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Background: Earlier diagnosis followed by multi-factorial cardiovascular risk intervention may improve outcomes in Type 2 Diabetes Mellitus (T2DM). Latent phase identification through screening requires structured, appropriately targeted population-based approaches. Providers responsible for implementing screening policy await evidence of clinical and cost effectiveness from randomised intervention trials in screen-detected T2DM cases. UK South Asians are at particularly high risk of abnormal glucose tolerance and T2DM. To be effective national screening programmes must achieve good coverage across the population by identifying barriers to the detection of disease and adapting to the delivery of earlier care. Here we describe the rationale and methods of a systematic community screening programme and randomised controlled trial of cardiovascular risk management within a UK multiethnic setting (ADDITION-Leicester). Design: A single-blind cluster randomised, parallel group trial among people with screen-detected T2DM comparing a protocol driven intensive multi-factorial treatment with conventional care. Methods: ADDITION-Leicester consists of community-based screening and intervention phases within 20 general practices coordinated from a single academic research centre. Screening adopts a universal diagnostic approach via repeated 75g-Oral Glucose Tolerance Tests within an eligible non-diabetic population of 66,320 individuals aged 40-75 years (25-75 years South Asian). Volunteers also provide detailed medical and family histories; complete health questionnaires, undergo anthropometric measures, lipid profiling and a proteinuria assessment. Primary outcome is reduction in modelled Coronary Heart Disease (UKPDS CHD) risk at five years. Seven thousand (30% of South Asian ethnic origin) volunteers over three years will be recruited to identify a screen-detected T2DM cohort (n = 285) powered to detected a 6% relative difference (80% power, alpha 0.05) between treatment groups at one year. Randomisation will occur at practice-level with newly diagnosed T2DM cases receiving either conventional (according to current national guidelines) or intensive (algorithmic target-driven multi-factorial cardiovascular risk intervention) treatments. Discussion: ADDITION-Leicester is the largest multiethnic (targeting >30% South Asian recruitment) community T2DM and vascular risk screening programme in the UK. By assessing feasibility and efficacy of T2DM screening, it will inform national disease prevention policy and contribute significantly to our understanding of the health care needs of UK South Asians. Trial registration: Clinicaltrial.gov (NCT00318032). [ABSTRACT FROM AUTHOR]

Objective: To review the effectiveness of interventions targeted at health care professionals and/or the structure of care in order to improve the management of diabetes in primary care, outpatient, and community settings.Research Design and Methods: A systematic review of controlled trials evaluating the effectiveness of interventions targeted at health care professionals and aimed at improving the process of care or patient outcomes for patients with diabetes was performed. Standard search methods of the Cochrane Effective Practice and Organization of Care Group were used.Results: A total of 41 studies met the inclusion criteria. The studies identified were heterogeneous in terms of interventions, participants, settings, and reported outcomes. In all studies, the interventions were multifaceted. The interventions were targeted at health care professionals only in 12 studies, at the organization of care only in 9 studies, and at both in 20 studies. Complex professional interventions improved the process of care, but the effect on patient outcomes remained less clear because such outcomes were rarely assessed. Organizational interventions that facilitated the structured and regular review of patients also showed a favorable effect on process measures. Complex interventions in which patient education was added and/or the role of a nurse was enhanced led to improvements in patient outcomes as well as the process of care.Conclusions: Multifaceted professional interventions and organizational interventions that facilitate structured and regular review of patients were effective in improving the process of care. The addition of patient education to these interventions and the enhancement of the role of nurses in diabetes care led to improvements in patient outcomes and the process of care. [ABSTRACT FROM AUTHOR]

Objectives The aims of this study were to quantify the proportion of people diagnosed as having type 2 diabetes by standard 75 g oral glucose tolerance test, in a hypothetical screening programme, who would actually be false positives (false positive percentage), and the effect on the false positive percentage of varying the time between repeat screens. We also calculated the duration in person years of exposure to undiagnosed disease in the population for each screening interval. Setting Ely, Cambridgeshire, UK. Methods We used the glucose tolerance data from 965 participants of the Ely Diabetes Project, who were tested 4.5 years apart, to calculate the population's between and within person variance for 2 hour plasma glucose, and constructed a probability matrix of observed v true glucose tolerance categories. The progression of the population between glucose tolerance categories was modelled assuming exponential times to progression. Results After one year, 47.5% of test positives were disease free: almost half of those labelled with diabetes would not have the disease. For a 5 year interval, the false positive percentage was 27.6%, but the population would have been exposed to undiagnosed diabetes for 144 person years. Conclusions Screening can be associated with both benefit and harm; the balance is dependent on characteristics of the disease and the screening programme. This study has quantified the trade off between exposure to undiagnosed diabetes and false positive results to inform the debate about screening for type 2 diabetes. [ABSTRACT FROM AUTHOR]

