Effects of immobilization on articular cartilage: Autohistoradiographic findings with S35

The effect of immobilization on the articular cartilage of rabbits was studied by light microscope. The knee joint of each rabbit was immobilized in a plaster in a position midway between flexion and extension for a 10 to 120 days period. Degenerative changes in the articular cartilage of increasing severity were observed. The fixation of the labeled SO4 by cartilage cells was decreased in advanced immobilization

Factors affecting basal and post-exercise prolactin secretion in horses

There has been thorough documentation to support the role of dopamine in the control of prolactin production and secretion in various mammalian species, including the horse. However, there is evidence that other factors are involved in prolactin secretion. Seven experiments were conducted to assess factors that potentially might affect prolactin secretion in the horse. The first two experiments were conducted (separately) to test whether arginine vasopressin (AVP) or vasoactive intestinal polypeptide (VIP) affected prolactin secretion. In each experiment, AVP or VIP was administered intravenously and blood samples were collected to determine the effect on prolactin secretion. Neither peptide produced any alteration in plasma prolactin concentrations compared to simultaneous saline-injected controls (P \u3e 0.1). Five subsequent experiments were conducted to assess the effects of various drugs on prolactin secretion in response to acute exercise. Pre-exercise treatments included dexamethasone (a glucocorticoid analog, administered 15 h before exercise), naloxone (an opiod antagonist, administered 2 min before exercise), cabergoline (a dopaminergic agonist, administered 15 h before exercise), flunixin meglumine (a prostaglandin inhibitor, administered 15 min before exercise), and sulpiride (a dopamine antagonist that causes the release of prolactin, administered 1.5 h before exercise). In all experiments, exercise induced an immediate increase (P \u3c 0.05) in plasma prolactin concentrations in control horses. Pretreatment with dexamethasone, naloxone, or flunixin meglumine did not alter (P \u3e 0.1) plasma prolactin concentrations relative to saline-treated controls. Pretreatment with cabergoline completely obliterated (P \u3c 0.01) the exercise induced rise in prolactin concentrations. Pretreatment with sulpiride caused an immediate increase (P \u3c 0.001) in prolactin concentrations relative to controls, but resulted in no change in prolactin response to exercise 90 min later relative to controls. It is concluded that the only drug that had a significant effect on prolactin secretion was the dopaminergic agonist cabergoline. Direct administration of AVP or VIP, or perturbations of the adrenal cortical axis, the opioid system, or the prostaglandin system, had no effect on prolactin secretion as has been reported previously for other species

The effectiveness of manual stretching in the treatment of plantar heel pain: a systematic review

Background: Plantar heel pain is a commonly occurring foot complaint. Stretching is frequently utilised as a treatment, yet a systematic review focusing only on its effectiveness has not been published. This review aimed to assess the effectiveness of stretching on pain and function in people with plantar heel pain. Methods: Medline, EMBASE, CINAHL, AMED, and The Cochrane Library were searched from inception to July 2010. Studies fulfilling the inclusion criteria were independently assessed, and their quality evaluated using the modified PEDro scale. Results: Six studies including 365 symptomatic participants were included. Two compared stretching with a control, one study compared stretching to an alternative intervention, one study compared stretching to both alternative and control interventions, and two compared different stretching techniques and durations. Quality rating on the modified Pedro scale varied from two to eight out of a maximum of ten points. The methodologies and interventions varied significantly between studies, making meta-analysis inappropriate. Most participants improved over the course of the studies, but when stretching was compared to alternative or control interventions, the changes only reached statistical significance in one study that used a combination of calf muscle stretches and plantar fascia stretches in their stretching programme. Another study comparing different stretching techniques, showed a statistically significant reduction in some aspects of pain in favour of plantar fascia stretching over calf stretches in the short term. Conclusions: There were too few studies to assess whether stretching is effective compared to control or other interventions, for either pain or function. However, there is some evidence that plantar fascia stretching may be more effective than Achilles tendon stretching alone in the short-term. Appropriately powered randomised controlled trials, utilizing validated outcome measures, blinded assessors and long-term follow up are needed to assess the efficacy of stretching

Two Novel Fish Paralogs Provide Insights Into the Rid Family of Imine Deaminases Active in Pre-Empting enamine/imine Metabolic Damage

