Glutamine Metabolism in Osteoprogenitors Is Required for Bone Mass Accrual and PTH-Induced Bone Anabolism in Male Mice

Skeletal homeostasis critically depends on the proper anabolic functioning of osteolineage cells. Proliferation and matrix synthesis are highly demanding in terms of biosynthesis and bioenergetics, but the nutritional requirements that support these processes in bone-forming cells are not fully understood. Here, we show that glutamine metabolism is a major determinant of osteoprogenitor function during bone mass accrual. Genetic inactivation of the rate-limiting enzyme glutaminase 1 (GLS1) results in decreased postnatal bone mass, caused by impaired biosynthesis and cell survival. Mechanistically, we uncovered that GLS1-mediated glutamine catabolism supports nucleotide and amino acid synthesis, required for proliferation and matrix production. In addition, glutamine-derived glutathione prevents accumulation of reactive oxygen species and thereby safeguards cell viability. The pro-anabolic role of glutamine metabolism was further underscored in a model of parathyroid hormone (PTH)-induced bone formation. PTH administration increases glutamine uptake and catabolism, and GLS1 deletion fully blunts the PTH-induced osteoanabolic response. Taken together, our findings indicate that glutamine metabolism in osteoprogenitors is indispensable for bone formation. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Sex Differences in Voyeuristic and Exhibitionistic Interests: Exploring the Mediating Roles of Sociosexuality and Sexual Compulsivity from an Evolutionary Perspective

Sociosexuality and sexual compulsivity predict sex differences in voyeuristic interest in the population. In this study, we used a sample of 1113 participants from the UK (46% men) to consider whether sociosexuality and sexual compulsivity interacted to explain these sex differences and whether this relationship extended to the related domain of exhibitionism. In doing so, we tested novel predictions derived from an evolutionary perspective which views voyeuristic and exhibitionistic interest as manifestations of a short-term mating strategy. Participants reported their levels of repulsion toward voyeurism and exhibitionism and their interest in performing such acts under different levels of risk. There were clear sex differences in voyeuristic and exhibitionistic repulsion that were partially mediated by the serial combination of sociosexuality and sexual compulsivity. Examining the sexes separately revealed qualitatively different relationships between sociosexuality and sexual compulsivity when predicting exhibitionistic, but not voyeuristic, repulsion. Combined, sociosexuality and sexual compulsivity also mediated the sex difference in willingness to commit acts of voyeurism, but not exhibitionism, which was equally low for both sexes. The results highlight the role sociosexuality plays in voyeuristic and exhibitionistic interest, which coupled with an evolutionary perspective, may have implications for how we view courtship disorders.

     

Methimazole as a protectant against cisplatin-induced nephrotoxicity using the dog as a model

Dexniguldipine-HCl (DNIG) — a prospective clinical modulator of p170-glycoprotein (pgp170)-mediated multidrug resistance (MRD) — was evaluated in a drug-accumulation assay in MDR murine leukemia cell strain F4-6RADR expressing pgp170. The compound elevated low accumulation of either doxorubicin (DOX), daunorubicin (DNR), or mitoxantrone (MITO) in resistant F4-6RADR cells to the very levels observed in drug-sensitive F4-6 precursor cells. In parallel with the increase in DNR content (F4-6RADR, solvent: 303±27 pmol/mg protein; DNIG (3.3 mol/l): 1,067±174 pmol/mg protein; F4-6P, solvent: 948±110 pmol/mg protein;n=8–9, SEM), the amount of DNR tightly bound to the acid precipitate pellet obtained from F4-6RADR (i.e., protein, DNA, RNA) increased 3.9-times to the levels observed in sensitive F4-6 cells. The main pyridine metabolite of DNIG displayed similar activity. Concentration-response analysis revealed that DNIG and R,S-verapamil (VER) induced 100% reversal of the DNR accumulation shortage associated with the MDR phenotype but DNIG was 8 times more potent than VER (50% inhibitory concentration (IC₅₀), 0.73 vs 5.4 mol/l). In keeping with the accumulation assay, DNIG was about 10 times more potent than VER in sensitizing F4-6RADR cells to the cytostatic and cytotoxic effects of DNR in proliferation assays. In conclusion, DNIG is a potent in vitro modulator, improving (a) the accumulation of anthracycline-like cytostatics, (B) drug access to cellular binding sites, and (c) the cytostatic action of DNR in F4-6RADR leukemia cells of the MDR phenotype.Abbreviations DOX doxorubicin - CSA cyclosporin A - DMSO dimethylsulfoxide - DNIG dexniguldipine-HCl - DNR daunorubicin - MDR multidrug resistance - MITO mitoxantrone - pgp170 permease glycoprotein 170 - VER R.S.-verapamil Dexniguldipine-HCl is the proposed INN for compound B859-35, the R-enantiomer of niguldipine. Segments of this work have been reported in the abstract form     

