Influence of acute hypoxia on fat metabolism during moderate training exercise

Wir stellten uns die Frage, ob es bei einer Laufausdauerbelastung in moderater, normobarer Hypoxie zu einer veränderten Fettutilisation kommt, oder nicht. Mit derselben Fragestellung wurden daneben die intramyozellulären Fette betrachtet. In die Studie wurden 8 erfahrene und ausdauertrainierte Langstreckenläufer eingeschlossen, die eine zweistündige Belastung auf dem Laufband (Steigung 1%) mit einer Geschwindigkeit absolvierten, die 70% der Laufgeschwindigkeit ihrer individuellen anaeroben Schwelle (IAS) entspricht. Ein Versuchsteil wurde in Normoxie [N] (Sauerstoffkonzentration von 20,9%) und der andere in Hypoxie [H] (Sauerstoffgehalt der Einatemluft 15,5%, entsprechend 2500m über NN) durchgeführt. Direkt vor und nach der Belastung wurden die Probanden einer Kernspinuntersuchung unterzogen, um die intramyozellulären Fette [IMCL] im M. soleus [SOL] und M. tibialis anterior [TA] zu ermitteln. Während der gesamten Belastung wurden Herzfrequenz, Spirometriegrößen, venöses Blut, Blutgase und Laktat bestimmt, sowie das Befinden über Beschwerdescores und der Borgskala erfaßt. Ein Proband musste den Versuch in H wegen Erschöpfung abbrechen und wurde folglich nicht in die Datenerhebung und -auswertung miteinbezogen. Im Versuch fanden sich in H deutlich gesteigerte Konzentrationen der FFS und des Glyzerols. Die Glukose stieg ebenfalls im Verlauf der Belastung an, wenn auch nicht so ausgeprägt wie die FFS. Der über die Spirometrie errechnete respiratorische Quotient stieg in H auf Werte um die 1 an, in N auf etwa 0,87-0,90 und deutete demnach in beiden Versuchsteilen auf eine gesteigerte Utilisation der Kohlenhydrate hin. Der Verlauf der ermittelten Stimulatoren der Lipolyse (Adrenalin, Noradrenalin, Dopamin, IL-6 und Kortisol) und des Inhibitors (Insulin) konnte mit diesem Ergebnis in Einklang gebracht werden. Bei den IMCL zeigten sich sowohl in H, als auch in N signifikante Abnahmen der Konzentrationen durch die Belastung. Diese Reduktionen fanden in beiden Muskeln in ähnlichem Maße statt (SOL H -27,1% vs. SOL N -20,5%, TA H -18,8% vs. TA N -20,6%), wobei die Utilisation in H gleichbedeutend verlief. Zusammenfassend lässt sich festhalten, dass eine 2-stündige moderate Laufausdauerbelastung in akuter normobarer Hypoxie von 2500m über NN zu einer gesteigerten Nutzung von Kohlenhydraten als Energiesubstrat führt. Ungeachtet dessen werden die IMCL sowohl in N, als auch in H verstoffwechselt und unterstreichen demzufolge deren Bedeutung als weiteres Energiesubstrat. Dagegen scheinen die peripher mobilisierten FFS vermindert oxidiert zu werden. Bei Belastung in moderater Hypoxie muß demnach wohl von einer kombinierten Utilisation der Kohlenhydrate und der IMCL ausgegangen werden.Endurance training in high altitude induces changes in substrate utilization. We asked if there are differences in fat metabolism during moderate endurance exercise in acute hypoxia (AH) compared to normoxia (N). We examined 8 trained endurance athletes who performed a continuous treadmill run of 120min with an intensity of 70% individual anaerobic threshold (IAT) under acute hypoxia (15,5% O2 corresponding to an altitude of 2500m) and under sea level conditions (20,9% O2). Intramyocellular lipids (IMCL) considered to be a major source of non-plasma-derived FFA were quantified by 1H-MR spectroscopy in the tibialis anterior (TA) and soleus (SOL) muscles prior to and after exercise. One athlete did not finish exercise because of exhaustion, so all data used, correspond to the 7 athletes who finished performance. All athletes (7 men; age 31,6±7,5; average training experience in years 11,0±5,4; height 174,6±7,5 cm; weight 66,2±7,9 kg; IAS 15,2±1,5; HfIAS 162,2±5,2 [n=6]; average performing distance within the last 3 months in km/week 53,6±32,8; average performing time within the last 3 months in h/week 6,9±3,3) were examined by 1H-MRS before and after exercise, continuously checked by ECG and spirometry, got half-hourly examination of venous and capillary blood and were questioned about complaints and strains (via scale of Bork). Concentrations of free fatty acids (FFA) and glycerol augmented while exercising in AH, same as utilization of carbohydrates (CHO). Spirometry data showed increasing levels of respiratory quotient (RQ) in AH about 1, in N levels up to 0,87 - 0,90. These results point to an increased utilization of CHO under both conditions. Results of stimulating parameters of lipolysis (Epinephrine, norepinephrine, dopamine, Il-6 and cortisol) and inhibitors of lipolysis (insuline) are according with these findings. We found significant decreases in IMCL content in SOL and TA after exercise in AH and N (TAN -20,6%; TAAH -18,8% and p<0,05; SOLN -20,5%; SOLAH -27,1% and p<0,05). The decrease was approximately the same in SOL and TA, despite different tissue composition. There were no significant changes between AH and N. In summary, we suggest that during moderate running exercise under acute hypoxia carbohydrate utilization is altered and plasma free fatty acids play a subordinate position. On the other hand, the use of intramyocellular lipids in hypoxia should not be neglected

