Alterations of Peripheral Lymphocyte Subsets in Isolated Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Adaptive immune dysfunction may play a crucial role in Parkinson's disease (PD) development. Isolated rapid eye movement sleep behavior disorder (iRBD) represents the prodromal stage of synucleinopathies, including PD. Elucidating the peripheral adaptive immune system is crucial in iRBD, but current knowledge remains limited. OBJECTIVE: This study aimed to characterize peripheral lymphocyte profiles in iRBD patients compared with healthy control subjects (HCs). METHODS: This cross-sectional study recruited polysomnography-confirmed iRBD patients and age- and sex-matched HCs. Venous blood was collected from each participant. Flow cytometry was used to evaluate surface markers and intracellular cytokine production in peripheral blood mononuclear cells. RESULTS: Forty-four iRBD patients and 36 HCs were included. Compared with HCs, patients with iRBD exhibited significant decreases in absolute counts of total lymphocytes and CD3+ T cells. In terms of T cell subsets, iRBD patients showed higher frequencies and counts of proinflammatory T helper 1 cells and INF-γ+ CD8+ T cells, along with lower frequencies and counts of anti-inflammatory T helper 2 cells. A significant increase in the frequency of central memory T cells in CD8+ T cells was also observed in iRBD. Regarding B cells, iRBD patients demonstrated reduced frequencies and counts of double-negative memory B cells compared with control subjects. CONCLUSIONS: This study demonstrated alterations in the peripheral adaptive immune system in iRBD, specifically in CD4+ and INF-γ+ CD8+ T cell subsets. An overall shift toward a proinflammatory state of adaptive immunity was already evident in iRBD. These observations might provide insights into the optimal timing for initiating immune interventions in PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Aß1-42-containing platelet-derived extracellular vesicle is associated with cognitive decline in Parkinson's disease.

Background: Cortical amyloid deposition is a common observation in Parkinson's disease dementia (PDD) patients. Aß1-42 is linked to a more rapid progression of dementia. Platelets, which degranulate upon activation, are a primary source of Aß. It has been repeatedly reported that peripheral extracellular vesicles (EVs) can partially reach the central nervous system. Thus, we speculate that activated platelet-derived Aß1-42-containing EVs (PEV-Aß1-42) play a crucial role in the cognitive decline of PD patients. Methods: The study included 189 participants: 66 with non-dementia PD, 73 with PDD, and 50 healthy controls. All participants underwent blood collection and clinical assessments. Twenty PD patients underwent re-examination and repeated blood collection 14 months later. A nano-scale flow cytometry assay was used to detect PEVs and PEV-Aß1-42 using fluorescence-labeled CD62P and Aß1-42 antibodies. Results: Parkinson's disease dementia patients had higher PEV-Aß1-42 concentrations than healthy controls (p = 0.028). The ratio of PEV-Aß1-42 to PEV was significantly higher in PDD patients compared to those in non-dementia PD and healthy controls (p PD-ND < 0.001, p HC = 0.041). The PEV-Aß1-42/PEV ratio appears to influence the odds of developing dementia (OR = 1.76, p < 0.001). The change in the PEV-Aß1-42/PEV ratio was also correlated with cognitive decline over 14 months (r = -0.447, p < 0.05). Conclusion: The plasma PEV-Aß1-42/PEV ratio may serve as a diagnostic and prognostic biomarker for PDD patients.

Comparative efficacy and safety of monoamine oxidase type B inhibitors plus channel blockers and monoamine oxidase type B inhibitors as adjuvant therapy to levodopa in the treatment of Parkinson's disease: a network meta-analysis of randomized controlled trials.

