Search

South Asians have a higher risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) than white Caucasians, for a given BMI. Premature biological ageing, assessed by reduction in telomere length (TL), may be mediated by factors resulting from altered metabolic profiles associated with obesity. We hypothesise that ethnicity and metabolic status represent detrimental factors contributing to premature biological ageing. Therefore we assessed TL in two South Asian, age and BMI-matched cohorts [T2DM (n=142) versus non-T2DM (n=76)] to determine the effects of BMI, gender, lipid and CVD profile on biological ageing. Genomic DNA was obtained from the UKADS cohort; biochemical and anthropometric data was collected and TL was measured by quantitative real-time PCR. Our findings indicated a gender-specific effect with reduced TL in T2DM men compared with non-T2DM men (P=0.006). Additionally, in T2DM men, TL was inversely correlated with triglycerides and total cholesterol (r=−0.419,P<0.01;r=−0.443,P<0.01). In summary, TL was reduced amongst South Asian T2DM men and correlated with triglycerides and total cholesterol. This study highlights enhanced biological ageing among South Asian, T2DM men, which appears to be tracked by changes in lipids and BMI, suggesting that raised lipids and BMI may directly contribute to premature ageing.

Objective - This study investigated and compared the prevalence of microalbuminuria and overt proteinuria and their determinants in a cohort of UK resident patients of white European or south Asian ethnicity with type 2 diabetes mellitus. Research design and methods - A total of 1978 patients, comprising 1486 of south Asian and 492 of white European ethnicity, in 25 general practices in Coventry and Birmingham inner city areas in England were studied in a cross-sectional study. Demographic and risk factor data were collected and presence of microalbuminuria and overt proteinuria assessed. Main outcome measures - Prevalences of microalbuminuria and overt proteinuria. Results - Urinary albumin:creatinine measurements were available for 1852 (94%) patients. The south Asian group had a lower prevalence of microalbuminuria, 19% vs. 23% and a higher prevalence of overt proteinuria, 8% vs. 3%, X2?=?15.85, 2df, P?=?0.0004. In multiple logistic regression models, adjusted for confounding factors, significantly increased risk for the south Asian vs. white European patients for overt proteinuria was shown; OR (95% CI) 2.17 (1.05, 4.49), P?=?0.0365. For microalbuminuria, an interaction effect for ethnicity and duration of diabetes suggested that risk for south Asian patients was lower in early years following diagnosis; OR for SA vs. WH at durations 0 and 1 year were 0.56 (0.37, 0.86) and 0.59 (0.39, 0.89) respectively. After 20 years’ duration, OR?=?1.40 (0.63, 3.08). Limitations - Comparability of ethnicity defined groups; statistical methods controlled for differences between groups, but residual confounding may remain. Analyses are based on a single measure of albumin:creatinine ratio. Conclusions - There were significant differences between ethnicity groups in risk factor profiles and microalbuminuria and overt proteinuria outcomes. Whilst south Asian patients had no excess risk of microalbuminuria, the risk of overt proteinuria was elevated significantly, which might be explained by faster progression of renal dysfunction in patients of south Asian ethnicity.

Background: The Meta-Analysis of Glucose and Insulin related traits Consortium (MAGIC) recently identified 16 loci robustly\ud associated with fasting glucose, some of which were also associated with type 2 diabetes. The purpose of our study was to\ud explore the role of these variants in South Asian populations of Punjabi ancestry, originating predominantly from the\ud District of Mirpur, Pakistan.\ud Methodology/Principal Findings: Sixteen single nucleotide polymorphisms (SNPs) were genotyped in 1678 subjects with\ud type 2 diabetes and 1584 normoglycaemic controls from two Punjabi populations; one resident in the UK and one\ud indigenous to the District of Mirpur. In the normoglycaemic controls investigated for fasting glucose associations, 12 of 16\ud SNPs displayed b values with the same direction of effect as that seen in European studies, although only the SLC30A8\ud rs11558471 SNP was nominally associated with fasting glucose (b = 0.063 [95% CI: 0.013, 0.113] p = 0.015). Of interest, the\ud MTNR1B rs10830963 SNP displayed a negative b value for fasting glucose in our study; this effect size was significantly lower\ud than that seen in Europeans (p = 1.2961024). In addition to previously reported type 2 diabetes risk variants in TCF7L2 and\ud SLC30A8, SNPs in ADCY5 (rs11708067) and GLIS3 (rs7034200) displayed evidence for association with type 2 diabetes, with\ud odds ratios of 1.23 (95% CI: 1.09, 1.39; p = 9.161024) and 1.16 (95% CI: 1.05, 1.29; p = 3.4961023) respectively.\ud Conclusions/Significance: Although only the SLC30A8 rs11558471 SNP was nominally associated with fasting glucose in our\ud study, the finding that 12 out of 16 SNPs displayed a direction of effect consistent with European studies suggests that a\ud number of these variants may contribute to fasting glucose variation in individuals of South Asian ancestry. We also provide\ud evidence for the first time in South Asians that alleles of SNPs in GLIS3 and ADCY5 may confer risk of type 2 diabetes.

