Cavo-portal transposition in rat: a new simple model

Background  

Liver transplantation in presence of diffuse portal vein thrombosis is possible by using caval blood as portal inflow, through cavo-portal transposition. However, clinical results are heterogeneous and experimental studies are needed, but similar hemodynamic conditions are difficult to obtain, especially in small animals. Herein we describe a new simple model of cavo-portal transposition in rat.     

Semen analysis and seminal plasma biochemistry in two brothers with familial reciprocal translocation 46,XY,t(8;9)(p10;p10) transmitted by the father

Here we report familial balanced translocation (46,XY,t(8;9)(p10;p10) inherited by two brothers from the father. The first subject, 33 years old, was examined after 3 years of childless marriage. Semen analysis showed severe oligozoospermia, hypomotility and teratozoospermia. His brother, 29 years old, volunteered to join this study. He had not yet tried to start a family. Semen analysis showed dyspermia, but the condition was much less serious than his brother's. In both subjects, the secretory function of the epididymis and the genital tract accessory glands did not seem to be affected by this particular translocation. This case report highlights the importance of cytogenetic analysis in dealing with infertile patients suffering from severe dyspermia apparently sine causa. This is particularly the case when certain Assisted Reproductive Technology (ART) programs are recommended, where natural selection of the sperm no longer takes place (e.g. ICSI). The possible risk of an increase in fetal chromosomal abnormalities would suggest genetic counselling in all such situations.     

Assessment of pulmonary toxicity of MgO nanoparticles in rats

In this study, we have evaluated the pulmonary toxicity of MgO nanoparticles (MgO NPs) in rats following their exposure. NPs in phosphate buffered saline + 1% Tween 80 were exposed via intratracheal instillation at a doses of 1 mg/kg or 5 mg/kg into rat lungs and evaluated for various tissue damage markers like alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid and histopathology of lungs at 1, 7, and 30 days of post‐exposure intervals. A dose‐dependant increase in ALP and LDH activity was observed in BAL fluids of rat lungs than sham control at all post‐exposure periods (P <0.05), and a dose‐dependant infiltration of interstitial lymphocytes, peribronchiolar lymphocytic infiltration, and dilated and/or congested vessels at 1 day post‐exposure period, worsened at 1 week period, and were reduced at 1 month at histology, indicating the pulmonary toxicity of MgO NPs. In conclusion, MgO NPs exposure produced a dose‐dependent pulmonary toxicity in rats and was comparable with that of Quartz particles. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 308–314, 2015.     

A non-ATP-competitive inhibitor of BCR-ABL overrides imatinib resistance

Imatinib, which is an inhibitor of the BCR-ABL tyrosine kinase, has been a remarkable success for the treatment of Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemias (CMLs). However, a significant proportion of patients chronically treated with imatinib develop resistance because of the acquisition of mutations in the kinase domain of BCR-ABL. Mutations occur at residues directly implicated in imatinib binding or, more commonly, at residues important for the ability of the kinase to adopt the specific closed (inactive) conformation to which imatinib binds. In our quest to develop new BCR-ABL inhibitors, we chose to target regions outside the ATP-binding site of this enzyme because these compounds offer the potential to be unaffected by mutations that make CML cells resistant to imatinib. Here we describe the activity of one compound, ON012380, that can specifically inhibit BCR-ABL and induce cell death of Ph+ CML cells at a concentration of <10 nM. Kinetic studies demonstrate that this compound is not ATP-competitive but is substrate-competitive and works synergistically with imatinib in wild-type BCR-ABL inhibition. More importantly, ON012380 was found to induce apoptosis of all of the known imatinib-resistant mutants at concentrations of <10 nM concentration in vitro and cause regression of leukemias induced by i.v. injection of 32Dcl3 cells expressing the imatinib-resistant BCR-ABL isoform T315I. Daily i.v. dosing for up to 3 weeks with a >100 mg/kg concentration of this agent is well tolerated in rodents, without any hematotoxicity.     

