Objective To investigate the antidepressant effects of Yuanzhi(Polygalae Radix;PR)aqueous extract on chronic unpredictable mild stress(CUMS)-induced depression rat models and the underlying mechanisms.Methods A total ...Objective To investigate the antidepressant effects of Yuanzhi(Polygalae Radix;PR)aqueous extract on chronic unpredictable mild stress(CUMS)-induced depression rat models and the underlying mechanisms.Methods A total of 40 male Sprague Dawley(SD)rats were randomly divided into control;model;low dose of PR(PR-L;0.5 g/kg);high dose of PR(PR-H;1 g/kg);and fluoxetine(10 mg/kg)groups;with 8 rats in each group.Except for the rats in control group;those in the other four groups underwent CUMS-induced depression modeling.PR and fluoxetine were administered intragastrically once daily;30 min prior to the CUMS procedure;for 14 consecu-tive days until the behavioral tests were performed.After CUMS modeling;the sucrose prefer-ence test(SPT);open field test(OFT);novelty-suppressed feeding test(NSFT);forced swim test(FST);and tail suspension test(TST)were employed to assess the pharmacological ef-fects of PR on the mitigation of depressive-like behaviors in rat models.Additionally;the en-zyme-linked immunosorbent assay(ELISA)was utilized to quantify the serum levels of tumor necrosis factor(TNF)-α;interleukin(IL)-6;and IL-1βin the rats.Western blot analysis was al-so conducted to evaluate the protein expression levels of nuclear factor kappa-B(NF-κB);in-ducible nitric oxide synthase(iNOS);cyclooxygenase-2(COX-2);nucleotide-binding oligomerization domain(NOD)-like receptor family pyrin domain containing 3(NLRP3);apoptosis-associated speck-like protein containing caspase recruitment domain(ASC);and caspase-1 in the hippocampal tissues of the rats.Immunofluorescence staining was per-formed to observe the morphological changes in ionized calcium-binding adapter molecule 1 positive(Iba-1+)cells in the dentate gyrus(DG)of rats with CUMS-induced depression.Results(i)Treatment with PR-H and fluoxetine resulted in significant enhancements in both the total distance and time the rats moved during tests(P<0.01 and P<0.05;respectively).Post-administration of PR-H and fluoxetine also led to statistically significant increase in su-crose preference among rats(P<0.05).Besides;PR-L;PR-H;and fluoxetine treatment markedly decreased the latency of ingestion(P<0.05;P<0.05;and P<0.01;respectively).As observed from the FST;PR-L;PR-H;and fluoxetine presented antidepressant effects on rats with CUMS-induced depression;leading to the reduction in time of their immobility(P<0.05;P<0.01;and P<0.01;respectively).The results of TST indicated reduced immobility time in rats receiving PR-H and fluoxetine treatment as well(P<0.01).(ii)Rats in model group showed an increase in the levels of Iba-1+microglia in their left and right brains in compari-son with control group(P<0.01).However;such increase was negated post PR treatment(P<0.01).Treatment with PR-L;PR-H;and fluoxetine considerably reduced the levels of inflam-matory factors(TNF-α;IL-1β;and IL-6;P<0.01).In addition;treatment of PR-L and PR-H ef-fectively counteracted the elevated levels of NLRP3;ASC;and caspase-1;and markedly down-regulated the expression levels of phosphorylated p65(p-p65);COX-2;and iNOS in rats’hip-pocampus(P<0.01).Conclusion Collectively;these findings indicate that PR exerts an antidepressant effect on rats with CUMS-induced depression partially through the modulation of the NLRP3 and NF-κB signaling pathways.展开更多
Objective:Inflammation in the central nervous system plays a crucial role in the occurrence and development of sepsis-associated encephalopathy.This study aims to explore the effects of maresin 1(MaR1),an anti-inflamm...Objective:Inflammation in the central nervous system plays a crucial role in the occurrence and development of sepsis-associated encephalopathy.This study aims to explore the effects of maresin 1(MaR1),an anti-inflammatory and pro-resolving lipid mediator,on sepsis-induced neuroinflammation and cognitive impairment.Methods:Mice were randomly assigned to 4 groups:A sham group(sham operation+vehicle),a cecal ligation and puncture(CLP)group(CLP operation+vehicle),a MaR1-LD group(CLP operation+1 ng MaR1),and a MaR1-HD group(CLP operation+10 ng MaR1).MaR1 or vehicle was intraperitoneally administered starting 1 h before CLP operation,then every other day for 7 days.Survival rates were monitored,and serum inflammatory cytokines[tumor necrosis factor alpha(TNF-α),interleukin(IL)-1β,and IL-6]were measured 24 h after operation using enzyme-linked immunosorbent assay(ELISA).Cognitive function was assessed 7 days after operation using the Morris water maze(MWM)test and novel object recognition(NOR)task.The mRNA expression of TNF-α,IL-1β,IL-6,inducible nitric oxide synthase(iNOS),IL-4,IL-10,and arginase 1(Arg1)in cortical and hippocampal tissues was determined by real-time reverse transcription PCR(RT-PCR).Western blotting was used to determine the protein expression of iNOS,Arg1,signal transducer and activator of transcription 6(STAT6),peroxisome proliferator-activated receptor gamma(PPARγ),and phosphorylated STAT6(p-STAT6)in hippocampal tissue.Microglia activation was visualized via immunofluorescence.Mice were also treated with the PPARγantagonist GW9662 to confirm the involvement of this pathway in MaR1’s effects.Results:CLP increased serum levels of TNF-α,IL-1β,and IL-6,and reduced body weight and survival rates(all P<0.05).Both 1 ng and 10 ng doses of MaR1 significantly reduced serum TNF-α,IL-1β,and IL-6 levels,improved body weight,and increased survival rates(all P<0.05).No significant difference in efficacy was observed between the 2 doses(all P>0.05).MWM test and NOR task indicated that CLP impaired spatial learning,which MaR1 mitigated.However,GW9662 partially reversed MaR1’s protective effects.Real-time RTPCR results demonstrated that,compared to the sham group,mRNA expression of TNF-α,IL-1β,and iNOS significantly increased in hippocampal tissues following CLP(all P<0.05),while IL-4,IL-10,and Arg1 showed a slight decrease,though the differences were not statistically significant(all P>0.05).Compared to the CLP group,both 1 ng and 10 ng MaR1 decreased TNF-α,IL-1β,and iNOS mRNA expression in hippocampal tissues and increased IL-4,IL-10,and Arg1 mRNA expression(all P<0.05).Immunofluorescence results indicated a significant increase in Iba1-positive microglia in the hippocampus after CLP compared to the sham group(P<0.05).Administration of 1 ng and 10 ng MaR1 reduced the percentage area of Iba1-positive cells in the hippocampus compared to the CLP group(both P<0.05).Western blotting results showed that,compared to the CLP group,both 1 ng and 10 ng MaR1 down-regulated the iNOS expression,while up-regulated the expression of Arg1,PPARγ,and p-STAT6(all P<0.05).However,the inclusion of GW9662 counteracted the MaR1-induced upregulation of Arg1 and PPARγcompared to the MaR1-LD group(all P<0.05).Conclusion:MaR1 inhibits the classical activation of hippocampal microglia,promotes alternative activation,reduces sepsis-induced neuroinflammation,and improves cognitive decline.展开更多
