Mesenchymal stem cell-derived HGF attenuates radiation-induced senescence in salivary glands via compensatory proliferation.

BACKGROUND & AIM: Irradiation of the salivary glands during head and neck cancer treatment induces cellular senescence in response to DNA damage and contributes to radiation-induced hyposalivation by affecting the salivary gland stem/progenitor cell (SGSC) niche. Cellular senescence, such as that induced by radiation, is a state of cell-cycle arrest, accompanied by an altered pro-inflammatory secretome known as the senescence-associated secretory phenotype (SASP) with potential detrimental effects on the surrounding microenvironment. We hypothesized that the pro-regenerative properties of mesenchymal stem cells (MSCs) may attenuate cellular senescence post-irradiation. Therefore, here we evaluated the effects of adipose-derived MSCs (ADSCs) on the radiation-induced response of salivary gland organoids (SGOs). METHODS: Proteomic analyses to identify soluble mediators released by ADSCs co-cultured with SGOS revealed secretion of hepatocyte growth factor (HGF) in ADSCs, suggesting a possible role in the stem cell crosstalk. Next, the effect of recombinant HGF in the culture media of ex vivo grown salivary gland cells was tested in 2D monolayers and 3D organoid models. RESULTS: Treatment with HGF robustly increased salivary gland cell proliferation. Importantly, HGF supplementation post-irradiation enhanced proliferation at lower doses of radiation (0, 3, 7 Gy), but not at higher doses (10, 14 Gy) where most cells stained positive for senescence-associated beta-galactosidase. Furthermore, HGF had no effect on the senescence-associated secretory phenotype (SASP) of irradiated SGOs, suggesting there may be compensatory proliferation by cell-division competent cells instead of a reversal of cellular senescence after irradiation. CONCLUSION: ADSCs may positively influence radiation recovery through HGF secretion and can promote the ex vivo expansion of salivary gland stem/progenitor cells to enhance the effects of co-transplanted SGSC.

ß-Adrenergic signaling induces Notch-mediated salivary gland progenitor cell control.

ß-Adrenergic signaling blockade is a mainstay of hypertension management. One percent of patients taking ß-blockers develop reduced salivary gland (SG) function. Here we investigate the role of SG progenitor cells in ß-blocker-induced hyposalivation, using human SG organoid cultures (SGOs). Compared with control SGs, initial low SG progenitor cell yield from patients taking ß-blockers was observed. When passaged, these SGOs recovered self-renewal and upregulated Notch pathway expression. Notch signaling was downregulated in situ in ß-adrenergic receptor-expressing luminal intercalated duct (ID) cells of patients taking ß-blockers. Control SGOs treated with ß-adrenergic agonist isoproterenol demonstrated increased proportion of luminal ID SGO cells with active Notch signaling. Control SGOs exposed to isoproterenol differentiated into more mature SGOs (mSGOs) expressing markers of acinar cells. We propose that ß-blocker-induced Notch signaling reduction in luminal ID cells hampers their ability to proliferate and differentiate into acinar cells, inducing a persistent hyposalivation in some patients taking ß-blocking medication.

Cost-effectiveness of mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage: an economic evaluation based on the MifeMiso trial.

