Endoscopic ultrasound-guided ethanol ablation versus surgical resection of insulinomas.

PURPOSE: Insulinoma is a rare tumor of the pancreas that can lead to hypoglycemia. To date, the standard therapy is surgical resection. After the first case report of successful endoscopic ultrasound-guided (EUS) ethanol injection 16 years ago, the need for establishing an alternative treatment method remains unchanged given the high morbidity rates of surgery and its unsuitability in some patients. MATERIALS AND METHODS: Here, we provide retrospective data from 33 insulinoma patients that were treated at our center between 2010 and 2021. Of these, 9 patients were treated with EUS-guided ethanol injection and 24 underwent pancreatic surgery. RESULTS: The ethanol group was older (ethanol: mean ± SE 67.8±11.2 years vs. surgery: 52.3±15.7, p=0.014) with a higher Charlson Comorbidity Index (3.0 (1.0;4.0) vs. 1.0 (0.0;2.0), p=0.008). The lowest glucose values were similar between groups before (ethanol: 2.09±0.17 mmol/l vs. surgery: 1.81±0.08, p=0.158) and after (4.95±0.74 vs. 5.41±0.28, p=0.581) the respective treatments. Complications occurred more frequently in the surgery group (11 % vs. 54 %, p=0.026). One patient after prior partial pancreatectomy died postoperatively. The hospitalization time was significantly shorter in the ethanol group (4.78±0.78 days vs. 19.88±4.07, p<0.001). CONCLUSION: EUS-guided ethanol injection can be similarly effective for the treatment of hyperinsulinemic hypoglycemia compared with pancreatic surgery but seems to be associated with less severe complications. This implies the need for prospective randomized trials in insulinoma patients with a low risk for malignancy.

Digital Health Applications in the Area of Mental Health.

BACKGROUND: The introduction of digital health applications (DiGA) is a fundamental innovation in Germany. In the field of mental health, numerous applications are already available whose efficacy has been tested in clinical trials. We investigated whether, and to what extent, the use of DiGA can be recommended on the basis of the available evidence. METHODS: In this scoping review, we summarize the evidence supporting the use of DiGA in the mental health field through an examination of relevant publications that were retrieved by a systematic literature search. We provide an annotated tabular listing and discuss the current advantages of, and obstacles to, the care of mentally ill patients with the aid of DiGA. RESULTS: We identified 17 DiGA for use in depression, anxiety disorders, addiction disorders, sleep disorders, stress/burnout, vaginismus, and chronic pain. These DiGA have been evaluated to date in 3 meta-analyses, 39 randomized controlled trials (RCTs), and two single-armed intervention trials. 23 of the 36 published trials were carried out with the direct participation of the manufacturers. 29 of the 39 RCTs were not blinded or contained no information regarding blinding. Active controls were used in 6 of the 39 RCTs. The reported effect sizes, with the exclusion of pre-post analyses, ranged from 0.16 to 1.79. CONCLUSION: Most of the published studies display a high risk of bias, both because of the manufacturers' participation and because of methodological deficiencies. DiGA are an increasingly important therapeutic modality in psychiatry. The available evidence indicates that treatment effects are indeed present, but prospective comparisons with established treatments are still entirely lacking.

Atrial natriuretic peptide and leptin interactions in healthy men.

Introduction: Atrial natriuretic peptide (ANP), a hormone secreted from the heart, controls cardiovascular and renal functions including arterial blood pressure and natriuresis. ANP also exerts metabolic effects in adipose tissue, liver and skeletal muscle, and interacts with the secretion of adipokines. We tested the hypothesis that ANP lowers concentrations of the anorexigenic adipokine leptin in healthy humans in vivo. Methods: Human ANP or matching placebo was infused intravenously (iv) into healthy men in a controlled clinical trial. Results: Within 135 minutes of iv ANP infusion, we observed an acute decrease in plasma leptin levels compared to controls. Free fatty acids markedly increased with ANP infusion in vivo, indicating activated lipolysis. In human SGBS adipocytes, ANP suppressed leptin release. Discussion: The study shows that the cardiac hormone ANP reduces the levels of the anorexigenic adipokine leptin in healthy humans, providing further support for ANP as a cardiomyokine in a heart - adipose tissue axis. (registered in the German Clinical Trials Register and the WHO International Clinical Trials Registry Platform was granted under DRKS00024559).

Potassium channels and the development of arousal-relevant action potential trains in primary hindbrain neurons.

Neurons in nucleus gigantocellularis (NGC) have been shown by many lines of evidence to be important for regulating generalized CNS arousal. Our previous study on mouse pups suggested that the development of NGC neurons' capability to fire action potential (AP) trains may both lead to the development of behavioral arousal and may itself depend on an increase in delayed rectifier currents. Here with whole-cell patch clamp we studied delayed rectifier currents in two stages. First, primary cultured neurons isolated from E12.5 embryonic hindbrain (HB), a dissection which contains all of NGC, were used to take advantage of studying neurons in vitro over using neurons in situ or in brain slices. HB neurons were tested with Guangxitoxin-1E and Resveratrol, two inhibitors of Kv2 channels which mediate the main bulk of delayed rectifier currents. Both inhibitors depressed delayed rectifier currents, but differentially: Resveratrol, but not Guangxitoxin-1E, reduced or abolished action potentials in AP trains. Since Resveratrol affects the Kv2.2 subtype, the development of the delayed rectifier mediated through Kv2.2 channels may lead to the development of HB neurons' capability to generate AP trains. Stage Two in this work found that electrophysiological properties of the primary HB neurons recorded are essentially the same as those of NGC neurons. Thus, from the two stages combined, we propose that currents mediated through Kv2.2 are crucial for generating AP trains which, in turn, lead to the development of mouse pup behavioral arousal.

