Objective. The lack of randomized controlled trials (RCTs) in pulmonary fibrosis in systemic sclerosis (SSc) has hampered an evidence-based approach to treatment. This RCT was undertaken to investigate the effects of intravenous (IV) cyclophosphamide (CYC) followed by azathioprine (AZA) treatment in pulmonary fibrosis in SSc.Methods. Forty-five patients were randomized to receive low-dose prednisolone and 6 infusions (monthly) of CYC followed by oral AZA, or placebo. Primary outcome measures were change in percent predicted forced vital capacity (FVC) and change in single-breath diffusing capacity for carbon monoxide (DLCO). Secondary outcome measures included changes in appearance on high-resolution computed tomography and dyspnea scores. An intent-to-treat statistical analysis was performed.Results. At baseline, there were no significant group differences in factors linked to outcome, including severity of pulmonary fibrosis and autoantibody status. Sixty-two percent of the patients completed the first year of treatment. Withdrawals included 9 patients (6 from the placebo group) with significant decline in lung function, 2 with treatment side effects (both from the active treatment group), and 6 with non-trialrelated comorbidity. No hemorrhagic cystitis or bone marrow suppression was observed. Estimation of the relative treatment effect (active treatment versus placebo) adjusted for baseline FVC and treatment center revealed a favorable outcome for FVC of 4.19%; this between-group difference showed a trend toward statistical significance (P ‫؍‬ 0.08). No improvements in DLCO or secondary outcome measures were identified.Conclusion. This trial did not demonstrate significant improvement in the primary or secondary end points in the active treatment group versus the group receiving placebo. However, for FVC there was a trend toward statistical significance between the 2 groups. This suggests that treatment of pulmonary fibrosis in SSc with low-dose prednisolone and IV CYC followed by AZA stabilizes lung function in a subset of patients with the disease. Therapy was well tolerated with no increase in serious adverse events.

The inhalation rate is important when patients use an inhaler. Dry powder inhalers (DPIs) require an inhalation rate >30 L min(-1) whereas metered dose inhalers (MDIs) should be used at <90 L min(-1). Within the setting of a routine clinic, we have measured peak inhalation flows (PIF) of COPD patients when they used a Diskus (SDSK), Turbuhaler (STBH), Handihaler (SHAND) and MDI. Subjects were then randomised into trained (VT) and non-trained (NT) groups. One hundred and sixty-three patients with a mean (S.D.) age and % predicted FEV(1) of 72.5 (9.9) years and 47.8 (22.2)% completed the study. Of the patients, 4.9%, 14.2% and 57.0% inhaled <30 L min(-1) through SDSK, STHB and SHAND, respectively and 59.5% inhaled >90 L min(-1) with the MDI. Generally, the more severe the COPD, the slower was their PIF with all inhalers. The MDI PIF values in the VT group (n=84) post-training were significantly (p<0.001) slower but there was no change for the DPIs. Of the 55 VT patients inhaling >90 L min(-1) through the MDI only 7 (p<0.001) inhaled too fast post-training. Pre-training 3, 15 and 46 VT subjects inhaled <30 L min(-1) through the SDSK, STBH and SHAND and after training none, 5 and 26 did not inhale faster than this minimum required rate. Some COPD patients have problems achieving required PIFs through DPIs but training is useful to help some exceed the minimum required rate despite only small improvements. The patients found it easier to slow their PIF through the MDI.

