P-glycoproteins encoded by mdr 1b in murine gravid uterus and multidrug resistant tumor cell lines are differentially glycosylated

AbstractThere are 3 members of the multidrug-resitance gene family expressed in mouse. Only one of these, mdr lb, and its gene product P-glycoprotein are induced to high levels in the mouse endometrium during pregnancy. It is shown here that P-glycoprotein in the gravid uterus is significantly larger (Mr 155000) compared to P-glycoprotein encoded by mdr lb in a murine multidrug-resistant cell line (Mr 140000). However, both species co-migrate after enzymatic removal of N-linked sugars (Mr 125000). These results demonstrate that differential glycosylation of the mdr lb gene product contributes to molecular heterogeneity found in P-glycoprotein from normal and multidrug-resistant cells

Vehicle Systems Panel deliberations

The Vehicle Systems Panel addressed materials and structures technology issues related to launch and space vehicle systems not directly associated with the propulsion or entry systems. The Vehicle Systems Panel was comprised of two subpanels - Expendable Launch Vehicles & Cryotanks (ELVC) and Reusable Vehicles (RV). Tom Bales, LaRC, and Tom Modlin, JSC, chaired the expendable and reusable vehicles subpanels, respectively, and co-chaired the Vehicle Systems Panel. The following four papers are discussed in this section: (1) Net Section components for Weldalite Cryogenic Tanks, by Don Bolstad; (2) Build-up Structures for Cryogenic Tanks and Dry Bay Structural Applications, by Barry Lisagor; (3) Composite Materials Program, by Robert Van Siclen; (4) Shuttle Technology (and M&S Lessons Learned), by Stan Greenberg

Human Model Reaching, Grasping, Looking and Sitting Using Smart Objects

Manually creating convincing animated human motion in a 3D ergonomic test environment is tedious and time consuming. However, procedural motion generators help animators efficiently produce complex and realistic motions. Using the concept of a Human Modeling Software Testbed (HMST), we created novel procedural methods for animating reaching, grasping, looking, and sitting using the environmental context of ‘smart’ objects that parametrically guide human model ergonomic motions. This approach enabled complicated procedures such as collision-free leg reach and contextual sitting motion generation. By procedurally adding small secondary details to the animation, such as head/eye vision constraints and prehensile grasps, the animated motions look more natural with minimal animator input. A ‘smart’ object in the scene graph provides specific parameters to produce proper motions and final positions. These parameters are applied to the desired figure procedurally to create any secondary motions, and further generalize to any environment. Our system allows users to proceed with any required ergonomic analyses with confidence in the visual validity of the automated motions

Vehicle systems

Perspectives of the subpanel on expendable launch vehicle structures and cryotanks are: (1) new materials which provide the primary weight savings effect on vehicle mass/size; (2) today's investment; (3) typically 10-20 years to mature and fully characterize new materials

Increased accumulation of doxorubicin and doxorubicinol in cardiac tissue of mice lacking mdr1a P-glycoprotein

To gain more insight into the pharmacological role of endogenous P-glycoprotein in the metabolism of the widely used substrate drug doxorubicin, we have studied the plasma pharmacokinetics, tissue distribution and excretion of this compound in mdr1a(–/– and wild-type mice. Doxorubicin was administered as an i.v. bolus injection at a dose level of 5 mg kg−1. Drug and metabolite concentrations were determined in plasma, tissues, urine and faeces by high-performance liquid chromatography. In comparison with wild-type mice, the terminal half-life and the area under the plasma concentration–time curve of doxorubicin in it>mdr1a(–/–) mice were 1.6- and 1.2-fold higher respectively.The retention of both doxorubicin and its metabolite doxorubicinol in the hearts of mdr1a(–/–) mice was substantially prolonged. In addition, a significantly increased drug accumulation was observed in the brain and the liver of mdr1a(–/–) mice. The relative accumulation in most other tissues was not or only slightly increased. The differences in cumulative faecal and urinary excretion of doxorubicin and metabolites between both types of mice were small. These experiments demonstrate that the absence of mdr1a P-glycoprotein only slightly alters the plasma pharmacokinetics of oxorubicin. Furthermore, the substantially prolonged presence of both doxorubicin and doxorubicinol in cardiac tissue of mdr1a(–/–) mice suggests that a blockade of endogenous P-glycoprotein in patients, for example by a reversal agent, may enhance the risk of cardiotoxicity upon administration of doxorubicin. © 1999 Cancer Research Campaig