The longevity gene mIndy (I'm Not Dead, Yet) affects blood pressure through sympathoadrenal mechanisms.

Reduced expression of the plasma membrane citrate transporter INDY (acronym I'm Not Dead, Yet) extends life span in lower organisms. Deletion of the mammalian Indy (mIndy) gene in rodents improves metabolism via mechanisms akin to caloric restriction, known to lower blood pressure (BP) by sympathoadrenal inhibition. We hypothesized that mIndy deletion attenuates sympathoadrenal support of BP. Continuous arterial BP and heart rate (HR) were reduced in mINDY-KO mice. Concomitantly, urinary catecholamine content was lower, and the decreases in BP and HR by mIndy deletion were attenuated after autonomic ganglionic blockade. Catecholamine biosynthesis pathways were reduced in mINDY-KO adrenals using unbiased microarray analysis. Citrate, the main mINDY substrate, increased catecholamine content in pheochromocytoma cells, while pharmacological inhibition of citrate uptake blunted the effect. Our data suggest that deletion of mIndy reduces sympathoadrenal support of BP and HR by attenuating catecholamine biosynthesis. Deletion of mIndy recapitulates beneficial cardiovascular and metabolic responses to caloric restriction, making it an attractive therapeutic target.

Molecular profiling of reticular gigantocellularis neurons indicates that eNOS modulates environmentally dependent levels of arousal.

Neurons of the medullary reticular nucleus gigantocellularis (NGC) and their targets have recently been a focus of research on mechanisms supporting generalized CNS arousal (GA) required for proper cognitive functions. Using the retro-TRAP method, we characterized transcripts enriched in NGC neurons which have projections to the thalamus. The unique expression and activation of the endothelial nitric oxide (eNOS) signaling pathway in these cells and their intimate connections with blood vessels indicate that these neurons exert direct neurovascular coupling. Production of nitric oxide (NO) within eNOS-positive NGC neurons increases after environmental perturbations, indicating a role for eNOS/NO in modulating environmentally appropriate levels of GA. Inhibition of NO production causes dysregulated behavioral arousal after exposure to environmental perturbation. Further, our findings suggest interpretations for associations between psychiatric disorders and mutations in the eNOS locus.

Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5).

Reducing the expression of the Indy (I'm Not Dead Yet) gene in lower organisms extends life span by mechanisms resembling caloric restriction. Similarly, deletion of the mammalian homolog, mIndy (Slc13a5), encoding for a plasma membrane tricarboxylate transporter, protects from aging- and diet-induced adiposity and insulin resistance in mice. The organ specific contribution to this phenotype is unknown. We examined the impact of selective inducible hepatic knockdown of mIndy on whole body lipid and glucose metabolism using 2'-O-methoxyethyl chimeric anti-sense oligonucleotides (ASOs) in high-fat fed rats. 4-week treatment with 2'-O-methoxyethyl chimeric ASO reduced mIndy mRNA expression by 91% (P=0.001) compared to control ASO. Besides similar body weights between both groups, mIndy-ASO treatment lead to a 74% reduction in fasting plasma insulin concentrations as well as a 35% reduction in plasma triglycerides. Moreover, hepatic triglyceride content was significantly reduced by the knockdown of mIndy, likely mediating a trend to decreased basal rates of endogenous glucose production as well as an increased suppression of hepatic glucose production by 25% during a hyperinsulinemic-euglycemic clamp. Together, these data suggest that inducible liver-selective reduction of mIndy in rats is able to ameliorate hepatic steatosis and insulin resistance, conditions occurring with high calorie diets and during aging.

Differential response of the natriuretic peptide system to weight loss and exercise in overweight or obese patients.

OBJECTIVE: Relative atrial natriuretic peptide (ANP) deficiency has been implicated in the pathogenesis of obesity-associated cardiovascular and metabolic disease. We tested the hypothesis that more than 5% body weight reduction through 6 months hypocaloric dieting alters ANP release at rest and more so during exercise in overweight or obese patients. METHODS: Venous mid-regional pro-ANP concentration was assessed at rest and after incremental exhaustive exercise testing before and after weight reduction. We also measured natriuretic peptide receptor A and C mRNA expression in subcutaneous adipose tissue to gauge both ANP responsiveness and clearance mechanisms. RESULTS: The average weight reduction of 9.1 ±â€Š3.8  kg was associated with reductions in visceral and subcutaneous abdominal fat mass, liver fat content, insulin resistance, and ambulatory blood pressure. However, mid-regional pro-ANP plasma concentrations were unchanged with weight loss (51 ±â€Š24 vs. 53 ±â€Š24  pmol/l). Exercise elicited similar acute mid-regional pro-ANP increases before and after weight loss. Adipose tissue natriuretic peptide receptor type A mRNA expression remained unchanged, whereas natriuretic peptide receptor type C mRNA decreased with weight loss. CONCLUSIONS: We conclude that physical exercise acutely increases ANP release in obese patients, whereas modest diet-induced weight loss primarily affects ANP clearance mechanisms. Interventions combining weight loss and regular physical exercise may be particularly efficacious in reversing obesity-associated relative natriuretic peptide deficiency.