Decorin deficiency promotes hepatic carcinogenesis

Hepatocellular carcinoma represents one of the most-rapidly spreading cancers in the world. In the majority of cases, an inflammation-driven fibrosis or cirrhosis precedes the development of the tumor. During malignant transformation, the tumor microenvironment undergoes qualitative and quantitative changes that modulate the behavior of the malignant cells. A key constituent for the hepatic microenvironment is the small leucine-rich proteoglycan decorin, known to interfere with cellular events of tumorigenesis mainly by blocking various receptor tyrosine kinases (RTK) such as EGFR, Met, IGF-IR, PDGFR and VEGFR2. In this study, we characterized cell signaling events evoked by decorin deficiency in two experimental models of hepatocarcinogenesis using thioacetamide or diethyl nitrosamine as carcinogens. Genetic ablation of decorin led to enhanced tumor occurrence as compared to wild-type animals. These findings correlated with decreased levels of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 and a concurrent elevation in retinoblastoma protein phosphorylation via cyclin dependent kinase 4. Decreased steady state p21Waf1/Cip1 levels correlated with enhanced expression of transcription factor AP4, a known transcriptional repressor of p21Waf1/Cip1, and enhanced c-Myc protein levels. In addition, translocation of beta-catenin was a typical event in diethyl nitrosamine-evoked tumors. In parallel, decreased phosphorylation of both c-Myc and beta-catenin was observed in Dcn-/- livers likely due to the hindered GSK3beta-mediated targeting of these proteins to proteasomal degradation. We discovered that in a genetic background lacking decorin, four RTKs were constitutively activated (phosphorylated), including three known targets of decorin such as PDGFRalpha, EGFR, IGF-IR, and a novel RTK MSPR/RON. Our findings provide powerful genetic evidence for a crucial in vivo role of decorin during hepatocarcinogenesis as lack of decorin in the liver and hepatic stroma facilitates experimental carcinogenesis by providing an environment devoid of this potent pan-RTK inhibitor. Thus, our results support future utilization of decorin as an antitumor agent in liver cancer

Levosimendan Administration in Limb Ischemia: Multicomponent Signaling Serving Kidney Protection

AIMS AND OBJECTIVES: Acute renal failure is a severe complication of lower extremity major arterial reconstructions, which could even be fatal. Levosimendan is a dual-acting positive inotropic and vasodilatory agent, which is suspected to have protective effects against cardiac ischemia. However, there is no data available on lower limb or remote organ ischemic injuries therefore the aim of the study was to investigate the effect of levosimendan on lower limb ischemia-reperfusion injury and the corollary renal dysfunction. METHODS: Male Wistar rats underwent 180 min bilateral lower limb ischemia followed by 4 or 24 hours of reperfusion. Intravenous Levosimendan was administered continuously (0.2mug/bwkg/min) throughout the whole course of ischemia and the first 3h of reperfusion. Results were compared with sham-operated and ischemia-reperfusion groups. Hemodynamic monitoring was performed by invasive arterial blood pressure measurement. Kidney and lower limb muscle microcirculation was registered by a laser Doppler flowmeter. After 4h and 24h of reperfusion, serum, urine and histological samples were collected. RESULTS: Systemic hemodynamic parameters and microcirculation of kidney and the lower limb significantly improved in the Levosimendan treated group. Muscle viability was significantly preserved 4 and 24 hours after reperfusion. At the same time, renal functional laboratory tests and kidney histology demonstrated significantly less expressive kidney injury in Levosimendan groups. TNF-alpha levels were significantly less elevated in the Levosimendan group 4 hours after reperfusion. CONCLUSION: The results claim a protective role for Levosimendan administration during major vascular surgeries to prevent renal complications

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Rumination in Borderline Personality Disorder: Meta-Analysis

