Increasing capacity to deliver diabetes self-management education: results of the DESMOND lay educator non-randomized controlled equivalence trial.

AIM: To develop and test a format of delivery of diabetes self-management education by paired professional and lay educators. METHODS: We conducted an equivalence trial with non-randomized participant allocation to a Diabetes Education and Self Management for Ongoing and Newly Diagnosed Type 2 diabetes (DESMOND) course, delivered in the standard format by two trained healthcare professional educators (to the control group) or by one trained lay educator and one professional educator (to the intervention group). A total of 260 people with Type 2 diabetes diagnosed within the previous 12 months were referred for self-management education as part of routine care and attended either a control or intervention format DESMOND course. The primary outcome measure was change in illness coherence score (derived from the Diabetes Illness Perception Questionnaire-Revised) between baseline and 4 months after attending education sessions. Secondary outcome measures included change in HbA1c level. The trial was conducted in four primary care organizations across England and Scotland. RESULTS: The 95% CI for the between-group difference in positive change in coherence scores was within the pre-set limits of equivalence (difference = 0.22, 95% CI 1.07 to 1.52). Equivalent changes related to secondary outcome measures were also observed, including equivalent reductions in HbA1c levels. CONCLUSION: Diabetes education delivered jointly by a trained lay person and a healthcare professional educator with the same educator role can provide equivalent patient benefits. This could provide a method that increases capacity, maintains quality and is cost-effective, while increasing access to self-management education.

Does nausea and vomiting of pregnancy play a role in the association found between maternal caffeine intake and fetal growth restriction?

The aim of this study was to explore the relationships between nausea and vomiting in pregnancy and (a) fetal growth restriction; and (b) maternal caffeine metabolism and fetal growth restriction. A cohort of 2,643 pregnant women, aged 18-45 years, attending two UK maternity units between 8 and 12 weeks gestation, was recruited. A validated tool assessed caffeine intake at different stages of pregnancy and caffeine metabolism was assessed from a caffeine challenge test. Experience of nausea and vomiting of pregnancy was self-reported for each trimester. Adjustment was made for confounders, including salivary cotinine as a biomarker of current smoking status. There were no significant associations between fetal growth restriction and nausea and vomiting in pregnancy, even after adjustment for smoking and alcohol intake. There were no significant differences in the relationship between caffeine intake and fetal growth restriction between those experiencing symptoms of nausea and vomiting and those who did not, for either the first (p = 0.50) or second trimester (p = 0.61) after adjustment for smoking, alcohol intake and caffeine half-life. There were also no significant differences in the relationship between caffeine half-life and fetal growth restriction between those experiencing symptoms of nausea and vomiting and those who did not, for either the first trimester (p = 0.91) or the second trimester (p = 0.45) after adjusting for smoking, alcohol intake and caffeine intake. The results from this study show no evidence that the relationship between maternal caffeine intake and fetal growth restriction is modified by nausea and vomiting in pregnancy.

Detection of impaired glucose regulation and/or type 2 diabetes mellitus, using primary care electronic data, in a multiethnic UK community setting.