BACKGROUND AND PURPOSE: The monoamine oxidase type B inhibitors plus channel blockers (MAO-BIs plus) are a new class of antiparkinsonian drug with additional mechanisms of action for their property as ion channel blockers. The present study aimed to compare the efficacy and safety of MAO-BIs plus and conventional MAO-BIs, as well as their corresponding doses, as adjuvant therapy to levodopa in the treatment of Parkinson's disease (PD). METHOD: Randomized controlled trials enrolling PD patients treated with selegiline, rasagiline, safinamide or zonisamide as adjuvant therapy to levodopa were identified. Bayesian network meta-analysis was conducted. RESULTS: Thirty-one randomized controlled trials comprising 7142 PD patients were included. Compared with levodopa monotherapy, the combination therapy of MAO-BIs and levodopa was significantly more effective, with a mean difference of 2.74 (1.26-4.18) on the Unified Parkinson's Disease Rating Scale (UPDRS) III score change for selegiline, 2.67 (1.45-3.87) for safinamide, 2.2 (0.98-3.64) for zonisamide and 2.04 (1.24-2.87) for rasagiline. No significant difference was detected amongst MAO-BIs. The surface under the cumulative ranking results showed that safinamide 100 mg and rasagiline 1 mg ranked first in improving UPDRS III and UPDRS II, respectively. Zonisamide 100 mg ranked first in reducing OFF time. For safety outcomes, rasagiline was associated with a higher incidence of adverse events than placebo and safinamide. MAO-BIs plus had a higher probability of being safer agents compared to conventional MAO-BIs. CONCLUSIONS: Monoamine oxidase type B inhibitors plus, conventional MAO-BIs and the corresponding doses are similar in efficacy in PD treatment. MAO-BIs plus might be safer than conventional MAO-BIs. Head-to-head comparisons are needed for further investigation.

Alpha-Synuclein species in oral mucosa as potential biomarkers for multiple system atrophy.

Background: The definitive diagnosis of Multiple system atrophy (MSA) requires the evidence of abnormal deposition of α-Synuclein (α-Syn) through brain pathology which is unable to achieve in vivo. Deposition of α-Syn is not limited to the central nervous system (CNS), but also extended to peripheral tissues. Detection of pathological α-Syn deposition in extracerebral tissues also contributes to the diagnosis of MSA. We recently reported the increased expressions of α-Syn, phosphorylated α-Synuclein at Ser129 (pS129), and α-Syn aggregates in oral mucosal cells of Parkinson's disease (PD), which serve as potential biomarkers for PD. To date, little is known about the α-Syn expression pattern in oral mucosa of MSA which is also a synucleinopathy. Here, we intend to investigate whether abnormal α-Syn deposition occurs in oral mucosal cells of MSA, and to determine whether α-Syn, pS129, and α-Syn aggregates in oral mucosa are potential biomarkers for MSA. Methods: The oral mucosal cells were collected by using cytobrush from 42 MSA patients (23 MSA-P and 19 MSA-C) and 47 age-matched healthy controls (HCs). Immunofluorescence analysis was used to investigate the presence of α-Syn, pS129, and α-Syn aggregates in the oral mucosal cells. Then, the concentrations of α-Syn species in oral mucosa samples were measured using electrochemiluminescence assays. Results: Immunofluorescence images indicated elevated α-Syn, pS129, and α-Syn aggregates levels in oral mucosal cells of MSA than HCs. The concentrations of three α-Syn species were significantly higher in oral mucosal cells of MSA than HCs (α-Syn, p < 0.001; pS129, p = 0.042; α-Syn aggregates, p < 0.0001). In MSA patients, the oral mucosa α-Syn levels negatively correlated with disease duration (r = -0.398, p = 0.009). The area under curve (AUC) of receiver operating characteristic (ROC) analysis using an integrative model including age, gender, α-Syn, pS129, and α-Syn aggregates for MSA diagnosis was 0.825, with 73.8% sensitivity and 78.7% specificity. Conclusion: The α-Syn levels in oral mucosal cells elevated in patients with MSA, which may be promising biomarkers for MSA.

Freezing of gait in Parkinson's disease is associated with the microstructural and functional changes of globus pallidus internus.