1. Fully automated inhibition screens for the major human hepatic cytochrome P450s have been developed and validated. Probe assays were the fluorometric-based ethoxyresorufin O -deethylation for CYP1A2 and radiometric analysis of erythromycin N demethylation for CYP3A4, dextromethorphan O -demethylation for CYP2D6, naproxen O -demethylation for CYP2C9 and diazepam N -demethylation for CYP2C19. For the radiometric assays 99.7% of C-labelled substrate was routinely extracted from incubations by solid-phase extraction. 2. Furafylline, sulphaphenazole, omeprazole, quinidine and ketoconazole were identified as specific markers for the respective CYP1A2 (IC=6muM), CYP2C9 (0.7muM), CYP2C19 (6muM), CYP2D6 (0.02muM) and CYP3A4 (0.2muM) inhibition screens. 3. For the radiometric methods, a two-point IC estimate was validated by correlating the IC obtained with a full (seven-point) assay (r=0.98, p 0.001). The two-point IC estimate is useful for initial screening, while the full IC method provides more definitive quantitation, where required. 4. IC determined for a series of test compounds in human liver microsomes and cytochrome P450 cDNA-expressed enzymes were similar (r=0.89, p 0.001). In particular, the CYP1A2, CYP2D6 and CYP3A4 screens demonstrated the flexibility to accept either enzyme source. As a result of incomplete substrate selectivity, expressed enzymes were utilized for analysis of CYP2C9 and CYP2C19 inhibition. Good agreement was demonstrated between IC determined in these assays to IC published by other laboratories using a wide range of analytical techniques, which provided confidence in the universality of these inhibition screens. 5. These automated screens for initial assessment of P450 inhibition potential allow rapid determination of IC. The radiometric assays are flexible, sensitive, robust and free from analytical interference, and they should permit the identification and eradication of inhibitory structural motifs within a series of potential drug candidates. [ABSTRACT FROM AUTHOR]

Psychiatric symptoms and cognition were assessed in 13 patients with schizophrenia, one patient with schizoaffective disorder, and one patient with psychosis not otherwise specified while they received a conventional neuroleptic and again after an average of 15 months on clozapine. Despite improvements in psychiatric symptoms, attention, memory, and higher-level problem-solving were essentially unchanged. This suggests that certain cognitive deficits are relatively independent of psychotic symptoms in schizophrenia, and are probably central and enduring features of the disorder. Cognitive disability appeared to have been rate-limiting in the sample's rehabilitation, as patients' social and vocational adjustment remained marginal during the study. We also observed that treatment with clozapine was associated with a decline in some memory functions; the potent anticholinergic properties of the drug may have been responsible for this. [ABSTRACT FROM AUTHOR]

The articles examines the effectiveness of the exercise referral scheme Active for Life in Forest Heath in West Suffolk, England. It mentions that 35% of men and 24% of women tend to meet the recommended physical activity targets in Great Britain. Under the exercise referral scheme, inhabitants are referred to local leisure centres to undergo a 10-week tailored exercise programme. It is concluded that small improvements in both clinical and psychosocial aspects were exhibited by the participants.

The article focuses on spectrum effect which describes the variation in test performance among different population groups. Topics covered include the factors affecting the performance of tests, the simulation of a situation to illustrate the effects and the need for clinicians to examine the relevance of the study sample when reviewing a study of a new risk prediction or diagnostic test.

The article discusses a study which examined whether genetic risk communication motivates risk-reducing behaviour change. Topics covered include the primary outcomes of the study such as improving diet or increasing levels of physical activity and the lack of significant effects of communicating DNA based risk estimates on risk-reducing behaviours.

Objective To examine the association between meeting behavioural goals and diabetes incidence over 10 years in a large, representative Swedish population. Methods Population-based prospective cohort study of 32,120 individuals aged 35 to 55 years participating in a health promotion intervention in Västerbotten County, Sweden (1990 to 2013). Participants underwent an oral glucose tolerance test, clinical measures, and completed diet and activity questionnaires. Poisson regression quantified the association between achieving six behavioural goals at baseline - body mass index (BMI) < 25 kg/m², moderate physical activity, non-smoker, fat intake < 30% of energy, fibre intake ≥ 15 g/4184 kJ and alcohol intake ≤ 20 g/day - and diabetes incidence over 10 years. Results Median interquartile range (IQR) follow-up time was 9.9 (0.3) years; 2211 individuals (7%) developed diabetes. Only 4.4% of participants met all 6 goals (n = 1245) and compared to these individuals, participants meeting 0/1 goals had a 3.74 times higher diabetes incidence (95% confidence interval (CI) = 2.50 to 5.59), adjusting for sex, age, calendar period, education, family history of diabetes, history of myocardial infarction and long-term illness. If everyone achieved at least four behavioural goals, 14.1% (95% CI: 11.7 to 16.5%) of incident diabetes cases might be avoided. Conclusion Interventions promoting the achievement of behavioural goals in the general population could significantly reduce diabetes incidence. [ABSTRACT FROM AUTHOR]