AIMS/HYPOTHESIS: The aim of this study was to develop and validate a score for detecting the glycaemic categories of impaired glucose regulation (IGR) and type 2 diabetes using the WHO 2011 diagnostic criteria. METHODS: We used data from 6,390 individuals aged 40-75 years from a multiethnic population based screening study. We developed a logistic regression model for predicting IGR and type 2 diabetes (diagnosed using OGTT or HbA(1c) ≥ 6.5% [48 mmol/mol]) from data which are routinely stored in primary care. We developed the score by summing the ß coefficients. We externally validated the score using data from 3,225 participants aged 40-75 years screened as part of another study. RESULTS: The score includes age, ethnicity, sex, family history of diabetes, antihypertensive therapy and BMI. Fifty per cent of a population would need to be invited for testing to detect type 2 diabetes mellitus on OGTT with 80% sensitivity; this is slightly raised to 54% that need to be invited if using HbA(1c). Inviting the top 10% for testing, 9% of these would have type 2 diabetes mellitus using an OGTT (positive predictive value [PPV] 8.9% [95% CI 5.8%,12.8%]), 26% would have IGR (PPV 25.9% [95% CI 20.9%, 31.4%]). Using HbA(1c) increases the PPV to 19% for type 2 diabetes mellitus (PPV 18.6% [95% CI 14.2%, 23.7%]) and 28% for an HbA(1c) between 6.0% and 6.4% (PPV 28.3% [95% CI 23.1%, 34.0%]). CONCLUSIONS: The score can be used to reliably identify those with undiagnosed IGR and type 2 diabetes in multiethnic populations. This is the first score developed taking into account HbA(1c) in the diagnosis of type 2 diabetes.

Validity of self-assessed waist circumference in a multi-ethnic UK population.

AIMS: To investigate validity of waist circumference measurements obtained by self-report and self-measurement with non-verbal pictorial instructions among a multi-ethnic population. METHODS: Five hundred and twenty-six individuals aged 40-75 years (91 South Asian, 430 White European and five other), who attended a screening programme for Type 2 diabetes, estimated their waist circumference and measured their waist with a paper tape measure. Participants were also provided with simple pictorial instructions for measurement of waist circumference in their preferred language and remeasured their waist circumference. We calculated 95% limits of agreement with measures undertaken by a healthcare professional unaware of prior measures. RESULTS: Mean age was 56.8 years (sd 9.0), mean BMI 30.0 kg/m(2) (sd 5.6) and mean waist circumference 98.4 cm (sd 14.1). Seventy-nine per cent had high waist circumference according to International Diabetes Federation criteria. The mean of participants' self-reported value was 6.8 cm lower than the healthcare professional measure (sd 8.8; 95% limits of agreement -10.4 to 24.0 cm), with significant differences by sex and ethnicity (South Asian men 7.5 cm, South Asian women 0.1 cm, White European men 7.8 cm, White European women 7.0 cm, P < 0.001). Compared with healthcare professional measures, mean self-measured waist circumference was very similar, both with instructions (0.4 cm higher; sd 5.5 cm; -11.1 to 10.4 cm) and without instructions (0.5 cm lower; sd 5.6; -10.4 to 11.4 cm), but with significant differences by sex and ethnicity (P < 0.001). CONCLUSIONS: There was systematic underestimation of self-reported waist circumference in this multi-ethnic UK population. The magnitude of underestimation might reduce the performance of risk scores; however, this can be corrected through self-measurement with pictorial instructions.

Predicting outcome of assertive outreach across England.

BACKGROUND: Assertive community treatment for the severely mentally ill is being implemented increasingly internationally. It is unclear whether recommended characteristics of assertive outreach (AO) teams influence care and outcomes. We hypothesised that recommended characteristics of AO teams such as joint health and social care management would predict reduced hospitalisation in the first year of an AO client programme and related outcomes throughout England. METHODS: A two-stage design was used: a stratified sample of 100 of the 186 'stand-alone' AO teams in England and a systematic sample of clients from each team with stratification for black and ethnic minority patients. Team characteristics, treatment and outcomes were collected from teams. Analyses took account of patients' histories, clustering and ethnic minority over-sampling. RESULTS: Under AO the proportion of time spent in hospital following admission decreased. Only 3/1,096 patients went missing in 9 months. Although patient' histories significantly predicted outcomes almost no team characteristics predicted re-admission or other patient outcomes after 1 and 3 years. Ethnic minority clients were more likely to be on compulsory orders only on jointly managed teams (P = 0.030). Multidisciplinary teams and teams not working out of hours significantly predicted that patients received psychological interventions, but only 17% of sampled patients received such treatments. CONCLUSIONS: Characteristics of AO teams do not explain long-term patient outcomes. Since recommended team characteristics are not effective new models of care should be developed and the process of care tested. Managing teams to implement evidence-based psychological interventions might improve outcomes.

