Hemichorea caused by nonketotic hyperosmolar state: A case report and review of the literature.

Our report involves a case of hemichorea caused by the nonketotic hyperosmolar state. We have analyzed the clinical data and relevant features of a patient who presented herself to the Affiliated Hospital of Xuzhou Medical University. The patient had unilateral involuntary movements for 1 month. We discovered that her blood glucose levels were very high. The patient underwent computed tomography (CT), magnetic resonance imaging (MRI), and magnetic resonance angiography (MRA), indicating right basal ganglia lesion. Control of the patient's blood glucose plus supportive treatment resulted in a significant improvement of her clinical state.

RNA interference targeting Bcl-6 ameliorates experimental autoimmune myasthenia gravis in mice.

Follicular helper T (Tfh) cells are dedicated to providing help to B cells and are strongly associated with antibody-mediated autoimmune disease. B cell lymphoma 6 (Bcl-6) is a key transcription factor of Tfh cells, and IL-21 is known to be a critical cytokine produced by Tfh cells. We silenced Bcl-6 gene expression using RNA interference (RNAi) delivered by a lentiviral vector, to evaluate the therapeutic role of Bcl-6 short hairpin RNAs (shRNAs) in experimental autoimmune myasthenia gravis (EAMG). Our data demonstrate that CD4(+)CXCR5(+)PD-1(+) Tfh cells, Bcl-6 and IL-21 were significantly increased in EAMG mice, compared with controls. In addition, we found that frequencies of Tfh cells were positively correlated with the levels of serum anti-AChR Ab. In-vivo transduction of lenti-siRNA-Bcl6 ameliorates the severity of ongoing EAMG with decreased Tfh cells, Bcl-6 and IL-21 expression, and leads to decreased anti-AChR antibody levels. Furthermore, we found that siRNA knockdown of Bcl-6 expression increases the expression of Th1(IFN-γ, T-bet) and Th2 markers (IL-4 and GATA3), but failed to alter the expression of Th17-related markers (RORγt, IL-17) and Treg markers (FoxP3). Our study suggests that Tfh cells contribute to the antibody production and could be one of the most important T cell subsets responsible for development and progression of EAMG or MG. Bcl-6 provides a promising therapeutic target for immunotherapy not only for MG, but also for other antibody-mediated autoimmune diseases.

Value of neutrophil-to-lymphocyte ratio in neuronal intranuclear inclusion disease.

Background and objectives: The neutrophil-to-lymphocyte ratio (NLR) is a widely recognized marker of inflammation in peripheral blood. However, its specific role in neuronal intranuclear inclusion disease (NIID) has not been reported. This study aims to investigate the relationship between NIID and NLR. Methods: A multicenter database was collected, including 157 NIID patients from seven hospitals (The Affiliated Hospital of Xuzhou Medical University, Yantai Yuhuangding Hospital, Tengzhou Central People's Hospital,The Affiliated Brain Hospital of Nanjing Medical University, Liaocheng People's Hospital,The Second Hospital of Shandong University, Inner Mongolia People's Hospital, Xuanwu Hospital Capital Medical University,The First Affiliated Hospital of USTC), along with 157 age- and gender-matched healthy control subjects. White blood cell counts (including neutrophils, lymphocytes, monocytes, eosinophils, and basophils) were obtained, and the NLR was calculated. Additionally, cognitive impairment was assessed using clinical evaluation scores. Results: NIID patients exhibited significantly higher NLR values compared to the healthy control group (p < 0.001). The plasma NLR levels in NIID patients showed a weak positive correlation with disease duration (r = 0.219, p = 0.016). However, no significant correlations were found between NLR and age of onset or cognitive impairment (p > 0.05). Conclusion: There is a significant association between NLR and NIID, suggesting a potential role of peripheral blood inflammation in the pathogenesis of NIID.

Clinical Value of Inflammatory Cytokines in Patients with Aneurysmal Subarachnoid Hemorrhage.

