Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans With Prediabetes: A Randomized,Double-Blind,Placebo-Controlled,Phase 2 Trial

OBJECTIVEInsulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates body fat mass and its distribution. Obesity and type 2 diabetes are often associated with brain insulin resistance, resulting in impaired brain-derived modulation of peripheral metabolism. So far, no pharmacological treatment for brain insulin resistance has been established. Since sodium–glucose cotransporter 2 (SGLT2) inhibitors lower glucose levels and modulate energy metabolism, we hypothesized that SGLT2 inhibition may be a pharmacological approach to reverse brain insulin resistance.RESEARCH DESIGN AND METHODSIn this randomized, double-blind, placebo-controlled clinical trial, 40 patients (mean ± SD; age 60 ± 9 years; BMI 31.5 ± 3.8 kg/m²) with prediabetes were randomized to receive 25 mg empagliflozin every day or placebo. Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with intranasal administration of insulin to the brain.RESULTSWe identified a significant interaction between time and treatment in the hypothalamic response to insulin. Post hoc analyses revealed that only empagliflozin-treated patients experienced increased hypothalamic insulin responsiveness. Hypothalamic insulin action significantly mediated the empagliflozin-induced decrease in fasting glucose and liver fat.CONCLUSIONSOur results corroborate insulin resistance of the hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity, a favorable response that could contribute to the beneficial effects of SGLT2 inhibitors. Our findings position SGLT2 inhibition as the first pharmacological approach to reverse brain insulin resistance, with potential benefits for adiposity and whole-body metabolism.     

Feldionen- und Elektronenstoß-Massenspektrometrie von Polymeren und Copolymeren, 3. Copolymere des α-Methylstyrols mit Methylmethacrylat und Acrylnitril

Pyro-field ion mass spectrometry was used to study the primary fragments as well as the depolymerization behaviour of some α-methylstyrene (α-MS) copolymers. α-MS-methyl methacrylate (MMA) copolymers, when pyrolyzed, decompose mainly into the two monomers. The zip-depolymerization usually proceeds through the whole chain, disregarding the hetero-links between different monomeric units. Hetero-fragments are formed only with a small probability; still lower is the concentration of homo-dimers in the pyrolysate. Primary fragments of poly(acrylonitrile) (PAN) are acrylonitrile (AN), (AN)₂, (AN)₃, HCN, C₃H₅CN, C₄H₇CN, C₅H₉CN and higher nitriles. During pyrolysis of α-MS-AN copolymers, α-MS sequences zipdepolymerize with formation of the monomer. This retropolymerization stops at heterolinks, and fragments of the type α-MS-AN or α-MS-(AN)₂ are formed. Long AN sequences in the copolymer cause, as PAN itself, formation of AN oligomeres as well as higher alkene cyanides. Isolated AN units lead to the formation of monomeric AN.     

Cross-modal integration between odors and abstract symbols

This study aimed to investigate the cross-modal association of an “abstract symbol,” designed for representation of an odor, with its corresponding odor. First, to explore the associations of abstract symbols with odors, participants were asked to match 8 odors with 19 different abstract symbols (Experiment 1). Next, we determined whether congruent symbols could modulate olfactory perception and olfactory event-related potentials (ERPs) (Experiment 2). One of two odors (phenylethanol (PEA) or 1-butanol) was presented with one of three conditions (congruent or incongruent symbol, no-symbol), and participants were asked to rate odor intensity and pleasantness during olfactory ERP recordings. Experiment 1 demonstrated that certain abstract symbols could be paired with specific odors. In Experiment 2 congruent symbol enhanced the intensity of PEA compared to no-symbol presentation. In addition, the respective congruent symbol increased the pleasantness of PEA and the unpleasantness of 1-butanol. Finally, compared to the incongruent symbol, the congruent symbol produced significantly higher amplitudes and shorter latencies in the N1 peak of olfactory ERPs. In conclusion, our findings demonstrated that abstract symbols may be associated with specific odors.     

Left-sided CHILD syndrome caused by a nonsense mutation in the NSDHL gene

Congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome is a rare X-linked dominant malformation syndrome characterized by unilaterally distributed ichthyosiform nevi, often sharply delimited at the midline, and ipsilateral limb defects. At least two-thirds of cases demonstrate involvement of the right side. Mutations in an essential enzyme of cholesterol biosynthesis, NAD(P)H steroid dehydrogenase-like [NSDHL], have been reported in five unrelated patients with right-sided CHILD syndrome and in a sixth patient with bilaterally, symmetric nevi and mild skeletal anomalies, but not with CHILD syndrome as originally defined. Although all of the molecularly diagnosed cases with the CHILD phenotype to date have had right-sided disease, we report here a novel nonsense mutation (E151X) of NSDHL in an infant with left-sided CHILD syndrome. This result demonstrates that both right- and left-sided CHILD syndrome can be caused by mutations in the same gene.     

Application of Artificial Neural Networks in Renal Transplantation: Classification of Nephrotoxicity and Acute Cellular Rejection Episodes

Complications associated with kidney transplantation and immunosuppression can be prevented or treated effectively if diagnosed in the early stages by posttransplant monitoring. One of the major problems is diseases that occur during the first year after kidney transplantation. For this purpose, we used different classifiers to predict events of nephrotoxicity versus acute cellular rejection episodes. The classifiers were evaluated according to values of sensitivity, specificity and area under ROC curves (RCA). The classifier with better accuracy rate for nephrotoxicity achieved the value of 75.68% and RCA classifier reached the accuracy of 80.89%. These results are encouraging, with rates of accuracy and error consistent with work purpose.     

Inhibitory and excitatory intracortical circuits across the human sleep–wake cycle using paired-pulse transcranial magnetic stimulation

Studies using single-pulse transcranial magnetic stimulation (TMS) have shown that excitability of the corticospinal system is systematically reduced in natural human sleep as compared to wakefulness with significant differences between sleep stages. However, the underlying excitatory and inhibitory interactions on the corticospinal system across the sleep–wake cycle are poorly understood. Here, we specifically asked whether in the motor cortex short intracortical inhibition (SICI) and facilitation (ICF) can be elicited at all in sleep using the paired-pulse TMS protocol, and if so, how SICI and ICF vary across sleep stages. We studied 28 healthy subjects at interstimulus intervals of 3 ms (SICI) and 10 ms (ICF), respectively. Magnetic stimulation was performed over the hand area of the motor cortex using a focal coil and evoked motor potentials were recorded from the contralateral first dorsal interosseus muscle (1DI). Relevant data was obtained from 13 subjects (NREM 2: n = 7; NREM 3/4: n = 7; REM: n = 7). Results show that both SICI and ICF were present in NREM sleep. SICI was significantly enhanced in NREM 3/4 as compared to wakefulness and all other sleep stages whereas in NREM 2 neither SICI nor ICF differed from wakefulness. In REM sleep SICI was in the same range as in wakefulness, but ICF was entirely absent. These results in humans support the hypothesis derived from animal experiments which suggests that intracortical inhibitory mechanisms are involved in the control of neocortical pyramidal cells in NREM and REM sleep, but along different intraneuronal circuits. Further, our findings suggest that cortical mechanisms may additionally contribute to the inhibition of spinal motoneurones in REM sleep.