Hamstring tendon grafts for reconstruction of the anterior cruciate ligament: biomechanical evaluation of the use of multiple strands and tensioning techniques

BACKGROUND: Our hypothesis that multiple, equally tensioned strands of hamstring graft used for reconstruction of the anterior cruciate ligament are stronger and stiffer than ten-millimeter patellar ligament grafts was tested biomechanically with use of tendons from cadavera. METHODS: In the first part of the study, we measured the strength and stiffness of one, two, and four-strand hamstring grafts, from fresh-frozen cadaveric knees, that had been tensioned equally when clamped. In the second part of the study, we compared four-strand grafts to which tension had been applied by hand and then clamped with similar grafts to which tension had been applied with weights and then clamped. The grafts for the two experiments were obtained from thirty-four paired and ten unpaired knees. We also studied the effects of cooling on the biomechanical properties of grafts by comparing patellar ligament grafts tested at 13 degrees Celsius with those tested at room temperature. RESULTS: Two equally tensioned gracilis strands had 185 percent of the strength and 210 percent of the stiffness (1550+/-428 newtons and 336+/-141 newtons per millimeter, respectively) of one gracilis strand (837+/- 138 newtons and 160+/-44 newtons per millimeter, respectively). Two equally tensioned semitendinosus strands had 220 percent of the strength and 220 percent of the stiffness (2330+/-452 newtons and 469+/-185 newtons per millimeter, respectively) of one semitendinosus strand (1060+/-227 newtons and 213+/-44 newtons per millimeter, respectively). Four combined strands (two gracilis strands and two semitendinosus strands) that were equally tensioned with weights and clamped had the additive tensile properties of the individual strands. With the numbers available, four combined strands that were manually tensioned and clamped were not found to be significantly stronger or stiffer than two semitendinosus strands that were equally tensioned with weights (p>0.07). CONCLUSIONS: Four combined strands that were equally tensioned with weights and clamped were stronger and stiffer than all ten-millimeter patellar ligament grafts that have been described in previous reports. All strands of a hamstring graft must be equally tensioned for the composite to have its optimum biomechanical properties. CLINICAL RELEVANCE: Because of the well recognized donor-site morbidity associated with the use of patellar ligament grafts for reconstruction of the anterior cruciate ligament, multiple-strand hamstring-tendon grafts have become an increasingly popular choice. Our data demonstrate that equally tensioned four-strand hamstring-tendon grafts have initial tensile properties that are higher than those reported for ten-millimeter patellar-ligament grafts; thus, from a biomechanical point of view, they seem to be a reasonable alternative.     

