Medicine (RMH) - Research Publications
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ItemCarpal Tunnel Syndrome in Fabry Disease(SPRINGER-VERLAG BERLIN, 2012)Carpal tunnel syndrome (CTS) is a common peripheral mononeuropathy affecting up to 4% of the general population, typically women in late middle age. The incidence in patients with Fabry disease (FD) is unclear, but may affect 25% of patients with this X-linked lysosomal storage disease. We report three cases of CTS in young Caucasian male patients with classical FD, who developed CTS symptoms with supportive nerve conduction study (NCS) findings. Two patients had bilateral CTS and two had evidence of concurrent ulnar nerve neuropathy on NCS, suggesting a systemic process contributed to nerve compression. All were receiving enzyme replacement therapy (ERT) and had a moderate burden of FD complications. It is possible that an increase in connective tissue in the intracarpal canal in FD patients may be incited by injury to fibroblasts, via either accumulation of globotriaosylceramide (GL3) or local ischaemia through endothelial injury. The former hypothesis may be a more plausible explanation for the development of CTS, as histology of the flexor retinaculae from our patients has demonstrated fibroblasts with characteristic vacuolation and excessive myxomatous stroma, despite endothelial clearance of GL3 in these patients receiving ERT. CTS should not be overlooked in FD patients and young patients presenting with CTS should be evaluated for an underlying systemic or genetic disorder. Surgical carpal tunnel decompression was effective in our patients, already troubled by long-standing acroparesthesia, in providing sustained relief of symptoms.
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ItemNo Preview AvailableGata-3 Negatively Regulates the Tumor-Initiating Capacity of Mammary Luminal Progenitor Cells and Targets the Putative Tumor Suppressor Caspase-14(AMER SOC MICROBIOLOGY, 2011-11)The transcription factor Gata-3 is a definitive marker of luminal breast cancers and a key regulator of mammary morphogenesis. Here we have explored a role for Gata-3 in tumor initiation and the underlying cellular mechanisms using a mouse model of "luminal-like" cancer. Loss of a single Gata-3 allele markedly accelerated tumor progression in mice carrying the mouse mammary tumor virus promoter-driven polyomavirus middle T antigen (MMTV-PyMT mice), while overexpression of Gata-3 curtailed tumorigenesis. Through the identification of two distinct luminal progenitor cells in the mammary gland, we demonstrate that Gata-3 haplo-insufficiency increases the tumor-initiating capacity of these progenitors but not the stem cell-enriched population. Overexpression of a conditional Gata-3 transgene in the PyMT model promoted cellular differentiation and led to reduced tumor-initiating capacity as well as diminished angiogenesis. Transcript profiling studies identified caspase-14 as a novel downstream target of Gata-3, in keeping with its roles in differentiation and tumorigenesis. A strong association was evident between GATA-3 and caspase-14 expression in preinvasive ductal carcinoma in situ samples, where GATA-3 also displayed prognostic significance. Overall, these studies identify GATA-3 as an important regulator of tumor initiation through its ability to promote the differentiation of committed luminal progenitor cells.
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ItemNo Preview AvailableRefugee health update(Medicine Today, 2012-03-01)
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ItemNo Preview AvailablePrevalence and risk factors for symptoms of common mental disorders in early and late pregnancy in Vietnamese women: A prospective population-based study(Elsevier, 2013-04-05)BACKGROUND: Little is known about the prevalence of and risk factors for common mental disorders (CMD) in pregnant women in low-income countries. The aim of this study was to establish the prevalence of and psychosocial risk factors for clinically significant symptoms of CMD in early and late pregnancy in women in rural Viet Nam. METHODS: A population-based sample of women was surveyed in early and late pregnancy. CMD were assessed by the Edinburgh Postnatal Depression Scale-Viet Nam Validation and psychosocial risks by study-specific structured interviews. RESULTS: In total 497/523 (97%) eligible women were recruited and 419 (84%) provided complete data. Prevalence of CMD only in early pregnancy was 22.4% (95% CI 18.4-26.4); only in late pregnancy was 10.7% (95% CI 7.8-13.7) and at both assessment waves was 17.4% (95% CI 13.8-21.1). Non-economic and economic coincidental life adversity, intimate partner violence, past pregnancy loss, and childhood abuse were positively associated with persistent antenatal CMD. Older age, having a preference for the baby's sex, and nulli- or primiparity were risk factors for CMD in early pregnancy. CONCLUSIONS: Persistent antenatal CMD are prevalent in rural areas of Viet Nam. Psychosocial risk factors play a major role in this significant public health problem.