Abcg2 labels multiple cell types in skeletal muscle and participates in muscle regeneration

Abcg2-expressing cells proliferate after muscle injury and are required for effective regeneration of multiple muscle cell lineages

Nitric oxide differentially regulates renal ATP-binding cassette transporters during endotoxemia

Nitric oxide (NO) is an important regulator of renal transport processes. In the present study, we investigated the role of NO, produced by inducible NO synthase (iNOS), in the regulation of renal ATP-binding cassette (ABC) transporters in vivo during endotoxemia. Wistar–Hannover rats were injected with lipopolysaccharide (LPS+) alone or in combination with the iNOS inhibitor, aminoguanidine. Controls received detoxified LPS (LPS−). After LPS+, proximal tubular damage and a reduction in renal function were observed. Furthermore, iNOS mRNA and protein, and the amount of NO metabolites in plasma and urine, increased compared to the LPS− group. Coadministration with aminoguanidine resulted in an attenuation of iNOS induction and reduction of renal damage. Gene expression of 20 ABC transporters was determined. After LPS+, a clear up-regulation in Abca1, Abcb1/P-glycoprotein (P-gp), Abcb11/bile salt export pump (Bsep), and Abcc2/multidrug resistance protein (Mrp2) was found, whereas Abcc8 was down-regulated. Up-regulation of Abcc2/Mrp2 was accompanied by enhanced calcein excretion. Aminoguanidine attenuated the effects on transporter expression. Our data indicate that NO, produced locally by renal iNOS, regulates the expression of ABC transporters in vivo. Furthermore, we showed, for the first time, expression and subcellular localization of Abcb11/Bsep in rat kidney

Serious adverse events reported in placebo randomised controlled trials of oral naltrexone: a systematic review and meta-analysis

Background Naltrexone is an opioid antagonist used in many different conditions, both licensed and unlicensed. It is used at widely varying doses from 3 - 250 mg. The aim of this review was to evaluate the safety of oral naltrexone by examining the risk of serious adverse events (SAEs) in randomised controlled trials (RCTs) of naltrexone compared to placebo. Methods A systematic search of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, other databases and clinical trials registries was undertaken up to March 2018. Parallel placebo-controlled RCTs longer than 4 weeks published after 1/1/2001, of oral naltrexone at any dose were selected. Any condition and age group were included, excluding only studies for opioid or ex-opioid users, due to possible opioid/opioid antagonist interactions. The systematic review used the guidance of the Cochrane Handbook throughout. Numerical data was independently extracted by two people and cross-checked. Risk of bias was assessed with the Cochrane Risk of Bias Tool. Meta-analyses were performed using Stata 15 and R, using random and fixed effects models throughout. Results Eighty-nine RCTs with 11194 participants were found, studying alcohol use disorders, various psychiatric disorders, impulse control disorders, other addictions, obesity, Crohn’s disease, fibromyalgia and cancers. Twenty-six studies (4,960 participants) recorded SAEs occurring by arm of study. There was no evidence of increased risk of SAEs for naltrexone compared to placebo, relative risk (RR) 0.84 (95% CI: 0.66 to 1.06). Sensitivity analyses pooling risk differences supported this conclusion (RD = -0.01 (-0.02, 0.00)) and subgroup analyses showed that results were consistent across different doses and disease groups. The quality of evidence for this outcome was judged high using the GRADE criteria. Conclusions Naltrexone does not appear to increase the risk of SAEs over placebo. These findings confirm the safety of naltrexone when used in licensed indications and encourage investments to undertake efficacy studies in unlicensed indications