Case report: Ofatumumab treatment in anti-DPPX autoimmune encephalitis.

Dipeptidyl peptidase-like protein 6 (DPPX) antibody encephalitis is a rare autoimmune encephalitis. Diagnosis and treatment of DPPX remain challenging, particularly in patients with refractory disease. Herein, we report the first case of anti-DPPX encephalitis treated with ofatumumab. The patient had a chronic insidious onset and predominantly presented with severe neuropsychiatric symptoms and the typical triad of symptoms (weight loss, central nervous system hyperexcitability, and cognitive dysfunction). Positive anti-DPPX antibodies in the serum (1:1,000) and cerebrospinal fluid (CSF) (1:100) were detected at the disease peak. The patient was unresponsive to four types of standard immunotherapies (intravenous globulin, plasma exchange, steroids, and tacrolimus), resulting in a treatment switch to ofatumumab. After five doses of injection and 12 months of follow-up, the patient improved well, with only a mild cognitive deficit.

The role of self-esteem and emotion regulation in the associations between childhood trauma and mental health in adulthood: a moderated mediation model.

BACKGROUND: High levels of childhood trauma (CT) have been observed in adults with mental health problems. Herein, we investigated whether self-esteem (SE) and emotion regulation strategies (cognitive reappraisal (CR) and expressive suppression (ES)) affect the association between CT and mental health in adulthood, including depression and anxiety symptoms. METHODS: We performed a cross-sectional study of 6057 individuals (39.99% women, median age = 34 y), recruited across China via the internet, who completed the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Childhood Trauma Questionnaire (CTQ), Self-esteem Scale (SES), and Emotion Regulation Questionnaire (ERQ). Multivariate linear regression analysis and bias-corrected percentile bootstrap methodologies were used to assess the mediating effect of SE, and hierarchical regression analysis and subgroup approach were performed to examine the moderating effects of emotion regulation strategies. RESULTS: After controlling for age and sex, we found that (1) SE mediated the associations between CT and depression symptoms in adulthood (indirect effect = 0.05, 95% confidence interval [CI]: 0.04-0.05, 36.2% mediated), and CT and anxiety symptoms in adulthood (indirect effect = 0.03, 95% CI: 0.03-0.04, 32.0% mediated); (2) CR moderated the association between CT and SE; and (3) ES moderated the association between of CT and mental health in adulthood via SE, and such that both the CT-SE and SE-mental health pathways were stronger when ES is high rather than low, resulting the indirect effect was stronger for high ES than for low ES. CONCLUSIONS: These findings suggested that SE plays a partially mediating role in the association between CT and mental health in adulthood. Furthermore, ES aggravated the negative effect of CT on mental health in adulthood via SE. Interventions such as emotional expression training may help reduce the detrimental effects of CT on mental health. TRIAL REGISTRATION: The study was registered on http://www.chictr.org.cn/index.aspx and the registration number was ChiCTR2200059155.

Effects of a online brief modified mindfulness-based stress reduction therapy for anxiety among Chinese adults: A randomized clinical trial.

The COVID-19 pandemic has exacerbated anxiety and related symptoms among the general population. In order to cope with the mental health burden, we developed an online brief modified mindfulness-based stress reduction (mMBSR) therapy. We performed a parallel-group randomized controlled trial to evaluate the efficacy of the mMBSR for adult anxiety with cognitive-behavioral therapy (CBT) as an active control. Participants were randomized to mMBSR, CBT or waitlist group. Those in the intervention arms performed each therapy for 6 sections in 3 weeks. Measurements were conducted at baseline, post-treatment and 6 months post-treatment by Generalized Anxiety Disorder-7, Patient Health Questionnaire-9, Patient Health Questionnaire-15, reverse scored Cohen Perceived Stress scale, Insomnia Severity Index, and Snaith-Hamilton Pleasure Scale. 150 participants with anxiety symptoms were randomized to mMBSR, CBT or waitlist group. Post intervention assessments showed that mMBSR improved the scores of all the six mental problem dimensions (anxiety, depression, somatization, stress, insomnia, and the experience of pleasure) significantly compared to the waitlist group. During 6-month post treatment assessment, the scores of all six mental problem dimensions in the mMBSR group still showed improvement compared to baseline and showed no significant difference with the CBT group. Our results provide positive evidence for the efficacy and feasibility of an online brief modified MBSR program to alleviate anxiety and related symptoms of individuals from the general population, and the therapeutic benefits of mMBSR persisted for up to six months. This low resource-consuming intervention could facilitate the challenges of supplying psychological health therapy to large scale of population.

