Biomedical subjects
Publications and source records attributed to S Welch.
Explore the source record for details and available documents.
OBJECTIVE: To test whether there is any relationship between asthma prevalence and BCG immunization or tuberculin skin text reaction. DESIGN: Cross-sectional survey. SETTING: Secondary school in Haringey, North London, U.K. SUBJECTS: 780 children aged 11-18 years (median 13.35 years). INTERVENTIONS: Administration of tuberculin skin text and questionnaire. MAIN OUTCOME MEASURES: Diagnosis of asthma, presence of nocturnal cough, exercise-induced wheeze or wheeze with viral respiratory infections; diameter of induration with tuberculin skin text; history of BCG immunization. RESULTS: 57 of 629 children (8.5%) had a significantly positive Mantoux reaction (>or=15 millimeters of induration). Children with and without a history of BCG immunization did not differ significantly in prevalence of asthma diagnosis (11.8% vs 14.1%, p > 0.6), exercise-induced wheeze (16.9% vs 21.2%, p>0.4), viral induced wheeze (15.4% vs 7%, p>0.6) or nocturnal cough (32.3% vs 32.7%, p> 0.6). We also found no significant correlation of the prevalence of asthma diagnosis or symptoms with diameter of Mantoux test reaction. CONCLUSION: There is no evidence of an effect of BCG immunization or tuberculin reactivity on the incidence of asthma in secondary school children in Haringey, North London and the exposure to tuberculosis is high in these children.
Explore the source record for details and available documents.
Cardiovascular disease risk is higher in men than women, but the basis for this discrepancy remains controversial. Estrogenic stimulation of the myocardium or isolated cardiomyocytes has been purported to exert multiple beneficial effects associated with inhibition of maladaptive responses to pathogenic insults. This report describes a significant difference between the sexes in myocardial activation of Akt, a protein kinase that regulates a broad range of physiological responses including metabolism, gene transcription, and cell survival. We find that young women possess higher levels of nuclear-localized phospho-Akt(473) relative to comparably aged men or postmenopausal women. Both localization of phospho-Akt(473) in myocardial nuclei of sexually mature female mice versus males and Akt kinase activity in nuclear extracts of hearts from female mice versus males are elevated. Cytosolic localization of phospho-forkhead, a downstream nuclear target of Akt, is also increased in female relative to male mice, suggesting a potential mechanism for cardioprotective nuclear signaling resulting from Akt activation. Phospho-Akt(473) levels and localization at cardiac nuclei are similarly increased in transgenic mice with myocardium-specific expression of insulin-like growth factor I, a proven stimulus for Akt activation. Phospho-Akt(473) is also localized to the nucleus of cultured cardiomyocytes after exposure to 17beta-estradiol or genistein (a phytoestrogen in soy protein-based diets), and neonatal exposure of litters to genistein elevated nuclear phospho-Akt(473) localization. The activation of Akt in a gender-dependent manner may help explain differences observed in cardiovascular disease risk between the sexes and supports the potential beneficial effects of estrogenic stimulation.