Current hypothesis of neuronal degeneration in Parkinson's disease (PD) have been proposed, including formation of free radicals and oxidative stress, mitochondrial dysfunction, excitotoxicity, trophic factor defic...Current hypothesis of neuronal degeneration in Parkinson's disease (PD) have been proposed, including formation of free radicals and oxidative stress, mitochondrial dysfunction, excitotoxicity, trophic factor deficiency, inflammatory processes, genetic factors, environmental impact factors, toxic action of nitric oxide, apoptosis, and so on. This review mainly discussed oxidative stress, environmental impact factors, and inflammatory processes in PD.展开更多
Objective To investigate lipopolysaccharide (LPS) induced acute cerebral inflammatory damage and the therapeutic effect of ginkgolide B (BN52021). Methods Thirty Sprague-Dawley rats were randomly divided into 3 gr...Objective To investigate lipopolysaccharide (LPS) induced acute cerebral inflammatory damage and the therapeutic effect of ginkgolide B (BN52021). Methods Thirty Sprague-Dawley rats were randomly divided into 3 groups (n = 10 for each group): Control group, Model group and Treatment group (treated with BN52021). LPS were injected into the fourth ventricle of rat to make a neuroinflammatory murine model. Morris water maze was used to detect the learning and memory ability of rats; changes of synapse number and subcellular ultrastructures were observed under a transmission electron microscope; OX-42 positive microglia in the brain was detected by immunohistochemical method. Results The average escape latency in the Treatment group were significantly shortened than that in the Model group; and the percentage of swimming distance traveled in platform quadrant accounting for total distance increased markedly. The rough endoplasmic reticulum and polyribosomes in the Treatment group were more than that in the Model group, but the number of synapses seemed to have no obvious change. The number of OX-42 positive microglia in the Treatment group decreased markedly than that in the Model group, and the grey density of OX-42-positive cells increased significantly. Conclusion LPS can induce inflammatory damages to the brain, but the damage could be antagonized by BN52021. Platelet activating factor receptor antagonist may offer an effective therapy for neurodegeneration diseases.展开更多
Current hypothesis of neuronal degeneration in Parkinson’s disease (PD) have been proposed, including formation of free radicals and oxidative stress, mitochondrial dysfunction, excitotoxicity, trophic factor deficie...Current hypothesis of neuronal degeneration in Parkinson’s disease (PD) have been proposed, including formation of free radicals and oxidative stress, mitochondrial dysfunction, excitotoxicity, trophic factor deficiency, inflam- matory processes, genetic factors, environmental impact factors, toxic action of nitric oxide, apoptosis, and so on. This review mainly discussed oxidative stress, environmental impact factors, and inflammatory processes in PD.展开更多
We report a case of a patient presenting with clinical,radiological and endoscopic features of colitis due to a compressive left para-aortic mass. Total open surgical excision was performed,which resulted in complete ...We report a case of a patient presenting with clinical,radiological and endoscopic features of colitis due to a compressive left para-aortic mass. Total open surgical excision was performed,which resulted in complete resolution of colitis. Histopathology and immunohistochemistry revealed benign retroperitoneal schwannoma. These neural sheath tumors rarely occur in the retroperitoneum. They are usually asymptomatic but as they enlarge they may compress adjacent structures,which leads to a wide spectrum of non-specific symptoms,including lumbar pain,headache,secondary hypertension,abdominal pain and renal colicky pain. CT and MR findings show characteristic features,but none are specific. Schwannoma can be isolated sporadic lesions,or associated with schwannomatosis or neurofibromatosis type Ⅱ (NF2). Although they vary in biological and clinical behavior,their presence is,in nearly every case,due to alterations or absence of the NF2 gene,which is involved in the growth regulation of Schwann cells. Both conditions were excluded by thorough mutation analysis. Diagnosis is based on histopathological examination and immunohistochemistry. Total excision is therapeutic and has a good prognosis. Schwannomatosis and NF2 should be excluded through clinical diagnostic criteria. Genetic testing of NF2 is probably not justified in the presence of a solitary retroperitoneal schwannoma.展开更多
AIM: To prove the hypothesis that patients with chronic pancreatitis would show increased theta activity during painful visceral stimulation. METHODS: Eight patients and 12 healthy controls underwent an experiment whe...AIM: To prove the hypothesis that patients with chronic pancreatitis would show increased theta activity during painful visceral stimulation. METHODS: Eight patients and 12 healthy controls underwent an experiment where the esophagus was electrically stimulated at the pain threshold using a nasal endoscope. The electroencephalogram (EEG) was recorded from 64 surface electrodes and "topographic matching pursuit" was used to extract the EEG information in the early brain activation after stimulation. RESULTS: A major difference between controls and patients were seen in delta and theta bands, whereas there were only minor differences in other frequency bands. In the theta band, the patients showed higher activity than controls persisting throughout the 450 ms of analysis with synchronous brain activation betweenthe channels. The main theta components oscillated with 4.4 Hz in the patients and 5.5 Hz in the controls. The energy in the delta (0.5-3.5 Hz) band was higher in the controls, whereas the patients only showed scattered activity in this band. CONCLUSION: The differences in the theta band indicate that neuropathic pain mechanisms are involved in chronic pancreatitis. This has important implications for the understanding and treatment of pain in these patients, which should be directed against drugs with effects on neuropathic pain disorders.展开更多
Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal malignancies. Adenocarcinoma is the commonest type of colorectal neoplasm associated with ulcerative colitis (UC) and Crohn's dis...Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal malignancies. Adenocarcinoma is the commonest type of colorectal neoplasm associated with ulcerative colitis (UC) and Crohn's disease, but other types of epithelial and non-epithelial tumors have also been described in inflamed bowel. With regards to non-epithelial malignancies, lymphomas and sarcomas represent the largest group of tumors reported in association with IBD, especially in immunosuppressed patients. Carcinoids and in particular neuroendocrine neoplasms other than carcinoids (NENs) are rare tumors and are infrequently described in the setting of IBD. Thus, this association requires further investigation. We report two cases of neoplasms arising in mild left-sided UC with immuno- histochemical staining for neuroendocrine markers: a large cell and a small cell neuroendocrine carcinoma of the rectum. The two patients were different in age (35 years vs 77 years) and disease duration (11 years vs 27 years), and both had never received immunosuppressant drugs. Although the patients underwent regular endoscopic and histological follow-up, the two neoplasms were locally advanced at diagnosis. One of the two patients developed multiple liver metastases and died 15 mo after diagnosis. These findings confirm the aggressiveness and the poor prognosis of NENs compared to colorectal adenocarcinoma. While carcinoids seem to be coincidentally associated with IBD, NENs may also arise in this setting. In fact, long-standing inflammation could be directly responsible for the development of pancellular dysplasia involving epithelial, goblet, Paneth and neuroendocrine cells. It has yet to be established which IBD patients have a higher risk of developing NENs.展开更多