To study the diurnal variation and the effect of insulin on adiponectin multimers and nuclear factor-kappaB (NF-κB) activity in human endothelial cells.We utilized a prolonged insulin-glucose infusion in six healthy human subjects. HMW and total adiponectin levels were higher in the morning and lower at night; NF-κB activities in serum treated human microvascular endothelial cells (HMEC-1) cells were lower in the morning and higher at night. Hyperinsulinemic induction significantly decreased HMW and total adiponectin levels but increased NF-κB activity in serum treated HMEC-1 cells (P0.05, P0.01). There were no significant changes to MMW and LMW adiponectin levels (P0.05).Circadian rhythm of HMW adiponectin and NF-κB activity are altered by hyperinsulinemia providing novel insights adiponectin and NF-κB biology, which may be pertinent to insulin resistant states, e.g. obesity and type 2 diabetes mellitus.

Background/Aim: People of south Asian origin have an excessive risk of morbidity and mortality from cardiovascular disease. We examined the effect of ethnicity on known risk factors and analysed the risk of cardiovascular events and mortality in UK south Asian and white Europeans patients with type 2 diabetes over a 2 year period. Methods: A total of 1486 south Asian (SA) and 492 white European (WE) subjects with type 2 diabetes were recruited from 25 general practices in Coventry and Birmingham, UK. Baseline data included clinical history, anthropometry and measurements of traditional risk factors-blood pressure, total cholesterol, HbA1c. Multiple linear regression models were used to examine ethnicity differences in individual risk factors. Ten-year cardiovascular risk was estimated using the Framingham and UKPDS equations. All subjects were followed up for 2 years. Cardiovascular events (CVD) and mortality between the two groups were compared. Trial registration number: ISRCTN 38297969. Findings: Significant differences were noted in risk profiles between both groups. After adjustment for clustering and confounding a significant ethnicity effect remained only for higher HbA1c (0.50 [0.22 to 0.77]; P=0.0004) and lower HDL (-0.09 [-0.17 to -0.01]; P=0.0266). Baseline CVD history was predictive of CVD events during follow-up for SA (P

A post-prandial increase in saturated fatty acids (SFAs) and glucose (Glc) activates an inflammatory response, which may be prolonged following restoration of physiological SFAs and Glc levels — a finding referred to as ‘metabolic memory'. This study examined chronic and oscillating SFAs and Glc on the inflammatory signalling pathway in human adipose tissue (AT) and adipocytes (Ads) and determined whether Ads are subject to “metabolic memory.” Abdominal (Abd) subcutaneous (Sc) explants and Ads were treated with chronic low glucose (L-Glc): 5.6 mM and high glucose (H-Glc): 17.5 mM, with low (0.2 mM) and high (2 mM) SFA for 48 h. Abd Sc explants and Ads were also exposed to the aforementioned treatment regimen for 12-h periods, with alternating rest periods of 12 h in L-Glc. Chronic treatment with L-Glc and high SFAs, H-Glc and high SFAs up-regulated key factors of the nuclear factor-κB (NFκB) pathway in Abd Sc AT and Ads (TLR4, NFκB; P

A 20-in (51-cm) diam schlieren system was convereted to a genrualized holographic flow visualization system. The system has been used successfully in producing the following types of visualization from a single holographic plate: three-dimensional photography, variable focus shadowgraph, variable knife-edge position schlieren, color-schlieren, and interferometry. All of these except for holographic color schlieren have previously been reported with varying degrees of success. This paper presents a technique for producing color schlierent photographs from holograms formed in the above system and shows preliminary results of the application. The method possesses a number of advantages over conventional color schlieren photography.

In a randomised cross-over study we compared human isophane insulin (Human InsulatardTM) with human crystalline insulin zinc suspension (Human UltratardTM) as longer-acting, night-time insulins given thrice daily soluble insulin in the management of diabetes. We studied 20 insulin-dependent patients aged 20–47 years. At the end of each 12-week study period, total daily insulin dose was 56.9 ± 3.9U with Human InsulatardTM and 59.4 ± 4.4U with Human UltratardTM (no significant difference). The amount of longer-acting insulin used was lower with Human InsulatardTM than with Human UltratardTM (23.3 ± 2.5 vs 29.0 ± 3.2U per day, p