Inconsistent approaches of the G-BA regarding acceptance of primary study endpoints as being relevant to patients - an analysis of three disease areas: oncological, metabolic, and infectious diseases

Abstract Background Previous evaluations of oncological medicines in the German early benefit assessment (EBA) procedure have demonstrated inconsistent acceptance of endpoints by regulatory authorities and the Federal Joint Committee (G-BA). Accepted standard endpoints for regulatory purposes are frequently not considered as patient-relevant in the German EBA system. In this study the acceptance of clinically acknowledged primary endpoints (PEPs) from regulatory trials in EBAs conducted by the G-BA was evaluated across three therapeutic areas. Methods Medicines for oncological, metabolic and infectious diseases with EBAs finalised before 25 January 2016 were evaluated. Respective manufacturer’s dossiers, regulatory assessments, G-BA appraisals and oral hearing minutes were reviewed, and PEPs were examined to determine whether they were considered relevant to patients by the G-BA. Furthermore, the acceptance of symptomatic vs asymptomatic PEPs was also analysed. Results A total of 65 EBAs were evaluated. Mortality PEPs were widely accepted as patient-relevant but were only used in a minority of EBAs and exclusively in oncological diseases. Morbidity PEPs constituted around 72 % of assessed PEPs, but were excluded from the EBA in over half of the corresponding assessments as they were not considered patient-relevant. Symptomatic endpoints were largely deemed patient-relevant, whereas acceptance of asymptomatic endpoints varied between therapeutic areas. Conclusions This evaluation identified inconsistencies in patient relevance of morbidity-related PEPs as well as in acceptance of asymptomatic endpoints by the G-BA in all three disease areas examined. Better harmonisation between the regulatory authorities and the G-BA is still required after 5 years of AMNOG health technology assessment in Germany

Additional file 1: Table S1. of Inconsistent approaches of the G-BA regarding acceptance of primary study endpoints as being relevant to patients - an analysis of three disease areas: oncological, metabolic, and infectious diseases

Rationale of categorisation of PEPs as symptomatic and asymptomatic. List of the rationale of categorisation as symptomatic and asymptomatic for all PEPs included in the analysis. (DOCX 14 kb

A case of multiple familial trichoepitheliomas responding to treatment with the Hedgehog signaling pathway inhibitor vismodegib

Multiple familial trichoepitheliomas (MFT) is an autosomal dominantly inherited disease characterized by multiple skin appendage tumors. We describe a patient showing a continuous spectrum of follicular differentiated neoplasms including classical trichoepitheliomas but also infiltrative growing and finally metastasizing malignant follicular differentiated tumors. Germline mutation analysis revealed a nonsense mutation in the cylindromatosis (CYLD) gene. Gene expression analysis by real-time PCR of tumor tissue showed overexpression of glioma-associated oncogene Glil mRNA. Treatment with the Hedgehog pathway inhibitor vismodegib resulted in a significant regression of the highly differentiated trichoepitheliomas. Gli upregulation is indicative of an active Hedgehog signaling pathway. We hypothesize that its upregulation is indirectly caused by CYLD mutation which promotes tumor development. Vismodegib treatment could thus provide a new treatment option for patients with this debilitating disorder

Aetiology, comorbidities and cofactors of chronic leg ulcers: retrospective evaluation of 1 000 patients from 10 specialised dermatological wound care centers in Germany

Numerous comorbidities and cofactors have been known to influence wound healing processes. In this multicentre study, clinical data of 1 000 patients with chronic leg ulcers from ten specialised dermatological wound care centers were analysed. The patient cohort comprised 567 females and 433 males with an average age of 69.9 years. The wounds persisted on average for 40.8months and had a mean size of 43.7 cm(2). Venous leg ulcers represented the most common entity accounting for 51.3% of all chronic wounds, followed by mixed-type ulcers in 12.9% and arterial ulcerations in 11.0% of the patients. Vasculitis was diagnosed in 4.5%, trauma in 3.2%, pyoderma gangrenosum in 2.8%, lymphoedema in 1.7%, neoplasia in 1.0% and delayed post-surgical wound healing in 0.6% of the included patients. In total, 70.5% of patients suffered from arterial hypertension, 45.2% were obese, 27.2% had non-insulin dependent diabetes, and 24.4% dyslipidaemia. Altogether 18.4% suffered from metabolic syndrome. Cofactors and comorbidities of patients with chronic leg ulcers have previously been studied but not in detail. Here, we were able to demonstrate the existence of several potentially relevant cofactors, comorbidities of their associations and geographical distributions, which should be routinely examined in patients with chronic leg ulcers and - if possible - treated