Sensory or motor peripheral neuropathy may be observed in a significant proportion of hepatitis C virus (HCV)-infected patients.However,central nervous system (CNS) involvement is uncommon,especially in cryoglobulin-n...Sensory or motor peripheral neuropathy may be observed in a significant proportion of hepatitis C virus (HCV)-infected patients.However,central nervous system (CNS) involvement is uncommon,especially in cryoglobulin-negative subjects.We describe a case of peripheral neuropathy combined with an ischemic CNS event as primary manifestations of chronic HCV infection without cryoglobulinemia.Significant improvement was observed after antiviral therapy.We discuss the spectrum of neurological manifestations of HCV infection and review the literature.展开更多
AIM: To determine the and clinical features of prevalence, histologic types primary epithelial tumours of the vermiform appendix in a predominantly black population.METHODS: All cases of primary tumours of the appen...AIM: To determine the and clinical features of prevalence, histologic types primary epithelial tumours of the vermiform appendix in a predominantly black population.METHODS: All cases of primary tumours of the appendix identified by review of the histopathology records at the University of the West Indies between January 1987 and June 2007 were selected. Relevant pathologic and clinical data were extracted with supplementation from patient charts where available. Non-epithelial tumours were excluded. The total number of appendectomy specimens over the period was also ascertained.RESULTS: Forty-two primary epithelial tumours were identified out of 6 824 appendectomies yielding a prevalence rate of approximately 0.62%. Welldifferentiated neuroendocrine cell tumours (carcinoids, 47.6%) and benign non-endocrine cell tumours (adenomas, 45.2%) were most common with nearly equal frequency. The median age was 43 years, with no sex predilection. Carcinoid tumours occurred in younger patients (mean age 32 years), with a male-to-female ratio of 1.2:1. A clinical diagnosis of acute appendicitis was the most common reason for appendectomy (57.1%) and was histologically confirmed in 75% (18 of 24) of cases. In total, 16.7% of cases were diagnosed after incidental appendectomy.CONCLUSION: Appendiceal epithelial tumours are rare in our experience, and are represented principally by carcinoid turnours and adenornas. Carcinoid tumours occurred in younger patients but were slightly more common in men than women. Tumours were not suspected clinically and were diagnosed incidentally in specimens submitted for acute appendicitis supporting the need for histological evaluation in all resection specimens.展开更多
Slow transit constipation has been traditionally considered and classified as a functional disorder. However, clinical and manometric evidence has been accumulating that suggests how most of the motility alterations i...Slow transit constipation has been traditionally considered and classified as a functional disorder. However, clinical and manometric evidence has been accumulating that suggests how most of the motility alterations in STC might be considered of neuropathic type.In addition, further investigations showed that subtle alterations of the enteric nervous system, not evident to conventional histological examination, may be present in these patients. In the present article we will discuss these evidences, and will try to put them in relation with the abnormal motor function of the large bowel documented in this pathological condition.展开更多
Objective To investigate the Churg-Strauss syndrome (CSS) associated lung involvement, concentrating on clinical characteristics, pathological findings of tung involvements, response to treatment, and prognosis. Me...Objective To investigate the Churg-Strauss syndrome (CSS) associated lung involvement, concentrating on clinical characteristics, pathological findings of tung involvements, response to treatment, and prognosis. Methods We retrospectively analyzed the characters of the clinical manifestations, thin-section CT and pathological findings of CSS. The study involved 16 patients. Clinical data were obtained by chart review All patients underwent transbronchial lung biopsy (TBLB). Six of them underwent surgical lung biopsy as well. Results The patients included 7 men and 9 women, aged from 14 to 61 years (median, 47.5 years). Extrathoracic organs involved included nervous system (7/16) and skin (5/16). Respiratory symptoms included cough (12/16), exertional dyspnea (11/16), hemoptysis (4/16), and chest pain (3/16). CT findings included bilateral ground-glass opacities (12 / 16), bilateral patchy opacities (12 / 16), and centrilobular nodules (6/16). The pathological findings of TBLB demonstrated increased eosinophils (3/16), vasculitis (3/16), and interstitial pneumonia (16/16). The pathological fmdings of surgical lung biopsy of 6 cases showed necrotizing vasculitis in 4 cases, capillaries in 5, eosinophilic pneumonia in 3, granulomas in 2, and airway abnormalities in 3. All patients improved in symptoms after therapy during the study period (range, 3 to 51 months; median, 15 months). Conclusions Asthma may be present in CSS patient when there is bronchial involvement. Grotmd-glass opacities and consolidation seen on high-resolution CT reflect the presence of eosinophilic pneumonia, vasculitis, and pulmonary alveolar hemorrhage. TBLB has significant limitations for the diagnosis of CSS. Early diagnosis and therapy can result in satisfactory prognosis.展开更多
The diagnosis of the recurrent optic neuritis is commonly established clinically,and sometimes it could be challenging because the involved optic nerve does not always show significant enhancement on conventional cont...The diagnosis of the recurrent optic neuritis is commonly established clinically,and sometimes it could be challenging because the involved optic nerve does not always show significant enhancement on conventional contrast enhanced-T1 weighted imaging(CE-T1W1).In this paper,we reported a middle-aged female with early diagnosis of recurrent optic neuritis using contrast-enhanced T2 fluid-attenuated inversion recovery imaging(CET2FLAIR).The involved optic nerve presented evident enhancement on CE-T2FLAIR and no enhancement on CE-T1W1.This case suggested that the CE-T2FLAIR may be a useful diagnostic tool specifically for the recurrent optic neuritis in clinical practice.展开更多
