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Neuropathic pain is a significant and persistent issue for individuals with spinal cord injuries (SCI), severely impacting their quality of life. While changes at the peripheral and spinal levels are known to contribute to SCI-related pain, whether and how supraspinal centers contribute to post SCI chronic neuropathic pain is poorly understood. Here, we first validated delayed development of chronic neuropathic pain in mice with moderate contusion SCI. To identify supraspinal regions involved in the pathology of neuropathic pain after SCI, we next performed an activity dependent genetic screening and identified multiple cortical and subcortical regions that were activated by innocuous tactile stimuli at a late stage following contusion SCI. Notably, chemogenetic inactivation of pain trapped neurons in the lateral thalamus alleviated neuropathic pain and reduced tactile stimuli evoked cortical overactivation. Retrograde tracing showed that contusion SCI led to enhanced corticothalamic axonal sprouting and over-activation of corticospinal neurons. Mechanistically, ablation or silencing of corticospinal neurons prevented the establishment or maintenance of chronic neuropathic pain following contusion SCI. These results highlighted a corticospinal-lateral thalamic feed-forward loop whose activation is required for the development and maintenance of chronic neuropathic pain after SCI. Our data thus shed lights into the central mechanisms underlying chronic neuropathic pain associated with SCI and the development of novel therapeutic avenues to treat refractory pain caused by traumatic brain or spinal cord injuries.
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BACKGROUND: To assess the safety and efficacy of ultrasound-assisted sagittal view for retrograde puncture of the P2 segment of popliteal artery (PA) for treating femoropopliteal lesions. METHODS: A retrospective study was conducted on consecutive patients who underwent retrograde puncture of the PA for the recanalization of femoropopliteal lesions. A retrograde access was made to either the P2 or P3 segment of the PA in 23 cases. In 10 cases (8 men; mean age 68 ± 9 years), ultrasound-guided retrograde PA (P2 segment) puncture using the long-axis in-the-plane approach was performed, and in 13 cases (11 men; mean age 69 ± 5 years), angiography-guided retrograde PA (P3 segment) puncture was performed. Clinical data was compared preintraoperatively and postoperatively in the 2 groups. RESULTS: All occluded lesions were successfully recanalized via dual channel intervention. Puncture success were 100% (10/10) in the P2 group compared with 92.3% (12/13) in the P3 group (P > 0.05). The mean puncture time in the P2 group was significantly shorter when compared to the P3 group (4.70 ± 0.95 mins vs 11.33 ± 6.37 mins; P < 0.05). There was no difference in mean hemostasis time between the 2 groups (6.11 ± 2.20 mins vs 8.46 ± 3.76 mins; P > 0.05). There were no in-hospital deaths in all patients. The occurrence of puncture-related complications in the P2 group was 10% compared with 15% in the P3 group (P > 0.05). A low-flow arteriovenous fistula was observed in one case in the P3 group. None of the patients reported any access-related complication at a mean follow-up of 11.3 ± 5.5 months. CONCLUSIONS: Ultrasound-assisted sagittal view for retrograde puncture of the P2 segment of PA is at least as safe as angiography-guided retrograde puncture of the P3 segment for femoropopliteal lesions. Furthermore, this technique appears to be more suitable for patients with tandem iliofemoral artery occlusion, as it allows for the creation of a retrograde access.
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The effect of ß-sheet ratio and chain length on all-ß proteins was investigated by MD simulations. Protein samples composed of different repeating units with various ß-sheet ratios or a different number of repeating units were simulated under a broad temperature range. The simulation results show that the smaller radius of gyration was achieved by the protein with the higher proportion of ß-sheet secondary structure, which had the lower nonbonded energy with more HBs within the protein. The root mean square deviation (RMSD) and the root mean square fluctuation (RMSF) both increased with temperature, especially in the case of a longer chain. The visible period was also shown according to the repeated secondary structure. Several minimum values of RMSF were located on the skeleton of Cα atoms participating in the ß-sheet, indicating that it is a kind of stable secondary structure. We also concluded that proteins with a short chain or a lower ratio of ß-sheet could easily transform their oriented and compact structures to other ones, such as random coils, turns, and even α-helices. These results clarified the relationship from the primary level to the 3D structure of proteins and potentially predicted protein folding.
