The Water Fraction of Calendula officinalis Hydroethanol Extract Stimulates In Vitro and In Vivo Proliferation of Dermal Fibroblasts in Wound Healing

The active fraction and/or compounds of Calendula officinalis responsible for wound healing are not known yet. In this work we studied the molecular target of C. officinalis hydroethanol extract (CEE) and its active fraction (water fraction of hydroethanol extract, WCEE) on primary human dermal fibroblasts (HDF). In vivo, CEE or WCEE were topically applied on excisional wounds of BALB/c mice and the rate of wound contraction and immunohistological studies were carried out. We found that CEE and only its WCEE significantly stimulated the proliferation as well as the migration of HDF cells. Also they up‐regulate the expression of connective tissue growth factor (CTGF) and α‐smooth muscle actin (α‐SMA) in vitro. In vivo, CEE or WCEE treated mice groups showed faster wound healing and increased expression of CTGF and α‐SMA compared to placebo control group. The increased expression of both the proteins during granulation phase of wound repair demonstrated the potential role of C. officinalis in wound healing. In addition, HPLC‐ESI MS analysis of the active water fraction revealed the presence of two major compounds, rutin and quercetin‐3‐O‐glucoside. Thus, our results showed that C. officinalis potentiated wound healing by stimulating the expression of CTGF and α‐SMA and further we identified active compounds. Copyright © 2016 John Wiley & Sons, Ltd.     

Accuracy of central venous pressure monitoring during simultaneous continuous infusion through the same catheter

Continuous central pressure monitoring and simultaneous continuous infusion via the same central venous catheter are sometimes necessary. Based on theoretical calculations and experimental measurements, we have determined that pressure monitoring is essentially unaffected if the continuous infusion rate is 50 ml.h(-1) or less for an adult and a paediatric central catheter. At rates > 200 ml.h(-1), the central venous pressure is exaggerated by up to 4 mmHg and 8 mmHg for the adult and paediatric catheters, respectively.     

Role of circulating tumor cells in patients with metastatic clear-cell renal cell carcinoma

PurposeCirculating tumor cells (CTC) have been demonstrated to have prognostic and predictive role in certain human cancers. However, studies exploring their role in metastatic renal cell carcinoma (mRCC) are scarce. We aimed to evaluate the prognostic and predictive role of CTC in mRCC.Materials and methodsIn this prospective study, 35 patients with mRCC were analyzed for the presence of CTC before starting tyrosine kinase inhibitors (TKI). Progression-free and overall survival rates were estimated using the Kaplan-Meier curves and log-rank test. The prediction to TKI therapy was calculated with the response to treatment determined by standard imaging techniques.ResultsOutcomes were assessed according to the CTC positivity at baseline, before the patients started TKI for mRCC. At a mean follow-up of 12.4 ± 4.1 months, disease progression was noted in 17 patients (48.6%) including 8 deaths (22.9%). CTC positive patients had a significantly lower progression-free survival rate (12.5% vs. 64.1%, respectively; P = 0.009) but not in the overall survival rate (75% vs. 76.3%, respectively; P = 0.88) in the Kaplan–Meier estimation curves. CTC positivity at baseline significantly predicted a poorer response to TKI (87.5% vs. 37.1%, P = 0.01). The multivariate Cox proportional hazards analysis showed that CTC at baseline was the most significant predictor of progression-free survival (hazard ratio 4.17, 95% confidence interval 1.41–11.99, P = 0.01).ConclusionsBaseline CTC detection can be an important prognostic factor of progression-free survival and significant predictor of poor response to TKI in patients with metastatic RCC.     

Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models

Background & Aims

Non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH) are common clinico‐pathological conditions that affect millions of patients worldwide. In this study, the efficacy of saroglitazar, a novel PPARα/γ agonist, was assessed in models of NAFLD/NASH.

Methods & Results

HepG2 cells treated with palmitic acid (PA;0.75 mM) showed decreased expression of various antioxidant biomarkers (SOD1, SOD2, glutathione peroxidase and catalase) and increased expression of inflammatory markers (TNFα, IL1β and IL6). These effects were blocked by saroglitazar, pioglitazone and fenofibrate (all tested at 10μM concentration). Furthermore, these agents reversed PA‐mediated changes in mitochondrial dysfunction, ATP production, NFkB phosphorylation and stellate cell activation in HepG2 and HepG2‐LX2 Coculture studies. In mice with choline‐deficient high‐fat diet‐induced NASH, saroglitazar reduced hepatic steatosis, inflammation, ballooning and prevented development of fibrosis. It also reduced serum alanine aminotransferase, aspartate aminotransferase and expression of inflammatory and fibrosis biomarkers. In this model, the reduction in the overall NAFLD activity score by saroglitazar (3 mg/kg) was significantly more prominent than pioglitazone (25 mg/kg) and fenofibrate (100 mg/kg). Pioglitazone and fenofibrate did not show any improvement in steatosis, but partially improved inflammation and liver function. Antifibrotic effect of saroglitazar (4 mg/kg) was also observed in carbon tetrachloride‐induced fibrosis model.

Conclusions

Saroglitazar, a dual PPARα/γ agonist with predominant PPARα activity, shows an overall improvement in NASH. The effects of saroglitazar appear better than pure PPARα agonist, fenofibrate and PPARγ agonist pioglitazone.     

Continuous thoracic paravertebral infusion of bupivacaine for pain management in patients with multiple fractured ribs

STUDY OBJECTIVE: To evaluate the efficacy of a continuous thoracic paravertebral infusion of bupivacaine for pain management in patients with unilateral multiple fractured ribs (MFR). DESIGN: Prospective nonrandomized case series. SETTING: Multidisciplinary tertiary hospital. PATIENTS: Fifteen patients with unilateral MFR. INTERVENTIONS: Insertion of a catheter into the thoracic paravertebral space. We administered an initial injection of 0.3 mL/kg (1.5 mg/kg) bupivacaine 0.5% with 1:200,000 epinephrine followed 30 min later by an infusion of bupivacaine 0.25% at 0.1 to 0.2 mL/kg/h for 4 days. Measurements and results: The following parameters were measured during the initial assessment before thoracic paravertebral block (TPVB), 30 min after the initial injection, and during follow-up on day 1 and day 4 after commencing the infusion of bupivacaine: visual analog pain score at rest and during coughing; respiratory rate; arterial oxygen saturation (SaO(2)); bedside spirometry (ie, FVC, FEV(1), FEV(1)/FVC ratio, and peak expiratory flow rate [PEFR]); arterial blood gas measurements; and O(2) index (ie, PaO(2)/fraction of inspired oxygen ratio). There were significant improvements in pain scores (at rest, p = 0.002; during coughing, p = 0.001), respiratory rate (p < 0.0001), FVC (p = 0.007), PEFR (p = 0.01), SaO(2) (p = 0.04), and O(2) index (p = 0.01) 30 min after the initial injection, which were sustained for the 4 days that the thoracic paravertebral infusion was in use (p < 0.05). PaCO(2) did not change significantly after the initial injection, but on day 4 it was significantly lower than the post-TPVB value (p = 0.04). One patient had an inadvertent epidural injection, and another developed transient ipsilateral Horner syndrome with sensory changes in the arm. No patient exhibited clinical signs of inadvertent intravascular injection or local anesthetic toxicity. CONCLUSION: Our results confirmed that continuous thoracic paravertebral infusion of bupivacaine is a simple and effective method of providing continuous pain relief in patients with unilateral MFR. It also produced a sustained improvement in respiratory parameters and oxygenation.