Publications by authors named "Robert Wagner"

213 Publications

Pathophysiology-based subphenotyping of individuals at elevated risk for type 2 diabetes.

Nat Med 2021 01 4;27(1):49-57. Epub 2021 Jan 4.

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.

The state of intermediate hyperglycemia is indicative of elevated risk of developing type 2 diabetes. However, the current definition of prediabetes neither reflects subphenotypes of pathophysiology of type 2 diabetes nor is predictive of future metabolic trajectories. We used partitioning on variables derived from oral glucose tolerance tests, MRI-measured body fat distribution, liver fat content and genetic risk in a cohort of extensively phenotyped individuals who are at increased risk for type 2 diabetes to identify six distinct clusters of subphenotypes. Three of the identified subphenotypes have increased glycemia (clusters 3, 5 and 6), but only individuals in clusters 5 and 3 have imminent diabetes risks. By contrast, those in cluster 6 have moderate risk of type 2 diabetes, but an increased risk of kidney disease and all-cause mortality. Findings were replicated in an independent cohort using simple anthropomorphic and glycemic constructs. This proof-of-concept study demonstrates that pathophysiological heterogeneity exists before diagnosis of type 2 diabetes and highlights a group of individuals who have an increased risk of complications without rapid progression to overt type 2 diabetes.
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http://dx.doi.org/10.1038/s41591-020-1116-9DOI Listing
January 2021

Cowpea Mosaic Virus Nanoparticle Enhancement of Hypofractionated Radiation in a B16 Murine Melanoma Model.

Front Oncol 2020 16;10:594614. Epub 2020 Dec 16.

Geisel School of Medicine, Dartmouth College, Hanover, NH, United States.

Introduction: Virus and virus-like nanoparticles (VNPs) have been used for a variety of preclinical treatments, including anti-cancer vaccination. The Cowpea mosaic virus (CPMV) is a VNP that has shown the ability to stimulate an anti-cancer immune response. The hypothesis of this study is two-fold: that intratumoral CPMV enhances the immunogenetic and cytotoxic response of hypofractionated radiation (15 Gy or 3 x 8 Gy), and that the effect differs between fraction regimens in the murine B16 flank melanoma model.

Methods: CPMV nanoparticles were delivered intratumorally, 100 μg/tumor to B16 murine melanoma flank tumors alone, and in combination with either 15 Gy or 3 x 8 Gy (3 consecutive days). Tumors were assessed for immune and cytotoxic gene and protein expression, and cytotoxic T cell infiltration 4 days post treatment. Treatment based tumor control was assessed by a 3-fold tumor growth assay.

Results: Both CPMV and radiation alone demonstrated the activation of a number of important immune and cytotoxic genes including natural killer cell and T cell mediated cytotoxicity pathways. However, the combination treatment activated greater expression than either treatment alone. CPMV combined with a single dose of 15 Gy demonstrated greater immune and cytotoxic gene expression, protein expression, CD8+ T cell infiltration activity, and greater tumor growth delay compared to 3 x 8 Gy with CPMV.

Conclusion: CPMV presents a unique and promising hypofractionated radiation adjuvant that leads to increased anti-tumor cytotoxic and immune signaling, especially with respect to the immune mediated cytotoxicity, immune signaling, and toll-like receptor signaling pathways. This improvement was greater with a single dose than with a fractionated dose.
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http://dx.doi.org/10.3389/fonc.2020.594614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773968PMC
December 2020

Reduced insulin clearance is linked to subclinical atherosclerosis in individuals at risk for type 2 diabetes mellitus.

Sci Rep 2020 12 31;10(1):22453. Epub 2020 Dec 31.

Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.

Hyperglycemia and insulin resistance contribute to vascular damage and are regulated by different pathophysiological processes. The aim of the study was to systematically investigate the relative contributions of multiple fasting state- and oral glucose tolerance test (oGTT)-derived glycemic traits to carotid intima-media thickness (cIMT), a surrogate parameter of subclinical atherosclerosis, in individuals with increased risk for type 2 diabetes mellitus (T2D). 667 volunteers (417 women and 250 men, mean age 44.1 years), who were free of cardiovascular disease (CVD), were included in this cross-sectional study. Glucose tolerance, insulin sensitivity, insulin secretion and insulin clearance were assessed by frequently sampled 75 g oGTT. CIMT was measured by high-resolution ultrasound. Insulin clearance was associated with cIMT in univariate analysis (ß = - 0.17, p < 0.0001) and in a stepwise regression analysis on 15 variables possibly affecting cIMT, age (r = 0.3923, p < 0.0001), insulin clearance (r = 0.4564, p < 0.0001), systolic blood pressure (r = 0.4733, p < 0.0001), body mass index (BMI) (r = 0.4804, p = 0.002), gender (r = 0.4831, p = 0.013), and fasting insulin clearance (r = 0.4857, p = 0.030) turned out to be significant determinants of cIMT. In a cross-validated model resulting from this analysis, insulin clearance was found to be an independent determinant of cIMT (ß = - 0.16, p < 0.0001) even after adjusting for traditional CVD risk factors. Reduced insulin clearance may be an early marker of damage on the vasculature, independent of classical CVD risk factors. Reduced insulin clearance should be considered with regard to vascular insulin resistance.
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http://dx.doi.org/10.1038/s41598-020-80581-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775444PMC
December 2020

Elevated Circulating Glutamate Is Associated With Subclinical Atherosclerosis Independently of Established Risk Markers: A Cross-Sectional Study.

J Clin Endocrinol Metab 2021 Jan;106(2):e982-e989

Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich, Tübingen, Germany.

Objective: Elevated plasma glutamate levels are associated with an increased risk of cardiovascular disease (CVD). Because plasma glutamate levels are also strongly associated with visceral adiposity, nonalcoholic fatty liver disease, insulin resistance, and high circulating levels of branched-chain amino acids (BCAAs), it is unknown to what extent elevated circulating glutamate is an independent marker of an increased risk of atherosclerosis.

Methods: Plasma levels of glutamate and BCAAs were measured in 102 individuals who were precisely phenotyped for body fat mass and distribution (magnetic resonance [MR] tomography), liver fat content (1H-MR spectroscopy), insulin sensitivity (oral glucose tolerance test and hyperinsulinemic, euglycemic clamp [N = 57]), and carotid intima media thickness (cIMT).