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Simulación de Dinámica Molecular , Conformación Proteica en Lámina beta , Proteínas , Proteínas/química , Pliegue de Proteína , Estructura Secundaria de Proteína , TemperaturaRESUMEN
Rationale: Hydrocephalus is a substantial complication after intracerebral hemorrhage (ICH) or intraventricular hemorrhage (IVH) that leads to impaired cerebrospinal fluid (CSF) circulation. Recently, brain meningeal lymphatic vessels (mLVs) were shown to serve as critical drainage pathways for CSF. Our previous studies indicated that the degradation of neutrophil extracellular traps (NETs) after ICH/IVH alleviates hydrocephalus. However, the mechanisms by which NET degradation exerts beneficial effects in hydrocephalus remain unclear. Methods: A mouse model of hydrocephalus following IVH was established by infusing autologous blood into both wildtype and Cx3cr1-/- mice. By studying the features and processes of the model, we investigated the contribution of mLVs and NETs to the development and progression of hydrocephalus following secondary IVH. Results: This study observed the widespread presence of neutrophils, fibrin and NETs in mLVs following IVH, and the degradation of NETs alleviated hydrocephalus and brain injury. Importantly, the degradation of NETs improved CSF drainage by enhancing the recovery of lymphatic endothelial cells (LECs). Furthermore, our study showed that NETs activated the membrane protein CX3CR1 on LECs after IVH. In contrast, the repair of mLVs was promoted and the effects of hydrocephalus were ameliorated after CX3CR1 knockdown and in Cx3cr1-/- mice. Conclusion: Our findings indicated that mLVs participate in the development of brain injury and secondary hydrocephalus after IVH and that NETs contribute to acute LEC injury and lymphatic thrombosis. CX3CR1 is a key molecule in NET-induced LEC damage and meningeal lymphatic thrombosis, which leads to mLV dysfunction and exacerbates hydrocephalus and brain injury. NETs may be a critical target for preventing the obstruction of meningeal lymphatic drainage after IVH.
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Lesiones Encefálicas , Trampas Extracelulares , Hidrocefalia , Trombosis , Ratones , Animales , Trampas Extracelulares/metabolismo , Células Endoteliales/metabolismo , Hemorragia Cerebral/complicaciones , Hidrocefalia/complicaciones , Hidrocefalia/metabolismoRESUMEN
INTRODUCTION: Therapeutic options to improve myelodysplastic syndrome (MDS)-related cytopenias in patients with lower-risk MDS are limited, and cyclosporin A (CSA) is an available option. METHODS: We retrospectively analysed the clinical data of 153 consecutive patients with lower-risk MDS at our institution from July 1997 to October 2017. Propensity score matching method was used to balance the influence of confounding factors between patients with MDS treated with CSA and other conventional treatments (excluding CSA), and 50 pairs of cases were successfully identified for the final analysis. We assessed response rates, progression-free survival (PFS), overall survival (OS), and factors affecting response and survival. RESULTS: Haematological improvement (HI) was observed in 35 (70%) patients treated with CSA and in 25 (50%) patients treated with conventional therapies (P < 0.05), respectively. Treatment with CSA was a favourable prognostic factor for HI in lower-risk MDS patients of both cohorts in univariate analysis [odds ratio (OR) 2.333, P < 0.05], but not in multivariate analysis. In the multivariate analysis, hypocellular marrow was the only independent prognostic factor for HI in the CSA group (OR 6.259, P < 0.05), and in the overall cohort (OR 3.102, P < 0.05).CSA treatment did not improve PFS or OS (P > 0.05). CONCLUSION: CSA is a safe treatment and can significantly improve cytopenias in a substantial proportion of patients with MDS, especially in individuals with hypocellular bone marrow. However, CSA is not associated with PFS or OS.
