Hepatocyte ploidy in regenerating livers after partial hepatectomy,drug-induced necrosis,and cirrhosis

The hepatocyte ploidy was investigated by flow cytometry in regenerating Sprague-Dawley rat livers following either drug-induced acute necrosis (single sublethal doses of D-galactosamine or thioacetamide) or drug-induced chronic cirrhosis (repeated thioacetamide injections for 10-18 weeks) and in regenerating livers following 70% partial hepatectomy and was compared with that of normal hepatocytes. Twenty-four hours after partial hepatectomy, a significant decrease in 2n (1 diploid nucleus) hepatocytes and a significant increase in 8n (1 octoploid nucleus) hepatocytes occurred. In contrast, 24 h following induction of acute hepatic failure by single D-galactosamine or thioacetamide injections, a significant increase in 2n hepatocytes was observed, whereas the proportion of 8n hepatocytes remained unchanged. The liver ploidy returned to basal values within 21 days in all cases. In cirrhotic livers induced by chronic thioacetamide injections, the rate of 2n hepatocytes was about ten times that of the controls having the same age, while 4n (1 tetraploid nucleus) and 8n hepatocytes were one third of controls. The binucleation rate was also significantly decreased.     

[6]-Gingerol inhibits de novo fatty acid synthesis and carnitine palmitoyltransferase-1 activity which triggers apoptosis in HepG2

The de novo fatty acid synthesis catalyzed by key lipogenic enzymes, including fatty acid synthase (FASN) has emerged as one of the novel targets of anti-cancer approaches. The present study explored the possible inhibitory efficacy of [6]-gingerol on de novo fatty acid synthesis associated with mitochondrial-dependent apoptotic induction in HepG2 cells. We observed a dissipation of mitochondrial membrane potential accompanied by a reduction of fatty acid levels. [6]-gingerol administration manifested inhibition of FASN expression, indicating FASN is a major target of [6]-gingerol inducing apoptosis in HepG2 cells. Indeed, we found that increased ROS generation could likely be a mediator of the anti-cancer effect of [6]-gingerol. A reduction of fatty acid levels and induction of apoptosis were restored by inhibition of acetyl-CoA carboxylase (ACC) activity, suggesting an accumulation of malonyl-CoA level could be the major cause of apoptotic induction of [6]-gingerol in HepG2 cells. The present study also showed that depletion of fatty acid following [6]-gingerol treatment caused an inhibitory effect on carnitine palmitoyltransferase-1 activity (CPT-1), whereas C75 augmented CPT-1 activity, indicating that [6]-gingerol exhibits the therapeutic benefit on suppression of fatty acid β-oxidation.     

Experimental models of acute and chronic liver failure in nude mice to study hepatocyte transplantation

Although hepatocyte transplantation is a promising therapy for acute liver failure in human, there is still a lack of animal models suffering from hepatic injury in which the benefits of hepatocyte transplantation could be evaluated solely, without the bias caused by immunosuppression. As a consequence, the aim of the study was first to develop reproducible models of partial hepatectomy and of thioacetamide (TA)- or Jo2-induced acute liver failure in nude mice. Chronic liver disease was also investigated by repeated injections of sublethal doses of thioacetamide. Survival rates, routine histologic observations, alanin aminotransferase sera content, Ki67, and caspase 3 immunodetection were investigated both after 40% partial hepatectomy and after toxic-induced damages. Liver injuries were more severe and/or precocious in nude mice than in Balb/c mice for a given treatment with a maximum of acute injury obtained 24 h after single toxic injection, and were found to be transitory and reversible within 10 days. Toxics induced apoptosis followed by necrosis, confirming recent published data. Onset of fibrosis leading to reproducible chronic cirrhosis in nude mice correlated with increasing number of Ki67-positive cells, indicating that high levels of cell proliferation occurred. Chronic cirrhosis progressively reversed to fibrosis when the treatment ceased. Preliminary results demonstrated that engrafted xenogeneic hepatocytes could be detected in the host liver by anti-MHC class I immunohistochemistry. Fractions enriched in 2n or 4n hepatocytes by cell sorting using a flow cytometer were equivalent to the unpurified fraction in terms of engraftment in control nude mice or in nude mice subjected to PH. However, in mice suffering from liver injury 24 h after Jo2 or TA treatment, the engraftment of 2n hepatocytes was about twice that of an unpurified hepatocyte population or of a population enriched in 4n hepatocytes.     

Nursing residency program: a solution to introduce new grads into critical care more safely while improving accessibility to services

Purpose: Critical care units are particularly affected by the shortage of nurses. In order to overcome this problem, many organizations have increased the hiring of newly graduated nurses. This paper describes a residency program developed to facilitate the safe integration of those nurses into critical care and its outcomes. Methods: A one-year nursing residency program dedicated to nurses with less than a year of experience was implemented in 2008. Recruitment and retention rates, as well as accessibility to critical care, were evaluated. Results: A 46% increase in recruitment rate of newly graduated nurses was observed when comparing the same period of time before and after implementation of the program. Moreover, the one-year retention rate rose by 26%; the retention rate, without considering the time since the beginning of employment, rose by 71%. As for accessibility to critical care, it increased by 50% (from 24 to 36 beds). Finally, the program was favourably evaluated by experienced nurses in terms of skills and critical thinking development among nursing residents. Conclusion: A nursing residency program developed to meet the needs of inexperienced nurses and integrate them into high-acuity settings appears to be one solution to resolving undesirable limited access to safe-quality critical care.     

