, and prednisolone (triple immunosuppression) is the most commonly used immunosuppressive regimen early after renal transplantation, but the risks and benefits of maintaining the steroid component of this regimen in the long term are uncertain. METHODS: A randomised controlled trial of steroid withdrawal was conducted among renal transplant patients receiving triple immunosuppression. Between one and six years after transplantation, 100 such patients were randomised either to reduce prednisolone treatment to zero over about four months or to maintain their triple immunosuppression unchanged. Outcome was analysed according to "Intention-to-treat". FINDINGS: In 42 (86%) of 49 patients allocated to steroid withdrawal, complete steroid withdrawal was achieved. Although these patients did not experience defined acute rejection episodes, insidious increases in plasma creatinine were observed more frequently in this group than in the controls. In 97 patients surviving one year after trial entry, plasma creatinine exceeded the baseline by more than 25% at some time in the first year in 25 (53%) of 47 in the steroid withdrawal group compared with 9 (18%) of 50 in the control group (p < 0.001, chi-square test). In some cases these increases were transient. However, when corrected for the baseline (entry) value significant differences between groups were apparent in both mean plasma creatinine and mean creatinine clearance; mean (SD) plasma creatinine values at entry, immediately after withdrawal, and at one year were 138 (27), 151 (36), and 150 (36) mumol/L in the steroid withdrawal group versus 138 (34), 140 (51), and 139 (47) mumol/L in the control group (p = 0.017, analysis of covariance). Steroid withdrawal patients showed a further rise in mean plasma creatinine to 160 (44) and 161 (65) mumol/L at two and three years from trial entry. Changes in several clinical and metabolic indices were also observed in association with steroid withdrawal. Blood pressure declined but the reduction was incompletely sustained, being more evident immediately after steroid withdrawal than at one year. Total cholesterol declined about 1 mmol/L in the steroid withdrawal group. Other changes associated with steroid withdrawal were reductions in white cell count and haemoglobin and increases in plasma phosphate and alkaline phosphatase. INTERPRETATION: Late steroid withdrawal is feasible in most patients with stable graft function on triple immunosuppression and has potentially beneficial metabolic effects. However, a substantial proportion of patients show a reduction in graft function, indicating a need for caution in considering the long term outcome.

Adult↗
PubMed1996

The soluble catalytic domain of membrane type 1 matrix metalloproteinase cleaves the propeptide of progelatinase A and initiates autoproteolytic activation. Regulation by TIMP-2 and TIMP-3.

It has been proposed that the cell-mediated activation of progelatinase A requires binding of the C-terminal domain of the proenzyme to a membrane-associated complex of the membrane type matrix metalloproteinase MT1-MMP and TIMP-2. Subsequent sequential proteolysis of the propeptide by MT1-MMP and gelatinase A is thought to generate the active form of gelatinase A. We have prepared the proform of the catalytic domain of the MT1-MMP and demonstrated that this may be activated in vitro by trypsin proteolysis to yield a functional proteinase capable of cleaving typical metalloproteinase peptide substrates, gelatin and casein. The active catalytic domain of MT1-MMP was also shown to activate progelatinase A to a fully active form. Using the inactive mutant pro-E375A gelatinase A, we dissected the propeptide processing events that occur. MT1-MMP cleaves the propeptide at the sequence Asn37-Leu38 only. Further cleavage of the mutant enzyme propeptide at Asn80-Tyr81, equivalent to that of the active wild type gelatinase A, could only be effected by addition of gelatinase A to the system. TIMP-1 was essentially unable to prevent MT1-MMP processing of wild type or E375A progelatinase A, whereas TIMP-2 and TIMP-3 were good inhibitors of these events. Analysis of the rate of binding of TIMPs to the catalytic domain of MT1-MMP using kinetic methods showed that TIMP-1 is an extremely poor inhibitor of MT1-MMP. In comparison, TIMP-2 and TIMP-3 are excellent inhibitors, binding more rapidly to the catalytic domain of MT1-MMP than to the catalytic domain of gelatinase A. These data demonstrate the basic mechanism of MT1-MMP action on progelatinase A and the reason for the lack of inhibition by TIMP-1 previously demonstrated in cell-based activation studies.

Amino Acid Sequence↗
PubMed1996

Cellular mechanisms for human procollagenase-3 (MMP-13) activation. Evidence that MT1-MMP (MMP-14) and gelatinase a (MMP-2) are able to generate active enzyme.