Effects of an integrated poultry value chain,nutrition, gender and WASH intervention (SELEVER) on hygiene and child morbidity and anthropometry in Burkina Faso: A secondary outcome analysis of a cluster randomised trial

Nutrition-sensitive agriculture programmes have the potential to improve child nutrition outcomes, but livestock intensification may pose risks related to water, sanitation and hygiene (WASH) conditions. We assessed the impact of SELEVER, a nutrition- and gender-sensitive poultry intervention, with and without added WASH focus, on hygiene practices, morbidity and anthropometric indices of nutrition in children aged 2−4 years in Burkina Faso. A 3-year cluster randomised controlled trial was implemented in 120 villages in 60 communes (districts) supported by the SELEVER project. Communes were randomly assigned using restricted randomisation to one of three groups: (1) SELEVER intervention (n = 446 households); (2) SELEVER plus WASH intervention (n = 432 households); and (3) control without intervention (n = 899 households). The study population included women aged 15−49 years with an index child aged 2−4 years. We assessed the effects 1.5-years (WASH substudy) and 3-years (endline) post-intervention on child morbidity and child anthropometry secondary trial outcomes using mixed effects regression models. Participation in intervention activities was low in the SELEVER groups, ranging from 25% at 1.5 years and 10% at endline. At endline, households in the SELEVER groups had higher caregiver knowledge of WASH-livestock risks (∆ = 0.10, 95% confidence interval [CI] [0.04−0.16]) and were more likely to keep children separated from poultry (∆ = 0.09, 95% CI [0.03−0.15]) than in the control group. No differences were found for other hygiene practices, child morbidity symptoms or anthropometry indicators. Integrating livestock WASH interventions alongside poultry and nutrition interventions can increase knowledge of livestock-related risks and improve livestock-hygiene-related practices, yet may not be sufficient to improve the morbidity and nutritional status of young children.     

Induction of ovulation with pulsatile GnRH: comparison between subcutaneous and intravenous administration in the same patients

In this study we compared the results obtained during GnRH pulsatile therapy for ovulation induction in the same patients receiving successively GnRH by subcutaneous (10 mcg/90') and intravenous route (2.5 or 5 mcg/90'). Our data suggest that intravenous administration is the most effective procedure for restoring fertility, either in terms of hormonal levels (oestradiol and gonadotropin peaks) or ovulation rate (100% of ovulatory cycles on GnRH treatment versus 25% on subcutaneous administration). With regard to intravenous GnRH therapy, the dose of 2.5 mcg/90' may be more advisable and safe from ovarian overstimulation.     

Alcohol Abstinence and Orthotopic Liver Transplantation in Alcoholic Liver Cirrhosis

Patients diagnosed with acute alcoholic hepatitis (AAH) are routinely managed medically and not considered suitable for orthotopic liver transplantation (OLT). The eligibility for OLT in these patients has been questioned due to the social stigma associated with alcohol abuse, based on the fact that AAH is “self-induced” with an unacceptably high recidivism rate. Many centers in Europe and the United States require abstinence periods between 6 and 12 months before OLT listing. AAH outcomes in the literature are poor, in particular due to patient noncompliance during the immediate 3 months preceeding OLT. Between January 1997 and December 2007, 246 patients were evaluated in our center for alcoholic liver disease: 133 (54%) were listed for OLT (I-OLT), including 110 (83%) who underwent transplantation and 8 (6%) still listed as well as 15 (11%) removed from consideration. One hundred thirteen (46%) patients had no indication for OLT (NO I-OLT), including 18 (16%) who died, 81 (71%) still monitored, and 14 (12%) lost to follow-up. Patient survival rates post-OLT were 79%, 74%, 68%, and 64% at 1, 3, 5, and 10 years, respectively. Explant (native liver) pathologic examination revealed AAH in 8 (7.2%) patients who underwent OLT. In this group, patient survival and the post-OLT recidivism rate were statistically identical to the overall group of transplant recipients.     