Borderline personality disorder (BPD) is characterized by deficits in emotion regulation and affective liability. Of this domain, ruminative behaviors have been considered a core feature of emotion dysregulation difficulties. Despite this, inconsistencies have existed in the literature regarding which rumination type is most prominent in those with BPD symptoms. Moreover, no meta-analytic review has been performed to date on rumination in BPD. Taking this into consideration, a meta-analysis was performed to assess how BPD symptoms correlate with rumination, while also considering clinical moderator variables (i.e., BPD symptom domain, co-morbidities, GAF score) and demographic moderator variables (i.e., age, gender, sample type, and education level). Analysis of correlation across rumination domains for the entire sample revealed a medium overall correlation between BPD symptoms and rumination. When assessing types of rumination, the largest correlation was among pain rumination followed by anger, depressive, and anxious rumination. Among BPD symptom domain, affective instability had the strongest correlation with increased rumination, followed by unstable relationships, identity disturbance, and self-harm/ impulsivity, respectively. Demographic variables showed no significance. Clinical implications are considered and further therapeutic interventions are discussed in the context of rumination

Rumination in Borderline Personality Disorder: Meta-Analysis

Borderline personality disorder (BPD) is characterized by deficits in emotion regulation and affective liability. Of this domain, ruminative behaviors have been considered a core feature of emotion dysregulation difficulties. Despite this, inconsistencies have existed in the literature regarding which rumination type is most prominent in those with BPD symptoms. Moreover, no meta-analytic review has been performed to date on rumination in BPD. Taking this into consideration, a meta-analysis was performed to assess how BPD symptoms correlate with rumination, while also considering clinical moderator variables (i.e., BPD symptom domain, co-morbidities, GAF score) and demographic moderator variables (i.e., age, gender, sample type, and education level). Analysis of correlation across rumination domains for the entire sample revealed a medium overall correlation between BPD symptoms and rumination. When assessing types of rumination, the largest correlation was among pain rumination followed by anger, depressive, and anxious rumination. Among BPD symptom domain, affective instability had the strongest correlation with increased rumination, followed by unstable relationships, identity disturbance, and self-harm/ impulsivity, respectively. Demographic variables showed no significance. Clinical implications are considered and further therapeutic interventions are discussed in the context of rumination

Rumination in Borderline Personality Disorder: A Meta-analytic Review

Borderline personality disorder (BPD) is characterized by deficits in emotion regulation and affective liability, specifically rumination. Despite this, inconsistencies have existed in the literature regarding which rumination type is most prominent in BPD. Taking this into consideration, a meta-analysis was performed to look at how BPD symptoms correlate with rumination, while also considering clinical moderator variables (i.e., BPD symptom domain, comorbidities, GAF score) and demographic moderator variables (i.e., age, gender, sample type, and education level). Analysis of rumination domains for the entire sample revealed a medium correlation between BPD symptoms and rumination. When types of rumination were assessed, the largest correlation was among pain rumination followed by anger, depressive, and anxious rumination. Among BPD symptom domain, affective instability had the strongest correlation with increased rumination, followed by unstable relationships, identity disturbance, and self-harm/impulsivity. Demographic variables showed no significance. Clinical implications and further therapeutic interventions are discussed considering rumination

Kidney cortex microcirculation measured with laser Doppler flowmeter.

<p>Measured flux is expressed as a percentage of the baseline flux before the aortic clamping. Flux remained at the baseline level after clamping of the infrarenal aorta in all three animal groups. After revascularization of the limbs, a constant impairment of the kidney cortex microcirculatory flux was observed in the ischemia-reperfusion (IR) group (marked with a broken line), while flux was preserved in the Levosimendan (unbroken line) and the Sham (dotted line) groups. Values are expressed as means ± SD, ‡: p<0.001 vs. Sham, §: p<0.001 vs. IR.</p

Laboratory measurements and calculated parameters for kidney function.

<p>Laboratory measurements and calculated parameters for kidney function.</p

TNF-α concentration.

<p>TNF-α concentrations were significantly higher in the IR (ischemia-reperfusion) group compared to the Sham-operated group after 4 hours of reperfusion. TNF-α levels were significantly less elevated by Levosimendan treatment after 4 hours of reperfusion. 24 hours after reperfusion there were no significant differences among the three experimental groups. Values are expressed as means ± SD, ‡: p<0.001 vs. Sham, §: p<0.001 vs. IR.</p