Pwl Ho

Neuromyelitis optica-IgG in idiopathic inflammatory demyelinating disorders amongst Hong Kong Chinese

Background:  Idiopathic inflammatory demyelinating disorders (IIDD) affect the central nervous system. In classical multiple sclerosis (CMS), brain, optic nerves [optic neuritis (ON)] and spinal cord [acute transverse myelitis (ATM)] are affected. In neuromyelitis optica (NMO), optic nerves and spinal cord are predominantly affected. NMO‐IgG, an autoantibody targeting aquaporin‐4, is a marker for NMO. We studied the frequency and clinical relevance of NMO‐IgG seropositivity in IIDD patients.

Plasma amyloid-β oligomers level is a biomarker for Alzheimer’s disease diagnosis

Amyloid beta (Aβ), especially Aβ oligomers, is important in Alzheimers disease (AD) pathogenesis. We studied plasma Aβ(40), Aβ(42), and Aβ oligomers levels in 44 AD patients and 22 non-demented controls. Cognitive functions were assessed by Chinese version of mini-mental state examination (MMSE), Abbreviated Metal Test (AMT), Alzheimers Disease Assessment Scale Cognitive Subscale (ADAS-cog). Plasma Aβ monomers and oligomers levels were measured by ELISA. We found that the median plasma Aβ(40) and Aβ(42) levels were similar between AD and controls, and without significant correlation with cognition. Plasma Aβ oligomers level was higher in AD than controls (642.54 ng/ml [range 103.33-2676.93] versus 444.18 ng/ml [range 150.19-1311.18], p=0.047), and negatively correlated with cognition. In multivariate logistic regression analysis, the highest tertile of Aβ oligomers levels showed an increased risk of AD than the combined group of middle and lowest tertiles (OR=8.85, p=0.013), after adjustment of gender, age and APOE4 genotype. Increased plasma Aβ oligomers level was associated with decreased MMSE and AMT scores (p=0.037, p=0.043, respectively) and increased ADAS-cog score (p=0.036), suggesting negative correlation with cognitive function. We concluded that plasma Aβ oligomers level is an useful biomarker for AD diagnosis.

Aquaporin-4 water channel expression by thymoma of patients with and without myasthenia gravis.

BACKGROUND Neuromyelitis optica (NMO) is a serious idiopathic inflammatory demyelinating disorder characterized by acute transverse myelitis and optic neuritis. A significant proportion of NMO patients are seropositive for NMO-IgG, an autoantibody targeting aquaporin-4 (AQP4) water channel. Paraneoplastic NMO associated various tumors were recently reported. AIM We studied the expression of AQP4 by thymoma from patients with and without myasthenia gravis (MG). METHODS Thymoma obtained from thymomectomy in patients with and without MG were studied by immunohistochemistry and western blot. RESULTS Ten thymoma patients (9 with MG) and two control patients without thymoma or MG were studied. Immunohistochemistry revealed AQP4 immunoreactivity in cell membrane of thymoma cells from all ten thymoma specimens whereas thymic tissues from patients without thymoma or MG were negative for AQP4 immunoreactivity. Western blot revealed that lysates of nine of the ten thymoma specimens reacted with anti-human AQP4 antibody with a band of ~30 kDa compatible with the molecular weight of AQP4. Interestingly, immunofluorescence revealed that IgG isolated from 2 NMO patients seropositive for NMO-IgG bound to cell membrane of thymoma cells from all ten thymoma specimens while IgG from healthy control subject did not. CONCLUSION Thymoma cells of patients with and without MG express AQP4. AQP4 autoantibodies from serum of NMO patients bound to AQP4 expressed on thymoma cell membrane.

Estrogenic phenol and catechol metabolites of PCBs modulate catechol-o-methyltransferase expression via the estrogen receptor: Potential contribution to cancer risk