OBJECTIVE: To assess the cost-effectiveness of mifepristone and misoprostol (MifeMiso) compared with misoprostol only for the medical management of a missed miscarriage. DESIGN: Within-trial economic evaluation and model-based analysis to set the findings in the context of the wider economic evidence for a range of comparators. Incremental costs and outcomes were calculated using nonparametric bootstrapping and reported using cost-effectiveness acceptability curves. Analyses were performed from the perspective of the UK's National Health Service (NHS). SETTING: Twenty-eight UK NHS early pregnancy units. SAMPLE: A cohort of 711 women aged 16-39 years with ultrasound evidence of a missed miscarriage. METHODS: Treatment with mifepristone and misoprostol or with matched placebo and misoprostol tablets. MAIN OUTCOME MEASURES: Cost per additional successfully managed miscarriage and quality-adjusted life years (QALYs). RESULTS: For the within-trial analysis, MifeMiso intervention resulted in an absolute effect difference of 6.6% (95% CI 0.7-12.5%) per successfully managed miscarriage and a QALYs difference of 0.04% (95% CI -0.01 to 0.1%). The average cost per successfully managed miscarriage was lower in the MifeMiso arm than in the placebo and misoprostol arm, with a cost saving of £182 (95% CI £26-£338). Hence, the MifeMiso intervention dominated the use of misoprostol alone. The model-based analysis showed that the MifeMiso intervention is preferable, compared with expectant management, and this is the current medical management strategy. However, the model-based evidence suggests that the intervention is a less effective but less costly strategy than surgical management. CONCLUSIONS: The within-trial analysis found that based on cost-effectiveness grounds, the MifeMiso intervention is likely to be recommended by decision makers for the medical management of women presenting with a missed miscarriage. TWEETABLE ABSTRACT: The combination of mifepristone and misoprostol is more effective and less costly than misoprostol alone for the management of missed miscarriages.

Creating an e-learning module from learning objects using a commentary or 'personal learning assistant'.

The use of learning objects (LOs), small chunks of learning stored digitally and reused or referenced to support learning, was described as a promising approach to the creation of e-learning modules or programmes. In practice, however, the early enthusiasm has waned and the approach has not been widely adopted. It is argued that this was due, at least in part, to a neglect of the pedagogy and an emphasis on the technical aspects of interoperability and reusability. This article describes a practical approach to constructing a learning module using LOs where a commentary links LOs selected for inclusion in the programme. The commentary tells the story of the e-learning module and provides the learner with a context for an LO. It can be viewed as a 'personal learning assistant' that advises students about the management of their learning and relates the e-learning module to the overall learning outcomes for the curriculum. The commentary also allows the lecturer to comment on LOs selected for inclusion in the programme which otherwise might have to be adapted or excluded when the programme was constructed. The use of a commentary to link and introduce LOs has been successfully adopted in the development of e-learning programmes. Teachers are encouraged to consider the approach and to look again at the use of LOs to create e-learning resources.

Integration of e-learning resources into a medical school curriculum.

BACKGROUND: E-learning has the potential to make important contributions to medical education, but there has been limited study of a blended approach in which the digital resources are introduced alongside traditional teaching methods such as lectures. METHODS: We describe the successful embedding of an e-learning resource into 3 of the 5 weeks of cardiovascular system teaching for 164 first-year medical students by providing scheduled slots in the timetables. A questionnaire completed by the students at the end of the 5 weeks had a response rate of 66%. Students varied in how they made use of the resource, some systematically working through it and others browsing and studying sections felt to be personally most relevant. RESULTS: Almost all (96%) rated the e-learning resources as probably or definitely of value: they particularly valued interactive activities, animations, video demonstrations, video clips of experts and self-assessment exercises. Graduate students had a significantly more favourable assessment of the e-learning resources than their undergraduate colleagues, while female students felt the value in supporting existing learning opportunities more strongly than male students. CONCLUSIONS: It should not be assumed that all students will choose to use an e-learning resource in the same way and instructional design should enable alternative approaches. The sequence in which the e-learning resource is used in relation to the other learning opportunities, such as lectures and PBL group discussions, may be important and merits further consideration. The experiences reported in this study provide encouragement and pointers for others engaged in the integration of e-learning in their curriculum.

Mesenchymal differentiation propensity of a human embryonic stem cell line.

