Immune activation by combination human lymphokine-activated killer and dendritic cell therapy.

BACKGROUND: Optimal cellular immunotherapy for cancer should ideally harness both the innate and adaptive arms of the immune response. Lymphokine-activated killer cells (LAKs) can trigger early innate killing of tumour targets, whereas long-term adaptive-specific tumour control requires priming of CD8+ cytotoxic lymphocytes (CTLs) following acquisition of tumour-associated antigens (TAAs) by antigen-presenting cells such as dendritic cells (DCs). As DCs stimulate both innate and adaptive effectors, combination cell therapy using LAKs and DCs has the potential to maximise anti-tumour immune priming. METHODS: Reciprocal activation between human clinical grade LAKs and DCs on co-culture, and its immune consequences, was monitored by cell phenotype, cytokine release and priming of both innate and adaptive cytotoxicity against melanoma targets. RESULTS: Co-culture of DCs and LAKs led to phenotypic activation of natural killer (NK) cells within the LAK population, which was associated with increased production of inflammatory cytokines and enhanced innate cytotoxicity against tumour cell targets. The LAKs reciprocally matured DCs, and the combination of LAKs and DCs, on addition of melanoma cells, supported priming of specific anti-tumour CTLs better than DCs alone. CONCLUSION: Clinical-grade LAKs/DCs represents a practical, effective combination cell immunotherapy for stimulation of both innate and adaptive anti-tumour immunity in cancer patients

Cost-effectiveness of initial stress cardiovascular MR, stress SPECT or stress echocardiography as a gate-keeper test, compared with upfront invasive coronary angiography in the investigation and management of patients with stable chest pain: Mid-term outcomes from the CECaT randomised controlled trial

Objectives: To compare outcomes and cost-effectiveness of various initial imaging strategies in the management of stable chest pain in a long-term prospective randomised trial. Setting: Regional cardiothoracic referral centre in the east of England. Participants: 898 patients (69% man) entered the study with 869 alive at 2 years of follow-up. Patients were included if they presented for assessment of stable chest pain with a positive exercise test and no prior history of ischaemic heart disease. Exclusion criteria were recent infarction, unstable symptoms or any contraindication to stress MRI. Primary outcome measures: The primary outcomes of this follow-up study were survival up to a minimum of 2 years post-treatment, quality-adjusted survival and cost-utility of each strategy. Results: 898 patients were randomised. Compared with angiography, mortality was marginally higher in the groups randomised to cardiac MR (HR 2.6, 95% CI 1.1 to 6.2), but similar in the single photon emission CT-methoxyisobutylisonitrile (SPECT-MIBI; HR 1.0, 95% CI 0.4 to 2.9) and ECHO groups (HR 1.6, 95% CI 0.6 to 4.0). Although SPECT-MIBI was marginally superior to other non-invasive tests there were no other significant differences between the groups in mortality, quality-adjusted survival or costs. Conclusions: Non-invasive cardiac imaging can be used safely as the initial diagnostic test to diagnose coronary artery disease without adverse effects on patient outcomes or increased costs, relative to angiography. These results should be interpreted in the context of recent advances in imaging technology. Trial registration: ISRCTN 47108462, UKCRN 3696

Pre-Meal Whey Protein Alters Postprandial Insulinemia by Enhancing β-Cell Function and Reducing Insulin Clearance in T2D

CONTEXT: Treatments that reduce postprandial glycemia (PPG) independent of stimulating insulin secretion are appealing for the management of type 2 diabetes (T2D). Consuming pre-meal whey protein (WP) reduces PPG by delaying gastric emptying and increasing plasma insulin concentrations. However, its effects on β-cell function and insulin kinetics remains unclear. OBJECTIVE: To examine the PPG-regulatory effects of pre-meal WP by modeling insulin secretion rates (ISR), insulin clearance, and β-cell function. METHODS: This was a single-blind, randomized, placebo-controlled, crossover design study in 18 adults with T2D (HbA1c, 56.7 ± 8.8 mmol/mol) who underwent 2 240-minute mixed-meal tolerance tests. Participants consumed WP (15 g protein) or placebo (0 g protein) 10 minutes before a mixed-macronutrient breakfast meal. PPG, pancreatic islet, and incretin hormones were measured throughout. ISR was calculated by C-peptide deconvolution. Estimates of insulin clearance and β-cell function were modeled from glucose, insulin, and ISR. Changes in PPG incremental area under the curve (iAUC; prespecified) and insulin clearance (post hoc) were measured. RESULTS: β-cell function was 40% greater after WP (P = .001) and was accompanied with a -22% reduction in postprandial insulin clearance vs placebo (P < .0001). Both the peak change and PPG iAUC were reduced by WP (-1.5 mmol/L and -16%, respectively; both P < .05). Pre-meal WP augmented a 5.9-fold increase in glucagon and glucagon-like peptide 1 iAUC (both P < .0001), and a 1.5-fold increase in insulin iAUC (P < .001). Although the plasma insulin response was greater following WP, ISR was unaffected (P = .133). CONCLUSION: In adults with T2D, pre-meal WP reduced PPG by coordinating an enhancement in β-cell function with a reduction in insulin clearance. This enabled an efficient postprandial insulinemic profile to be achieved without requiring further β-cell stimulation.Trial registry ISRCTN ID: ISRCTN17563146 Website link: www.isrctn.com/ISRCTN17563146