Background: Inflammation is closely associated with prognosis in patients with aneurysmal subarachnoid hemorrhage (aSAH), which is orchestrated by inflammatory cytokines. Therefore, this study aimed to investigate the levels of inflammatory cytokines in the early stage of aSAH and their predictive value for prognosis. Methods: In this retrospective study, 206 patients with aSAH were recruited and assigned to a severe group (WFNS grade ≥ 4) and a mild group (WFNS grade < 4) according to the severity of patients on admission. Flow cytometry was performed to detect the levels of 12 inflammatory cytokines in the serum of patients. Then, patients were grouped into a poor prognosis group (mRS score ≥ 4) and a good prognosis group (mRS score < 4) based on their prognosis after 3 months of discharge to compare the relationship between cytokines and prognosis. Propensity score matching (PSM) was utilized to control confounding factors. The correlation between inflammatory factors and prognosis was determined using Spearman correlation, and the predictive efficacy of inflammatory factors was tested by a receiver operating characteristic curve. Results: Serum IL-1ß, IL-5, IL-6, IL-8, IL-10, IFN-γ, and TNF-α levels were significantly higher in the mild group than in the severe group and in the poor prognosis group than in the good prognosis group. After PSM, the differences in IL-1ß, IL-5, IFN-α, and IFN-γ levels disappeared between the two groups, whereas IL-2, IL-6, IL-8, IL-10, and TNF-α levels remained higher in the poor prognosis group than in the good prognosis group. Additionally, IL-2, IL-6, IL-8, and IL-10 levels were positively correlated with mRS scores. Moreover, the predictive value was found to be the highest for IL-6 and the lowest for TNF-α. Conclusion: Inflammation degree was related to the severity of aSAH. Inflammatory markers, including IL-6, IL-10, IL-8, IL-2, and TNF-α, might predict the poor prognosis of aSAH.

Oncogenic role of Tc17 cells in cervical cancer development.

BACKGROUND: As one of the subsets of CD8+ T cells, Tc17 cells have recently been identified and are characterized by the secretion of interleukin (IL)-17, which is related to inflammatory diseases. AIM: To assess the status of Tc17 cells in cervical cancer and investigate the biological function of Tc17 cells in cervical cancer development. METHODS: Flow cytometry assay, immunohistochemistry, and immunofluorescence were performed to detect the levels and phenotype of Tc17 cells in blood and tumor samples from patients with cervical cancer. Prior to cell suspension culture, ELISA was carried out to measure the production of IL-6, IL-1ß, IL-23, CXCL12, and IL-17 in tumor tissue supernatant and co-cultured supernatant of patients with cervical cancer. In addition, multivariate analysis was performed to identify factors associated with overall survival using the Cox proportional hazards model. RESULTS: Compared with normal tissues, Tc17 cells specifically accumulated in tumor tissues of cervical cancer patients. Cancer cells produced a greater amount of IL-6, IL-1ß, and IL-23, which in turn promoted Tc17 cell polarization. Unlike the traditional cytotoxic CD8+ T cells, Tc17 cells secreted IL-17, which subsequently promoted CXCL12 expression in tumor cells, eventually enhancing the proliferation and migration of tumor cells. Thus, the ratio of tumor-infiltrating Tc17 cells was highly correlated with poor clinical outcome in patients with cervical cancer. CONCLUSION: Our data identified the oncogenic role of Tc17 cells in the development of cervical cancer. We propose that the ratio of Tc17 cells may be a useful index in the prognosis of patients with cervical cancer.

Inhibition of NK1R attenuates LPS-induced microglial inflammation and consequent death of PC12 cells.

Microglia, the resident immune cells in the central nervous system, play a critical role under physiological conditions, but they may be activated and exaggerate the pathological development of Parkinson's disease (PD). Recent reports have suggested that neurokinin 1 receptor (NK1R) is involved in various inflammatory diseases, including PD. However, whether neurokinin 1 (NK1) is involved in the activation of microglial cells remains unclear. In the present study, we found that (1) NK1R is located in microglial cells and upregulated in lipopolysaccharide (LPS)-activated BV2 microglia. Application of CP-99994, a selective antagonist of NK1R, inhibited the production of inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1ß), IL-6, inducible macrophage-type nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) in activated BV2 cells. (2) NK1R antagonist suppressed the morphological changes in LPS-stimulated BV2. (3) Microglial inactivation by NK1R antagonist resulted in decreased microglial migration. (4) NK1R antagonist reduced nuclear translocation of nuclear factor kappa-B (NF-κB) and attenuated phosphorylation of mitogen-activated protein kinases (MAPKs) in LPS-stimulated BV2. (5) The cell death of PC12 induced by microglia-mediated neuroinflammation was reversed in a Transwell co-culture system by NK1R antagonist. Collectively, these results showed that inhibition of NK1R attenuates LPS-induced microglial inflammatory response and dopaminergic neurotoxicity, which may be due to the decreased MAPK/NF-κB signal pathway. Thus, NK1R may be a therapeutic target in neuroinflammation, especially in PD.

Activated mGluR5 protects BV2 cells against OGD/R induced cytotoxicity by modulating BDNF-TrkB pathway.

Activated Metabotropic glutamate receptors 5(mGluR5) exhibits protective effects against ischemic brain damage, but the underlying mechanisms are not clearly known. Brain-derived neurotrophic factor (BDNF), as a valuable member of neurotrophic factor family, exerts its protection by combining with its high-affinity receptor tyrosine protein kinase B (TrkB). To investigate the role of activated mGluR5 against oxygen-glucose deprivation (OGD)/reoxygenation (R)-mediated cytotoxicity, the cell viability, apoptosis, the release of inflammatory cytokines and accumulation of reactive oxygen species (ROS) were evaluated in BV2 cells (Microglia cell line) with or without OGD/R exposure. Our data show that CHPG (the selective mGluR5 agonist) pretreatment, as an mGluR5 agonist, protected BV2 cells against OGD/R-induced cytotoxicity, apoptosis, the release of inflammatory cytokines, and the accumulation of ROS. However, these effects were significantly reversed by the mGluR5 antagonist MPEP pretreatment. Our data also show that the expressions of BDNF and TrkB were significantly decreased in BV2 cells with OGD/R exposure. CHPG pretreatment significantly enhanced the expressions of BDNF and TrkB in BV2 cells with OGD/R exposure. However, the increased expressions were significantly abrogated by MPEP pretreatment. In addition, inhibition of BDNF/TrKB pathway by K252a also attenuated the protective effects of activated mGluR5 against OGD/R-induced cytotoxicity, apoptosis and the release of inflammatory cytokines. Morever, pretreatment with exogenous BDNF protected BV2 cells against OGD/R induced apoptosis and release of inflammatory cytokines. These data suggested that BDNF/TrKB pathway may be involved in regulating activated mGluR5' protective effects against OGD/R induced cytotoxicity in BV2 cells.

Intranigral administration of substance P receptor antagonist attenuated levodopa-induced dyskinesia in a rat model of Parkinson's disease.

Levodopa (L-dopa) remains the most effective drug in the treatment of Parkinson's disease (PD). However, L-dopa-induced dyskinesia (LID) has hindered its use for PD patients. The mechanisms of LID are not fully understood. Substance P (SP) receptor antagonist has been shown to reduce parkinsonism in animal models of PD, and ameliorate LID in PD rats. But the concrete mechanism is not fully understood. To address this issue, we produced a rat model of PD using 6-hydroxydompamine (6-OHDA) injections, and valid PD rats were intranigrally administrated with different doses of SP receptor antagonist LY303870 (5 nmol/day, 10 nmol/day and 20 nmol/day) following L-dopa (6 mg/kg/day, i.p.) plus benserazide (12 mg/kg/day, i.p.) for 23 days. We found that nigral SP levels were increased on days 3, 7 and 14 and decreased on day 21 after 6-hydroxydompamine lesions. But nigral SP levels kept increasing after repeated L-dopa administration in PD rats. Intranigral administration of low and moderate LY303870 reduced abnormal involuntary movements (AIMs) while improving motor deficits in PD rats treated with L-dopa plus benserazide. Microdialysis revealed that LY303870 (10 nmol/day) treatment attenuated the increase of striatal dopamine and the reduction of γ-aminobutyric acid in ventromedial thalamus of PD rats primed with L-dopa. Additionally, LY303870 (10 nmol/day) treatment prior to L-dopa administration reduced the phosphorylated levels of dopamine- and cyclic adenosine monophosphate-regulated phosphoprotein of 32 kDa at Thr 34 and extracellular signal-regulated kinases 1/2 as well as the levels of activity-regulated cytoskeleton-associated protein and Penk in L-dopa-primed PD rats. Taken together, these data showed that low and moderate SP receptor antagonists LY303870 could ameliorate LID via neurokinin 1 receptor without affecting therapeutic effect of L-dopa.

Intranasal administration of human umbilical cord mesenchymal stem cells-conditioned medium enhances vascular remodeling after stroke.

