published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Objective The goal of this study is to report on the linguistic validation and reliability of the Hong Kong Chinese version of the Pediatric Quality of Life Inventory™ (PedsQL™) End-stage Renal Disease Module for Children with end-stage renal disease (ESRD) in Hong Kong, and its use to assess health-related quality of life (HRQOL) in end-stage renal disease children receiving different treatment modalities: peritoneal dialysis, haemodialysis and renal transplantation. Methods In part 1, forward and backward translations following a stringent validation protocol produced the Chinese translation version. Content validity of the translated instrument was assessed. In part 2, internal consistency and reliability of the questionnaire was evaluated by 38 pairs of parents and children with end-stage renal disease aged 5 to 18. The data was further analysed according to different treatment modalities. Results The translated Hong Kong Chinese version of the Pediatric Quality of Life Inventory ™ (PedsQL™) End-stage Renal Disease Module (PedsQL™ 3.0 ESRD Module-HKC) was found to have good content validity and was acceptable to most patients and parents. Internal consistency was excellent (Cronbach’s α = 0.91 in Patient version and = 0.94 in Parent version). Test-retest reliability, determined with the intraclass correlation coefficients, was excellent (0.89 in Patient version and 0.93 in Parent version). It was found that there was significant better HRQOL in patient received renal transplantation compared with Dialysis (peritoneal dialysis or haemodialysis, p=0.006.) Conclusions This study suggested good content validity, internal consistency, and reliability of the Chinese version of the Pediatric Quality of Life Inventory ™ (PedsQL™) End-stage Renal Disease Module (PedsQL™ 3.0 ESRD Module-HKC). It opened a new dimension of health care assessment for end-stage renal disease children in Hong Kong. Transplantation was reported to have a significant better quality of life score. Further studies with larger samples should be performed to confirm the psychometric properties of this translated instrument. / published_or_final_version / Public Health / Master / Master of Public Health

Neuromyelitis optica (NMO) is a central nervous system inflammatory demyelinating disorders (CNS IDD) characterized by acute myelitis (AM) and optic neuritis (ON), especially clinically severe longitudinally extensive transverse myelitis (LETM) and simultaneous bilateral ON. Patients with recurrent AM especially LETM without ON, and patients with recurrent ON without AM may have disorders belonging to the spectrum of NMO, neuromyelitis optica spectrum disorders (NMOSD). NMO is likely autoimmune in nature as a significant proportion of patients are seropositive for aquaporin-4 (AQP4) autoantibodies. I studied the clinical features of local Chinese NMOSD patients and their AQP4 autoantibodies seropositivity rates of by indirect immunofluorescence using tissue slides containing primate cerebellum (tissued-based immunofluorescence assay) in patients with 1) NMO, 2) classical multiple sclerosis (CMS), 3) acute disseminated encephalomyelitis (ADEM), 4) single attack or relapsing AM, 5) single attack or relapsing ON, and 6) other neurological disorders. The results showed that NMOSD are severe CNS IDD affecting patients with a wide range of onset ages. Chinese NMOSD patients predominantly have relapsing NMO and relapsing LETM with severe attack of LETM and/or ON. The six-year mortality rate of patients with NMO or relapsing myelitis with LETM was about 12%. Two-thirds of patients have poor neurological outcome at a mean duration of 6.0 years. The results confirmed that AQP4 autoantibodies are specific for NMOSD, and detection of AQP4 autoantibodies is clinically useful for early diagnosis of NMOSD and distinction from CMS. I proceeded to study a cell-based immunofluorescence assay using transfected human embryonic kidney cells overexpressing human AQP4 on cell membrane and found that cell-based assay has higher sensitivity than tissue-based assay in detection of AQP4 autoantibodies in NMO (78% versus 61%). As our NMOSD patients frequently presented clinically with severe brainstem symptoms and signs and lesions in brainstem and other brain regions on magnetic resonance imaging (MRI), I studied the clinical and neuroradiological characteristics of Chinese NMOSD patients with brain involvement. I found that 59% of NMOSD patients have clinical and/or radiological evidence of brain involvement. Importantly, brainstem is the most frequently affected brain region and 24% of NMOSD patients had clinical manifestation of brainstem encephalitis. I also studied the pathogenicity of AQP4 autoantibodies in the absence of complement activation by passive transfer of IgG isolated from sera of NMOSD patients into mice pretreated with complete Freund’s adjuvant (CFA, containing heat-killed mycobacterium tuberculosis) and pertussis toxin (PTx). I observed that pretreatment with CFA and PTx led to breach of BBB in mouse, and IgG isolated from sera of NMOSD patients seropositive for AQP4 autoantibodies led to asymptomatic loss of AQP4 in gray and white matter in mouse spinal cord without inflammatory cell infiltration, demyelination or astrocytic loss in the absence of complement activation (human IgG cannot activate mouse complements). My findings support that 1) AQP4 autoantibodies binding to astrocytic AQP4 per se can cause downregulation of AQP4 in the absence of complement activation, and 2) complement activation with resultant complement activation products play key roles in the inflammation, demyelination and astrocyte cytotoxicity in NMO. / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