Results: Plasma glutamate levels, adjusted for age, sex, body fat mass, and visceral fat mass, correlated positively with liver fat content and cIMT (all std β ≥ .22, all P ≤ .023) and negatively with insulin sensitivity (std β ≤ -.31, P ≤ .002). Glutamate levels also were associated with cIMT, independently of additional adjustment for liver fat content, insulin sensitivity and BCAAs levels (std β ≥ .24, P ≤ .02). Furthermore, an independent positive association of glutamate and interleukin-6 (IL-6) levels was observed (N = 50; std β = .39, P = .03). Although glutamate, adjusted for age, sex, body fat mass, and visceral fat mass, also correlated positively with cIMT in this subgroup (std β = .31, P = .02), after additional adjustment for the parameters liver fat content, insulin sensitivity, BCAAs, or IL-6 levels, adjustment for IL-6 most strongly attenuated this relationship (std β = .28, P = .05).

Conclusions: Elevated plasma glutamate levels are associated with increased cIMT, independently of established CVD risk factors, and this relationship may in part be explained by IL-6-associated subclinical inflammation.
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http://dx.doi.org/10.1210/clinem/dgaa898DOI Listing
January 2021

No modulation of postprandial metabolism by transcutaneous auricular vagus nerve stimulation: a cross-over study in 15 healthy men.

Sci Rep 2020 11 24;10(1):20466. Epub 2020 Nov 24.

Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.

Experimental evidence suggests a crucial role of the autonomic nervous system in whole body metabolism with major regulatory effects of the parasympathetic branch in postprandial adaptation. However, the relative contribution of this mechanism is still not fully clear in humans. We therefore compared the effects of transcutaneous auricular vagus nerve stimulation (taVNS, Cerbomed Nemos) with sham stimulation during an oral glucose tolerance test in a randomized, single-blind, cross-over design in 15 healthy lean men. Stimulation was performed for 150 min, 30 min before and during the entire oral glucose tolerance test with stimulation cycles of 30 s of on-phase and 30 s of off-phase and a 25 Hz impulse. Heart rate variability and plasma catecholamine levels were assessed as proxies of autonomic tone in the periphery. Neither analyzed heart rate variability parameters nor plasma catecholamine levels were significantly different between the two conditions. Plasma glucose, insulin sensitivity and insulin secretion were also comparable between conditions. Thus, the applied taVNS device or protocol was unable to achieve significant effects on autonomic innervation in peripheral organs. Accordingly, glucose metabolism remained unaltered. Therefore, alternative approaches are necessary to investigate the importance of the autonomic nervous system in postprandial human metabolism.
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http://dx.doi.org/10.1038/s41598-020-77430-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686306PMC
November 2020

Insulin sensitivity predicts cognitive decline in individuals with prediabetes.

BMJ Open Diabetes Res Care 2020 11;8(2)

Department of Internal Medicine IV, University Hospital of Tübingen, Tübingen, Germany

Introduction: Epidemiological studies indicate an association between type 2 diabetes and cognitive dysfunction that appear to start already in the prediabetic state. Although cross-sectional studies have linked insulin resistance to impaired cognition, the potential predictive value of insulin resistance has not yet been sufficiently studied longitudinally without confounding by overt diabetes (and its pharmacological treatment).

Research Design And Methods: We investigated longitudinal data from participants of the 'Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration' Study. Subjects underwent a neurocognitive assessment battery (CERAD Plus battery; Consortium to Establish a Registry for Alzheimer's Disease) at baseline and followed every 2 years (median follow-up 4.0 Q1-3: 2.2-4.3 years). Subjects within a pre-diabetic glycated hemoglobin range of 5.6%-6.5% underwent 5-point 75 g oral glucose tolerance tests (OGTTs) with assessment of insulin sensitivity and insulin secretion (n=175). Subjects with newly diagnosed diabetes mellitus or with major depressivity (Beck Depression Inventory >20) were excluded (n=15). Data were analyzed by mixed models using sex, age and glycemic trait as fixed effects. Subject and time since first measurement were used as random effects.

Results: Insulin sensitivity was positively associated with the CERAD sum score (higher is better) in a time-dependent manner (p=0.0057). This result is mainly driven by a steeper decrease in the memory domain associated with lower insulin sensitivity (p=0.029). The interaction between age and insulin sensitivity was independent of glycemia (p=0.02). There was also no association between insulin secretion and cognition.

Conclusions: Insulin resistance rather than sole elevation of blood glucose predicts cognitive decline, specifically in the memory domain, in persons with prediabetes. Treatments of diabetes that improve insulin sensitivity might therefore have the potential to postpone or even prevent cognitive decline in patients with diabetes.
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http://dx.doi.org/10.1136/bmjdrc-2020-001741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674089PMC
November 2020

A porcine model of phenylketonuria generated by CRISPR/Cas9 genome editing.

JCI Insight 2020 Oct 15;5(20). Epub 2020 Oct 15.

Division of Medical Genetics, Department of Pediatrics, University of Pittsburgh School of Medicine, and Universityof Pittsburgh Medical Center (UPMC) Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Phenylalanine hydroxylase-deficient (PAH-deficient) phenylketonuria (PKU) results in systemic hyperphenylalaninemia, leading to neurotoxicity with severe developmental disabilities. Dietary phenylalanine (Phe) restriction prevents the most deleterious effects of hyperphenylalaninemia, but adherence to diet is poor in adult and adolescent patients, resulting in characteristic neurobehavioral phenotypes. Thus, an urgent need exists for new treatments. Additionally, rodent models of PKU do not adequately reflect neurocognitive phenotypes, and thus there is a need for improved animal models. To this end, we have developed PAH-null pigs. After selection of optimal CRISPR/Cas9 genome-editing reagents by using an in vitro cell model, zygote injection of 2 sgRNAs and Cas9 mRNA demonstrated deletions in preimplantation embryos, with embryo transfer to a surrogate leading to 2 founder animals. One pig was heterozygous for a PAH exon 6 deletion allele, while the other was compound heterozygous for deletions of exon 6 and of exons 6-7. The affected pig exhibited hyperphenylalaninemia (2000-5000 μM) that was treatable by dietary Phe restriction, consistent with classical PKU, along with juvenile growth retardation, hypopigmentation, ventriculomegaly, and decreased brain gray matter volume. In conclusion, we have established a large-animal preclinical model of PKU to investigate pathophysiology and to assess new therapeutic interventions.
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http://dx.doi.org/10.1172/jci.insight.141523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605535PMC
October 2020

Characterization of Hormone-Dependent Pathways in Six Human Prostate-Cancer Cell Lines: A Gene-Expression Study.