Commercial PCB mixtures have been shown to induce liver tumors in female rats and this effect has been attributed to the effects of PCBs on estrogen metabolism. Catechol metabolites of PCBs are potent inhibitors of COMT activity and are likely to contribute significantly to reduced clearance of genotoxic catechol metabolites of estrogen. The effect of PCB metabolites on COMT expression in cultured cells was investigated to explore potential mechanisms by which PCB exposure alters catechol estrogen clearance. We hypothesize that estrogenic PCB metabolites may contribute to reduction of COMT expression via interaction with the estrogen receptor. To test this hypothesis, human MCF-7 cells were exposed to PCB analogues and the expression of COMT determined. Western blot analysis demonstrated that COMT protein levels were statistically significantly reduced by both the phenolic and the catechol compounds, an effect which was abolished by the anti-estrogen, ICI182780. The above suggests that COMT levels may be reduced by estrogenic PCB metabolites, via interactions between PCB metabolites and the ER. It supports the hypothesis that both phenolic and catechol metabolites of PCBs may contribute to PCB-mediated carcinogenesis through reduction of COMT levels and activities and subsequent reduction in clearance of endogenous and xenobiotic catechols.

Clinical outcome of relapsing remitting multiple sclerosis among Hong Kong Chinese.

BACKGROUND Clinical outcome of Chinese relapsing remitting multiple sclerosis (RRMS) patients is uncertain. AIM To study the long-term clinical outcome of Chinese RRMS patients. METHOD RRMS patients with duration of 10 years or longer followed up in our hospital is retrospectively studied. RESULTS 61 RRMS patients (75% female) were studied. Their mean symptom onset age was 25.9 years and mean duration was 20.6 years (range 10-33); 36% patients had received β-interferon and 30% azathioprine. Their mean EDSS scores were 3.3 (range 1-7) and 4.7 (range 1-8) at 10 years and latest follow-up (mean duration 20.6 years) respectively. At 10 years, 30% patients had EDSS score ≤2, 34% EDSS 2.5-3.5, 20% EDSS 4.0-5.5 and 16% ≥6; 18% developed SPMS. At latest follow-up, 15% patients had EDSS ≤2, 20% EDSS 2.5-3.5, 19% EDSS 4.0-5.5 and 46% ≥6.0; 53% developed SPMS. The median time from symptom onset to EDSS 6 was 22 years. No differences were detected in demographic characteristics, presenting neurological features, number of attacks in first 2 years, neuroradiological findings and disease modifying therapies between patients with EDSS <6 and ≥6 at ten years. EDSS scores at 10 years and latest follow-up were similar for patients who had received β-interferon and those who had not. CONCLUSION Hong Kong Chinese RRMS patients may have worse long-term clinical outcome than Caucasian patients.

Central nervous system inflammatory demyelinating disorders among Hong Kong Chinese

Classical multiple sclerosis (CMS) and neuromyelitis optica spectrum disorders (NMOSD) are distinct central nervous system inflammatory demyelinating disorders (CNS IDD). Early diagnosis of CNS IDD is important as appropriate immunotherapies to optimize prognosis. We studied the diagnoses of CNS IDD among Hong Kong Chinese in a hospital-based setting. Consecutive Chinese patients who presented to our hospital with clinically isolated syndrome and subsequently diagnosed to have CNS IDD from 1980 to 2010 were reviewed. Patients with known diagnosis of CNS IDD referred for further care were excluded. Serial sera were assayed for aquaporin-4 autoantibodies (AQP4 Ab), at least 3 assays within 2-5years. A total of 210 patients diagnosed to have CNS IDD with disease duration of at least 2years were studied. Among 198 patients with serial sera available, 40 (20.2%, 20 had NMO and 20 other NMOSD) were AQP4 Ab-positive. Four patients who were AQP4 Ab-negative on the initial assay converted to AQP4 Ab-positive on repeated assays. The diagnoses of 210 patients were CMS in 88 (41.9%), NMOSD 47 (22.4%, 27 NMO, 20 other NMOSD), single attack of myelitis 23 (11.0%), single attack of optic neuritis 21 (10.0%), relapsing myelitis 10 (4.8%), acute disseminated encephalomyelitis (ADEM) 9 (4.3%), relapsing optic neuritis in 6 (2.9%), opticospinal multiple sclerosis 3 (1.4%) and single attack of brainstem encephalitis 3 (1.4%). Compared to CMS, NMOSD patients had older onset age, lower frequencies of brain MRI abnormalities and CSF OCB, higher frequency of LETM, higher CNS inflammation attack frequency in the first 2years, worse clinical outcome with higher EDSS score and mortality rate. This hospital-based study suggests that CMS (41.9%) and NMOSD (22.4%) are the most common CNS IDD among Hong Kong Chinese. NMOSD has worse clinical outcome than CMS. Detection of AQP4 Ab facilitates early diagnosis and prompts immunotherapies of NMOSD.

