Continuous inhibition of 11ß-hydroxysteroid dehydrogenase type I in adipose tissue leads to tachyphylaxis in humans and rats but not in mice.

BACKGROUND AND PURPOSE: 11ß-hydroxysteroid dehydrogenase type I (11ß-HSD1), a target for Type 2 diabetes mellitus, converts inactive glucocorticoids into bioactive forms, increasing tissue concentrations. We have compared the pharmacokinetic-pharmacodynamic (PK/PD) relationship of target inhibition after acute and repeat administration of inhibitors of 11ß-HSD1 activity in human, rat and mouse adipose tissue (AT). EXPERIMENTAL APPROACH: Studies included abdominally obese human volunteers, rats and mice. Two specific 11ß-HSD1 inhibitors (AZD8329 and COMPOUND-20) were administered as single oral doses or repeat daily doses for 7-9 days. 11ß-HSD1 activity in AT was measured ex vivo by conversion of (3) H-cortisone to (3) H-cortisol. KEY RESULTS: In human and rat AT, inhibition of 11ß-HSD1 activity was lost after repeat dosing of AZD8329, compared with acute administration. Similarly, in rat AT, there was loss of inhibition of 11ß-HSD1 activity after repeat dosing with COMPOUND-20 with continuous drug cover, but effects were substantially reduced if a 'drug holiday' period was maintained daily. Inhibition of 11ß-HSD1 activity was not lost in mouse AT after continuous cover with COMPOUND-20 for 7 days. CONCLUSIONS AND IMPLICATIONS: Human and rat AT, but not mouse AT, exhibited tachyphylaxis for inhibition of 11ß-HSD1 activity after repeat dosing. Translation of observed efficacy in murine disease models to human for 11ß-HSD1 inhibitors may be misleading. Investigators of the effects of 11ß-HSD1 inhibitors should confirm that desired levels of enzyme inhibition in AT can be maintained over time after repeat dosing and not rely on results following a single dose.

Severe paediatric ulcerative colitis: incidence, outcomes and optimal timing for second-line therapy.

BACKGROUND: Despite the predominance of extensive disease in children with ulcerative colitis, data concerning severe paediatric ulcerative colitis are sparse. We reviewed rates and predictors of response to intravenous-corticosteroid therapy in a single-centre cohort with long-term follow-up. METHODS: 99 children (49% males; age 2-17 years) were hospitalised (1991-2000) for treatment of severe ulcerative colitis (90% extensive; 49% new onset ulcerative colitis). Clinical, laboratory and radiographic data were reviewed. A population-based subset was used to assess incidence. Predictors of corticosteroid response were analysed using univariate and multivariate analyses at days 3 and 5 of therapy. Colectomy rates were calculated using Kaplan-Meier survival analyses. RESULTS: 28% (95% CI, 23 to 34%) of children with ulcerative colitis resident in the Greater Toronto Area required admission for intravenous corticosteroid therapy, of whom 53 (53%; 95% CI, 44 to 63%) responded. Several predictors were associated with corticosteroid failure, but in multivariable modelling only C-reactive protein [OR = 3.5 (1.4 to 8.4)] and number of nocturnal stools [OR = 3.2 (1.6 to 6.6)] remained significant at both days 3 and 5. The Pediatric Ulcerative Colitis Activity Index (PUCAI), Travis and Lindgren's indices strongly predicted non-response. Radiographically, the upper range of colonic luminal width was 40 mm in children younger than 11 years versus 60 mm in older patients. Cumulative colectomy rates at discharge, 1 year and 6 years were 42%, 58% and 61%, respectively. CONCLUSIONS: Children with ulcerative colitis commonly experience at least one severe exacerbation. Response to intravenous corticosteroids is poor. The PUCAI, determined at day 3 (>45 points) should be used to screen for patients likely to fail corticosteroids and at day 5 (>70 points) to dictate the introduction of second-line therapies.

Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 reduces food intake and weight gain but maintains energy expenditure in diet-induced obese mice.

