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Fatigue of the hip abductor muscles may influence lower limb biomechanics and potentially contribute to anterior cruciate ligament (ACL) injury risk. However, the effects of targeted hip abductor fatigue on trunk, pelvis and lower limb coordination during landing tasks remain unclear. The present study aimed to investigate how targeted hip abductor fatigue alters the biomechanics of the trunk, pelvis, and lower extremity during single-leg landing (SLL). Twenty healthy male recreational athletes performed SLL before and after a targeted hip abductor fatigue protocol. Kinematic and kinetic data were collected using a three-dimensional motion capture system and force plates, with analysis focused on the timing of peak vertical ground reaction force. Following fatigue, participants exhibited increased hip abduction angle and trunk right inclination, as well as decreased hip flexion and external hip abduction moment. Notably, the external knee abduction moment significantly increased post-fatigue, though it remained negative in absolute value. Increased pelvic left rotation was also observed, indicating compensatory adjustments in trunk-pelvis coordination. These adaptations indicate that targeted muscle fatigue induces complex biomechanical responses across the kinetic chain, rather than uniformly increasing injury risk through valgus-prone mechanics. While the observed changes may reflect stabilizing strategies under fatigue, their implications for ACL loading require further clarification. The current study highlights the relevance of considering whole-body biomechanical responses to targeted fatigue and contributes to a more detailed understanding of neuromuscular control during landing. These findings may support the refinement of injury prevention approaches that address segmental coordination under fatigued conditions.

Impairment of peripheral neurons by anti-cancer agents, including taxanes and platinum derivatives, has been considered to be a major cause of chemotherapy-induced peripheral neuropathy (CIPN), however, the precise underlying mechanisms are not fully understood. Here, we examined the direct effects of anti-cancer agents on Schwann cells. Exposure of primary cultured rat Schwann cells to paclitaxel (0.01 μM), cisplatin (1 μM), or oxaliplatin (3 μM) for 48 h induced cytotoxicity and reduced myelin basic protein expression at concentrations lower than those required to induce neurotoxicity in cultured rat dorsal root ganglion (DRG) neurons. Similarly, these anti-cancer drugs disrupted myelin formation in Schwann cell/DRG neuron co-cultures without affecting nerve axons. Cisplatin and oxaliplatin, but not paclitaxel, caused mitochondrial dysfunction in cultured Schwann cells. By contrast, paclitaxel led to dedifferentiation of Schwann cells into an immature state, characterized by increased expression of p75 and galectin-3. Consistent with in vitro findings, repeated injection of paclitaxel increased expression of p75 and galectin-3 in Schwann cells within the mouse sciatic nerve. These results suggest that taxanes and platinum derivatives impair Schwan cells by inducing dedifferentiation and mitochondrial dysfunction, respectively, which may be important in the development of CIPN in conjunction with their direct impairment in peripheral neurons.

The initial step in bacterial infection is adherence of the bacterium to the target cell surface. Helicobacter pylori exploits the interaction of bacterial adhesin protein HopQ with human epithelial CEACAMs (CEACAM1, 5, and 6) to stably adhere to gastric epithelial cells, which is necessary for delivery of the H. pylori CagA oncoprotein into the epithelial cells via a type IV secretion system. In contrast to human CEACAMs, however, HopQ does not interact with Ceacam1 (mouse CEACAM1) in vitro or in CHO cells ectopically expressing Ceacam1. Since the mouse genome lacks Ceacam5 and Ceacam6, no significant HopQ–Ceacam interaction may occur in mouse gastric epithelial cells. Here, we found that the mouse stomach has a much lower expression level of Ceacam1 than the expression level of CEACAM1 in the human stomach. Consistently, mouse gastric epithelial cells resist CagA delivery by cagA-positive H. pylori, and the delivery is restored by ectopic expression of human CEACAM1 or CEACAM5 in mouse gastric epithelial cells. Thus, despite the fact that mice are routinely used for H. pylori infection studies, a low expression level of Ceacam1 in the mouse stomach together with the loss or greatly reduced interaction of HopQ with Ceacams make the mouse an inappropriate model for studying the role of H. pylori-delivered CagA in gastric pathogenesis, including the development of gastric cancer.

Background Diabetic peripheral neuropathy is a common long-term complication of diabetes. Accumulating evidence suggests that vascular impairment plays important roles in the pathogenesis of diabetic peripheral neuropathy, while the mechanism remains unclear. We recently reported that transient receptor potential ankyrin 1 (TRPA1) is sensitized by hypoxia, which can contribute to cold hypersensitivity. In this study, we investigated the involvement of TRPA1 and vascular impairment in painful diabetic peripheral neuropathy using streptozotocin-induced diabetic model mice. Results Streptozotocin-induced diabetic model mice showed mechanical and cold hypersensitivity with a peak at two weeks after the streptozotocin administration, which were likely to be paralleled with the decrease in the skin blood flow of the hindpaw. Streptozotocin-induced cold hypersensitivity was significantly inhibited by an antagonist HC-030031 (100 mg/kg) or deficiency for TRPA1, whereas mechanical hypersensitivity was unaltered. Consistent with these results, the nocifensive behaviors evoked by an intraplantar injection of the TRPA1 agonist allyl isothiocyanate (AITC) were enhanced two weeks after the streptozotocin administration. Both streptozotocin-induced cold hypersensitivity and the enhanced AITC-evoked nocifensive behaviors were significantly inhibited by a vasodilator, tadalafil (10 mg/kg), with recovery of the decreased skin blood flow. Similarly, in a mouse model of hindlimb ischemia induced by the ligation of the external iliac artery, AITC-evoked nocifensive behaviors were significantly enhanced three and seven days after the ischemic operation, whereas mechanical hypersensitivity was unaltered in TRPA1-knockout mice. However, no difference was observed between wild-type and TRPA1-knockout mice in the hyposensitivity for current or mechanical stimulation or the deceased density of intraepidermal nerve fibers eight weeks after the streptozotocin administration. Conclusion These results suggest that TRPA1 sensitization during diabetic vascular impairment causes cold, but not mechanical, hypersensitivity in the early painful phase of diabetic peripheral neuropathy. However, TRPA1 may play little or no role in the progression of diabetic peripheral neuropathy.

Background The glutamate type 1 transporter (GLT1) plays a major role in glutamate homeostasis in the brain. Although alterations of GLT1 activity have been linked to persistent pain, the significance of these changes is poorly understood. Focusing on the rostral ventromedial medulla, a key site in pain modulation, we examined the expression and function of GLT1 and related transcription factor kappa B-motif binding phosphoprotein (KBBP) in rats after adjuvant-induced hind paw inflammation. Results After inflammation, GLT1 and KBBP showed an early upregulation and gradual transition to downregulation that lasted throughout the eight-week observation period. Nitration of GLT1 was reduced at 30 min and increased at eight weeks after inflammation, suggesting an initial increase and later decrease in transporter activity. Mechanical hyperalgesia and paw edema exhibited an initial developing phase with peak hyperalgesia at 4 to 24 h, a subsequent attenuating phase, followed by a late persistent phase that lasted for months. The downregulation of GLT1 occurred at a time when hyperalgesia transitioned into the persistent phase. In the rostral ventromedial medulla, pharmacological block with dihydrokainic acid and RNAi of GLT1 and KBBP increased nociception and overexpression of GLT1 reversed persistent hyperalgesia. Further, the initial upregulation of GLT1 and KBBP was blocked by local anesthetic block, and pretreatment with dihydrokainic acid facilitated the development of hyperalgesia. Conclusions These results suggest that the initial increased GLT1 activity depends on injury input and serves to dampen the development of hyperalgesia. However, later downregulation of GLT1 fosters the net descending facilitation as injury persists, leading to the emergence of persistent pain.

Background Acute postoperative pain is induced by most incisional surgeries and usually resolves with wound repair. However, many patients experience moderate to severe pain despite receiving currently available postoperative pain relief. Accumulating evidence suggests that inflammatory cells, neutrophils, and macrophages infiltrating the wound site contribute to the acute inflammation, pain, and subsequent wound repair. Colchicine is commonly used to relieve pain in gout by inhibiting the infiltration of granulocytes and other motile cells. In this study, we examined the effects of colchicine on acute postoperative pain and wound repair by correlating the infiltration of neutrophils and macrophages in a mouse model of postoperative pain induced by plantar incision. Furthermore, these effects of colchicine were compared with clodronate liposomes, which selectively deplete circulating macrophages. Results Plantar incision induced mechanical hypersensitivity in the ipsilateral hind paw that peaked one day and lasted for three days after the surgery. Treatment with colchicine significantly attenuated the early infiltration of Gr1-positive cells (neutrophils) around the incision site and mechanical hypersensitivity, which was accompanied with inhibition of the subsequent infiltration of Iba1-positive cells (macrophages) and macrophage polarization toward the proinflammatory M1 phenotype. By contrast, an intravenous injection of clodronate liposomes significantly inhibited the infiltration of macrophages around the incision site but had little effect on the infiltration of neutrophils or mechanical hypersensitivity. Importantly, colchicine treatment significantly delayed wound closure after the incisional surgery, whereas clodronate liposome administration had no effect on wound closure. Conclusion These results suggest that colchicine can alleviate acute postoperative pain and also enhance the risk of delayed wound repair, which are associated with the suppression of neutrophil and subsequent proinflammatory M1 macrophage infiltration around the incision site, while the involvement of macrophages may be limited.

For the optimum efficacy of disease-modifying anti-rheumatic drugs (DMARDs), patients need to be adherent to their medication regimen. To clarify the effects of medication adherence on disease activity in Japanese patients with rheumatoid arthritis (RA), we conducted a cohort study in patients with various stages of RA. Patients were enrolled from the Kyoto University RA Management Alliance cohort, and followed up prospectively for 12 months. In this study, a total of 475 patients were analyzed and divided into 9 groups according to their medication adherence and the RA disease duration. The primary outcomes were based on the rate of a disease flare. The secondary outcomes were the changes in disease activity score using 28 joints (DAS28-ESR), simplified disease activity index (SDAI) and physical disability by health assessment questionnaire-disability index (HAQ). The changes in DAS28-ESR, HAQ, and the risk of disease flare in the highly adherent patients were significantly lower than those of the less adherent patients among the groups with RA ≤ 4.6 years but not those among the other groups. Taken together, this study identified a significant association between medication adherence and the disease flare during early-stage RA or short disease duration. These results emphasize the need to pay more attention to medication adherence in preventing the disease progression of RA.

Riboflavin transporter 3 (RFVT3), encoded by the SLC52A3 gene, is important for riboflavin homeostasis in the small intestine, kidney, and placenta. Our previous study demonstrated that Slc52a3 knockout ( Slc52a3 −/−) mice exhibited neonatal lethality and metabolic disorder due to riboflavin deficiency. Here, we investigated the influence of Slc52a3 gene disruption on brain development using Slc52a3 −/− embryos. Slc52a3 −/− mice at postnatal day 0 showed hypoplasia of the brain and reduced thickness of cortical layers. At embryonic day 13.5, the formation of Tuj1 + neurons and Tbr2 + intermediate neural progenitors was significantly decreased; no significant difference was observed in the total number and proliferative rate of Pax6 + radial glia. Importantly, the hypoplastic phenotype was rescued upon riboflavin supplementation. Thus, it can be concluded that RFVT3 contributes to riboflavin homeostasis in embryos and that riboflavin itself is required during embryonic development of the cerebral cortex in mice.

Systemic infusion of bone marrow stromal cells (BMSCs), a major type of multipotent stromal cells, produces pain relief (antihyperalgesia) that lasts for months. However, studies have shown that the majority of BMSCs are trapped in the lungs immediately after intravenous infusion and their survival time in the host is inconsistent with their lengthy antihyperalgesia. Here we show that long-lasting antihyperalgesia produced by BMSCs required their chemotactic factors such as CCL4 and CCR2, the integrations with the monocytes/macrophages population, and BMSC-induced monocyte CXCL1. The activation of central mu-opioid receptors related to CXCL1-CXCR2 signaling plays an important role in BMSC-produced antihyperalgesia. Our findings suggest that the maintenance of antihypergesia can be achieved by immune regulation without actual engraftment of BMSCs. In the capacity of therapeutic use of BMSCs other than structural repair and replacement, more attention should be directed to their role as immune modulators and subsequent alterations in the immune system.

Long-term prescribing of benzodiazepine receptor agonists (BZRAs) is a problem worldwide, but there are no detailed reports on the effects or side effects of reducing or discontinuing the dose. We retrospectively investigated the efficacy and safety of discontinuing or reducing the dose of BZRAs hypnotics after long-term use. Between April 2018 and May 2019, patients with insomnia after long-term use of BZRA hypnotics had BZRA hypnotics discontinued or their dose reduced, and their sleep conditions and anxiety symptoms were assessed. Insomnia severity (primary endpoint) was assessed as the change from baseline after discontinuation or reduction of BZRA hypnotics using the Insomnia Severity Index Japanese version (ISI-J). Changes from baseline in sleep quality and anxiety symptoms (secondary endpoint) from baseline were assessed using the Pittsburgh Sleep Quality Index Japanese version (PSQI-J) and Generalized Anxiety Disorder-7 (GAD-7), respectively. The adverse events were recorded during the study period. Statistical analysis was performed using the Wilcoxon matched-pairs signed rank test for changes in BZRA and concomitant medication dose, PSQI-J and GAD-7, and the paired -test for changes in ISI-J. The changes in ISI-J (discontinuation group: p = 0.07, reduction group: p = 0.91), PSQI-J (discontinuation group: p = 0.19, reduction group: p = 0.19), and GAD-7 scores (discontinuation group, p = 0.27; reduction group, p = 0.81) were not significant after the BZRA hypnotics were discontinued or reduced. Concomitant medications (antipsychotics and antidepressants) did not change from the baseline. The incidence of each adverse event did not change during the study period. BZRA hypnotics can be discontinued or their dose reduced after long-term use without worsening sleep conditions and anxiety symptoms. Our results may provide a basis for the safe and effective discontinuation or dose reduction of long-term benzodiazepine hypnotics use.