Genes (Basel) 2020 Oct 7;11(10). Epub 2020 Oct 7.

Department of Internal Medicine IV, Division of Diabetology, Endocrinology, and Nephrology, University Hospital Tübingen, 72076 Tübingen, Germany.

Prostate cancer (PCa), the most incident cancer in men, is tightly regulated by endocrine signals. A number of different PCa cell lines are commonly used for in vitro experiments, but these are of diverse origin, and have very different cell-proliferation rates and hormone-response capacities. By analyzing the gene-expression pattern of main hormone pathways, we systematically compared six PCa cell lines and parental primary cells. We compared these cell lines (i) with each other and (ii) with PCa tissue samples from 11 patients. We found major differences in the gene-expression levels of androgen, insulin, estrogen, and oxysterol signaling between PCa tissue and cell lines, and between different cell lines. Our systematic characterization gives researchers a solid basis to choose the appropriate PCa cell model for the hormone pathway of interest.
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http://dx.doi.org/10.3390/genes11101174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599530PMC
October 2020

Considering Insulin Secretory Capacity as Measured by a Fasting C-Peptide/Glucose Ratio in Selecting Glucose-Lowering Medications.

Exp Clin Endocrinol Diabetes 2020 Sep 18. Epub 2020 Sep 18.

German Center for Diabetes Research (DZD), Neuherberg.

Type 2 diabetes mellitus is a heterogeneous disease. Recently introduced new subclassifications promise more efficacious, tailored treatments which could complement current guidelines. In the differentiation of the new diabetes subphenotypes, assessment of insulin secretion is one of the essential components. Based on a large number of insulin secretion measurements, we propose fasting C-peptide/glucose ratio (CGR) as an adequate and practicable estimate of insulin secretion. CGR discriminates insulin deficiency from insulin hypersecretion. We suggest using insulin secretion, determined from CGR, as an essential input for therapeutic decisions at the beginning or modification of diabetes treatment. Furthermore, we propose 3 practical steps to guide decisions in the subtype-specific therapy of diabetes mellitus. The first step consists of detecting insulin deficiency indicated by a low CGR with the need for immediate insulin therapy. The second step is related to high CGR and aims at lowering cardiovascular risk associated with diabetes. The third step is the consideration of a de-escalation of glucose-lowering therapy in individuals with mild diabetes subphenotypes.
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http://dx.doi.org/10.1055/a-1242-9809DOI Listing
September 2020

The TUDID Study - Background and Design of a Prospective Cohort.

Exp Clin Endocrinol Diabetes 2020 Sep 10. Epub 2020 Sep 10.

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.

Prevalence of both type 1 and type 2 diabetes mellitus is growing worldwide and one major cause for morbidity and mortality. However, not every patient develops diabetes-related complications, but causes for the individual susceptibility are still not fully understood. As a platform to address this, we initiated the TUDID (TUebingen DIabetes Database) study, a prospective, monocentric, observational study that includes adults with diabetes mellitus who are treated in the inpatient clinic of a University Hospital in southern Germany. Besides a thorough clinical examination and extensive laboratory tests (with integrated biobanking), major study focuses are the kidneys, the eyes, the vasculature as well as cognition and mood where standardized investigations for early stages for diabetes complications are performed. Analyses of the data generated by this precise characterization of diabetes-related complications will contribute to our understanding of the development and course of such complications, and thus facilitate the implementation of tailored treatment options that can reduce the risk and severity of diabetes-related complications.
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http://dx.doi.org/10.1055/a-1221-9618DOI Listing
September 2020

mNP hyperthermia and hypofractionated radiation activate similar immunogenetic and cytotoxic pathways.

Int J Hyperthermia 2020 ;37(1):929-937

Thayer School of Engineering, Dartmouth College, Hanover, NH, USA.

Objective: The goal of this study is to better understand the immunogenetic expression and related cytotoxic responses of moderate but clinically relevant doses of hypofractionated radiation (1x15 Gy and 3x8 Gy) and magnetic nanoparticle hyperthermia (mNPH, CEM43 30).

Methods: Genetic, protein, immunopathology and tumor growth delay assessments were used to determine the immune and cytotoxic responses following radiation and mNPH alone and in combination. Although the thermal dose used, 43 C°/30 min (CEM43 30), typically results in modest independent cytotoxicity, it has shown the ability to stimulate an immune response and enhance other cancer treatments. The radiation doses studied (15 Gy and 3x8 Gy) are commonly used in preclinical research and are effective in selected stereotactic and palliative treatment settings, however they are not commonly used as first-line primary tumor treatment regimens.

Results: Our RNA-based genetic results suggest that while many of the cytotoxic and immune gene and protein pathways for radiation and hyperthermia are similar, radiation, at the doses used, results in a more consistent and expansive anti-cancer immune/cytotoxic expression profile. These results were supported by immunohistochemistry based cytotoxic T-cell tumor infiltration and tumor growth delay studies. When used together radiation and hyperthermia led to greater immune and cytotoxic activity than either modality alone.

Conclusion: This study clearly shows that modest, but commonly used hypofractionated radiation and hyperthermia doses share many important immune and cytotoxic pathways and that combining the treatments, as compared to either treatment alone, results in genetic and biological anti-cancer benefits.
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http://dx.doi.org/10.1080/02656736.2020.1802070DOI Listing
January 2020

Pancreatic Steatosis Associates With Impaired Insulin Secretion in Genetically Predisposed Individuals.

J Clin Endocrinol Metab 2020 11;105(11)

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.

Context: Pancreatic steatosis leading to beta-cell failure might be involved in type 2 diabetes (T2D) pathogenesis.

Objective: We hypothesized that the genetic background modulates the effect of pancreatic fat on beta-cell function and investigated genotype × pancreatic fat interactions on insulin secretion.

Design: Two observational studies.

Setting: University hospital.

