Determinants and pharmacologic modulation of fasting substrate oxidation in humans

Alterations in substrate oxidation are a potential contributor to the pathogenesis of metabolic diseases as they might foster ectopic lipid accumulation. Longitudinal studies identified predominant carbohydrate oxidation to predispose for subsequent weight gain. However, determinants of fasting substrate oxidation remain elusive and evidence for substrate oxidation as a potential pharmacologic target is lacking. To investigate alterations in energy metabolism that can be involved in the pathogenesis of metabolic diseases, this research project aimed to elucidate determinants of fasting substrate oxidation. This thesis furthermore tested whether the latter can be pharmacologically modulated by the sodium glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin to identify therapeutic approaches for altered fuel use. Moreover, implications of modulated fasting substrate oxidation on intrapancreatic fat and insulin secretion were evaluated with the aim to detect potential approaches for the prevention of type 2 diabetes (T2DM). These research questions were addressed in three publications embedded in this thesis. In order to elucidate determining factors of substrate oxidation in the fasted state, a cross‑sectional analysis was performed, including 192 individuals with a wide range of BMI as well as different glycemic categories. Following the assessment of fasting respiratory quotient (RQ=VCO2/VO2) by indirect calorimetry as a measure of substrate oxidation, participants underwent a 5-point 75 g oral glucose tolerance test (OGTT). The latter allows to estimate insulin sensitivity and determine the glycemic status beside quantification of several clinical parameters from basal blood. In the fasting state, high free fatty acid (FFA) concentrations were strongly linked to a low RQ, indicative of predominant fat oxidation. Participants with high levels of the ketone body β‑hydroxybutyric acid had significantly lower RQ values, while glucose and insulin levels were not correlated to RQ. Unlike glucagon-like-peptide 1 (GLP-1), fasting levels of glucose‑dependent insulinotropic polypeptide (GIP) and glicentin associated positively with fasting RQ. There was neither a correlation between BMI nor the total amount or the allocation of body fat compartments with fasting RQ. Hyperglycemia, insulin sensitivity or the metabolic syndrome were not related to RQ. In a double-blind, placebo-controlled randomized trial, 40 participants with prediabetes were treated with empagliflozin or placebo once daily for 8 weeks. Subsequent to overnight fasting, indirect calorimetry as well as a 75 g OGTT were performed before and after treatment. Body fat compartments including lipids in the liver as well as intrapancreatic fat were quantified using magnetic resonance imaging (MRI). A combination of intranasal insulin application with functional MRI was used to determine hypothalamic insulin sensitivity. Empagliflozin reduced fasting RQ, lowered fasting glucose as well as liver fat content and increased hypothalamic insulin sensitivity. Pancreatic fat content as well as insulin secretion remained unaffected upon empagliflozin treatment. Data of this work support the role of FFA as independent determinants of fuel selection, while metabolic disorders were not linked to substrate preferences. This work gained hints for glicentin and GIP to be involved in fuel choice in the fasting state, representing a promising pharmaceutic target to modulate substrate oxidation with possible implications on whole-body metabolism. Upcoming therapeutic approaches in the preclinical as well as clinical phase targeting GIP receptor highlight the relevance of our results. Beside the empagliflozin-induced switch towards predominant fat use, intrahepatic lipids were diminished upon SGLT2 inhibition. This demonstrates the potential of pharmacologic modulation of substrate utilization. Since we detected such changes already in prediabetes, substrate oxidation is an interesting target for the development of preventive strategies of metabolic diseases as T2DM. Discussed underlying mechanisms for the empagliflozin-induced change in substrate oxidation are a restoration of diurnal rhythm by caloric restriction, centrally mediated effects and direct cellular effects of SGLT2i interfering with lipid metabolism. Beside SGLT2i, further antidiabetic drugs such as GLP-1 receptor agonists and metformin may have the potential to modulate substrate oxidation. Therefore, approaches to modulate substrate oxidation should be further evaluated and optimized in future studies. Since the observed increase in fat oxidation was neither accompanied by reductions in pancreatic fat nor by enhanced insulin secretion, this work argues for tissue-specific regulation in substrate oxidation and fat mobilization which should be untangled in future studies. It is however possible that prolongation of treatment duration or a population with higher pancreatic fat content might have led to different results. Since lifestyle intervention trials achieved pancreatic fat reduction, approaches to reduce fat in the pancreas remain a promising strategy to improve insulin secretion for the prevention or therapy of T2DM. Future research should put a spotlight on tailored medicine and find out which sub-groups of persons with prediabetes and T2DM could especially profit from such therapies that target substrate oxidation and reduce ectopic fat deposition