A safe, potent and broad-spectrum antiviral is urgently needed to combat emerging viral respiratory diseases such as avian influenza H5N1 and H7N9, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Previous studies carried out by PhD students in our lab found that mouse β-defenisn 4 (mBD4) shows highly antiviral activity in vitro. However, the recombinant mBD4 (rmBD4) expressed by E.coli is limited to very small scale of production and is very expensive. Thus, in this study, we firstly screened 16 short peptides derived from mBD4 and other mouse and human β-defensins for identifying their antiviral effects. One short peptide P9 (30 amino acids), derived from mBD4, exhibited potent and broad-spectrum antiviral effects against multiple respiratory viruses, including influenza A viruses H1N1, H3N2, H5N1, H7N7 and H7N9, SARS coronavirus (SARS-CoV)and MERS coronavirus (MERS-CoV). This P9 showed very high selectivity index (970), which was higher than that of the full-length peptide of synthetic mBD4 (smBD4) and rmBD4 in vitro. Secondly, the prophylactic and therapeutic effects of P9 against the infection of H1N1 virus were further detected in animal model. The survival rate of P9-pretreated mice challenged by lethal dose of H1N1 virus was 100%. The therapeutic effects of P9 protecting mice from lethal challenge of H1N1 virus were also statistically significant. The survival rate of mice could reach up to 67% by intranasal inoculation and 56% by intraperitoneal injection, respectively. To investigate the antiviral mechanism, we firstly elucidated that P9 could inhibit viral infection but not viral replication or release. Secondly, we detected whether P9 inhibited viral infection by binding to the surface of target cells or viral particles. The results showed that P9 only bound to viral particles but not to the cell surface. It was further identified that P9 bound to viral surface glycoprotein HA but not NA. Thirdly, we demonstrated that P9 did not inhibit virus binding to its receptor and block the virus entry into cells by endocytosis. Instead, P9 inhibited the acidification in late endosomes and thusP9 blocked virus-membrane fusion and subsequent viral disassembly and viral RNA release. Finally, we elucidated that the antiviral activity of P9 was attributed to its high binding affinity to viral HA and the abundance of basic amino acids in its composition. In this study, we have demonstrated that a short peptide P9, which is derived from mBD4, showed potent antiviral activity against multiple respiratory viruses. This peptide can be developed to a new promising prophylactic and therapeutic agent with broad-spectrum antiviral activity and low possibility to cause drug resistance. Moreover, this study has also revealed a novel antiviral mechanism for P9 and paved a path for the development of new antiviral agents with broad-spectrum antiviral activity against emerging respiratory viruses, such as avian influenza H5N1 and H7N9, as well as SARS-CoV and MERS-CoV. / published_or_final_version / Microbiology / Doctoral / Doctor of Philosophy

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published_or_final_version / Community Medicine / Master / Master of Philosophy

No description available.

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