One hundred alleged victims of child sexual abuse (aged 4-13; M ¼ 9.3 years) were interviewed by police investigators about their alleged experiences. Half of the children were interviewed using the National Institute of Child Health and Human Development (NICHD) structured interview Protocol, whereas the other children, matched with respect to their age, relationship with the alleged perpetrator, and seriousness of the alleged offenses, were interviewed by investigators following the Memorandum of Good Practice. Protocol-guided interviews elicited more information using freerecall invitations and less information using directive, option-posing and suggestive questions than did standard Memorandum interviews. There were no age differences in the proportion of total information provided in response to open-ended invitations in either condition, but there was a significant increase with age in the proportion of central information provided in response to openended invitations. Published in

Asphyxia, which occurs during obstructive sleep apnoeic events, alters the baroreceptor reflex and this may lead to hypertension. We have recently reported that breathing an asphyxic gas resets the baroreceptor-vascular resistance reflex towards higher pressures. The present study was designed to determine whether this effect was caused by the reduced oxygen tension, which affects mainly peripheral chemoreceptors, or by the increased carbon dioxide, which acts mainly on central chemoreceptors. We studied 11 healthy volunteer subjects aged between 20 and 55 years old (6 male). The stimulus to the carotid baroreceptors was changed using graded pressures of −40 to +60 mmHg applied to a neck chamber. Responses of vascular resistance were assessed in the forearm from changes in blood pressure (Finapres) divided by brachial blood flow velocity (Doppler) and cardiac responses from the changes in RR interval and heart rate. Stimulus-response curves were defined during (i) air breathing, (ii) hypoxia (12% O 2 in N 2 ), and (iii) hypercapnia (5% CO 2 in 95% O 2 ). Responses during air breathing were assessed both prior to and after either hypoxia or hypercapnia. We applied a sigmoid function or third order polynomial to the curves and determined the maximal differential (equivalent to peak sensitivity) and the corresponding carotid sinus pressure (equivalent to 'set point'). Hypoxia resulted in an increase in heart rate but no significant change in mean blood pressure or vascular resistance. However, there was an increase in vascular resistance in the post-stimulus period. Hypoxia had no significant effect on baroreflex sensitivity or 'set point' for the control of RR interval, heart rate or mean arterial pressure. Peak sensitivity of the vascular resistance response to baroreceptor stimulation was significantly reduced from −2.5 ± 0.4 units to −1.4 ± 0.1 units (P < 0.05) and this was restored in the post-stimulus period to −2.6 ± 0.5 units. There was no effect on 'set point'. Hypercapnia, on the other hand, resulted in a decrease in heart rate, which remained reduced in the post-stimulus period and significantly increased mean blood pressure. Baseline vascular resistance was significantly increased and then further increased in the post-control period. Like hypoxia, hypercapnia had no effect on baroreflex control of RR interval, heart rate or mean arterial pressure. There was, also no significant change in the sensitivity of the vascular resistance responses, however, 'set point' was significantly increased from 74.7 ± 4 to 87.0 ± 2 mmHg (P < 0.02). This was not completely restored to pre-stimulus control levels in the post-stimulus control period (82.2 ± 3 mmHg). These results suggest that the hypoxic component of asphyxia reduces baroreceptor-vascular resistance reflex sensitivity, whilst the hypercapnic component is responsible for increasing blood pressure and reflex 'set point'. Hypercapnia appears to have a lasting effect after the removal of the stimulus. Thus the effect of both peripheral and central chemorecepto...

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The term double diabetes (DD) has been used to refer to individuals with type 1 diabetes (T1D) who are overweight, have a family history of type 2 diabetes and/or clinical features of insulin resistance. Several pieces of evidence indicate that individuals who display features of DD are at higher risk of developing future diabetes complications, independently of average glucose control, measured as glycated haemoglobin (HbA1c) concentration. Given the increased prevalence of individuals with features of DD, pragmatic criteria are urgently required to identify and stratify this group, which will help with subsequent implementation of more effective personalized interventions. In this review, we discuss the potential criteria for the clinical identification of individuals with DD, highlighting the strengths and weaknesses of each definition. We also cover potential mechanisms of DD and how these contribute to increased risk of diabetes complications. Special emphasis is placed on the role of estimated glucose disposal rate (eGDR) in the diagnosis of DD, which can be easily incorporated into clinical practice and is predictive of adverse clinical outcome. In addition to the identification of individuals with DD, eGDR has potential utility in monitoring response to different interventions. T1D is a more heterogeneous condition than initially envisaged, and those with features of DD represent a subgroup at higher risk of complications. Pragmatic criteria for the diagnosis of individuals with DD will help with risk stratification, allowing a more personalized and targeted management strategy to improve outcome and quality of life in this population.

