Medicine (RMH) - Research Publications
Now showing items 1-12 of 787
Investigating well-being, work limitations and preferences for self-management education and peer support among younger people with hip and knee osteoarthritis: protocol for a cross-sectional study
(BMJ PUBLISHING GROUP, 2013-12-01)
Introduction: Osteoarthritis (OA) has traditionally been considered a condition of older age. However, younger people are also affected by hip and knee OA, often as a result of sporting and work-related injuries. As OA studies have generally focused on older individuals, little is known about the experience of younger adults with hip or knee OA who can face a distinct set of pressures including work responsibilities and parenting roles. This study aims to investigate well-being and work participation among younger people with hip or knee OA, as well as preferences for OA education and support.Methods and analysis: 200 people aged 2055 years with a diagnosis of hip and/or knee OA will be recruited for this cross-sectional study. Participants will be recruited from three major public hospitals in the state of Victoria, Australia following screening of orthopaedic outpatient clinic lists and referrals, and through community-based advertisements. A study questionnaire will be mailed to all participants and written informed consent obtained. Validated measures of Health-Related Quality of Life (HRQoL), health status, psychological distress and work limitations will be used. Information on health services use will be collected, in addition to information on the perceived utility and accessibility of a range of existing and proposed education and peer support models. HRQoL data will be compared with Australian population norms using independent t tests, and associations between HRQoL, health status, psychological distress, work limitations and demographic factors will be evaluated using univariate and multivariate analyses. Data on the perceived utility and accessibility of education and peer support models will be analysed descriptively.Ethics and dissemination: Ethics approval for the study has been obtained. The study findings will be submitted to peer-reviewed journals and arthritis consumer organisations for broader dissemination, and presented at national and international scientific meetings.
Left Septal Atrial Tachycardias: Electrocardiographic and Electrophysiologic Characterization of a Paraseptal Focus
Left Septal Atrial Tachycardias.Objective: The objective was to characterize the electrocardiographic and electrophysiological features of focal atrial tachycardia (FAT) originating from the left septum (LS). Background: FAT is recognized to occur at predefined anatomic locations rather than randomly throughout the atria. We describe the ECG and EP features of ATs originating from the LS as an important site for apparent perinodal tachycardias. Methods: Nine patients presenting with LS FAT from a consecutive series of 384 underwent EP/RFA for symptomatic FAT. Results: The mean age was 56 +/- 12 years; 7 female with symptoms for 36 +/- 28 months. P wave morphology (PWM) was negative/positive in lead V1 and across the precordial leads and negative or negative/positive in inferior leads in all patients. Tachycardia was incessant in 6 out of 9 patients with a mean tachycardia cycle length 421 +/- 56 milliseconds. His A was ahead of P wave in all patients (mean 15 +/- 5 milliseconds) and earlier than CS proximal (mean 4 +/- 9 milliseconds). Successful acute focal ablation achieved at a mean of 31 +/- 12 milliseconds ahead of P wave with no recurrences at a mean follow-up of 30 +/- 28 months. Conclusion: Although the left septum is an uncommon site for focal AT an awareness of this location for harboring foci is particularly important when mapping apparently right-sided septal tachycardias. (J Cardiovasc Electrophysiol, Vol. 24, pp. 413-418, April 2013)
Anti-EGFR therapeutic efficacy correlates directly with inhibition of STAT3 activity
(LANDES BIOSCIENCE, 2014-05-27)
Several agents targeting the epidermal growth factor receptor (EGFR) have been FDA-approved to treat cancer patients with varying tumor types including metastatic colorectal cancer. Many patients treated with anti-EGFR therapy however do not respond and those that do initially respond often acquire resistance. Here we show a clear correlation between the efficacy of anti-EGFR inhibitors with their ability to inhibit STAT3 activity in A431 epidermoid carcinoma cells and in a series of wt K-RAS expressing human colon cancer cell lines. Furthermore, the ability of cetuximab to inhibit growth also correlated with its ability to inhibit STAT3 activity in tumor xenograft animal studies. In addition, stable knockdown of the STAT3 phosphatase, protein tyrosine phosphatase receptor delta (PTPRD) resulted in enhanced STAT3 activity and subsequent resistance to cetuximab in DIFI colon carcinoma cells. This resistance could be reversed by STAT3 inhibition. Finally, HN5 cells with acquired resistance to the EGFR tyrosine kinase inhibitor, AG1478 displayed greater STAT3 activity than the HN5 control cell line. These AG1478-refractory HN5 cells were re-sensitized to AG1478, cetuximab and erlotinib when co-treated with a STAT3 inhibitor. Taken together, our current data indicates a key role of STAT3 activity in promoting resistance to anti-EGFR therapy and suggests that anti-EGFR therapy in combination with inhibitors that block STAT3 may provide therapeutic benefit for patients with mCRC and other EGFR driven tumor types.