Reactive Intermediate Deaminase (Rid) protein superfamily includes eight families among which the RidA is conserved in all domains of life. RidA proteins accelerate the deamination of the reactive 2-aminoacrylate (2AA), an enamine produced by some pyridoxal phosphate (PLP)-dependent enzymes. 2AA accumulation inhibits target enzymes with a detrimental impact on fitness. As a consequence of whole genome duplication, teleost fish have two ridA paralogs, while other extant vertebrates contain a single-copy gene. We investigated the biochemical properties of the products of two paralogs, identified in Salmo salar. SsRidA-1 and SsRidA-2 complemented the growth defect of a Salmonella enterica ridA mutant, an in vivo model of 2AA stress. In vitro, both proteins hydrolyzed 2-imino acids (IA) to keto-acids and ammonia. SsRidA-1 was active on IA derived from nonpolar amino acids and poorly active or inactive on IA derived from other amino acids tested. In contrast, SsRidA-2 had a generally low catalytic efficiency, but showed a relatively higher activity with IA derived from L-Glu and aromatic amino acids. The crystal structures of SsRidA-1 and SsRidA-2 provided hints of the remarkably different conformational stability and substrate specificity. Overall, SsRidA-1 is similar to the mammalian orthologs whereas SsRidA-2 displays unique properties likely generated by functional specialization of a duplicated ancestral gene

Mitochondrial ROS drive resistance to chemotherapy and immune-killing in hypoxic non-small cell lung cancer

BACKGROUND: Solid tumors subjected to intermittent hypoxia are characterized by resistance to chemotherapy and immune-killing by effector T-lymphocytes, particularly tumor-infiltrating Vγ9Vδ2 T-lymphocytes. The molecular circuitries determining this double resistance are not known. METHODS: We analyzed a panel of 28 human non-small cell lung cancer (NSCLC) lines, using an in vitro system simulating continuous and intermittent hypoxia. Chemosensitivity to cisplatin and docetaxel was evaluated by chemiluminescence, ex vivo Vγ9Vδ2 T-lymphocyte expansion and immune-killing by flow cytometry. Targeted transcriptomics identified efflux transporters and nuclear factors involved in this chemo-immuno-resistance. The molecular mechanism linking Hypoxia-inducible factor-1α (HIF-1α), CCAAT/Enhancer Binding Protein-β (C/EBP-β) isoforms LAP and LIP, ABCB1, ABCC1 and ABCA1 transporters were evaluated by immunoblotting, RT-PCR, RNA-IP, ChIP. Oxidative phosphorylation, mitochondrial ATP, ROS, depolarization, O(2) consumption were monitored by spectrophotometer and electronic sensors. The role of ROS/HIF-1α/LAP axis was validated in knocked-out or overexpressing cells, and in humanized (Hu-CD34(+)NSG) mice bearing LAP-overexpressing tumors. The clinical meaning of LAP was assessed in 60 NSCLC patients prospectively enrolled, treated with chemotherapy. RESULTS: By up-regulating ABCB1 and ABCC1, and down-regulating ABCA1, intermittent hypoxia induced a stronger chemo-immuno-resistance than continuous hypoxia in NSCLC cells. Intermittent hypoxia impaired the electron transport chain and reduced O(2) consumption, increasing mitochondrial ROS that favor the stabilization of C/EBP-β mRNA mediated by HIF-1α. HIF-1α/C/EBP-β mRNA binding increases the splicing of C/EBP-β toward the production of LAP isoform that transcriptionally induces ABCB1 and ABCC1, promoting the efflux of cisplatin and docetaxel. LAP also decreases ABCA1, limiting the efflux of isopentenyl pyrophosphate, i.e. the endogenous activator of Vγ9Vδ2 T-cells, and reducing the immune-killing. In NSCLC patients subjected to cisplatin-based chemotherapy, C/EBP-β LAP was abundant in hypoxic tumors and was associated with lower response to treatment and survival. LAP-overexpressing tumors in Hu-CD34(+)NSG mice recapitulated the patients’ chemo-immuno-resistant phenotype. Interestingly, the ROS scavenger mitoquinol chemo-immuno-sensitized immuno-xenografts, by disrupting the ROS/HIF-1α/LAP cascade. CONCLUSIONS: The impairment of mitochondrial metabolism induced by intermittent hypoxia increases the ROS-dependent stabilization of HIF-1α/LAP complex in NSCLC, producing chemo-immuno-resistance. Clinically used mitochondrial ROS scavengers may counteract such double resistance. Moreover, we suggest C/EBP-β LAP as a new predictive and prognostic factor in NSCLC patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02447-6