AIM: To compare the effects of neurolytic celiac plexus block (NCPB) and videothoracoscopic splanchnicectomy (VSPL) on pain and quality of life of chronic pancreatitis (CP) patients.METHODS: Forty-eight small duct CP ...AIM: To compare the effects of neurolytic celiac plexus block (NCPB) and videothoracoscopic splanchnicectomy (VSPL) on pain and quality of life of chronic pancreatitis (CP) patients.METHODS: Forty-eight small duct CP patients were treated invasively with NCPB (n = 30) or VSPL (n = 18) in two non-randomized, prospective, case-controlled protocols due to chronic pain syndrome, and compared to a control group who were treated conservatively (n = 32). Visual analog scales were used to assess pain and opioid consumption rate was evaluated. In addition, the quality of life was measured using QLQ C-30 for NCPB and FACIT for VSPL.Although both questionnaires covered similar problems,they could not be compared directly one with another.Therefore, the studies were compared by meta-analysis methodology.RESULTS: Both procedures resulted in a significant positive effect on pain of CP patients. Opioids were withdrawn totally in 47.0% of NCPB and 36.4% of VSPL patients,and reduced in 53.0% and 45.4% of the respective patient groups. No reduction in opioid usage was observed in the control group. In addition, fatigue and emotional well-being showed improvements. Finally, NCPB demonstrated stronger positive effects on social support, which might possibly be attributed to earlier presentation of patients treated with NCPB.CONCLUSION: Both invasive pain treatment methods are effective in CP patients with chronic pain.展开更多
A 37oyear old woman presented with a 9oyear history of hepatitis of unknown origin and aminotransferases within a 3-fold upper limit of normal. Autoimmune hepatitis (AIH) was diagnosed on the basis of elevated amino...A 37oyear old woman presented with a 9oyear history of hepatitis of unknown origin and aminotransferases within a 3-fold upper limit of normal. Autoimmune hepatitis (AIH) was diagnosed on the basis of elevated aminotransferases, soluble liver antigen/liver pancreas (SLA/LP) autoantibodies and characteristic histology. Immunosuppressive therapy led to rapid normalization of aminotransferases. Two years later, the patient developed left sided hemisensory deficits under maintenance therapy of prednisolone and azathioprine (AZT). Later she developed right foot drop and paraesthesia in the ulnar innervation territory on both sides. Magnetic resonance imaging (MRI) and cerebral panangiography suggested cerebral vasculitis. Neurological investigation and electromyography disclosed multiplex neuritis (MN) probably due to vasculitis. Consistent with this diagnosis, autoantibodies to extractable nuclear antigens were detectable in serum. Immunosuppression was changed to oral 150 mg cyclophosphamide (CPMO) per day. Prednisolone was increased to 40 mg/d and then gradually tapered to 5 mg. Oral CPM was administered up to a total dose of 40 g and then substituted by 6 times of an intervall infusion therapy of CPM (600 mg/m^2). Almost complete motoric remission was achieved after 3 mo of CPM. Sensibility remained reduced in the right peroneal innervation territory. Follow-up of cranial MRI provided stable findings without any new or progressive lesions. This is the first report of multiplex neuritis in a patient with autoimmune hepatitis.展开更多
Neuromyelitis optica spectrum disorder(NMOSD)is an inflammatory disorder of the central nervous system predominantly targeting optic nerves and the spinal cord.The prevalence of the disease is much higher in Asia than...Neuromyelitis optica spectrum disorder(NMOSD)is an inflammatory disorder of the central nervous system predominantly targeting optic nerves and the spinal cord.The prevalence of the disease is much higher in Asia than in other parts of the world.Pain can be detected in more than 80%of NMOSD patients,with evoked pain mostly being caused by painful tonic muscle spasms and neuropathic pain as the most characteristic types.Depression is often comorbid with pain,and their comorbidity can severely influence quality of life.In recent years,studies have found considerable overlaps between the mechanisms of pain and depression;however,their association remains unclear.This article reviews the epidemiology,mechanism,evaluation and treatment of paindepression comorbidity in NMOSD patients.展开更多
Objective To identify the protective effect of lipopolysaccharide (LPS) preconditioning against LPS-induced inflammatory damage in dopaminergic neurons of midbrain slice culture and the possible mechanisms. Methods ...Objective To identify the protective effect of lipopolysaccharide (LPS) preconditioning against LPS-induced inflammatory damage in dopaminergic neurons of midbrain slice culture and the possible mechanisms. Methods After cultured in vitro for 14 d, the rat organotypic midbrain slices were pretreated with different concentrations (0, 1, 3, 6 or 10 ng/mL) of LPS for 24 h followed by treatment with 100 ng/mL LPS for 72 h. The whole slice viability was detelmined by measurement of the activity of lactic acid dehydrogenase (LDH). Tyrosine hydroxylase-immunoreactive (TH-IR) neurons and CD 1 1 b/c equivalent-immunoreactive (OX-42-IR) microglia in the slices were observed by immunohistochemical method, and tumor necrosis factor-α (TNF-α levels in the culture media were detected by enzymelinked immunosorbent assays (ELISA). Results In the slices treated with 100 ng/mL LPS for 72 h, the number of TH-IR neurons reduced from 191± 12 in the control slices to 46±4, and the LDH activity elevated obviously (P 〈 0.01), along with remarkably increased number of OX-42-IR cells and production of TNF-α (P 〈 0.01). Preconditioning with 3 or 6 ng/mL LPS attenuated neuron loss (the number of TH-IR neurons increased to 126± 12 and 180± 13, respectively) and markedly reduced LDH levels (P 〈 0.05), accompanied by significant decreases of OX-42-IR microglia activation and TNF-α production (P 〈 0.05). Conclusion Low-dose LPS preconditioning could protect dopaminergic neurons against inflammatory damage in rat midbrain slice culture, and inhibition of microglial activation and reduction of the proinflammatory factor TNF-α production may contribute to this protective effect. Further understanding the underlying mechanism of LPS preconditioning may open a new window for treatment of Parkinson's disease.展开更多
Inflammatory bowel disease(IBD) is often associated with extraintestinal manifestations(EIMs) such as optic neuritis(ON),although this has been described in only a few adult patients so far,all of whom were affected w...Inflammatory bowel disease(IBD) is often associated with extraintestinal manifestations(EIMs) such as optic neuritis(ON),although this has been described in only a few adult patients so far,all of whom were affected with Crohn's disease(CD).Furthermore,ON and demyelinating diseases have been demonstrated to be more frequent in IBD patients than in control populations.In our current case report,we describe a child with active CD who developed sudden blindness due to bilateral ON that was not related to any known cause,and that promptly responded to a high dose of steroids.Investigations and a clinical follow-up have so far ruled out the development of demyelinating diseases in this patient.To our knowledge,this is the first report of ON in a pediatric patient with CD.Possible explanations for this case include an episodic EIM of an active bowel disease,an associated autoimmune disorder such as a recurrent isolated ON,the first manifestation of multiple sclerosis,or another demyelinating disease that could appear in a later follow-up.展开更多
基金International Cooperative Project of Traditional Chinese Medicine(GZYYG2020023)CAMS Innovation Fund for Medical Sciences(CIFMS)Grant(2021-I2M-1-034)Key Research Project of Hunan Province(222SK2018).