Objectives: To examine the association between diet and physical activity and sedentary behaviours in 9-10-year-old children. Study design: A cross-sectional study using data from the SPEEDY (Sport, Physical activity and Eating behaviour: Environmental Determinants in Young People) study undertaken in Norfolk, UK. Methods: Data from 4-day food diaries and 7 days of accelerometery were matched on concurrent days. Time spent in moderate-to-vigorous physical activity (MVPA), time spent in sedentary behaviour and various measures of dietary intake were collected. Covariates included age, sex, weight status, family socio-economic status, and energy intake reporting quality. Multivariable regression models, adjusted for clustering of children by school and stratified by sex, were fitted to examine the associations between dietary measures and physical activity and sedentary outcomes. Results: In total, 1317 children (584 boys and 733 girls) provided concurrent data. Boys in the highest quartile of energy percentage from protein spent approximately 6 min [95% confidence interval (CI) 0-12] less in MVPA compared with boys in the lowest quartile. Those in the highest quartiles of fruit and vegetable intake and fruit juice intake had respective average activity counts per minute that were 56 above (95% CI 8-105) and 48 below (95% CI 2-95) those in the lowest quartiles, whilst those in the highest quartile of fizzy drink consumption spent approximately 7 min (95% CI 2-13) more in MVPA and approximately 14 min (95% CI 5-24 min) less in sedentary behaviour. Boys in the highest quartile of savoury snack consumption spent approximately 8 min (95% CI 2-13 min) more in MVPA per day, and approximately 12 min (95% CI 2-23) less in sedentary behaviour. No significant associations were apparent among girls. Conclusions: Few associations were detected, and the directions of those that were apparent were mainly counterintuitive. The extent to which this reflects a true lack of association or is associated with the measurement methods used for diet and physical activity needs further investigation. [ABSTRACT FROM AUTHOR]

Background: It is unclear whether cardiovascular risk factor modification influences the development of renal disease in people with type 2 diabetes identified through screening. We determined predictors of albuminuria 5 years after a diagnosis of screen-detected diabetes within the ADDITION-Europe study, a pragmatic cardiovascular outcome trial of multifactorial cardiovascular risk management., Methods: In 1826 participants with newly diagnosed, screen-detected diabetes without albuminuria, we explored associations between risk of new albuminuria (≥2.5 mg mmol -1 for males and ≥3.5 mg mmol -1 for females) and (1) baseline cardio-metabolic risk factors and (2) changes from baseline to 1 year in systolic blood pressure (ΔSBP) and glycated haemoglobin (ΔHbA 1c ) using logistic regression., Results: Albuminuria developed in 268 (15%) participants; baseline body mass index and active smoking were independently associated with new onset albuminuria in 5 years after detection of diabetes. In a model adjusted for age, gender, baseline HbA 1c and blood pressure, a 1% decrease in HbA 1c and 5-mm Hg decrease in SBP during the first year were independently associated with lower risks of albuminuria (odds ratio), 95% confidence interval: 0.76, 0.62 to 0.91 and 0.94, 0.88 to 1.01, respectively. Further adjustment did not materially change these estimates. There was no interaction between ΔSBP and ΔHbA 1c in relation to albuminuria risk, suggesting likely additive effects on renal microvascular disease., Conclusions: Baseline measurements and changes in HbA 1c and SBP a year after diagnosis of diabetes through screening independently associate with new onset albuminuria 4 years later. Established multifactorial treatment for diabetes applies to cases identified through screening., (Copyright © 2016 John Wiley & Sons, Ltd.)

Introduction: The treatment of large renal stones (≥1 cm) in paediatric patients is challenging. The usual treatment options include percutaneous nephrolithotomy (PCNL) or shockwave lithotripsy (SWL). There is a rise in the use of ureteroscopy and laser stone fragmentation (URSL) for paediatric stones; however, outcomes of treatment for large renal stones in this age group are still largely unknown., Objective: To investigate the outcome of URSL for large paediatric renal stones ≥1 cm treated at the present institution over the last 5 years., Methods: A retrospective review was performed of outcomes from the prospectively maintained stone database. Only paediatric patients undergoing ureteroscopic (rigid or flexible ureteroscopy (URS)) procedures for stones ≥1 cm were included. Patient demographics, operative details, stone burden, hospital stay, complications and stone clearance were recorded and analysed., Results: From April 2010 to June 2015, 18 paediatric patients with a mean age of 10.4 years (range 3.6-15) underwent 35 ureteroscopic procedures for large stones (≥1 cm). The stone location was in the kidney (n = 14), ureter (n = 1), and in both the kidney and ureter for the remaining three patients. Nine patients had multiple stones. There was a preceding history of PCNL in four patients, with one patient having URS combined with a PCNL. The mean follow-up was 2.7 years (range 0-5). A postoperative stent was inserted in 21 (60%) patients. The overall stone-free rate (SFR) was 89% for a mean of 1.8 procedures per patient (range 1-4) - see Summary Table below. There was an inability to access stone within a lower pole calyx in one patient, despite maximum deflection of the ureteroscope. No intra- or post-operative complications were noted, and mean hospital stay was 1.1 days (range 0-5)., Discussion: Published papers in adult literature have shown that ureteroscopy and laser fragmentation (URSL) is a viable alternative to PCNL. Newer equipment and improved techniques have resulted in SFRs being comparable with PCNL. A recent systematic review reported an SFR of 91% for large adult stones (>2 cm) for a mean 1.45 procedures per patient, and an overall complication rate of 8.6%. The present study has also demonstrated excellent outcomes in the use of ureteroscopy and laser fragmentation for the management of large paediatric stones with no complications., Conclusion: The results show that paediatric URSL for large stones achieves a good SFR with minimal morbidity and is a good treatment option in established endourological units., (Copyright © 2016. Published by Elsevier Ltd.)

