ECS-Komplex – ein neuer Biomarker bei Wachstumshormonstörungen?

Störungen im Metabolismus des Wachstumshormons können sich als Wachstumshormonmangel oder -überschuss (Akromegalie) äußern. In beiden Fällen handelt es sich um seltene Krankheiten, die aufwendig behandelt werden müssen, da jeder Patient anders auf seine jeweilige Medikation anspricht. Zur Bestimmung des individuellen Ansprechverhaltens auf die medikamentöse Behandlung wird Insulin-like Growth Factor 1 verwendet, das jedoch als unzuverlässig für die Therapiekontrolle gilt. Um die Diagnostik und Therapie von Wachstumshormonstörungen zu verbessern, wurde in dieser Pilotstudie der Nutzen des neuen potenziellen Biomarkers Elongin B/C-Cullin5-Socs-box Komplex (ECS-Komplex) überprüft. Die fünf Proteine des Komplexes üben zusammen einen negativen Feedback-Mechanismus auf den Wachstumshormonrezeptor aus und regulieren ihn in Abhängigkeit vom Wachstumshormonspiegel im Blut. Für diese Pilotstudie wurden vier Patienten mit Wachstumshormondefizienz und 15 Patienten mit Akromegalie rekrutiert. Die Messung von Unterschieden in der Expression der Gene auf RNA-Ebene in Blutproben der Patienten erlaubt erste Aussagen über deren Eignung als therapeutische Marker für diese Krankheiten.Growth hormone (GH) dysfunctions can occur as a GH-deficiency (GHD) or an overproduction of GH, leading to acromegaly. Both are rare diseases, which have to be treated for many years before the correct individual dosage is found and a mitigation of symptoms can be achieved. Current medical therapy is determined by the levels of the insulin-like growth factor-1, which is considered to be an unreliable theranostic tool. In order to improve the diagnosis and therapy of patients with GH-dysfunctions, we investigated the benefits of the novel potential biomarker Elongin B/C-Cullin5-Socs-box complex (ECS-complex). Together, these proteins regulate the growth hormone receptor levels according to the blood GH concentration through a negative feedback loop. For this study, we were able to recruit four patients with a GHD and 15 patients with acromegaly. The detected differential expression of the ECS-complex in patients with growth hormone dysfunctions allows for first conclusions about the potential of those proteins as predictive biomarker molecules for individualized therapies

Impaired transmission in the corticospinal tract and gait disability in spinal cord injured persons

Rehabilitation following spinal cord injury is likely to depend on recovery of corticospinal systems. Here we investigate whether transmission in the corticospinal tract may explain foot drop (inability to dorsiflex ankle) in persons with spinal cord lesion. The study was performed in 24 persons with incomplete spinal cord lesion (C1 to L1) and 15 healthy controls. Coherence in the 10- to 20-Hz frequency band between paired tibialis anterior muscle (TA) electromyographic recordings obtained in the swing phase of walking, which was taken as a measure of motor unit synchronization. It was significantly correlated with the degree of foot drop, as measured by toe elevation and ankle angle excursion in the first part of swing. Transcranial magnetic stimulation was used to elicit motor-evoked potentials (MEPs) in the TA. The amplitude of the MEPs at rest and their latency during contraction were correlated to the degree of foot drop. Spinal cord injured participants who exhibited a large foot drop had little or no MEP at rest in the TA muscle and had little or no coherence in the same muscle during walking. Gait speed was correlated to foot drop, and was the lowest in participants with no MEP at rest. The data confirm that transmission in the corticospinal tract is of importance for lifting the foot during the swing phase of human gait

The effect of neonatal vitamin A supplementation on growth in the first year of life among low-birth-weight infants in Guinea-Bissau:two by two factorial randomised controlled trial

