Molecular dissection of Meis1 reveals 2 domains required for leukemia induction and a key role for Hoxa gene activation

The Hoxa9 and Meis1 genes represent important oncogenic collaborators activated in a significant proportion of human leukemias with genetic alterations in the MLL gene. In this study, we show that the transforming property of Meis1 is modulated by 3 conserved domains, namely the Pbx interaction motif (PIM), the homeodomain, and the C-terminal region recently described to possess transactivating properties. Meis1 and Pbx1 interaction domain-swapping mutants are dysfunctional separately, but restore the full oncogenic activity of Meis1 when cotransduced in primary cells engineered to overexpress Hoxa9, thus implying a modular nature for PIM in Meis1-accelerated transformation. Moreover, we show that the transactivating domain of VP16 can restore, and even enhance, the oncogenic potential of the Meis1 mutant lacking the C-terminal 49 amino acids. In contrast to Meis1, the fusion VP16-Meis1 is spontaneously oncogenic, and all leukemias harbor genetic activation of endogenous Hoxa9 and/or Hoxa7, suggesting that Hoxa gene activation represents a key event required for the oncogenic activity of VP16-Meis1.     

An investigation by electron microscopy of chylomicron remnant uptake by human monocyte-derived macrophages

Human monocyte-derived macrophages (HMM) internalise proatherogenic chylomicron remnants via several high affinity receptor pathways. However, the endocytic ultrastructures responsible for the uptake of chylomicron remnants by macrophages have not previously been described. In this study, we have utilised transmission electron microscopy together with colloidal gold-labelling of chylomicron remnants to investigate the pathways involved in macrophage uptake of chylomicron remnants. We found that macrophages internalise chylomicron remnants via surface-connected compartments of up to 600 nm as well as non-clathrin coated pits. Chylomicron remnants were found to be distributed internally in a number of endocytic vesicles including early cysternal endosomes, spherical late endosomes and tubular vesicular compartments. Uptake of chylomicron remnants by HMM via phagocytosis or macropinocytosis was excluded based on the observations that lipoproteins were not found in phagolysosomes nor modified by inhibitors of these two processes, respectively. The latter observation contrasts with previous reports of chylomicron remnant internalisation by macrophages of other species.     

Gene silencing in bovine zygotes: siRNA transfection versus microinjection

The aim of this study was to compare gene silencing in bovine zygotes when small interfering RNAs (siRNAs) were introduced into bovine zygotes by microinjection or lipid-based transfection. In Experiment 1, E-cadherin siRNA was injected at 100 or 375 μM and compared with PBS-injected and non-injected controls. Embryos were then cultured in vitro for 7 days and periodically assessed for development. For transfection, zona-free zygotes were incubated in transfection medium with siRNA for 1h at 39°C and then cultured to Day 7. Injection of PBS or 375 μM E-cadherin siRNA resulted in a decrease in the number of embryos reaching the 8-cell stage (51.5% and 45.5%) or the blastocyst stage (39.0 and 32.5%) compared with non-injected controls (62.9 and 45.0%, respectively; P<0.05). Messenger RNA abundance was suppressed by 36 and 46% when siRNA targeting E-cadherin was injected at 100 and 375 μM, respectively, compared with controls (P<0.05). Transfection with 100 nM E-cadherin siRNA decreased development to the 8-cell stage (20.3 versus 53.0%) and blastocyst stage (7.2 versus 18.2%) compared with controls (P<0.05). Messenger RNA relative abundance was not different between controls (non-transfected or transfected with GAPDH or scrambled siRNA). However, transfection of zygotes with 100 and 200 nM E-cadherin siRNA led to a 72 and 38% reduction, respectively, in E-cadherin mRNA relative abundance in Day 7 blastocysts compared with controls (P<0.05).     

A Systematic Review of the MDMA Model to Address Social Impairment in Autism

Background Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterised by repetitive behaviours, cognitive rigidity/inflexibility, and social-affective impairment. Unfortunately, no gold-standard treatments exist to alleviate the core socio-behavioural impairments of ASD. Meanwhile, the prosocial empathogen/entactogen 3,4-methylene-dioxy-methamphetamine (MDMA) is known to enhance sociability and empathy in both humans and animal models of psychological disorders.Objective We review the evidence obtained from behavioural tests across the current literature, showing how MDMA can induce prosocial effects in animals and humans, where controlled experiments were able to be performed.Methods Six electronic databases were consulted. The search strategy was tailored to each database. Only English-language papers were reviewed. Behaviours not screened in this review may have affected the core ASD behaviours studied. Molecular analogues of MDMA have not been investigated.Results We find that the social impairments may potentially be alleviated by postnatal administration of MDMA producing prosocial behaviours in mostly the animal model.Conclusion MDMA and/or MDMA-like molecules appear to be an effective pharmacological treatment for the social impairments of autism, at least in animal models. Notably, clinical trials based on MDMA use are now in progress. Nevertheless, larger and more extended clinical studies are warranted to prove the assumption that MDMA and MDMA-like molecules have a role in the management of the social impairments of autism.     