Background: With the Nordic consensus statement advocating orchidopexy at an earlier age, the present study sought to investigate the outcomes of primary paediatric orchidopexy at a tertiary UK centre., Objective: To prospectively assess testicular atrophy following primary orchidopexy for undescended testes in a paediatric population. Secondary outcomes were complication rates and whether outcomes were dependent on grade of operating surgeon., Study Design: Prospective data regarding age at operation, classification of the undescended testis, length of follow-up, and subjective comparison of intraoperative and postoperative testicular volumes compared with the contralateral testis were collected. Testicular atrophy was defined as >50% loss of testicular volume or a postoperative testicular volume <25% of the volume of the contralateral testis. Patients were excluded for incomplete data and follow-up <6 months., Results: Data for 234 patients were analysed. Testicular atrophy occurred in 2.6% of cases. There was no reported testicular re-ascent. All secondary acquired cases underwent a previous ipsilateral hernia repair. There was no significant difference in outcomes comparing the grade of surgeon (consultant n = 8, trainee/staff-grade surgeon n = 7-8). There was a trend towards postoperative catch-up growth in approximately one fifth of cases., Discussion: Previous studies have reported a testicular atrophy rate of 5%. The present study reported a similar rate of 2.6%. In agreement with a previous publication, it was also found that testicular atrophy was not dependent on the grade of operating surgeon. The mechanism for testicular catch-up growth is not well understood. Animal studies have supported the hypothesis that increased temperature has a detrimental effect on testicular volume. However, follow-up in the present cohort was short (median 6.9 months), making interpretation of this finding difficult. It is acknowledged that clinical palpation alone to determine testicular volume potentially introduces intra-observer and inter-observer error. However, prospective studies using ultrasound to determine testicular volumes following orchidopexy have reported catch-up growth., Conclusion: This study represented one of the larger collections of prospective assessments of outcomes following primary orchidopexy. It was acknowledged that subjectively assessing testicular volume is not ideal; however, the data correlated with similar studies., (Copyright © 2016 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Background: Mechanisms linking changes to the environment with changes in physical activity are poorly understood. Insights into mechanisms of interventions can help strengthen causal attribution and improve understanding of divergent response patterns. We examined the causal pathways linking exposure to new transport infrastructure with changes in cycling to work., Methods: We used baseline (2009) and follow-up (2012) data (N=469) from the Commuting and Health in Cambridge natural experimental study (Cambridge, UK). Exposure to new infrastructure in the form of the Cambridgeshire Guided Busway was defined using residential proximity. Mediators studied were changes in perceptions of the route to work, theory of planned behaviour constructs and self-reported use of the new infrastructure. Outcomes were modelled as an increase, decrease or no change in weekly cycle commuting time. We used regression analyses to identify combinations of mediators forming potential pathways between exposure and outcome. We then tested these pathways in a path model and stratified analyses by baseline level of active commuting., Results: We identified changes in perceptions of the route to work, and use of the cycle path, as potential mediators. Of these potential mediators, only use of the path significantly explained (85%) the effect of the infrastructure in increasing cycling. Path use also explained a decrease in cycling among more active commuters., Conclusion: The findings strengthen the causal argument that changing the environment led to changes in health-related behaviour via use of the new infrastructure, but also show how some commuters may have spent less time cycling as a result., (Copyright © 2016. Published by Elsevier Inc.)