A Phase I/II first-line study of R-CHOP plus B-cell receptor/NF-κB-double-targeting to molecularly assess therapy response

The ImbruVeRCHOP trial is an investigator-initiated, multicenter, single-arm, open label Phase I/II study for patients 61-80 years of age with newly diagnosed CD20+ diffuse large B-cell lymphoma and a higher risk profile (International Prognostic Index ≥2). Patients receive standard chemotherapy (CHOP) plus immunotherapy (Rituximab), a biological agent (the proteasome inhibitor Bortezomib) and a signaling inhibitor (the Bruton's Tyrosine Kinase-targeting therapeutic Ibrutinib). Using an all-comers approach, but subjecting patients to another lymphoma biopsy acutely under first-cycle immune-chemo drug exposure, ImbruVeRCHOP seeks to identify an unbiased molecular responder signature that marks diffuse large B-cell lymphoma patients at risk and likely to benefit from this regimen as a double, proximal and distal B-cell receptor/NF-κB-co-targeting extension of the current R-CHOP standard of care. EudraCT-Number: 2015-003429-32; ClinicalTrials.gov identifier: NCT03129828

Increasing food intake affects digesta retention, digestibility and gut fill but not chewing efficiency in domestic rabbits (Oryctolagus cuniculus)

In ruminants, the level of food intake affects net chewing efficiency and hence faecal particle size. For nonruminants, corresponding data are lacking. Here, we report the effect of an increased food intake of a mixed diet in four domestic rabbit does due to lactation, and assess changes in particle size (as determined by wet sieving analysis) along the rabbit digestive tract. During lactation, rabbits achieved a distinctively higher dry matter intake than at maintenance, with a concomitant reduction in mean retention times of solute and particle markers, an increase in dry matter gut fill, a reduction in apparent digestibility of dry matter, and an overall increase in digestible dry matter intake. By contrast, there was no change in faecal mean particle size (mean   SD: 0.58   0.02 vs. 0.56   0.01 mm). A comparison of diet, stomach content and faecal mean particle size suggested that 98% of particle size reduction occurred due to ingestive mastication and 2% due to digestive processes. Very fine particles passing the finest sieve, putatively not only of dietary but mainly of microbial origin, were particularly concentrated in caecum contents, which corresponds to retention of microbes via a ‘wash‐back' colonic separation mechanism, to concentrate them in caecotrophs that are re‐ingested. This study gives rise to the hypothesis that chewing efficiency on a consistent diet is not impaired by intake level in nonruminant mammals

Women with a History of Childhood Maltreatment Exhibit more Activation in Association Areas Following Non-Traumatic Olfactory Stimuli: A fMRI Study

Background: The aim of this study was investigating how women with a history of childhood maltreatment (CM) process non-threatening and non-trauma related olfactory stimuli. The focus on olfactory perception is based on the overlap of brain areas often proposed to be affected in CM patients and the projection areas of the olfactory system, including the amygdala, orbitofrontal cortex, insula and hippocampus. Methods: Twelve women with CM and 10 controls participated in the study. All participants were, or have been, patients in a psychosomatic clinic. Participants underwent a fMRI investigation during olfactory stimulation with a neutral (coffee) and a pleasant (peach) odor. Furthermore, odor threshold and odor identification (Sniffin ’ Sticks) were tested. Principal Findings: Both groups showed normal activation in the olfactory projection areas. However, in the CM-group we found additionally enhanced activation in multiple, mainly neocortical, areas that are part of those involved in associative networks. These include the precentral frontal lobe, inferior and middle frontal structures, posterior parietal lobe, occipital lobe, and the posterior cingulate cortex. Conclusions: The results indicate that in this group of patients, CM was associated with an altered processing of olfactory stimuli, but not development of a functional olfactory deficit. This complements other studies on CM insofar as we found th