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We investigate the spectral and temporal atomic coherence interaction based on out-of-phase fluorescence (FL) and spontaneous parametric four-wave mixing (SFWM) from the hexagonal phase of Eu3+ : NaYF4 and different phases of Eu3+ : BiPO4. Spectral and temporal interactions are interrelated and reduced by about 2 times due to two-photon nested dressing in contrast to the sum of each laser excitation. As the lifetime of photons increases, off-resonance profile cross-interaction decreases because cross-interaction reverses the signal at the near time gate position and keeps it consistent at the far time gate position. Moreover, the thermal phonon dressing at 300 K exhibits 6 times more eminent and obvious temporal interaction than that at 77 K. In a different phase of Eu3+ : BiPO4, there are three dark dips having stronger self-interaction; however, Eu3+ : NaYF4 has two dark dips as Eu3+ : BiPO4 has two phonon dressing. Further, the pure hexagonal phase of Eu3+ : BiPO4 demonstrates the strongest cross-interaction and longest coherent time under the dressing effect due to the smallest dressing phonon detuning and off-resonance profile cross-interaction at PMT2 because the angle quantization is the strongest. Such results can be used for designing novel quantum devices and have potential applications in quantum memory devices.
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Since the World Health Organization(WHO)officially announced COVID-19 as a global pandemic in 2020,114 countries or regions in the world have been affected to varying degrees.The arrival of the post-epidemic era requires countries to take new epidemic prevention and control measures to deal with the problems and challenges that may arise in the future.In order to help China consolidate its epidemic prevention achievements over the years and gain a larger development window in the post-epidemic era,this study explored the changes in the global epidemic situation and the major national prevention and control policies in different countries,summarized the development and changes of China's epidemic prevention and control policies,and proposed new family-centered precision prevention and control measures that adapt to China's national conditions.
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AIM To identify the endophytic fungus G-(JK)-2 from Orixa japonica Thunb.and to study its secondary metabolites and their α-glucosidase inhibitory activities.METHODS Through the ITS sequence,the evolutionary tree that identifies the endophytic fungus G-(JK)-2 was established.Then 45 days rice solid medium of endophytic fungus G-(JK)-2 was extracted by methanol,and then by ethyl acetate.The ethyl acetate extract was separated and purified by silica gel chromatography,Sephadex LH-20,and semi-preparative HPLC.The structures of obtained compounds were identified by physicochemical properties and spectral data.Their α-glucosidase inhibitory activities were evaluated by PNPG method.RESULTS The endophytic fungus G-(JK)-2 from O.japonica was identified as Fusarium nematophilum.Thirteen compounds were isolated and identified as p-hydroxybenzaldehyde(G1),4-hydroxyacetophenone(G2),anhydromevalonolactone(G3),flazine(G4),salicylic acid(G5),p-hydroxybenzoic acid(G6),di-(2-ethylhexyl)-phthalate(G7),terephthalic acid bis(2-ethyl-hexyl)ester(G8),thymine(G9),uridine(G10),adenosine(G11),2′-deoxyuridine(G12),nicotinic acid(G13).The inhibitory effect of each compound on α-glucosidase was in sequence of G4>G11>G10>G13>G12.CONCLUSION All compounds are first isolated from the endophytic fungi of the O.japonica,and G10,G11,G13 are first isolated from the endophytic fungi of Fusarium.G4 and G11 have mild inhibition to α-glucosidase.
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Background The number of persons with thyroid nodules has increased rapidly in recent years, and thyroid cancer caused by malignant nodules has become a key problem endangering the health of young and middle-aged groups in China. Objective To explore work and lifestyle influencing factors for developing thyroid cancer among young and middle-aged patients with thyroid nodules. Methods The subjects with thyroid nodules were reported by routine physical examines ordered at the Huadong Sanatorium. We conducted a 1∶4 matched case-control study in which 232 patients diagnosed with thyroid cancer from 2012 to 2022 were matched to 928 controls by gender and age (±5 years). A validated questionnaire was used to collect data on work and lifestyle behaviors. Univariate and multivariate logistic regression models were applied to explore potential relationships