BACKGROUND: Vitamin A supplementation (VAS) may amplify the effect of vaccines. We therefore investigated if neonatal VAS given with and without Bacille Calmette-Guérin (BCG) vaccine to low-birth-weight (LBW) neonates had an effect on growth in the first year of life. We hypothesised that VAS would be particularly beneficial when provided with BCG. METHODS: We conducted a randomised two-by-two factorial trial in Guinea-Bissau; 1,717 LBW neonates were randomly allocated to VAS or placebo at birth as well as early or the usual postponed BCG vaccination. Anthropometric measurements were obtained at 2, 6, and 12 months after inclusion. RESULTS: Overall there was no effect of neonatal VAS on growth in the first year of life. By 2 months, VAS tended to have a beneficial effect on weight and head circumference when given with BCG but not when given without BCG (interaction: weight-for-age p = 0.07 and head circumference-for-age: p = 0.06). By 6 months, there was a beneficial effect of VAS on head circumference and weight among children who had not received DTP vaccine 2 months after inclusion (weight: 0.18 (0.00; 0.36) and head circumference 0.27 (0.06; 0.48)), but no beneficial effect among those who had received DTP. CONCLUSION: The results support other trials indicating that neonatal VAS does not have consistent effects on childhood growth and if anything the effects seem to be temporary. They also show that the effect may differ by vaccination status, being beneficial when given with BCG at birth and when DTP is delayed. TRIAL REGISTRATION: http://www.ClinicalTrials.gov (NCT00168610) (nct00168610

Adaptação de longo prazo ao treinamento cíclico induzido eletricamente em indivíduos com severa lesão na medula espinhal