Impact of pulmonary rehabilitation on patients’ health care needs and asthma control:a quasi-experimental study

Background!#!Pulmonary rehabilitation offers potential benefits to people with asthma. It is however unknown if rehabilitation favourably affects patients' health care needs. We therefore examined if rehabilitation reduced needs and, in addition, if it improved asthma control.!##!Methods!#!One hundred fifty patients with asthma were surveyed in three rehabilitation clinics at admission and at discharge. Additionally, we surveyed 78 participants with asthma twice 4 weeks apart. The latter sample (i.e. the control group) was recruited through other pathways than rehabilitation clinics. The Patient Needs in Asthma Treatment (NEAT) questionnaire and the Asthma Control Test (ACT) were completed at baseline and follow-up. Differences between baseline and follow-up and between rehabilitation and control group were examined by t-tests and chi-squared-tests. Univariate ANCOVAS were used to examine if NEAT and ACT follow-up scores differed significantly between groups. Within the rehabilitation group, linear regressions were used to examine if self-reported utilization of more interventions that addressed needs were associated with NEAT scores at follow-up.!##!Results!#!At baseline, there were no differences between the rehabilitation and the control group regarding needs and asthma control. At follow-up, the rehabilitation group showed reduced needs (t(149) = 10.33, p <  0.01) and increased asthma control (t(130) = -6.67, p <  0.01), whereas members of the control group exhibited no changes. Univariate ANCOVAS showed that unmet follow-up needs (F(1, 212) = 36.46, p <  0.001) and follow-up asthma control (F(1, 195) = 6.97, p = 0.009) differed significantly between groups. In the rehabilitation group, self-reported utilization of more interventions was associated with reduced needs (β = 0.21; p = 0.03).!##!Conclusions!#!This study provides preliminary evidence suggestion that pulmonary rehabilitation in adults with asthma may reduce asthma-related needs and confirms previous findings that rehabilitation may improve asthma control

Prevalência de danos neurológicos graves e perfil clínico de pacientes em Unidade de Terapia Intensiva

Objective: to identify the prevalent neurological damage in patients admitted to an Intensive Care Unit and their relationship with social and clinical characteristics, care, and clinical outcome. Method: cross-sectional study with analysis of 83 medical records of patients with neurological damage and hospitalized in the period from 2016 to 2018. Results: predominance of Hemorrhagic Stroke (55.4%). Traumatic Brain Injury affected only men (16.9%). Systemic Arterial Hypertension was the main comorbidity evidenced (51.8%). Altered muscle strength was the main sign of severe neurological damage (36.2%). Analgesia prevailed among intensive care dedicated to patients with severe neurological damage (95.1%). Death as clinical outcome predominated (85.6%). Conclusion: Hemorrhagic stroke predominates, especially in women. Analgesia is the main care evidenced, and the mortality rate was higher than the rates found in the literature.Objetivo: identificar os danos neurológicos prevalentes em pacientes internados em Unidade de Terapia Intensiva e a relação destes com as características sociais e clínicas, os cuidados e o desfecho clínico. Método: estudo transversal com análise de 83 prontuários de pacientes com danos neurológicos e internados no período de 2016 a 2018. Resultados: predomínio do Acidente Vascular Encefálico Hemorrágico (55,4%). O Traumatismo Cranioencefálico acometeu apenas homens (16,9%). A Hipertensão Arterial Sistêmica foi a principal comorbidade evidenciada (51,8%). A alteração da força muscular foi o principal sinal de dano neurológico grave (36,2%). A analgesia prevaleceu entre os cuidados intensivos dedicados aos pacientes com danos neurológicos graves (95,1%). Predomínio do óbito como desfecho clínico (85,6%). Conclusão: predomina o Acidente Vascular Encefálico Hemorrágico, especialmente em mulheres. A analgesia é o principal cuidado evidenciado, e a taxa de mortalidade foi superior à dos índices encontrados na literatura

