Moderate exercise protects against joint disease in a murine model of osteoarthritis.

Exercise is recommended as a non-pharmacological therapy for osteoarthritis (OA). Various exercise regimes, with differing intensities and duration, have been used in a range of OA rodent models. These studies show gentle or moderate exercise reduces the severity of OA parameters while high intensity load bearing exercise is detrimental. However, these studies were largely conducted in rats or in mouse models induced by severe injury, age or obesity, whilst destabilization of the medial meniscus (DMM) in mice has become a widely accepted model due to its lower variability, moderate progression and timescale. The present study was undertaken to provide insight into the effect of moderate exercise on early joint pathology in the DMM mouse model. Exercise was induced a week after induction by forced wheel walking for three or 7 weeks. Joints were analyzed by microcomputed tomography and histology. Assessment of skeletal parameters revealed that exercise offered protection against cartilage damage after 7 weeks of exercise, and a temporary protection against osteosclerosis was displayed after 3 weeks of exercise. Furthermore, exercise modified the metaphyseal trabecular microarchitecture of the osteoarthritic leg in both time points examined. Collectively, our findings corroborate previous studies showing that exercise has an important effect on bone in OA, which subsequently, at 8 weeks post-induction, translates into less cartilage damage. Thus, providing an exercise protocol in a surgical mouse model of OA, which can be used in the future to further dissect the mechanisms by which moderate exercise ameliorates OA.

Is curvature of the force-velocity relationship affected by oxygen availability? Evidence from studies in ex vivo and in situ rat muscles.

The power of shortening contractions in skeletal muscle is determined by the force-velocity relationship. Fatigue has been reported to either increase or decrease the force-velocity curvature depending on experimental circumstances. These discrepant findings may be related to experimental differences in oxygen availability. We therefore investigated how the curvature of the force-velocity relationship in soleus and gastrocnemius rat muscles is affected during fatigue, in both an ex vivo setup without an intact blood perfusion and in an in situ setup with an intact blood perfusion. Furthermore, we investigated the effect of reduced oxygen concentrations and reduced diffusion distance on the curvature of the force-velocity relationship in ex vivo muscles, where muscle oxygen uptake relies on diffusion from the incubation medium. Muscles were electrically stimulated to perform repeated shortening contractions and force-velocity curves were determined in rested and fatigued conditions. The curvature increased during fatigue in the soleus muscles (both in situ and ex vivo), and decreased for the gastrocnemius muscles (in situ) or remained unchanged (ex vivo). Furthermore, under ex vivo conditions, neither reduced oxygen concentrations nor reduced diffusion distance conferred any substantial effect on the force-velocity curvature. In contrast, reduced oxygen availability and increased diffusion distance did increase the loss of maximal power during fatigue, mainly due to additional decreases in isometric force. We conclude that oxygen availability does not influence the fatigue-induced changes in force-velocity curvature. Rather, the observed variable fatigue profiles with regard to changes in curvature seem to be linked to the muscle fiber-type composition.

Experience on the use of Vagus Nerve Stimulation during pregnancy.

OBJECTIVE: Vagus Nerve Stimulation (VNS) is a neuromodulation device approved for the treatment of medically refractory epilepsy. Worldwide, only 35 cases of pregnancies that has been described. This study aims to continue to increase the limited knowledge of the use of VNS during pregnancy. METHODS: We interrogated the database of the Epilepsy program at Western University (1998-2018), and identified those patients who were implanted with VNS and became pregnant. RESULTS: From 114 patients implanted with VNS in our centre, four patients had a total of seven pregnancies. This is the first report with one woman implanted with VNS having three pregnancies. Three patients had genetic generalized epilepsy and one focal epilepsy due to periventricular nodular heterotopia. The median duration since implantation was 3.17 years (IQR: 1.33-4.33) and the output was 2.75 mA (IQR: 1.5-3.5). No modifications in stimulation settings were made in any patient during pregnancy. Three patients had obstetric complications, requiring c-sections. All babies were healthy, except one with intellectual disabilities of unclear severity. CONCLUSION: Our small sample suggests VNS could increase the obstetrical complications, but is likely safe for the fetus. However, a larger sample size should be collected to determine safety and potential teratogenicity of VNS.

Randomised clinical study: inulin short-chain fatty acid esters for targeted delivery of short-chain fatty acids to the human colon.

BACKGROUND: Short-chain fatty acids (SCFA) produced through fermentation of nondigestible carbohydrates by the gut microbiota are associated with positive metabolic effects. However, well-controlled trials are limited in humans. AIMS: To develop a methodology to deliver SCFA directly to the colon, and to optimise colonic propionate delivery in humans, to determine its role in appetite regulation and food intake. METHODS: Inulin SCFA esters were developed and tested as site-specific delivery vehicles for SCFA to the proximal colon. Inulin propionate esters containing 0-61 wt% (IPE-0-IPE-61) propionate were assessed in vitro using batch faecal fermentations. In a randomised, controlled, crossover study, with inulin as control, ad libitum food intake (kcal) was compared after 7 days on IPE-27 or IPE-54 (10 g/day all treatments). Propionate release was determined using (13) C-labelled IPE variants. RESULTS: In vitro, IPE-27-IPE-54 wt% propionate resulted in a sevenfold increase in propionate production compared with inulin (P < 0.05). In vivo, IPE-27 led to greater (13) C recovery in breath CO2 than IPE-54 (64.9 vs. 24.9%, P = 0.001). IPE-27 also led to a reduction in energy intake during the ad libitum test meal compared with both inulin (439.5 vs. 703.9 kcal, P = 0.025) and IPE-54 (439.5 vs. 659.3 kcal, P = 0.025), whereas IPE-54 was not significantly different from inulin control. CONCLUSIONS: IPE-27 significantly reduced food intake suggesting colonic propionate plays a role in appetite regulation. Inulin short-chain fatty acid esters provide a novel tool for probing the diet-gut microbiome-host metabolism axis in humans.

Interaction of benzylidene-anabaseine analogues with agonist and allosteric sites on muscle nicotinic acetylcholine receptors.

BACKGROUND AND PURPOSE: Benzylidene-anabaseines (BAs) are partial agonists of the alpha7 nicotinic acetylcholine receptor (nAChR) but their mechanism(s) of action are unknown. Our study explores several possibilities, including direct interactions of BAs with the nAChR channel. EXPERIMENTAL APPROACH: Functional and radioligand-binding assays were used to examine the interaction of two BA analogues, 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXBA) and its primary metabolite 3-(4-hydroxy-2-methoxybenzylidene)-anabaseine (4OH-DMXBA) with both agonist and non-competitive antagonist (NCA)-binding sites on muscle-type nAChRs. KEY RESULTS: Both BAs non-competitively inhibited ACh activation of human fetal muscle nAChRs and sterically inhibited the specific binding of the NCAs [piperidyl-3,4-3H(N)]-(N-(1-(2-thienyl)cyclohexyl)-3,4-piperidine ([(3)H]TCP) and [(3)H]dizocilpine to Torpedo nAChRs in the desensitized state. These compounds modulated [(3)H]tetracaine, [(14)C]amobarbital and [(3)H]TCP binding to resting nAChRs by allosteric mechanisms. Both BAs enhanced [(3)H]TCP binding when the nAChR was initially in the resting but activatable state, suggesting that both compounds desensitized the Torpedo nAChR. Although DMXBA failed to activate human fetal muscle nAChRs, 4OH-DMXBA was found to be a partial agonist. [(3)H]Nicotine competition-binding experiments confirmed that 4OH-DMXBA has higher affinity than DMXBA for the agonist sites, and that DMXBA is also a competitive antagonist. CONCLUSIONS AND IMPLICATIONS: 3-(4-hydroxy-2-methoxybenzylidene)-anabaseine is a partial agonist for human fetal muscle nAChRs, whereas DMXBA only has competitive and NCA activities. The NCA-binding site for BAs overlaps both the phencyclidine- and dizocilpine-binding sites in the desensitized Torpedo nAChR ion channel. The desensitizing property of BAs suggests another possible mode of non-competitive inhibition in addition to direct channel-blocking mechanisms.

A case study using larval therapy in the community setting.

This article discusses the use of larval therapy by district nurses in wound bed preparation in the community. A case study is presented of a patient with a persistently necrotic and painful anterior tibial wound post-fasciotomy. The case study offers an insight into the practicalities involved in the use of larvae as effective and safe debriders of tissue for wound bed preparation. It is concluded that larval therapy is an underused and misunderstood resource when considering effective wound care and this treatment should be actively considered as an alternative therapy in wound care. There is a need for both qualitative and quantitative research in this field, enabling a more thorough discussion to be entered into by all practitioners with an interest in this subject.

Effects of walking on ventilatory and cardiac function in intact and cardiac-impaired lobsters.

Decapod crustaceans with normal heart function respond to the increased oxygen delivery requirements during walking with a step increase in heart and ventilation rate. In American lobsters, ventilation rate increased by the same amount during exercise at two walking speeds (2.4 and 8 m min(-1)); however, ventilation volume was significantly greater at the fastest walking speed (280 mL min(-1)) compared to animals at rest or walking at the slower speed (180 mL min(-1)). The heart responded in a similar manner to locomotion. Heart rate was elevated to the same level at the two different walking speeds, but cardiac stroke volume was greater, implying increased cardiac output, at the faster walking speed. The communication and compensation between the cardiac and ventilatory systems was revealed when the function of one was impaired. Ventilatory rate was significantly elevated when cardiac output was impaired by sectioning two of the alary ligaments and/or the regulatory nerves to the heart. When cardiac output was more severely impaired, ventilation rate was greater. Despite ventilatory compensation, anaerobic metabolism made a greater contribution to energy production with impaired heart function. Hemolymph lactate concentration was three to five times greater in impaired animals than controls. It is known that the ventilatory and cardiac systems of lobsters are coregulated. These data demonstrate that the performance of one system can respond to compensate for impaired function in the other.