Indivíduos com lesão da medula espinhal (LME) mais freqüentemente adquirem essa condição na juventude e são relegados a uma vida de maior ou menor inatividade física. Em adição às implicações primárias da LME, indivíduos com LME severa são estigmatizados e relegados a uma condição de vida física inativa. É desconhecido se essas condições relatadas são potencialmente reversíveis e o objetivo do presente estudo foi, portanto, examinar os efeitos do exercício em indivíduos com LME. Então, 10 indivíduos (6 com tetraplegia e 4 com paraplegia; idade de 27 a 45 anos; tempo de lesão de 3 a 23 anos) foram treinados por 1 ano em cicloergometria com estimulação elétrica controlada por feedback. Eles treinaram 3 vezes por semana (média 2,3 vezes), 30 minutos em cada sessão. Os músculos glúteos, isquiotibiais e quadríceps foram estimulados por eletrodos colocados na superfície da pele sobre seus pontos motores. Durante o primeiro treino, uma variação substancial na performance foi observada entre os pacientes. A maioria dos indivíduos foi capaz de realizar o exercício por 30 minutos na primeira sessão, mas dois indivíduos foram capazes de realizar o exercício por apenas poucos minutos. Depois do treino de 1 ano, todos os indivíduos foram capazes de realizar 30 minutos contínuos de treino e o trabalho produzido teve aumento de 4 ± 1 (média de “erro-padrão” EP) para 17 ± 2 kJ por sessão de treino (P < 0,05). A taxa de captação máxima de O2 durante o exercício com estimulação elétrica aumentou de 1,20 ± 0,08 l/min, mensurada depois de poucas semanas de exercício, para 1,43 ± 0,09 l/min após 1 ano de treinamento (P < 0,05). Imagens de corte com ressonância magnética foram feitas na coxa para avaliar a massa muscular, que teve um aumento de 12% (média, P < 0,05) em 1 ano de treinamento. Em biópsias feitas antes do exercício, vários estados de atrofia foram observados nas fibras musculares dos indivíduos, um fenômeno que foi parcialmente normalizado em todos os pacientes depois do treinamento. É sabido que a distribuição do tipo de fibra no músculo esquelético é alterada para fibras do tipo II B (contração rápida, rapidamente fatigável, glicolíticas) dentro dos primeiros 2 anos após a lesão medular. Nessa avaliação, os músculos continham 63% de miosina de cadeia pesada (MHC) isoforme II B, 33% de MHC isoforme II A (contração rápida e resistentes à fadiga) e menos de 5% de MHC isoforme I (fibras de contração lenta) antes do treinamento. Uma transformação para obterem-se fibras com proteínas contráteis mais resistentes à fadiga foi encontrada após 1 ano de treinamento. A porcentagem de MHC isoforme II A aumentou para 61% do total de proteínas contráteis e houve uma diminuição de 32% nas fibras rapidamente fatigáveis do tipo MHC isoforme II, enquanto as MHC isoformes I somente compunham 7% da quantidade total de MHC. Essa alteração foi acompanhada de um aumento de 100% na atividade enzimática da citrato sintetase, como um indicador da capacidade oxidativa mitocondrial. Conclui-se que as alterações na performance, nesse exercício e nas características do músculo esquelético, associadas à inatividade que ocorre em indivíduos com LME, são reversíveis, mesmo até 20 anos após a lesão. Sucede que o treino com exercícios induzidos por estimulação elétrica dos músculos paralisados é uma efetiva ferramenta de reabilitação que deveria ser oferecida aos indivíduos com LME no futuro.Spinal cord injured (SCI) individuals most often contract their injury at a young age and are deemed to a life of more or less physical inactivity. In addition to the primary implications of the SCI, severe SCI individuals are stigmatized by conditions related to their physically inactive lifestyle. It is unknown if these inactivity related conditions are potentially reversible and the aim of the present study was, therefore, to examine the effect of exercise on SCI individuals. Ten such individuals (six with tetraplegia and four with paraplegia; age 27-45 years; time since injury 3-23 years) were exercise trained for 1 year using an electrically induced computerized feedback controlled cycle ergometer. They trained for up to three times week (mean 2.3 times), 30 min on each occasion. The gluteal, hamstring and quadriceps muscles were stimulated via lectrodes placed on the skin over their motor points. During lie first training bouts, a substantial variation in performance was seen between the subjects. A majority of them were capable of performing 30 min of exercise in the first bout, however, two individuals were only able to perform a few minutes of exercise. After training for 1 year all of the subjects were able to perform 30 min of continuous training and the work output had increased from 4±1 (mean±SE) to 17±2 kilo Joules per training bout (P<0.05). The maximal oxygen uptake during electrically induced exercise increased from 1.20±0.08 litres per minute measured after a few weeks habituation to the exercise to 1.43±0.09 litres per minute after training for 1 year (P<0.05). Magnetic resonance cross sectional images of the thigh were performed to estimate muscle mass and an increase of 12% (mean, P<0.05) was seen in response to 1 year of training. In biopsies taken before exercise various degrees of atrophy were observed in the individual muscle fibres, a phenomenon that was partially normalized in all subjects after training. The fibre type distribution in skeletal muscles is known to shift towards type IIB fibres (fast twitch, fast fatiguable, glycolytic fibres) within the first 2 years after the spinal cord injury. The muscle in the present investigation contained 63% of myosin heavy chain (MHQ isoform IIB, 33% MHC isoform IIA (fast twitch, fatigue resistant) and less than 5% MHC isoform I (slow twitch) before training. A shift towards more fatigue resistant contractile proteins was found after 1 year of training. The percentage of MHC isoform IIA increased to 61% of all contractile protein and a corresponding decrease to 32% was seen in the fast fatiguable MHC isoform IIB, where as MHC 1 only comprised 7% of the total amount of MHC. This shift was accompanied by a doubling of the enzymatic activity of citrate synthase, as an indicator of mitochondrial oxidative capacity. It is concluded that inactivity-associated changes in exercise perfomance capacity and skeletal muscle occurring in SCI individuals after injury are reversible, even up to over 20 years after the injury. It follows that electrically induced exercise training of the paralysed limbs is an effective rehabilitation tool that should be offered to SCI individuals in the future

Efficacy and safety of once-monthly pasireotide in Cushing's disease: A 12 month clinical trial