Clinical and imaging analysis to evaluate the response of patients with anti-DPPX encephalitis to immunotherapy.

BACKGROUND: To report the main spectrum and new clinical and imaging characteristics of dipeptidyl-peptidase-like protein 6 (DPPX) antibody-associated encephalitis, and to evaluate the effect of immunotherapy. METHODS: A retrospective analysis of nine patients with anti-DPPX encephalitis was performed, and all previously reported cases in the literature were reviewed. A cell-based indirect immunofluorescence assay using human embryonic kidney 293 cells transfected with DPPX was used. RESULTS: Nine patients were identified (median age, 51 years; range, 14-65 years) with prodromal fever, diarrhea, or weight loss, followed by rapid progressive encephalopathy characterized by cognitive disorder. One patient who received methylprednisolone therapy and a trial of tacrolimus showed substantial improvement and had no relapse by the 6-month follow-up. Our comprehensive literature review demonstrated that 53 cases were reported, of which more than half had prodromal weight loss (52.8%) and gastrointestinal disorders (58.5%). Cognitive disorders (74.6%) and brainstem/spinal cord disorders (75.5%) were the most common major symptoms. A greater proportion of Chinese patients than non-Chinese patients had abnormalities on brain magnetic resonance imaging specific for encephalitis (70.0% vs. 23.3%, P < 0.001). Our study is the first to report three patients with anti-DPPX encephalitis who had sleep disorders with rapid eye movement sleep behavior disorder, limb paralysis (two), severe pleocytosis, elevated protein levels (two) in the cerebrospinal fluid, and increased T2/FLAIR signal abnormalities in the bilateral hippocampus, temporal lobe, amygdala, basal ganglia, thalamus, centrum semiovale, and frontal and parietal lobes in seven patients (77.8%). CONCLUSION: Our study expands the clinical and imaging phenotypes of anti-DPPX encephalitis. Further studies elucidating the entire clinical spectrum of anti-DPPX encephalitis, its pathogenic mechanisms, and prognosis under long-term immunosuppressive therapy are warranted.

A single center retrospective study of paraneoplastic neurological syndromes with positive onconeural antibodies.

Paraneoplastic neurological syndromes (PNS) are rare immune-mediated disorders, and the detection of onconeural antibodies is helpful for PNS diagnosis. The aim of this study was to investigate the clinical characteristics of patients with PNS with positive onconeural antibodies in a single center in Hubei, China. We retrospectively analyzed the clinical characteristics of 54 patients with positive onconeural antibodies from January 2016 to September 2020. Among 780 patients with suspected PNS, 54 (6.9%) had positive onconeural antibodies. Of those 54 patients, 28 (51.8%) were diagnosed with definite PNS and 13 (24.1%) with possible PNS. Eighteen (33.3%) patients were confirmed with cancer. Ten PNS syndromes were detected among the 28 patients with definite PNS, and they had either classical (12/28, 42.8%) or non-classical syndromes (17/28, 60.7%). Peripheral neuropathy (9/28, 32.1%), subacute cerebellar degeneration (4/28, 14.3%), and limbic encephalitis (4/28, 14.3%) were the most common PNS syndromes. The anti-CV2/CRMP5-antibody was observed most frequently. Lung cancer was the most common tumor type. For patients with possible PNS, peripheral neuropathy was the most common PNS syndrome, and the anti-Tr-antibody was the most frequent onconeural antibody. Immunotherapy was effective in treating PNS. The anti-CV2/CRMP5-antibody was the most subsequently observed antibody. The manifestations of PNS are diverse and include peripheral neuropathy, subacute cerebellar degeneration, and limbic encephalitis. In patients with PNS, lung cancer was the most common tumor.

The Rho-associated kinase inhibitors Y27632 and fasudil promote microglial migration in the spinal cord via the ERK signaling pathway.