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ItemDiffuse myocardial fibrosis in hypertrophic cardiomyopathy can be identified by cardiovascular magnetic resonance, and is associated with left ventricular diastolic dysfunction(BMC, 2012-10-29)BACKGROUND: The presence of myocardial fibrosis is associated with worse clinical outcomes in hypertrophic cardiomyopathy (HCM). Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) sequences can detect regional, but not diffuse myocardial fibrosis. Post-contrast T(1) mapping is an emerging CMR technique that may enable the non-invasive evaluation of diffuse myocardial fibrosis in HCM. The purpose of this study was to non-invasively detect and quantify diffuse myocardial fibrosis in HCM with CMR and examine its relationship to diastolic performance. METHODS: We performed CMR on 76 patients - 51 with asymmetric septal hypertrophy due to HCM and 25 healthy controls. Left ventricular (LV) morphology, function and distribution of regional myocardial fibrosis were evaluated with cine imaging and LGE. A CMR T(1) mapping sequence determined the post-contrast myocardial T(1) time as an index of diffuse myocardial fibrosis. Diastolic function was assessed by transthoracic echocardiography. RESULTS: Regional myocardial fibrosis was observed in 84% of the HCM group. Post-contrast myocardial T(1) time was significantly shorter in patients with HCM compared to controls, consistent with diffuse myocardial fibrosis (498 ± 80 ms vs. 561 ± 47 ms, p < 0.001). In HCM patients, post-contrast myocardial T(1) time correlated with mean E/e' (r = -0.48, p < 0.001). CONCLUSIONS: Patients with HCM have shorter post-contrast myocardial T(1) times, consistent with diffuse myocardial fibrosis, which correlate with estimated LV filling pressure, suggesting a mechanistic link between diffuse myocardial fibrosis and abnormal diastolic function in HCM.
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ItemSphingosine-1-phosphate promotes the differentiation of human umbilical cord mesenchymal stem cells into cardiomyocytes under the designated culturing conditions.(Springer Science and Business Media LLC, 2011-06-07)BACKGROUND: It is of growing interest to develop novel approaches to initiate differentiation of mesenchymal stem cells (MSCs) into cardiomyocytes. The purpose of this investigation was to determine if Sphingosine-1-phosphate (S1P), a native circulating bioactive lipid metabolite, plays a role in differentiation of human umbilical cord mesenchymal stem cells (HUMSCs) into cardiomyocytes. We also developed an engineered cell sheet from these HUMSCs derived cardiomyocytes by using a temperature-responsive polymer, poly(N-isopropylacrylamide) (PIPAAm) cell sheet technology. METHODS: Cardiomyogenic differentiation of HUMSCs was performed by culturing these cells with either designated cardiomyocytes conditioned medium (CMCM) alone, or with 1 μM S1P; or DMEM with 10% FBS + 1 μM S1P. Cardiomyogenic differentiation was determined by immunocytochemical analysis of expression of cardiomyocyte markers and patch clamping recording of the action potential. RESULTS: A cardiomyocyte-like morphology and the expression of α-actinin and myosin heavy chain (MHC) proteins can be observed in both CMCM culturing or CMCM+S1P culturing groups after 5 days' culturing, however, only the cells in CMCM+S1P culture condition present cardiomyocyte-like action potential and voltage gated currents. A new approach was used to form PIPAAm based temperature-responsive culture surfaces and this successfully produced cell sheets from HUMSCs derived cardiomyocytes. CONCLUSIONS: This study for the first time demonstrates that S1P potentiates differentiation of HUMSCs towards functional cardiomyocytes under the designated culture conditions. Our engineered cell sheets may provide a potential for clinically applicable myocardial tissues should promote cardiac tissue engineering research.
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ItemPET imaging of brain inflammation during early epileptogenesis in a rat model of temporal lobe epilepsy.(Springer Science and Business Media LLC, 2012-11-08)BACKGROUND: Recently, inflammatory cascades have been suggested as a target for epilepsy therapy. Positron emission tomography (PET) imaging offers the unique possibility to evaluate brain inflammation longitudinally in a non-invasive translational manner. This study investigated brain inflammation during early epileptogenesis in the post-kainic acid-induced status epilepticus (KASE) model with post-mortem histology and in vivo with [18F]-PBR111 PET. METHODS: Status epilepticus (SE) was induced (N = 13) by low-dose injections of KA, while controls (N = 9) received saline. Translocator protein (TSPO) expression and microglia activation were assessed with [125I]-CLINDE autoradiography and OX-42 immunohistochemistry, respectively, 7 days post-SE. In a subgroup of rats, [18F]-PBR111 PET imaging with metabolite-corrected input function was performed before post-mortem evaluation. [18F]-PBR111 volume of distribution (Vt) in volume of interests (VOIs) was quantified by means of kinetic modelling and a VOI/metabolite-corrected plasma activity ratio. RESULTS: Animals with substantial SE showed huge overexpression of TSPO in vitro in relevant brain regions such as the hippocampus and amygdala (P < 0.001), while animals with mild symptoms displayed a smaller increase in TSPO in amygdala only (P < 0.001). TSPO expression was associated with OX-42 signal but without obvious cell loss. Similar in vivo [18F]-PBR111 increases in Vt and the simplified ratio were found in key regions such as the hippocampus (P < 0.05) and amygdala (P < 0.01). CONCLUSION: Both post-mortem and in vivo methods substantiate that the brain regions important in seizure generation display significant brain inflammation during epileptogenesis in the KASE model. This work enables future longitudinal investigation of the role of brain inflammation during epileptogenesis and evaluation of anti-inflammatory treatments.
