Circulating branched-chain amino acid (BCAA) levels are elevated in obesity/diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers ...plasma BCAA levels through induction of hepatic protein expression and activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway. Selective induction of hypothalamic insulin signaling in rats and genetic modulation of brain insulin receptors in mice demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Short-term overfeeding impairs the ability of brain insulin to lower BCAAs in rats. High-fat feeding in nonhuman primates and obesity and/or diabetes in humans is associated with reduced BCKDH protein in liver. These findings support the concept that decreased hepatic BCKDH is a major cause of increased plasma BCAAs and that hypothalamic insulin resistance may account for impaired BCAA metabolism in obesity and diabetes.
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•Insulin, but not glucose, is a major regulator of circulating BCAAs•Hypothalamic insulin lowers plasma BCAAs and induces hepatic BCAA catabolism•Acute overfeeding impairs the ability of brain insulin to lower circulating BCAAs•High-fat feeding in primates or obese/diabetic humans decreases hepatic BCKDH
Circulating branched-chain amino acid (BCAA) levels are elevated in obesity and diabetes. Shin et al. describe a brain insulin pathway that decreases BCAA levels by enhancing its degradation in the liver. High-fat-fed rodents and nonhuman primates, as well as diabetics, have reduced amounts of the enzyme responsible for degradation.
Abstract Currently available data on prognostic implication of additional neoplasms in GIST miss comprehensive information on patient outcome with regard to overall or disease specific and disease ...free survival. Registry data of GIST patients with and without additional neoplasm were compared in retrospective case series. We investigated a total of 836 patients from the multi-center Ulmer GIST registry. Additionally, a second cohort encompassing 143 consecutively recruited patients of a single oncology center were analyzed. The frequency of additional malignant neoplasms in GIST patients was 31.9% and 42.0% in both cohorts with a mean follow-up time of 54 and 65 months (median 48 and 60 months), respectively. The spectrum of additional neoplasms in both cohorts encompasses gastrointestinal tumors (43.5%), uro-genital and breast cancers (34.1%), hematological malignancies (7.3%), skin cancer (7.3%) and others. Additional neoplasms have had a significant impact on patient outcome. The five year overall survival in GIST with additional malignant neoplasms ( n = 267) was 62.8% compared to 83.4% in patients without other tumors ( n = 569) ( P < .001, HR=0.397, 95% CI: 0.298-0.530). Five-year disease specific survival was not different between both groups (90.8% versus 90.9%). 34.2% of all deaths ( n = 66 of n = 193) were GIST-related. The presented data suggest a close association between the duration of follow-up and the rate of additional malignancies in GIST patients. Moreover the data indicate a strong impact of additional malignant neoplasms in GIST on patient outcome. A comprehensive follow-up strategy of GIST patients appears to be warranted.
The tumour suppressor p53 prevents tumour formation after DNA damage by halting cell cycle progression to allow DNA repair or by inducing apoptotic cell death. Loss of wild‐type p53 function renders ...cells resistant to DNA damage‐induced cell cycle arrest and ultimately leads to genomic instabilities including gene amplifications, translocations and aneuploidy. Some of these chromosomal lesions are based on mechanisms that involve recombinatorial events. Here we report that p53 physically interacts with key factors of homologous recombination: the human RAD51 protein and its prokaryotic homologue RecA. In vitro, wild‐type p53 inhibits defined biochemical activities of RecA protein, such as three‐way DNA strand exchange and single strand DNA‐dependent ATPase activity. In vivo, temperature‐sensitive p53 forms complexes with RAD51 only in wild‐type but not in mutant conformation. These observations suggest that functional wild‐type p53 may select directly the appropriate pathway for DNA repair and control the extent and timing of the production of genetic variation via homologous recombination. Gene amplification an other types of chromosome rearrangements involved in tumour progression might occur not only as result of inappropriate cell proliferation but as a direct consequence of a defect in p53‐mediated control of homologous recombination processes due to mutations in the p53 gene.
The serine/threonine-specific casein kinase I delta (CKIdelta) is ubiquitously expressed in all tissues, is p53 dependently induced in stress situations and plays an important role in various ...cellular processes. Our immunohistochemical analysis of the human placenta revealed strongest expression of CKIdelta in extravillous trophoblast cells and in choriocarcinomas. Investigation of the functional role of CKIdelta in an extravillous trophoblast hybrid cell line revealed that CKIdelta was constitutively localized at the centrosomes and the mitotic spindle. Inhibition of CKIdelta with the CKI-specific inhibitor IC261 led to structural alterations of the centrosomes, the formation of multipolar spindles, the inhibition of mitosis and, in contrast to other cell lines, the induction of apoptosis. Our findings indicate that CKIdelta plays an important role in the mitotic progression and in the survival of cells of trophoblast origin. Therefore, IC261 could provide a new tool in treating choriocarcinomas.