Rho-associated kinase (ROCK) is a key regulatory protein involved in inflammatory secretion in microglia in the central nervous system. Our previous studies showed that ROCK inhibition enhances phagocytic activity in microglia through the extracellular signal-regulated kinase (ERK) signaling pathway, but its effect on microglial migration was unknown. Therefore, in this study, we investigated the effects of the ROCK inhibitors Y27632 and fasudil on the migratory activity of primary cultured microglia isolated from the spinal cord, and we examined the underlying mechanisms. The microglia were treated with Y27632, fasudil and/or the ERK inhibitor U0126. Cellular morphology was observed by immunofluorescence. Transwell chambers were used to assess cell migration. ERK levels were measured by in-cell western blot assay. Y27632 and fasudil increased microglial migration, and the microglia were irregularly shaped and had many small processes. These inhibitors also upregulated the levels of phosphorylated ERK protein. The ERK inhibitor U0126 suppressed these effects of Y27632 and fasudil. These findings suggest that the ROCK inhibitors Y27632 and fasudil promote microglial migration in the spinal cord through the ERK signaling pathway.

NKCC1 Inhibition Attenuates Chronic Cerebral Hypoperfusion-Induced White Matter Lesions by Enhancing Progenitor Cells of Oligodendrocyte Proliferation.

Cerebral white matter is vulnerable to ischemic condition. However, no effective treatment to alleviate or restore the myelin damage caused by chronic cerebral hypoperfusion has been found. Na+-K+-Cl- cotransporter 1 (NKCC1), a Na+-K+-Cl- cotransporter widely expressed in the central nervous system (CNS), involves in regulation of cell swelling, EAA release, cell apoptosis, and proliferation. Nevertheless, the role of NKCC1 in chronic hypoperfusion-induced white matter lesions (WMLs) has not been explored. Here, mice subjected to bilateral common carotid artery stenosis (BCAS) were used as model of chronic cerebral hypoperfusion; density of progenitor cells of oligodendrocyte (OPCs), oligodendrocytes (OLs), astrocytes, and microglia was assessed by immunofluorescent staining and Western blot analysis; working memory was examined by eight-arm radial maze test; expression of MAPK signaling pathway was determined by Western blot analysis. After BCAS, white matter integrity disruption and working memory impairment were observed. NKCC1 inhibition by bumetanide administration enhanced OPC proliferation, attenuated chronic hypoperfusion-induced white matter damage, and promoted recovery of neurological function. However, NKCC1 inhibition caused no significant change in the densities of GFAP- and Iba-1-positive cells in the corpus callosum. Bumetanide administration significantly increased the expression of p-ERK and decreased the expression of p-JNK and p-p38 in comparison to vehicle-BCAS groups. In conclusion, NKCC1 inhibition might significantly ameliorate chronic cerebral hypoperfusion-induced WMLs and cognitive impairment by enhancing progenitor cells of oligodendrocyte proliferation, and this protective function of bumetanide might be mediated by modulation of the MAPK signaling pathway.

ROCK inhibition with fasudil promotes early functional recovery of spinal cord injury in rats by enhancing microglia phagocytosis.

Emerging evidence indicates that microglia activation plays an important role in spinal cord injury (SCI) caused by trauma. Studies have found that inhibiting the Rho/Rho-associated protein kinase (ROCK) signaling pathway can reduce inflammatory cytokine production by microglia. In this study, Western blotting was conducted to detect ROCK2 expression after the SCI; the ROCK Activity Assay kit was used for assay of ROCK pathway activity; microglia morphology was examined using the CD11b antibody; electron microscopy was used to detect microglia phagocytosis; TUNEL was used to detect tissue cell apoptosis; myelin staining was performed using an antibody against myelin basic protein (MBP); behavioral outcomes were evaluated according to the methods of Basso, Beattie, and Bresnahan (BBB). We observed an increase in ROCK activity and microglial activation after SCI. The microglia became larger and rounder and contained myelin-like substances. Furthermore, treatment with fasudil inhibited neuronal cells apoptosis, alleviated demyelination and the formation of cavities, and improved motor recovery. The experimental evidence reveals that the ROCK inhibitor fasudil can regulate microglial activation, promote cell phagocytosis, and improve the SCI microenvironment to promote SCI repair. Thus, fasudil may be useful for the treatment of SCI.

Rho-Associated Kinase Inhibitors Promote Microglial Uptake Via the ERK Signaling Pathway.