Self-administration of cocaine analogs by rats

  Rationale: A novel scheme for the synthesis of cocaine analogs from vinylcarbenoid precursors has made available compounds that have a diverse range of affinities for the DA and 5-HT transporters. These compounds were used to explore the relationship between their biochemical properties and their reinforcing effects. Objectives: The objective was to assess the reinforcing efficacy of selected cocaine analogs and compare the results with their selectivity in binding to DA and 5-HT transporters. Methods: Rats were prepared with chronically indwelling intravenous cannulae and trained to self-administer cocaine on a progressive ratio (PR) schedule. A range of doses of seven cocaine analogs were substituted for cocaine in separate groups of animals. Results: The results demonstrate a wide range of reinforcing efficacies and potencies among the seven selected drugs. Four tropane analogs (WF-11, WF-23, WF-24, WF-55) were found to support self-administration behavior on a PR schedule while three did not (WF-31, WF-54 and WF-60). The DA/5-HT selectivity ratio was found to be a better predictor of self-administration behavior than affinity at the DA transporter alone. Conclusion: These data suggest that drugs with a higher affinity for the DA versus the 5-HT transporter are more likely to be self-administered. Received: 29 October 1998 / Final version: 5 February 1999     

Dynamic regulation of middle cerebral artery blood flow velocity in aging and hypertension

BACKGROUND AND PURPOSE: Although aging and hypertension may predispose hypertensive elderly subjects to cerebral hypoperfusion during orthostatic stress, their effects on the acute cerebral autoregulatory response to hypotension are not known. METHODS: Continuous middle cerebral artery blood flow velocity (BFV) (transcranial Doppler ultrasound) and mean arterial pressure (MAP, Finapres) were measured in response to (1) acute hypotension during standing, (2) steady-state sitting and standing, and (3) hypercarbia during CO(2) rebreathing in 10 healthy young subjects (age 24+/-1 years), 10 healthy elderly subjects (age 72+/-3 years), and 10 previously treated hypertensive elderly (age 72+/-2 years) subjects. CO(2) reactivity was computed as the slope of cerebrovascular conductance (CVC=BFV/MAP) versus end-expiratory CO(2). Coherence, transfer magnitudes, and phases between low-frequency MAP and BFV signals were computed from their autospectra during 5 minutes of sitting and standing. RESULTS: MAP fell to a similar extent in all groups by an average of 21 to 26 mm Hg (22% to 26%) within 30 seconds of standing. Mean BFV also fell in all subjects but significantly less in the older subjects (-4.7+/-0. 7 cm/s in hypertensives and -5.3+/-1.2 cm/s in normotensives, P=NS) compared with younger subjects (-10.1+/-1.1 cm/s, P<0.05). CO(2) reactivity was greater in the young subjects (0.19+/-0.01) compared with normotensive (0.14+/-0.01, P<0.05) and hypertensive elderly subjects (0.11+/-0.02, P<0.05) (P=NS between elderly groups). Fewer hypertensive subjects had coherence between MAP and BFV signals; for subjects with coherence, there were no significant group differences in phase or transfer magnitudes in either sitting or standing positions. CONCLUSIONS: Despite reduced CO(2) reactivity, elderly normotensive and previously treated hypertensive subjects retain cerebral autoregulatory capacity in response to acute orthostatic hypotension.     

Training Staff in an Adolescent Inpatient Psychiatric Unit in Positive Approaches to Managing Aggressive and Harmful Behaviour: Does it Improve Confidence and Knowledge?

This study examined the implementation of a model of managing aggressive and harmful behaviour in an adolescent in-patient psychiatric unit. This model, Positive Behaviour Management, replaced a previous model, Control and Restraint, which was considered unsuitable. Both models included the use of physical interventions, and the research into such techniques is considered. The aims of the study were to evaluate the effects of three training courses on staff confidence in managing aggressive behaviour, knowledge about good practice and staff satisfaction with the new model. A multiple baseline design was used to examine change before, during and after the training period, and at one-year follow-up. The study found that staff confidence increased significantly following training but had returned to baseline levels by the time of follow-up. Staff knowledge significantly increased during the study periods but did not appear to be directly linked to the training courses, and was maintained at one-year follow-up. Staff reported significantly higher levels of satisfaction with the new model than with the previous model, which were maintained at follow-up. The findings of the study and the difficulties encountered are discussed in relation to similar findings elsewhere.