Medicine (RMH) - Research Publications
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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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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.
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ItemFactors associated with long-term functional outcomes, psychological sequelae and quality of life in persons after primary brain tumour(SPRINGER, 2013-02)To examine factors impacting long-term functional outcomes and psychological sequelae in persons with primary brain tumours (BT) in an Australian community cohort. Participants (n = 106) following definitive treatment for BT in the community were reviewed in rehabilitation clinics to assess impact on participants' current activity and restriction in participation, using validated questionnaires: Functional Independence Measure (FIM), Perceived Impact Problem Profile (PIPP), Depression Anxiety Stress Scale, Cancer Rehabilitation Evaluation System-Short Form and Cancer Survivor Unmet Needs Measure. Mean age of the participants was 51 years (range 21-77 years), majority were female (56 %) with median time since BT diagnosis 2.1 years and a third (39 %) had high grade tumours. Majority showed good functional recovery (median motor FIM score 75). Over half reported pain (56 %), of which 42 % had headaches. Other impairments included: ataxia (44 %), seizures (43 %); paresis (37 %), cognitive dysfunction (36 %) and visual impairment (35 %). About 20 % reported high levels of depression, compared with only 13 % in an Australian normative sample. Two-third (60 %) participants reported highest impact on the PIPP subscales for psychological wellbeing (scores of >3 on 6-point scale) and participation (45 %). Factors significantly associated with poorer current level of functioning and wellbeing included: younger participants (≤40 years), recent diagnoses, aggressive tumour types and presence of pain. No significant differences in scale scores were found across various treatments (surgery, chemotherapy or radiotherapy) on outcomes used. Rehabilitation for BT survivors is challenging and requires long-term management of psychological sequelae impacting activity and participation. More research into participatory limitation is needed to guide treating clinicians.
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ItemAssociations Between Fibrocytes and Postcontrast Myocardial T1 Times in Hypertrophic Cardiomyopathy(WILEY, 2013-10)BACKGROUND: Fibrocytes are bone marrow-derived mesenchymal progenitors that have been linked to various fibrotic disorders. This study was undertaken to investigate whether fibrocytes are increased in diffuse myocardial fibrosis in humans. METHODS AND RESULTS: Thirty-seven patients with hypertrophic cardiomyopathy (HCM) and 20 healthy controls were recruited. Cardiac magnetic resonance imaging with postcontrast T1 mapping was performed to non-invasively quantify diffuse myocardial fibrosis and these patients were classified into 2 groups (T1 < 470 ms or T1 ≥ 470 ms, as likely or unlikely to have diffuse fibrosis, respectively). Circulating fibrocytes (CD45+/CD34+/collagen I+) were measured by flow cytometry. Peripheral blood mononuclear cells (PBMCs) were cultured for 13 days and fibrocytes were quantitated by flow cytometry (CD45+/collagen I+) and real-time PCR (gene expression of matrix proteins). Plasma cytokines/chemokines mediating fibrocyte trafficking and differentiation were measured by multiplex assays. Circulating fibrocytes were decreased in HCM patients compared to controls. The proportion of fibrocytes derived from PBMCs was increased in patients with diffuse fibrosis compared with those without or controls (31.1 ± 4.1% versus 18.9 ± 3.9% and 10.9 ± 2.0%, P < 0.05 and P < 0.001, respectively), and the proportion of fibrocytes was inversely correlated with T1 time (r = -0.37, P = 0.03). Plasma levels of stromal cell-derived factor-1 were elevated in patients with diffuse fibrosis compared with those without or controls (5131 ± 271 pg/mL versus 3893 ± 356 pg/mL and 4172 ± 185 pg/mL, respectively, both P < 0.05). CONCLUSIONS: HCM patients with diffuse fibrosis as assessed by postcontrast T1 mapping have elevated plasma SDF and an enhanced ability of PBMCs to differentiate into fibrocytes, suggesting that fibrocytes may contribute to the pathogenesis of myocardial fibrosis.
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ItemUrocortin protects chondrocytes from NO-induced apoptosis: a future therapy for osteoarthritis?(Springer Science and Business Media LLC, 2013-07-11)Osteoarthritis (OA) is characterized by a loss of joint mobility and pain resulting from progressive destruction and loss of articular cartilage secondary to chondrocyte death and/ or senescence. Certain stimuli including nitric oxide (NO) and the pro-inflammatory cytokine tumor necrosis factor α (TNF-α have been implicated in this chondrocyte death and the subsequent accelerated damage to cartilage. In this study, we demonstrate that a corticotrophin releasing factor (CRF) family peptide, urocortin (Ucn), is produced by a human chondrocyte cell line, C-20/A4, and acts both as an endogenous survival signal and as a cytoprotective agent reducing the induction of apoptosis by NO but not TNF-α when added exogenously. Furthermore, treatment with the NO donor S-nitroso-N-acetyl-D-L-penicillamine upregulates chondrocyte Ucn expression, whereas treatment with TNF-α does not. The chondroprotective effects of Ucn are abolished by both specific ligand depletion (with an anti-Ucn antibody) and by CRF receptor blockade with the pan-CRFR antagonist α-helical CRH(9-41). CRFR expression was confirmed by reverse transcription-PCR with subsequent amplicon sequence analysis and demonstrates that C-20/A4 cells express both CRFR1 and CRFR2, specifically CRFR1α and CRFR2β. Protein expression of these receptors was confirmed by western blotting. The presence of both Ucn and its receptors in these cells, coupled with the induction of Ucn by NO, suggests the existence of an endogenous autocrine/paracrine chondroprotective mechanism against stimuli inducing chondrocyte apoptosis via the intrinsic/mitochondrial pathway.