Tacrolimus concentration to dose ratio in solid organ transplant patients treated with fecal microbiota transplantation for recurrent Clostridium difficile infection

Fecal microbiota transplantation (FMT ) is increasingly being performed for Clostridium difficile infection in solid organ transplant (SOT ) patients; however, little is known about the potential pharmacokinetic or pharmacomicrobial effects this may have on tacrolimus levels. We reviewed the medical records of 10 SOT patients from September 2012‐December 2016 who were taking tacrolimus at time of FMT for recurrent C. difficile infection. We compared the differences in tacrolimus concentration/dose ratio (C/D ratio) 3 months prior to FMT vs 3 months after FMT . The mean of the differences in C/D ratio calculated as (ng/mL)/(mg/kg/d) was ?17.65 (95% CI ?1.25 to 0.58) (ng/mL)/(mg/kg/d), P ‐value .43 by Wilcoxon signed‐rank test. The mean of the differences in C/D ratio calculated as (ng/mL)/(mg/d) was ?0.33 (95% CI ?1.25 to 0.58) (ng/mL)/(mg/d), P ‐value .28 by Wilcoxon signed‐rank test. Of these patients, 2/10 underwent allograft biopsy for allograft dysfunction in the year after FMT , with no evidence of allograft rejection on pathology. These preliminary data suggest that FMT may not predictably alter tacrolimus levels and support its safety for SOT patients however further study in randomized trials is needed.     

Low Dose vs Standard Dose of Antipsychotics for Relapse Prevention in Schizophrenia: Meta-analysis

Background: It remains unknown as to whether the antipsychotic dose needed for the acute-phase treatment of schizophrenia is also necessary for relapse prevention. Aim: To compare the efficacy between standard dose [(World Health Organization daily defined dose (DDD)] vs low dose (≥50% to <1 DDD) or very low dose (<50% DDD) for relapse prevention in schizophrenia. Data source: Double-blind, randomized, controlled trials with a follow-up duration of ≥24 weeks, including ≥2 dosage groups of the same antipsychotic drug for relapse prevention in schizophrenia, were searched using MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE (last search: August 2009). Data extraction: Data on overall treatment failure, hospitalization, relapse, and dropouts due to side effects were extracted and combined in a meta-analysis. Data synthesis: Thirteen studies with 1395 subjects were included in this meta-analysis. Compared with the standard-dose treatment, the low-dose therapy did not show any statistically significant difference in overall treatment failure or hospitalization, while the standard dose showed a trend-level (P = .05) superiority in risk of relapse. The very low–dose group was inferior to the standard-dose group in all efficacy parameters. No significant difference was found in the rate of dropouts due to side effects between either standard dose vs low dose or very low dose. Conclusions: Although antipsychotic treatment with ≥50% to <1 DDD may be as effective as standard-dose therapy, there are insufficient clinical trial data to draw firm conclusions on standard- vs low-dose maintenance antipsychotic therapy for schizophrenia.     

Impact assessment of gilgel gibe hydroelectric dam on schitosomiasis: a cross sectional study in southwest ethiopia

Background

Intestinal schistosomiasis is prevalent in East Africa including Ethiopia. Constructed five years back, Gilgel Gibe dam is suspected to harbor the intermediate host for transmission of schistosomiasis. The objective of this study was to determine the prevalence of intestinal schistosomiasis and risk factors among school children.

Methods

A comparative cross-sectional study was carried out in October 2008 in four Woredas bordering Gilgel Gibe dam, within 10 kilometers, and Bulbul, which is 30 Kms away from the dam. Children attending grades 1–8 in the schools located adjacent to the dam constituted the cases and those living in Bulbul constitute the controls. Using Epinfo version 6.0 for cross-sectional study, a sample size of 937 was determined. Sample size allocation was done 2:1 for cases and control. After interview, stool sample was collected and analyzed. Screening for the presence of intermediate host and physiochemical analyses of selected water bodies along the major water contact sites of the reservoir was also done Data were entered into computer and analyzed using SPSS for windows version 13.0.1.

Results

Out of 624 sampled cases and 312 controls, 585 and 270 participated in the study giving a response rate of 93.8% and 86.5%, respectively. Four hundred seventy four (81.0% of the cases and 203 (75.2%) controls use latrine regularly. On stool examination, 406 (47.5%) children, 295 (50.4%) cases and 111 (41.1%) controls) were positive to intestinal parasites but only two children, both from the control groups, were positive for Schistosoma mansoni. The three river water samples on which malacological survey was done had similar physicochemical characteristics in many ways except high conductivity, pH and percent of dissolved oxygen concentration (milligram per liter) at one site where uninfected Biomphilaria Pfeifferi was found

Conclusion

The study revealed that schistosomiasis is not yet a problem at Gilgel-Gibe dam. But, continuous surveying is required as the intermediate host is prevalent, the water bodies are suitable for the intermediate host and cases of schistosomiasis are identified 30 kms away the dam, in control area.