Cancer incidence and mortality in 23 000 patients with type 1 diabetes in the UK: Long-term follow-up.

Type 2 diabetes is associated with raised risk of several cancers, but for type 1 diabetes risk data are fewer and inconsistent We assembled a cohort of 23 473 UK patients with insulin-treated diabetes diagnosed at ages <30, almost all of whom will have had type 1 diabetes, and for comparison 5058 diagnosed at ages 30 to 49, of whom we estimate two-thirds will have had type 2, and followed them for an average of 30 years for cancer incidence and mortality compared with general population rates. Patients aged <30 at diabetes diagnosis had significantly raised risks only for ovarian (standardised incidence ratio = 1.58; 95% confidence interval 1.16-2.11; P < .01) and vulval (3.55; 1.94-5.96; P < .001) cancers, with greatest risk when diabetes was diagnosed at ages 10-14. Risks of cancer overall (0.89; 0.84-0.95; P < .001) and sites including lung and larynx were significantly diminished. Patients diagnosed with diabetes at ages 30 to 49 had significantly raised risks of liver (1.76;1.08-2.72) and kidney (1.46;1.03-2.00) cancers, and reduced risk of cancer overall (0.89; 0.84-0.95). The raised ovarian and vulval cancer risks in patients with type 1 diabetes, especially with diabetes diagnosed around pubertal ages, suggest possible susceptibility of these organs at puberty to metabolic disruption at diabetes onset. Reduced risk of cancer overall, particularly smoking and alcohol-related sites, might reflect adoption of a healthy lifestyle.

Characterization of inosine-uridine nucleoside hydrolase (RihC) from Escherichia coli.

A non-specific nucleoside hydrolase from Escherichia coli (RihC) has been cloned, overexpressed, and purified to greater than 95% homogeneity. Size exclusion chromatography and sodium dodecyl sulfate polyacrylamide gel electrophoresis show that the protein exists as a homodimer. The enzyme showed significant activity against the standard ribonucleosides with uridine, xanthosine, and inosine having the greatest activity. The Michaelis constants were relatively constant for uridine, cytidine, inosine, adenosine, xanthosine, and ribothymidine at approximately 480µM. No activity was exhibited against 2'-OH and 3'-OH deoxynucleosides. Nucleosides in which additional groups have been added to the exocyclic N6 amino group also exhibited no activity. Nucleosides lacking the 5'-OH group or with the 2'-OH group in the arabino configuration exhibited greatly reduced activity. Purine nucleosides and pyrimidine nucleosides in which the N7 or N3 nitrogens respectively were replaced with carbon also had no activity.

High affinity protein surface binding through co-engineering of nanoparticles and proteins.

Control over supramolecular recognition between proteins and nanoparticles (NPs) is of fundamental importance in therapeutic applications and sensor development. Most NP-protein binding approaches use 'tags' such as biotin or His-tags to provide high affinity; protein surface recognition provides a versatile alternative strategy. Generating high affinity NP-protein interactions is challenging however, due to dielectric screening at physiological ionic strengths. We report here the co-engineering of nanoparticles and protein to provide high affinity binding. In this strategy, 'supercharged' proteins provide enhanced interfacial electrostatic interactions with complementarily charged nanoparticles, generating high affinity complexes. Significantly, the co-engineered protein-nanoparticle assemblies feature high binding affinity even at physiologically relevant ionic strength conditions. Computational studies identify both hydrophobic and electrostatic interactions as drivers for these high affinity NP-protein complexes.

A phase 1 study of donor regulatory T-cell infusion plus low-dose interleukin-2 for steroid-refractory chronic graft-vs-host disease.

Chronic graft-versus-host disease (cGVHD) remains a frequent cause of nonrelapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Despite recent advances, options for steroid-refractory (SR) cGVHD are limited. In previous trials of low-dose interleukin-2 (LD IL-2), the immunomodulatory properties of regulatory T cells (Tregs) have been harnessed to treat SR-cGVHD safely and effectively. In the present study, we combined a single infusion of Treg-enriched lymphocytes (Treg DLI) from the original stem cell donor with in vivo Treg expansion using LD IL-2 (1 × 106 IU/m2 per day for 8 weeks) in 25 adult patients with SR-cGVHD. Treg were not expanded ex vivo. Treg DLI was initiated at 0.1 × 106 cells per kg patient and escalated to a maximum dose of 1 × 106 cells per kg. Treg DLI plus LD IL-2 was well tolerated and led to partial responses (PR) in 5 of 25 patients (20%) after 8 weeks of therapy. Ten additional patients (40%) had stable disease with minor responses not meeting PR criteria. Patients at all dose levels had similar Treg expansion without significant changes in CD4+ conventional T cells or CD8+ T cells. High-throughput sequencing of the T-cell receptor ß locus showed selective improvement of Treg diversity. A subset of DLI-derived Treg clones showed preferential expansion at week 8 and long-term persistence 1-year postinfusion. We demonstrate for the first time that infusion of polyclonal healthy donor Tregs followed by expansion with LD IL-2 is safe in patients with SR-cGVHD, thus establishing a foundation for future adoptive Treg therapies in the posttransplant setting. This trial was registered at www.clinicaltrials.gov as #NCT01937468.

