A randomised controlled study of high intensity exercise as a dishabituating stimulus to improve hypoglycaemia awareness in people with type 1 diabetes:a proof of concept study

Aims/hypothesis Approximately 25% of people with type 1 diabetes have suppressed counterregulatory hormonal and symptomatic responses to insulin-induced hypoglycaemia, which renders them at increased risk of severe, disabling hypoglycaemia. This is called impaired awareness of hypoglycaemia (IAH), the cause of which is unknown. We recently proposed that IAH develops through habituation, a form of adaptive memory to preceding hypoglycaemia. Consistent with this hypothesis, we demonstrated restoration of defective counterregulatory hormonal responses to hypoglycaemia (referred to as dishabituation) in a rodent model of IAH following introduction of a novel stress stimulus (high intensity training [HIT]). In this proof-of-concept study we sought to further test this hypothesis by examining whether a single episode of HIT would amplify counterregulatory responses to subsequent hypoglycaemia in people with type 1 diabetes who had IAH (assessed by Gold score ≥4, modified Clarke score ≥4 or Dose Adjustment For Normal Eating (DAFNE) hypoglycaemia awareness rating 2 or 3). The primary outcome was the difference in adrenaline response to hypoglycaemia following both a single episode of HIT and rest. Methods In this randomised, crossover study 12 participants aged between 18 and 55 years with type 1 diabetes for ≥5 years and an HbA1c < 75 mmol/mol (9%) were recruited. Individuals were randomised using computer generated block randomisation to start with one episode of HIT (4 × 30 s cycle sprints [2 min recovery] at 150% of maximum wattage achieved during V˙O2peak assessment) or rest (control). The following day they underwent a 90 min hyperinsulinaemic–hypoglycaemic clamp study at 2.5 mmol/l with measurement of hormonal counterregulatory response, symptom scores and cognitive testing (four-choice reaction time and digit symbol substitution test). Each intervention and subsequent clamp study was separated by at least 2 weeks. The participants and investigators were not blinded to the intervention or measurements during the study. The investigators were blinded to the primary outcome and blood analysis results. Results All participants (six male and six female, age 19–54 years, median [IQR] duration of type 1 diabetes 24.5 [17.3–29.0] years, mean [SEM] HbA1c 56 [3.67] mmol/mol; 7.3% [0.34%]) completed the study (both interventions and two clamps). In comparison with the rest study, a single episode of HIT led to a 29% increase in the adrenaline (epinephrine) response (mean [SEM]) (2286.5 [343.1] vs 2953.8 [384.9] pmol/l); a significant increase in total symptom scores (Edinburgh Hypoglycaemia Symptom Scale: 24.25 [2.960 vs 27.5 [3.9]; p < 0.05), and a significant prolongation of four-choice reaction time (591.8 [22.5] vs 659.9 [39.86] ms; p < 0.01] during equivalent hypoglycaemia induced the following day. Conclusions/interpretation These findings are consistent with the hypothesis that IAH develops in people with type 1 diabetes as a habituated response and that introduction of a novel stressor can restore, at least partially, the adapted counterregulatory hormonal, symptomatic and cognitive responses to hypoglycaemia.Output Status: Forthcoming/Available Onlin

Age composition, growth, and reproduction of koi carp (Cyprinus carpio L.) in the lower Waikato, New Zealand

A total of 566 koi carp (Cyprinus carpio) from the lower Waikato region were aged from scales and opercular bones, and growth was modelled with the von Bertalanffy growth function. There was no difference in growth rate between male and female carp. Growth of koi carp between zero and 3 years of age was lower than that of common carp in Europe and Australia. However, after 5 years of age the growth of koi carp was higher than that of common carp in Europe, but still below that of carp in Australia. Males rarely lived in excess of 8 years, whereas females lived to 12 years. Mean total fecundity calculated from 44 running-ripe females was 299 000 oocytes (±195 600 SD) (range 29 800–771 000). Relative fecundity ranged from 19 300 to 216 000 oocytes kg–1 total body weight, with a mean of 97 200 (±35 000 SD) oocytes kg–1. Feral koi carp in the Waikato are capable of multiple spawnings within their lifetimes. Within a spawning season, Waikato populations of feral koi carp contained females that spawned once, and females that had the potential to have spawned repeatedly. Female gonadosomatic index (GSI) varied with season and was negatively related to water temperature