1 We have studied the effects of single oral doses of 80 mg propranolol and 100 mg metoprolol on the cardiovascular and respiratory responses to progressive exercise in nine healthy men in doubleblind, placebo-controlled experiment. As judged by their effects on exercise heart rate and cardiac output the doses of the two drugs used were equivalent.2 fp-adrenoceptor blockade reduced oxygen consumption by 3.5% over the whole work range with an increase in the respiratory exchange ratio of 0.056 units. Carbon dioxide production and exercise ventilation were unchanged. The two drugs had similar effects. Possible mechanisms for these observations are discussed.3 Perceived exertion during exercise was increased by both the f-adrenoceptor blocking drugs and this may be of relevance to the symptom of fatigue reported by patients on these drugs. Endurance, assessed as either total work done or maximal work achieved, was reduced by 15%.One of the main therapeutic uses of f-adrenergic receptor blocking drugs has been in the management of angina pectoris. Many authors have reported improved exercise tolerance in these patients with delayed onset of both ischaemic pain and ECG abnormalities and reduced dependence on coronary vasodilators- (Comerford & Besterman, 1976). 0-adrenoceptor blocking drugs are also widely used in the control of hypertension, often in patients whose exercise tolerance is presumably normal. As adrenergic mechanisms play a major role in facilitating oxygen transport through their involvement in the control of cardiovascular and respiratory adjustments during exercise, it is important to establish the effect of f-adrenoceptor blockade on exercise tolerance, particularly as there is now evidence that the cardiovascular reserves of untrained but otherwise healthy people are more limited than generaly appreciated (Wasserman, Whipp, Koyal & Beaver, 1973). Using normal individuals we have measured cardio-respiratory variables and the level ofperceived exertion during a standard progressive exercise test. Nine subjects were exercised to exhaustion while taking either metoprolol, propranolol or placebo. In this way the effects of both non-selective and more cardio-selective ,B-adrenergic receptor blockade have been studied. MethedsNine healthy adult male volunteers with normal lung function were used as subjects. They were aged 25 to 42 years (mean + s.d. 35 + 7 years), and gave their informed consent to a protocol which had been approved by the Ethical Committee of the Department of Physiology and Pharmacology.Identical tablets containing either 80 mg propranolol (Inderal, ICI) or 100 mg metoprolol (Betaloc, Astra) or lactose were used, and neither the subjects nor the experimenters were aware of the code used to identify the tablets. Three experiments were performed on each subject and at least 48 h elapsed between experiments on any individual. The order of the drugs was randomized between individuals to reduce bias due to any training effect of the procedure. Each experiment took 1.5 h and it started

To investigate the effect of vagal blockade with atropine on nocturnal fall in peak expiratory flow rate 10 patients with asthma who had a diurnal variation in peak expiratory flow rate of >20% were given 30 μg/kg of intravenous atropine or a placebo at 4 am and 4 pm. Vagal blockade caused significant bronchodilatation at 4 am and 4 pm (peak expiratory flow rate rose from 260 to 390 l/min at 4 am and 400 to 440 l/min at 4 pm) and significantly increased the pulse rate from 60 to 121 beats/minute at 4 am and from 76 to 122 beats/minute at 4 pm. Nocturnal asthma was almost totally reversed, implying that vagal mechanisms are fundamental in its pathophysiology. Other mechanisms—diurnal changes in plasma adrenaline concentration, the activity of non-adrenergic non-cholinergic nerves, and circadian rhythms of inflammatory mediator activity—may also be implicated.