文摘Objective To investigate the antidepressant effects of Yuanzhi(Polygalae Radix;PR)aqueous extract on chronic unpredictable mild stress(CUMS)-induced depression rat models and the underlying mechanisms.Methods A total of 40 male Sprague Dawley(SD)rats were randomly divided into control;model;low dose of PR(PR-L;0.5 g/kg);high dose of PR(PR-H;1 g/kg);and fluoxetine(10 mg/kg)groups;with 8 rats in each group.Except for the rats in control group;those in the other four groups underwent CUMS-induced depression modeling.PR and fluoxetine were administered intragastrically once daily;30 min prior to the CUMS procedure;for 14 consecu-tive days until the behavioral tests were performed.After CUMS modeling;the sucrose prefer-ence test(SPT);open field test(OFT);novelty-suppressed feeding test(NSFT);forced swim test(FST);and tail suspension test(TST)were employed to assess the pharmacological ef-fects of PR on the mitigation of depressive-like behaviors in rat models.Additionally;the en-zyme-linked immunosorbent assay(ELISA)was utilized to quantify the serum levels of tumor necrosis factor(TNF)-α;interleukin(IL)-6;and IL-1βin the rats.Western blot analysis was al-so conducted to evaluate the protein expression levels of nuclear factor kappa-B(NF-κB);in-ducible nitric oxide synthase(iNOS);cyclooxygenase-2(COX-2);nucleotide-binding oligomerization domain(NOD)-like receptor family pyrin domain containing 3(NLRP3);apoptosis-associated speck-like protein containing caspase recruitment domain(ASC);and caspase-1 in the hippocampal tissues of the rats.Immunofluorescence staining was per-formed to observe the morphological changes in ionized calcium-binding adapter molecule 1 positive(Iba-1+)cells in the dentate gyrus(DG)of rats with CUMS-induced depression.Results(i)Treatment with PR-H and fluoxetine resulted in significant enhancements in both the total distance and time the rats moved during tests(P<0.01 and P<0.05;respectively).Post-administration of PR-H and fluoxetine also led to statistically significant increase in su-crose preference among rats(P<0.05).Besides;PR-L;PR-H;and fluoxetine treatment markedly decreased the latency of ingestion(P<0.05;P<0.05;and P<0.01;respectively).As observed from the FST;PR-L;PR-H;and fluoxetine presented antidepressant effects on rats with CUMS-induced depression;leading to the reduction in time of their immobility(P<0.05;P<0.01;and P<0.01;respectively).The results of TST indicated reduced immobility time in rats receiving PR-H and fluoxetine treatment as well(P<0.01).(ii)Rats in model group showed an increase in the levels of Iba-1+microglia in their left and right brains in compari-son with control group(P<0.01).However;such increase was negated post PR treatment(P<0.01).Treatment with PR-L;PR-H;and fluoxetine considerably reduced the levels of inflam-matory factors(TNF-α;IL-1β;and IL-6;P<0.01).In addition;treatment of PR-L and PR-H ef-fectively counteracted the elevated levels of NLRP3;ASC;and caspase-1;and markedly down-regulated the expression levels of phosphorylated p65(p-p65);COX-2;and iNOS in rats’hip-pocampus(P<0.01).Conclusion Collectively;these findings indicate that PR exerts an antidepressant effect on rats with CUMS-induced depression partially through the modulation of the NLRP3 and NF-κB signaling pathways.