Objective To determine whether weight gain due to renal sodium and water retention occurs in the luteal phase of the normal menstrual cycle. Design Prospective observational study. Setting Research laboratory installed with modified spa bath. Subjects Ten normal healthy women. Intervention Each subject underwent two experiments, one in each phase of the menstrual cycle, involving 3 h head-out water immersion and a pre- and post immersion control hour. 25 ml blood samples were obtained every hour before, during and after water immersion. Main outcome measures Renal and hormonal responses to water immersion during the luteal and proliferative phases of the cycle. Results There was no change in weight, creatinine clearance, basal sodium excretion or plasma atrial natriuretic peptide between the two phases of the cycle. There was a significant rise in basal progesterone, plasma aldosterone and plasma renin activity in the luteal phase of the ovulatory cycles. Renal and hormonal responses to immersion including sodium and calcium excretion, elevation of atrial natriuretic peptide (ANP) and suppression of plasma aldosterone and plasma renin activity were identical in the two phases of the menstrual cycle. Conclusion We found no evidence to support the hypothesis that renal sodium and water retention occurs in the luteal phase of the normal menstrual cycle.

Ghrelin, an important central acting orexigenic hormone, is predominantly secreted in the gastrointestinal tract. However little is known about the action of ghrelin in human adipose tissue (AT).To study the expression of ghrelin in AT, the effects of octanoyl-(OTG) and des-acyl (DSG) ghrelin on lipolysis and lipogenesis, leptin release and potential peripheral signalling through the Y1 receptor.Ex vivo human AT was obtained from women undergoing elective surgery (46 (mean +/- SD) 6.8 years, body mass index (BMI): 25.6 +/- 5.0 kg/m(2), n = 20). Abdominal-subcutaneous (AbdSc) adipocytes were isolated and treated with recombinant human (rh) OTG and DSG to assess lipid metabolism leptin release and the influence of Y1-receptor blocker.Ghrelin was expressed in AbdScAT and negatively correlated with BMI (lean: 3.6 +/- 0.74 optical-density-units (OD), obese: 1.64 +/- 0.45 OD, *P0.05). Only DSG significantly suppressed glycerol release (Control (C): 286 +/- 58 microl/l; DSG 1 nm: 224 +/- 38 microl/l downward arrow*; DSG 100 nm: 172 +/- 13 microl/l downward arrow*,* downward arrow P0.05, n = 7) and reduced hormone sensitive lipase expression (C: 1.0 +/- 0.3 OD; DSG 1 nm: 0.8 +/- 0.3 OD downward arrow*; DSG 100 nm: 0.6 +/- 0.1 OD downward arrow*, n = 4). However, both isoforms increased lipoprotein lipase expression (C: 1.0 +/- 0.3OD; DSG 100 nm: 0.2 +/- 0.4 OD upward arrow*; OTG 100 nm: 2.5 +/- 0.3 OD upward arrow*, n = 4), whilst blockade of Y1 eliminated this effect in both. Leptin was down-regulated by DSG only (DSG 1 nm: 5.3 +/- 0.7 ng/ml; DSG 100 nm: 4.1 +/- 0.7 ng/ml*) and was significant after BMI adjustment (P = 0.029).Ghrelin was expressed in human AbdSc AT. In vitro, both OGT and DSG appear to mediate fat deposition with the lipogenic effects in part mediated by the Y1 receptor, whilst the influence of DSG affected lipolysis, lipogenesis and leptin secretion. Taken together, these studies support a local action for ghrelin isoforms on lipid and adipokine metabolism that further supports a cross talk between organs.

Background Recent studies have implicated variants of the transcription factor 7-like 2 (TCF7L2) gene in genetic susceptibility to type 2 diabetes mellitus in several different populations. The aim of this study was to determine whether variants of this gene are also risk factors for type 2 diabetes development in a UK-resident South Asian cohort of Punjabi ancestry. Methods We genotyped four single nucleotide polymorphisms (SNPs) of TCF7L2 (rs7901695, rs7903146, rs11196205 and rs12255372) in 831 subjects with diabetes and 437 control subjects. Results The minor allele of each variant was significantly associated with type 2 diabetes; the greatest risk of developing the disease was conferred by rs7903146, with an allelic odds ratio (OR) of 1.31 (95% CI: 1.11 – 1.56, p = 1.96 × 10-3). For each variant, disease risk associated with homozygosity for the minor allele was greater than that for heterozygotes, with the exception of rs12255372. To determine the effect on the observed associations of including young control subjects in our data set, we reanalysed the data using subsets of the control group defined by different minimum age thresholds. Increasing the minimum age of our control subjects resulted in a corresponding increase in OR for all variants of the gene (p ≤ 1.04 × 10-7). Conclusion Our results support recent findings that TCF7L2 is an important genetic risk factor for the development of type 2 diabetes in multiple ethnic groups.