Gelatinase A and membrane-type metalloproteinase (MT1-MMP) were able to process human procollagenase-3 (Mr 60,000) to the fully active enzyme (Tyr85 N terminus; Mr 48,000). MT1-MMP activated procollagenase-3 via a Mr 56,000 intermediate (Ile36 N terminus) to 48,000 which was the result of the cleavage of the Glu84-Tyr85 peptide bond. We have established that the activation rate of procollagenase-3 by MT1-MMP was enhanced in the presence of progelatinase A, thereby demonstrating a unique new activation cascade consisting of three members of the matrix metalloproteinase family. In addition, procollagenase-3 can be activated by plasmin, which cleaved the Lys38-Glu39 and Arg76-Cys77 peptide bonds in the propeptide domain. Autoproteolysis then resulted in the release of the rest of the propeptide domain generating Tyr85 N-terminal active collagenase-3. However, plasmin cleaved the C-terminal domain of collagenase-3 which results in the loss of its collagenolytic activity. Concanavalin A-stimulated fibroblasts expressing MT1-MMP and fibroblast-derived plasma membranes were able to process human procollagenase-3 via a Mr 56,000 intermediate form to the final Mr 48,000 active enzyme which, by analogy with progelatinase A activation, may represent a model system for in vivo activation. Inhibition experiments using tissue inhibitor of metalloproteinases, plasminogen activator inhibitor-2, or aprotinin demonstrated that activation in the cellular model system was due to MT1-MMP/gelatinase A and excluded the participation of serine proteinases such as plasmin during procollagenase-3 activation. We have established that progelatinase A can considerably potentiate the activation rate of procollagenase-3 by crude plasma membrane preparations from concanavalin A-stimulated fibroblasts, thus confirming our results using purified progelatinase A and MT1-MMP. This new activation cascade may be significant in human breast cancer pathology, where all three enzymes have been implicated as playing important roles.

Amino Acid Sequence↗
PubMed1996

The serotonin transporter is a potential susceptibility factor for bipolar affective disorder.

The serotonin transporter is a strong candidate for aetiological involvement in affective disorders and psychosis. We analysed a VNTR in intron 2 of the human serotonin transporter gene (hSERT) for allelic association with bipolar affective disorder, unipolar depression and schizophrenia. An increased frequency of allele 12 of the VNTR was observed in subjects with bipolar affective disorder (n = 191; chi 2 p = 0.00048 by allele) but not unipolar depression (n = 86; chi 2 p = 0.18, ns) or schizophrenia (n = 129; chi 2 p = 0.08, ns), although a trend towards an excess of allele 12 was observed for the latter. There was also a significant difference in the frequency of allele 12 between bipolar affective disorder and unipolar depression (p = 0.0087). The relative risk for bipolar affective disorder with respect to allele 12 was 1.84 (95% CI 0.97-3.56) for heterozygotes, and 3.10 (95% CI 1.60-6.07) for homozygotes, with evidence for a gene-dosage effect. Because allele 12 is common in the population, the attributable risk is 50.8% (95% CI 14.5%-73.3%). We hypothesize that either the VNTR affects regulation of expression of hSERT at the transcriptional level or it is in linkage disequilibrium with another functional polymorphism in the gene, and this results in an increased risk for the development of bipolar affective disorder.

Alleles↗
PubMed1996

Characterization of a novel component of the peroxisomal protein import apparatus using fluorescent peroxisomal proteins.

Fluorescent peroxisomal probes were developed by fusing green fluorescent protein (GFP) to the matrix peroxisomal targeting signals PTS1 and PTS2, as well as to an integral peroxisomal membrane protein (IPMP). These proteins were used to identify and characterize novel peroxisome assembly (pas) mutants in the yeast Pichia pastoris. Mutant cells lacking the PAS10 gene mislocalized both PTS1-GFP and PTS2-GFP to the cytoplasm but did incorporate IPMP-GFP into peroxisome membranes. Similar distributions were observed for endogenous peroxisomal matrix and membrane proteins. While peroxisomes from translocation-competent pas mutants sediment in sucrose gradients at the density of normal peroxisomes, >98% of peroxisomes from pas10 cells migrated to a much lower density and had an extremely low ratio of matrix:membrane protein. These data indicate that Pas10p plays an important role in protein translocation across the peroxisome membrane. Consistent with this hypothesis, we find that Pas10p is an integral protein of the peroxisome membrane. In addition, Pas10p contains a cytoplasmically-oriented C3HC4 zinc binding domain that is essential for its biological activity.

Amino Acid Sequence↗
PubMed1996

Biochemical characterization of human collagenase-3.

