International consensus on standard outcome measures for neurodevelopmental disorders: A consensus statement

Importance: The use of evidence-based standardized outcome measures is increasingly recognized as key to guiding clinical decision-making in mental health. Implementation of these measures into clinical practice has been hampered by lack of clarity on what to measure and how to do this in a reliable and standardized way. Objective: To develop a core set of outcome measures for specific neurodevelopmental disorders (NDDs), such as attention-deficit/hyperactivity disorder (ADHD), communication disorders, specific learning disorders, and motor disorders, that may be used across a range of geographic and cultural settings. Evidence Review: An international working group composed of clinical and research experts and service users (n = 27) was convened to develop a standard core set of accessible, valid, and reliable outcome measures for children and adolescents with NDDs. The working group participated in 9 video conference calls and 8 surveys between March 1, 2021, and June 30, 2022. A modified Delphi approach defined the scope, outcomes, included measures, case-mix variables, and measurement time points. After development, the NDD set was distributed to professionals and service users for open review, feedback, and external validation. Findings: The final set recommends measuring 12 outcomes across 3 key domains: (1) core symptoms related to the diagnosis; (2) impact, functioning, and quality of life; and (3) common coexisting problems. The following 14 measures should be administered at least every 6 months to monitor these outcomes: ADHD Rating Scale 5, Vanderbilt ADHD Diagnostic Rating Scale, or Swanson, Nolan, and Pelham Rating Scale IV; Affective Reactivity Index; Children’s Communication Checklist 2; Colorado Learning Disabilities Questionnaire; Children’s Sleep Habits Questionnaire; Developmental-Disability Children’s Global Assessment Scale; Developmental Coordination Disorder Questionnaire; Family Strain Index; Intelligibility in Context Scale; Vineland Adaptive Behavior Scale or Repetitive Behavior Scale–Revised and Social Responsiveness Scale; Revised Child Anxiety and Depression Scales; and Yale Global Tic Severity Scale. The external review survey was completed by 32 professionals and 40 service users. The NDD set items were endorsed by more than 70% of professionals and service users in the open review survey. Conclusions and Relevance: The NDD set covers outcomes of most concern to patients and caregivers. Use of the NDD set has the potential to improve clinical practice and research

Fatty acids prevent Hypoxia-Inducible Factor 1α signalling in type 2 diabetes

SUMMARYHypoxia-inducible factor (HIF)-1ais essential following a myocardial infarction (MI), and diabetic patients havepoorer prognosis post-MI. Could HIF-1aactivation be abnormal in the diabetic heart, and could metabolism becausing this? Diabetic hearts had decreased HIF-1aprotein following ischemia, and insulin-resistant cardio-myocytes had decreased HIF-1a-mediated signaling and adaptation to hypoxia. This was due to elevated fattyacid (FA) metabolism preventing HIF-1aprotein stabilization. FAs exerted their effect by decreasing succinateconcentrations, a HIF-1aactivator that inhibits the regulatory HIF hydroxylase enzymes. In vivo and in vitropharmacological HIF hydroxylase inhibition restored HIF-1aaccumulation and improved post-ischemic func-tional recovery in diabetes

L-Carnitine Stimulates In Vivo Carbohydrate Metabolism in the Type 1 Diabetic Heart as Demonstrated by Hyperpolarized MRI.