Over-representation of diabetic patients with renal anaemia in the primary care setting.

UNLABELLED: AIMS. Anaemia is a complication of chronic kidney disease (CKD); the National Institute for Clinical Excellence (NICE) have defined renal anaemia as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 and haemoglobin (HB) <11.0 g/dl. The purpose of this study was to see if diabetic patients have a higher prevalence in primary care of this new anaemia definition. Furthermore, we wished to determine whether diabetic patients were over-represented above HB 11.0 g/dl, which may lead to developing renal anaemia. METHODS: We used an observational prevalence study in primary care from one Staffordshire practice in 2005-2006. Egton Medical Information Systems Ltd computer database was searched for patients with two Modification of Diet in Renal Disease eGFRs separated by 3 months, HB levels and medications. RESULTS: From a list size of 1830 patients, 362 had two eGFRs <60; of those, 308 had a HB available. In all, 29 (9.4%) patients had NICE renal anaemia, with over-representation of diabetic patients, 13 (16%) against 16 (7%) without diabetes (P < 0.02). We found that diabetic patients were also over-represented at HB 11.0 to <12.5 g/dl, 26 (32%) with diabetes and 39 (17.6%) without (P < 0.001). Mean HB was significantly lower for the diabetic group (n = 81, 26%), 12.8 g/dl (95% Confidence Intervals (CI) 12.4-13.1) against non-diabetic group (n = 227, 74%), 13.4 g/dl (95% CI 13.2-13.6), P < 0.01. Predictors of HB on multivariate regression analysis were female gender, eGFR and diabetes (all P < 0.001). CONCLUSIONS: Diabetic patients were more likely to have NICE defined renal anaemia in this primary care population with CKD stages 3-5. This is similar to observations in secondary care settings. We observed over-representation of diabetic patients above NICE definition at HB 11.0 to <12.5 g/dl.

Protein Delivery into the Cell Cytosol using Non-Viral Nanocarriers.

Protein delivery into cells is a potentially transformative tool for treating "undruggable" targets in diseases associated with protein deficiencies or mutations. The vast majority of these targets are accessed via the cytosol, a challenging prospect for proteins with therapeutic and diagnostic relevance. In this review we will present promising non-viral approaches for intracellular and ultimately cytosolic delivery of proteins using nanocarriers. We will also discuss the mechanistic properties that govern the efficacy of nanocarrier-mediated protein delivery, applications of nanomaterials, and key challenges and opportunities in the use of nanocarriers for intracellular protein delivery.

Randomised controlled trial of near-patient testing for glycated haemoglobin in people with type 2 diabetes mellitus.

BACKGROUND: Tight glycaemic control in people with type 2 diabetes can lead to a reduction in microvascular and possibly macrovascular complications. The use of near-patient (rapid) testing offers a potential method to improve glycaemic control. AIM: To assess the effect and costs of rapid testing for glycated haemoglobin (HbA1c) in people with type 2 diabetes. DESIGN OF STUDY: Pragmatic open randomised controlled trial. SETTING: Eight practices in Leicestershire, UK. METHOD: Patients were randomised to receive instant results for HbA1c or to routine care. The principal outcome measure was the proportion of patients with an HbA1c <7% at 12 months. We also assessed costs for the two groups. RESULTS: Of the 681 patients recruited to the study 638 (94%) were included in the analysis. The mean age at baseline was 65.7 years (SD = 10.8 years) with a median (interquartile range) duration of diabetes of 4(1-8) years. The proportion of patients with HbA1c < 7% did not differ significantly between the intervention and control groups (37 versus 38%, odds ratio 0.95 [95% confidence interval = 0.69 to 1.31]) at 12 months follow up. The total cost for diabetes-related care was 390 UK pounds per patient for the control group and 370 UK pounds for the intervention group. This difference was not statistically significant. CONCLUSION: Near-patient testing for HbA1c alone does not lead to outcome or cost benefits in managing people with type 2 diabetes in primary care. Further research is required into the use of rapid testing as part of an optimised patient management model including arrangements for patient review and testing.

Psychosocial and socioeconomic risk factors for premature death in young people with type 1 diabetes.