Microglia are immunocompetent cells in the central nervous system that take up tissue debris and pathogens. Rho-associated kinase (ROCK) has been identified as an important regulator of uptake, proliferation, secretion, and differentiation in a number of cell types. Although ROCK plays critical roles in the microglial secretion of inflammatory factors, migration, and morphology, its effects on microglial uptake activity have not been well characterized. In the present study, we found that treatment of BV2 microglia and primary microglia with the ROCK inhibitors Y27632 and fasudil increased uptake activity and was associated with morphological changes. Furthermore, western blots showed that this increase in uptake activity was mediated through the extracellular-signal-regulated kinase (ERK) signaling cascade, indicating the importance of ROCK in regulating microglial uptake activity.

Bumetanide-induced NKCC1 inhibition attenuates oxygen-glucose deprivation-induced decrease in proliferative activity and cell cycle progression arrest in cultured OPCs via p-38 MAPKs.

The Na-K-Cl co-transporter 1 (NKCC1; a member of the cation-chloride co-transporter family) mediates the coupled movement of Na(+) and/or K(+) with Cl(-) across the plasma membrane of cells (Haas and Forbush, 2000, Annu. Rev. Physiol., 62, 515-534; Russell, 2000, Physiol. Rev., 80, 211-276). Although it acts as an important regulator of cell volume, secretion, and modulator of cell apoptosis and proliferation (Chen et al., 2005, J. Cereb. Blood Flow Metab., 25, 54-66; Kahle et al., 2008, Nat. Clin. Pract. Neurol., 4, 490-503; Kidokoro et al., 2014, Am. J. Physiol. Ren. Physiol., 306, F1155-F1160; Wang et al., 2011, Cell. Physiol. Biochem., 28, 703-714), NKCC1׳s effects on oligodendrocyte precursor cells (OPCs) have not been characterized. The aim of this study was to investigate whether and to what extent inhibition of NKCC1 alters oxygen glucose deprivation (OGD)-induced cell cycle progression. In the present study, we demonstrated that inhibition of NKCC1 with bumetanide attenuates the decrease in OGD-induced DNA synthesis in cultured OPCs. Western blots showed that NKCC1 inhibition led to an increased expression of cyclin D1, CDK 4, and cyclin E in OGD-treated cells. Furthermore, our results showed bumetanide attenuated the decrease in OGD-induced proliferation and arrest of cell cycle progression via the P-38 MAPK signaling cascade. Thus, NKCC1 plays important roles in the proliferation of OPCs under OGD-induced stress.

[Treatment of autotransplantation of NT-3 gene modified OECs and NSCs complex adhering to scaffold on spontaneous cerebral hemorrhage].

OBJECTIVE: To explore the effects of autotransplantation of NT-3 gene modified olfactory ensheathing cell (OEC) and neural stem cell (NSC) complex adhering to collagen protein-heparin sulfate scaffold on motor function of rats with cerebral hemorrhage. METHODS: The cerebral hemorrhage model was established with caudate nucleus bleeding in Wistar rats. The animals were randomly divided into 4 groups: A (transplantation of NT-3 modified OEC-NSC complex adhering to scaffold), B (transplantation of NT-3 modified OEC-NSC complex), C (transplantation of scaffold) and D (blank control group). The motor function of hind limbs was assessed at Day 1, 3, 7, 14 and 30 post-transplantation respectively. The survival, distribution and differentiation of transplanted cells were tested by immunohistochemistry and fluorescent staining. RESULTS: The neurological functional score of group A (2.12 ± 0.12, 1.50 ± 0.11, 0.52 ± 0.08) or B (2.10 ± 0.16, 1.79 ± 0.09, 0.91 ± 0.10) was obviously inferior to group C/D at Days 7, 14 and 30. No significant difference existed between groups C and D (P > 0.05) . The scores of A were markedly lower than those of B at Days 14 and 30 (P < 0.05, P < 0.01) . The numbers of surviving NSCs and cells migrating to focal area after transplantation was much more in group A than those in other groups. CONCLUSION: Autotransplantation of NT-3 gene modified OEC-NSC complex adhering to collagen protein-heparin sulfate scaffold may markedly ameliorate the motor function of cerebral hemorrhagic in rats. And the transplanted NSCs have better capacities of survival, migration and differentiation.

Lingo-1 inhibited by RNA interference promotes functional recovery of experimental autoimmune encephalomyelitis.