Aims: Establishing a balance between the benefits and harms of treatment is important among individuals with screen-detected diabetes, for whom the burden of treatment might be higher than the burden of the disease. We described the association between cardio-protective medication and health-related quality of life (HRQoL) among individuals with screen-detected diabetes., Methods: 867 participants with screen-detected diabetes underwent clinical measurements at diagnosis, one and five years. General HRQoL (EQ5D) was measured at baseline, one- and five-years, and diabetes-specific HRQoL (ADDQoL-AWI) and health status (SF-36) at one and five years. Multivariable linear regression was used to quantify the association between change in HRQoL and change in cardio-protective medication., Results: The median (IQR) number of prescribed cardio-protective agents was 2 (1 to 3) at diagnosis, 3 (2 to 4) at one year and 4 (3 to 5) at five years. Change in cardio-protective medication was not associated with change in HRQoL from diagnosis to one year. From one year to five years, change in cardio-protective agents was not associated with change in the SF-36 mental health score. One additional agent was associated with an increase in the SF-36 physical health score (2.1; 95%CI 0.4, 3.8) and an increase in the EQ-5D (0.05; 95%CI 0.02, 0.08). Conversely, one additional agent was associated with a decrease in the ADDQoL-AWI (-0.32; 95%CI -0.51, -0.13), compared to no change., Conclusions: We found little evidence that increases in the number of cardio-protective medications impacted negatively on HRQoL among individuals with screen-detected diabetes over five years., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Objective: Botulinum type-A toxin is increasingly used for refractory idiopathic detrusor overactivity (IDO) in children. We reviewed our experience and sought to ascertain the influence of dose and functional bladder capacity on outcome., Patients and Methods: Thirty patients, aged 6-16 years, with urodynamically proven IDO, had intravesical injections of 400-500 iu of Dysport(®). Outcome was assessed clinically at least 5 months after the injection., Results: Data were available for 27 patients. Urinary frequency was improved in 10; nocturia was improved in 7. Urgency resolved in 10 patients and urge incontinence in 12 (44%). Complications reported were UTI (7), urinary retention (1) and bladder pain (1). The dose of Dysport(®) used was not significantly higher (14 iu/kg v 13 iu/kg) in patients dry at follow up than in those who remained wet (p = 0.45). Functional bladder capacity was not significantly different in patients dry after treatment (p = 0.82)., Conclusion: This retrospective study demonstrates similar response to a single treatment with intravesical Botulinum type-A toxin to previous series. We did not demonstrate a correlation between dose or functional bladder capacity and resolution of incontinence. A multi-centre study is required to further investigate this promising treatment., (Copyright © 2012 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Aims/hypothesis: Although a family history of type 2 diabetes is a strong risk factor for the disease, the factors mediating this excess risk are poorly understood. In the InterAct case-cohort study, we investigated the association between a family history of diabetes among different family members and the incidence of type 2 diabetes, as well as the extent to which genetic, anthropometric and lifestyle risk factors mediated this association., Methods: A total of 13,869 individuals (including 6,168 incident cases of type 2 diabetes) had family history data available, and 6,887 individuals had complete data on all mediators. Country-specific Prentice-weighted Cox models were fitted within country, and HRs were combined using random effects meta-analysis. Lifestyle and anthropometric measurements were performed at baseline, and a genetic risk score comprising 35 polymorphisms associated with type 2 diabetes was created., Results: A family history of type 2 diabetes was associated with a higher incidence of the condition (HR 2.72, 95% CI 2.48, 2.99). Adjustment for established risk factors including BMI and waist circumference only modestly attenuated this association (HR 2.44, 95% CI 2.03, 2.95); the genetic score alone explained only 2% of the family history-associated risk of type 2 diabetes. The greatest risk of type 2 diabetes was observed in those with a biparental history of type 2 diabetes (HR 5.14, 95% CI 3.74, 7.07) and those whose parents had been diagnosed with diabetes at a younger age (<50 years; HR 4.69, 95% CI 3.35, 6.58), an effect largely confined to a maternal family history., Conclusions/interpretation: Prominent lifestyle, anthropometric and genetic risk factors explained only a marginal proportion of the excess risk associated with family history, highlighting the fact that family history remains a strong, independent and easily assessed risk factor for type 2 diabetes. Discovering factors that will explain the association of family history with type 2 diabetes risk will provide important insight into the aetiology of type 2 diabetes.