Funder: Danish Council for Strategic Research; Grant(s): “LIFE-DNP: hyperpolarized magnetic resonance for in vivo quantification of lipid, sugar and amino acid metabolism in lifestyle related diseases”The diabetic heart is energetically and metabolically abnormal, with increased fatty acid oxidation and decreased glucose oxidation. One factor contributing to the metabolic dysfunction in diabetes may be abnormal handling of acetyl and acyl groups by the mitochondria. L-carnitine is responsible for their transfer across the mitochondrial membrane, therefore, supplementation with L-carnitine may provide a route to improve the metabolic state of the diabetic heart. The primary aim of this study was to use hyperpolarized magnetic resonance imaging (MRI) to investigate the effects of L-carnitine supplementation on the in vivo metabolism of [1-13C]pyruvate in diabetes. Male Wistar rats were injected with either vehicle or streptozotocin (55 mg/kg) to induce type-1 diabetes. Three weeks of daily i.p. treatment with either saline or L-carnitine (3 g/kg/day) was subsequently undertaken. In vivo cardiac function and metabolism were assessed with CINE and hyperpolarized MRI, respectively. L-carnitine supplementation prevented the progression of hyperglycemia, which was observed in untreated streptozotocin injected animals and led to reductions in plasma triglyceride and ß-hydroxybutyrate concentrations. Hyperpolarized MRI revealed that L-carnitine treatment elevated pyruvate dehydrogenase flux by 3-fold in the diabetic animals, potentially through increased buffering of excess acetyl-CoA units in the mitochondria. Improved functional recovery following ischemia was also observed in the L-carnitine treated diabetic animals

Inhibition of sarcolemmal FAT/CD36 by sulfo-N-succinimidyl oleate rapidly corrects metabolism and restores function in the diabetic heart following hypoxia/reoxygenation.

AIMS: The type 2 diabetic heart oxidizes more fat and less glucose, which can impair metabolic flexibility and function. Increased sarcolemmal fatty acid translocase (FAT/CD36) imports more fatty acid into the diabetic myocardium, feeding increased fatty acid oxidation and elevated lipid deposition. Unlike other metabolic modulators that target mitochondrial fatty acid oxidation, we proposed that pharmacologically inhibiting fatty acid uptake, as the primary step in the pathway, would provide an alternative mechanism to rebalance metabolism and prevent lipid accumulation following hypoxic stress. METHODS AND RESULTS: Hearts from type 2 diabetic and control male Wistar rats were perfused in normoxia, hypoxia and reoxygenation, with the FAT/CD36 inhibitor sulfo-N-succinimidyl oleate (SSO) infused 4 min before hypoxia. SSO infusion into diabetic hearts decreased the fatty acid oxidation rate by 29% and myocardial triglyceride concentration by 48% compared with untreated diabetic hearts, restoring fatty acid metabolism to control levels following hypoxia-reoxygenation. SSO infusion increased the glycolytic rate by 46% in diabetic hearts during hypoxia, increased pyruvate dehydrogenase activity by 53% and decreased lactate efflux rate by 56% compared with untreated diabetic hearts during reoxygenation. In addition, SSO treatment of diabetic hearts increased intermediates within the second span of the Krebs cycle, namely fumarate, oxaloacetate, and the FAD total pool. The cardiac dysfunction in diabetic hearts following decreased oxygen availability was prevented by SSO-infusion prior to the hypoxic stress. Infusing SSO into diabetic hearts increased rate pressure product by 60% during hypoxia and by 32% following reoxygenation, restoring function to control levels. CONCLUSIONS: Diabetic hearts have limited metabolic flexibility and cardiac dysfunction when stressed, which can be rapidly rectified by reducing fatty acid uptake with the FAT/CD36 inhibitor, SSO. This novel therapeutic approach not only reduces fat oxidation but also lipotoxicity, by targeting the primary step in the fatty acid metabolism pathway

Increased oxidative metabolism following hypoxia in the type 2 diabetic heart, despite normal hypoxia signalling and metabolic adaptation

Hypoxia activates the hypoxia-inducible factor (HIF), promoting glycolysis and suppressing mitochondrial respiration. In the type 2 diabetic heart, glycolysis is suppressed whereas fatty acid metabolism is promoted. The diabetic heart experiences chronic hypoxia as a consequence of increased obstructive sleep apnoea and cardiovascular disease. Given the opposing metabolic effects of hypoxia and diabetes, we questioned whether diabetes affects cardiac metabolic adaptation to hypoxia. Control and type 2 diabetic rats were housed for 3 weeks in normoxia or 11% oxygen. Metabolism and function were measured in the isolated perfused heart using radiolabelled substrates. Following chronic hypoxia, both control and diabetic hearts upregulated glycolysis, lactate efflux and glycogen content and decreased fatty acid oxidation rates, with similar activation of HIF signalling pathways. However, hypoxia-induced changes were superimposed on diabetic hearts that were metabolically abnormal in normoxia, resulting in glycolytic rates 30% lower, and fatty acid oxidation 36% higher, in hypoxic diabetic hearts than hypoxic controls. Peroxisome proliferator-activated receptor α target proteins were suppressed by hypoxia, but activated by diabetes. Mitochondrial respiration in diabetic hearts was divergently activated following hypoxia compared with controls. These differences in metabolism were associated with decreased contractile recovery of the hypoxic diabetic heart following an acute hypoxic insult. In conclusion, type 2 diabetic hearts retain metabolic flexibility to adapt to hypoxia, with normal HIF signalling pathways. However, they are more dependent on oxidative metabolism following hypoxia due to abnormal normoxic metabolism, which was associated with a functional deficit in response to stress

