Use of humanised mice to study antiviral activity of human γδ-T cells against influenza A viruses

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The effect of ageing on female fertility in an assisted reproduction programme in Hong Kong: retrospective study.

OBJECTIVE: To analyse the effect of ageing on female fertility in an in vitro fertilisation programme in Hong Kong. DESIGN: Retrospective study. SETTING: University teaching hospital, Hong Kong. PATIENTS: Seven hundred and seventy-one women in whom 1336 cycles of in vitro fertilisation were initiated between 1 January 1986 and 31 December 1995. MAIN OUTCOME MEASURES: Patient age and indications for treatment; hormonal response; and the number of cancelled cycles, oocytes retrieved, oocytes fertilised, cleaving embryos, embryos transferred, and clinical pregnancies. RESULTS: Compared with women aged or =36 years (n=398) had a significantly higher cycle cancellation rate (19.3% versus 10.4%), fewer oocytes retrieved per retrieval cycle (6.6 versus 9.0), fewer oocytes fertilised per retrieval cycle (5.0 versus 7.0), fewer cleaving embryos per retrieval cycle (4.8 versus 6.8), and lower serum oestradiol level (9735 [standard deviation, 5681] pmol/L versus 10 708 [5916] pmol/L) despite a larger amount of human menopausal gonadotrophin having been used (all variables, P<0.01; Chi squared test). The clinical pregnancy rate per initiated cycle (range, 7.5%-13.0%) decreased with advancing age (P<0.01; Chi squared test). CONCLUSION: Ageing has a significant deleterious effect on women's reproductive capability. Women should be encouraged to seek early medical advice and treatment for subfertility.published_or_final_versio

Severe mycobacterial infections in two pairs of Chinese siblings with interleukin-12 receptor β1 deficiency

postprin

Deletions within the azoospermia factor subregions of the Y chromosome in Hong Kong Chinese men with severe male-factor infertility: controlled clinical study.

OBJECTIVE: To determine the patterns and the prevalence of microdeletions in the azoospermia factor subregions of the Y chromosome in Hong Kong Chinese men with severe male-factor infertility. DESIGN: Controlled clinical study. SETTING: Reproductive centre of a university teaching hospital, Hong Kong. PARTICIPANTS: Fifty-eight men with severe male-factor infertility who participated in the in vitro fertilisation programme from May 1998 through March 1999, and 46 male volunteers with proven fertility. MAIN OUTCOME MEASURES: Polymerase chain reaction analysis of DNA from peripheral blood lymphocytes using six loci spanning the AZFa, AZFb, and AZFc subregions of the Y chromosome. RESULTS. No microdeletions were detected in the fertile controls or in patients with obstructive azoospermia. Deletions within the AZFc subregion were found in 9% (4/44) of men with non-obstructive azoospermia or severe oligospermia. Neither AZFa nor AZFb deletions were detected in any participants. CONCLUSION: Deletions within the azoospermia factor subregions of the Y chromosome are associated with severe male-factor infertility in Hong Kong Chinese men.published_or_final_versio

Problem-based learning : a teaching method to enhance learning experience for students in service-learning

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Autosomal Dominant Gain-of-function STAT1 Mutation is a Novel Genetic Etiology of Penicillium Marneffei Infection

Symposium / Free Paper 4: ImmunologyConference Theme: Inflammatory Basis of Perinatal and Childhood DiseasesBackground: Penicillium marneffei infection is indigenous to Southeast Asia. Majority of cases occur in patients with AIDS and secondary immunodeficiencies. We previously reported 4 HIV-negative children with chronic mucocutaneous candidiasis (CMC) and severe penicilliosis. Hyper-IgE syndrome was diagnosed in one of them, but extensive genetic studies on IL12-IFNγ axis, CARD9 and AIRE were unrevealing for the rest. Recently, STAT1 hyperphosphorylation causing defective Th1 and Th17 immunity is recognized as a cause of CMC. Objective: To investigate the genetic and functional defects of STAT1 signaling in children affected by penicilliosis. Methods: Targeted sequencing of STAT1 gene or total exome sequencing was performed in 3 patients with CMC and penicilliosis. PBMCs were isolated from patients and normal controls. Intracellular STAT1 phosphorylation (pSTAT1) towards interferon-α and interferon-γ stimulation was evaluated by flow cytometry. Cytokine production in PBMCs towards PMA and ionomycin stimulation was assessed. PBMCs were co-cultured with live Candida albicans and P. marneffei to evaluate interferon-γ response. Results: Heterozygous STAT1 missense mutations were identified in all 3 patients. Two mutations were located in the coiled-coil domain (P1 and P2) and one in the DNA-binding domain (P3). All 3 patients recovered from penicilliosis, but P1 eventually died of fulminant aspergillosis. The percentage of pSTAT1-positive PBMCs induced by interferon-α and interferon-γ was significantly higher in all 3 patients than normal controls, indicating that they had gain-of-function mutations. PBMCs from all patients displayed defective interferon-γ and interleukin-17 production towards PMA and PMA plus ionomycin, respectively. Interferon-γ production induced by C. albicans and P. marneffei in P2 was significantly lower than normal controls. Conclusions: For the first time, we demonstrated STAT1 gain-of-function mutation as an important and novel genetic etiology of invasive mycosis including penicilliosis and aspergillosis. Penicilliosis should be regarded as an indicator disease for primary immunodeficiencies in children without HIV infection unless proven otherwise.published_or_final_versio