between selected factors (including environment, working hours, stress, diet, exercise, and mental health) and thyroid cancer. Spearman rank correlation was used to analyze the correlations between variables. Results The results of univariate logistic regression showed a history of thyroid cancer reported among first-degree relatives (OR=6.059, 95%CI: 1.007, 36.473), obesity (OR=1.973, 95%CI: 1.296, 3.004), noise and vibration exposure (OR=1.988, 95%CI: 1.143, 3.456), frequent stress (OR=2.093, 95%CI: 1.231, 3.559), frequent depression (OR=2.034, 95%CI: 1.048, 3.947), frequent anger (OR=1.791, 95%CI: 1.066, 3.012), frequent fried food diet (OR=1.535, 95%CI: 1.026, 2.297), and frequent fast food diet (OR=1.836, 95%CI: 1.048, 3.215) were risk factors for reporting thyroid cancer developing from thyroid nodules, while regular meals (OR=0.245, 95%CI: 0.061, 0.989) and frequent exercise (OR=0.571, 95%CI: 0.342, 0.952) were protective factors for reporting no thyroid cancer. The results of Spearman correlation analysis showed that body mass index was positively correlated with frequent fried food, fast food, and sugary beverage diets (r=0.123, 0.083, 0.077, P<0.01), and negatively correlated with frequent depression and anger (r=−0.090, −0.070, P<0.05). The results of multiple logistic regression found that a history of thyroid cancer reported among first-degree relatives (OR=6.712, 95%CI: 1.071, 42.066), obesity (OR=2.032, 95%CI: 1.321, 3.125), noise and vibration exposure (OR=1.991, 95%CI: 1.089, 3.637), and frequent stress (OR=2.468, 95%CI: 1.417, 4.300) were associated with an elevated risk of reporting thyroid cancer developing from thyroid nodules patients. Regular exercise (frequency≥3 times·week−1, > 30 min per episode) (OR=0.516, 95%CI: 0.300, 0.890) was associated with a lowered risk of reporting thyroid cancer. Conclusions Multiple risk factors associated with reporting thyroid cancer among young and middle-aged groups with thyroid nodules are identified, such as obesity, noise and vibration exposure, frequent stress, and lack of exercise.
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Sesquiterpenoids are widely found in nature, while nitrobenzoyl sesquiterpenoids are relatively rare. Twelve natural nitrobenzoyl sesquiterpenoids were all derived from marine Aspergillus fungi, which are typical natural products with marine characteristics. These natural products exhibit good antitumor, antiviral, and inhibition of osteoclast differentiation activity, especially in the treatment of osteoclast-related diseases, showing good medicinal development value. This article reviews the natural product sources, chemical structure, chemical synthesis, biosynthesis, bioactivity, and pharmacological mechanisms of nitrobenzoyl sesquiterpenoids and predicts and discusses their absorption, distribution, metabolism, excretion, toxicity (ADME/T), and drug-likeness, providing a comprehensive understanding of the natural products of nitrobenzoyl sesquiterpenoids from marine sources and their potential for pharmaceutical development.
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BACKGROUND: Hematoma expansion is a determinant of poor outcome of intracerebral hemorrhage but occurs frequently, especially in warfarin-associated intracerebral hemorrhage (W-ICH). In the present study, we employ the warfarin-associated intracerebral hemorrhage (W-ICH) rat model, to explore the efficacy and potential mechanism of glibenclamide pretreatment on hematoma expansion after intracerebral hemorrhage, hoping to provide proof of concept that glibenclamide in stroke primary and secondary prevention is also potentially beneficial for intracerebral hemorrhage patients at early stage. METHODS: In the present study, we tested whether glibenclamide, a common hypoglycemic drug, could attenuate hematoma expansion in a rat model of W-ICH. Hematoma expansion was evaluated using magnetic resonance imaging; brain injury was evaluated by brain edema and neuronal death; and functional outcome was evaluated by neurological scores. Then blood-brain barrier integrity was assessed using Evans blue extravasation and tight junction-related protein. RESULTS: The data indicated that glibenclamide pretreatment significantly attenuated hematoma expansion at 24 h after W-ICH, thus mitigating brain edema and neuronal death and promoting neurological function recovery, which may benefit from alleviating blood-brain barrier disruption by suppressing matrix metallopeptidase-9. CONCLUSIONS: The results indicate that glibenclamide pretreatment in stroke primary and secondary prevention might be a promising therapy for hematoma expansion at the early stage of W-ICH.
