New Zealand blackcurrant extract modulates the heat shock response in men during exercise in hot ambient conditions.

PURPOSE: To determine if 7d of New Zealand blackcurrant (NZBC) extract alters the heat shock, inflammatory and apoptotic response during prolonged exertional-heat stress. METHODS: Ten men (Age: 29 ± 2 years, Stature: 1.82 ± 0.02 m, Mass: 80.3 ± 2.7 kg, V̇O2max: 56 ± 2 mL·kg-1·min-1) ingested two capsules of CurraNZ™ (NZBC extract: 210 mg anthocyanins·day-1) or PLACEBO for 7d prior to 1 h treadmill run (65% V̇O2max) in hot ambient conditions (34 °C/40% RH). Blood samples were collected before (Pre), immediately after (Post), 1 h after (1-Post), and 4 h after (4-Post) exercise. Heat shock proteins (HSP90, HSP70, HSP32) were measured in plasma. HSP and protein markers of inflammatory capacity (TLR4, NF-κB) and apoptosis (BAX/BCL-2, Caspase 9) were measured in peripheral blood mononuclear cells (PBMC). RESULTS: eHSP32 was elevated at baseline in NZBC(+ 31%; p < 0.001). In PLACEBO HSP32 content in PBMC was elevated at 4-Post(+ 98%; p = 0.002), whereas in NZBC it fell at Post(- 45%; p = 0.030) and 1-Post(- 48%; p = 0.026). eHSP70 was increased at Post in PLACEBO(+ 55.6%, p = 0.001) and NZBC (+ 50.7%, p = 0.010). eHSP90 was increased at Post(+ 77.9%, p < 0.001) and 1-Post(+ 73.2%, p < 0.001) in PLACEBO, with similar increases being shown in NZBC (+ 49.0%, p = 0.006 and + 66.2%, p = 0.001; respectively). TLR4 and NF-κB were both elevated in NZBC at PRE(+ 54%, p = 0.003 and + 57%, p = 0.004; respectively). Main effects of study condition were also shown for BAX/BCL-2(p = 0.025) and Caspase 9 (p = 0.043); both were higher in NZBC. CONCLUSION: 7d of NZBC extract supplementation increased eHSP32 and PBMC HSP32 content. It also increased inflammatory and apoptotic markers in PBMC, suggesting that NZBC supports the putative inflammatory response that accompanies exertional-heat stress.

Anthocyanin-Rich Blackcurrant Extract Preserves Gastrointestinal Barrier Permeability and Reduces Enterocyte Damage but Has No Effect on Microbial Translocation and Inflammation After Exertional Heat Stress.

This study investigated the effects of 7 days of 600 mg/day anthocyanin-rich blackcurrant extract intake on small intestinal permeability, enterocyte damage, microbial translocation, and inflammation following exertional heat stress. Twelve recreationally active men (maximal aerobic capacity = 55.6 ± 6.0 ml·kg-1·min-1) ran (70% VO2max) for 60 min in an environmental chamber (34 °C, 40% relative humidity) on two occasions (placebo/blackcurrant, randomized double-blind crossover). Permeability was assessed from a 4-hr urinary excretion of lactulose and rhamnose and expressed as a ratio of lactulose/rhamnose. Venous blood samples were taken at rest and 20, 60, and 240 min after exercise to measure enterocyte damage (intestinal fatty acid-binding protein); microbial translocation (soluble CD14, lipopolysaccharide-binding protein); and interleukins 6, interleukins 10, and interleukins 1 receptor antagonist. Exercise increased rectal temperature (by ∼2.8 °C) and heart rate (by ∼123 beats/min) in each condition. Blackcurrant supplementation led to a ∼12% reduction in lactulose/rhamnose ratio (p < .0034) and enterocyte damage (∼40% reduction in intestinal fatty acid-binding protein area under the curve; p < .0001) relative to placebo. No between-condition differences were observed immediately after exercise for lipopolysaccharide-binding protein (mean, 95% confidence interval [CI]; +80%, 95% CI [+61%, +99%]); soluble CD14 (+37%, 95% CI [+22%, +51%]); interleukins 6 (+494%, 95% CI [+394%, +690%]); interleukins 10 (+288%, 95% CI [+105%, +470%]); or interleukins 1 receptor antagonist (+47%, 95% CI [+13%, +80%]; all time main effects). No between-condition differences for these markers were observed after 60 or 240 min of recovery. Blackcurrant extract preserves the GI barrier; however, at subclinical levels, this had no effect on microbial translocation and downstream inflammatory processes.

CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial.

Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3-5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL.

Dietary supplementation with New Zealand blackcurrant extract enhances fat oxidation during submaximal exercise in the heat.

OBJECTIVES: This study investigated the effect of 7 days' supplementation with New Zealand blackcurrant extract on thermoregulation and substrate metabolism during running in the heat. DESIGN: Randomized, double-blind, cross-over study. METHODS: Twelve men and six women (mean±SD: Age 27±6 years, height 1.76±0.10m, mass 74±12kg, V̇O2max 53.4±7.0mLkg-1min-1) completed one assessment of maximal aerobic capacity and one familiarisation trial (18°C, 40% relative humidity, RH), before ingesting 2×300mgday-1 capsules of CurraNZ™ (each containing 105mg anthocyanin) or a visually matched placebo (2×300mg microcrystalline cellulose M102) for 7 days (washout 14 days). On day 7 of each supplementation period, participants completed 60min of fasted running at 65% V̇O2max in hot ambient conditions (34°C and 40% relative humidity). RESULTS: Carbohydrate oxidation was decreased in the NZBC trial [by 0.24gmin-1 (95% CI: 0.21-0.27gmin-1)] compared to placebo (p= 0.014, d=0.46), and fat oxidation was increased in the NZBC trial [by 0.12gmin-1 (95% CI: 0.10 to 0.15gmin-1)], compared to placebo (p=0.008, d=0.57). NZBC did not influence heart rate (p=0.963), rectal temperature (p=0.380), skin temperature (p=0.955), body temperature (p=0.214) or physiological strain index (p=0.705) during exercise. CONCLUSIONS: Seven-days intake of 600mg NZBC extract increased fat oxidation without influencing cardiorespiratory or thermoregulatory variables during prolonged moderate intensity running in hot conditions.

AUDIT OF OXYGEN PRESCRIBING IN A CHILDREN'S HOSPITAL.

AIM: To audit oxygen prescribing in a children's hospital following the introduction of a new paediatric medication chart, which incorporates an oxygen prescription section. METHOD: In June 2015 a 1-day snapshot audit was carried out across all wards in the children's hospital. All patients receiving oxygen on that day were included:▸ The audit was repeated in July 2015.▸ The standards for the audit were set at 100% in accordance with our local guidelines.1 ▸ All patients receiving oxygen should have a prescription. Of these:▸ All patients should have target saturations identified.▸ All patients should have an administration device identified.▸ All patients should have a nurse signature on the chart within the last 12 hrs. RESULTS: In June, 13 patients were receiving oxygen on the audit day. 0/14 had a prescription.In July, 18 patients were receiving oxygen on the audit day. (14 critical care, 4 medicine).4/18 had an oxygen prescription (22%). These were all medical patients. Of these, 4 patients had a target saturation identified (100%), 1 had a device prescribed (25%), and 4 had a nurse signature within the last 12 hrs (100%). CONCLUSION: The initial audit showed no compliance with either local or national guidance for oxygen prescribing.1 2 The re-audit showed improved prescribing on the medical wards but not within critical care. The new paediatric medication chart was launched early in 2015, along with a training package for doctors, nurses and pharmacists. This was in response to the National Patient Safety Agency (NPSA) rapid response report on oxygen safety in hospitals.3 There was a gap between the training and the new charts being available which may have led to the poor results in the first audit. Increased awareness of the charts and the initial audit results probably helped improve prescribing in the re-audit. For medical patients, prescribing and monitoring was good, although device was infrequently prescribed. Critical care have not engaged with the new chart and oxygen prescription process. Although the British Thoracic Society guidelines indicate that oxygen for adult patients must be prescribed, these do not currently cover critical care or children under 16 years.2 There are guidelines for children in development which are likely to advocate the same. This could be another reason why there is no prescribing in critical care.Patient numbers were small in this snapshot audit which could limit its validity. Future work will include re-audit in our hospital and audit across the whole region where the new charts have been introduced.