A 10 min “no‐touch” time – is it enough in DCD? A DCD Animal Study

Donation after cardiac death (DCD) is under investigation because of the lack of human donor organs. Required times of cardiac arrest vary between 75s and 27min until the declaration of the patients' death worldwide. The aim of this study was to investigate brain death in pigs after different times of cardiac arrest with subsequent cardiopulmonary resuscitation (CPR) as a DCD paradigm. DCD was simulated in 20 pigs after direct electrical induction of ventricular fibrillation. The "no-touch" time varied from 2min up to 10min; then 30min of CPR were performed. Brain death was determined by established clinical and electrophysiological criteria. In all animals with cardiac arrest of at least 6min, a persistent loss of brainstem reflexes and no reappearance of bioelectric brain activity occurred. Reappearance of EEG activity was found until 4.5min of cardiac arrest and subsequent CPR. Brainstem reflexes were detectable until 5min of cardiac arrest and subsequent CPR. According to our experiments, the suggestion of 10min of cardiac arrest being equivalent to brain death exceeds the minimum time after which clinical and electrophysiological criteria of brain death are fulfilled. Therefore shorter "no-touch" times might be ethically acceptable to reduce warm ischemia time.     

DC isoketal-modified proteins activate T cells and promote hypertension

Oxidative damage and inflammation are both implicated in the genesis of hypertension; however, the mechanisms by which these stimuli promote hypertension are not fully understood. Here, we have described a pathway in which hypertensive stimuli promote dendritic cell (DC) activation of T cells, ultimately leading to hypertension. Using multiple murine models of hypertension, we determined that proteins oxidatively modified by highly reactive γ-ketoaldehydes (isoketals) are formed in hypertension and accumulate in DCs. Isoketal accumulation was associated with DC production of IL-6, IL-1β, and IL-23 and an increase in costimulatory proteins CD80 and CD86. These activated DCs promoted T cell, particularly CD8⁺ T cell, proliferation; production of IFN-γ and IL-17A; and hypertension. Moreover, isoketal scavengers prevented these hypertension-associated events. Plasma F2-isoprostanes, which are formed in concert with isoketals, were found to be elevated in humans with treated hypertension and were markedly elevated in patients with resistant hypertension. Isoketal-modified proteins were also markedly elevated in circulating monocytes and DCs from humans with hypertension. Our data reveal that hypertension activates DCs, in large part by promoting the formation of isoketals, and suggest that reducing isoketals has potential as a treatment strategy for this disease.     

Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production

Chronic hyperglycemia impairs insulin action, resulting in glucotoxicity, which can be ameliorated in animal models by inducing glucosuria with renal glucose transport inhibitors. Here, we examined whether reduction of plasma glucose with a sodium-glucose cotransporter 2 (SGLT2) inhibitor could improve insulin-mediated tissue glucose disposal in patients with type 2 diabetes. Eighteen diabetic men were randomized to receive either dapagliflozin (n = 12) or placebo (n = 6) for 2 weeks. We measured insulin-mediated whole body glucose uptake and endogenous glucose production (EGP) at baseline and 2 weeks after treatment using the euglycemic hyperinsulinemic clamp technique. Dapagliflozin treatment induced glucosuria and markedly lowered fasting plasma glucose. Insulin-mediated tissue glucose disposal increased by approximately 18% after 2 weeks of dapagliflozin treatment, while placebo-treated subjects had no change in insulin sensitivity. Surprisingly, following dapagliflozin treatment, EGP increased substantially and was accompanied by an increase in fasting plasma glucagon concentration. Together, our data indicate that reduction of plasma glucose with an agent that works specifically on the kidney to induce glucosuria improves muscle insulin sensitivity. However, glucosuria induction following SGLT2 inhibition is associated with a paradoxical increase in EGP. These results provide support for the glucotoxicity hypothesis, which suggests that chronic hyperglycemia impairs insulin action in individuals with type 2 diabetes.     

A pilot study: dose adaptation of capecitabine using mobile phone toxicity monitoring — supporting patients in their homes

Purpose

Real-time symptom monitoring using a mobile phone is potentially advantageous for patients receiving oral chemotherapy. We therefore conducted a pilot study of patient dose adaptation using mobile phone monitoring of specific symptoms to investigate relative dose intensity of capecitabine, level of toxicity and perceived supportive care.

Methods

Patients with breast or colorectal cancer receiving capecitabine completed a symptom, temperature and dose diary twice a day using a mobile phone application. This information was encrypted and automatically transmitted in real time to a secure server, with moderate levels of toxicity automatically prompting self-care symptom management messages on the screen of the patient’s mobile phone or in severe cases, a call from a specialist nurse to advise on care according to an agreed protocol.

Results

Patients (n?=?26) completed the mobile phone diary on 92.6 % of occasions. Twelve patients had a maximum toxicity grade of 3 (46.2 %). The average dose intensity for all patients as a percentage of standard dose was 90 %. In eight patients, the dose of capecitabine was reduced, and in eight patients, the dose of capecitabine was increased. Patients and healthcare professionals involved felt reassured by the novel monitoring system, in particular, during out of hours.

Conclusion

It is possible to optimise the individual dose of oral chemotherapy safely including dose increase and to manage chemotherapy side effects effectively using real-time mobile phone monitoring of toxicity parameters entered by the patient.     

Perceived pain during rapid maxillary expansion in children with different expanders:: A prospective study

ObjectivesTo evaluate and compare the intensity of pain caused by rapid maxillary expansion (RME) with two expanders: Hyrax and Haas type, in growing patients.Materials and MethodsThirty-nine patients (23 girls and 16 boys) with an average age of 9.3 years (SD = 1.39 years) were randomized into two groups and treated with Hyrax- and Haas-type expanders. In both groups, initial activation of the expander screw was one full turn on the first day followed by 2/4 of a turn two times a day (morning and night) for 7 days. Inclusion criteria were patients presenting with a posterior crossbite or maxillary atresia between 7 and 12 years old. To evaluate the intensity of pain during the active phase of the treatment, a combination of the Numerical Rating Scale and Wong-Baker Faces Pain Scale was used. Mann-Whitney test was used to compare the two treatment groups.ResultsThere was significant inverse correlation between days following insertion and pain. During the expansion period, 100% of the children reported some pain. Hyrax expander subjects reported greater pain than those treated with the Haas-type expander only on the first day. The level of pain remained greater in girls throughout treatment.ConclusionsPain was reported regardless of the type of expander and was higher in the Hyrax group only on the first day of activation.     

Transplantation of CD34+ cells for myocardial ischemia

CD34+ cells are multipotent hematopoietic stem cells also known as endothelial progenitor cells and are useful in regenerative medicine. Naturally, these cells are mobilized from the bone marrow into peripheral circulation in response to ischemic tissue injury. CD34+ cells are known for their high proliferative and differentiation capacities that play a crucial role in the repair process of myocardial damage. They have an important paracrine activity in secreting factors to stimulate vasculogenesis, reduce endothelial cells and cardiomyocytes apoptosis, remodel extracellular matrix and activate additional progenitor cells. Once they migrate to the target site, they enhance angiogenesis, neovascularization and tissue regeneration. Several trials have demonstrated the safety and efficacy of CD34+ cell therapy in different settings, such as peripheral limb ischemia, stroke and cardiovascular disease. Herein, we review the potential utility of CD34+ cell transplantation in acute myocardial infarction, refractory angina and ischemic heart failure.