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Excessive light exposure can damage photoreceptors and lead to blindness. Oxidative stress serves a key role in photo-induced retinal damage. Free radical scavengers have been proven to protect against photo-damaged retinal degeneration. Fullerol, a potent antioxidant, has the potential to protect against ultraviolet-B (UVB)-induced cornea injury by activating the endogenous stem cells. However, its effects on cell fate determination of Müller glia (MG) between gliosis and de-differentiation remain unclear. Therefore, we established a MG lineage-tracing mouse model of light-induced retinal damage to examine the therapeutic effects of fullerol. Fullerol exhibited superior protection against light-induced retinal injury compared to glutathione (GSH) and reduced oxidative stress levels, inhibited gliosis by suppressing the TGF-ß pathway, and enhanced the de-differentiation of MG cells. RNA sequencing revealed that transcription candidate pathways, including Nrf2 and Wnt10a pathways, were involved in fullerol-induced neuroprotection. Fullerol-mediated transcriptional changes were validated by qPCR, Western blotting, and immunostaining using mouse retinas and human-derived Müller cell lines MIO-M1 cells, confirming that fullerol possibly modulated the Nrf2, Wnt10a, and TGF-ß pathways in MG, which suppressed gliosis and promoted the de-differentiation of MG in light-induced retinal degeneration, indicating its potential in treating retinal diseases.
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Células Ependimogliales , Degeneración Retiniana , Animales , Ratones , Humanos , Células Ependimogliales/metabolismo , Degeneración Retiniana/tratamiento farmacológico , Degeneración Retiniana/etiología , Degeneración Retiniana/metabolismo , Gliosis/tratamiento farmacológico , Gliosis/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Retina/metabolismo , Neuroglía , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
On December 10, 2021, the FDA expanded the indications for ribociclib to include male patients for the treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. Ribociclib is now indicated in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy in adult patients, or with fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy (ET), in postmenopausal women or in men. The efficacy of ribociclib + AI for male patients was primarily based on previous favorable benefit-risk assessments of ribociclib from MONALEESA-2 and MONALEESA-7 trials, and supported by COMPLEEMENT-1, an open-label, single-arm, multicenter clinical trial, in which 39 male patients (n = 3,246 total patients) received ribociclib + letrozole + goserelin/leuprolide. The overall response rate (ORR) based on confirmed responses in male patients with measurable disease at baseline was 46.9% [95% confidence interval (CI), 29.1-65.3], consistent with an ORR of 43.6% (95% CI, 41.5-45.8) in the overall population. Overall, adverse reactions occurring in male patients were similar to those occurring in female patients treated with ribociclib + ET. The efficacy of ribociclib + fulvestrant for male patients was primarily based on the previous findings of a favorable benefit-risk assessment from the MONALEESA-3 trial, supported by FDA review of clinical data of a limited number of male patients treated in clinical practice receiving ribociclib + fulvestrant. The known mechanism of action, biologic rationale, and clinical information available adequately demonstrate that the efficacy and safety of ribociclib + AI/fulvestrant are similar in male and female patients. This article summarizes the FDA's decision-making and data supporting the approval of ribociclib in male patients with breast cancer, and discusses regulatory insights.
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Neoplasias de la Mama , Receptores de Estrógenos , Adulto , Femenino , Humanos , Masculino , Letrozol , Fulvestrant/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Aminopiridinas , Inhibidores de la Aromatasa/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Receptor ErbB-2/uso terapéuticoRESUMEN
Small biomolecules play a critical role in the fundamental processes that sustain life and are essential for the proper functioning of the human body. The detection of small biomolecules has garnered significant interest in various fields, including disease diagnosis and medicine. Electrochemical techniques are commonly employed in the detection of critical biomolecules through the principle of redox reactions. It is also a very convenient, cheap, simple, fast, and accurate measurement method in analytical chemistry. Zeolitic imidazolate frameworks (ZIFs) are a unique type of metal-organic framework (MOF) composed of porous crystals with extended three-dimensional structures. These frameworks are made up of metal ions and imidazolate linkers, which form a highly porous and stable structure. In addition to their many advantages in other applications, ZIFs have emerged as promising candidates for electrochemical sensors. Their large surface area, pore diameter, and stability make them ideal for use in sensing applications, particularly in the detection of small molecules and ions. This review summarizes the critical role of small biomolecules in the human body, the standard features of electrochemical analysis, and the utilization of various types of ZIF materials (including carbon composites, metal-based composites, ZIF polymer materials, and ZIF-derived materials) for the detection of important small biomolecules in human body fluids. Lastly, we provide an overview of the current status, challenges, and future outlook for research on ZIF materials.