Insulin therapy and dietary adjustments to normalize glycaemia and prevent nocturnal hypoglycaemia after evening exercise in type 1 diabetes: a randomized controlled trial

Introduction Evening-time exercise is a frequent cause of severe hypoglycemia in type 1 diabetes, fear of which deters participation in regular exercise. Recommendations for normalizing glycemia around exercise consist of prandial adjustments to bolus insulin therapy and food composition, but this carries only short-lasting protection from hypoglycemia. Therefore, this study aimed to examine the impact of a combined basal-bolus insulin dose reduction and carbohydrate feeding strategy on glycemia and metabolic parameters following evening exercise in type 1 diabetes. Methods Ten male participants (glycated hemoglobin: 52.4±2.2 mmol/mol), treated with multiple daily injections, completed two randomized study-days, whereby administration of total daily basal insulin dose was unchanged (100%), or reduced by 20% (80%). Participants attended the laboratory at ∼08:00 h for a fasted blood sample, before returning in the evening. On arrival (∼17:00 h), participants consumed a carbohydrate meal and administered a 75% reduced rapid-acting insulin dose and 60 min later performed 45 min of treadmill running. At 60 min postexercise, participants consumed a low glycemic index (LGI) meal and administered a 50% reduced rapid-acting insulin dose, before returning home. At ∼23:00 h, participants consumed a LGI bedtime snack and returned to the laboratory the following morning (∼08:00 h) for a fasted blood sample. Venous blood samples were analyzed for glucose, glucoregulatory hormones, non-esterified fatty acids, β-hydroxybutyrate, interleukin 6, and tumor necrosis factor α. Interstitial glucose was monitored for 24 h pre-exercise and postexercise. Results Glycemia was similar until 6 h postexercise, with no hypoglycemic episodes. Beyond 6 h glucose levels fell during 100%, and nine participants experienced nocturnal hypoglycemia. Conversely, all participants during 80% were protected from nocturnal hypoglycemia, and remained protected for 24 h postexercise. All metabolic parameters were similar. Conclusions Reducing basal insulin dose with reduced prandial bolus insulin and LGI carbohydrate feeding provides protection from hypoglycemia during and for 24 h following evening exercise. This strategy is not associated with hyperglycemia, or adverse metabolic disturbances

Gut microbiota of Type 1 diabetes patients with good glycaemic control and high physical fitness is similar to people without diabetes: an observational study

Type 1 diabetes is the product of a complex interplay between genetic susceptibility and exposure to environmental factors. Existing bacterial profiling studies focus on people who are most at risk at the time of diagnosis; there are limited data on the gut microbiota of people with long-standing Type 1 diabetes. This study compared the gut microbiota of patients with Type 1 diabetes and good glycaemic control and high levels of physical-fitness with that of matched controls without diabetes.Ten males with Type 1 diabetes and ten matched controls without diabetes were recruited; groups were matched for gender, age, BMI, peak oxygen uptake (VO2max ), and exercise habits. Stool samples were analysed using next-generation sequencing of the 16S rRNA gene to obtain bacterial profiles from each individual. Phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) was implemented to predict the functional content of the bacterial operational taxonomic units.Faecalibacterium sp., Roseburia sp. and Bacteroides sp. were typically the most abundant members of the community in both patients with Type 1 diabetes and controls, and were present in every sample in the cohort. Each bacterial profile was relatively individual and no significant difference was reported between the bacterial profiles or the Shannon diversity indices of Type 1 diabetes compared with controls. The functional profiles were more conserved and the Type 1 diabetes group were comparable with the control group.We show that both gut microbiota and resulting functional bacterial profiles from patients with long-standing Type 1 diabetes in good glycaemic control and high physical fitness levels are comparable with those of matched people without diabetes. This article is protected by copyright. All rights reserved

The inflammation, vascular repair and injury responses to exercise in fit males with and without Type 1 diabetes: an observational study.