Thiazolidinediones cause sodium retention and edema by a direct effect on the kidneys. The aim of this study was to use the technique of head-out water immersion to investigate the effects of rosiglitazone on sodium and volume homeostasis in subjects with type 2 diabetes mellitus. The volume expansion response to water immersion was compared with the response on a non-immersion control day in 12 nondiabetic male subjects and 8 diet-controlled male type 2 diabetic subjects with hourly blood and urine sampling over a 4-h period. This was repeated after both groups had taken 4 mg of rosiglitazone daily for 7 days. Immersion produced a natriuresis in both groups ( P < 0.001). An impairment of this natriuresis was seen in the diabetic subjects ( P = 0.006). However, when rosiglitazone was taken, there was no significant difference in immersion-induced natriuresis compared with nondiabetic controls ( P = 0.2). There was an immersion-induced rise in atrial natriuretic peptide (ANP) and urinary cyclic guanosine monophosphate (cGMP), in the healthy subjects (ANP P = 0.001, cGMP P = 0.043), which was not seen in the diabetic subjects (ANP P = 0.51, cGMP P = 0.74). Rosiglitazone restored the immersion-induced increase in cGMP excretion and rise of ANP in the diabetic group (ANP P = 0.048, cGMP P = 0.009). This study confirms that type 2 diabetic subjects have an impaired natriuretic response to acute volume expansion, which appears to be enhanced rather than diminished by rosiglitazone. This may be related to its effects in increasing natriuretic peptides and restoring the impaired cGMP excretion to volume expansion.

Background: Dulaglutide is a new, long-acting glucagon-like peptide analogue in the treatment of type 2 diabetes. It is available in two doses, 0.75 and 1.5 mg, given by injection once weekly. This systematic review reports the effectiveness and safety of dulaglutide in type 2 diabetes in dual and triple therapy. Methods: MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, and conference abstracts were searched from 2005 to August 2014, and updated in January 2015. Company websites and references of included studies were checked for potentially relevant studies. European Medicines Agency and US Food and Drug Administration websites were searched. Results: Four trials were included. All were manufacturer-funded randomized controlled trials from the Assessment of Weekly Administration of Dulaglutide in Diabetes (AWARD) program. AWARD-1 compared dulaglutide 1.5 mg against exenatide 10 µg twice daily and placebo, AWARD-2 compared dulaglutide 0.75 and 1.5 mg against insulin glargine, AWARD-5 compared dulaglutide 0.75 and 1.5 mg against sitagliptin 100 mg and placebo, and AWARD-6 compared dulaglutide 1.5 mg against liraglutide 1.8 mg. The duration of follow-up in the trials ranged from 26 to 104 weeks. The primary outcome of all the included trials was change in HbA1c. At 26 weeks, greater HbA1c reductions were seen with dulaglutide than with twice daily exenatide (dulaglutide 1.5/0.75 mg: −1.5%/−1.3%; exe: 0.99%) and sitagliptin (1.5/0.75 mg −1.22%/−1.01%; sitagliptin: −0.6%). HbA1c change was greater with dulaglutide 1.5 mg (−1.08%) than with glargine (−0.63%), but not with dulaglutide 0.75 mg (−0.76%). Dulaglutide 1.5 mg was found to be noninferior to liraglutide 1.8 mg. More patients treated with dulaglutide achieved HbA1c targets of

“Common sense is not so common” – Voltaire (1694–1778) The latest NICE guidelines for the management of type 2 diabetes are now available for consultation. They contain sensible recommendations regarding lifestyle, patient education, monitoring and targets. Unfortunately, the pharmacotherapy section shows a distinct failure of common sense. The recommendations include using the insulin secretagogue repaglinide as a first-line agent, where metformin is not tolerated or contraindicated, or second-line in combination with metformin. Pioglitazone is recommended as the principal second-line therapy with metformin. The advice on glucagon-like peptide-1 receptor agonist (GLP-1ra) usage and assessment of efficacy and failure to recommend long acting analogue insulins over isophane are also major concerns. The recommendations appear to be based on meta- analyses and pharmacoeconomics, driven by an imperative on costs and failing to appreciate the “value” of the options under consideration. The cost to patients and the health service of the serious side-effects of these treatments is underestimated. Given the emphasis in these guidelines on the importance of lifestyle changes, including weight loss, plus an over-riding need to avoid hypoglycaemia, these pharmacotherapeutic recommendations appear paradoxical in the extreme. We believe that these recommendations, if enacted, will undermine seriously the reputation of NICE both nationally and internationally.