Patients Or Participants: A total of 360 nondiabetic individuals with elevated risk for T2D (Tuebingen Family Study [TUEF]), and 64 patients undergoing pancreatectomy (Pancreas Biobank [PB], HbA1c <9%, no insulin therapy).

Main Outcome Measures: Insulin secretion calculated from 5-point oral glucose tolerance test (TUEF) and fasting blood collection before surgery (PB). A genome-wide polygenic score for T2D was computed from 484,788 genotyped variants. The interaction of magnetic resonance imaging-measured and histologically quantified pancreatic fat with the polygenic score was investigated. Partitioned risk scores using genome-wide significant variants were also computed to gain insight into potential mechanisms.

Results: Pancreatic steatosis interacted with genome-wide polygenic score on insulin secretion (P = 0.003), which was similar in the replication cohort with histological measurements (P = 0.03). There was a negative association between pancreatic fat and insulin secretion in participants with high genetic risk, whereas individuals with low genetic risk showed a positive correlation between pancreatic fat and insulin secretion. Consistent interactions were found with insulin resistance-specific and a liver/lipid-specific polygenic scores.

Conclusions: The associations suggest that pancreatic steatosis only impairs beta-cell function in subjects at high genetic risk for diabetes. Genetically determined insulin resistance specifically renders pancreatic fat deleterious for insulin secretion.
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http://dx.doi.org/10.1210/clinem/dgaa435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497818PMC
November 2020

Normalized Indices Derived from Visceral Adipose Mass Assessed by Magnetic Resonance Imaging and Their Correlation with Markers for Insulin Resistance and Prediabetes.

Nutrients 2020 Jul 11;12(7). Epub 2020 Jul 11.

Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London W1W 6UW, UK.

Visceral adipose tissue (VAT) plays an important role in the pathogenesis of insulin resistance (IR), prediabetes and type 2 diabetes. However, VAT volume alone might not be the best marker for insulin resistance and prediabetes or diabetes, as a given VAT volume may impact differently on these metabolic traits based on body height, gender, age and ethnicity. In a cohort of 1295 subjects from the Tübingen Diabetes Family Study (TDFS) and in 9978 subjects from the UK Biobank (UKBB) undergoing magnetic resonance imaging for quantification of VAT volume, total adipose tissue (TAT) in the TDFS, total abdominal adipose tissue (TAAT) in the UKBB, and total lean tissue (TLT), VAT volume and several VAT-indices were investigated for their relationships with insulin resistance and glycemic traits. VAT-related indices were calculated by correcting for body height (VAT/m:VAT/body height; VAT/m:VAT/(body height), and VAT/m:VAT/(body height)), TAT (%VAT), TLT (VAT/TLT) and weight (VAT/WEI), with closest equivalents used within the UKBB dataset. Prognostic values of VAT and VAT-related indices for insulin sensitivity, HbA1c levels and prediabetes/diabetes were analyzed for males and females. Males had higher VAT volume and VAT-related indices than females in both cohorts ( < 0.0001) and VAT volume has shown to be a stronger determinant for insulin sensitivity than anthropometric variables. Among the parameters uncorrected VAT and derived indices, VAT/m most strongly correlated negatively with insulin sensitivity and positively with HbA1c levels and prediabetes/diabetes in the TDFS (R = 0.375/0.305 for females/males for insulin sensitivity, 0.178/0.148 for HbA1c levels vs., e.g., 0..355/0.293 and 0.144/0.133 for VAT, respectively) and positively with HbA1c (R = 0.046/0.042) in the UKBB for females and males. Furthermore, VAT/m was found to be a significantly better determinant of insulin resistance or prediabetes than uncorrected VAT volume ( < 0.001/0.019 for females/males regarding insulin sensitivity, < 0.001/< 0.001 for females/males regarding HbA1c).Evaluation of several indices derived from VAT volume identified VAT/m to correlate most strongly with insulin sensitivity and glucose metabolism. Thus, VAT/m appears to provide better indications of metabolic characteristics (insulin sensitivity and pre-diabetes/diabetes) than VAT volume alone.
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http://dx.doi.org/10.3390/nu12072064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400828PMC
July 2020

A reply to "A modern approach to Advanced Non-Small Cell Lung Cancer: Minimally-invasive procedures and in parallel multiple DNA/RNA high-throughput sequencing".

Lung Cancer 2020 08 3;146:389-390. Epub 2020 Jul 3.

Department of Medical Oncology and Pneumology, Eberhard Karls University, Tuebingen, Germany; Division of Pulmonology, Cantonal Hospital Winterthur, Zurich, Switzerland.

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http://dx.doi.org/10.1016/j.lungcan.2020.07.004DOI Listing
August 2020

Physiologic effects and functional outcome after treatment of dysfunctional right ventricular outflow tract in congenital heart disease using a two-stage intervention.

Int J Cardiol 2020 Dec 25;321:69-74. Epub 2020 Jun 25.

Heart Center Leipzig at University Leipzig, Department of Internal Medicine/Cardiology, Germany. Electronic address:

Background: Pathophysiological differences in relief of pulmonary stenosis (PS) as opposed to pulmonary regurgitation (PR) by percutaneous pulmonary valve implantation (PPVI) remain elusive, but might impact current assessment of procedural success and ultimately indications.

Methods: Invasive pressure measurements, cardiac magnetic resonance imaging and cardiopulmonary exercise testing were performed before pre-stenting (BMS), after BMS and after PPVI in patients with either PS or PR.

Results: In PS (n = 14), BMS reduced the right ventricular (RV) to systemic pressure ratio (0.8 ± 0.2 vs. 0.4 ± 0.1%; p < .01), improved RF EF (53 ± 14 vs. 59 ± 12%; p = .01) but introduced free PR (PR fraction post 39 ± 12%; p < .01) with no changes in effective RV stroke volume (SV). PPVI eliminated PR (PR fraction 5 ± 3%; p < .01) and improved effective RV SV (p < .01) with no changes in RV EF (p = .47). Peak VO2 improved significantly after BMS, with no changes following PPVI (26 ± 9 vs. 30 ± 11 vs. 31 ± 10 ml/kg*min). In PR (n = 14), BMS exaggerated PR (PR fraction post 47 ± 10) with reduction in effective RV SV (pre 43 ± 9 vs. post 38 ± 8 ml/m; p = .01), which improved after PPVI (post PPVI 49 ± 9 ml/m; p < .01), secondary to elimination of PR (PR fraction 5 ± 4%; p < .01). RV EF (pre 53 ± 11 vs. post 53 ± 9 vs. post PPVI 50 ± 9%) and Peak VO2 (pre 22 ± 7 vs. post 21 ± 7 vs. post PPVI 23 ± 7 ml/kg*min) remained unchanged.