Detection of endocrine disruptors - from simple assays to whole genome scanning.

Endocrine disruptors frequently bear little structural relationship to the hormone whose actions they disrupt. Consequently, the threat of an uninvestigated chemical cannot easily be assessed. Here three different approaches to assessment are discussed. The first presumes an endocrine-disrupting property, following which a cell model capable of responding to such a hormone is used. Although simple and cheap, it provides limited data. A second approach involves multiple assays to detect multiple hormones. Increasing the amount of data increased the difficulty in assessing the significance of results. To meet this problem, cluster analysis based on a simple mathematical matrix was adopted. The matrix was used to determine (i) a limited number of assays to identify a maximum number of endocrine disruptors and (ii) the chemicals with the most wide-ranging effects. A third approach was a whole genome expression analysis based on expression of mRNAs in human TE671 medulloblastoma cells. Expression of individual mRNAs was assessed using the Affymetrix GeneChip(®) Human Genome U133 Plus 2.0 chip. The significance of differential expressed genes was assessed based on gene ontology and pathways analyses using DAVID and GenMaPP programs. The results illustrated the very wide-ranging effects of these chemicals across the genome.

Aquaporin-4 autoantibodies cause asymptomatic aquaporin-4 loss and activate astrocytes in mouse☆ , ☆☆

BACKGROUND Neuromyelitis optica (NMO) is a central nervous system inflammatory demyelinating disorder. Up to 90% of patients are seropositive for aquaporin-4 autoantibodies (AQP4 Ab). The pathogenetic mechanisms underlying clinical onset and relapse of NMO are uncertain. OBJECTIVE Study the pathogenicity of AQP4 Ab in the absence of complement activation. METHODS Female C57BL/6N mice (human IgG cannot activate mouse complements) pretreated with complete Freunds adjuvant (CFA, day 0) and pertussis toxin (PTx, day 0 and day 2) were transferred with IgG isolated from serum of healthy subjects or NMO patients (AQP4 Ab-positive or negative) intraperitoneally (day 7-9). Mice were observed for signs of experimental autoimmune encephalomyelitis (EAE) by standard 6-grade EAE scores. Spinal cord was obtained at day 11 for immunohistochemistry. RESULTS None of the mice had clinical signs of encephalomyelitis, inflammatory cells infiltration or demyelination of spinal cord. CFA and PTx induce BBB breakdown evidenced by leakage of human IgG into cord parenchyma. Patchy areas of AQP4 loss were observed in spinal cord of mice transferred with IgG from AQP4 Ab-positive NMO patients but not in mice transferred with IgG from AQP4 Ab-negative NMO patients or healthy subjects; but there was no loss of glial fibrillary acidic protein immunoreactivity in all mice. Markedly increased proliferation of astrocytic processes suggestive of astrocytic activation was observed in mice transferred with IgG from AQP4 Ab-positive patients. CONCLUSION AQP4 Ab cause asymptomatic AQP4 loss and astrocytic activation but not myelitis, demyelination or astrocytic cytotoxicity in spinal cord of mouse in the absence of complement activation.

Effects of Plasticisers and Related Compounds on the Expression of the Soluble Form of Catechol-O-Methyltransferase in MCF-7 Cells

Previously we have shown that E2 down regulates S-COMT expression. Here the effects of four phthalate esters and 4-(tert-octyl)phenol on the intra-cellular levels of S-COMT and COMT activity were studied in MCF-7 cells as a measure of estrogenic activity of these compounds. The four phthalate esters caused significant reductions in both S-COMT protein and COMT activity levels. These effects were inhibited by the ERalpha receptor antagonist ICI182780. 4-(tert-octyl)phenol also caused reductions in these parameters, but the effects were not abolished by ICI182780. Assay of S-COMT protein levels represents a simple and convenient method of assessing the estrogenic potential of a compound.

Impaired Stress-induced Mitophagy In Parkinsonian LRRK2(R1441G) Knockin Mutant Mice

Objective: The aim of this work is to evaluate clinimetric properties of a method for measuring Parkinson’s disease (PD) upper limb temporal irregularities during spiral drawing tasks.Background: B ...Basic Science Abstracts - Session Title: Parkinsons Disease: Pathophysiology: abstract no. 518