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ItemStargazin and AMPA receptor membrane expression is increased in the somatosensory cortex of Genetic Absence Epilepsy Rats from Strasbourg(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2011-04)Absence-like seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model are believed to arise in hyperexcitable somatosensory cortical neurons, however the cellular basis of this increased excitability remains unknown. We have previously shown that expression of the Transmembrane AMPA receptor Regulatory Protein (TARP), stargazin, is elevated in the somatosensory cortex of GAERS. TARPs are critical regulators of the trafficking and function of AMPA receptors. Here we examine the developmental expression of stargazin and the impact this may have on AMPA receptor trafficking in the GAERS model. We show that elevated stargazin in GAERS is associated with an increase in AMPA receptor proteins, GluA1 and GluA2 in the somatosensory cortex plasma membrane of adult epileptic GAERS. Elevated stargazin expression is not seen in the epileptic WAG/Rij rat, which is a genetically distinct but phenotypically similar rat model also manifesting absence seizures, indicating that the changes seen in GAERS are unlikely to be a secondary consequence of the seizures. In juvenile (6 week old) GAERS, at the age when seizures are just starting to be expressed, there is elevated stargazin mRNA, but not protein expression for stargazin or the AMPA receptor subunits. In neonatal (7 day old) pre-epileptic GAERS there was no alteration in stargazin mRNA expression in any brain region examined. These data demonstrate that stargazin and AMPA receptor membrane targeting is altered in GAERS, potentially contributing to hyperexcitability in somatosensory cortex, with a developmental time course that would suggest a pathophysiological role in the epilepsy phenotype.
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ItemRandomised Comparison of the AMBU AuraOnce Laryngeal Mask and the LMA Unique Laryngeal Mask Airway in Spontaneously Breathing Adults(HINDAWI LTD, 2012)We conducted a randomised single-blind controlled trial comparing the LMA-Unique (LMAU) and the AMBU AuraOnce (AMBU) disposable laryngeal mask in spontaneously breathing adult patients undergoing general anaesthesia. Eighty-two adult patients (ASA status I-IV) were randomly allocated to receive the LMAU or AMBU and were blinded to device selection. Patients received a standardized anesthetic and all airway devices were inserted by trained anaesthetists. Size selection was guided by manufacturer recommendations. All data were collected by a single, unblinded observer. When compared with the LMAU, the AMBU produced significantly higher airway sealing pressures (AMBU 20 ± 6; LMAU 15 ± 7 cm H(2)O; P = 0.001). There was no statistical difference between the two devices for overall success rate, insertion time, number of adjustments, laryngeal alignment, blood-staining, and sore throat (P ≥ 0.05). The AMBU AuraOnce disposable laryngeal mask provided a higher oropharyngeal leak pressure compared to the LMA Unique in spontaneously breathing adult patients.
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ItemEndovascular stenting for atherosclerotic subclavian artery stenosis in patients with other craniocervical artery stenosis(SPRINGER, 2013-01)Atherosclerotic subclavian artery stenosis (SAS) accompanied with other craniocervical artery stenosis (OCAS) is not uncommon in practice. We sought to investigate the safety and efficacy of endovascular stenting for SAS in patients with OCAS. Between January 2004 and February 2012, 71 consecutive atherosclerotic SAS patients who underwent primary stenting in our medical center were included. The enrolled patients were divided into combined-SAS group (n = 51) and solitary-SAS group (n = 20) depending on the presence or absence of OCAS. Data of demographics, procedure, and the followed-up were retrieved and analyzed. The technical success rate was 95.8%; the clinical success rate was 90.1%. There was no catheter-related major stroke or death. The immediate outcomes had no statistical difference between groups. During a mean of 27 ± 20 months (range 2-88 months) followed-up, 7 (10.3%) restenosis and 12 (17.6%) clinical events were identified. The primary patency rate was 95.3, 84.9 and 84.9% at 12, 24 months, and final followed-up respectively, which had no statistical difference between groups (odds ratio (OR), 2.60; 95% confidence interval (CI), 0.54-12.53; P = 0.232). The overall clinical event-free survival rate was 93.5, 86.2 and 54.6%, respectively, where the result of combined-SAS group was inferior to that of the solitary-SAS group (OR, 3.34; 95% CI, 1.02-11.00; P = 0.047). Endovascular stenting was safe and feasible for atherosclerotic SAS in patients with OCAS, although the combined OCAS may have a significant influence on the long-term outcome. Further studies are warrant to investigate the effects of revascularization for multiple craniocervical artery stenoses on the cerebral hemodynamics and long-term outcomes.