The Therapeutic Effect of Pamidronate on Lethal Avian Influenza A H7N9 Virus Infected Humanized Mice

A novel avian influenza virus H7N9 infection occurred among human populations since 2013. Although the lack of sustained human-to-human transmission limited the epidemics caused by H7N9, the late presentation of most patients and the emergence of neuraminidase-resistant strains made the development of novel antiviral strategy against H7N9 in urgent demands. In this study, we evaluated the potential of pamidronate, a pharmacological phosphoantigen that can specifically boost human Vδ2-T-cell, on treating H7N9 virus-infected humanized mice. Our results showed that intraperitoneal injection of pamidronate could potently decrease the morbidity and mortality of H7N9-infected mice through controlling both viral replication and inflammation in affected lungs. More importantly, pamidronate treatment starting from 3 days after infection could still significantly ameliorate the severity of diseases in infected mice and improve their survival chance, whereas orally oseltamivir treatment starting at the same time showed no therapeutic effects. As for the mechanisms underlying pamidronate-based therapy, our in vitro data demonstrated that its antiviral effects were partly mediated by IFN-γ secreted from human Vδ2-T cells. Meanwhile, human Vδ2-T cells could directly kill virus-infected host cells in a perforin-, granzyme B- and CD137-dependent manner. As pamidronate has been used for osteoporosis treatment for more than 20 years, pamidronate-based therapy represents for a safe and readily available option for clinical trials to treat H7N9 infection.published_or_final_versio

The Therapeutic Effect of Pamidronate on Lethal Avian Influenza A H7N9 Virus Infected Humanized Mice

A novel avian influenza virus H7N9 infection occurred among human populations since 2013. Although the lack of sustained human-to-human transmission limited the epidemics caused by H7N9, the late presentation of most patients and the emergence of neuraminidase-resistant strains made the development of novel antiviral strategy against H7N9 in urgent demands. In this study, we evaluated the potential of pamidronate, a pharmacological phosphoantigen that can specifically boost human Vδ2-T-cell, on treating H7N9 virus-infected humanized mice. Our results showed that intraperitoneal injection of pamidronate could potently decrease the morbidity and mortality of H7N9-infected mice through controlling both viral replication and inflammation in affected lungs. More importantly, pamidronate treatment starting from 3 days after infection could still significantly ameliorate the severity of diseases in infected mice and improve their survival chance, whereas orally oseltamivir treatment starting at the same time showed no therapeutic effects. As for the mechanisms underlying pamidronate-based therapy, our in vitro data demonstrated that its antiviral effects were partly mediated by IFN-γ secreted from human Vδ2-T cells. Meanwhile, human Vδ2-T cells could directly kill virus-infected host cells in a perforin-, granzyme B- and CD137-dependent manner. As pamidronate has been used for osteoporosis treatment for more than 20 years, pamidronate-based therapy represents for a safe and readily available option for clinical trials to treat H7N9 infection.published_or_final_versio

Situational Awareness of Influenza Activity Based on Multiple Streams of Surveillance Data Using Multivariate Dynamic Linear Model

BACKGROUND: Multiple sources of influenza surveillance data are becoming more available; however integration of these data streams for situational awareness of influenza activity is less explored. METHODS AND RESULTS: We applied multivariate time-series methods to sentinel outpatient and school absenteeism surveillance data in Hong Kong during 2004-2009. School absenteeism data and outpatient surveillance data experienced interruptions due to school holidays and changes in public health guidelines during the pandemic, including school closures and the establishment of special designated flu clinics, which in turn provided 'drop-in' fever counts surveillance data. A multivariate dynamic linear model was used to monitor influenza activity throughout epidemics based on all available data. The inferred level followed influenza activity closely at different times, while the inferred trend was less competent with low influenza activity. Correlations between inferred level and trend from the multivariate model and reference influenza activity, measured by the product of weekly laboratory influenza detection rates and weekly general practitioner influenza-like illness consultation rates, were calculated and compared with those from univariate models. Over the whole study period, there was a significantly higher correlation (rho = 0.82, p</=0.02) for the inferred trend based on the multivariate model compared to other univariate models, while the inferred trend from the multivariate model performed as well as the best univariate model in the pre-pandemic and the pandemic period. The inferred trend and level from the multivariate model was able to match, if not outperform, the best univariate model albeit with missing data plus drop-in and drop-out of different surveillance data streams. An overall influenza index combining level and trend was constructed to demonstrate another potential use of the method. CONCLUSIONS: Our results demonstrate the potential use of multiple streams of influenza surveillance data to promote situational awareness about the level and trend of seasonal and pandemic influenza activity.published_or_final_versio

Harvesting convalescent plasma for hyperimmune intravenous globulin production: a multicentre randomised double-blind controlled trial for treatment of patients with serious S-OIV H1N1 infection

Poster Presentations: Emerging / Infectious Diseases: abstract no. P107-Ab0089Symposium Theme: Translating Health Research into Policy and Practice for Health of the Populationpublished_or_final_versio