© 2017 Elsevier Ltd. Background: Cushing's disease is a rare debilitating endocrine disorder for which few prospective interventional studies have been done. We report results of the first phase 3 trial assessing long-acting intramuscular pasireotide in patients with Cushing's disease. Methods: In this phase 3 clinical trial we recruited patients aged 18 years or older with persistent, recurrent, or de-novo (non-surgical candidates) Cushing's disease who had a mean urinary free cortisol (mUFC) concentration (from three 24 h samples) of 1·5-5·0 times the upper limit of normal (ULN), a normal or greater than normal morning plasma adrenocorticotropic hormone concentration, and a pituitary source of Cushing's syndrome, from 57 sites across 19 countries. Exclusion criteria included previous pasireotide treatment, mitotane therapy within 6 months, and pituitary irradiation within 10 years. We randomly allocated patients 1:1 (block size of four) using an interactive-response-technology system to intramuscular pasireotide 10 mg or 30 mg every 4 weeks for 12 months (in the core phase). We stratified randomisation by screening mUFC concentration (1·5 to < 2·0 × ULN and 2·0-5·0 × ULN). The dose could be uptitrated (from 10 mg to 30 mg or from 30 mg to 40 mg) at month 4 if the mUFC concentration was greater than 1·5 × ULN, and at month 7, month 9, or month 12 if the mUFC concentration was greater than 1·0 × ULN. Investigators, patients, site personnel, and those assessing outcomes were masked to dose group allocation. The primary endpoint was the proportion of patients in each group with an mUFC concentration of less than or equal to the ULN at month 7. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01374906. Findings: Between Dec 28, 2011, and Dec 9, 2014, we randomly allocated 150 patients to receive pasireotide 10 mg (74 [49%] patients) or 30 mg (76 [51%] patients). The primary efficacy endpoint was met by 31 (41·9% [95% CI 30·5-53·9]) of 74 patients in the 10 mg group and 31 (40·8% [29·7-52·7] ) of 76 in the 30 mg group. The most common adverse events were hyperglycaemia (36 [49%] in the 10 mg group and 36 [47%] in the 30 mg group), diarrhoea (26 [35%] and 33 [43%] ), cholelithiasis (15 [20%] and 34 [45%] ), diabetes mellitus (14 [19%] and 18 [24%] ), and nausea (15 [20%] and 16 [21%] ). Serious adverse events suspected to be study drug related were reported in eight (11%) patients in the 10 mg group and four (5%) in the 30 mg group. Two (3%) patients in the 30 mg group died during the study (pulmonary artery thrombosis and cardiorespiratory failure); neither death was judged to be related to the study drug. Interpretation: Long-acting pasireotide normalised mUFC concentration in about 40% of patients with Cushing's disease at month 7 and had a similar safety profile to that of twice-daily subcutaneous pasireotide. Long-acting pasireotide is an efficacious treatment option for some patients with Cushing's disease who have persistent or recurrent disease after initial surgery or are not surgical candidates, and provides a convenient monthly administration schedule. Funding: Novartis Pharma AG

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Kauphegðun. Áhrif líkamsræktar á kaup matvæla

Markmið þessarar rannsóknar var að kanna kauphegðun neytenda í tengslum við það hvort að líkamsrækt hefði áhrif á kaupvenjur þeirra varðandi matvæli og neyslu þeirra. Á Íslandi eru fleiri líkamsræktarstövar miðað við höfðatölu en í öðrum löndum og hreyfing og hollt mataræði er orðin viðurkennd staðreynd. Til að nálgast viðfangsefnið var byrjað á því að skoða fræðilegar ástæður fyrir kauphegðun neytenda og í ljós kom að menningarlegir, félagslegir, persónulegir og sálfræðilegir þættir hafa áhrif á hvernig kauphegðun einstaklinga er háttað ásamt fjárhagslegri getu þeirra. Neyslumarkaðurinn einkennist af markaðsáreiti sem hefur áhrif á kaupferli neysluvara. Áhugi hefur aukist undanfarin ár á að borða hollan mat og stunda líkamsrækt og markaðsáreiti tengist því að selja slíkar vörur. Matvæla- og næringarfræðingar hafa verið að reyna að auka neyslu á hollum og næringarríkum mat og hefur markaðsþróun breyst undanfarin ár hvað það varðar. Þegar fræðilegir þætti kauphegðunar höfðu verið skoðaðir hóf höfundur að gera megindlega rannsókn, sem framkvæmd var á vefsíðunni Google Docs og voru þátttakendur í þessari rannsókn 130 einstaklingar