This article aims to provide an updated summary of diabetes prevention efforts by reviewing relevant literature published between 2007 and 2009. These include results from the long-term follow-up of diabetes prevention trials and the roll-out of community-based interventions in "real world" settings. Some countries have begun to implement population-based strategies for chronic disease prevention, but investment in developing and evaluating population-level interventions remains inadequate. By focussing on the "small change" approach and involving a number of different agencies, it may be possible to shift the population distribution of risk factors for diabetes and cardiovascular disease in a favourable direction. The cost-effectiveness of primary prevention strategies for type 2 diabetes has not been universally demonstrated. Some of the uncertainties relating to screening for diabetes have now been resolved but longer-term data on hard cardiovascular outcomes are still needed. In summary, individual countries should aim to develop and evaluate cost-effective, setting-specific diabetes risk identification and prevention strategies based on available resources. These should be linked to initiatives aimed at reducing the burden of cardiovascular disease, and complemented with population-based strategies focusing on the control and reduction of behavioural and cardiovascular risk factors by targeting their key determinants., (2009 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To evaluate our results with a new method of intravesical ureteric reimplantation using laparoscopic pneumovesicum in children., Materials and Methods: Seventy-two patients (mean age 4.2 years, range 0.5-20 years) with primary vesicoureteral reflux (VUR) underwent a laparoscopic transtrigonal ureteric reimplantation with CO(2) pneumovesicum. Ports were inserted suprapubically - 5mm for the camera and two 3-5-mm working ports. Having mobilized the ureter(s) intravesically, a submucosal tunnel is created and ureteric reimplantation performed with 5/0 and 6/0 absorbable sutures. Bladder drainage was maintained for 2-3 days postoperatively. Patients were followed up with clinical assessment and renal ultrasonography+/-voiding cystourethrogram., Results: Ninety percent had VUR grade > or =3. A total of 113 ureters were reimplanted. The mean operative time was 82min for unilateral and 130min for bilateral reimplantation. Four cases (6%) were converted. Three patients presented with temporary ureteric dilatation without symptoms on follow-up renal ultrasound. Seven patients had postoperative urinary tract infection without persistent reflux on cystography. Follow-up cystogram was performed in 50 patients (81 ureters). Reflux persisted in four patients (8%)., Conclusions: Laparoscopic ureteric reimplantation with CO(2) pneumovesicum is technically feasible with a high success rate (92%). The role of this new technique in the treatment of VUR remains to be determined.

Purpose: To compare the effectiveness, potential advantages and complications of classical open pyeloplasty with retroperitoneoscopic pyeloplasty in children., Materials and Methods: Two patient cohorts with confirmed ureteropelvic junction obstruction (UPJO) undergoing open or retroperitoneoscopic pyeloplasty over a 7-year period were analysed comparatively., Results: Operative time was significantly longer in the retroperitoneoscopic group (mean 155 min) compared to the open pyeloplasty group (mean 98 min, P<0.05). Mean hospital stay was shorter in the retroperitoneoscopic group (mean 4.1 days, compared to 5.1 days, open). Complication rates were similar (open, 27% vs retroperitoneoscopic, 29%). These included anastomotic urinary leakage, stenosis and infection. Anastomotic leakage was more common in the retroperitoneoscopic group. There was a 6.6% conversion rate in the retroperitoneoscopic group. Success, defined as improved ultrasonic or renographic parameters, with resolution of symptoms where discernable, was noted in 96% of the open group and 97% of the retroperitoneoscopic group with a mean follow up of 38 and 25 months, respectively., Conclusions: Retroperitoneoscopic pyeloplasty is as safe and effective as open pyeloplasty. This technique is now our procedure of choice for children>4 months old. The advantages are more obvious in children over 4 years than in infants. This technique remains difficult to perform and teach.

Objective: To report the presentation and treatment outcomes on a series of 12 paediatric bulbar or posterior urethral strictures that were possibly congenital in origin, identified in a 9-year period., Methods: A retrospective case-note review of all cases of urethral strictures thought to be congenital in origin, prospectively collected into the departmental database., Results: The age at presentation had a bimodal distribution with 6/12 presenting in the first year of life of which four had antenatal hydronephrosis and 5/12 presenting after the age of 11 years. All six patients under 1-year old had a successful outcome following urethrotomy and urethral dilatation. Four of five over 11 years of age ultimately required an urethroplasty and one 3-year-old may well require an urethroplasty in the future., Conclusion: This outcome, in conjunction with the bimodal age distribution at presentation, would suggest a different aetiology in older children, and we would urge caution in classifying strictures in ambulant children as genuinely congenital, as this population may represent the long-term manifestation of unrecorded bulbar urethral trauma or asymptomatic inflammation. Optical urethrotomy or dilatation is durable when treated in infancy, but older patients do not experience prolonged resolution and we would recommend treatment along adult lines for these.

This review assesses the incidence and aetiology of faecal incontinence in childhood. We then systematically address the presentation, clinical assessment, investigation and management of these children. Under management, both medical and surgical approaches and their complications are discussed.

Aims/hypothesis: Our aim was to examine the association between change in physical activity energy expenditure (PAEE), total body movement (counts per day) and aerobic fitness (maximum oxygen consumption [VO2max] over 1 year and metabolic risk among individuals with a family history of diabetes., Methods: Three hundred and sixty-five offspring of people with type 2 diabetes underwent measurement of energy expenditure (PAEE measured using the flex heart rate method), total body movement (daily activity counts from accelerometry data), [VO2max] predicted from a submaximal graded treadmill exercise test and anthropometric and metabolic status at baseline and 1 year (n = 321) in the ProActive trial. Clustered metabolic risk was calculated by summing standardised values for waist circumference, fasting triacylglycerol, insulin and glucose, blood pressure and the inverse of HDL-cholesterol. Linear regression was used to quantify the association between changes in PAEE, total body movement and fitness and clustered metabolic risk at follow-up., Results: Participants increased their activity by 0.01 units PAEE kJ kg(-1) day(-1) over 1 year. Total body movement increased by an average of 9,848 counts per day. Change in total body movement (beta = -0.066, p = 0.004) and fitness (beta = -0.056, p = 0.003) was associated with clustered metabolic risk at follow-up, independently of age, sex, smoking status, socioeconomic status and baseline metabolic score., Conclusions/interpretation: Small increases in activity and fitness were associated with a reduction in clustered metabolic risk in this cohort of carefully characterised at-risk individuals. Further research to quantify the reduction in risk of type 2 diabetes associated with feasible changes in these variables should inform preventive interventions.