Insight Into the Pathogenesis of Fetal Growth Restriction in Placental Malaria: Decreased Placental Glucose Transporter Isoform 1 Expression
(OXFORD UNIV PRESS INC, 2014-05-27)
Placental malaria, especially when complicated with intervillositis, can cause fetal growth restriction. Transplacental glucose transport by glucose transporter isoform 1 (GLUT-1) on the syncytiotrophoblast microvillous and basal plasma membranes regulates fetal growth. We found that GLUT-1 expression in the microvillous plasma membrane of Plasmodium falciparum-negative placenta biopsy specimens was comparable to that in P. falciparum-positive placenta biopsy specimens with or without intervillositis, whereas GLUT-1 expression in the basal plasma membrane was lowest in P. falciparum-positive placenta biopsy specimens with intervillositis, compared with the other 2 specimen types (P = .0016). GLUT-1 expression in the basal plasma membrane also correlated negatively with monocyte infiltrate density (r = -0.43; P = .003) and positively with birth weight (r = 0.28; P = .06). These findings suggest that intervillositis, more than placental malaria per se, might cause fetal growth restriction, through impaired transplacental glucose transport.
Ethosuximide reduces epileptogenesis and behavioral comorbidity in the GAERS model of genetic generalized epilepsy
Purpose Ethosuximide (ESX) is a drug of choice for the symptomatic treatment of absence seizures. Chronic treatment with ESX has been reported to have disease-modifying antiepileptogenic activity in the WAG/Rij rat model of genetic generalized epilepsy (GGE) with absence seizures. Here we examined whether chronic treatment with ESX (1) possesses antiepileptogenic effects in the genetic absence epilepsy rats from Strasbourg (GAERS) model of GGE, (2) is associated with a mitigation of behavioral comorbidities, and (3) influences gene expression in the somatosensory cortex region where seizures are thought to originate. Methods GAERS and nonepileptic control (NEC) rats were chronically treated with ESX (in drinking water) or control (tap water) from 3 to 22weeks of age. Subsequently, all animals received tap water only for another 12weeks to assess enduring effects of treatment. Seizure frequency and anxiety-like behaviors were serially assessed throughout the experimental paradigm. Treatment effects on the expression of key components of the epigenetic molecular machinery, the DNA methyltransferase enzymes, were assessed using quantitative polymerase chain reaction (qPCR). Key Findings ESX treatment significantly reduced seizures in GAERS during the treatment phase, and this effect was maintained during the 12-week posttreatment phase (p<0.05). Furthermore, the anxiety-like behaviors present in GAERS were reduced by ESX treatment (p<0.05). Molecular analysis revealed that ESX treatment was associated with increased expression of DNA methyltransferase enzyme messenger RNA (mRNA) in cortex. Significance Chronic ESX treatment has disease-modifying effects in the GAERS model of GGE, with antiepileptogenic effects against absence seizures and mitigation of behavioral comorbidities. The cellular mechanism for these effects may involve epigenetic modifications.