Aims/hypothesis Adiponectin is an adipocyte-derived secretory factor that is specifically produced in adipocytes. It exerts effects on energy homeostasis via peripheral and central mechanisms. However, it is not clear whether adiponectin crosses the blood–brain barrier in humans. In serum, adiponectin circulates in several different complexes, each of which has distinct functions. Here, we wanted to test whether adiponectin can be found in human cerebrospinal fluid (CSF) and whether specific adiponectin complexes are enriched in CSF compared with peripheral serum samples. We also wanted to establish whether there is a sex-related difference with regard to the distribution of adiponectin oligomers in CSF. Materials and methods We studied 22 subjects (11 men, 11 women) in this study. Their average BMI was 28.0± 4.7 kg/m 2 ; average age was 70±7 years. Results Analysis of total adiponectin revealed that adiponectin protein is present in human CSF at approximately 0.1% of serum concentration. The distribution of adiponectin oligomers differs considerably in CSF from that of serum within matched samples from the same patients. Only the adiponectin trimeric and low-molecular-mass hexameric complexes are found in CSF, with a bias towards the trimeric form in most patients. Male subjects have a higher CSF: serum ratio of total adiponectin (p

Microalbuminuria is more common in South Asian individuals compared to white Europeans. The aim of this study was to determine the relationship between blood pressure and microalbuminuria in a cohort of patients with type 2 diabetes in these two ethnic groups. These further data were analysed from 552 patients (311 South Asian patients and 241 white Europeans) who had microalbuminuria screening data collected. Prevalence of microalbuminuria was significantly higher in South Asian compared with white European patients (31% versus 20%, p=0.007). Among patients with normal, untreated blood pressure, the proportion who had microalbuminuria was three times higher among South Asian patients compared with the white European group (30.7% versus 10.1%, p=0.049, relative risk = 3.1 [1.0–9.5]). In addition, despite their higher cardiovascular risk, South Asian patients were less likely to be prescribed a statin or antihypertensive drug treatment. In conclusion, thresholds and targets for treatment of cardiovascular risk factors in South Asians may need to be lower than those for white Europeans, and targeted intervention will be required to achieve this.

Objectives: To review systematically the evidence on the performance of diagnostic tests used to identify infection in diabetic foot ulcers (DFUs) and of interventions to treat infected DFUs. To use estimates derived from the systematic reviews to create a decision analytic model in order to identify the most effective method of diagnosing and treating infection and to identify areas of research that would lead to large reductions in clinical uncertainty. Data sources: Electronic databases covering period from inception of the database to November 2002. Review methods: Selected studies were assessed against validated criteria and described in a narrative review. The structure of a decision analytic model was derived for two groups of patients in whom diagnostic tests were likely to be used. Results: Three studies that investigated the performance of diagnostic tests for infection on populations including people with DFUs found that there was no evidence that single items on a clinical examination checklist were reliable in identifying infection in DFUs, that wound swabs perform poorly against wound biopsies, and that semi-quantitative analysis of wound swabs may be a useful alternative to quantitative analysis. However, few people with DFUs were included, so it was not possible to tell whether diagnostic performance differs for DFUs relative to wounds of other aetiologies. Twenty-three studies investigated the effectiveness (n = 23) or cost-effectiveness ( n = 2) of antimicrobial agents for DFUs. Eight studied intravenous antibiotics, five oral antibiotics, four different topical agents such as dressings, four subcutaneous granulocyte colony stimulating factor (G-CSF), one evaluated oral and topical Ayurvedic preparations and one compared topical sugar versus antibiotics versus standard care. The majority of trials were underpowered and were too dissimilar to be pooled. There was no strong evidence for recommending any particular antimicrobial agent for the prevention of amputation, resolution of infection or ulcer healing. Topical pexiganan cream may be as effective as oral antibiotic treatment with ofloxacin for the resolution of local infection. Ampicillin and sulbactam were less costly than imipenem and cilastatin, a growth factor (G-CSF) was less costly than standard care and cadexomer iodine dressings may be less costly than daily dressings. A decision analytic model was derived for two groups of people, those for whom diagnostic testing would inform treatment people with ulcers which do not appear infected but whose ulcer is not progressing despite optimal concurrent treatment - and those in whom a first course of antibiotics ( prescribed empirically) have failed. There was insufficient information from the systematic reviews or interviews with experts to populate the model with transition probabilities for the sensitivity and specificity of diagnosis of infection in DFUs. Similarly, there was insufficient information on the probabilities of healing, amputation or death in the intervention studies for the two populations of interest. Therefore, we were unable to run the model to inform the most effective diagnostic and treatment strategy. Conclusions: The available evidence is too weak to be able to draw reliable implications for practice. This means that, in terms of diagnosis, infection in DFUs cannot be reliably identified using clinical assessment. This has implications for determining which patients need formal diagnostic testing for infection, on whether empirical treatment with antibiotics ( before the results of diagnostic tests are available) leads to better outcomes, and on identifying the optimal methods of diagnostic testing. With respect to treatment, it is not known whether treatment with systemic or local antibiotics leads to better outcomes or whether any particular agent is more effective. Limited evidence suggests that both G-CSF and cadexomer iodine dressings may be less expensive than 'standard' care, that ampicillin/ sulbactam may be less costly than imipenem/ cilastatin, and that an unlicensed cream ( pexiganan) may be as effective as oral ofloxacin. Further research is needed to ascertain the characteristics of infection in people with DFUs that influence healing and amputation outcomes, to determine whether detecting infection prior to treatment offers any benefit over empirical therapy, and to establish the most effective and cost-effective methods for detecting infection, as well as the relative effectiveness and cost-effectiveness of antimicrobial interventions for DFU infection.