BACKGROUND: As many as 15% of hospitalized patients have oropharyngeal dysphagia. The incidence and causes of postoperative oropharyngeal dysphagia (OD) in patients having cardiac operations are poorly documented and the best treatment is uncertain. We undertook a study to evaluate OD in patients having cardiac operations. METHODS: As part of a quality improvement project, all patients operated on in 1998 and 1999 were monitored for the signs or symptoms of OD. Patients with OD had diagnostic and therapeutic interventions to limit adverse outcomes. At the end of the 2-year evaluation period, patient risk factors, diagnoses, results of interventions, and outcomes were measured. RESULTS: Thirty-one out of 1,042, patients (3%) had OD. OD is more common in older patients (p < 0.0001) with diabetes (p = 0.02), renal insufficiency (p = 0.012), hyperlipidemia (p = 0.046), and preoperative congestive heart failure (p < 0.0001), and in those having noncoronary artery bypass procedures (p < 0.0001). One patient with OD died from respiratory arrest, presumably secondary to aspiration. Modified barium swallow (MBS) identified oral dysphagia in 2 patients, pharyngeal dysphagia in 7 patients, and both oral and pharyngeal dysphagia in 17 patients. One patient had a structural defect (cervical osteophyte) causing dysphagia and 4 patients had no identifiable cause of dysphagia on MBS. Postoperative neurologic complications are more common in patients with OD. Ten of 31 patients (32%) with OD had some new neurologic complication after operation compared with 36 of 1,011 (3.5%) who had a postoperative neurologic problem without OD. In 19 patients with OD no cause for swallowing difficulty was identified. Specifically, no metabolic, myopathic, or infectious abnormalities were identified in any patient with OD. Hospital charges were significantly increased in patients with OD ($69,320 versus $36,087, p < 0.0001). Therapy consisting of modification of eating behavior and swallowing technique and in some severe cases enteral or parenteral feeding was successful in all patients except 1, but 4 patients required more than 4 months of supportive care before return to oral feeding was possible. CONCLUSIONS: OD is associated with increased cost and morbidity. Older patients with diabetes, preoperative heart failure, and renal insufficiency are at increased risk for OD. Early recognition and intervention is likely to result in satisfactory outcome but may be associated with a protracted postoperative course.
Explore the source record for details and available documents.
OBJECTIVE: Dilation and hypertrophy often occur concurrently in cardiomyopathy, yet the interaction between these two functionally distinct conditions remains unknown. METHODS: Combinatorial effects of hypertrophy and dilation were investigated by cross-breeding of two cardiomyopathic transgenic mouse lines which develop either hypertrophy (calcineurin-mediated) or dilation (tropomodulin-mediated). RESULTS: Altering the intensity of signals driving hypertrophy and dilation in cross-bred litters resulted in novel disease phenotypes different from either parental line. Augmenting the calcineurin-dependent hypertrophic stimulus in tropomodulin overexpressing transgenics elevated heart:body weight ratios, increased ventricular wall thickness, and significantly accelerated mortality. These effects were evident in calcineurin cross-breeding to tropomodulin backgrounds of transgene homozygosity (severe dilation) or heterozygosity (mild dilation to asymptomatic). Molecular analyses indicated that tropomodulin and calcineurin signaling events in the first week after birth were critical for determination of disease outcome, substantiated by demonstration that temporary neonatal inhibition of tropomodulin expression prevents dilation. CONCLUSIONS: This study shows that postnatal timing of altered signaling in cardiomyopathic transgenic mouse models is a pivotal part of determining outcome. In addition, intensifying hypertrophic stimulation exacerbates dilated cardiomyopathy, supporting the concept of shared molecular signaling between hypertrophy and dilation.