Peripheral Blood Mononuclear Cells Derived from Grand Multigravidae Display a Distinct Cytokine Profile in Response to P. falciparum Infected Erythrocytes
(PUBLIC LIBRARY SCIENCE, 2014)
Immunopathology of placental malaria is most significant in women in their first pregnancy especially in endemic areas, due to a lack of protective immunity to Plasmodium falciparum, which is acquired in successive pregnancies. In some studies (but not all), grand multigravidae (defined as 5 or more pregnancies, G5-7) are more susceptible to poor birth outcomes associated with malaria compared to earlier gravidities. By comparing peripheral cellular responses in primigravidae (G1), women in their second to fourth pregnancy (G2-4) and grand multigravidae we sought to identify key components of the dysregulated immune response. PBMC were exposed to CS2-infected erythrocytes (IE) opsonised with autologous plasma or unopsonised IE, and cytokine and chemokine secretion was measured. Higher levels of opsonising antibody were present in plasma derived from multigravid compared to primigravid women. Significant differences in the levels of cytokines and chemokines secreted in response to IE were observed. Less IL-10, IL-1 beta, IL-6 and TNF but more CXCL8, CCL8, IFN gamma and CXCL10 were detected in G5-7 compared to G2-4 women. Our study provides fresh insight into the modulation of peripheral blood cell function and effects on the balance between host protection and immunopathology during placental malaria infection.
Does Malaria Affect Placental Development? Evidence from In Vitro Models
(PUBLIC LIBRARY SCIENCE, 2013)
Background: Malaria in early pregnancy is difficult to study but has recently been associated with fetal growth restriction (FGR). The pathogenic mechanisms underlying malarial FGR are poorly characterized, but may include impaired placental development. We used in vitro methods that model migration and invasion of placental trophoblast into the uterine wall to investigate whether soluble factors released into maternal blood in malaria infection might impair placental development. Because trophoblast invasion is enhanced by a number of hormones and chemokines, and is inhibited by pro-inflammatory cytokines, many of which are dysregulated in malaria in pregnancy, we further compared concentrations of these factors in blood between malaria-infected and uninfected pregnancies.Methodology/Principal Findings: We measured trophoblast invasion, migration and viability in response to treatment with serum or plasma from two independent cohorts of Papua New Guinean women infected with Plasmodium falciparum or Plasmodium vivax in early pregnancy. Compared to uninfected women, serum and plasma from women with P. falciparum reduced trophoblast invasion (P = .06) and migration (P = .004). P. vivax infection did not alter trophoblast migration (P = .64). The P. falciparum-specific negative effect on placental development was independent of trophoblast viability, but associated with high-density infections. Serum from P. falciparum infected women tended to have lower levels of trophoblast invasion promoting hormones and factors and higher levels of invasion-inhibitory inflammatory factors.Conclusion/Significance: We demonstrate that in vitro models of placental development can be adapted to indirectly study the impact of malaria in early pregnancy. These infections could result in impaired trophoblast invasion with reduced transformation of maternal spiral arteries due to maternal hormonal and inflammatory disturbances, which may contribute to FGR by limiting the delivery of maternal blood to the placenta. Future prevention strategies for malaria in pregnancy should include protection in the first half of pregnancy.
Access to self-management education, conservative treatment and surgery for arthritis according to socioeconomic status
There is now a considerable body of research investigating inequities in access to health care for arthritis according to socioeconomic status (SES). Conducted in a range of settings internationally, studies have examined specific socioeconomic factors (including education, income, deprivation and health insurance status) in relation to access to treatment. This chapter provides a comprehensive review of the available evidence on disparities in access to self-management education, conservative therapy and surgical treatment for arthritis, according to SES. There is some evidence of SES disparities in access to self-management education and advice, primary care, specialist care, physical therapy and medications, and strong evidence that people with less education or lower income experience significant disparities in access to joint replacement surgery. In view of research indicating that disparities may adversely affect patient outcomes, examples of initiatives designed to optimise access to care for disadvantaged groups are also described.