Background: Freezing of gait (FOG) is a common motor symptom in advanced Parkinson's disease (PD). However, the pathophysiology mechanism of FOG is not fully understood. The purpose of this study was to investigate microstructural abnormalities in subcortical gray matter and alterations in functional connectivity of the nuclei with microstructural changes. In addition, the correlations between these microstructural and functional changes and the severity of FOG were measured. Materials and methods: Twenty-four patients with FOG (PD-FOG), 22 PD patients without FOG (PD-nFOG), and 27 healthy controls (HC) were recruited. FOG Questionnaire (FOGQ) and Gait and Falling Questionnaire (GFQ) were assessed, and Timed Up and Go (TUG) tests were performed in PD-FOG patients. All subjects underwent diffusion tensor imaging (DTI) and resting-state functional MRI scanning. The DTI measures, including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD), were extracted and measured from basal ganglia, thalamus, and substantia nigra. The nuclei with microstructural alterations were selected as seed regions to perform the seed-based resting-state functional connectivity. Results: The MD and RD values of the right globus pallidus internus (GPi) were significantly higher in patients with PD-FOG compared with PD-nFOG patients and HC. In PD-FOG patients, the MD and RD values of the right GPi were significantly correlated with the time of the TUG test in both ON and OFF states. The MD values were also correlated with the GFQ scores in PD-FOG patients. Resting-state functional connectivity between the right GPi and left middle occipital gyri decreased significantly in PD-FOG patients compared to PD-nFOG patients, and was negatively correlated with GFQ scores as well as the time of ON state TUG in PD-FOG patients. Conclusion: Microstructural alterations in the right GPi and functional connectivity between the right GPi and visual cortex may be associated with the pathophysiological mechanisms of FOG in PD patients.

Modification of Microfluidic Paper-Based Devices with an Oxidant Layer for Distance Readout of Reducing Substances.

We developed a novel strategy for modification of paper cellulose with water-insoluble oxidants for distance readout of reducing substances on microfluidic paper-based analytical devices (µPADs). Water-insoluble oxidants were formed and modified onto paper cellulose through the redox reaction that occurred between paper cellulose and potassium permanganate deposited on the paper channel, developing a yellowish-brown color on the channel. As aqueous solutions containing reducing substances flowed along the channel, reducing substances were consumed owing to the redox reaction that occurred between oxidants and reducing substances until the reducing substances were depleted, forming a discolored zone on the yellowish-brown channel. The redox reaction between insoluble oxidants and reducing substances on the paper cellulose could be used for distance-based detection of a wide variety of reducing substances, which is similar to the classical potassium permanganate titration that employs the redox reaction that occurred between potassium permanganate and reducing substances. We believe that this method will broaden the analytical applications of distance-based detection on µPADs. This method was applied to ascorbic acid assay and captopril assay in real samples with analytical results comparing well with the labeled values, demonstrating its great potential in real sample analysis.

Clinical outcome of photodynamic therapy for the treatment of cervical intraepithelial neoplasia grade 2.

Five-aminolaevulinic acid photodynamic therapy (ALA-PDT) was used to treat 79 cervical intraepithelial neoplasia 2 (CIN 2) patients who desired preservation of fertility ,between Oct 2018 and Dec 2020. Three months after treatment, among the 65 patients who returned for follow-up, full recovery and improvement rates were 43/65 and 16/65, respectively, resulting in a total response rate of 90.77%. This suggests that ALA-PDT is worthy of clinical application, even as monotherapy. The result of immune testing also indicated significant promotion of CD4+T expression during the recovery process, highlighting the importance of immune responses in different prognoses.

Oral Mucosa Derived α-Synuclein as a Potential Diagnostic Biomarker for Parkinson's Disease.

Background: Pathological α-synuclein (α-Syn) is not only exclusive to the central nervous system (CNS) in Parkinson's disease (PD), but also extended to biofluids and peripheral tissues including oral cavity. Both oral mucosa and nervous system are derived from ectodermal tissue, and potentially share common disease-specific characteristics. Oral mucosal exfoliative cytology is a non-invasive technique, which is an easily acceptable for patients and ordinary people. The purpose of this study was to determine the abnormal accumulation of α-Syn in oral mucosa of PD patients and to learn the diagnostic utility of oral mucosa α-Syn for PD. Methods: The oral mucosa samples were obtained from 57 patients with PD and 51 age-matched controls by cytological brush. Immunofluorescence analysis was used to investigate the presence and subcellular localization of α-Syn, phosphorylated α-Syn at Ser129 (pS129) and oligomeric α-Syn in the oral mucosa cells of PD patients and controls. Images taken as Z-stacks were analyzed for 3D reconstruction to visualize the α-Syn intracellular localization. Then, the concentrations of α-Syn, pS129, and oligomeric α-Syn in oral mucosa samples were measured using electrochemiluminescence assays. Results: Immunofluorescence images revealed the increased α-Syn, pS129, and oligomeric α-Syn levels in oral mucosa cells of PD patients than age-matched controls. The intracellular distributions of α-Syn species were determine by Z-stack images with 3D reconstruction, and α-Syn was detected in both the nucleus and cytoplasm. However, pS129 was mainly located in the cytoplasm, and oligomeric α-Syn was highly expressed in the nucleus and perinuclear cytoplasm. The concentrations of three α-Syn species were significantly increased in the oral mucosa cell samples of PD patients than controls (α-Syn, p = 0.001; pS129, p = 0.002; oligomeric α-Syn, p = 0.013). In PD patients, the oral mucosa α-Syn and oligomeric α-Syn levels were significantly correlated with Hoehn-Yahr scales (α-Syn, r = 0.495, p = 0.001; oligomeric α-Syn, r = 0.324, p = 0.03). The area under curve (AUC) of ROC analysis using an integrative model including α-Syn, pS129, and oligomeric α-Syn for PD diagnosis was 0.749, with 66.7% sensitivity and 72.5% specificity. Conclusion: This study for the first time demonstrated increased expressions of α-Syn, pS129, and oligomeric α-Syn in oral mucosa cells from PD patients, which serve as useful and non-invasive PD diagnostic biomarkers.

Evaluating the effect of immersive virtual reality technology on gait rehabilitation in stroke patients: a study protocol for a randomized controlled trial.

BACKGROUND: The high incidence of cerebral apoplexy makes it one of the most important causes of adult disability. Gait disorder is one of the hallmark symptoms in the sequelae of cerebral apoplexy. The recovery of walking ability is critical for improving patients' quality of life. Innovative virtual reality technology has been widely used in post-stroke rehabilitation, whose effectiveness and safety have been widely verified. To date, however, there are few studies evaluating the effect of immersive virtual reality on stroke-related gait rehabilitation. This study outlines the application of immersive VR-assisted rehabilitation for gait rehabilitation of stroke patients for comparative evaluation with traditional rehabilitation. METHODS: The study describes a prospective, randomized controlled clinical trial. Thirty-six stroke patients will be screened and enrolled as subjects within 1 month of initial stroke and randomized into two groups. The VRT group (n = 18) will receive VR-assisted training (30 min) 5 days/week for 3 weeks. The non-VRT group (n = 18) will receive functional gait rehabilitation training (30 min) 5 days/week for 3 weeks. The primary outcomes and secondary outcomes will be conducted before intervention, 3 weeks after intervention, and 6 months after intervention. The primary outcomes will include time "up & go" test (TUGT). The secondary outcomes will include MMT muscle strength grading standard (MMT), Fugal-Meyer scale (FMA), motor function assessment scale (MAS), improved Barthel index scale (ADL), step with maximum knee angle, total support time, step frequency, step length, pace, and stride length. DISCUSSION: Virtual reality is an innovative technology with broad applications, current and prospective. Immersive VR-assisted rehabilitation in patients with vivid treatment scenarios in the form of virtual games will stimulate patients' interest through active participation. The feedback of VR games can also provide patients with performance awareness and effect feedback, which could be incentivizing. This study may reveal an improved method of stroke rehabilitation which can be helpful for clinical decision-making and future practice. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900025375 . Registered on 25 August 2019.

Engineering Macrophages via Nanotechnology and Genetic Manipulation for Cancer Therapy.