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ItemComparisons between intragastric and small intestinal delivery of enteral nutrition in the critically ill: a systematic review and meta-analysis(BMC, 2013)INTRODUCTION: The largest cohort of critically ill patients evaluating intragastric and small intestinal delivery of nutrients was recently reported. This systematic review included recent data to compare the effects of small bowel and intragastric delivery of enteral nutrients in adult critically ill patients. METHODS: This is a systematic review of all randomised controlled studies published between 1990 and March 2013 that reported the effects of the route of enteral feeding in the critically ill on clinically important outcomes. RESULTS: Data from 15 level-2 studies were included. Small bowel feeding was associated with a reduced risk of pneumonia (Relative Risk, RR, small intestinal vs. intragastric: 0.75 (95% confidence interval 0.60 to 0.93); P=0.01; I2=11%). The point estimate was similar when only studies using microbiological data were included. Duration of ventilation (weighted mean difference: -0.36 days (-2.02 to 1.30); P=0.65; I2=42%), length of ICU stay (WMD: 0.49 days, (-1.36 to 2.33); P=0.60; I2=81%) and mortality (RR 1.01 (0.83 to 1.24); P=0.92; I2=0%) were unaffected by the route of feeding. While data were limited, and there was substantial statistical heterogeneity, there was significantly improved nutrient intake via the small intestinal route (% goal rate received: 11% (5 to 16%); P=0.0004; I2=88%). CONCLUSIONS: Use of small intestinal feeding may improve nutritional intake and reduce the incidence of ICU-acquired pneumonia. In unselected critically ill patients other clinically important outcomes were unaffected by the site of the feeding tube.
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ItemFuture Directions for Intra-Arterial Therapy for Acute Ischaemic Stroke: Is There Life after Three Negative Randomized Controlled Studies?(KARGER, 2013)BACKGROUND: The three randomised controlled trials, Interventional Management of Stroke III (IMS3), Mechanical Retrieval and Revascularization of Stroke Clots Using Embolectomy (MR RESCUE) and Synthesis Expanasion: A Randomized Controlled Trial on Intra-Arterial Versus Intravenous Thrombolysis in Acute Ischaemic Stroke (SYNTHESIS EXP) showed no significant difference in clinical outcomes comparing intra-arterial (IA) therapy with intravenous thrombolysis. This article will explore the reasons for failure to show superiority of IA therapy. SUMMARY: There are many reasons for the disappointing results of the three randomised controlled trials. Opposing views on IA therapy exist. Critics argue that only a small percentage of patients will be eligible for IA therapy and that it will never be cost-effective. Additionally, current trials have failed to address superior recanalization rates of new generation devices and lack of patient selection by advanced imaging. Time-to-treatment is longer in these randomised controlled trials and stroke outcomes were worse than anticipated. The current randomised controlled trials also took long periods to complete. There is emerging evidence that general anesthetic negatively influences outcome. Next generation trials will attempt to address these issues. Key Messages: There are disparate explanations for the disappointing results from the three IA therapy randomized controlled studies. Poor recanalisation rates with first generation endovascular devices, lack of advanced neuroimaging to aid in patient selection, lack of data surrounding the use of general anaesthesia, and prolonged time-to-treatment are potential contributors to negative results. The new generation of trials has the potential of addressing these pressing issues.
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ItemNo Preview AvailableFine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects(PUBLIC LIBRARY SCIENCE, 2013-11)The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.
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ItemNo Preview AvailableOvercoming Antigenic Diversity by Enhancing the Immunogenicity of Conserved Epitopes on the Malaria Vaccine Candidate Apical Membrane Antigen-1(PUBLIC LIBRARY SCIENCE, 2013-12)Malaria vaccine candidate Apical Membrane Antigen-1 (AMA1) induces protection, but only against parasite strains that are closely related to the vaccine. Overcoming the AMA1 diversity problem will require an understanding of the structural basis of cross-strain invasion inhibition. A vaccine containing four diverse allelic proteins 3D7, FVO, HB3 and W2mef (AMA1 Quadvax or QV) elicited polyclonal rabbit antibodies that similarly inhibited the invasion of four vaccine and 22 non-vaccine strains of P. falciparum. Comparing polyclonal anti-QV with antibodies against a strain-specific, monovalent, 3D7 AMA1 vaccine revealed that QV induced higher levels of broadly inhibitory antibodies which were associated with increased conserved face and domain-3 responses and reduced domain-2 response. Inhibitory monoclonal antibodies (mAb) raised against the QV reacted with a novel cross-reactive epitope at the rim of the hydrophobic trough on domain-1; this epitope mapped to the conserved face of AMA1 and it encompassed the 1e-loop. MAbs binding to the 1e-loop region (1B10, 4E8 and 4E11) were ∼10-fold more potent than previously characterized AMA1-inhibitory mAbs and a mode of action of these 1e-loop mAbs was the inhibition of AMA1 binding to its ligand RON2. Unlike the epitope of a previously characterized 3D7-specific mAb, 1F9, the 1e-loop inhibitory epitope was partially conserved across strains. Another novel mAb, 1E10, which bound to domain-3, was broadly inhibitory and it blocked the proteolytic processing of AMA1. By itself mAb 1E10 was weakly inhibitory but it synergized with a previously characterized, strain-transcending mAb, 4G2, which binds close to the hydrophobic trough on the conserved face and inhibits RON2 binding to AMA1. Novel inhibition susceptible regions and epitopes, identified here, can form the basis for improving the antigenic breadth and inhibitory response of AMA1 vaccines. Vaccination with a few diverse antigenic proteins could provide universal coverage by redirecting the immune response towards conserved epitopes.
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ItemNo Preview AvailableDe novo mutations in epileptic encephalopathies(NATURE PUBLISHING GROUP, 2013-09-12)Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.