Pharmacological manipulation of hypoxic signalling as a therapeutic target to improve metabolism and function in the type 2 diabetic heart

The work presented in this thesis investigates the metabolic and functional benefits of metabolic modulatory treatment strategies in a rodent model of type 2 diabetes. The first strategy, using a fatty acid translocase (FAT/CD36) inhibitor was investigated, in an attempt to reduce fatty acid oxidation and force glucose uptake and glycolysis. A second strategy, using prolyl hydroxylase domain (PHD) inhibitors, was investigated, to activate hypoxia inducible factor 1 alpha (HIF-1–) to stimulate glycolysis and inhibit fatty acid oxidation. Type 2 diabetes was induced using high fat feeding and low dose streptozotocin in male Wistar rats. Hearts were excised for Langendorff perfusion, to assess substrate metabolism and cardiac function in the intact contracting organ. The use of ex vivo treatment with fatty acid uptake inhibitor sulfo-N-succinimidyl oleate (SSO) was investigated using a protocol of acute hypoxia and reoxygenation. The use of in vivo treatment with the prolyl hydroxylase domain inhibitors, dimethyloxalylglycine (DMOG) and Molidustat, (BAY85-3934) was investigated using a protocol of acute low-flow ischaemia and reperfusion. Diabetic hearts showed a significant impairment in functional recovery following both hypoxia-reoxygenation and ischaemia-reperfusion, and this was associated with lower glycolytic rates, and higher fatty acid oxidation rates, compared with controls. Metabolomics analysis revealed non-uniform changes to the Krebs cycle intermediates in diabetes, with a depletion of intermediates in the first span of the cycle, and accumulation of intermediates within the second span. When perfused hearts were given SSO just four minutes prior to the onset of hypoxia, a significant improvement in functional recovery was seen in diabetic hearts, which displayed similar recovery levels to control hearts. This improvement was associated with decreased fatty acid oxidation rates, increased glycolytic rates, and decreased triacylglyceride accumulation following hypoxia. Diabetic hearts from rats given three doses of DMOG (40 mg/kg) in vivo showed significantly improved functional recovery following ischaemia-reperfusion. However, this was not accompanied by the predicted improvement in susbtrate metabolism. No significant changes were seen in glycolytic rate, instead fatty acid oxidation was found to be significantly increased in DMOG-treated diabetics. Changes in several metabolites found through metabolomics suggested the metabolic effect seen with DMOG treatment was likely due to off-target effects on other –-ketoglutaratedependent enzymes. No evidence was found for significant upregulation of HIF-1 signalling with DMOG treatment, other than increased VEGFA mRNA. Additionally, hearts from control rats that received DMOG recovered to a much lesser extent than untreated control hearts following ischaemia-reperfusion. Diabetic hearts from rats treated with five daily oral doses of Molidustat (5 mg/kg) in vivo also showed significantly improved functional recovery following ischaemia-reperfusion. This was paired with increased baseline glycolytic rates, and decreased fatty acid oxidation rates. Molidustat treatment resulted in significantly increased blood haemoglobin levels in both control and diabetic rats, suggesting stimulation of HIF-1 signalling, although no increases in HIF-1– protein or downstream target glucose transporter 1 (GLUT1, SLC2A1) were found in cardiac tissue from treated rats. This work has validated the potential of metabolic modulation as a therapeutic avenue for the treatment of the diabetic heart, harnessing substrate metabolism as a driving force for functional improvement, and to improve function under stress conditions. We have shown that metabolic modulation improves the diabetic heart’s ability to recover in acute hypoxia, and that hypoxic signalling upregulation improves recovery in ischaemia. This provides a new opportunity for the investigation and development of drugs which can selectively target metabolism in the heart to relieve the long-term maladaptation caused by diabetes, allowing it to regain its inherent metabolic flexibility, which is critical for survival under stress.</p