Macrophages play critical roles in tumor progression. In the tumor microenvironment, macrophages display highly diverse phenotypes and may perform antitumorigenic or protumorigenic functions in a context-dependent manner. Recent studies have shown that macrophages can be engineered to transport drug nanoparticles (NPs) to tumor sites in a targeted manner, thereby exerting significant anticancer effects. In addition, macrophages engineered to express chimeric antigen receptors (CARs) were shown to actively migrate to tumor sites and eliminate tumor cells through phagocytosis. Importantly, after reaching tumor sites, these engineered macrophages can significantly change the otherwise immune-suppressive tumor microenvironment and thereby enhance T cell-mediated anticancer immune responses. In this review, we first introduce the multifaceted activities of macrophages and the principles of nanotechnology in cancer therapy and then elaborate on macrophage engineering via nanotechnology or genetic approaches and discuss the effects, mechanisms, and limitations of such engineered macrophages, with a focus on using live macrophages as carriers to actively deliver NP drugs to tumor sites. Several new directions in macrophage engineering are reviewed, such as transporting NP drugs through macrophage cell membranes or extracellular vesicles, reprogramming tumor-associated macrophages (TAMs) by nanotechnology, and engineering macrophages with CARs. Finally, we discuss the possibility of combining engineered macrophages and other treatments to improve outcomes in cancer therapy.

Application of 5-aminolevulinic acid photodynamic therapy for vaginal intraepithelial neoplasia, a report of six cases.

BACKGROUND: Vaginal intraepithelial neoplasia (VAIN) has a high-risk for recurrence and may precede genital cancers, such as vaginal cancer and/or other invasive diseases. Human papillomavirus (HPV)-induced VAIN may occur after loop electrosurgical excision procedures (LEEPs) or panhysterectomy. 5-aminolevulinic acid (ALA) photodynamic therapy (ALA-PDT) has demonstrated utility in preventing the recurrence of cervical intraepithelial neoplasia (CIN); however, evaluation of its effect on VAIN has not been performed. METHODS: The effectiveness of ALA-PDT was evaluated in 6 women diagnosed with HPV-induced VAIN. Lesion treatment was performed 3 h after ALA using light at a wavelength of 635 nm and light density of 80 mw/cm2. Therapeutic effect was assessed using HPV-DNA tests combined with liquid-based cervical cytology (LCT). RESULTS: Six women, aged 49-54 years, who were diagnosed VAIN grade 1/2 or 2 after LEEP or panhysterectomy or no surgery underwent ALA-PDT (range, 4-8 treatments). Four of the 6 women were HPV negative on retesting 3-4 months after ALA-PDT. Most patients exhibited no signs of recurrence during the follow-up period. CONCLUSIONS: Direct use of ALA-PDT or after panhysterectomy did not necessarily lead to a negative result; however, ALA-PDT after LEEP or panhysterectomy combined with LEEP yielded a satisfactory curative effect on VAIN. Although recurrence rates need to be monitored in longer-term studies, the absence of post-treatment complications in this study supports the potential utility of the technique.

Pedunculopontine Nucleus Deep Brain Stimulation Improves Gait Disorder in Parkinson's Disease: A Systematic Review and Meta-analysis.

Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) has been proposed as a treatment strategy for gait disorder in patients with Parkinson's disease (PD). We thus performed a systematic review and meta-analysis of randomized and nonrandomized controlled trials to assess the effect of this treatment on gait disorder in patients with PD. We systematically searched PubMed, Cochrane, Web of Knowledge, Wan Fang and WIP for randomized and nonrandomized controlled trials (published before July 29, 2014; no language restrictions) comparing PPN-DBS with other treatments. We assessed pooled data using a random effects model and a fixed effects model. Of 130 identified studies, 14 were eligible and were included in our analysis (N = 82 participants). Compared to those presurgery, the Unified Parkinson Disease Rating Scale (UPDRS) 27-30 scores for patients were lowered by PPN-DBS [3.94 (95% confidence interval, CI = 1.23 to 6.65)]. The UPDRS 13 and 14 scores did not improve with levodopa treatment [0.43 (- 0.35 to 1.20); 0.35 (- 0.50 to 1.19)], whereas the UPDRS 27-30 scores could be improved by the therapy [1.42 (95% CI 0.34 to 2.51)]. The Gait and Falls Questionnaire and UPDRS 13 and 14 scores showed significant improvements after PPN-DBS under the medication-off (MED-OFF) status [15.44 (95% CI = 8.44 to 22.45); 1.57 (95% CI = 0.84 to 2.30); 1.34 (95% CI = 0.84 to 1.84)]. PPN-DBS is a potential therapeutic target that could improve gait and fall disorders in patients with PD. Our findings will help improve the clinical application of DBS in PD patients with gait disorder.