Screening for diabetes using an oral glucose tolerance test within a western multi-ethnic population identifies modifiable cardiovascular risk: the ADDITION-Leicester study.

AIMS/HYPOTHESIS: The aim of this study was to determine the frequency of undiagnosed glucose abnormalities and the burden of cardiovascular disease (CVD) risk among south Asians and white Europeans attending a systematic screening programme for type 2 diabetes (ADDITION-Leicester) and to estimate the achievable risk reduction in individuals identified with glucose disorders. METHODS: Random samples of individuals (n = 66,320) from 20 general practices were invited for a 75 g OGTT and CVD risk assessment. Ten-year CVD risk among screen-detected people with diabetes or impaired glucose regulation (IGR) (impaired fasting glycaemia and/or impaired glucose tolerance [IGT]) was computed using the Framingham-based ETHRISK engine and achievable risk reduction was predicted using relative reductions for treatments extracted from published trials. RESULTS: A total of 6,041 participants (48% male, 22% south Asian) aged 40-75 years inclusive were included. Undiagnosed glucose disorders occurred more frequently in south Asians than white Europeans; age and sex adjusted odds ratios were 1.74 (95% CI 1.42-2.13) and 2.30 (95% CI 1.68-3.16) for IGT and diabetes respectively. Prevalence of any undetected glucose disorder was 17.5% in the whole cohort. Adjusted 10-year risk was similar in screen-detected people with IGR and diabetes (18.3% vs 21.6%), and was higher in south Asians across the glucose spectrum. Absolute CVD risk reductions of up to 13% in those with screen-detected type 2 diabetes and 6% in IGR are achievable using existing cardioprotective therapies. CONCLUSIONS/INTERPRETATION: Population screening with an OGTT identifies a significant burden of modifiable CVD risk, especially within south Asian groups. Strategies enticing this population to consider screening programmes are urgently needed as significant risk reduction is possible once a glucose abnormality is identified. TRIAL REGISTRATION: ClinicalTrials.gov NCT00318032. FUNDING: The project is funded for support and treatment costs by NHS Department of Health Support for Science and project grants.

Association of cardiac and non-cardiac chronic disease comorbidity on glycaemic control in a multi-ethnic population with type 1 and type 2 diabetes.

AIMS: To determine the prevalence of chronic disease comorbidity in south Asians (SAs) and white Europeans (WEs) with diabetes and to quantify the relationship of cardiac disease comorbidity (CDCM) and non-cardiac disease comorbidity (NCCM) to glycaemic control in SAs and WEs with type 1 and type 2 diabetes mellitus. METHODS: A cross-sectional study using a database of patients of SA (25.5%) and WE (74.5%) origin attending a specialist diabetes clinic in the UK between 2003 and 2005 (n=5664). RESULTS: The prevalence of SAs and WEs with type 1 diabetes was 12% and 88%, respectively; for those with type 2 diabetes the prevalence was 30% and 70%, respectively. Overall, the prevalence of comorbidity in people with type 1 diabetes was 25.5% and with type 2 diabetes was 47%. NCCM was more prevalent in WEs than SAs (17.6% vs 12.8%, p<0.001). In type 2 diabetes, the prevalence of suboptimal glycaemic control was significantly greater in SAs compared to WEs with NCCM and CDCM (79% vs 62%, p<0.001; 78% vs 65%, p<0.001, respectively). SAs with type 2 diabetes and comorbidity had excess odds of suboptimal glycaemic control compared to WEs: OR 2.27 (95% CI 1.50 to 3.43) for those with NCCM and OR 1.91 (95% CI 1.49 to 2.44) for those with CDCM. CONCLUSIONS: The prevalence of CDCM is higher in SAs compared to WEs with type 2 diabetes, whereas the prevalence of NCCM is higher in WEs compared to SAs. Taking into account comorbidities, SAs (compared to WEs) with type 2 diabetes had an excess risk of having HbA1c ≥7% ranging from 1.86- to 2.27-fold. Further research is needed to identify the reasons for unfavourable metabolic conditions in SAs and also develop and evaluate interventions.