OBJECTIVES: To characterize basal differentiation tendencies of a human embryonic stem (hES) cell line, KCL-002. MATERIALS AND METHODS: In vitro specification and differentiation of hES cells were carried out using embryoid body (EB) cultures and tests of pluripotency and in vivo differentiation were performed by teratoma assays in SCID mice. Real-time PCR, immunohistochemistry, flow cytometry and histological analyses were used to identify expression of genes and proteins associated with the ectodermal, endodermal and mesodermal germ layers. RESULTS: Undifferentiated KCL-002 cells expressed characteristic markers of pluripotent stem cells such as Nanog, Sox-2, Oct-4 and TRA 1-60. When differentiated in vitro as EB cultures, expression of pluripotency, endodermal and ectodermal markers decreased rapidly. In contrast, mesodermal and mesenchymal markers such as VEGFR-2, α-actin and vimentin increased during EB differentiation as shown by qPCR, immunostaining and flow cytometric analyses. Teratoma formation in SCID mice demonstrated the potential to form all germ layers in vivo with a greater proportion of the tumours containing mesenchymal derivatives. CONCLUSIONS: The data presented suggest that the KCL-002 hES cell line is pluripotent and harbours a bias in basal differentiation tendencies towards mesodermal and mesenchymal lineage cells. Characterizing innate differentiation propensities of hES cell lines is important for understanding heterogeneity between different cell lines and for further studies aimed at deriving specific lineages from hES cells.

Randomised prospective single-blinded study comparing 'inside-out' versus 'outside-in' transobturator tapes in the management of urodynamic stress incontinence: 1-year outcomes from the E-TOT study.

OBJECTIVE: To compare the 'inside-out' versus 'outside-in' routes for transobturator tape insertion for urodynamic stress incontinence, and to identify independent risk factors for failure at 1 year. DESIGN: Prospective single-blinded randomised trial. SETTING: Tertiary urogynaecology centre. POPULATION: A cohort of 341 women undergoing transobturator tape procedures between April 2005 and April 2007. METHODS: Women were randomised to tension-free vaginal tape-obturator (TVT)-O for the 'inside-out' route (n = 170) and transobturator tape (TOT)-ARIS for the 'outside-in' route (n = 171). Participants completed validated symptom-severity, quality-of-life and sexual-function questionnaires before and after surgery. In addition, they completed the patient global impression of improvement questionnaire (PGI-I) and standard 1-hour pad test postoperatively. MAIN OUTCOME MEASURES: The primary outcome was the patient-reported success rate reported on the PGI-I scale. Secondary outcomes included objective cure rate and improvement in King's Health Questionnaire scores. RESULTS: A total of 341 women were recruited: 171 women to the 'outside-in' (TOT-ARIS) group and 170 to the 'inside-out' (TVT-O) group; 299 completed the 1-year follow up. The patient-reported success rate was 80% with no statistically significant differences between the groups ('outside-in' 77.6% versus 'inside-out' 81.2%; OR 1.25; 95% CI 0.71, 2.20; P = 0.54). The objective cure rate was 91% with no statistically significant difference between the groups ('outside-in' 88% versus 'inside-out' 94%; OR 2.21; 95% CI 0.85, 5.75; P = 0.157). Previous incontinence surgery (OR 1.41; 95% CI 1.18, 1.91; P = 0.029) and preoperative urgency incontinence (OR 1.78; 95% CI 1.21, 3.91, P = 0.048) were significant risk factors for failure of transobturator tape at the 1-year follow up. CONCLUSIONS: There are no significant differences in patient reported and objective cure rates between 'inside-out' and 'outside-in' transobturator tapes. Quality of life and sexual function significantly improved following surgery. Both previous incontinence surgery and preoperative urgency incontinence are associated with significantly lower patient-reported cure rates.

Secondhand smoke exposure and survival following acute coronary syndrome: prospective cohort study of 1261 consecutive admissions among never-smokers.