Conclusions: Exercise capacity in patients with right ventricular outflow tract dysfunction is primarily afterload-dependent.
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http://dx.doi.org/10.1016/j.ijcard.2020.06.026DOI Listing
December 2020

Study of Modified Area of Polymer Samples Exposed to a He Atmospheric Pressure Plasma Jet Using Different Treatment Conditions.

Polymers (Basel) 2020 May 1;12(5). Epub 2020 May 1.

Faculty of Engineering (FEG)-São Paulo State University (UNESP), Guaratinguetá (SP) 12516-410, Brazil.

In the last decade atmospheric pressure plasma jets (APPJs) have been routinely employed for surface processing of polymers due to their capability of generating very reactive chemistry at near-ambient temperature conditions. Usually, the plasma jet modification effect spans over a limited area (typically a few cm²), therefore, for industrial applications, where treatment of large and irregular surfaces is needed, jet and/or sample manipulations are required. More specifically, for treating hollow objects, like pipes and containers, the plasma jet must be introduced inside of them. In this case, a normal jet incidence to treated surface is difficult if not impossible to maintain. In this paper, a plasma jet produced at the end of a long flexible plastic tube was used to treat polyethylene terephthalate (PET) samples with different incidence angles and using different process parameters. Decreasing the angle formed between the plasma plume and the substrate leads to increase in the modified area as detected by surface wettability analysis. The same trend was confirmed by the distribution of reactive oxygen species (ROS), expanding on starch-iodine-agar plates, where a greater area was covered when the APPJ was tilted. Additionally, UV-VUV irradiation profiles obtained from the plasma jet spreading on the surface confirms such behavior.
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http://dx.doi.org/10.3390/polym12051028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284806PMC
May 2020

[Reclassification of diabetes mellitus based on pathophysiologic and genetic features].

Dtsch Med Wochenschr 2020 05 29;145(9):601-608. Epub 2020 Apr 29.

Diabetes mellitus has been defined by hyperglycemia, but in addition to hyperglycemia, there are several other factors determining the clinical course and complications. We review the current classification of diabetes and recent attempts to identify new subphenotypes. Notably, there are anthropometry-pathophysiology based and genome-based subphenotyping approaches. They aim to improve the prediction of disease course and complications and could pave the way for precision medicine in the therapy of diabetes.
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http://dx.doi.org/10.1055/a-0983-0349DOI Listing
May 2020

Brain insulin sensitivity is linked to adiposity and body fat distribution.

Nat Commun 2020 04 15;11(1):1841. Epub 2020 Apr 15.

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.

Brain insulin action regulates eating behavior and energy fluxes throughout the body. However, numerous people are brain insulin resistant. How brain insulin responsiveness affects long-term weight and body fat composition in humans is still unknown. Here we show that high brain insulin sensitivity before lifestyle intervention associates with a more pronounced reduction in total and visceral fat during the program. High brain insulin sensitivity is also associated with less regain of fat mass during a nine year follow-up. Cross-sectionally, strong insulin responsiveness of the hypothalamus associates with less visceral fat, while subcutaneous fat is unrelated. Our results demonstrate that high brain insulin sensitivity is linked to weight loss during lifestyle intervention and associates with a favorable body fat distribution. Since visceral fat is strongly linked to diabetes, cardiovascular risk and cancer, these findings have implications beyond metabolic diseases and indicate the necessity of strategies to resolve brain insulin resistance.
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http://dx.doi.org/10.1038/s41467-020-15686-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160151PMC
April 2020

Cryobiopsy increases the EGFR detection rate in non-small cell lung cancer.

Lung Cancer 2020 03 7;141:56-63. Epub 2020 Jan 7.

Department of Medical Oncology and Pneumology, Eberhard Karls University, Tuebingen, Germany.

Objectives: Detection of activating epidermal growth factor receptor (EGFR) mutation is crucial for individualized treatment of advanced non-small-cell lung cancer (NSCLC). However little is known about how biopsy technique affects the detection rate of EGFR mutations. This retrospective, single center study evaluated the detection rate of EGFR mutations in tissue obtained by bronchoscopic cryobiopsy and compared this to other standard tissue sampling techniques.

Materials And Methods: We retrospectively analyzed 414 patients with histologically confirmed NSCLC and known EGFR mutation status between 3/2008-7/2014. Tumor specimens obtained by tissue preserving bronchoscopic cryobiopsy were compared to those obtained by other techniques.

Results And Conclusion: Analysis of bronchoscopic cryobiopsy tissue detected 29 activating EGFR mutations in 27 (21.6 %) out of 125 patients, while analysis of tissue obtained by non-cryobiopsy techniques (bronchoscopic forceps biopsies, fine needle aspiration, imaging guided transthoracical and surgical procedures) detected 42 EGFR mutations in 40 (13.8 %) out of 298 patients (p < 0.05). Cryobiopsy increased detection rate of EGFR mutations in central tumors compared with forceps biopsy (19.6 % versus 6.5 %, p < 0.05), while an insignificant trend was detected also for peripheral tumors (33.3 % versus 26.9 %). Bronchosopic cryobiopsy increases the detection rate of activating EGFR mutations in NSCLC in comparison to other tissue sampling techniques. This will help to optimize individualized treatment of patients with advanced tumors. Because of the retrospective nature of this analysis, a prospective trial is mandatory for final assessment.
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http://dx.doi.org/10.1016/j.lungcan.2019.12.008DOI Listing
March 2020

Glucose homeostasis is regulated by pancreatic β-cell cilia via endosomal EphA-processing.

Nat Commun 2019 12 12;10(1):5686. Epub 2019 Dec 12.

Institute for Diabetes and Regeneration Research, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.