The Leicester Risk Assessment score for detecting undiagnosed Type 2 diabetes and impaired glucose regulation for use in a multiethnic UK setting.

AIMS: Risk assessment scores identify those at high risk of impaired glucose regulation and Type 2 diabetes mellitus. To date no risk assessment scores that can be completed by a lay person have been developed and validated specifically for multiethnic populations in the UK. METHODS: We used data on 6186 subjects aged 40-75 years from a multiethnic UK screening study (73% white European, 22% South Asian). All participants were given a 75 g oral glucose tolerance test. We developed logistic regression models for predicting current impaired glucose regulation (impaired fasting glycaemia/impaired glucose tolerance) or Type 2 diabetes mellitus using data from anthropometric measurements and self-reported questionnaires. Using the best-fitting model, we developed the Leicester Risk Assessment score. We externally validated the score using data from 3171 subjects aged 40-75 years from a separate screening study. RESULTS: The components of the final model are age, ethnicity [white European vs. other (predominantly South Asian)], sex, first degree family history of diabetes, antihypertensive therapy or history of hypertension, waist circumference and body mass index. The score ranges from 0 to 47. Validating this model using the data from the second screening study gave an area under the receiver operator characteristic curve of 72% (95% confidence interval, 69-74%). A cut point of 16 had a sensitivity of 81% and a specificity of 45%. CONCLUSIONS: The Leicester Risk Assessment score can be used to identify those at high risk of impaired glucose regulation and Type 2 diabetes mellitus in UK multiethnic populations. The score is simple (seven questions) and non-invasive.

Patient safety systems in the primary health care of diabetes­a story of missed opportunities?

AIMS: Key elements of a patient safety system include mechanisms for identifying errors or safety events, methods for investigating the events and processes for acting on the findings of the investigations. A patient safety system for management of diabetes in primary care might help to reduce adverse outcomes. The aims of this study were to review the current state of research into patient safety systems for people with diabetes in primary care. METHODS: MEDLINE, EMBASE and nine other biomedical and health management databases were searched for articles published up to April 2009. Selection and review of abstracts were carried out independently by two authors. RESULTS: Abstracts of 1659 articles were identified, of which only three fulfilled the selection criteria, and these did not appear in mainstream primary care journals. These papers covered the applications of root cause analysis, videoconferencing and automated telephone support to patient safety systems for managing diabetes in primary care. CONCLUSIONS: There is very little evidence on how patient safety systems for the management of primary care diabetes can be implemented, or on how the effectiveness of such systems can be maximized. If patient safety systems do have potential to improve the processes and outcomes of care, the lack of relevant research may be regarded as a missed opportunity­investigation into the reasons for the situation is needed, with the aim of motivating and enabling further research on a range of problems identified here.

Searching for the right outcome? A systematic review and meta-analysis of controlled trials using carotid intima-media thickness or pulse wave velocity to infer antiatherogenic properties of thiazolidinediones.