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Líquidos Corporales , Zeolitas , Humanos , Imidazoles/química , Zeolitas/química , Cuerpo Humano , IonesRESUMEN
Vagus nerve stimulation (VNS) is a promising neuromodulation technique, which has been demonstrated to promote functional recovery after spinal cord injury (SCI) in our previous study. But the underlying mechanism remains to be explored. Using a compressed SCI model, our present study first demonstrated that activated microglia produce abundant tumor necrosis factor-α (TNF-α) to induce endothelial necroptosis via receptor-interacting protein kinase 1 (RIP1)/RIP3/mixed lineage kinase domain-like protein (MLKL) pathway, thus destroying the blood-spinal cord barrier (BSCB) after SCI. While both TNF-α specifical antibody (infliximab) and necroptosis inhibitor (necrostatin-1) alleviate BSCB disruption. Then our study found that VNS significantly inhibits microglia-derived TNF-α production and reduces expression of p-RIP3 and p-MLKL in endothelial cells. As expected, further results indicated that VNS mitigates the BSCB disruption, thus reducing inflammatory cells infiltration and neural damage. Finally, both electrophysiological evaluation and locomotor test demonstrated that VNS promotes motor function recovery after SCI. In conclusion, our data demonstrated VNS restricts microglia-derived TNF-α to prevent RIP1/RIP3/MLKL mediated endothelial necroptosis, thus alleviating the decisive pathophysiological BSCB disruption to reduce neuroinflammation and neural damage, which ultimately promotes motor function recovery after SCI. Therefore, these results further elaborate that VNS might be a promising therapeutic strategy for SCI. Vagus nerve stimulation prevents microglia-derived TNF-α induced endothelial necroptosis to alleviate blood-spinal cord barrier disruption after spinal cord injury.
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Traumatismos de la Médula Espinal , Estimulación del Nervio Vago , Humanos , Factor de Necrosis Tumoral alfa , Necroptosis , Células Endoteliales/metabolismo , Médula Espinal/patología , Traumatismos de la Médula Espinal/patologíaRESUMEN
As radiation therapy is increasingly utilized in the treatment of cancer, neuropathic pain (NP) is a common radiotherapy-related adverse effect and has a significant impact on clinical outcomes negatively. However, despite an improved understanding of neuropathic pain management, pain is often undertreated in patients with cancer. Herein, we reported two cases with radiotherapy-related neuropathic pain (RRNP) who presented a positive reaction to acupuncture. Patient 1 (a 73-year-old woman) with gynecologic cancer complained of burning and electric shock-like pain in the lower limb after radiotherapy. With the accepted combination of acupuncture and drugs, the pain was alleviated completely in 8 weeks. Patient 2 (a 64-year-old woman) accepted acupuncture in the absence of medication because of her inability to tolerate the adverse events of anticonvulsant drugs. She achieved remission of pain 4 weeks later. The results of this study showed that acupuncture might be promising for controlling the RRNP in patients with cancer, especially who were intolerant or unresponsive to medications.
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The limitations of significant tool wear and tool breakage of commercially available fluted micro-end mill tools often lead to ineffective and inefficient manufacturing, while surface quality and geometric dimensions remain unacceptably poor. This is especially true for machining of difficult-to-machine (DTM) materials, such as super alloys and ceramics. Such conventional fluted micro-tool designs are generally down scaled from the macro-milling tool designs. However, simply scaling such designs from the macro to micro domain leads to inherent design flaws, such as poor tool rigidity, poor tool strength and weak cutting edges, ultimately ending in tool failure. Therefore, in this article a design process is first established to determine optimal micro-end mill tool designs for machining some typical DTM materials commonly used in manufacturing orthopaedic implants and micro-feature moulds. The design process focuses on achieving robust stiffness and mechanical strength to reduce tool wear, avoid tool chipping and tool breakage in order to efficiently machine very hard materials. Then, static stress and deflection finite element analysis (FEA) is carried out to identify stiffness and rigidity of the tool design in relation to the maximum deformations, as well as the Von Mises stress distribution at the cutting edge of the designed tools. Following analysis and further optimisation of the FEA results, a verified optimum tool design is established for micro-milling DTM materials. An experimental study is then carried out to compare the optimum tool design to commercial tools, in regards to cutting forces, tool wear and surface quality.