The cDNA of a novel matrix metalloproteinase, collagenase-3 (MMP-13) has been isolated from a breast tumor library (Freije, J. M. P., Dicz-Itza, I., Balbin, M., Sanchez, L. M., Blasco, R., Tolivia, J., and López-Otin, C. (1994) J. Biol. Chem. 269, 16766-16773), and a potential role in tumor progression has been proposed for this enzyme. In order to establish the possible role of collagenase-3 in connective tissue turnover, we have expressed and purified recombinant human procollagenase-3 and characterized the enzyme biochemically. The purified procollagenase-3 was shown to be glycosylated and displayed a M(r) of 60,000, the N-terminal sequence being LPLPSGGD, which is consistent with the cDNA-predicted sequence. The proenzyme was activated by p-aminophenylmercuric acetate or stromelysin, yielding an intermediate form of M(r) 50,000, which displayed the N-terminal sequence L58EVTGK. Further processing resulted in cleavage of the Glu84-Tyr85 peptide bond to the final active enzyme (M(r) 48,000). Trypsin activation of procollagenase-3 also generated a Tyr85 N terminus, but it was evident that the C-terminal domain was rapidly lost, and hence the collagenolytic activity diminished. Analysis of the substrate specificity of collagenase-3 revealed that soluble type II collagen was preferentially hydrolyzed, while the enzyme was 5 or 6 times less efficient at cleaving type I or III collagen. Fibrillar type I collagen was cleaved with comparable efficiency to the fibroblast and neutrophil collagenases (MMP-1 and MMP-8), respectively. Unlike these collagenases, gelatin and the peptide substrates Mea-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 and Mca-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH2 were efficiently hydrolyzed as well, as would be predicted from the similarities between the active site sequence of collagenase-3 (MMP-13) and the gelatinases A and B. Active collagenase-3 was inhibited in a 1:1 stoichiometric fashion by the tissue inhibitors of metalloproteinases, TIMP-1, TIMP-2, and TIMP-3. These results suggest that in vivo collagenase-3 could play a significant role in the turnover of connective tissue matrix constituents.

Amino Acid Sequence↗
PubMed1996

Noncompliance and treatment failure in children with asthma.

BACKGROUND: Accurate and reliable information about children's use of inhaled medications is needed because of the growing reliance on these drugs in the treatment of asthma and the excessive morbidity and mortality attributable to this disease. OBJECTIVE: This study was designed to evaluate the adherence of children with asthma to regimens of inhaled corticosteroids and beta-agonists. METHODS: Data collected electronically by metered-dose inhaler monitors were compared with data recorded by patients on traditional diary cards. A volunteer sample of 24 children, between 8 and 12 years old, who had asthma for which they were receiving both inhaled corticosteroids and beta-agonists, participated over a 13-week period. Each child was accompanied by a parent to all study visits. The main outcome measures were the use of medication as reported by diary card entries and recorded by electronic monitoring and disease exacerbation, as indicated by requirement for oral corticosteroids. RESULTS: The median use of inhaled corticosteroids reported by patients on their diaries was 95.4%, whereas the median actual use was 58.4%. More than 90% of patients exaggerated their use of inhaled steroids, and diary entries of even the least compliant subjects reflected a high level of adherence. The children who experienced exacerbation of disease sufficient to require a burst of oral corticosteroids differed markedly from the others in their adherence to prescribed therapy as recorded by the electronic monitors. The median compliance with inhaled corticosteroids was 13.7% for those who experienced exacerbations and 68.2% for those who did not. CONCLUSIONS: Electronic monitoring demonstrated much lower adherence to prescribed therapy than was reported by patients on diary cards. Low rates of compliance with prescribed inhaled corticosteroids were associated with exacerbation of disease. Poor control of asthma should alert the physician to the possibility of noncompliance.

Administration, Inhalation↗
PubMed1996

Reverse transcriptase-polymerase chain reaction for expression of tyrosinase to identify malignant melanoma cells in peripheral blood.

BACKGROUND: Circulating tumour cells in the peripheral blood may be important for haematogenous spread of disease. The detection of these cells may therefore be a poor prognostic indicator. Reverse-transcriptase polymerase chain reaction (RT-PCR) of target tumour-specific protein expression has been used as a sensitive and specific method for the detection of these tumour cells. Initial reports by our laboratory and other suggested RT-PCR amplification of the enzyme tyrosinase is a useful method for detection of melanoma cells in peripheral blood [1-3]. PATIENTS AND METHODS: In this report, we have evaluated the application of RT-PCR for tyrosinase mRNA as a detection method for melanoma cells in a series of 24 patients with advanced, metastatic malignant melanoma. A single round RT-PCR method is described. RESULTS: The single round RT-PCR was as sensitive as previously described nested PCR methods, and had the advantage of reduced contamination risks. Blood samples from three out of the twenty-four patients were positive. CONCLUSIONS: The frequency of tumour cell detection in peripheral blood from patients with advanced disease was lower than previously reported. It may be only small numbers of circulating tumour cells are present at any one time in the peripheral blood of patients with malignant melanoma. If this is the case increased sampling will improve detection frequency. Alternatively, dissemination of melanoma through peripheral blood may be a rare event. In our experience, RT-PCR for tyrosinase mRNA as a staging test for melanoma patients must be interpreted cautiously.

Adult↗