INTRODUCTION: Recent meta-analyses cast doubt over purported beneficial effects of Peroxisome Proliferator Activated Receptor-Gamma (PPAR-gamma) receptor agonists. Thiazolidinedione (TZD) trials using surrogate outcomes to postulate an antiatherogenic paradigm have been criticised as misinformative. We conducted an independent systematic review and meta-analysis of controlled TZD studies incorporating carotid intima-media thickness (CIMT) or pulse wave velocity (PWV) as primary outcome measures. The aim was to provide an evidence-based overview of TZD intervention studies using markers prospectively linked to vascular outcome in type 2 diabetes. METHODS: Systematic search of known databases for TZD intervention trials using mean thickness CIMT(n = 9) and ankle-brachial PWV(n = 6) as primary outcome measures was performed. CIMT and PWV pooled weighted mean difference was calculated using a random effects model accounting for heterogeneity and publication bias. An indirect meta-analysis provided a comparison of rosiglitazone and pioglitazone effects. RESULTS: A composite of combined placebo and comparator controlled trials demonstrated a significant weighted mean difference of-0.06 mm for CIMT (95% CI-0.09 to-0.02, p = 0.001) and-0.72 ms(-1) for PWV (95% CI-1.28 to-0.16, p = 0.011) in favour of thiazolidiendione treatment. No TZD intraclass variation in CIMT (p = 0.96) or PWV (p = 0.33) change was observed. CONCLUSION: TZDs exhibit significant beneficial effects on aorto-carotid atherosclerosis when assessed using prospectively validated non-invasive techniques. Inferring clinical benefit in the absence of confirmatory outcome trials is questionable and caution should be exercised when interpreting intervention data with surrogate endpoints. TZD-induced congestive cardiac failure or other unknown PPAR-gamma adverse effects are plausible explanations for the conflicting results of intervention trials using markers of atherosclerosis and clinical event outcomes.

Late endosomal traffic of the epidermal growth factor receptor ensures spatial and temporal fidelity of mitogen-activated protein kinase signaling.

Mitogen-activated protein kinase (MAPK) signaling is regulated by assembling distinct scaffold complexes at the plasma membrane and on endosomes. Thus, spatial resolution might be critical to determine signaling specificity. Therefore, we investigated whether epidermal growth factor receptor (EGFR) traffic through the endosomal system provides spatial information for MAPK signaling. To mislocalize late endosomes to the cell periphery we used the dynein subunit p50 dynamitin. The peripheral translocation of late endosomes resulted in a prolonged EGFR activation on late endosomes and a slow down in EGFR degradation. Continuous EGFR signaling from late endosomes caused sustained extracellular signal-regulated kinase and p38 signaling and resulted in hyperactivation of nuclear targets, such as Elk-1. In contrast, clustering late endosomes in the perinuclear region by expression of dominant active Rab7 delayed the entry of the EGFR into late endosomes, which caused a delay in EGFR degradation and a sustained MAPK signaling. Surprisingly, the activation of nuclear targets was reduced. Thus, we conclude that appropriate trafficking of the activated EGFR through endosomes controls the spatial and temporal regulation of MAPK signaling.

Prevalence of diagnosed depression in South Asian and white European people with type 1 and type 2 diabetes mellitus in a UK secondary care population.

AIM: To examine the prevalence and correlates of diagnosed depression among South Asians and white Europeans with type 1 and type 2 diabetes mellitus, attending a specialist diabetes clinic in the UK. STUDY DESIGN AND METHODS: A cross-sectional study was conducted using the hospital clinic's computerised database. Medical and demographic data were extracted for 6230 people with diabetes attending the clinic between 2003 and 2005. Multiple logistic regression was used to model ethnic differences in the probability of diagnosed depression after controlling for demographic and diabetes related factors. Analyses were conducted separately for type 1 and type 2 diabetes. RESULTS: The unadjusted prevalence of depression in people with type 1 and type 2 diabetes was 8.0% and 9.3%, respectively. Risk factors for depression in type 1 diabetes included female gender, diabetes related complications, and comorbidities. In people with type 2 diabetes the risk factors for depression included younger age, diabetes related complications, comorbidities, insulin use and deprivation. In addition, white Europeans were significantly more likely to be diagnosed with depression compared to South Asians (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.21 to 2.08; p<0.001). Further interaction analyses revealed no evidence that the association between ethnicity and depression differed according to any of the other factors examined in this study. CONCLUSIONS: The findings add to the limited body of knowledge regarding ethnic differences in depression and diabetes. Among those with type 2 diabetes, white Europeans had nearly 60% higher adjusted odds of diagnosed depression compared to South Asians. Disparities may be due to differences in presentation or identification of depression between these two ethnic groups.

The prospective experience of a maxillofacial surgeon with the percutaneous endoscopic gastrostomy technique.

Insertion of a percutaneous endoscopic gastrostomy (PEG) was attempted on 225 occasions, mainly for oral malignancy. Seventy-five percent (169/225) were inserted at the time of definitive surgery. There were significant incidental findings during 5% (11/225). The rate of successful insertion was 97% (219/225). The incidence of minor complications was 12% (26/225) and major complications 3% (7/225). There was no procedure-related mortality. The 30-day mortality rate, including those with terminal malignant disease, was 6% (14/225). An increased risk of death was associated with age of 65 years and over (P=0.004). The median PEG duration was 337 (SE 31) days. Duration was significantly longer for stage T3-4 tumours (P=0.028), N1 or greater neck disease (P=0.034), following surgery with radiotherapy when compared to surgery alone (P<0.001), particularly glossectomy (P=0.038) and maxillectomy procedures (P=0.003), after two separate surgical procedures and radiotherapy (P=0.046) and following a composite bone resection (P=0.031), or radiotherapy alone when compared to surgery alone (P=0.003). There was no relationship to the type of flap used for reconstruction. Four patients have a long-term PEG. Only two patients did not use the PEG. The early insertion of a PEG in all patients undergoing free or pedicled flap reconstruction appears to be appropriate. The PEG procedure may be safely performed by an appropriately trained maxillofacial surgeon.

The epidemiology of fractures of the scaphoid: impact of age, gender, deprivation and seasonality.

AIMS: This study explores the epidemiology of patients with a fracture of the scaphoid presenting to a regional teaching hospital. PATIENTS AND METHODS: All patients with a confirmed fracture of the scaphoid over a retrospective period between January 2010 and May 2013 were included. Their demographics, deprivation status and when the fracture occurred was noted and assessed. There were 415 fractures in 365 males and 50 females. RESULTS: The incidence of fracture of the scaphoid was 12.4 in 100 000 each year in the general population. The mean age of the patients was 22 years (nine to 35); the highest incidence was in males aged between 15 and 19 years. We calculate the annual incidence in the United Kingdom to be 7265 each year. Patients with the lowest socioeconomic status had an incidence of 18.57 in 100 000 whereas the least deprived patients had an incidence of 9.98 (p < 0.001). There was evidence of a seasonal trend (p = 0.022) with the highest monthly rate found in June (16.96 in 100 000 each year) and the lowest was in December (7.61 in 100 000 each year). There were significantly fewer presentations of fracture at the weekend (p < 0.001), and the highest incidence was on Mondays. Most fractures occurred at the waist (64%) and tubercle (18.1%). TAKE HOME MESSAGE: In this large-scale epidemiological study, we confirmed that young men are most at risk of sustaining a fracture of the scaphoid, and report new factors in relation to social deprivation and seasonality that influence scaphoid fractures. Cite this article: Bone Joint J 2016;98-B:654-9.

Clinical and lesion morphologic determinants of coronary angioplasty success and complications: current experience.