The major drug-metabolizing human hepatic cytochrome P-450s (CYPs; CYP1A2, 2C9, 2C19, 2D6, and 3A4) coexpressed functionally in Escherichia coli with human NADPH-P-450 reductase have been validated as surrogates to their counterparts in human liver microsomes (HLM) using automated technology. The dealkylation of ethoxyresorufin, dextromethorphan, and erythromycin were all shown to be specific reactions for CYP1A2, CYP2D6, and CYP3A4 that allowed direct comparison with kinetic data for HLM. For CYP2C9 and CYP2C19, the kinetics for the discrete oxidations of naproxen and diazepam were compared to data obtained using established, commercial CYP preparations. Turnover numbers of CYPs expressed in E. coli toward these substrates were generally equal to or even greater than those of the major commercial suppliers [CYP1A2 (ethoxyresorufin), E. coli 0.6 +/- 0.2 min(-1) versus B lymphoblasts 0.4 +/- 0.1 min(-1); CYP2C9 (naproxen), 6.7 +/- 0.9 versus 4.9 min(-1); CYP2C19 (diazepam), 3.7 +/- 0.3 versus 0.2 +/- 0.1 min(-1); CYP2D6 (dextromethorphan), 4.7 +/- 0.1 versus 4.4 +/- 0.1 min(-1); CYP3A4 (erythromycin), 3 +/- 1.2 versus 1.6 min(-1)]. The apparent K(m) values for the specific reactions were also similar (K(m) ranges for expressed CYPs and HLM were: ethoxyresorufin 0.5-1.0 microM, dextromethorphan 1.3-5.9 microM, and erythromycin 18-57 microM), indicating little if any effect of N-terminal modification on the E. coli-expressed CYPs. The data generated for all the probe substrates by HLM and recombinant CYPs also agreed well with literature values. In summary, E. coli-expressed CYPs appear faithful surrogates for the native (HLM) enzyme, and these data suggest that such recombinant enzymes may be suitable for predictive human metabolism studies.

In a randomised trial, general practitioners and nurses in 21 practices were trained in patient-centred consulting and use of materials for people with Type 2 diabetes (GPs 0.5 days; nurses 1.5 days; two optional follow-up half-days). Twenty practices formed the comparison group. Professional beliefs, attitudes and behaviour were measured (pre-trial, close-of-course and end-of-trial), supported by patient reports of nurse behaviour (141 trained: 108 comparison patients, 1 year after diagnosis). A total of 49 practice nurses responded (29 trained; 20 comparison). Trained nurses rated relative importance of patient-centred to professional-centred care as greater than comparison nurses. Trained nurses became less keen on the approach during the trial, and perceived time constraints persisted. Patients diagnosed later in the study were less likely to recognise intervention materials. Trained nurses rated delivery of important aspects of care and satisfaction with style of care as lower than comparison nurses, but patients were more positive about delivery of care from trained than comparison nurses. Although nurses rated patient-centred care as important, whether or not they had been trained as part of the trial, the short, generalizable training programme significantly reduced nurse perceptions of their ability to deliver it. Nonetheless, patients reported that important aspects of diabetes care were delivered more if their nurses had been trained in patient-centred consulting. This raises issues concerning measurement scales completed by trained professionals.

Diabetes mellitus requires lifelong self-management with regular health professional support and supervision. Estimates of the prevalence of failed appointments at diabetes clinics vary but at less than 10% appear to be lower than for other non-chronic conditions. Yet the patients who do not attend have significantly more risk factors and complications than those who keep their appointments. In addition, failed appointments reduce clinic efficiency. To date, research on non-attendance for health care has largely focused on the characteristics of defaulters and evaluation of simple interventions aimed at directly altering their appointment-keeping behaviour, such as mailed reminders. However, like the broader issue of adherence, there are many factors that predispose to non-attendance ranging from patient health beliefs and attitudes of health professionals, the organization of the clinic and the financial costs of attendance, to the degree of patient participation within consultations. Consequently, there is a range of strategies from patient reminders and induction videos, logistical and administrative changes in the clinic, to training in consultation skills for health professionals that have the potential to decrease the numbers of patients lost to follow-up. Whether these will reduce morbidity efficiently should be the subject of further work.