Black holes admitting a Freudenthal dual

The quantised charges x of four dimensional stringy black holes may be assigned to elements of an integral Freudenthal triple system whose automorphism group is the corresponding U-duality and whose U-invariant quartic norm Delta(x) determines the lowest order entropy. Here we introduce a Freudenthal duality x -> \tilde{x}, for which \tilde{\tilde{x}}=-x. Although distinct from U-duality it nevertheless leaves Delta(x) invariant. However, the requirement that \tilde{x} be integer restricts us to the subset of black holes for which Delta(x) is necessarily a perfect square. The issue of higher-order corrections remains open as some, but not all, of the discrete U-duality invariants are Freudenthal invariant. Similarly, the quantised charges A of five dimensional black holes and strings may be assigned to elements of an integral Jordan algebra, whose cubic norm N(A) determines the lowest order entropy. We introduce an analogous Jordan dual A*, with N(A) necessarily a perfect cube, for which A**=A and which leaves N(A) invariant. The two dualities are related by a 4D/5D lift.Comment: 32 pages revtex, 10 tables; minor corrections, references adde

Entropy on Spin Factors

Recently it has been demonstrated that the Shannon entropy or the von Neuman entropy are the only entropy functions that generate a local Bregman divergences as long as the state space has rank 3 or higher. In this paper we will study the properties of Bregman divergences for convex bodies of rank 2. The two most important convex bodies of rank 2 can be identified with the bit and the qubit. We demonstrate that if a convex body of rank 2 has a Bregman divergence that satisfies sufficiency then the convex body is spectral and if the Bregman divergence is monotone then the convex body has the shape of a ball. A ball can be represented as the state space of a spin factor, which is the most simple type of Jordan algebra. We also study the existence of recovery maps for Bregman divergences on spin factors. In general the convex bodies of rank 2 appear as faces of state spaces of higher rank. Therefore our results give strong restrictions on which convex bodies could be the state space of a physical system with a well-behaved entropy function.Comment: 30 pages, 6 figure

Response of selected plant and insect species to simulated solid rocket exhaust mixtures and to exhaust components from solid rocket fuels

The effects of solid rocket fuel (SRF) exhaust on selected plant and and insect species in the Merritt Island, Florida area was investigated in order to determine if the exhaust clouds generated by shuttle launches would adversely affect the native, plants of the Merritt Island Wildlife Refuge, the citrus production, or the beekeeping industry of the island. Conditions were simulated in greenhouse exposure chambers and field chambers constructed to model the ideal continuous stirred tank reactor. A plant exposure system was developed for dispensing and monitoring the two major chemicals in SRF exhaust, HCl and Al203, and for dispensing and monitoring SRF exhaust (controlled fuel burns). Plants native to Merritt Island, Florida were grown and used as test species. Dose-response relationships were determined for short term exposure of selected plant species to HCl, Al203, and mixtures of the two to SRF exhaust

Three fermions with six single particle states can be entangled in two inequivalent ways

Using a generalization of Cayley's hyperdeterminant as a new measure of tripartite fermionic entanglement we obtain the SLOCC classification of three-fermion systems with six single particle states. A special subclass of such three-fermion systems is shown to have the same properties as the well-known three-qubit ones. Our results can be presented in a unified way using Freudenthal triple systems based on cubic Jordan algebras. For systems with an arbitrary number of fermions and single particle states we propose the Pl\"ucker relations as a sufficient and necessary condition of separability.Comment: 23 pages LATE

Observations on Integral and Continuous U-duality Orbits in N=8 Supergravity

One would often like to know when two a priori distinct extremal black p-brane solutions are in fact U-duality related. In the classical supergravity limit the answer for a large class of theories has been known for some time. However, in the full quantum theory the U-duality group is broken to a discrete subgroup and the question of U-duality orbits in this case is a nuanced matter. In the present work we address this issue in the context of N=8 supergravity in four, five and six dimensions. The purpose of this note is to present and clarify what is currently known about these discrete orbits while at the same time filling in some of the details not yet appearing in the literature. To this end we exploit the mathematical framework of integral Jordan algebras and Freudenthal triple systems. The charge vector of the dyonic black string in D=6 is SO(5,5;Z) related to a two-charge reduced canonical form uniquely specified by a set of two arithmetic U-duality invariants. Similarly, the black hole (string) charge vectors in D=5 are E_{6(6)}(Z) equivalent to a three-charge canonical form, again uniquely fixed by a set of three arithmetic U-duality invariants. The situation in four dimensions is less clear: while black holes preserving more than 1/8 of the supersymmetries may be fully classified by known arithmetic E_{7(7)}(Z) invariants, 1/8-BPS and non-BPS black holes yield increasingly subtle orbit structures, which remain to be properly understood. However, for the very special subclass of projective black holes a complete classification is known. All projective black holes are E_{7(7)}(Z) related to a four or five charge canonical form determined uniquely by the set of known arithmetic U-duality invariants. Moreover, E_{7(7)}(Z) acts transitively on the charge vectors of black holes with a given leading-order entropy.Comment: 43 pages, 8 tables; minor corrections, references added; version to appear in Class. Quantum Gra