Challenges in evaluating an arthritis self-management program for people with hip and knee osteoarthritis in ‘real world’ clinical settings
(Journal of Rheumatology Publishing Company Limited, 2012)
Objective: To evaluate the influence of a 6-week Arthritis Self-Management Program (ASMP) on health-related quality of life (HRQOL) and self-management skills in clinical settings. Methods: Individuals with hip or knee osteoarthritis referred to orthopedic surgeons or rheumatologists at 6 hospitals in Victoria, Australia, were recruited. In a randomized controlled trial, participants received the Stanford ASMP and self-help book (intervention) or book only (control). Assessments included the Assessment of Quality of Life instrument (AQoL; range –0.04 to 1.00) and Health Education Impact Questionnaire (heiQ; range 1–6) at baseline and up to 12 months. The primary outcome was HRQOL at 12 months (assessed using the AQoL). Results: Recruitment was concluded early due to persistent challenges including infrequent referrals and patient inability or disinterest in participating. Of 1125 individuals screened, only 120 were randomized (control, n = 62; intervention, n = 58). Seven ASMP were conducted while 18 scheduled ASMP were cancelled. Forty-four of 58 intervention group participants received the intervention as allocated (76%); all control group participants were sent the book (100%). Ninety-four participants (78%) completed 12-month assessments (control, 90%; intervention, 66%). There was no difference in HRQOL at 12 months (adjusted mean difference –0.02, 95% CI –0.09 to 0.05). At 6 weeks, the intervention group reported higher heiQ skill and technique acquisition scores (adjusted mean difference 0.29, 95% CI 0.04 to 0.55); however, this dissipated by 3 months. Conclusion: Significant challenges hampered this evaluation of the ASMP. The observed lack of enthusiasm from potential referrers and patients raises doubts about the practicality of this intervention in real-world settings.
Obesity and increased burden of hip and knee joint disease in Australia: results from a national survey
(Biomed Central, 2012)
Background: Research involving more representative samples is needed to extend our understanding of the broader impact of obesity in hip or knee joint disease (arthritis and OA) beyond clinical settings. Although population-based research has been conducted in the United States, how these findings translate to other countries is unclear. Using a national approach, this study explored associations between obesity and the burden of hip and knee joint disease in Australia (in terms of prevalence, pain, stiffness, function, Health-Related Quality of Life (HRQoL) and disease severity). Methods: A random sample of 5000 Australians (≥39 years) from the federal electoral roll was invited to complete a mailed questionnaire to identify doctor-diagnosed hip arthritis, hip OA, knee arthritis and knee OA and evaluate the burden of these conditions. Validated questionnaires included the WOMAC Index, Assessment of Quality of Life instrument and Multi Attribute Prioritisation Tool. Body Mass Index (BMI) was classified into underweight/normal weight (≤24.99 kg/m2), overweight (25–29.99) or obese (≥30). Multiple logistic regression was used to estimate odds of arthritis and OA, with demographic and socioeconomic variables included in the models. Associations between BMI and other variables were investigated using analysis of covariance, with adjustment for age and sex. Results: Data were available from 1,157 participants (23%). Overweight participants had increased odds of knee arthritis (adjusted OR (AOR) 1.87, 95%CI 1.14-3.07) and knee OA (AOR 2.11, 95%CI 1.07-4.15). Obesity was associated with higher prevalence of hip arthritis (AOR 2.18, 95%CI 1.17-4.06), knee arthritis (AOR 5.47, 95%CI 3.35-8.95) and knee OA (AOR 7.35, 95%CI 3.85-14.02). Of those with arthritis or OA, obese individuals reported more pain (for hip arthritis, hip OA and knee OA), greater stiffness (for hip arthritis, knee arthritis and knee OA), worse function (all diagnoses), lower HRQoL (for hip arthritis and hip OA) and greater disease severity (all diagnoses). Conclusions: This national study has demonstrated that the odds of arthritis and OA was up to 7 times higher for obese individuals, compared with those classified as underweight/normal weight. Concurrent obesity and joint disease had a marked impact on several key aspects of wellbeing, highlighting the need for public health interventions.
Risk of relapse phenotype recurrence in multiple sclerosis
Objectives: To analyse risk of relapse phenotype recurrence in MS and to characterise the effect of demographic and clinical features on this phenotype. Methods: Information about relapses was collected using MSBase, an international observational registry. Associations between relapse phenotypes and history of similar relapses or patient characteristics were tested with multivariable logistic regression models. Tendency of relapse phenotypes to recur sequentially was assessed with principal component analysis. Results: Among 14,969 eligible patients (89,949 patient-years), 49,279 phenotypically characterised relapses were recorded. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were more frequent in early or non-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women presented more often with sensory or visual symptoms. Men were more prone to pyramidal, brainstem and cerebellar relapses. Importantly, relapse phenotype was predicted by the phenotypes of previous relapses. (OR=1.8-5, p=10-14). Sensory, visual and brainstem relapses showed better recovery than other relapse phenotypes. Relapse severity increased and the ability to recover decreased with age or more advanced disease. Conclusion: Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance.