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Pain and joint stiffness contribute to functional limitation in the postoperative period following proximal humeral fractures (PHF). Photobiomodulation (PBM) has demonstrated positive outcomes in fracture repair, analgesia, and functional improvement, as evidenced by randomized controlled trials (RCTs) and experimental animal studies. Clinical studies have shown PBM’s efficacy in reducing pain and improving functional outcomes, while preclinical studies have demonstrated enhanced bone regeneration through PBM application. This clinical study is a randomized, double-blind, controlled trial to investigate the effects of PBM on the shoulder functional recovery after proximal humerus fractures. A total of forty-two participants, aged 18–65 years of both genders, will be randomly divided into two groups: the Control group (receiving physiotherapy combined with simulated PBM) and the PBM group (receiving physiotherapy combined with active PBM). The PBM application (10 minutes) will be performed daily by the participants at home, using a device equipped with 318 light-emitting diodes (LEDs), consisting of 159 LEDs at 660 nm (28.5 mW; 12 J/cm²; 17 J per LED) and 159 LEDs at 850 nm (23 mW; 10 J/cm²; 14 J per LED). The PBM sessions, along with physiotherapy sessions (30 minutes, twice weekly), will be conducted over a 12-week period. Participants will be blinded to their group allocation and will be assessed by a single evaluator at 24 hours, 1 week, 2 weeks, 4 weeks, 8 weeks, and 12 weeks post-surgery. The evaluator will also be blinded to the participants’ group assignments. The primary outcome will be shoulder functional recovery after proximal humerus fractures, assessed using the Quick-DASH scale at all experimental time points. Secondary outcomes will include range of motion (measured with a digital goniometer), quality of life (evaluated using the SF-6D questionnaire), pain on pressure and the incidence of adverse effects, all assessed at each time point. Spontaneous pain, nocturnal pain and analgesic use will be evaluated over a 12-week period. Fracture consolidation will be assessed through radiography at weeks 4, 8, and 12. Muscle strength will be measured through dumbbell lifting at weeks 8 and 12. If the data are normally distributed, ANOVA will be used, and results will be presented as means ± standard deviation (SD). If the data are not normally distributed, they will be presented as medians and interquartile ranges, with comparisons made using non-parametric tests. A p-value of less than 0.05 will be considered statistically significant.

The kidneys are critical organs in peptide receptor radiation therapy (PRRT). Renal function loss may become apparent many years after PRRT. We analyzed the time course of decline in creatinine clearance (CLR) in patients during a follow-up of at least 18 mo after the start of PRRT with (90)Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA),Tyr(3)-octreotide ((90)Y-DOTATOC) or (177)Lu-DOTA(0),Tyr(3)-octreotate ((177)Lu-DOTATATE). Twenty-eight patients with metastasized neuroendocrine tumors received 1-5 cycles of (90)Y-DOTATOC, leading to renal radiation doses of 5.9-26.9 Gy per cycle and a total of 18.3-38.7 Gy. Median follow-up was 2.9 y (range, 1.5-5.4 y), with a median of 16 measurements (range, 5-53) per patient. Thirty-seven patients with metastasized neuroendocrine tumors received 3-7 cycles of (177)Lu-DOTATATE, leading to renal radiation doses of 1.8-7.8 Gy per cycle and a total of 7.3-26.7 Gy. Median follow-up was 2.4 y (range, 1.7-4.0 y), with a median of 10 (range, 6-27) measurements per patient. All renal dose estimates were calculated with the MIRDOSE3 model. All patients were infused with renoprotective amino acids during the administration of the radioactive peptides. The time trend of CLR was determined by fitting a monoexponential function through the data of individual patients, yielding the decline in CLR in terms of percentage change per year. The median decline in CLR was 7.3% per y in patients treated with (90)Y-DOTATOC and 3.8% per y in patients treated with (177)Lu-DOTATATE (P = 0.06). The time trend of decline in CLR was sustained during the follow-up period. Eleven patients had a >15% per y decline in CLR. Cumulative renal radiation dose, per-cycle renal radiation dose, age, hypertension, and diabetes are probable contributing factors to the rate of decline in CLR after PRRT. This study showed that the time course of CLR after PRRT was compatible with the pattern of sustained CLR loss in progressive chronic kidney disease.

Background Neurotoxic microglia and astrocytes begin to activate and participate in pathological processes after spinal cord injury (SCI), subsequently causing severe secondary damage and affecting tissue repair. We have previously reported that photobiomodulation (PBM) can promote functional recovery by reducing neuroinflammation after SCI, but little is known about the underlying mechanism. Therefore, we aimed to investigate whether PBM ameliorates neuroinflammation by modulating the activation of microglia and astrocytes after SCI. Methods Male Sprague–Dawley rats were randomly divided into three groups: a sham control group, an SCI + vehicle group and an SCI + PBM group. PBM was performed for two consecutive weeks after clip-compression SCI models were established. The activation of neurotoxic microglia and astrocytes, the level of tissue apoptosis, the number of motor neurons and the recovery of motor function were evaluated at different days post-injury (1, 3, 7, 14, and 28 days post-injury, dpi). Lipocalin 2 (Lcn2) and Janus kinase-2 (JAK2)-signal transducer and activator of transcription-3 (STAT3) signaling were regarded as potential targets by which PBM affected neurotoxic microglia and astrocytes. In in vitro experiments, primary microglia and astrocytes were irradiated with PBM and cotreated with cucurbitacin I (a JAK2-STAT3 pathway inhibitor), an adenovirus (shRNA-Lcn2) and recombinant Lcn2 protein. Results PBM promoted the recovery of motor function, inhibited the activation of neurotoxic microglia and astrocytes, alleviated neuroinflammation and tissue apoptosis, and increased the number of neurons retained after SCI. The upregulation of Lcn2 and the activation of the JAK2-STAT3 pathway after SCI were suppressed by PBM. In vitro experiments also showed that Lcn2 and JAK2-STAT3 were mutually promoted and that PBM interfered with this interaction, inhibiting the activation of microglia and astrocytes. Conclusion Lcn2/JAK2-STAT3 crosstalk is involved in the activation of neurotoxic microglia and astrocytes after SCI, and this process can be suppressed by PBM.

Significance Stroke is the leading cause of disability in the United States and has very limited treatment options. Brain stimulation techniques that promote recovery after stroke are a promising area of research; however, current stimulation techniques nonspecifically activate/inhibit the target area, which not only leads to undesired side effects but also makes it difficult to understand which cell types and mechanisms drive recovery. We used the optogenetic technique to specifically stimulate only neurons after stroke and demonstrate that selective neuronal stimulations can activate beneficial mechanisms and promote recovery. Understanding the cell type and mechanisms driving recovery may identify potential drug targets for stroke treatment, as well as ultimately help develop precise brain stimulation techniques for stroke therapy.

Head and neck cancer is the fifth most common malignancy and accounts for 3% of all new cancer cases each year. Despite relatively high survival rates, the quality of life of these patients is severely compromised because of radiation-induced impairment of salivary gland function and consequential xerostomia (dry mouth syndrome). In this study, a clinically applicable method for the restoration of radiation-impaired salivary gland function using salivary gland stem cell transplantation was developed. Salivary gland cells were isolated from murine submandibular glands and cultured in vitro as salispheres, which contained cells expressing the stem cell markers Sca-1, c-Kit and Musashi-1. In vitro, the cells differentiated into salivary gland duct cells and mucin and amylase producing acinar cells. Stem cell enrichment was performed by flow cytrometric selection using c-Kit as a marker. In vitro, the cells differentiated into amylase producing acinar cells. In vivo, intra-glandular transplantation of a small number of c-Kit(+) cells resulted in long-term restoration of salivary gland morphology and function. Moreover, donor-derived stem cells could be isolated from primary recipients, cultured as secondary spheres and after re-transplantation ameliorate radiation damage. Our approach is the first proof for the potential use of stem cell transplantation to functionally rescue salivary gland deficiency.

Severe joint inflammation following trauma, arthroscopic surgery or infection can damage articular cartilage, thus every effort should be made to protect cartilage from the catabolic effects of pro‐inflammatory cytokines and stimulate cartilage anabolic activities. Previous pre‐clinical studies have shown that pulsed electromagnetic fields (PEMFs) can protect articular cartilage from the catabolic effects of pro‐inflammatory cytokines, and prevent its degeneration, finally resulting in chondroprotection. These findings provide the rational to support the study of the effect of PEMFs in humans after arthroscopic surgery. The purpose of this pilot, randomized, prospective and double‐blind study was to evaluate the effects of PEMFs in patients undergoing arthroscopic treatment of knee cartilage. Patients with knee pain were recruited and treated by arthroscopy with chondroabrasion and/or perforations and/or radiofrequencies. They were randomized into two groups: a control group (magnetic field at 0.05 mT) and an active group (magnetic field of 1.5 mT). All patients were instructed to use PEMFs for 90 days, 6 h per day. The patients were evaluated by the Knee injury and Osteoarthritis Outcome Score (KOOS) test before arthroscopy, and after 45 and 90 days. The use of non‐steroidal anti‐inflammatory drugs (NSAIDs) to control pain was also recorded. Patients were interviewed for the long‐term outcome 3 years after arthroscopic surgery. Thirty‐one patients completed the treatment. KOOS values at 45 and 90 days were higher in the active group and the difference was significant at 90 days ( P < 0.05). The percentage of patients who used NSAIDs was 26% in the active group and 75% in the control group ( P = 0.015). At 3 years follow‐up, the number of patients who completely recovered was higher in the active group compared to the control group ( P < 0.05). Treatment with I‐ONE aided patient recovery after arthroscopic surgery, reduced the use of NSAIDs, and also had a positive long‐term effect.

Background Photobiomodulation (PBM) utilizing 1064 nm near-infrared light, renowned for its deep tissue penetration capabilities, has demonstrated significant therapeutic potential in addressing brain disorders; however, its specific effects and underlying mechanisms in traumatic brain injury (TBI) remain poorly understood. Methods This study investigated the therapeutic efficacy of 1064 nm light-emitting diodes (LED) treatment on emotional and cognitive impairments in a murine TBI model, and elucidating potential molecular mechanisms. C57BL/6 mice were systematically allocated into Sham, TBI, and TBI + PBM intervention groups, with the latter receiving daily 1064 nm light treatment (25 mW/cm 2 , 12 min/day) for 14 consecutive days post-TBI induction. Comprehensive behavioral assessments were conducted to evaluate emotional and cognitive functions. Advanced molecular analyses encompassing transcriptome sequencing, immunofluorescence, quantitative RT-PCR, and Western blot were employed to examine brain tissue damage, neurogenesis, synaptic remodeling, and inflammatory responses. Results The 1064 nm LED treatment demonstrated remarkable therapeutic effects, significantly ameliorating anxiety, depression-like behaviors, and spatial cognitive deficits in TBI mice. Behavioral improvements were evidenced by enhanced rotarod performance, increased exploratory behavior in open field and elevated plus maze tests, and improved Y-maze alternation rates. At the molecular level, PBM intervention exhibited multifaceted neuroprotective effects, including inhibition of neuronal apoptosis, reduction of brain injury, promotion of neurogenesis and synaptic remodeling, and upregulation of neurotrophic factors. Furthermore, the treatment enhanced blood–brain barrier integrity through upregulation of tight junction proteins and modulated neuroinflammation by shifting microglia and astrocytes toward anti-inflammatory phenotypes. Conclusions These findings collectively demonstrate that 1064 nm wavelength PBM treatment effectively promotes functional recovery and mitigates both emotional and cognitive impairments in TBI mice, providing novel mechanistic insights and a promising wavelength option for PBM-based therapeutic strategies in TBI management.

Macrophages and resident microglia play an import role in the secondary neuroinflammation response following spinal cord injury. Reprogramming of macrophage/microglia polarization is an import strategy for spinal cord injury restoration. Low-level laser therapy (LLLT) is a noninvasive treatment that has been widely used in neurotrauma and neurodegenerative diseases. However, the influence of low-level laser on polarization of macrophage/microglia following spinal cord injury remains unknown. The present study applied low-level laser therapy on a crush spinal cord injury rat model. Using immunofluorescence, flow cytometry, RT-qPCR, and western blot assays, we found that low-level laser therapy altered the polarization state to a M2 tendency. A greater number of neurons survived in the pare injury site, which was accompanied by higher BBB scores in the LLLT group. Furthermore, low-level laser therapy elevated expression of interleukin 4 (IL-4) and interleukin 13 (IL-13). Results from this study show that low-level laser therapy has the potential for reducing inflammation, regulating macrophage/microglia polarization, and promoting neuronal survival. These beneficial effects demonstrate that low-level laser therapy may be an effective candidate for clinical treatment of spinal cord injury.

Background After focal brain injuries occur, in addition to the effects that are attributable to the primary site of damage, the resulting functional impairments depend highly on changes that occur in regions that are remote but functionally connected to the site of injury. Such effects are associated with apoptotic and inflammatory cascades and are considered to be important predictors of outcome. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique that is used to treat various central nervous system (CNS) pathologies and enhance functional recovery after brain damage. Objective This study examined the efficacy of rTMS in mitigating remote degeneration and inflammation and in improving functional recovery in a model of focal brain damage. Methods Rats that were undergoing hemicerebellectomy (HCb) were treated with an rTMS protocol for 7 days, and neuronal death indices, glial activation, and functional recovery were assessed. Results rTMS significantly reduced neuronal death and glial activation in remote regions and improved functional recovery. Conclusions Our finding opens up a completely new scenario for exploiting the potential of rTMS as an anti-apoptotic and anti-inflammatory treatment.

Low-level laser light therapy (LLLT) exerts beneficial effects on motor and histopathological outcomes after experimental traumatic brain injury (TBI), and coherent near-infrared light has been reported to improve cognitive function in patients with chronic TBI. However, the effects of LLLT on cognitive recovery in experimental TBI are unknown. We hypothesized that LLLT administered after controlled cortical impact (CCI) would improve post-injury Morris water maze (MWM) performance. Low-level laser light (800 nm) was applied directly to the contused parenchyma or transcranially in mice beginning 60–80 min after CCI. Injured mice treated with 60 J/cm2 (500 mW/cm2×2 min) either transcranially or via an open craniotomy had modestly improved latency to the hidden platform (p<0.05 for group), and probe trial performance (p<0.01) compared to non-treated controls. The beneficial effects of LLLT in open craniotomy mice were associated with reduced microgliosis at 48 h (21.8±2.3 versus 39.2±4.2 IbA-1+ cells/200×field, p<0.05). Little or no effect of LLLT on post-injury cognitive function was observed using the other doses, a 4-h administration time point and 7-day administration of 60 J/cm2. No effect of LLLT (60 J/cm2 open craniotomy) was observed on post-injury motor function (days 1–7), brain edema (24 h), nitrosative stress (24 h), or lesion volume (14 days). Although further dose optimization and mechanism studies are needed, the data suggest that LLLT might be a therapeutic option to improve cognitive recovery and limit inflammation after TBI.