Type 1 diabetes is associated with raised inflammation, impaired endothelial progenitor cell mobilisation and increased markers of vascular injury. Both acute and chronic exercise is known to influence these markers in non-diabetic controls, but limited data exists in Type 1 diabetes. We assessed inflammation, vascular repair and injury at rest and after exercise in physically-fit males with and without Type 1 diabetes.Ten well-controlled type 1 diabetes (27 ± 2 years; BMI 24 ± 0.7 kg.m(2); HbA1c 53.3 ± 2.4 mmol/mol) and nine non-diabetic control males (27 ± 1 years; BMI 23 ± 0.8 kg.m(2)) matched for age, BMI and fitness completed 45-min of running. Venous blood samples were collected 60-min before and 60-min after exercise, and again on the following morning. Blood samples were processed for TNF-α using ELISA, and circulating endothelial progenitor cells (cEPCs; CD45(dim)CD34(+)VEGFR2(+)) and endothelial cells (cECs; CD45(dim)CD133(-)CD34(+)CD144(+)) counts using flow-cytometry.TNF-α concentrations were 4-fold higher at all-time points in Type 1 diabetes, when compared with control (P 0.05). Within the Type 1 diabetes group, the delta change in cEPCS from rest to the following morning was related to HbA1c (r = -0.65, P = 0.021) and TNF-α (r = -0.766, P = 0.005).Resting cEPCs and cECs in Type 1 diabetes patients with excellent HbA1c and high physical-fitness are comparable to healthy controls, despite eliciting 4-fold greater TNF-α. Furthermore, Type 1 diabetes patients appear to have a blunted post-exercise cEPCs response (vascular repair), whilst a biomarker of vascular injury (cECs) remained comparable to healthy controls

Rapid reduction versus abrupt quitting for smokers who want to stop soon: a randomised controlled non-inferiority trial

Background: The standard way to stop smoking is to stop abruptly on a quit day with no prior reduction in consumption of cigarettes. Many smokers feel that reduction is natural and if reduction programmes were offered, many more might take up treatment. Few trials of reduction versus abrupt cessation have been completed. Most are small, do not use pharmacotherapy, and do not meet the standards necessary to obtain a marketing authorisation for a pharmacotherapy.\ud Design/Methods: We will conduct a non-inferiority andomised trial of rapid reduction versus standard abrupt cessation among smokers who want to stop smoking. In the reduction arm,participants will be advised to reduce smoking consumption by half in the first week and to 25% of baseline in the second, leading up to a quit day at which participants will stop smoking completely.This will be assisted by nicotine patches and an acute form of nicotine replacement therapy. In the abrupt arm participants will use nicotine patches only, whilst smoking as normal, for two weeks prior to a quit day, at which they will also stop smoking completely. Smokers in either arm will have standard withdrawal orientated behavioural support programme with a combination of nicotine patches and acute nicotine replacement therapy post-cessation.\ud Outcomes/Follow-up: The primary outcome of interest will be prolonged abstinence from smoking, with secondary trial outcomes of point prevalence, urges to smoke and withdrawal\ud symptoms. Follow up will take place at 4 weeks, 8 weeks and 6 months post-quit day

The Clinical Application of Mealtime Whey Protein for the Treatment of Postprandial Hyperglycaemia for People With Type 2 Diabetes: A Long Whey to Go

© Copyright © 2020 Smith, Bowden Davies, Stevenson and West. Mitigating postprandial hyperglycaemic excursions may be effective in not only enhancing glycaemic control for people with type 2 diabetes but also reducing the onset of diabetes-related complications. However, there are growing concerns over the long-term efficacy of anti-hyperglycaemic pharmacotherapies, which coupled with their rising financial costs, underlines the need for further non-pharmaceutical treatments to regulate postprandial glycaemic excursions. One promising strategy that acutely improves postprandial glycaemia for people with type 2 diabetes is through the provision of mealtime whey protein, owing to the slowing of gastric emptying and increased secretion of insulin and the incretin peptides. The magnitude of this effect appears greater when whey protein is consumed before, rather than with, a meal. Herein, this dietary tool may offer a simple and inexpensive strategy in the management of postprandial hyperglycaemia for people with type 2 diabetes. However, there are insufficient long-term studies that have investigated the use of mealtime whey protein as a treatment option for individuals with type 2 diabetes. The methodological approaches applied in acute studies and outcomes reported may also not portray what is achievable long-term in practice. Therefore, studies are needed to refine the application of this mealtime strategy to maximize its clinical potential to treat hyperglycaemia and to apply these long-term to address key components of successful diabetes care. This review discusses evidence surrounding the provision of mealtime whey protein to treat postprandial hyperglycaemia in individuals with type 2 diabetes and highlights areas to help facilitate its clinical application