An isthmus at the caecocolical junction is an anatomical feature of domestic and wild equids

The isthmus at the caecocolical junction in domestic equids is well described. Like another isthmus between the ansa proximalis coli (the colonic fermentation chamber or ‘large colon') and the colon transversum (the distal or ‘small' colon), this spot represents not only a potential anatomical feature contributing to particle ingesta retention but also an explicit predilection site for intestinal obstructions. The question whether this anatomical feature also occurs in wild equids is therefore of both physiological and medical interest but has not been addressed so far. In this paper, we report dissections of the large intestine of a domestic pony (Equus caballus f. dom.), a Przewalski horse (Equus przewalski) and a plains zebra (Equus burchelli). The intestinal tract section of all three animals were similar in length; each species displayed the caecocolical isthmus as well as the abrupt narrowing of the intestinal tract between the ‘large' and the ‘small' colon. Graphical descriptions of wild equid gastrointestinal anatomy should include these feature

An isthmus at the caecocolical junction is an anatomical feature of domestic and wild equids

The isthmus at the caecocolical junction in domestic equids is well described. Like another isthmus between the ansa proximalis coli (the colonic fermentation chamber or 'large colon') and the colon transversum (the distal or 'mall' colon), this spot represents not only a potential anatomical feature contributing to particle ingesta retention but also an explicit predilection site for intestinal obstructions. The question whether this anatomical feature also occurs in wild equids is therefore of both physiological and medical interest but has not been addressed so far. In this paper, we report dissections of the large intestine of a domestic pony (Equus caballus f. dom.), a Przewalski horse (Equus przewalski) and a plains zebra (Equus burchelli). The intestinal tract section of all three animals were similar in length; each species displayed the caecocolical isthmus as well as the abrupt narrowing of the intestinal tract between the 'large' and the 'small' colon. Graphical descriptions of wild equid gastrointestinal anatomy should include these features

Implementing a psychosocial care approach in pediatric inpatient care: process evaluation of the pilot Child Life Specialist program at the University Hospital of Munich, Germany

BackgroundChild Life Specialists (CLSs) are psychosocial care professionals of child development and health who focus on the individual needs and rights of young patients. CLSs accompany sick children and focus on the children's perspective and their reality of life. CLS programs are already established in clinical settings in the United States and other Anglophone countries but have not yet been piloted in the German health care setting, neither has their implementation been evaluated in this context. This study aimed to explore the factors influencing the implementation of a pilot CLS program in pediatric inpatient care at the Dr. von Hauner Children's Hospital at the University Hospital of Munich, Germany.MethodsBuilding on methods commonly employed in the evaluation of complex interventions, we developed a logic model to guide the process evaluation of our program. Semi-structured interviews with four groups of stakeholders were conducted in person or via videoconferencing between June 2021 and January 2022. Data was analyzed collectively using the method of qualitative content analysis by Mayring.ResultsFifteen individual interviews were conducted with patients (children aged 5–17 years, n = 4), parents (n = 4), CLSs (n = 4) and other health professionals (n = 3). Factors influencing the implementation were identified on three levels: system, staff and intervention. On the system level, a clearer definition of CLSs’ tasks and responsibilities was perceived as important and would likely lead to a delineation from other (psychosocial) professions and a reduction of potential resistances. On the staff level, lacking training opportunities and feelings of being insufficiently skilled were limiting the CLSs professional self-confidence. On the intervention level, the emergence of a unique characteristic of the CLSs’ work (i.e., preparation for medical procedures) supported the acceptance of the new program.ConclusionsThe implementation of a CLS program into an established hospital system with existing psychosocial care services is challenging. Our results contribute to a better understanding of implementation processes of such an additional psychosocial care approach and provide recommendations for addressing upcoming challenges