A popular hypothesis for the greater prevalence of type 2 diabetes and cardiovascular disease in UK south Asians is that they have an increased susceptibility of developing insulin resistance in response to certain environmental factors, including obesity and adoption of a sedentary lifestyle. Insulin resistance is postulated as a central feature of the metabolic syndrome, culminating in type 2 diabetes, atherosclerotic vascular disease and CHD; a pathway potentially accelerated by migration/urbanisation. We describe and compare the prevalence of type 2 diabetes, cardiovascular disease and their associated risk factors in UK south Asian and white Caucasian populations to determine possible reasons for the increased preponderance of these diseases in south Asians, and highlight key evidence for optimal risk factor management. Finally, we describe a UK community-based programme that attempts to reduce the morbidity and mortality from type 2 diabetes and cardiovascular disease in south Asians through a new approach to management.

Background— Good screening performance of retinal photography and ophthalmoscopy together in screening for diabetic retinopathy in primary care have been reported. This study reanalysed the data to evaluate the screening performance of photography alone. Methods— One thousand and ten patients screened by fundal photography and ophthalmoscopy were studied retrospectively. Fundal photographs were quality graded with poor quality pictures being excluded from the analysis. Each patient was reviewed initially by both retinal photographs and ophthalmoscopy by an ophthalmologist, the “gold standard”. Six months later the fundal photographs were reviewed and reported in a blinded manner by the ophthalmologist. Results— Two thousand and fourteen photographs were obtained, of which 162 (8%) had to be excluded because of poor quality. On review of the remaining 18S2 photographs in isolation, of 77 cases of severe retinopathy as determined by the “gold standard”, 67 had severe changes on photography—detection rate 87%. Of the 1775 cases without sight threatening retinopathy only five were judged to have sight threatening changes on photography—false positive rate 0.3%. Considering sight threatening and background retinopathy together, the detection rate was 69% (2S7 of 375) and the false positive rate 1.6% (23 of 1477). Conclusion— Good quality fundal photographs alone seem specific enough to screen for sight threatening diabetic retinopathy, but will underdetect background retinopathy.

Little is known about the process of referral to Irish hospital outpatient medical clinics. We analysed pre-referral management, information quality and communication to a general medical outpatient clinic. 100 consecutive attendee referral letters were prospectively assessed for information, appropriateness, legibility and pre-referral management. Patients underwent a questionnaire. We documented the final diagnosis and management patterns. 16% of letters were largely illegible, Only 47% of letters gave examination findings and of those, 40% omitted significant details. Appropriate pre-referral investigations were performed in 55%. Where performed, results were not enclosed in 32%. In 61% of cases therapy could have been instituted prior to referral, of these treatment was not started in 36%. 16% of patients did not understand the reason for referral. 10% of referrals were inappropriate. In this limited study there were substantial communication deficiencies in patient referral. If standard criteria were set (e.g. by proforma) before a referral is accepted perhaps the quality of patient care might improve especially if treatment could be initiated earlier by referring doctors.

We report a case of simultaneous presentation of cerebral venous sinus thrombosis and thyrotoxicosis in a 28 year-old female subsequently found to have the Factor V Leiden mutation. She made an excellent neurological recovery with anticoagulation. The mode of presentation of the case was surprising, as she had no thrombotic episodes in two previous pregnancies. This suggests that thyrotoxicosis may give rise to a hypercoagulable state.

Atrial fibrillation (AF) is an important risk factor for stroke and anticoagulation is now indicated in many patients at increased risk. Studies however have shown that many patients at risk are not anticoagulated for reasons that are not well explored. We identified prospectively the reasons for non-anticoagulation in patients with AF in 94 consecutive hospital patients with cardiac or cerebrovascular disease who had AF. Patients with intermittent or lone AF and60 years were excluded n = 16. The remaining group had a mean age of 76 +/- 7 years with a mental test score of 7.4 +/- 2 (normal 10), 31 lived alone and they lived an average of 14 +/- 11 miles from the hospital laboratory. The reasons for non-anticoagulation overlapped and were: medical in 29: cognitive impairment/compliance in 32: and monitoring problems in 50. Anticoagulation for AF in the elderly is a complex enterprise which must take into account social and cognitive as well as medical issues.