AIM: To assess the feasibility of a randomized clinical trial of supervised injectable versus oral methadone maintenance and to assess medium-term treatment outcomes. DESIGN: Randomized clinical trial of supervised injectable versus supervised oral methadone maintenance treatment (MMT). Trial participants were dependent illicit opiate injectors allocated at intake to supervised injectable or oral methadone maintenance treatment. SETTING: Specialist addictions treatment centre in South London. SUBJECTS: Forty dependent illicit opiate injectors seeking methadone maintenance treatment. INTERVENTIONS: Daily supervised injectable and oral methadone maintenance, delivered at the treatment centre. MAIN OUTCOME MEASURES: Frequency of illicit heroin use and frequency of illicit drug injecting during 30 days before intake to treatment and prior to 6-month follow-up. SECONDARY OUTCOME MEASURES: frequency of use of illicit methadone, crack cocaine, benzodiazepines and alcohol, physical and psychological health symptoms and acquisitive crime. RESULTS: Injectable and oral MMT were both generally acceptable to the study participants: there was a high level of agreement to enter the randomized trial, and subsequent retention in treatment was good. The average number of days of illicit heroin use reduced from 22.2 to 7.6 for the injectable MMT group and from 22.4 to 8.7 for the oral MMT group. The average number of days of illicit injecting reduced from 25.7 to 10.8 days for the injectable group and from 20.1 to 11.9 days for the oral group. Patients' physical and psychological health symptoms and involvement in acquisitive crime also reduced in both groups. Treatment satisfaction ratings at follow-up were higher among patients in the injectable MMT group. The ratio for the actual medication costs between injectable and oral MMT was 6.8:1, and for the direct operational costs was 4.7:1. There was some evidence of a differential patient response with greater reductions in heroin use occurring among patients who were daily illicit injectors and had poorer psychological and physical health (at entry) who were allocated to injectable MMT. CONCLUSIONS: Conduct of the trial has demonstrated that it is feasible to implement supervised injectable methadone maintenance treatment in the context of (although separate from) a specialist oral methadone maintenance service. Patients assigned to receive either supervised injectable or oral MMT had broadly equivalent, positive during-treatment outcomes at 6-month follow-up. Future studies should seek to identify patient characteristics which are linked to good outcome in injectable MMT. Practical evidence-based guidance to physicians about determining which patients are more suitable for injectable MMT is urgently needed.
OBJECTIVES: To describe the mental health of lesbians in New Zealand, and to document their accounts of their experience of mental health services. METHOD: This is a descriptive cross-sectional study. A postal questionnaire, the Lesbian Mental Health Survey, was distributed via lesbian newsletters to 1222 women throughout New Zealand. Mental health measures included the General Health Questionnaire (GHQ-28), Interview Schedule for Social Interaction (ISSI), and respondents' histories of sexual abuse and psychiatric histories. Experiences of mental health services were sought. RESULTS: The estimated response rate was 50.8%. The respondent group were predominantly New Zealand European, highly educated, urban women between 25 and 50 years of age. Three-quarters had identified as lesbian for more than 5 years. Recent self-identification as lesbian was associated with higher GHQ score, as was being younger than 35, having a history of sexual abuse, and not living with a partner. Eighty percent of respondents had used mental health services sometime in their lives and nearly 30 percent of users had received 'lesbian-unfriendly' treatment at some point. One-sixth of respondents had experienced discrimination from service providers in the previous 5 years. CONCLUSION: While the mental health of lesbians is influenced by factors similar to those influencing women's mental health in general, because of social factors, such as stigma and isolation, lesbians may be more vulnerable to common mental illnesses. Health professionals, mental health professionals in particular, need to raise their awareness of the issues lesbians face in dealing with their sexuality, therapeutic relationships and mental health services. Increased training about sexuality for health professionals, as well as further research into areas such as stress and stigma, sexual abuse and attempted suicide among lesbian women, is recommended.
The ras family of small GTP-binding proteins exerts powerful effects upon cell structure and function. One member of this family, rac, induces actin cytoskeletal reorganization in nonmuscle cells and hypertrophic changes in cultured cardiomyocytes. To examine the effect of rac1 activation upon cardiac structure and function, transgenic mice were created that express constitutively activated rac1 specifically in the myocardium. Transgenic rac1 protein was expressed at levels comparable to endogenous rac levels, with activation of the rac1 signaling pathway resulting in two distinct cardiomyopathic phenotypes: a lethal dilated phenotype associated with neonatal activation of the transgene and a transient cardiac hypertrophy seen among juvenile mice that resolved with age. Neither phenotype showed myofibril disarray and hypertrophic hearts were hypercontractilein working heart analyses. The rac1 target p21-activated kinase translocated from a cytosolic to a cytoskeletal distribution, suggesting that rac1 activation was inducing focal adhesion reorganization. Corroborating results showed altered localizations of src in dilated cardiomyopathy and paxillin in both cardiomyopathic phenotypes. This study, the first examination of rac1-mediated cardiac effects in vivo, demonstrates that dilation and hypertrophy can share a common molecular origin and presents evidence that both timing and concurrent signaling from multiple pathways can influence cardiac remodeling.
Accurate interpretation of the results of GH stimulation tests is of pivotal importance not only in the evaluation of the etiology of growth retardation in children but also in the selection of the best candidates for GH therapy. We performed this study to test a novel immunofunctional GH ( IFGH) assay that makes use of the concept that one GH molecule dimerizes two GH receptors and compared the results with those obtained using two GH assays, the Diagnostic Systems Laboratories ELISA and a Hybritech immunoradiometric assay in 19 children with short stature undergoing routine GH stimulation testing. We also tested 13 normally statured control children to revisit the issue of what constitutes normal GH responses to stimuli, using all three assays and arginine and either L-dopa or insulin-induced hypoglycemia as secretagogues. Concentrations of IGF-I, IGF binding protein-3, and acid labile subunit were measured as well. There was a significant correlation between peak IFGH and Diagnostic Systems Laboratories ELISA GH responses to stimuli (r(2) = 0.93) as well as between the Diagnostic Systems Laboratories ELISA and Hybritech immunoradiometric assay (r(2) = 0.91). There were no significant differences between the short stature and normal group in peak or mean GH concentrations regardless of the assay used; however, the IGF-I, IGF binding protein-3, and acid labile subunit concentrations were substantially lower in the short stature group. There was a wide spectrum of GH concentrations in the normal group; approximately 50% of the children had peak GH concentrations <7 ng/mL, approximately 30% <5 ng/mL, and two pubertal normal subjects peaked to only 2 ng/mL with use of both the ELISA and IFGH assays. We conclude that 1) sensitive GH assays, ELISA and immunoradiometric assay, accurately detect a GH capable of generating a biologic signal comparable to an IFGH and 2) that normal GH stimulation test results can be substantially lower than previously accepted. GH-dependent growth factors may be more sensitive indicators of GH sufficiency than GH concentrations in response to pharmacologic stimuli.
We examined the effects of recombinant human (rh) insulin-like growth factor I (IGF-I) vs. rhGH in a variety of metabolic paths in a group of eight severely GH-deficient young adults using an array of contemporary tools. Protein, glucose, and calcium metabolism were studied using stable labeled tracer infusions of L-[1-13C]leucine, [6,6-2H2]glucose, and 42Ca and 44Ca; substrate oxidation rates were assessed using indirect calorimetry; muscle strength was determined by isokinetic and isometric dynamometry of the anterior quadriceps, as well as growth factors, hormones, glucose, and lipid concentrations in plasma before and after 8 weeks of rhIGF-I (60 microg/kg, sc, twice daily), followed by 4 weeks of washout, then 8 weeks ofrhGH (12.5 microg/kg-day, sc); the treatment order was randomized. In the doses administered, rhIGF-I and rhGH both increased fat-free mass and decreased the percent fat mass, with a more robust decrease in the percent fat mass after rhGH; both were associated with an increase in whole body protein synthesis rates and a decrease in protein oxidation. Neither hormone affected isokinetic or isometric measures of skeletal muscle strength. However, rhGH was more potent than rhIGF-I at increasing lipid oxidation rates and improving plasma lipid profiles. Both hormones increased hepatic glucose output, but rhGH treatment was also associated with decreased carbohydrate oxidation and increased glucose and insulin concentrations, indicating subtle insulin resistance. Neither hormone significantly affected bone calcium fluxes, supporting the concept that these hormones, by themselves, are not pivotal in bone calcium metabolism. In conclusion, rhIGF-I and rhGH share common effects on protein, muscle, and calcium metabolism, yet have divergent effects on lipid and carbohydrate metabolism in the GH-deficient state. These differences may allow for better selection of treatment modalities depending on the choice of desired effects in hypopituitarism.
Dilated cardiomyopathy is characterized by decreased contractile function and loss of myofibril organization. Previously unexplored structural and molecular events that precede and initiate dilation can now be studied in tropomodulin-overexpressing transgenic (TOT) mice exhibiting progressive dilated cardiomyopathy. Onset of dilation did not correspond to a change in transgene expression levels, which were more than threefold above normal at birth and remained elevated throughout postnatal life. Similarly, mitogen-activated protein kinase activation (p38, ERK1/ERK2, JNK1/JNK2) was not associated with dilation. In contrast, calcineurin was activated before dilation, presumably due to doubling of intracellular diastolic calcium levels in TOT cardiomyocytes. Amplitude of systolic calcium transients was greatly increased as well, demonstrating the novel and unique calcium handling profile of TOT cardiomyocytes. Loss of myofibril organization was not apparent by confocal microscopy until over 1 week after birth, although neonatal sarcomeric abnormalities were revealed by ultrastructural analysis. Rapid postnatal increases in heart:body weight ratio at 1.5 weeks were followed by two waves of mortality between 2 and 3 weeks after birth coincident with maturational stress. Ultimately, TOT pathogenesis is a compensatory response to altered sarcomeric structure driven by calcineurin activation within days after birth, making TOTs an excellent paradigm for studying the role of calcium overload in dilated cardiomyopathy.
STUDY OBJECTIVE: To assess the incidence and course of immediate and delayed hypersensitivity to Centruroides antivenom. METHODS: We performed a 12-month prospective observation study, with telephone follow-up, evaluating the incidence of anaphylaxis or anaphylactoid reactions and serum sickness after Centruroides antivenom administration. The setting for the study was a poison control center and tertiary care toxicology treatment center. Participants included all patients who received Centruroides antivenom, and no interventions were performed. RESULTS: For immediate hypersensitivity reactions, 116 patients with grade III or IV envenomation received Centruroides antivenom; 77 of these patients were younger than 13 years. Three patients completed the infusion despite development of rash. A fourth patient with a history of atopy and asthma received epinephrine infusion and an inhaled beta-agonist for transient wheezing that quickly resolved; she was admitted for observation. Nine patients without hypersensitivity reactions were admitted for social reasons, for inappropriate sedation from drugs used before antivenom, or to rule out aspiration; all were discharged within 24 hours. The remaining 106 patients were discharged from the emergency department after resolution of symptoms. Thus 4 of 116 patients had immediate reactions. For patients with delayed reactions, 17 patients were lost to follow-up. Of 99 remaining patients, serum sickness developed in 61% (n=60), as defined by using liberal criteria. Serum sickness responded to oral steroids, antihistamines, or both; mean duration of symptoms with medication was 2.8 days. CONCLUSION: Anaphylactic reactions are uncommon after Centruroides antivenom infusion. Self-limited serum sickness that is easily controlled with corticosteroids and antihistamines commonly follows the use of Centruroides antivenom.
AIMS: Before proceeding with the introduction of an overdose fatality prevention programme including teaching in cardio-pulmonary resuscitation and distribution of naloxone, a pre-launch study of treatment and community samples of injecting drug misusers has been undertaken to establish (i) the extent of witnessing overdoses, (ii) the acceptability of naloxone distribution and training; and (iii) the likely impact of such measures. DESIGN AND SETTING: Structured interview of two samples: (a) a community sample of injecting drug misusers recruited by selected privileged access interviewers (PAI) and interviewed by them in community settings and (b) a treatment sample of opiate addicts recruited from our methadone maintenance clinic (interviewed by in-house research staff). PARTICIPANTS: (a) Three hundred and twelve injecting drug misusers with a history of having injected and currently still using injectable drugs; and (b) 142 opiate addicts in treatment at our local catchment area methadone maintenance clinic in South London. FINDINGS: History of personal overdose was found with 38% of the community sample and 55% of the treatment sample--mainly involving opiates and in the company of friends. Most (54% and 92%, respectively) had witnessed at least one overdose (again mostly involving opiates), of whom a third had witnessed a fatal overdose. Only a few (35%) already knew of the existence and effects of naloxone. After explanation to the treatment sample, 70% considered naloxone distribution to be a good proposal. Of the 13% opposed to the proposal, half thought it may lead them to use more drugs. Eighty-nine per cent of those who had witnessed an overdose fatality would have administered naloxone if it had been available. We estimate that at least two-thirds of witnessed overdose fatalities could be prevented by administration of home-based supplies of naloxone. CONCLUSIONS: Substantial proportions of both community and treatment samples of drug misusers have witnessed an overdose death which could have been prevented through prior training in resuscitation techniques and administration of home-based supplies of naloxone. Such a new approach would be supported by most drug misusers. On the basis of these findings, we conclude that it is appropriate to proceed to a carefully constructed trial of naloxone distribution.
AIMS: To examine a range of biological indicators of illicit drug use, including blood, urine, hair and saliva, addressing both technological and practical issues relating to their application and interpretation. METHODS: The review process involved an examination of key reference texts and literature from the scientific fields of analytical and clinical toxicology. FINDINGS: Urine remains the biological tool of choice for qualitative detection of illicit drug use in a clinical setting, while quantitative accuracy remains strictly the domain of blood. The growing sophistication of laboratory analysis may additionally make possible the routine use of hair sampling which can provide a much longer time frame for assessment. Breath, saliva, sweat or breast milk remain possibilities in the future. CONCLUSIONS: Accurate interpretation of the screening tests within a clinical setting alongside other relevant information remains the key to the usefulness of any test.
Sudden cardiac death due to ventricular tachyarrhythmia remains a significant problem in the in-hospital setting. Although the probability of survival is closely correlated with the rapidity of a response by qualified personnel, response times can be prolonged, even in specialized care units. In an effort to decrease response time, a fully automatic external cardioverter defibrillator was recently devised. This device was evaluated in the in-hospital setting to assess safety and efficacy. A total of 79 patients were studied in a multicenter trial. Patients were monitored with fully functional devices in the electrophysiology laboratory (51 patients) and in the cardiac care unit (28 patients). Performance of the device was assessed by comparing automatic responses to any sustained change in cardiac rhythm, either spontaneous or induced, to a retrospective review of stored ECG data and programmed parameters. During a total duration of 964 hours of monitoring, there were 99 episodes of sustained tachycardia. Therapy was appropriately delivered or advised in all episodes. Therapy was advised in one episode of supraventricular tachycardia. There were no episodes of inappropriate therapy delivery. There were no complications or adverse events. The device performed with a sensitivity of 100% and specificity of 98.8% with an average response time of 22 seconds. In conclusion, this automatic external defibrillator was safe, effective, and functioned as designed. Significant improvement in response time to life-threatening ventricular tachyarrhythmia in the in-hospital setting would be expected if this technology was widely adopted.
Loss of myofibril organization is a common feature of chronic dilated and progressive cardiomyopathy. To study how the heart compensates for myofibril degeneration, transgenic mice were created that undergo progressive loss of myofibrils after birth. Myofibril degeneration was induced by overexpression of tropomodulin, a component of the thin filament complex which determines and maintains sarcomeric actin filament length. The tropomodulin cDNA was placed under control of the alpha-myosin heavy chain gene promoter to overexpress tropomodulin specifically in the myocardium. Offspring with the most severe phenotype showed cardiomyopathic changes between 2 and 4 wk after birth. Hearts from these mice present characteristics consistent with dilated cardiomyopathy and a failed hypertrophic response. Histological analysis showed widespread loss of myofibril organization. Confocal microscopy of isolated cardiomyocytes revealed intense tropomodulin immunoreactivity in transgenic mice together with abnormal coincidence of tropomodulin and alpha-actinin reactivity at Z discs. Contractile function was compromised severely as determined by echocardiographic analyses and isolated Langendorff heart preparations. This novel experimentally induced cardiomyopathy will be useful for understanding dilated cardiomyopathy and the effect of thin filament-based myofibril degeneration upon cardiac structure and function.