基金supported by the National Natural Science Foundation (81601728,31500726)the Natural Science Foundation of Hunan Province (2021JJ41002),China。
文摘Objective:Inflammation in the central nervous system plays a crucial role in the occurrence and development of sepsis-associated encephalopathy.This study aims to explore the effects of maresin 1(MaR1),an anti-inflammatory and pro-resolving lipid mediator,on sepsis-induced neuroinflammation and cognitive impairment.Methods:Mice were randomly assigned to 4 groups:A sham group(sham operation+vehicle),a cecal ligation and puncture(CLP)group(CLP operation+vehicle),a MaR1-LD group(CLP operation+1 ng MaR1),and a MaR1-HD group(CLP operation+10 ng MaR1).MaR1 or vehicle was intraperitoneally administered starting 1 h before CLP operation,then every other day for 7 days.Survival rates were monitored,and serum inflammatory cytokines[tumor necrosis factor alpha(TNF-α),interleukin(IL)-1β,and IL-6]were measured 24 h after operation using enzyme-linked immunosorbent assay(ELISA).Cognitive function was assessed 7 days after operation using the Morris water maze(MWM)test and novel object recognition(NOR)task.The mRNA expression of TNF-α,IL-1β,IL-6,inducible nitric oxide synthase(iNOS),IL-4,IL-10,and arginase 1(Arg1)in cortical and hippocampal tissues was determined by real-time reverse transcription PCR(RT-PCR).Western blotting was used to determine the protein expression of iNOS,Arg1,signal transducer and activator of transcription 6(STAT6),peroxisome proliferator-activated receptor gamma(PPARγ),and phosphorylated STAT6(p-STAT6)in hippocampal tissue.Microglia activation was visualized via immunofluorescence.Mice were also treated with the PPARγantagonist GW9662 to confirm the involvement of this pathway in MaR1’s effects.Results:CLP increased serum levels of TNF-α,IL-1β,and IL-6,and reduced body weight and survival rates(all P<0.05).Both 1 ng and 10 ng doses of MaR1 significantly reduced serum TNF-α,IL-1β,and IL-6 levels,improved body weight,and increased survival rates(all P<0.05).No significant difference in efficacy was observed between the 2 doses(all P>0.05).MWM test and NOR task indicated that CLP impaired spatial learning,which MaR1 mitigated.However,GW9662 partially reversed MaR1’s protective effects.Real-time RTPCR results demonstrated that,compared to the sham group,mRNA expression of TNF-α,IL-1β,and iNOS significantly increased in hippocampal tissues following CLP(all P<0.05),while IL-4,IL-10,and Arg1 showed a slight decrease,though the differences were not statistically significant(all P>0.05).Compared to the CLP group,both 1 ng and 10 ng MaR1 decreased TNF-α,IL-1β,and iNOS mRNA expression in hippocampal tissues and increased IL-4,IL-10,and Arg1 mRNA expression(all P<0.05).Immunofluorescence results indicated a significant increase in Iba1-positive microglia in the hippocampus after CLP compared to the sham group(P<0.05).Administration of 1 ng and 10 ng MaR1 reduced the percentage area of Iba1-positive cells in the hippocampus compared to the CLP group(both P<0.05).Western blotting results showed that,compared to the CLP group,both 1 ng and 10 ng MaR1 down-regulated the iNOS expression,while up-regulated the expression of Arg1,PPARγ,and p-STAT6(all P<0.05).However,the inclusion of GW9662 counteracted the MaR1-induced upregulation of Arg1 and PPARγcompared to the MaR1-LD group(all P<0.05).Conclusion:MaR1 inhibits the classical activation of hippocampal microglia,promotes alternative activation,reduces sepsis-induced neuroinflammation,and improves cognitive decline.
文摘Current hypothesis of neuronal degeneration in Parkinson's disease (PD) have been proposed, including formation of free radicals and oxidative stress, mitochondrial dysfunction, excitotoxicity, trophic factor deficiency, inflammatory processes, genetic factors, environmental impact factors, toxic action of nitric oxide, apoptosis, and so on. This review mainly discussed oxidative stress, environmental impact factors, and inflammatory processes in PD.
文摘Objective To investigate lipopolysaccharide (LPS) induced acute cerebral inflammatory damage and the therapeutic effect of ginkgolide B (BN52021). Methods Thirty Sprague-Dawley rats were randomly divided into 3 groups (n = 10 for each group): Control group, Model group and Treatment group (treated with BN52021). LPS were injected into the fourth ventricle of rat to make a neuroinflammatory murine model. Morris water maze was used to detect the learning and memory ability of rats; changes of synapse number and subcellular ultrastructures were observed under a transmission electron microscope; OX-42 positive microglia in the brain was detected by immunohistochemical method. Results The average escape latency in the Treatment group were significantly shortened than that in the Model group; and the percentage of swimming distance traveled in platform quadrant accounting for total distance increased markedly. The rough endoplasmic reticulum and polyribosomes in the Treatment group were more than that in the Model group, but the number of synapses seemed to have no obvious change. The number of OX-42 positive microglia in the Treatment group decreased markedly than that in the Model group, and the grey density of OX-42-positive cells increased significantly. Conclusion LPS can induce inflammatory damages to the brain, but the damage could be antagonized by BN52021. Platelet activating factor receptor antagonist may offer an effective therapy for neurodegeneration diseases.
文摘Current hypothesis of neuronal degeneration in Parkinson’s disease (PD) have been proposed, including formation of free radicals and oxidative stress, mitochondrial dysfunction, excitotoxicity, trophic factor deficiency, inflam- matory processes, genetic factors, environmental impact factors, toxic action of nitric oxide, apoptosis, and so on. This review mainly discussed oxidative stress, environmental impact factors, and inflammatory processes in PD.
文摘We report a case of a patient presenting with clinical,radiological and endoscopic features of colitis due to a compressive left para-aortic mass. Total open surgical excision was performed,which resulted in complete resolution of colitis. Histopathology and immunohistochemistry revealed benign retroperitoneal schwannoma. These neural sheath tumors rarely occur in the retroperitoneum. They are usually asymptomatic but as they enlarge they may compress adjacent structures,which leads to a wide spectrum of non-specific symptoms,including lumbar pain,headache,secondary hypertension,abdominal pain and renal colicky pain. CT and MR findings show characteristic features,but none are specific. Schwannoma can be isolated sporadic lesions,or associated with schwannomatosis or neurofibromatosis type Ⅱ (NF2). Although they vary in biological and clinical behavior,their presence is,in nearly every case,due to alterations or absence of the NF2 gene,which is involved in the growth regulation of Schwann cells. Both conditions were excluded by thorough mutation analysis. Diagnosis is based on histopathological examination and immunohistochemistry. Total excision is therapeutic and has a good prognosis. Schwannomatosis and NF2 should be excluded through clinical diagnostic criteria. Genetic testing of NF2 is probably not justified in the presence of a solitary retroperitoneal schwannoma.
基金"Nordjyllands Amts Forskningslegat" and the Danish Technical Research Council
文摘AIM: To prove the hypothesis that patients with chronic pancreatitis would show increased theta activity during painful visceral stimulation. METHODS: Eight patients and 12 healthy controls underwent an experiment where the esophagus was electrically stimulated at the pain threshold using a nasal endoscope. The electroencephalogram (EEG) was recorded from 64 surface electrodes and "topographic matching pursuit" was used to extract the EEG information in the early brain activation after stimulation. RESULTS: A major difference between controls and patients were seen in delta and theta bands, whereas there were only minor differences in other frequency bands. In the theta band, the patients showed higher activity than controls persisting throughout the 450 ms of analysis with synchronous brain activation betweenthe channels. The main theta components oscillated with 4.4 Hz in the patients and 5.5 Hz in the controls. The energy in the delta (0.5-3.5 Hz) band was higher in the controls, whereas the patients only showed scattered activity in this band. CONCLUSION: The differences in the theta band indicate that neuropathic pain mechanisms are involved in chronic pancreatitis. This has important implications for the understanding and treatment of pain in these patients, which should be directed against drugs with effects on neuropathic pain disorders.