OBJECTIVES: This study evaluated the validity of the American College of Cardiology/American Heart Association ABC lesion classification scheme and its modifications. BACKGROUND: With the continued refinement in angioplasty technique and equipment evolution, the lesion morphologic determinants of immediate angioplasty outcome have changed significantly. Hence, the validity of the classification scheme has been questioned. METHODS: We assessed the lesion morphologic determinants of immediate angioplasty outcome in 729 consecutive patients who underwent coronary angioplasty of 994 vessels and 1,248 lesions. RESULTS: Angioplasty success was achieved in 91% of lesions, and abrupt closure occurred in 3%. Success was achieved in 96%, 93% and 80% of type A, B and C lesions, respectively (A vs. B, p = NS; B vs. C, p < 0.001; A vs. C, p < 0.001; A vs. B1, p = NS; A vs. B2, p = 0.03; B1 vs. B2, p = 0.02; B2 vs. C, p < 0.001; C1 vs. C2, p = NS). Abrupt closure occurred in 2.1%, 2.6% and 5% of type A, B and C lesions, respectively (A vs. B, B vs. C, A vs. C and A vs. B1, all p = NS; B1 vs. B2, p = 0.01; B2 vs. C1, p = NS; C1 vs. C2, p = 0.04). Type B characteristics had a success rate ranging from 74% to 95% and an abrupt closure rate ranging from 2.2% to 14%. Type C characteristics had a success rate ranging from 57% to 88% and an abrupt closure rate ranging from 0% to 16%. Longer lesions, calcified lesions, diameter stenosis of 80% to 99% and presence of thrombus were predictive of a lower success rate. Longer lesions, angulated lesions, diameter stenosis of 80% to 99% and calcified lesions were predictive of an abrupt closure. CONCLUSIONS: The previously proposed classification schemes are outdated and need to be changed for application in current angioplasty practice. Analyzing specific lesion morphologic characteristics rather than applying a simple lesion classification score when evaluating angioplasty outcome may be more useful because it provides a more precise profile of the lesion and allows better patient stratification and selection.

Recalibration methods to enhance information on prevalence rates from large mental health surveys.

Comparisons between self-report and clinical psychiatric measures have revealed considerable disagreement. It is unsafe to consider these measures as directly equivalent, so it would be valuable to have a reliable recalibration of one measure in terms of the other. We evaluated multiple imputation incorporating a Bayesian approach, and a fully Bayesian method, to recalibrate diagnoses from a self-report survey interview in terms of those from a clinical interview with data from a two-phase national household survey for a practical application, and artificial data for simulation studies. The most important factors in obtaining a precise and accurate 'clinical' prevalence estimate from self-report data were (a) good agreement between the two diagnostic measures and (b) a sufficiently large set of calibration data with diagnoses based on both kinds of interview from the same group of subjects. From the case study, calibration data on 612 subjects were sufficient to yield estimates of the total prevalence of anxiety, depression or neurosis with a precision in the region of +/-2%. The limitations of the calibration method demonstrate the need to increase agreement between survey and reference measures by improving lay interviews and their diagnostic algorithms.

Malignant transformation of human prostatic epithelium is associated with the loss of androgen receptor immunoreactivity in the surrounding stroma.

The cellular pathways involved in the pathogenesis of hormone resistance remain unclear. Studies evaluating the role of changes in human androgen receptor (hAR) expression in the progression of prostatic tumors have been inconclusive. Androgenic influence over prostatic growth is mediated via the regulation of interactions between stromal and epithelial cells. We hypothesized that neoplastic transformation of the prostate would be associated with alterations in hAR expression in the adjacent stroma. Using immunohistochemical techniques, we determined hAR positivity in the epithelium and adjacent stroma of sections from 17 benign and 39 malignant prostatic glands. We found that whereas the expression of the receptor decreased in both cellular compartments as the tissues dedifferentiated, the depletion was more pronounced in the stromal nuclei (P<0.0001). However, in sections from both untreated and hormone-resistant prostate cancer tissues, although heterogeneity of hAR expression in malignant epithelia was increased, there appeared to be a unique field effect around the cancerous prostate glands that resulted in a decreased expression of the receptor in the adjacent benign glands and its total loss in the surrounding stroma. The loss of hAR in the stroma adjacent to malignant prostatic epithelium may play an important role in prostate cancer progression. Furthermore, the similarity of the lack of stromal hAR expression in newly diagnosed and hormone-resistant prostate cancer (P = 0.85) may be an indication that the mechanisms responsible for the acquisition of hormone independence are established early in the malignant transformation process.

Human lymphocyte sodium-hydrogen exchange. The influences of lipids, membrane fluidity, and insulin.