OBJECTIVE: To determine whether exposure to secondhand smoke is associated with early prognosis following acute coronary syndrome. DESIGN, SETTING AND PARTICIPANTS: We interviewed consecutive patients admitted to nine Scottish hospitals over 23 months. Information was obtained, via questionnaire, on age, sex, smoking status, postcode of residence and admission serum cotinine concentration was measured. Follow-up data were obtained from routine hospital admission and death databases. RESULTS: Of the 5815 participants, 1261 were never-smokers. Within 30 days, 50 (4%) had died and 35 (3%) had a non-fatal myocardial infarction. All-cause deaths increased from 10 (2.1%) in those with cotinine < or =0.1 ng/ml to 22 (7.5%) in those with cotinine >0.9 ng/ml (chi(2) test for trend p<0.001). This persisted after adjustment for potential confounders (cotinine >0.9 ng/ml: adjusted OR 4.80, 95% CI 1.95 to 11.83, p = 0.003). The same dose response was observed for cardiovascular deaths and death or myocardial infarction. CONCLUSIONS: Secondhand smoke exposure is associated with worse early prognosis following acute coronary syndrome. Non-smokers need to be protected from the harmful effects of secondhand smoke.

Impact on mortality following first acute myocardial infarction of distance between home and hospital: cohort study.

OBJECTIVE: To investigate the effect of distance between home and acute hospital on mortality outcome of patients experiencing an incident myocardial infarction (MI). DESIGN: Cohort study using a record linkage database. SETTING: Tayside, Scotland, UK. PATIENTS: 10,541 patients with incident acute MI between 1994 and 2003 were identified from Tayside hospital discharge data and from death certification data. MAIN OUTCOME MEASURES: MI mortality in the community, all-cause mortality in hospital and all-cause mortality during follow-up. RESULTS: 4133 subjects died following incident MI in the community (that is, were not hospitalised), 6408 patients survived to be hospitalised and 1010 of these (15.8%) died in hospital. Of 5398 discharged from hospital, 1907 (35.3%) died during a median of 3.2 years of follow-up. After adjustment for rurality and other known risk factors, distance between home and admitting hospital was significantly associated with increased mortality both before hospital admission (adjusted odds ratio (OR), 2.05, 95% CI 1.00 to 4.21 for >9 miles and 1.46, 1.09 to 1.95 for 3-9 miles when compared to <3 miles) and after hospitalisation (adjusted hazard ratio (HR) 1.90, 1.19 to 3.02 and 1.27, 0.96 to 1.68). However, there was no effect of distance on in-hospital mortality (adjusted OR 0.95, 0.45 to 2.03 and 1.02, 0.66 to 1.58). CONCLUSION: The distance between home and hospital of admission may predict mortality in subjects experiencing a first acute MI. This association was found both before and after hospitalisation. Further studies are needed to explore the reasons for this association. However these data provide support for policies that locate services for acute MI closer to where patients live.

Diagnosis of left ventricular systolic dysfunction (LVSD): development and validation of a clinical prediction rule in primary care.

BACKGROUND: Diagnosing suspected left ventricular systolic dysfunction (LVSD) in the community is a challenge for GPs. We developed and validated a clinical prediction rule (CPR) for LVSD based on history, examination and electrocardiogram (ECG). METHODS: Prospective cohort studies of 458 symptomatic patients (derivation cohort) and 535 patients (validation cohort) in 26 general practices in Tayside and Fife, Scotland. All patients underwent a structured clinical examination and ECG and the 'reference standard' investigation of echocardiography to establish the presence of LVSD. RESULTS: Four elements from the clinical history and examination were all independently associated with LVSD--male sex [adjusted odds ratio (OR) 2.5; 95% CI 1.1, 5.0], presence of orthopnoea (OR 5.4; 1.9, 13.8) history of myocardial infarction (OR 5.6; 2.3, 13.6) and elevated jugular venous pulsations (OR 15.1; 4.6, 49.3). Addition of ECG (OR 20.6; 2.7, 158.6) provides important diagnostic information in terms of probability of LVSD. A CPR based on the presence or absence of these five elements will generate probabilities ranging from 1% to 97% for LVSD when applied to an individual patient. In the validation cohort, the model under-predicted the probability of LVSD, particularly at lower levels of expected risk, reflecting differences in the risk-factor profiles of the derivation and validation cohorts. CONCLUSIONS: The derived CPR provides quantitative estimates of post-test probability for LVSD. This rule requires further validation in other populations and settings because of the difficulties encountered in the validation cohort.

Lower urinary tract injuries after transobturator tape insertion by different routes: a large retrospective study.

OBJECTIVES: To identify the rate of, and risk factors for, lower urinary tract (LUT) injuries associated with the transobturator tension-free vaginal tape (TOT) procedure. DESIGN: Retrospective cohort study. SETTING: Tertiary referral urogynaecology centre. POPULATION: 390 women who underwent transobturator suburethral tapes for management of urodynamic stress incontinence between July 2002 and January 2006. METHODS: Early cases were identified from theatre records and a case note review performed. From May 2005 (n = 94), data from an ongoing prospective audit were reviewed. Data for LUT injuries with TOT procedures were examined and routes of insertion were compared using Fischer's exact test. MAIN OUTCOME MEASURES: Rate of LUT injuries associated with the TOT procedures. Assessment of factors increasing risk of LUT injury, and comparison of the 'outside-in' and 'inside-out' techniques. RESULTS: 241 women underwent TOT outside-in technique and 148 of them underwent inside-out technique. Four LUT injuries occurred (1%): two urethral injuries (0.5%) and two bladder injuries (0.5%). All LUT injuries occurred in the outside-in group, although this difference did not reach significance (P = 0.146). Bladder injuries occurred in women who underwent concomitant vaginal surgery, while urethral injuries occurred in women undergoing secondary procedures. CONCLUSION: LUT injury is an uncommon complication of the TOT procedures, and in our hands only occurred with the outside-in technique. Intraoperative cystoscopy should be considered only in selected cases.

B-type natriuretic peptide can detect silent myocardial ischaemia in asymptomatic type 2 diabetes.

OBJECTIVE: To find out whether B-type natriuretic peptide (BNP) detects silent myocardial ischaemia in patients with type 2 diabetes, since many of these patients have silent ischaemia leading to unexpected cardiac deaths. DESIGN: Prospective cross-sectional study with consecutive recruitment of patients. SETTING: Outpatient, single centre. PATIENTS: 219 patients with type 2 diabetes. Patients were excluded if they had a history or evidence of cardiac failure. OUTCOME MEASURES: BNP, echocardiography and exercise tolerance test (ETT). BNP was compared with the ETT result in all patients and specifically in those who had no apparent ischaemic heart disease (IHD). RESULTS: 121 patients had no history of IHD or cardiac failure and of these patients 85 had a clearly abnormal or normal ETT result. BNP was higher in patients with an abnormal than with a normal ETT (mean 58.2 (SD 46.3) v 24.4 (SD 15.7) pg/ml, p < 0.001). In univariate analysis BNP was an independent predictor of an abnormal ETT (p < 0.001). In multivariate analysis BNP remained an independent predictor of the ETT result. BNP concentration over 20 pg/ml predicted an abnormal ETT result with a sensitivity of 87% and specificity of 37%, and BNP over 40 pg/ml had a sensitivity of 63% and a specificity of 81%. CONCLUSION: BNP is of value in predicting silent ischaemia on exercise testing in asymptomatic patients with type 2 diabetes.

Agreement between community echocardiography and hospital echocardiography in patients suspected of having left ventricular systolic dysfunction.

BACKGROUND: Smaller echocardiography machines, when used in hospitals, are accurate for detecting left ventricular dysfunction and valvular disease. This paper assessed the detection of left ventricular dysfunction and of valvular disease in the community setting by a smaller machine. AIMS: To measure the agreement in patients with suspected heart failure between community echocardiography and traditional echocardiography in the hospital in detecting left ventricular dysfunction and significant valve disease. METHODS: Suspected heart failure patients were referred to one of the authors (SJ) for community echocardiography using a Siemens Cypress machine. The patients had a second echocardiogram in the hospital by another sonographer who was blinded to the results of the first echocardiogram. The reports of the two sonographers were assessed for agreement using kappa statistics. RESULTS: 458 patients had a community echocardiogram and 136 agreed to a second echocardiogram in the hospital. There was excellent agreement, kappa = 0.87 (0.06 SE), for the detection of left ventricular dysfunction between community echocardiography and the hospital machine. The detection of significant valvular disease was good, kappa = 0.75 (0.06) between the community echocardiogram and hospital machines. CONCLUSIONS: In suspected heart failure patients, community echocardiography gives comparable results to traditional hospital echocardiography for left ventricular dysfunction detection and for significant valvular disease detection.

Adoption and integration of simulation-based learning technologies into the curriculum of a UK Undergraduate Education Programme.

CONTEXT: At a time of significant changes in medical education world-wide, the international dimensions and global issues relating to the application of new learning technologies have been recognised. OBJECTIVE: The aim of this paper is to describe the adoption and integration within the curriculum in one United Kingdom (UK) medical school of 'Harvey', the Cardiology Patient Simulator, and the UMedic multimedia computer-based cardiology curriculum - resources developed in a medical school in the USA. PARTICIPANTS: The integration of the resources into the curriculum is described by 3 teachers actively involved in the cardiology curriculum of the UK medical school and 3 teachers associated with the development of resources in the USA. ASPECTS CONSIDERED: The review considers the adoption of Harvey and UMedic in the UK in programmes in relation to: curricular issues, training needs, learning outcomes, curriculum content and sequences of content, educational strategies, teaching and learning methods, assessment, communication about the curriculum and management of the curriculum. CONCLUSIONS: Learning resources, in the form of simulators and computer-based learning modules, developed in one country can be successfully adopted and implemented in another. Facets that facilitated the adoption included close liaison between the developers of the resources in the USA and the implementers in the UK, and careful and systematic planning including in-depth integration of the simulation-based resources into the required curriculum rather than their relegation to a peripheral ad hoc position. The successful use of simulators such as Harvey requires the presence of a 'champion', a clinician educator and a supporting administrative staff who ensure the simulator's appropriate use.

Prospective observational cohort study of time saved by prehospital thrombolysis for ST elevation myocardial infarction delivered by paramedics.

OBJECTIVES: To evaluate a system of prehospital thrombolysis, delivered by paramedics, in meeting the national service framework's targets for the management of acute myocardial infarction. DESIGN: Prospective observational cohort study comparing patients with suspected acute myocardial infarction considered for thrombolysis in the prehospital environment with patients treated in hospital. SETTING: The catchment area of a large teaching hospital, including urban and rural areas. PARTICIPANTS: 201 patients presenting concurrently over a 12 month period who had changes to the electrocardiogram that were diagnostic of acute myocardial infarction or who received thrombolysis for suspected acute myocardial infarction. MAIN OUTCOME MEASURES: Time from first medical contact to initiation of thrombolysis (call to needle time), number of patients given thrombolysis appropriately, and all cause mortality in hospital. RESULTS: The median call to needle time for patients treated before arriving in hospital (n=28) was 52 (95% confidence interval 41 to 62) minutes. Patients from similar rural areas who were treated in hospital (n=43) had a median time of 125 (104 to 140) minutes. This represents a median time saved of 73 minutes (P < 0.001). Sixty minutes after medical contact 64% of patients (18/28) treated before arrival in hospital had received thrombolysis; this compares with 4% of patients (2/43) in a cohort from similar areas. Median call to needle time for patients from urban areas (n=107) was 80 (78 to 93) minutes. Myocardial infarction was confirmed in 89% of patients (25/28) who had received prehospital thrombolysis; this compares with 92% (138/150) in the two groups of patients receiving thrombolysis in hospital. CONCLUSIONS: Thrombolysis delivered by paramedics with support from the base hospital can meet the national targets for early thrombolysis. The system has been shown to work well and can be introduced without delay.

Serological markers of Chlamydia pneumoniae infection in men and women and subsequent coronary events; the Scottish Heart Health Study Cohort.

AIMS: To investigate the relationship between serum markers of Chlamydia pneumoniae infection and subsequent coronary events. METHODS AND RESULTS: In a nested case-control study, based on the Scottish Heart Health Study cohort, we estimated IgG, IgA and IgM antibodies to C. pneumoniae, and circulating immune complexes containing C. pneumoniae antigen in baseline serum samples from 217 cases experiencing a subsequent coronary event during follow-up (mean 7.5 years) and from their matched controls. In men, the proportion of specimens positive for IgG, IgA and IgM antibodies showed no case-control differences (80% vs 80%, 57% vs 53% and 3% vs 3%, respectively). The odds ratio for a coronary event was 1.00 (95% confidence interval 0.59-1.69) for the presence of IgG antibodies to C. pneumoniae; 1.21 (0.76-1.92) for IgA and 0.75 (0.17-3.35) for IgM. Similar results were seen in women. The proportion of specimens with circulating immune complexes with C. pneumoniae antigen also showed no case-control differences (12% vs 12%, both sexes combined) with an odds ratio of 1.00 (0.57-1.76). CONCLUSION: Prior infection with C. pneumoniae, as estimated by these markers, does not appear to be a risk factor for subsequent coronary heart disease.

Circadian variation in the effects of aldosterone blockade on heart rate variability and QT dispersion in congestive heart failure.

OBJECTIVES: The study was designed to comprehensively evaluate the circadian effects of aldosterone blockade on autonomic tone and QT dispersion in chronic heart failure (CHF). BACKGROUND: Spironolactone therapy given in addition to angiotensin-converting enzyme inhibitors improved survival in CHF, but the mechanism of its benefit is uncertain. Experimental evidence suggests that aldosterone may have detrimental effects on the autonomic nervous system, especially during the morning hours. METHODS: Twenty-eight patients with New York Heart Association class II to IV CHF received spironolactone 50 mg daily and placebo for four weeks each in a double-blind crossover fashion. After each treatment phase, a full circadian assessment was undertaken of spironolactone's autonomic effects. The assessment included monitoring heart rate, QT dispersion, continuous Holter recordings, heart rate variability (HRV) and norepinephrine kinetics. RESULTS: Spironolactone significantly reduced all indices of QT dispersion. The reductions in QTcmax, QTd and QTcd were greatest at 6 AM. In addition, spironolactone had favorable autonomic effects, which were limited to the morning (6-10 AM), including heart rate reduction and an improvement in HRV. CONCLUSIONS: Spironolactone reduced heart rate and improved HRV and QT dispersion in CHF. Its effects were particularly prominent during the morning hours.

Chest wall tenderness is unhelpful in the diagnosis of recurrent chest pain.

We investigated whether the presence of chest wall tenderness or fibromyalgia helped to distinguish between ischaemic and non-ischaemic chest pain. Seventy-one patients with recurrent chest pain, 36 with normal (group A) and 35 with abnormal coronary angiograms (group B), were assessed by investigator-administered questionnaires, and were examined for chest wall tenderness and fibromyalgia by a single blinded observer. Chest wall tenderness was greater in group A. However, it was much greater in women, who predominated in group A, than in men, who predominated in group B, and this explained the intergroup difference. Seven patients (25%) (six female, one male) in the group A and one patient (3%) (male) in group B (chi(2) p=0.027) fulfilled criteria for fibromyalgia. Patients with recurrent chest pain are more likely to have a ischaemic cause if they are male. Although our study suggests that chest wall tenderness alone in patients with recurrent chest pain has no value in excluding myocardial ischaemia as a cause, the confounding factor of gender prevents our study design from answering this question conclusively. Fibromyalgia is commoner in patients with chest pain and normal coronary angiograms, but may be related to the excess of females in this group. Its presence does not preclude the co-existence of ischaemic heart disease.