Skeletal muscle loss during chemotherapy and its association with survival and systemic treatment toxicity in metastatic colorectal cancer: An AGEO prospective multicenter study

PurposeWe showed in a previous study that the PG-SGA score is associated with survival and chemotherapy-related toxicities in metastatic colorectal cancer (mCRC) patients. The objective was to evaluate the association between pretherapeutic sarcopenia and variation in skeletal muscle index (SMI) during treatment with these outcomes in the same population.MethodsThis prospective, multicenter, observational study enrolled non-pretreated mCRC patients. SMI was measured on routine CT scan at day 0 (D0) and day 60 (D60). Nutritional factors were collected at D0. Progression-free survival (PFS) and overall survival (OS) were calculated from treatment start.Results149 patients were included from 7/2013 to 11/2016. Pretherapeutic sarcopenia was not significantly associated with survival or chemotherapy-related toxicities. The decrease in SMI > 14% was significantly associated with shorter PFS (6 vs 9 mo; HR 1.8, 95% CI 1.1?3.1, p = 0.02) and OS (8.5 vs 26 mo; HR 2.6, 95% CI 1.4?4.8, p = 0.002), independently of hypoalbuminemia and malnutrition defined by PG-SGA. Patients with a SMI decrease > 14% had a higher rate of grade ≥ 2 clinical toxicities (40% vs 22%, OR 3.0, 95% CI 1.2?7.7, p = 0.02), but the difference was not statistically significant in multivariable analysis.ConclusionTo our knowledge, this is the first study to assess prospectively the association of skeletal muscle loss with survival and treatment toxicities in non-pretreated patients with mCRC. Pretherapeutic sarcopenia was not associated with poor outcomes, but the loss of skeletal muscle mass within 60 days from treatment start was highly prognostic, independently of other prognostic and nutritional factors.     

Survival and evolution of vein grafts in otosclerosis surgery: structural and ultrastructural evidence.

The annular ligament of the stapes footplate measures 0.2 mm2 and contains elastic fibers that restrict perilymphatic movement to a molecular level. This resistance of the annular ligament prevents excessive movement of labyrinthine fluids that are potentially hazardous to the membranous and cellular structures of the inner ear. However, if the resistance of the annular ligament is overcome, then inner ear damage can occur. The vein graft, as used in our technique for otosclerosis surgery, occupies a space of 0.2 mm2 between the edge of the stapedotomy hole and the piston and has nearly the same compliance and resistance as the annular ligament of the stapes footplate. The vein graft becomes integrated with the middle-ear mucosa. It develops a rich and active blood supply and the smooth muscle cells and elastic fibers remain, although the latter show some modification of ultrastructural pattern. The graft becomes overlaid by the middle-ear epithelium. Even samples of vein graft that have been present for many years retain surviving elastic fibers, including those that have become fibrotic. In time, the number of elastic fibers increases as a result of the activity of fibroblasts, which build a poorly colored collagen.     

a-Series gangliosides mediate the effects of advanced glycation end products on pericyte and mesangial cell proliferation: a common mediator for retinal and renal microangiopathy?

Advanced glycation end products (AGEs) are involved in the development of microvascular complications, including alterations of retinal pericyte and renal mesangial cell growth occurring during diabetic retinopathy and diabetic nephropathy, respectively. Because gangliosides are implicated in the regulation of cell proliferation, we hypothesized that AGEs could exert cellular effects in part by modulating ganglioside levels. Results of the present study indicate that AGEs caused an inhibition of both bovine retinal pericyte (BRP) and rat renal mesangial cell (RMC) proliferation, associated with an increase of a-series gangliosides consecutive to GM3 synthase activity increase and GD3 synthase activity inhibition. Similar modifications were also found in the renal cortex of diabetic db/db mice compared with controls. Treatment of BRP and RMC with exogenous a-series gangliosides decreased proliferation and blockade of a-series gangliosides with specific antibodies partially protecting the two cell types from the AGE-induced proliferation decrease. Further, inhibition of GM3 synthase using specific SiRNA partially reversed the AGE effects on mesangial cell proliferation. These results suggest that a-series gangliosides are mediators of the adverse AGE effects on BRP and RMC proliferation. They also raise the hypothesis of common mechanisms involved in the development of diabetic retinopathy and diabetic nephropathy.     

Interim PET Response-adapted Strategy in Untreated Advanced Stage Hodgkin Lymphoma: Results of GOELAMS LH 2007 Phase 2 Multicentric Trial

Background

Patients with advanced stage Hodgkin lymphoma still present unsatisfactory outcomes.