Background
Treatment of individuals with asymptomatic carotid artery stenosis is still handled controversially. Recommendations for treatment of asymptomatic carotid stenosis with carotid ...endarterectomy (CEA) are based on trials having recruited patients more than 15 years ago. Registry data indicate that advances in best medical treatment (BMT) may lead to a markedly decreasing risk of stroke in asymptomatic carotid stenosis. The aim of the SPACE-2 trial (ISRCTN78592017) was to compare the stroke preventive effects of BMT alone with that of BMT in combination with CEA or carotid artery stenting (CAS), respectively, in patients with asymptomatic carotid artery stenosis of ≥70% European Carotid Surgery Trial (ECST) criteria.
Methods
SPACE-2 is a randomized, controlled, multicenter, open study. A major secondary endpoint was the cumulative rate of any stroke (ischemic or hemorrhagic) or death from any cause within 30 days plus an ipsilateral ischemic stroke within one year of follow-up. Safety was assessed as the rate of any stroke and death from any cause within 30 days after CEA or CAS. Protocol changes had to be implemented. The results on the one-year period after treatment are reported.
Findings
It was planned to enroll 3550 patients. Due to low recruitment, the enrollment of patients was stopped prematurely after randomization of 513 patients in 36 centers to CEA (n = 203), CAS (n = 197), or BMT (n = 113). The one-year rate of the major secondary endpoint did not significantly differ between groups (CEA 2.5%, CAS 3.0%, BMT 0.9%; p = 0.530) as well as rates of any stroke (CEA 3.9%, CAS 4.1%, BMT 0.9%; p = 0.256) and all-cause mortality (CEA 2.5%, CAS 1.0%, BMT 3.5%; p = 0.304). About half of all strokes occurred in the peri-interventional period. Higher albeit statistically non-significant rates of restenosis occurred in the stenting group (CEA 2.0% vs. CAS 5.6%; p = 0.068) without evidence of increased stroke rates.
Interpretation
The low sample size of this prematurely stopped trial of 513 patients implies that its power is not sufficient to show that CEA or CAS is superior to a modern medical therapy (BMT) in the primary prevention of ischemic stroke in patients with an asymptomatic carotid stenosis up to one year after treatment. Also, no evidence for differences in safety between CAS and CEA during the first year after treatment could be derived. Follow-up will be performed up to five years. Data may be used for pooled analysis with ongoing trials.
Currently available data on prognostic implication of additional neoplasms in GIST miss comprehensive information on patient outcome with regard to overall or disease specific and disease free ...survival. Registry data of GIST patients with and without additional neoplasm were compared in retrospective case series. We investigated a total of 836 patients from the multi-center Ulmer GIST registry. Additionally, a second cohort encompassing 143 consecutively recruited patients of a single oncology center were analyzed. The frequency of additional malignant neoplasms in GIST patients was 31.9% and 42.0% in both cohorts with a mean follow-up time of 54 and 65 months (median 48 and 60 months), respectively. The spectrum of additional neoplasms in both cohorts encompasses gastrointestinal tumors (43.5%), uro-genital and breast cancers (34.1%), hematological malignancies (7.3%), skin cancer (7.3%) and others. Additional neoplasms have had a significant impact on patient outcome. The five year overall survival in GIST with additional malignant neoplasms (
n
= 267) was 62.8% compared to 83.4% in patients without other tumors (
n
= 569) (
P
< .001, HR=0.397, 95% CI: 0.298-0.530). Five-year disease specific survival was not different between both groups (90.8% versus 90.9%). 34.2% of all deaths (
n
= 66 of
n
= 193) were GIST-related. The presented data suggest a close association between the duration of follow-up and the rate of additional malignancies in GIST patients. Moreover the data indicate a strong impact of additional malignant neoplasms in GIST on patient outcome. A comprehensive follow-up strategy of GIST patients appears to be warranted.
Zusammenfassung
Hintergrund
Die präklinische Notfallthorakotomie („prehospital resuscitative thoracotomy“,
PHRT
) ist eine von den aktuellen Reanimationsleitlinien des European Resuscitation Council ...(ERC) empfohlene, kontrovers diskutierte Maßnahme zur Akutbehandlung des traumatischen Herz-Kreislauf-Stillstands („traumatic cardiac arrest“, TCA). Ziel dieser Arbeit ist das vollständige Abbilden und Zusammenfassen der vorhandenen Literatur mit der zugrunde liegenden Hypothese, dass vorhandene Publikationen die Machbarkeit und das Überleben nach PHRT bei Patienten mit TCA mit gutem neurologischen Outcome zeigen.