OBJECTIVE: Mortality from acute diabetes-related events is greatly raised in young adults with type 1 diabetes. Psychosocial and socioeconomic risk factors are examined for deaths from acute events separately from deaths due to other causes. RESEARCH DESIGN AND METHODS: This study had a nested case-control design. The cases were patients from the Diabetes UK cohort who died before age 40 years. Deaths were categorized as acute events or chronic conditions related to diabetes. Where possible, two matched control subjects were selected for each case. Data relating to psychosocial and socioeconomic factors and variables related to diabetes complications were extracted from the case notes. Risks of death were estimated by calculation of odds ratios (ORs). RESULTS: Case notes were obtained for 98 case and 137 control subjects. Fifty-one deaths were attributed to acute causes, 34 to chronic conditions related to diabetes, and the remaining 13 were unrelated to diabetes. Living alone (OR 4.4), past drug abuse (5.7), and previous psychiatric referral (4.6) were all significantly associated with death from acute events but not death from chronic conditions. There was no association between deaths from acute events and nephropathy, hypertension, neuropathy, or retinopathy, although all of these were associated with deaths from chronic conditions. CONCLUSIONS: The results indicate that psychosocial factors are powerful risk factors for mortality from acute events in patients with type 1 diabetes, although not for mortality from chronic conditions. The data enable the identification of a high-risk group suitable for targeting with preventive measures to reduce acute event mortality.

Setting up a fast-track insulin start clinic for type 2 diabetes.

When people with established type 2 diabetes first need insulin therapy there is often a delay in accessing services. Since the report of the UK Prospective Diabetes Study was published it has been recognised that people with type 2 diabetes have a progressive disease and a need for increasing treatment. The authors set up a fast-track service to enable GPs and practice nurses to refer to a nurse-led service at the diabetes centre.

Mortality from cerebrovascular disease in a cohort of 23 000 patients with insulin-treated diabetes.

BACKGROUND AND PURPOSE: Disease of the cardiovascular system is the main cause of long-term complications and mortality in patients with type I (insulin-dependent) and type II (non-insulin-dependent) diabetes. Cerebrovascular mortality rates have been shown to be raised in patients with type II diabetes but have not previously been reported by age and sex in patients with type I diabetes. METHODS: A cohort of 23 751 patients with insulin-treated diabetes, diagnosed under the age of 30 years from throughout the United Kingdom, was identified during 1972 to 1993 and followed up for mortality until the end of December 2000. Age- and sex-specific mortality rates and standardized mortality ratios (SMRs) were calculated. RESULTS: There were 1437 deaths during the follow-up, 80 due to cerebrovascular disease. Overall, the cerebrovascular mortality rates in the cohort were higher than the corresponding rates in the general population, and the SMRs were 3.1 (95% CI, 2.2 to 4.3) for men and 4.4 (95% CI, 3.1 to 6.0) for women. When stratified by age, the SMRs were highest in the 20- to 39-year age group. After subdivision of cause of death into hemorrhagic and nonhemorrhagic origins, there remained a significant increase in mortality from stroke of nonhemorrhagic origin. CONCLUSIONS: Analyses of mortality from this cohort, essentially one of patients with type I diabetes, has shown for the first time that cerebrovascular mortality is raised at all ages in these patients. Type I diabetes is at least as great a risk factor for cerebrovascular mortality as type II diabetes.

An RCT into calculating insulin start dose in type 2 diabetes.

AIMS: This trial compares to methods used to find the insulin dose when starting insulin in people with type 2 diabetes in whom maximal tolerated oral hypoglycaemic agents have failed to control glycaemia. One method of initiating insulin (based on height, weight, and fasting blood plasma glucose and insulin resistance) was compared with a conventional method of initiating 10 units of isophane insulin twice daily. METHOD: Sixty subjects were randomised to calculated (CALC) or conventional (C). Follow-up was at three, six and 12 months with diabetes specialist nurse (DSN) support. The outcomes that were compared were glycated haemoglobin levels (HbA1c), hypoglycaemia, weight gain, insulin dose, quality of life, treatment satisfaction, blood pressure, and frequency of DSN contact. RESULTS: HbA1c levels values were reduced significantly in the CALC group during the first three months after starting insulin (p = 0.0001) and improved by one per cent overall during 12 months (p = 0.03). No difference was found in rates of hypoglycaemia, blood pressure, quality of life, and treatment satisfaction. Weight gain was seen in both groups but was significantly higher in the CALC group. People in the CALC group needed significantly less DSN time (p = 0.01). CONCLUSIONS: HbA1c target values were achieved more quickly and with less DSN contact using the CALC method. The difference in weight gain with the CALC method needs further investigation.