Stem cell-based treatments have been reported to be a potential strategy for stroke. However, tumorigenic potential and low survival rates of transplanted cells could attenuate the efficacy of the stem cell-based treatments. The application of stem cell-condition medium (CM) may be a practicable approach to conquer these limitations. In this study, we investigated whether intranasal administration of human umbilical cord mesenchymal stem cells (hUCMSCs)-CM has the therapeutic effects in rats after stroke. Adult male rats were subjected to middle cerebral artery occlusion (MCAo) and were treated by intranasal routine with or without hUCMSCs-CM (1 ml/kg/d), starting 24h after MCAo and daily for 14 days. Neurological functional tests, blood brain barrier (BBB) leakage, were measured. Angiogenesis and angiogenic factor expression were measured by immunohistochemistry, and Western blot, respectively. hUCMSCs-CM treatment of stroke by intranasal routine starting 24h after MCAo in rats significantly enhances BBB functional integrity and promotes functional outcome but does not decrease lesion volume compared to rats in DMEM/F12 medium control group and saline control group. Treatment of ischemic rats with hUCMSCs-CM by intranasal routine also significantly decreases the levels of Ang2 and increases the levels of both Ang1 and Tie2 in the ischemic brain. To take together, increased expression of Ang1 and Tie2 and decreased expression of Ang2, induced by hUCMSCs-CM treatment, contribute to vascular remodeling in the ischemic brain which plays an important role in functional outcome after stroke.

Ranitidine reduced levodopa-induced dyskinesia in a rat model of Parkinson's disease.

BACKGROUND: Chronic administration of levodopa in Parkinson's disease leads to debilitating involuntary movements, termed levodopa-induced dyskinesia (LID). The pathogenesis of LID is poorly understood. Previous research has shown that histamine H2 receptors are highly expressed in the input (striatum) and output (globus pallidus, substantia nigra) regions of the basal ganglia, particularly in the GABAergic striatopallidal and striatonigral pathways. Therefore, a histamine H2 receptor antagonist could be used to reduce LID. In the present work, we investigated whether ranitidine has the potential to diminish LID in rats with dyskinesia and explored the underlying mechanisms involved. METHODS: A rat model of PD was induced by 6-hydroxydopamine. Valid PD rats were then treated with levodopa (25 mg/kg, intraperitoneally) and benserazide (12.5 mg/kg, intraperitoneally) for 21 days to induce a rat model of LID. The acute and chronic effects of administration of ranitidine at different doses (5 mg/kg, 10 mg/kg, and 20 mg/kg) on abnormal involuntary movements, levodopa-induced rotations, and the forelimb adjusting steps test were investigated in LID rats. The chronic effect of ranitidine (10 mg/kg) on the expression of Arc and proenkephalin was also evaluated. RESULTS: Levodopa elicited increased dyskinesia in PD rats. Acute ranitidine treatment had no effect on LID, but chronic ranitidine administration (10 mg/kg, 20 mg/kg) reduced LID in rats with dyskinesia. Importantly, levodopa-induced rotations were not affected by chronic treatment with ranitidine. In addition, chronic ranitidine (10 mg/kg, 20 mg/kg) significantly improved stepping of the lesioned forepaw. Real-time polymerase chain reaction showed that Arc and proenkephalin levels were reduced by chronic ranitidine (10 mg/kg) in dyskinetic rats. CONCLUSION: These data indicate that ranitidine is a good adjunct for reducing LID in rats with dyskinesia. Inhibition of dopamine D1-mediated activation in the medium spiny neurons may account for the antidyskinetic effects of ranitidine in rats with dyskinesia.

Intracerebral administration of ultrasound-induced dissolution of lipid-coated GDNF microbubbles provides neuroprotection in a rat model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease characterized by loss of dopaminergic neurons in the substantia nigra. Neurotrophic factors, such as glial cell derived neurotrophic factor (GDNF), have been shown to provide a neuroprotective effect in PD rats. We have previously reported that ultrasound-induced lipid-coated GDNF microspheres, which release GDNF in a sustained manner after low frequency ultrasound stimulation, can reduce hypoxic-ischemic injury in neonatal rats. In the present study, we investigated whether lipid-coated GDNF microspheres can provide a neuroprotective effect in a rat model of PD. After a rat model of PD was produced by 6-hydroxydompamine (6-OHDA) injections, lipid-coated GDNF microspheres (1.5mg/kg) were injected into the striatum of PD rats. We found that GDNF levels were increased in the striatum of PD rats after lipid-coated GDNF microspheres administration following low frequency ultrasound stimulation (20kHz, 5min per day, daily for 4 weeks). Moreover, GDNF microspheres reduced apomorphine-induced rotations, and increased striatal dopamine and nigral tyrosine hydroxylase (TH) levels in PD rats. Additionally, GDNF microspheres reduced caspase-3, tumor necrosis factor-alpha, matrix metalloproteinase 9 (MMP-9) and OX-6 levels induced by 6-OHDA injections in PD rats. These data indicated that lipid-coated GDNF microspheres can provide a neuroprotective effect in PD rats.