Objective To examine the experiences of patients, health professionals and screeners; their interactions with and understandings of diabetic retinopathy screening (DRS); and how these influence uptake.\ud \ud Design Purposive, qualitative design using multiperspectival, semistructured interviews and thematic analysis.\ud \ud Setting Three UK Screening Programme regions with different service-delivery modes, minority ethnic and deprivation levels across rural, urban and inner-city areas, in general practitioner practices and patients’ homes.\ud \ud Participants 62 including 38 patients (22 regular-screening attenders, 16 non-regular attenders) and 24 professionals (15 primary care professionals and 9 screeners).\ud \ud Results Antecedents to attendance included knowledge about diabetic retinopathy and screening; antecedents to non-attendance included psychological, pragmatic and social factors. Confusion between photographs taken at routine eye tests and DRS photographs was identified. The differing regional invitation methods and screening locations were discussed, with convenience and transport safety being over-riding considerations for patients. Some patients mentioned significant pain and visual disturbance from mydriasis drops as a deterrent to attendance.\ud \ud Conclusions In this, the first study to consider multiperspectival experiential accounts, we identified that proactive coordination of care involving patients, primary care and screening programmes, prior to, during and after screening is required. Multiple factors, prior to, during and after screening, are involved in the attendance and non-attendance for DRS. Further research is needed to establish whether patient self-management educational interventions and the pharmacological reformulation of shorter acting mydriasis drops, may improve uptake of DRS. This might, in turn, reduce preventable vision loss and its associated costs to individuals and their families, and to health and social care providers, reducing current inequalities.

We report experiences in 3 patients with acromegaly while using the somatostatin analogue octreotide. In case 1, a 44 year old male developed pneumococcal meningitis 3 months after having transphenoidal surgery for a pituitary tumour. This occurred with the re-emergence of communication between the surgical tract and the C.S.F. In case 2 a 52 year old male with insulin resistant diabetes mellitus requiring 240 units/day, with greatly elevated growth hormone concentrations was able to stop insulin within 5 days of starting octreotide. In case 3, a 52 year old male with sleep apnoea syndrome, respiratory failure and resistant heart failure made a dramatic improvement which is maintained 2 years later. All cases were associated with substantial falls in growth hormone and insulin like growth factor-1 concentrations.

We examined patient behaviour and the components of delay to hospitalisation in 149 consecutive cases of proven acute myocardial infarction (AMI) prospectively. The median total delay from onset of chest pain to hospitalisation was 210 mns (range 5 mns to 7 days). The median delay before seeking medical help was 105 mns. Seventy-eight patients (52%) contacted a G.P. Median delay to G.P. contact was 15 mns. The median delay in transportation to hospital was 20 mns. There was no evident diurnal variation in the onset of symptoms. There was no significant differences in help seeking delay between the sexes, between young and old or between those with a previous history of ischaemic heart disease similar to studies in the U.S. and U.K. Patient delay to seeking help remains the major and most crucial component of delay in treating AMI.

Context:The novel adipokine, nesfatin-1/NUCB-2, reduces food intake, levels of which are elevated in overweight individuals. Objectives:The aim of the study was to investigate the mechanisms underlying brain nesfatin-1/NUCB-2 uptake and to determine whether reduced uptake may contribute to nesfatin-1/NUCB-2 resistance. Design:Cerebrospinal fluid (CSF) and corresponding plasma nesfatin-1/NUCB-2 were measured by ELISA [18 men and 20 women; age, 19–80 yr; body mass index (BMI), 16.2–38.1 kg/m2] and correlated to body adiposity and metabolic parameters. Results:CSF/plasma nesfatin-1/NUCB-2 ratio was significantly negatively associated with BMI, body weight, fat mass, and CSF glucose. BMI was predictive of CSF/plasma nesfatin-1/NUCB-2 ratio (β = −0.786; P = 0.045). CSF nesfatin-1/NUCB-2 was significantly positively associated with plasma nesfatin-1/NUCB-2 (R = 0.706; P < 0.01). There was a significant linear relation between CSF and plasma nesfatin-1/NUCB-2 in lean (BMI

The effect of head out water immersion on the excretion of catecholamines and serum sodium transport inhibitor (STI) was studied in healthy young women during the follicular and leuteal phases. Two way ANOVA showed that menstrual cycle had no effect on the excretion of noradrenaline (NA), dopamine (DA) or serum STI. Analysis of pooled data from follicular and leuteal phases showed that immersion caused a significant increase in sodium excretion and serum STI and a significant decrease in urinary NA excretion in healthy young women. After immersion, sodium excretion, DA excretion and serum STI decreased and NA increased.