AIMS/HYPOTHESIS: The 11beta-hydroxysteroid dehydrogenase type-1 inhibitor BVT.2733 lowers blood glucose and insulin in mutant mouse models of obesity and diabetes. Its effects on energy balance and body composition, and their contribution to improved glucose homeostasis have received little attention. MATERIALS AND METHODS: BVT.2733 (100 mg/kg, orally) was given twice daily to lean and diet-induced obese mice for 16 or 17 days. A group of obese mice was pair-fed to the amounts consumed by BVT.2733-treated mice. RESULTS: In both obese and lean mice, BVT.2733 reduced food intake and weight gain, but increased water intake. Pair-feeding caused almost as great a decrease in body weight as BVT.2733. Energy expenditure was 38+/-8% higher in the BVT.2733-treated obese mice than in the pair-fed mice. Terminal plasma corticosterone was raised, lean body weight reduced and percentage fat unchanged in the pair-fed mice (control, 47.8+/-2.6%; pair-fed, 47.1+/-1.9%), whereas BVT.2733 did not reduce lean mass, but did reduce percentage fat (40.9+/-2.0%). BVT.2733 but not pair-feeding reduced both the glucose tolerance AUC and the plasma insulin concentration 30 min after giving glucose. CONCLUSIONS/INTERPRETATION: BVT.2733 reduced food intake but prevented a concomitant reduction in lean body mass and energy expenditure. The latter effects may have contributed to improved glucose tolerance.

Commercial agencies and surrogate motherhood: a transaction cost approach.

In this paper we investigate the legal arrangements involved in UK surrogate motherhood from a transaction-cost perspective. We outline the specific forms the transaction costs take and critically comment on the way in which the UK institutional and organisational arrangements at present adversely influence transaction costs. We then focus specifically on the potential role of surrogacy agencies and look at UK and US evidence on commercial and voluntary agencies. Policy implications follow.

Effect of aging on the prognostic significance of ambulatory systolic, diastolic, and pulse pressure in essential hypertension.

BACKGROUND: This study compared the relative prognostic significance of 24 hour intra-arterial ambulatory systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP) parameters in middle-aged versus elderly hypertensives. METHODS AND RESULTS: A total of 546 subjects aged <60 years and 142 subjects aged >/=60 years who had undergone baseline pretreatment 24-hour intra-arterial ambulatory blood pressure monitoring were followed for 9.2+/-4.1 years. Multivariate analysis showed that in younger subjects, 24-hour, daytime, and nighttime DBP, MAP, and SBP, when considered individually, were positively related to morbid events; DBP parameters provided the best predictive values. In the group >/=60 years (elderly group), 24-hour, daytime, and nighttime PP and SBP were the most predictive parameters, whereas ambulatory DBP and MAP measurements failed to provide any prognostic value. When 24-hour values of SBP and DBP were jointly included in the baseline model, DBP (z=2.02, P=0.04) but not SBP (z=-0.43, P=0.67) was related to outcome in younger subjects, whereas in the elderly group, SBP (z=3.33, P=0.001) was positively and DBP (z=-1.75, P=0.07) was negatively related to outcome. Clinic blood pressure measurements failed to provide any independent prognostic value in either age group. CONCLUSIONS: The relative prognostic significance of ambulatory blood pressure components depends on age; DBP parameters provided the best prognostic value in middle-aged individuals, whereas PP parameters were the most predictive in the elderly. This may reflect differing underlying hemodynamic mechanisms of hypertension in these age groups.

Surrogate motherhood, rights and duties: a reply to Campbell.

In a recent article in Health Care Analysis (Vol. 8, No. 1), Campbell misrepresents our specific arguments about commercial surrogate motherhood (C.S.M.) and our general philosophical and political views by saying or suggesting that we are 'Millsian' liberals and consequentialists. He gives too the false impression that we do not oppose, in principle, slavery and child purchase. Here our position on C.S.M. is re-expressed and elaborated upon in order to eliminate possible confusion. Our general ethical and philosophical framework is also outlined and shown to be other than Campbell says that it is. In particular, a moral philosophy that is based on neither consequentialism nor Kantianism is presented. C.S.M., it is argued, is not child purchase. It is like it in some respects and unlike it in others. It is unlike it in the respects which, relative to the present discussion, matter.

Babies, child bearers and commodification: Anderson, Brazier et al., and the political economy of commercial surrogate motherhood.

It is argued by Anderson and also in the Brazier Report that Commercial Surrogate Motherhood (C.S.M.) contracts and agencies should be illegal on the grounds that C.S.M. involves the commodification of both mothers and babies. This paper takes issue with this view and argues that C.S.M. is not inconsistent with the proper respect for, and treatment of, children and women. A case for the legalization of C.S.M. is made.