Chronic High-Fat Feeding Affects the Mesenchymal Cell Population Expanded From Adipose Tissue but Not Cardiac Atria

Mesenchymal stem cells offer a promising approach to the treatment of myocardial infarction and prevention of heart failure. However, in the clinic, cells will be isolated from patients who may be suffering from comorbidities such as obesity and diabetes, which are known to adversely affect progenitor cells. Here we determined the effect of a high-fat diet (HFD) on mesenchymal stem cells from cardiac and adipose tissues. Mice were fed a HFD for 4 months, after which cardiosphere-derived cells (CDCs) were cultured from atrial tissue and adipose-derived mesenchymal cells (ADMSCs) were isolated from epididymal fat depots. HFD raised body weight, fasted plasma glucose, lactate, and insulin. Ventricle and liver tissue of HFD-fed mice showed protein changes associated with an early type 2 diabetic phenotype. At early passages, more ADMSCs were obtained from HFD-fed mice than from chow-fed mice, whereas CDC number was not affected by HFD. Migratory and clonogenic capacity and release of vascular endothelial growth factor did not differ between cells from HFD- and chow-fed animals. CDCs from chow-fed and HFD-fed mice showed no differences in surface marker expression, whereas ADMSCs from HFD-fed mice contained more cells positive for CD105, DDR2, and CD45, suggesting a high component of endothelial, fibroblast, and hematopoietic cells. Both Noggin and transforming growth factor \u3b2-supplemented medium induced an early stage of differentiation in CDCs toward the cardiomyocyte phenotype. Thus, although chronic high-fat feeding increased the number of fibroblasts and hematopoietic cells within the ADMSC population, it left cardiac progenitor cells largely unaffected

Increased oxidative metabolism following hypoxia in the type 2 diabetic heart, despite normal hypoxia signalling and metabolic adaptation

Hypoxia activates the hypoxia-inducible factor (HIF), promoting glycolysis and suppressing mitochondrial respiration. In the type 2 diabetic heart, glycolysis is suppressed whereas fatty acid metabolism is promoted. The diabetic heart experiences chronic hypoxia as a consequence of increased obstructive sleep apnoea and cardiovascular disease. Given the opposing metabolic effects of hypoxia and diabetes, we questioned whether diabetes affects cardiac metabolic adaptation to hypoxia. Control and type 2 diabetic rats were housed for 3 weeks in normoxia or 11% oxygen. Metabolism and function were measured in the isolated perfused heart using radiolabelled substrates. Following chronic hypoxia, both control and diabetic hearts upregulated glycolysis, lactate efflux and glycogen content and decreased fatty acid oxidation rates, with similar activation of HIF signalling pathways. However, hypoxia-induced changes were superimposed on diabetic hearts that were metabolically abnormal in normoxia, resulting in glycolytic rates 30% lower, and fatty acid oxidation 36% higher, in hypoxic diabetic hearts than hypoxic controls. Peroxisome proliferator-activated receptor α target proteins were suppressed by hypoxia, but activated by diabetes. Mitochondrial respiration in diabetic hearts was divergently activated following hypoxia compared with controls. These differences in metabolism were associated with decreased contractile recovery of the hypoxic diabetic heart following an acute hypoxic insult. In conclusion, type 2 diabetic hearts retain metabolic flexibility to adapt to hypoxia, with normal HIF signalling pathways. However, they are more dependent on oxidative metabolism following hypoxia due to abnormal normoxic metabolism, which was associated with a functional deficit in response to stress