Strategies for promoting anti-seizure effects of hippocampal fetal cells grafted into the hippocampus of rats exhibiting chronic temporal lobe epilepsy

Efficacy of hippocampal fetal cell (HFC) grafting for restraining spontaneous recurrent motor seizures (SRMS) in chronic temporal lobe epilepsy (TLE) is unknown. We investigated both survival and anti-seizure effects of 5'-bromodeoxyuridine (BrdU) labeled embryonic day 19 (E19) HFC grafts pretreated with different neurotrophic factors and a caspase inhibitor. Grafts were placed bilaterally into the hippocampi of F344 rats exhibiting kainate (KA) induced chronic TLE, where the frequency of SRMS varied from 3.0 to 3.5 seizures/8-h duration. The first group received standard (untreated) HFC grafts, the second group received HFC grafts pretreated and transplanted with brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and caspase inhibitor Ac-YVAD-cmk (BNC-treated HFC grafts), the third group received HFC grafts pretreated and transplanted with fibroblast growth factor-2 (FGF-2) and caspase inhibitor Ac-YVAD-cmk (FC-treated HFC grafts), and the fourth group served as epilepsy-only controls. Epileptic rats receiving standard HFC grafts exhibited 119% increase in the frequency of SRMS at 2 months post-grafting consistent with 125% increase in seizure frequency observed in epilepsy-only controls during the same period. However, in epileptic rats receiving HFC grafts treated with BNC or FC, the frequency of SRMS was 33-39% less than their pre-transplant scores and 73-76% less than rats receiving standard HFC grafts or epilepsy-only rats. The yield of surviving neurons was equivalent to 30% of injected cells in standard HFC grafts, 57% in HFC grafts treated with BNC and 98% in HFC grafts treated with FC. Thus, standard HFC grafts survive poorly in the chronically epileptic hippocampus and fail to restrain the progression of chronic TLE. In contrast, HFCs treated and grafted with BNC or FC survive robustly in the chronically epileptic hippocampus, considerably reduce the frequency of SRMS and blunt the progression of chronic TLE.     

Enhanced production and dendritic growth of new dentate granule cells in the middle-aged hippocampus following intracerebroventricular FGF-2 infusions

Declined production and diminished dendritic growth of new dentate granule cells in the middle-aged and aged hippocampus are correlated with diminished concentration of fibroblast growth factor-2 (FGF-2). This study examined whether increased FGF-2 concentration in the milieu boosts both production and dendritic growth of new dentate granule cells in the middle-aged hippocampus. The FGF-2 or vehicle was infused into the posterior lateral ventricle of middle-aged Fischer (F)344 rats for 2 weeks using osmotic minipumps. New cells born during the first 12 days of infusions were labeled via daily intraperitoneal injections of 5'-bromodeoxyuridine (BrdU) and analysed at 10 days after the last BrdU injection. Measurement of BrdU(+) cells revealed a considerably enhanced number of new cells in the subgranular zone (SGZ) and granule cell layer (GCL) of the dentate gyrus (DG) ipsilateral to FGF-2 infusions. Characterization of beta-III tubulin(+) neurons among newly born cells suggested an increased addition of new neurons to the SGZ/GCL ipsilateral to FGF-2 infusions. Quantification of DG neurogenesis at 8 days post-infusions via doublecortin (DCX) immunostaining also revealed the presence of an enhanced DG neurogenesis ipsilateral to FGF-2 infusions. Furthermore, DCX(+) neurons in FGF-2-infused rats exhibited enhanced dendritic growth compared with their counterparts in vehicle-infused rats. Thus, subchronic infusion of FGF-2 is efficacious for stimulating an enhanced DG neurogenesis from neural stem/progenitor cells in the middle-aged hippocampus. As dentate neurogenesis is important for hippocampal-dependent learning and memory and DG long-term potentiation, strategies that maintain increased FGF-2 concentration during ageing may be beneficial for thwarting some of the age-related cognitive impairments.