Loop electrosurgical excision procedure followed by 5-aminolevulinic acid photodynamic therapy for cervical intraepithelial neoplasia, a report of six cases.

BACKGROUND: Cervical intraepithelial neoplasia (CIN) may progress to cervical cancer if left untreated. The loop electrosurgical excision procedure (LEEP) of the transitional zone of the cervix is a standard form of treatment. However, human papillomavirus (HPV)-induced CIN may recur after LEEP. The purpose of this case report is to describe the successful use of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) as an adjunct to LEEP, in preventing the recurrence of CIN. METHODS: The effectiveness of this combined treatment was evaluated in six women. The diagnosis of HPV-induced CIN was determined using HPV DNA tests and liquid-based cervical cytology. Lesion removal was performed 3 h after application of ALA using a 635 nm light density of 80 mw/cm2. RESULTS: We treated 6 women aged 31-62 years who had persistent CIN following LEEP, with ALA-PDT (range, 4-7 treatments). Five of the 6 women were HPV negative on retesting 6-7 months after ALA-PDT. Most patients showed no signs of recurrence during the follow-up period. CONCLUSIONS: Use of ALA-PDT following LEEP may prevent the recurrence of CIN. Monitoring HPV status by means of DNA testing and liquid-based cytology may be used as a standard for clinical diagnosis and treatment. Post-treatment care should be carefully considered because improper post-treatment care might directly lead to relapse.

Effects of surface charge on interfacial interactions related to membrane fouling in a submerged membrane bioreactor based on thermodynamic analysis.

Effects of both membrane and sludge foulant surface zeta potentials on interfacial interactions between membrane and sludge foulant in different interaction scenarios were systematically investigated based on thermodynamic methods. Under conditions in this study, it was found that zeta potential had marginal effects on total interfacial interaction between two infinite planar surfaces, and the total interfacial interaction between foulant particles and membrane would be more repulsive with increase of absolute value of zeta potential. Adhesion of foulant particles on membrane surface should overcome an energy barrier. There exists a critical zeta potential below which energy barrier would disappear. Results also showed that rough surface membrane corresponded to significantly low strength of interfacial interactions. This study not only provided a series of methods to quantitatively assess the interfacial interactions between membrane and sludge foulants, but also reconciled the contradictory conclusions regarding effects of zeta potential in literature, giving important implications for membrane fouling mitigation.

Chronic fluoxetine treatment improves ischemia-induced spatial cognitive deficits through increasing hippocampal neurogenesis after stroke.

Cognitive deficits, including spatial memory impairment, are very common after ischemic stroke. Neurogenesis in the dentate gyrus (DG) contributes to forming spatial memory in the ischemic brain. Fluoxetine, a selective serotonin reuptake inhibitor, can enhance neurogenesis in the hippocampus in physiological situations and some neurological diseases. However, whether it has effects on ischemia-induced spatial cognitive impairment and hippocampal neurogenesis has not been determined. Here we report that fluoxetine treatment (10 mg kg(-1), i.p.) for 4 weeks promoted the survival of newborn cells in the ischemic hippocampus and, consequently, attenuated spatial memory impairment of mice after focal cerebral ischemia. Disrupting hippocampal neurogenesis blocked the beneficial effect of fluoxetine on ischemia-induced spatial cognitive impairment. These results suggest that chronic fluoxetine treatment benefits spatial cognitive function recovery following ischemic insult, and the improved cognitive function is associated with enhanced newborn cell survival in the hippocampus. Our results raise the possibility that fluoxetine can be used as a drug to treat poststroke spatial cognitive deficits.