文摘Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal malignancies. Adenocarcinoma is the commonest type of colorectal neoplasm associated with ulcerative colitis (UC) and Crohn's disease, but other types of epithelial and non-epithelial tumors have also been described in inflamed bowel. With regards to non-epithelial malignancies, lymphomas and sarcomas represent the largest group of tumors reported in association with IBD, especially in immunosuppressed patients. Carcinoids and in particular neuroendocrine neoplasms other than carcinoids (NENs) are rare tumors and are infrequently described in the setting of IBD. Thus, this association requires further investigation. We report two cases of neoplasms arising in mild left-sided UC with immuno- histochemical staining for neuroendocrine markers: a large cell and a small cell neuroendocrine carcinoma of the rectum. The two patients were different in age (35 years vs 77 years) and disease duration (11 years vs 27 years), and both had never received immunosuppressant drugs. Although the patients underwent regular endoscopic and histological follow-up, the two neoplasms were locally advanced at diagnosis. One of the two patients developed multiple liver metastases and died 15 mo after diagnosis. These findings confirm the aggressiveness and the poor prognosis of NENs compared to colorectal adenocarcinoma. While carcinoids seem to be coincidentally associated with IBD, NENs may also arise in this setting. In fact, long-standing inflammation could be directly responsible for the development of pancellular dysplasia involving epithelial, goblet, Paneth and neuroendocrine cells. It has yet to be established which IBD patients have a higher risk of developing NENs.
文摘Sensory or motor peripheral neuropathy may be observed in a significant proportion of hepatitis C virus (HCV)-infected patients.However,central nervous system (CNS) involvement is uncommon,especially in cryoglobulin-negative subjects.We describe a case of peripheral neuropathy combined with an ischemic CNS event as primary manifestations of chronic HCV infection without cryoglobulinemia.Significant improvement was observed after antiviral therapy.We discuss the spectrum of neurological manifestations of HCV infection and review the literature.
文摘AIM: To determine the and clinical features of prevalence, histologic types primary epithelial tumours of the vermiform appendix in a predominantly black population.METHODS: All cases of primary tumours of the appendix identified by review of the histopathology records at the University of the West Indies between January 1987 and June 2007 were selected. Relevant pathologic and clinical data were extracted with supplementation from patient charts where available. Non-epithelial tumours were excluded. The total number of appendectomy specimens over the period was also ascertained.RESULTS: Forty-two primary epithelial tumours were identified out of 6 824 appendectomies yielding a prevalence rate of approximately 0.62%. Welldifferentiated neuroendocrine cell tumours (carcinoids, 47.6%) and benign non-endocrine cell tumours (adenomas, 45.2%) were most common with nearly equal frequency. The median age was 43 years, with no sex predilection. Carcinoid tumours occurred in younger patients (mean age 32 years), with a male-to-female ratio of 1.2:1. A clinical diagnosis of acute appendicitis was the most common reason for appendectomy (57.1%) and was histologically confirmed in 75% (18 of 24) of cases. In total, 16.7% of cases were diagnosed after incidental appendectomy.CONCLUSION: Appendiceal epithelial tumours are rare in our experience, and are represented principally by carcinoid turnours and adenornas. Carcinoid tumours occurred in younger patients but were slightly more common in men than women. Tumours were not suspected clinically and were diagnosed incidentally in specimens submitted for acute appendicitis supporting the need for histological evaluation in all resection specimens.
文摘Slow transit constipation has been traditionally considered and classified as a functional disorder. However, clinical and manometric evidence has been accumulating that suggests how most of the motility alterations in STC might be considered of neuropathic type.In addition, further investigations showed that subtle alterations of the enteric nervous system, not evident to conventional histological examination, may be present in these patients. In the present article we will discuss these evidences, and will try to put them in relation with the abnormal motor function of the large bowel documented in this pathological condition.
文摘Objective To investigate the Churg-Strauss syndrome (CSS) associated lung involvement, concentrating on clinical characteristics, pathological findings of tung involvements, response to treatment, and prognosis. Methods We retrospectively analyzed the characters of the clinical manifestations, thin-section CT and pathological findings of CSS. The study involved 16 patients. Clinical data were obtained by chart review All patients underwent transbronchial lung biopsy (TBLB). Six of them underwent surgical lung biopsy as well. Results The patients included 7 men and 9 women, aged from 14 to 61 years (median, 47.5 years). Extrathoracic organs involved included nervous system (7/16) and skin (5/16). Respiratory symptoms included cough (12/16), exertional dyspnea (11/16), hemoptysis (4/16), and chest pain (3/16). CT findings included bilateral ground-glass opacities (12 / 16), bilateral patchy opacities (12 / 16), and centrilobular nodules (6/16). The pathological findings of TBLB demonstrated increased eosinophils (3/16), vasculitis (3/16), and interstitial pneumonia (16/16). The pathological fmdings of surgical lung biopsy of 6 cases showed necrotizing vasculitis in 4 cases, capillaries in 5, eosinophilic pneumonia in 3, granulomas in 2, and airway abnormalities in 3. All patients improved in symptoms after therapy during the study period (range, 3 to 51 months; median, 15 months). Conclusions Asthma may be present in CSS patient when there is bronchial involvement. Grotmd-glass opacities and consolidation seen on high-resolution CT reflect the presence of eosinophilic pneumonia, vasculitis, and pulmonary alveolar hemorrhage. TBLB has significant limitations for the diagnosis of CSS. Early diagnosis and therapy can result in satisfactory prognosis.
文摘The diagnosis of the recurrent optic neuritis is commonly established clinically,and sometimes it could be challenging because the involved optic nerve does not always show significant enhancement on conventional contrast enhanced-T1 weighted imaging(CE-T1W1).In this paper,we reported a middle-aged female with early diagnosis of recurrent optic neuritis using contrast-enhanced T2 fluid-attenuated inversion recovery imaging(CET2FLAIR).The involved optic nerve presented evident enhancement on CE-T2FLAIR and no enhancement on CE-T1W1.This case suggested that the CE-T2FLAIR may be a useful diagnostic tool specifically for the recurrent optic neuritis in clinical practice.