Lingo-1 is a negative regulator of myelination. Repairment of demyelinating diseases, such as multiple sclerosis (MS)/experimental autoimmune encephalomyelitis (EAE), requires activation of the myelination program. In this study, we observed the effect of RNA interference on Lingo-1 expression, and the impact of Lingo-1 suppression on functional recovery and myelination/remyelination in EAE mice. Lentiviral vectors encoding Lingo-1 short hairpin RNA (LV/Lingo-1-shRNA) were constructed to inhibit Lingo-1 expression. LV/Lingo-1-shRNA of different titers were transferred into myelin oligodendrocyte glycoprotein-induced EAE mice by intracerebroventricular (ICV) injection. Meanwhile, lentiviral vectors carrying nonsense gene sequence (LVCON053) were used as negative control. The Lingo-1 expression was detected and locomotor function was evaluated at different time points (on days 1,3,7,14,21, and 30 after ICV injection). Myelination was investigated by luxol fast blue (LFB) staining.LV/Lingo-1-shRNA administration via ICV injection could efficiently down-regulate the Lingo-1 mRNA and protein expression in EAE mice on days 7,14,21, and 30 (P < 0.01), especially in the 5 × 10(8) TU/mL and 5 × 10(9) TU/mL LV/Lingo-1-shRNA groups. The locomotor function score in the LV/Lingo-1-shRNA treated groups were significantly lower than the untreated or LVCON053 group from day 7 on. The 5 × 10(8) TU/mL LV/Lingo-1-shRNA group achieved the best functional improvement (0.87 ± 0.11 vs. 3.05 ± 0.13, P < 0.001). Enhanced myelination/remyelination was observed in the 5 × 10(7) , 5 × 10(8) , 5 × 10(9) TU/mL LV/Lingo-1-shRNA groups by LFB staining (P < 0.05, P < 0.01, and P < 0.05).The data showed that administering LV/Lingo-1-shRNA by ICV injection could efficiently knockdown Lingo-1 expression in vivo, improve functional recovery and enhance myelination/remyelination. Antagonism of Lingo-1 by RNA interference is, therefore, a promising approach for the treatment of demyelinating diseases, such as MS/EAE.

[LINGO-1 expression of brain tissue in experimental autoimmune encephalomyelitis mouse].

OBJECTIVE: To observe the changes of LINGO-1 expression with time after onset in EAE mouse. METHODS: C57/BL6 mice were completely randomly divided into EAE model group (n = 15) , adjuvant group (n = 15) and control group (n = 15) .LINGO-1 expression of brain tissue was detected on day 1, 7, 14, 21 and 30 after onset by RT-PCR and Western blot.RhoA and p-RhoA expression of brain tissue was analysed by Western blot. RESULTS: The LINGO-1mRNA levels in EAE model group were markedly higher than control group on day 1, 7and 14 after onset (4.63 ± 0.25, 2.72 ± 0.12, 1.98 ± 0.16, P < 0.01, P < 0.01, P < 0.05).On day 30, Lingo-1 mRNA was close to control group.Expression levels of Lingo-1 protein on day 1, 7, 14, 21, 30 were higher than control group (2.11 ± 0.15, 3.15 ± 0.09, 2.45 ± 0.12, 1.89 ± 0.17, 1.21 ± 0.05, P < 0.05, P < 0.01, P < 0.05, P < 0.05, P < 0.05. The levels of p-RhoA protein increased in EAE and the peak appeared on day 1 and day 7 (P < 0.01) . And there was no difference on RhoA expression among different groups. CONCLUSIONS: LINGO-1 expression of brain tissue of EAE mouse upregulates and changes with time after onset, which may inhibit myelination by RhoA activation.In clinic, the antagonist of LINGO-1 for MS should be applied as soon as possible.

ROCK inhibition with Y27632 promotes the proliferation and cell cycle progression of cultured astrocyte from spinal cord.

Rho-associated Kinase (ROCK) has been identified as an important regulator of proliferation and cell cycle progression in a number of cell types. Although its effects on astrocyte proliferation have not been well characterized, ROCK has been reported to play important roles in gap junction formation, morphology, and migration of astrocytes. In the present study, our aim was to investigate the effect of ROCK inhibition by [(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride] (Y27632) on proliferation and DNA synthesis in cultured astrocytes from rat spinal cord and the possible mechanism involved. Western blots showed that treatment of astrocytes with Y27632 increased their expression of cyclin D1, CDK4, and cyclin E, thereby causing cell cycle progression. Furthermore, Y27632-induced astrocyte proliferation was mediated through the extracellular-signal-regulated kinase signaling cascade. These results indicate the importance of ROCK in astrocyte proliferation.