Impaired hypoglycaemia awareness in type 1 diabetes:lessons from the lab

Hypoglycaemia remains the most common metabolic adverse effect of insulin and sulfonylurea therapy in diabetes. Repeated exposure to hypoglycaemia leads to a change in the symptom complex that characterises hypoglycaemia, culminating in a clinical phenomenon referred to as impaired awareness of hypoglycaemia (IAH). IAH effects approximately 20–25% of people with type 1 diabetes and increases the risk of severe hypoglycaemia. This review focuses on the mechanisms that are responsible for the much higher frequency of hypoglycaemia in people with diabetes compared with those without, and subsequently how repeated exposure to hypoglycaemia leads to the development of IAH. The mechanisms that result in IAH development are incompletely understood and likely to reflect changes in multiple aspects of the counterregulatory response to hypoglycaemia, from adaptations within glucose and non-glucose-sensing cells to changes in the integrative networks that govern glucose homeostasis. Finally, we propose that the general process that incorporates many of these changes and results in IAH following recurrent hypoglycaemia is a form of adaptive memory called ‘habituation’

Renal and Cardiovascular Effects of sodium–glucose cotransporter 2 (SGLT2) inhibition in combination with loop Diuretics in diabetic patients with Chronic Heart Failure (RECEDE-CHF):protocol for a randomised controlled double-blind cross-over trial

Introduction: Type 2 diabetes (T2D) and heart failure (HF) are a frequent combination, where treatment options remain limited. There has been increasing interest around the sodium-glucose co-transporter 2 (SGLT2) inhibitors and their use in patients with HF. Data on the effect of SGLT2 inhibitor use with diuretics is limited. We hypothesise that SGLT2 inhibition may augment the effects of loop diuretics. We hypothesise that the benefits of SGLT2 inhibitors extend beyond those of their metabolic (glycaemic parameters and weight loss) and haemodynamic parameters; that the effects of SGLT2 inhibitors as an osmotic diuretic and on natriuresis may underlie the cardiovascular and renal benefits demonstrated in the recent EMPA-REG study.Methods and Analysis: To assess the effect of SGLT2 inhibitors when used in combination with a loop diuretic, the RECEDE-CHF trial is a single centre, randomised double-blind, placebo-controlled, crossover trial conducted in a secondary care setting within NHS Tayside, Scotland. 34 eligible participants, aged between 18 to 80 years, with stable T2D and CHF will be recruited. Renal physiological testing will be performed at two points (week 1 and week 6) on each arm to assess the effect of 25 mg empagliflozin, on the primary and secondary outcomes. Participants will be enrolled in the trial for a total period between 14 to 16 weeks. The primary outcome will assess the effect of empagliflozin versus placebo on urine output. The secondary outcomes are to assess the effect of empagliflozin on glomerular filtration rate, cystatin C, urinary sodium excretion, urinary protein/creatinine ratio, and urinary albumin/creatinine ratio when compared to placebo.Ethics and Dissemination: Ethics approval was obtained by the East of Scotland Research Ethics Service. Results of the trial will be submitted for publication in a peer-reviewed journal.Registration Details: clinicaltrials.gov: NCT03226457. Registered: July 17, 2017

Nrf2-mediated neuroprotection response to recurrent hypoglycemia is insufficient to prevent cognitive impairment in a rodent model of type 1 diabetes

It remains uncertain whether recurrent nonsevere hypoglycemia (Hypo) results in long-term cognitive impairment in type 1 diabetes (T1D). This study tested the hypothesis that specifically in the T1D state, Hypo leads to cognitive impairment via a pathological response to oxidative stress. Wild-type (Control) and nuclear factor–erythroid 2 p45–related factor 2 (Nrf2) null mice were studied. Eight groups of mice (Control and Nrf2−/− ± T1D and ± Hypo) were subject to recurrent, twice-weekly, insulin or saline injections over 4 weeks, after which cognitive function was assessed and brain tissue analyzed. Recurrent moderate hypoglycemia in T1D, but not Control, mice significantly impaired cognitive performance, and this was associated with hippocampal oxidative damage and inflammation despite an enhanced expression of Nrf2 and its target genes Hmox1 and Nqo1. In Nrf2−/− mice, both T1D and Hypo independently resulted in impaired cognitive performance, and this was associated with oxidative cell damage and marked inflammation. Together, these data suggest that Hypo induces an Nrf2-dependent antioxidant response in the hippocampus, which counteracts oxidative damage. However, in T1D, this neuroprotective mechanism is insufficient to prevent neuronal oxidative damage, resulting in chronic deficits in working and long-term memory.</jats:p