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Background: The cerebellum is involved in the control and coordination of movements but it remains unclear whether stimulation of the cerebellum could improve the recovery of upper limb motor function. Therefore, this study aimed to explore whether cerebellar transcranial direct current stimulation (tDCS) therapy could promote the recovery of upper limb motor function in patients who suffered a stroke. Methods: In this randomized, double-blind, and sham-controlled prospective study, 77 stroke patients were recruited and randomly assigned to the tDCS group (n = 39) or the control group (n = 38). The patients received anodal (2 mA, 20 min) or sham tDCS therapy for 4 weeks. The primary outcome was the change in the Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score from baseline to the first day after 4 weeks of treatment (T1) and 60 days after 4 weeks of treatment (T2). The secondary outcomes were the FMA-UE response rates assessed at T1 and T2. Adverse events (AEs) related to the tDCS treatment were also recorded. Results: At T1, the mean FMA-UE score increased by 10.7 points [standard error of the mean (SEM) = 1.4] in the tDCS group and by 5.8 points (SEM = 1.3) in the control group (difference between the two groups was 4.9 points, P = 0.013). At T2, the mean FMA-UE score increased by 18.9 points (SEM = 2.1) in the tDCS group and by 12.7 points (SEM = 2.1) in the control group (the difference between the two groups was 6.2 points, P = 0.043). At T1, 26 (70.3%) patients in the tDCS group had a clinically meaningful response to the FMA-UE score compared to 12 (34.3%) patients in the control group (the difference between the two groups was 36.0%, P =0.002). At T2, 33 (89.2%) patients in the tDCS group had a clinically meaningful response to the FMA-UE score compared with 19 (54.3%) patients in the control group (the difference between the two groups was 34.9%, P = 0.001). There was no statistically significant difference in the incidence of adverse events between the two groups. In the subgroup analysis of different hemiplegic sides, the rehabilitation effect of patients with right hemiplegia was better than that of patients with left hemiplegia (P < 0.05); in the age subgroup analysis, different age groups of patients did not show a significant difference in the rehabilitation effect (P > 0.05). Conclusion: Cerebellar tDCS can be used as an effective and safe treatment to promote recovery of upper limb motor function in stroke patients. Trial registration: ChiCTR.org.cn, identifier: ChiCTR2200061838.
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Objective: Neuropathic pain is a common complication after spinal cord injury (SCI). Transcranial direct current stimulation (tDCS) has been confirmed to be effective in relieving neuropathic pain in patients with SCI. The aim of this study is to investigate the effect of tDCS on neuropathic pain induced by SCI and its underlying mechanism. Materials and methods: The SCI model was induced by a clip-compression injury and tDCS stimulation was performed for two courses (5 days/each). The motor function was evaluated by Basso-Beattie-Bresnahan (BBB) score, and the thermal withdrawal threshold was evaluated by the thermal radiation method. The effects of tDCS on the cerebral cortex, thalamus, midbrain, and medulla were detected by the enzyme-linked immunosorbent assay (ELISA) and immunofluorescence. Results: The results showed that SCI reduced the thermal withdrawal threshold and increased the concentration of inflammatory cytokines in the cortex, thalamus, midbrain, and medulla, including the tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). In addition, the activation of microglia and the proportion of M1 phenotypic polarization increased significantly in the ventral posterolateral (VPL), ventral tegmental (VTA), and periaqueductal gray (PAG) regions after SCI. After tDCS treatment, the thermal withdrawal threshold and motor function of SCI rats were significantly improved compared to the vehicle group. Meanwhile, tDCS effectively reduced the concentration of pro-inflammatory cytokines in the cortex, thalamus, midbrain, and medulla and increased the concentration of anti-inflammatory cytokines interleukin-10 (IL-10) in the thalamus. In addition, tDCS reduced the proportion of the M1 phenotype of microglia in VPL, VTA, and PAG regions and increase the proportion of the M2 phenotype. Conclusion: The results suggest that tDCS can effectively relieve SCI-induced neuropathic pain. Its mechanism may be related to regulating the inflammatory and anti-inflammatory cytokines in corresponding brain regions via promoting the phenotypic transformation of microglia.