A new class of dual-acting racemic thromboxane receptor antagonist/thromboxane synthase inhibitors is reported, based on the novel approach of linking the known thromboxane synthase inhibitors (TXSI) dazoxiben (2) or isbogrel (11) (separately) to thromboxane receptor antagonists (TXRA) from the 1,3-dioxane series, such as ICI 192605 (10). Dual activity was observed in vitro with inhibition of human microsomal thromboxane synthase in the range IC50 = 0.01-1.0 microM and receptor antagonist activity by inhibition of U46619-induced human platelet aggregation in the range pA2 = 5.5-7.0. The in vitro results also showed that very large groups could be tolerated at the selected substitution positions of the TXRA and TXSI components. Oral activity was observed in ex vivo tests in both rats and dogs at a dose of 10 mg/kg. Thus, (E)-7-[4-[[4-[(2SR,4SR,5RS)-5-[(Z)-5-carboxypent -2-enyl]-4-(2- hydroxyphenyl)-1,3-dioxan-2-yl]-benzyl]oxy]phenyl]-7-(3-pyridyl)he pt-6- enoic acid (110) was both an antagonist (pA2 = 6.7) and a synthase inhibitor (IC50 = 0.02 microM). On oral dosing (10 mg/kg) to rats and dogs, 110 showed significant TXRA activity [concentration ratio > 64 (rat, 3 h) and > 59 +/- 11.3 (dog, 2 h) vs ex vivo U46619-induced platelet aggregation]. Inhibition of thromboxane synthase at the respective time points in these experiments was 81 +/- 4.4% (rat) and 69 +/- 4.8% (dog).

The effects of amitriptyline (n = 14) or zimelidine (n = 13) on the sleep electroencephalogram of hospitalized depressed patients were assessed in a double-blind protocol involving 28 days of active dosing. Zimelidine induced no immediate improvement in sleep continuity, and even after 3 wk on zimelidine subjects tended to have longer sleep latency, more awakenings, and lighter non-rapid eye movement (REM) sleep than before taking the drug. Zimelidine did, however, induce a rapid and persistent alteration of sleep architecture and selected REM measures. REM sleep, which was suppressed over the first two nights on zimelidine, was maximally suppressed after 1 wk, but by 3 wk there was some tolerance for selected REM measures. While zimelidine induced none of the sedative effects of amitriptyline, both were equivalent in their REM-suppressant effects. These findings are discussed in terms of the differences in uptake blockade and anticholinergic potency in these two drugs.

The authors investigated the pharmacological treatment of delusional depression by assigning patients on a random double-blind basis to amitriptyline alone, perphenazine alone, or a combination of the two. Fourteen (78%) of the 18 patients assigned to amitriptyline plus perphenazine were responders, compared with seven (41%) of 17 patients treated with amitriptyline alone and three (19%) of the 16 patients treated with perphenazine alone. The combination of amitriptyline and perphenazine was clearly superior (p less than .01).

This study investigated the pharmacological treatment of delusional depressives by assigning patients on a random double-blind basis to amitriptyline (AT) alone, perphenazine (PER) alone, or AT + PER. As reported in an earlier paper, the combination of AT + PER was the superior treatment with a response rate of 78% compared with 41% for AT alone and 19% for PER alone. This difference is both clinically and statistically significant (p less than 0.01). In this second article, the authors report that the patients on AT + PER had higher plasma levels of AT and its pharmacologically active metabolite nortriptyline (NT) than the patients on AT alone. Although the response rate had a direct relationship to AT + NT plasma levels, an analysis of variance showed that the group of patients treated with AT + PER still had a significantly higher response rate, even after controlling for the plasma levels of AT + NT (p less than 0.05). There was also a correlation between PER plasma levels and clinical response.

Despite their widespread use, there are few data concerning the effects of tricyclic antidepressants on EEG sleep in depression. The present study documented the effects of desipramine (DMI, n = 17) and amitriptyline (AT, n = 16) upon EEG sleep in hospitalized depressed patients as part of a double-blind protocol involving 28 days of active treatment. Compared to placebo, patients receiving DMI showed somewhat worsened sleep continuity, particularly after 1 week of administration when the dose was 150 mg/day. On the other hand, sleep architecture and REM measures showed a rapid suppression of REM sleep, and then partial tolerance for this effect was observed with continued administration of DMI for 3 weeks. DMI was a more potent suppressor of REM sleep, while AT was more sedative. Based on these differences in effects upon EEG sleep, a discriminant function was derived and resulted in a correct classification of 87.5% of AT cases and 76.5% of DMI cases. These results are discussed in terms of the differences in pharmacological profiles for uptake blockade and anticholinergic potency for these two compounds.

Depressive symptoms were measured in 34 white male patients receiving propranolol treatment for cardiovascular illness. The Hamilton Rating Scale for Depression and the Hudson Generalized Contentment Scale were used to measure depressive symptoms. Patients with a positive personal or family history of depression had significantly higher depression scores than those with a negative history. Although there was no correlation between propranolol dosage and depressive symptoms for the population as a whole, among patients with a negative history there was a highly significant positive correlation between propranolol dosage and depression scores.