Right ventricular function in rats with hypoxic pulmonary hypertension

The function of the hypertrophic right ventricle (RV) was studied in adult rats with hypoxic pulmonary hypertension induced by intermittent high-altitude (IHA) exposure. The isolated RV working heart preparation that was employed enabled us to estimate ventricular contractile and pump performance under controlled loading conditions. In rats exposed to IHA hypoxia the elevated RV systolic pressure and maximum rate of pressure development were observed at various levels of preload or afterload. The peak indices of mechanical performance were almost doubled in these animals when compared with the normoxic group, while the index of contractility remained unchanged. Maximum ventricular performance was found to be a linear function of the relative RV weight. No evidence of RV pump dysfunction was detected in rats exposed to IHA; moreover, the ability of the ventricle to maintain cardiac output against increased pulmonary resistance was markedly improved. The prevention of tricuspid regurgitation by using an artificial valve did not influence the functional curves and the peak ventricular performance. The regression of hypertrophy was accompanied by a reversal of ventricular function to control values, except for the persisting slight increase of peak RV pressure. It may be concluded that the increase of the RV mass in IHA-exposed rats serves to improve maximum ventricular performance, which aids in overcoming an elevated pulmonary resistance without disturbing the pump function.     

Urinary zinc excretion and acute phase response in cancer patients

We investigated urinary zinc and serum levels of C-reactive protein, alpha-1 acid glycoprotein, haptoglobin, transferrin and prealbumin in 55 patients with solid tumors and 20 controls. Urinary zinc, serum C-reactive protein, alpha-1 acid glycoprotein and haptoglobin were significantly higher, and serum prealbumin was significantly lower in cancer patients. A significant positive correlation between urinary zinc and C-reactive protein, alpha-1 acid glycoprotein and haptoglobin, as well as a negative correlation with transferrin and prealbumin were observed. Hyperzincuria in cancer patients appears to be linked to the acute phase response. Our data provide further evidence implicating systemic inflammatory response in increased urinary zinc excretion. Correspondence to: B. Melichar     

Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma: Final Overall Survival Analysis of the Phase 3 PROTECT Trial

Most studies indicate no benefit of adjuvant therapy with VEGFR tyrosine kinase inhibitors in advanced renal cell carcinoma (RCC). PROTECT (NCT01235962) was a randomized, double-blind, placebo-controlled phase 3 study to evaluate adjuvant pazopanib in patients with locally advanced RCC at high risk of relapse after nephrectomy (pazopanib, n = 769; placebo, n = 769). The results of the primary analysis showed no difference in disease-free survival between pazopanib 600 mg and placebo. Here we report the final overall survival (OS) analysis (median follow-up: pazopanib, 76 mo, interquartile range [IQR] 66–84; placebo, 77 mo, IQR 69–85). There was no significant difference in OS between the pazopanib and placebo arms (hazard ratio 1.0, 95% confidence interval 0.80–1.26; nominal p > 0.9). OS was worse for patients with T4 disease compared to those with less advanced disease and was better for patients with body mass index (BMI) ≥30 kg/m² compared to those with lower BMI. OS was significantly better for patients who remained diseasefree at 2 yr after treatment compared with those who relapsed within 2 yr. These findings are consistent with the primary outcomes from PROTECT, indicating that adjuvant pazopanib does not confer a benefit in terms of OS for patients following resection of locally advanced RCC.Patient summaryIn the randomized, double-blind, placebo-controlled phase 3 PROTECT study, overall survival was similar for patients with locally advanced renal cell carcinoma (RCC) at high risk of relapse after nephrectomy who received adjuvant therapy with pazopanib or placebo. Pazopanib is not recommended as adjuvant therapy following resection of locally advanced RCC.This trial is registered at Clinicaltrials.gov as NCT01235962.     

Impact of Delayed Addition of Anti-EGFR Monoclonal Antibodies on the Outcome of First-Line Therapy in Metastatic Colorectal Cancer Patients: a Retrospective Registry-Based Analysis

Background

The addition of monoclonal antibodies targeting the epidermal growth factor receptor (anti-EGFR Abs) to chemotherapy for metastatic colorectal carcinoma (mCRC) is commonly delayed in the real-world clinical practice, usually because of late RAS testing results.

Objective

To determine whether delayed addition of anti-EGFR mAbs up to the fourth cycle of backbone chemotherapy adversely affected outcomes of mCRC patients treated with first-line regimens.