Diabetes mellitus affects one in eleven adults worldwide. Most suffer from Type 2 Diabetes which features elevated blood glucose levels and an inability to adequately secrete or respond to insulin. Insulin producing β-cells have primary cilia which are implicated in the regulation of glucose metabolism, insulin signaling and secretion. To better understand how β-cell cilia affect glucose handling, we ablate cilia from mature β-cells by deleting key cilia component Ift88. Here we report that glucose homeostasis and insulin secretion deteriorate over 12 weeks post-induction. Cilia/basal body components are required to suppress spontaneous auto-activation of EphA3 and hyper-phosphorylation of EphA receptors inhibits insulin secretion. In β-cells, loss of cilia/basal body function leads to polarity defects and epithelial-to-mesenchymal transition. Defective insulin secretion from IFT88-depleted human islets and elevated pEPHA3 in islets from diabetic donors both point to a role for cilia/basal body proteins in human glucose homeostasis.
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http://dx.doi.org/10.1038/s41467-019-12953-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908661PMC
December 2019

Plasma Levels of Myocardial MicroRNA-133a Increase by Intraoperative Cytokine Hemoadsorption in the Complex Cardiovascular Operation.

J Clin Med Res 2019 Dec 24;11(12):789-797. Epub 2019 Nov 24.

Department of Cardiovascular Surgery, Centre for Cardiovascular and Transplant Surgery (CKTCH), Pekarska 53, Brno, Czech Republic.

Background: Complex cardiovascular procedures may initiate a systemic inflammatory response syndrome (SIRS) with a massive cytokine release, which is involved in postoperative myocardial injury. Intraoperative cytokine hemoadsorption (HA) mitigates the inflammatory response. Micro ribonucleic acids (miRNAs) are emerging as a marker of myocardial injury.

Methods: This study evaluated if intraoperative cytokine reduction by HA modulates SIRS and affects myocardial injury as measured by miRNA-126, 223 and miRNA-1, 133a, respectively. Twenty-eight patients were assigned into HA (n = 15) and control (C) (n = 13) groups. HA was performed by integrating CytoSorb™ into the extracorporeal circuit.

Results: MiRNA-133a plasma levels were increased postoperatively in both groups but were much higher in the HA group than in the C group at 3 h (P = 0.037) and 18 h (P = 0.017) after reperfusion. MiRNA-1 and miRNA-223 plasma levels were significantly increased postoperatively, but did not differ between groups. The vascular miRNA-126 was not affected.

Conclusion: Intraoperative cytokine HA in cardiovascular operations increased the plasma levels of miRNA-133a, suggesting higher myocardial injury.
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http://dx.doi.org/10.14740/jocmr3989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879038PMC
December 2019

Immunogenetic effects of low dose (CEM43 30) magnetic nanoparticle hyperthermia and radiation in melanoma cells.

Int J Hyperthermia 2019 11;36(sup1):37-46

Thayer School of Engineering, Dartmouth College, Hanover, NH, USA.

In this in vitro study we have used an RNA quantification technique, nanoString, and a conventional protein analysis technique (Western Blot) to assess the genetic and protein expression of B16 murine melanoma cells following a modest magnetic nanoparticle hyperthermia (mNPH) dose equivalent to 30 minutes @ 43°C (CEM43 30) and/or a clinically relevant 8 Gy radiation dose. Melanoma cells with mNPs(2.5 μg Fe/106 cells) were pelleted and exposed to an alternating magnetic field (AMF) to generate the targeted thermal dose. Thermal dose was accurately monitored by a fiber optic probe and automatically maintained at CEM43 30. All cells were harvested 24 hours after treatment. The mNPH dose demonstrated notable elevations in the thermotolerance/immunogenic HSP70 gene and a number of chemoattractant and toll-like receptor gene pathways. The 8 Gy dose also upregulated a number of important immune and cytotoxic genetic and protein pathways. However, the mNPH/radiation combination was the most effective stimulator of a wide variety of immune and cytotoxic genes including HSP70, cancer regulating chemokines CXCL10, CXCL11, the T-cell trafficking chemokine CXCR3, innate immune activators TLR3, TLR4, the MDM2 and mTOR negative regulator of p53, the pro-apoptotic protein PUMA, and the cell death receptor Fas. Importantly a number of the genetic changes were accurately validated by protein expression changes, i.e., HSP70, p-mTOR, p-MDM2. These results not only show that low dose mNPH and radiation independently increase the expression of important immune and cytotoxic genes but that the effect is greatly enhanced when they are used in combination.
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http://dx.doi.org/10.1080/02656736.2019.1627433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943912PMC
November 2019

Insulin Action in the Hypothalamus Increases Second-Phase Insulin Secretion in Humans.

Neuroendocrinology 2020 5;110(11-12):929-937. Epub 2019 Nov 5.

Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital, Eberhard-Karls-University Tübingen, Tübingen, Germany.

Background: Animal studies and initial correlative data in humans indicate that insulin action in the brain may affect pancreatic insulin secretion. An important brain region for this process is the hypothalamus, an area that can develop insulin resistance.

Methods: Fifteen young, healthy men (27 ± 3 years) with a wide BMI spectrum (20-30 kg/m2) underwent 2 hyperglycemic clamps (target blood glucose: 10 mmol/L). In this double-blind study, subjects received 160 U of insulin or placebo as a nasal spray on 2 days in randomized order. On another day, insulin sensitivity of the hypothalamus was determined by functional magnetic resonance imaging.

Results: Glucose levels were comparable on both study days. In the whole group, C-peptide levels were not significantly different between conditions. Though, there was a significant interaction between insulin sensitivity of the hypothalamus × nasal spray × time on C-peptide levels (p = 10-6). The group was therefore divided according to median hypothalamic insulin sensitivity. C-peptide concentrations were higher after intranasal insulin compared to placebo spray in the group with a strong hypothalamic insulin response (p < 0.0001, β = 6.00 ± 1.24) and lower in the brain insulin-resistant group (p = 0.005, β = -2.68 ± 0.95). Neither somatostatin nor glucagon kinetics was altered by the nasal spray.

Conclusions: In participants with high hypothalamic insulin sensitivity, insulin action in the brain enhanced second-phase insulin secretion from pancreatic beta cells. This reaction could, for example, contribute to late postprandial glucose regulation by suppressing hepatic glucose production by portal venous insulin.
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http://dx.doi.org/10.1159/000504551DOI Listing
November 2019

Characterizing and Mitigating Bladder Radioactivity on F-Fluciclovine PET/CT.