The relation between serum lipids, membrane fluidity, insulin, and the activity of the sodium-hydrogen exchanger was investigated in human lymphocytes from 83 subjects. Subjects had a wide range of serum lipids and no concurrent disease. Lymphocyte membrane anisotropy (inversely related to membrane fluidity) was measured with a fluorescence polarization method. Sodium-hydrogen exchange maximal proton efflux rate, affinity for external sodium, and resting pH were determined with the intracellular pH-sensitive fluorochrome 2',5'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. Sodium-hydrogen exchange maximal proton efflux rate was negatively correlated with the age of the subject (p = 0.03). Membrane anisotropy correlated with serum triglyceride (p = 0.04). Multiple regression analysis demonstrated that the maximal proton efflux rate in human lymphocytes was significantly related to age (p = 0.005), systolic blood pressure (p = 0.04), membrane anisotropy (p = 0.03), and serum cholesterol (p = 0.03). Incubation of lymphocytes with insulin failed to affect sodium-hydrogen exchange kinetics, intracellular buffering power, or resting intracellular pH. These results suggest that membrane-bound transport proteins may be influenced by serum lipids and the fluidity of the lipid membrane in which they are bound, but they are unlikely to be affected by insulin.

Influence of nutritional status on clinical outcome after acute stroke.

A cause-and-effect relation between protein-energy malnutrition and poor outcome in acute stroke patients has not been definitively established. To measure the effect of the nutritional status of hospitalized stroke patients on clinical outcome, a prospective, observational study was performed. Acute stroke patients admitted to Leicester General Hospital from June 1994 to October 1995 had their nutritional status assessed with anthropometric, hematologic, and biochemical methods within 48 h of admission and after 2 and 4 wk. Outcome measures including disability, handicap, length of stay, morbidity (infective complications), discharge destination, and mortality were recorded during the hospital stay and at 3 mo. Nutritional status deteriorated significantly during the study period, but only serum albumin concentrations showed a significant association with various outcome measures. Stroke patients with hypoalbuminemia had a greater risk of infective complications (P<0.0001) and poor functional outcome during hospitalization than those with normal or higher serum albumin concentrations. Serum albumin concentrations were good predictors of the degree of disability and handicap during the hospital stay. After prognostic indicators of poor outcome were adjusted for, serum albumin concentration in the hospital was a strong and independent predictor of mortality at 3 mo after acute stroke [hazard ratio 0.91 (95% CI: 0.84, 0.99) for a 1-g/L higher serum albumin concentration]. Whether nutritional supplementation removes or mitigates the hazard of poor outcome associated with undernutrition after acute stroke needs to be determined.

Oxidisability of low density lipoproteins in patients with carotid or femoral artery atherosclerosis.

Oxidation of low density lipoprotein (LDL) is implicated in the pathogenesis of atherosclerosis. In this study the susceptibility to oxidation of LDL (from patients with atherosclerosis) is related to the progression of the disease. LDL were isolated from 37 patients with demonstrable atherosclerotic plaques. The susceptibility of LDL to oxidation (induced by an exogenous oxidative stress) was assessed by measuring the breakdown products of lipid peroxidation, the increased formation of conjugated dienes, and changes in surface charge of the apolipoprotein B (apo B). Progression of the atherosclerotic plaque was assessed by measuring the maximum velocity of blood through the narrowest portion of the vessel at inclusion and after one year. Twenty-nine of the 37 samples taken were found to have LDL that were partially oxidised, whereas 8 samples showed LDL whose state of oxidation was within the normal range. Progression of the atherosclerotic plaque occurred in 19 (66%) of the 29 patients whose lipoproteins were partially oxidised compared with only 2 (25%) of the 8 patients with normal lipoproteins (P = 0.055, Fisher's exact test). These data support an association between the progression of atherosclerotic plaques in carotid and femoral vessels and the susceptibility to oxidation of LDL.