Patients and Methods

Clinical data of patients with histologically verified, RAS wild-type mCRC treated with first-line systemic therapy regimens containing anti-EGFR mAbs were retrospectively analysed from a national database. Patients were divided into three groups according to the timing of anti-EGFR mAbs addition to the chemotherapy backbone. Cohort A (n?=?401) included patients in whom anti-EGFR mAbs were added to chemotherapy from the first cycle, cohort B (n?=?71) patients with anti-EGFR mAbs added to chemotherapy from the second cycle, and cohort C (n?=?101) patients who had anti-EGFR mAbs added to chemotherapy from the third or fourth cycle.

Results

Three hundred and thirty-six (58.6%) patients received panitumumab and 237 (41.4%) patients received cetuximab. The median progression-free survival (PFS) of the whole cohort was 12.2 months (95% confidence interval [CI] 10.9–13.5), and the median overall survival (OS) was 33.5 months (95% CI 27.6–39.4). The median PFS and OS for patients treated with anti-EGFR mAbs added to chemotherapy were 12.9 (95% CI 11.5–14.3) and 30.6 months (95% CI 25.2–36.1) for cohort A, 9.7 (95% CI 9.1–10.3) and not reached for cohort B, compared to 11.5 (95% CI 9.8–13.2) and 37.9 months (95% CI 28.6–47.3) for cohort C, respectively.

Conclusions

Delayed addition of anti-EGFR mAbs to first-line chemotherapy was not associated with inferior survival or response rates.

     

Epidermal growth factor reduces hepatic sequelae in experimental necrotizing enterocolitis

BACKGROUND AND AIM: Neonatal necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of premature infants. We recently demonstrated that the gut/liver axis plays an important role in the pathophysiology of NEC through the release of inflammatory mediators into the intestinal lumen. We have also shown that supplementation of formula with epidermal growth factor (EGF) dramatically decreases ileal pathology associated with experimental NEC. In this study, we examined the effects of EGF on the liver portion of the gut/liver axis in the neonatal rat model of NEC. METHODS: Newborn rats were divided into three experimental groups, NEC, hand-fed with growth-factor free formula; NEC + EGF, hand-fed with formula supplemented with 500 ng/ml rat EGF; or DF, dam fed. All animals were exposed to asphyxia and cold stress twice daily for 4 days to develop NEC. RESULTS: EGF receptor expression was significantly (p 相似文献   

Benzodiazepine dependence and its treatment with low dose flumazenil

Globally benzodiazepines remain one of the most prescribed medication groups, especially in the primary care setting. With such high levels of prescribing it is not surprising that benzodiazepine dependence is common, cutting across all socioeconomic levels. Despite recognition of the potential for the development of iatrogenic dependence and the lack of any effective treatment, benzodiazepines continue to be widely prescribed in general practice. Conventional dependence management, benzodiazepine tapering, is commonly a protracted process over several weeks or months. It is often associated with significant withdrawal symptoms and craving leading to patient drop out and return to use. Accordingly, there is a worldwide need to find effective pharmacotherapeutic interventions for benzodiazepine dependence. One drug of increasing interest is the GABA_A benzodiazepine receptor antagonist/partial agonist, flumazenil. Multiple bolus intravenous infusions of low dose flumazenil used either with or without benzodiazepine tapering can reduce withdrawal sequelae, and/or longer term symptoms in the months following withdrawal. Preliminary data suggest that continuous intravenous or subcutaneous flumazenil infusion for 4 days significantly reduces acute benzodiazepine withdrawal sequelae. The subcutaneous infusion was shown to be tissue compatible so the development of a longer acting (i.e. several weeks) depot flumazenil formulation has been explored. This could be capable of managing both acute and longer term benzodiazepine withdrawal sequelae. Preliminary in vitro water bath and in vivo biocompatibility data in sheep show that such an implant is feasible and so is likely to be used in clinical trials in the near future.     

Ulva flexuosa subsp. pilifera (Chlorophyta, Ulvophyceae) from the Wielkopolska region (West Poland): a new observation on the ultrastructure of vegetative cells

Ulva flexuosa subsp. pilifera previously known from northern Poland, from the channel near Szczecin and ponds near ?ód?, has recently been found in the Malta Reservoir in the Wielkopolska (West Poland) region. Specimens collected in the Wielkopolska region were examined in detail, also under a transmission electron microscope (TEM). The morphometric analysis of Ulva thalli (both young and mature specimens) was performed in order to study the differences in the ultrastructure of vegetative cells. Rectangular cells in young thalli measured from 32.21–55.81 μm to 20.24–35.12 μm, and they formed clear longitudinal rows, while cells in the mature specimens ranged from 25.09–47.66 μm to 18.90–31.56 μm. This study indicates that vegetative cells of the mature thalli show tendency towards distortions of both the longitudinal and transverse cells arrangement. This distortion is determined by the development of possible carbonate calcium crystals on the thalli surface. The ultrastructural analysis (TEM) confirmed that the structure and placement of thylakoids is genus/species specific.