J Nucl Med Technol 2020 Mar 11;48(1):24-29. Epub 2019 Oct 11.

Department of Radiology, Loyola University Medical Center, Maywood, Illinois

F-fluciclovine PET is approved for prostate cancer recurrence imaging. According to the radiopharmaceutical package insert, only 3% of the tracer is expected to be excreted in the urine over the first 4 h. Yet, in clinical practice we noticed a higher percentage of bladder excretion. We sought to evaluate and quantify early F-fluciclovine bladder radioactivity and determine whether refraining from voiding before F-fluciclovine injection would mitigate it. In total, 159 patients underwent F-fluciclovine PET/CT imaging as part of their clinical workup. The first 36 patients were instructed to void just before F-fluciclovine injection; the subsequent 123 patients were not asked to void. The SUV and SUV of the bladder, aorta, marrow, liver, and bladder volumes were determined. Comparing SUV of bladder to background, we characterized bladder radioactivity as insignificant (bladder < aorta), mild (bladder > aorta < marrow), moderate (bladder > marrow < liver), or intense (bladder > liver). Differences between the protocols were investigated. Overall, 22% (35/159) of patients had moderate bladder activity and 8.8% (14/159) had intense bladder activity. A negative association was found between bladder volume and SUV A significant difference was found between the voiding and nonvoiding groups, with 38.9% (14/36) versus 17.1% (21/123) of patients, respectively, having moderate bladder activity and 22.2% (8/36) versus 4.9% (6/123) of patients, respectively, having intense bladder activity. Refraining from voiding before F-fluciclovine injection results in significantly lower urinary bladder radioactivity than does purposeful voiding before injection. We have modified our practice accordingly, particularly as moderate and intense bladder activity may mask or mimic local prostate cancer recurrence. Mechanisms underlying this phenomenon should be further investigated.
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http://dx.doi.org/10.2967/jnmt.119.230581DOI Listing
March 2020

Severe heart failure and the need for mechanical circulatory support and heart transplantation in pediatric patients with myocarditis: Results from the prospective multicenter registry "MYKKE".

Pediatr Transplant 2019 11 11;23(7):e13548. Epub 2019 Jul 11.

Department of Congenital Heart Disease - Pediatric Cardiology, German Heart Center Berlin, Berlin, Germany.

Myocarditis represents an important cause for acute heart failure. MYKKE, a prospective multicenter registry of pediatric patients with myocarditis, aims to gain knowledge on courses, diagnostics, and therapy of pediatric myocarditis. The role of mechanical circulatory support (MCS) in children with severe heart failure and myocarditis is unclear. The aim of this study was to determine characteristics and outcome of patients with severe heart failure requiring MCS and/or heart transplantation. The MYKKE cohort between September 2013 and 2016 was analyzed. A total of 195 patients were prospectively enrolled by 17 German hospitals. Twenty-eight patients (14%) received MCS (median 1.5 years), more frequently in the youngest age group (0-2 years) than in the older groups (P < 0.001; 2-12 and 13-18 years). In the MCS group, 50% received a VAD, 36% ECMO, and 14% both, with a survival rate of 79%. The weaning rate was 43% (12/28). Nine (32%) patients were transplanted, one had ongoing support, and six (21%) died. Histology was positive for myocarditis in 63% of the MCS group. Patients within the whole cohort with age <2 years and/or ejection fraction <30% had a significantly worse survival with high risk for MCS, transplantation, and death (P < 0.001). Myocarditis represents a life-threatening disease with an overall mortality of 4.6% in this cohort. The fulminant form more often affected the youngest, leading to significantly higher rate of MCS, transplantation, and mortality. MCS represents an important and life-saving therapeutic option in children with myocarditis with a weaning rate of 43%.
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http://dx.doi.org/10.1111/petr.13548DOI Listing
November 2019

Best Practices for F-Fluciclovine PET/CT Imaging of Recurrent Prostate Cancer: A Guide for Technologists.

J Nucl Med Technol 2019 Dec 10;47(4):282-287. Epub 2019 Jun 10.

Division of Nuclear Medicine, Department of Radiology, Loyola University Medical Center, Maywood, Illinois

F-fluciclovine is a Food and Drug Administration-approved PET tracer indicated for patients suspected to have recurrent prostate cancer based on a prostate-specific antigen rise after prior therapy. F-fluciclovine PET/CT is performed significantly differently from F-FDG PET/CT and requires special attention to patient preparation, injection technique, and imaging time. This article aims to provide nuclear medicine technologists with the best-practice guidelines for the F-fluciclovine PET/CT protocol.
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http://dx.doi.org/10.2967/jnmt.119.227116DOI Listing
December 2019

What role do fat cells play in pancreatic tissue?

Mol Metab 2019 07 7;25:1-10. Epub 2019 May 7.

German Center for Diabetes Research (DZD), Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard Karls University of Tübingen, Tübingen, Germany. Electronic address:

Background: It is now generally accepted that obesity is a major risk factor for type 2 diabetes mellitus (T2DM). Hepatic steatosis in particular, as well as visceral and ectopic fat accumulation within tissues, is associated with the development of the disease. We recently presented the first study on isolated human pancreatic adipocytes and their interaction with islets [Gerst, F., Wagner, R., Kaiser, G., Panse, M., Heni, M., Machann, J., et al., 2017. Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion. Diabetologia 60(11):2240-2251.]. The results indicate that the function of adipocytes depends on the overall metabolic status in humans which, in turn, differentially affects islet hormone release.

Scope Of Review: This review summarizes former and recent studies on factors derived from adipocytes and their effects on insulin-secreting β-cells, with particular emphasis on the human pancreas. The adipocyte secretome is discussed with a special focus on its influence on insulin secretion, β-cell survival and apoptotic β-cell death.

Major Conclusions: Human pancreatic adipocytes store lipids and release adipokines, metabolites, and pro-inflammatory molecules in response to the overall metabolic, humoral, and neuronal status. The differentially regulated adipocyte secretome impacts on endocrine function, i.e., insulin secretion, β-cell survival and death which interferes with glycemic control. This review attempts to explain why the extent of pancreatic steatosis is associated with reduced insulin secretion in some studies but not in others.
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http://dx.doi.org/10.1016/j.molmet.2019.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600604PMC
July 2019

Metabolomic Characteristics of Fatty Pancreas.

Exp Clin Endocrinol Diabetes 2020 Dec 16;128(12):804-810. Epub 2019 May 16.

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.

Objective: Pancreatic steatosis is associated with impaired beta cell function in patients with prediabetes. The pathomechanisms underlying this association still remain to be elucidated. Recent data show that adipocytes are situated within the pancreatic parenchyma and therefore give raise to hypothesize that pancreatic fat together with known and unknown metabolites such as hepatokines affect insulin secretion. Applying a targeted metabolomic approach we investigated possible circulating markers of pancreatic fat in order to better understand its role in the pathophysiology of impaired beta cell function.

Methods: We included 361 Caucasians, at increased risk of type 2 diabetes, from the Tübingen Family Study. All participants underwent a frequently sampled oral glucose tolerance test to assess insulin secretion and a magnetic resonance imaging to quantify pancreatic fat content, total body fat and visceral fat. Among the 152 subjects with prediabetes (IFG and/or IGT), two groups each with 20 individuals, having the lowest and highest pancreatic fat content were selected. The groups were matched for sex, age, BMI, total fat content, visceral fat content, liver fat content and insulin sensitivity. Metabolites were analyzed using the AbsoluteIDQ p400 HR Kit by Biocrates.

Results: Pancreatic fat content of all 152 subjects with prediabetes was negatively associated with insulin secretion represented by AUC/AUC (p=0.04; β=- 3.24). Furthermore, pancreatic fat content was positively associated with BMI, total body and visceral fat (all p<0.005). Levels of aminoacids, biogenic amines and monosaccharides were similar between the groups with high/low pancreatic fat content (p>0.90). Also, levels of polar lipids such as lysophosphatidylcholines, phosphatidylcholines, sphingomyelins and ceramides did not differ significantly between the groups (p>0.90). Investigating the levels of neutral lipids such as aclycarnitines, diglycerides, triglycerides and cholesteryl esters also revealed no differences between the groups (p>0.90).

Conclusion: The amount of pancreatic fat is not associated with the metabolomic pattern in individuals with prediabetes. This might be due to the relatively low pancreatic fat content compared to the total amount of fat stored in other depots. The impact of pancreatic steatosis on insulin secretion might be mediated by paracrine effects which cannot be detected in the circulation.
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http://dx.doi.org/10.1055/a-0896-8671DOI Listing
December 2020

Safety and efficacy of mTOR inhibitor treatment in patients with tuberous sclerosis complex under 2 years of age - a multicenter retrospective study.

Orphanet J Rare Dis 2019 05 3;14(1):96. Epub 2019 May 3.

Division of Child Neurology and Metabolic Medicine, Center for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

Background: Tuberous sclerosis complex (TSC) is a multisystem disease with prominent neurologic manifestations such as epilepsy, cognitive impairment and autism spectrum disorder. mTOR inhibitors have successfully been used to treat TSC-related manifestations in older children and adults. However, data on their safety and efficacy in infants and young children are scarce. The objective of this study is to assess the utility and safety of mTOR inhibitor treatment in TSC patients under the age of 2 years.

Results: A total of 17 children (median age at study inclusion 2.4 years, range 0-6; 12 males, 5 females) with TSC who received early mTOR inhibitor therapy were studied. mTOR inhibitor treatment was started at a median age of 5 months (range 0-19 months). Reasons for initiation of treatment were cardiac rhabdomyomas (6 cases), subependymal giant cell astrocytomas (SEGA, 5 cases), combination of cardiac rhabdomyomas and SEGA (1 case), refractory epilepsy (4 cases) and disabling congenital focal lymphedema (1 case). In all cases everolimus was used. Everolimus therapy was overall well tolerated. Adverse events were classified according to the Common Terminology Criteria of Adverse Events (CTCAE, Version 5.0). Grade 1-2 adverse events occurred in 12 patients and included mild transient stomatitis (2 cases), worsening of infantile acne (1 case), increases of serum cholesterol and triglycerides (4 cases), changes in serum phosphate levels (2 cases), increase of cholinesterase (2 cases), transient neutropenia (2 cases), transient anemia (1 case), transient lymphopenia (1 case) and recurrent infections (7 cases). No grade 3-4 adverse events were reported. Treatment is currently continued in 13/17 patients. Benefits were reported in 14/17 patients and included decrease of cardiac rhabdomyoma size and improvement of arrhythmia, decrease of SEGA size, reduction of seizure frequency and regression of congenital focal lymphedema. Despite everolimus therapy, two patients treated for intractable epilepsy are still experiencing seizures and another one treated for SEGA showed no volume reduction.

Conclusion: This retrospective multicenter study demonstrates that mTOR inhibitor treatment with everolimus is safe in TSC patients under the age of 2 years and shows beneficial effects on cardiac manifestations, SEGA size and early epilepsy.
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http://dx.doi.org/10.1186/s13023-019-1077-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500021PMC
May 2019

Fast-timing microchannel plate photodetectors: Design, fabrication, and characterization.

Rev Sci Instrum 2019 Apr;90(4):043109

Argonne National Laboratory, 9700 S. Cass Ave., Lemont, Illinois 60439, USA.

We report a detailed design, fabrication, and characterization of 6 × 6 cm fast timing photodetectors based on next-generation microchannel plates (MCPs). The whole assembly is made of low-cost borosilicate glass materials and hermetically sealed with a bialkali photocathode in a vacuum. The flexible photodetector design provides the potential of modifying individual components as well as the entire configuration to fit for different applications. A series of prototype MCP-photodetectors were fabricated following a step-by-step process including functionalization of glass capillary array through atomic layer deposition, MCP baking and scrubbing, photocathode deposition, and hermetic thermo-compression sealing. The prototype MCP-photodetectors exhibit electron gains well beyond 10 level with good relative uniformity. An excellent rise time of 439 ps, timing distribution root-mean-square at a single photoelectron mode of 105 ps, a timing resolution of 20 ps, and magnetic field tolerance up to 1.3 T were achieved for a photodetector with 10 µm pore size MCPs, comparing to that of 536 ps, 205 ps, 63 ps, and 0.7 T for the one with 20 µm pore size MCPs.
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http://dx.doi.org/10.1063/1.5063825DOI Listing
April 2019