文摘AIM: To compare the effects of neurolytic celiac plexus block (NCPB) and videothoracoscopic splanchnicectomy (VSPL) on pain and quality of life of chronic pancreatitis (CP) patients.METHODS: Forty-eight small duct CP patients were treated invasively with NCPB (n = 30) or VSPL (n = 18) in two non-randomized, prospective, case-controlled protocols due to chronic pain syndrome, and compared to a control group who were treated conservatively (n = 32). Visual analog scales were used to assess pain and opioid consumption rate was evaluated. In addition, the quality of life was measured using QLQ C-30 for NCPB and FACIT for VSPL.Although both questionnaires covered similar problems,they could not be compared directly one with another.Therefore, the studies were compared by meta-analysis methodology.RESULTS: Both procedures resulted in a significant positive effect on pain of CP patients. Opioids were withdrawn totally in 47.0% of NCPB and 36.4% of VSPL patients,and reduced in 53.0% and 45.4% of the respective patient groups. No reduction in opioid usage was observed in the control group. In addition, fatigue and emotional well-being showed improvements. Finally, NCPB demonstrated stronger positive effects on social support, which might possibly be attributed to earlier presentation of patients treated with NCPB.CONCLUSION: Both invasive pain treatment methods are effective in CP patients with chronic pain.
基金Supported by the Deutsche Forschungsgemeinschaft (SFB 548)
文摘A 37oyear old woman presented with a 9oyear history of hepatitis of unknown origin and aminotransferases within a 3-fold upper limit of normal. Autoimmune hepatitis (AIH) was diagnosed on the basis of elevated aminotransferases, soluble liver antigen/liver pancreas (SLA/LP) autoantibodies and characteristic histology. Immunosuppressive therapy led to rapid normalization of aminotransferases. Two years later, the patient developed left sided hemisensory deficits under maintenance therapy of prednisolone and azathioprine (AZT). Later she developed right foot drop and paraesthesia in the ulnar innervation territory on both sides. Magnetic resonance imaging (MRI) and cerebral panangiography suggested cerebral vasculitis. Neurological investigation and electromyography disclosed multiplex neuritis (MN) probably due to vasculitis. Consistent with this diagnosis, autoantibodies to extractable nuclear antigens were detectable in serum. Immunosuppression was changed to oral 150 mg cyclophosphamide (CPMO) per day. Prednisolone was increased to 40 mg/d and then gradually tapered to 5 mg. Oral CPM was administered up to a total dose of 40 g and then substituted by 6 times of an intervall infusion therapy of CPM (600 mg/m^2). Almost complete motoric remission was achieved after 3 mo of CPM. Sensibility remained reduced in the right peroneal innervation territory. Follow-up of cranial MRI provided stable findings without any new or progressive lesions. This is the first report of multiplex neuritis in a patient with autoimmune hepatitis.
基金Supported by the Fundamental Research Funds for the Central Universities(3332021015)。
文摘Neuromyelitis optica spectrum disorder(NMOSD)is an inflammatory disorder of the central nervous system predominantly targeting optic nerves and the spinal cord.The prevalence of the disease is much higher in Asia than in other parts of the world.Pain can be detected in more than 80%of NMOSD patients,with evoked pain mostly being caused by painful tonic muscle spasms and neuropathic pain as the most characteristic types.Depression is often comorbid with pain,and their comorbidity can severely influence quality of life.In recent years,studies have found considerable overlaps between the mechanisms of pain and depression;however,their association remains unclear.This article reviews the epidemiology,mechanism,evaluation and treatment of paindepression comorbidity in NMOSD patients.
基金the Foundation of Beijing Municipal Commission of Education,China (No.200410025011)
文摘Objective To identify the protective effect of lipopolysaccharide (LPS) preconditioning against LPS-induced inflammatory damage in dopaminergic neurons of midbrain slice culture and the possible mechanisms. Methods After cultured in vitro for 14 d, the rat organotypic midbrain slices were pretreated with different concentrations (0, 1, 3, 6 or 10 ng/mL) of LPS for 24 h followed by treatment with 100 ng/mL LPS for 72 h. The whole slice viability was detelmined by measurement of the activity of lactic acid dehydrogenase (LDH). Tyrosine hydroxylase-immunoreactive (TH-IR) neurons and CD 1 1 b/c equivalent-immunoreactive (OX-42-IR) microglia in the slices were observed by immunohistochemical method, and tumor necrosis factor-α (TNF-α levels in the culture media were detected by enzymelinked immunosorbent assays (ELISA). Results In the slices treated with 100 ng/mL LPS for 72 h, the number of TH-IR neurons reduced from 191± 12 in the control slices to 46±4, and the LDH activity elevated obviously (P 〈 0.01), along with remarkably increased number of OX-42-IR cells and production of TNF-α (P 〈 0.01). Preconditioning with 3 or 6 ng/mL LPS attenuated neuron loss (the number of TH-IR neurons increased to 126± 12 and 180± 13, respectively) and markedly reduced LDH levels (P 〈 0.05), accompanied by significant decreases of OX-42-IR microglia activation and TNF-α production (P 〈 0.05). Conclusion Low-dose LPS preconditioning could protect dopaminergic neurons against inflammatory damage in rat midbrain slice culture, and inhibition of microglial activation and reduction of the proinflammatory factor TNF-α production may contribute to this protective effect. Further understanding the underlying mechanism of LPS preconditioning may open a new window for treatment of Parkinson's disease.
文摘Inflammatory bowel disease(IBD) is often associated with extraintestinal manifestations(EIMs) such as optic neuritis(ON),although this has been described in only a few adult patients so far,all of whom were affected with Crohn's disease(CD).Furthermore,ON and demyelinating diseases have been demonstrated to be more frequent in IBD patients than in control populations.In our current case report,we describe a child with active CD who developed sudden blindness due to bilateral ON that was not related to any known cause,and that promptly responded to a high dose of steroids.Investigations and a clinical follow-up have so far ruled out the development of demyelinating diseases in this patient.To our knowledge,this is the first report of ON in a pediatric patient with CD.Possible explanations for this case include an episodic EIM of an active bowel disease,an associated autoimmune disorder such as a recurrent isolated ON,the first manifestation of multiple sclerosis,or another demyelinating disease that could appear in a later follow-up.