Methode
Es erfolgte eine systematische Literaturrecherche in den Datenbanken
PubMed, EMBASE, Google Scholar
, SpringerLink und Cochrane. Die Studienauswahl, Datenextraktion und Bewertung des Verzerrungspotenzials wurden unabhängig von 2 Autoren durchgeführt. Als primärer Endpunkt wurde das Outcome der Patienten mit TCA nach präklinischer Notfallthorakotomie gewählt.
Ergebnisse
Es wurden 4616 Publikationen gesichtet, 21 Veröffentlichungen mit insgesamt 287 Patienten konnten eingeschlossen werden. Für eine detaillierte deskriptive Analyse eigneten sich 15 Publikationen mit insgesamt 205 Patienten. Der TCA dieser Patienten war am häufigsten durch eine Perikardtamponade, thorakale Gefäßverletzungen und schwere extrathorakale Mehrfachverletzungen verursacht. In 24 % der Fälle trat ein TCA im Beisein des Notarztes auf. Die „Clamshell“-Thorakotomie (53 %) wurde präklinisch häufiger als die anterolaterale Thorakotomie (47 %) angewandt. 12 % (25/205) der PHRT-Patienten nach TCA verließen lebend das Krankenhaus, 9 % (
n
= 19/205) mit gutem und 1 % (
n
= 3/205) mit schlechtem neurologischen Outcome (nach Glasgow Outcome Scale, GOS).
Schlussfolgerung
Die Prognose des TCA scheint deutlich besser zu sein als lange angenommen. Maßgeblich für den Erfolg von Reanimationsbemühungen beim TCA scheint die unverzügliche, teils invasive Therapie aller reversiblen Ursachen zu sein. Die von der ERC-Reanimationsleitlinien für den TCA empfohlenen Maßnahmen scheinen insbesondere für die Präklinik bisher unzureichend umgesetzt. Eine besondere Kontroverse hinsichtlich der Empfehlungen der Leitlinie besteht zur Frage, ob eine PHRT erfolgreich angewandt werden kann und deren flächendeckende Einführung in Deutschland sinnvoll erscheint. Die vorliegende systematische Übersichtsarbeit unterstreicht trotz Leitlinienempfehlung den Mangel an hochwertiger Evidenz zur PHRT, wobei eine Überlebenswahrscheinlichkeit bis zur Entlassung aus dem Krankenhaus von 12 %, in 75 % davon mit gutem neurologischen Outcome berichtet wird. Das Verzerrungspotenzial der Ergebnisse der einzelnen Publikationen sowie auch dieses Reviews ist hoch. Weitere systematische Forschung im Bereich der präklinischen Traumareanimation ist insbesondere auch zur Akzeptanz der Leitlinienvorgaben erforderlich.
Prehospital resuscitative thoracotomy (PHRT) is a controversially discussed measure for the acute treatment of traumatic cardiac arrest (TCA) recommended by the current guidelines of the European ...Resuscitation Council (ERC). The aim of this work is the comprehensive presentation and summary of the available literature with the underlying hypothesis that the available publications show the feasibility and survival following PHRT in patients with TCA with a good neurological outcome.
A systematic literature search was performed in the databases PubMed, EMBASE, Google Scholar, Springer LINK and Cochrane. The study selection, data extraction and evaluation of bias potential were performed independently by two authors. The outcome of patients with TCA after PHRT was selected as the primary endpoint.
A total of 4616 publications were found of which 21 publications with a total of 287 patients could be included in the analyses. For a detailed descriptive analysis, 15 publications with a total of 205 patients were suitable. The TCA of these patients was most commonly caused by pericardial tamponade, thoracic vascular injuries and severe extrathoracic multiple injuries. In 24% of the cases TCA occurred in the presence of the emergency physician. Clamshell thoracotomy (53%) was used preclinically more often than anterolateral thoracotomy (47%). Of the PHRT patients after TCA 12% (25/205) left the hospital alive, 9% (n = 19/205) with good neurological outcome and 1% (n = 3/205) with poor neurological outcome (according to the Glasgow outcome scale, GOS).
The prognosis of TCA seems to be much better than has long been assumed. Decisive for the success of resuscitation efforts in TCA seems to be the immediate, partly invasive treatment of all reversible causes. The measures for TCA recommended by the ERC resuscitation guidelines, seem to be poorly implemented, especially in the preclinical setting. A controversy regarding the recommendations of the guidelines is the question of whether a PHRT can be successfully implemented and if the comprehensive introduction in Germany seems to be meaningful. Despite the recommendation of the guidelines, this systematic review and meta-analysis underlines the lack of high-quality evidence on PHRT, whereby a survival probability to hospital discharge of 12% was reported, of which 75% had a good neurological outcome. The risk of bias of the results in individual publications as well as in this review is high. Further systematic research in the field of preclinical trauma resuscitation is particularly necessary also for acceptance of the guidelines.
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