This study compared the cardiorespiratory responses of eight healthy women (mean age 30.25 years) to submaximal exercise on land (LTm) and water treadmills (WTm) in chest-deep water (Aquaciser). In addition, the effects of two different water temperatures were examined (28 and 36 degrees C). Each exercise test consisted of three consecutive 5-min bouts at 3.5, 4.5 and 5.5 km x h(-1). Oxygen consumption (VO2) and heart rate (HR), measured using open-circuit spirometry and telemetry, respectively, increased linearly with increasing speed both in water and on land. At 3.5 km x h(-1) VO2 was similar across procedures [chi = 0.6 (0.05) l x min(-1)]. At 4.5 and 5.5 km x h(-1) VO2 was significantly higher in water than on land, but there was no temperature effect (WTm: 0.9 and 1.4, respectively; LTm: 0.8 and 0.9 l x min(-1), respectively). HR was significantly higher in WTm at 36 degrees C compared to WTm at 28 degrees C at all speeds, and compared to LTm at 4.5 and 5.5 km x h(-1) (Por = 0.003). The HR-VO2 relationship showed that at a VO2 of 0.9 l x min(-1) x HR was higher in water at 36 degrees C (115 beats x min[-1]) than either on land (100 beats min[-1]) or in water at 28 degrees C (99 beats x min[-1]). The Borg scale of perceived exertion showed that walking in water at 4.5 and 5.5 km x h(-1) was significantly harder than on land (WTm: 11.4 and 14, respectively; LTm: 9.9 and 11, respectively; Por = 0.001). These cardiorespiratory changes occurred despite a slower cadence in water (the mean difference at all speeds was 27 steps/min). Thus, walking in chest-deep water yields higher energy costs than walking at similar speeds on land. This data has implications for therapists working in hydrotherapy pools.

The biological effects of platelet-derived growth factor (PDGF) are mediated by alpha- and beta-PDGF receptors (PDGFR), which have an intracellular tyrosine kinase domain and an extracellular region comprising five immunoglobulin-like domains (D1-D5). Using deletion mutagenesis we mapped the PDGF binding site in each PDGFR to the D2-D3 region. In the case of alpha-PDGFR, 125I-PDGF AA and 125I-PDGF BB bound to the full-length extracellular domain, D1-D5, and D2-D3 with equal affinity (Kd = 0.21-0.42 nM). Identical results were obtained for 125I-PDGF BB binding to beta-PDGFR mutants D1-D5 and D2-D3, establishing that D1, D4, and D5 do not contribute to PDGF binding. Monoclonal antibodies (mAb) directed against individual PDGFR Ig-like domains were used to extend these observations. The anti-D1 mAb 1E10E2 and anti-D5 mAb 2D4G10 had no effect on alpha- or beta-PDGFR function, respectively. In contrast, mAb 2H7C5 and 2A1E2 directed against D2 of the alpha- and beta-receptor, respectively, blocked PDGF binding, receptor autophosphorylation and mitogenic signaling with IC50 values of 0.1-3.0 nM. An anti-D4 mAb 1C7D5 blocked beta-receptor autophosphorylation and signaling without inhibiting PDGF binding consistent with the observation that D4 is essential for PDGFR dimerization (Omura, T., Heldin, C.-H., and Ostman, A. (1997) J. Biol. Chem. 272, 12676-12682). mAbs identified here act as potent PDGFR antagonists that can be used as research tools and potentially as therapeutic agents for the treatment of diseases involving unwanted PDGFR signaling.

We report on a 25 yr old woman with primary autoimmune hyperthyroidism who was treated with carbimazole. Forty-three days later she developed agranulocytosis (64 x 10(6)/l). With 4 days treatment with recombinant human Granulocyte Colony Stimulating factor the granulocyte count rose to normal--4,350 cells x 10(6)/l. This is considerably faster than the rate of spontaneous recovery which usually takes one to 2 weeks.

In the patient with diabetes mellitus the onset of intermittent and then persistent proteinuria signals the development of established nephropathy. This heralds an extremely poor prognosis and mortality in this group has been estimated to be 80 to 100 times greater than that of an age-matched normal population. The excess mortality and its associated morbidity exists for both insulin-dependent and non-insulin-dependent patients who develop proteinuria. The final cause of death is often cardiovascular, such as myocardial infarction or a cerebrovascular accident, rather than end stage renal failure with death from uraemia. Strict and aggressive control of blood pressure during this stage is the only therapy that has been shown to slow the decline in glomerular filtration. To date, there have been no studies large enough to establish if this can produce the desired effect of reducing the excess mortality in this group. The newer antihypertensive agents may have a specific role but this also remains to be shown conclusively; their major advantage may be related to their fewer side-effects especially on cardiovascular risk factors in this highly susceptible group.

Oxygen consumption (VO,) and hear t ra te (HR), measured using open-circuit spirometry and telemetry respectively, increased linearly with increasing speed in water and on land. At 3.5 km/h-l. VO, was similar across procedures (x = 0.6 t 0.05 litres/min-l, At 4.5 and 5.5 km/h-1 VOz was significantly higher in water than on land but there was no temperature effect (WTm: 0.9 and 1.4, LTm: 0.8 and 0.9 litres/min-I). HR was significantly higher in water a t 36°C compared to WTm at 28°C at all speeds and to LTm at 4.5 and 5.5 kmk-1 (p 5 0.003). The HR-V02 relationship showed that a t a VO, of 0.9 litredmin-1, HR was higher in water a t 36°C (115 beats per minute bpm) than on land (100 bpm) or in water at 28°C (99 bpm).