Racial variation in cardiovascular morbidity and mortality in essential hypertension.

OBJECTIVES: To perform a longitudinal comparison of morbidity and mortality among white, south Asian and Afro-Caribbean hypertensive patients in relation to baseline demographic characteristics and clinic and ambulatory blood pressure variables. DESIGN: Observational follow up study. SETTING: District general hospital and community setting in Harrow, England. PATIENTS: 528 white, 106 south Asian, and 54 Afro-Caribbean subjects with essential hypertension who had undergone 24 hour ambulatory intra-arterial blood pressure monitoring. INTERVENTIONS: Follow up for assessment of all cause morbidity and mortality over a mean (SD) of 9.2 (4.1) years. MAIN OUTCOME MEASURES: Non-cardiovascular death, coronary death, cerebrovascular death, peripheral vascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularisation. RESULTS: South Asians had the highest all cause event rate of 3.46, compared with 2.50 (NS) and 0.90 (p = 0.002) events/100 patient-years for whites and Afro-Caribbeans, respectively. This was because of an excess of coronary events (2.86 v 1.32 events/100 patient-years in south Asians v whites, respectively; p = 0.002). Age (p < 0.001), sex (p < 0.001), race (south Asians : whites, hazard ratio 1.79; p = 0.008), diabetes (p = 0.05), previous history of cardiovascular disease (p < 0.001), and 24 hour ambulatory systolic blood pressure (p = 0.006) were independent predictors of time to a first event. Clinic blood pressure did not provide additional prognostic information. CONCLUSIONS: South Asian origin was an independent predictor of all cause events, mainly because of an excess of coronary events in this group. Ambulatory but not clinic blood pressure was of additional value in predicting subsequent morbidity and mortality.

Population advice on salt restriction: the social issues.

The scientific evidence that underlies public health advice depends upon critical integration of information from several sources. The most informative evidence relating to the effects of population reduction in salt intake comes from systematic reviews of clinical trials. Recent rigorous reviews of salt restriction trials in normal subjects show extremely small effects ranging from 1 to 2 mm Hg for systolic blood pressure and 0.1 to 1.0 mm Hg for diastolic pressure. These are the result of much greater reductions in sodium intake than can be achieved by population advice, and may be further amplified by publication bias and effects of changes in other dietary components. There is little trial evidence to enable possible benefits and adverse effects to be balanced. Reviews biased by the inclusion of nonrandomized studies exaggerate the apparent blood pressure fall 5- to 50-fold and create spurious apparent progressive falls in blood pressure. Nevertheless, citation analysis shows that they are quoted much more frequently than rigorous reviews reaching more negative conclusions. This appears to be the result of an attempt to create an impression of scientific consensus. The salt debate has important implications for social policy.

Evidence-based medicine and hypertension.

BACKGROUND: Evidence-based medicine (EBM) has been propagated as a revolutionary development which will improve the quality of clinical decision-making and guideline development Historically it follows an early 19th-century French attempt to introduce mathematical analysis into clinical practice. This met with resistance from both clinicians and scientists and was only accepted in more recent times with the development of clinical epidemiology and clinical trials. NATURE OF EBM: EMB claims to utilize the best available evidence to reach scientific conclusions, rejecting the appeal to expert authority. This involves a hierarchy of sources which places large controlled trials at the apex. Less value is attributed to arguments from clinical observation or pathophysiology. Systematic reviews and meta-analyses of trials therefore provide the strongest evidence for clinical decisions. THE CONCEPT OF EVIDENCE: The approach advocated in EBM is an over-simplification of the process of clinical thinking which involves interpretation and synthesis of relevant evidence from all sources and extrapolation to the clinical situation. In this process, there is no hierarchy of evidence. The relative value given to any particular evidence depends more upon its relevance and persuasiveness than the category to which it belongs. Discussion and debate amongst informed 'experts' is an integral feature of this process at each stage. IMPACT OF EBM: Although advocates of EBM acknowledge the contribution of all forms of evidence, the differential value attached to different sources has led to naïve and simplistic attempts to omit the traditional processes of interpretation, synthesis and extrapolation and to draw wide-ranging conclusions from trial data without adequate scientific discussion.