University General - Research Publications
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Low-dose rituximab and concurrent adjuvant therapy for pemphigus: Protocol and single-centre long-term review of nine patients
Pemphigus is an autoimmune B-cell mediated blistering disease associated with significant morbidity and mortality. Rituximab has proven effective for the treatment of steroid-refractory pemphigus, although there is controversy over the optimum dosing protocol. Additionally, effective disease control often requires long-term immunosuppression, even in disease-free periods. We present a case series of a single-centre long-term follow up of nine patients with pemphigus, treated with two 500-mg doses of rituximab separated by 14 days along with concurrent adjuvant therapy. In all these patients, low-dose rituximab resulted in B-cell depletion, along with a reduction in blistering disease. Three of these patients required repeat dosing cycles due to either relapsed disease or incomplete disease control following the first dosing cycle, and have remained disease free up to 154 weeks thus far. Six patients developed minor infections during the course of their treatment, but no major complications were observed.
Breast milk polyunsaturated fatty acids: associations with adolescent allergic disease and lung function
BACKGROUND: It has been hypothesized that n-3 PUFA in breast milk may assist immune and lung development. There are very limited data on possible long-term effects on allergic disease and lung function. The aim was to investigate associations of n-3 and n-6 PUFA levels in colostrum and breast milk with allergic disease and lung function at ages 12 and 18 years. METHODS: Polyunsaturated fatty acids were measured in 194 colostrum samples and in 118 three-month expressed breast milk samples from mothers of children enrolled in the Melbourne Atopy Cohort (MACS) Study, a high-risk birth cohort study. Associations with allergic diseases, skin prick tests and lung function assessed at 12 and 18 years were estimated using multivariable regression. RESULTS: Higher levels of n-3 but not n-6 PUFAs in colostrum were associated with a trend towards increased odds of allergic diseases, with strong associations observed for allergic rhinitis at 12 (OR = 5.69[95% CI: 1.83,17.60] per weight%) and 18 years (4.43[1.46,13.39]) and eczema at 18 years (9.89[1.44, 68.49]). Higher levels of colostrum n-3 PUFAs were associated with reduced sensitization (3.37[1.18, 9.6]), mean FEV1 (-166 ml [-332, -1]) and FEV1 /FVC ratio (-4.6%, [-8.1, -1.1]) at 12 years. CONCLUSION: Higher levels of colostrum n-3 PUFAs were associated with increased risks of allergic rhinitis and eczema up to 18 years, and sensitization and reduced lung function at 12 years. As residual confounding may have caused these associations, they should be replicated, but these results could indicate that strategies that increase maternal n-3 PUFA intake may not aid in allergic disease prevention.
Beyond the Storm: Comparison of Clinical Factors, Arrhythmogenic Substrate, and Catheter Ablation Outcomes in Structural Heart Disease Patients With versus Those Without a History of Ventricular Tachycardia Storm.
AIMS: Catheter ablation can be lifesaving in ventricular tachycardia (VT) storm, but the underlying substrate in patients with storm is not well characterized. We sought to compare the clinical factors, substrate, and outcomes differences in patients with sustained monomorphic VT who present for catheter ablation with VT storm versus those with a nonstorm presentation. METHODS: Consecutive ischemic (ICM; n = 554) or nonischemic cardiomyopathy patients (NICM; n = 369) with a storm versus nonstorm presentation were studied (ICM storm 186; NICM storm 101). RESULTS: In ICM, storm compared with nonstorm patients had significantly lower left ventricular (LV) ejection fraction (EF), greater number of antiarrhythmic drug (AAD) failures, slower VTs, greater number of scarred LV segments, higher incidence of anterior, septal, and apical endocardial LV scar (all P < 0.05). However, outcomes in follow-up were similar (12-month ventricular arrhythmia [VA]-free survival: 51% vs. 52%, P = 0.6; survival free of death/transplant 75% vs. 87%, P = 0.7). In addition to the above differences, NICM storm patients were also older; however, the extent and distribution of scar was similar except for a higher incidence of lateral endocardial scar in storm patients (P = 0.05). VA-free survival (36% vs. 47%, P = 0.004) and survival free of death/transplant, however, were worse in NICM storm than nonstorm patients (72% vs. 88%, P = 0.001). NICM storm patients had worse VA-free survival than ICM storm patients. CONCLUSION: There are differences in clinical factors and scar patterns in patients undergoing VT ablation who present with VT storm versus those with a nonstorm presentation. Clinical outcomes are worse in NICM storm patients.
Does serelaxin treatment alter passive mechanical wall properties in small resistance arteries?
The peptide hormone relaxin is recognized for its connective tissue remodeling actions in the reproductive tract during pregnancy and parturition, but it also has vascular remodeling actions independent of pregnancy. Recombinant human relaxin (serelaxin) treatment in male and non-pregnant female rodents enhances passive arterial compliance in the renal vasculature. This review focuses on serelaxin's actions on passive mechanical wall properties in small arteries and highlights the diversity of responses to serelaxin treatment in rodents. Different experimental approaches (duration of serelaxin treatment, rat strain, age) and animal models of disease (obesity, hypertension) will be considered. Most studies in young rodents demonstrate that serelaxin treatment fails to alter passive compliance in resistance-size arteries (mesenteric and femoral arteries and cerebral parenchymal arterioles), suggesting that serelaxin's beneficial effects are minimal in healthy animals. Short-term serelaxin treatment (5d) in aged, obese, and spontaneously hypertensive rats (SHRs) is largely without effect on passive mechanical wall properties. However, a longer duration of serelaxin treatment in SHRs (14d) enhances passive compliance in large muscular arteries as well as resistance-size arteries. In conclusion, serelaxin is capable of vascular remodeling. Its actions are vascular bed-dependent, more prominent in disease, and likely requires a longer duration of treatment to be effective.
Sites With Small Impedance Decrease During Catheter Ablation for Atrial Fibrillation Are Associated With Recovery of Pulmonary Vein Conduction
OBJECTIVE: To correlate impedance decrease during atrial fibrillation (AF) ablation with lesion durability and PV conduction recovery demonstrated during redo procedures. BACKGROUND: Markers of successful ablation beyond acute conduction block are needed to improve durability of pulmonary vein (PV) isolation (PVI). Local impedance decrease resulting from ablation is a real-time marker of tissue heating and is correlated with lesion creation. METHODS: Impedance changes associated with point-by-point radiofrequency ablation in the PV antra were recorded during 167 consecutive first-time AF ablations. During clinically indicated redo procedures, sites of recovered PV conduction were identified, and were correlated with the impedance change achieved during ablation at these locations during the initial procedure. RESULTS: Redo procedures were performed in 28 patients, in whom 19 sites of recovered PV conduction were documented. Most sites of PV reconnection (58%) occurred along the posterior PV antra. Ablation resulting in impedance decrease <10 ohms during the initial procedure was present in 89% (17/19) of sites with conduction recovery. Regions with adjacent ablation resulting in impedance decrease <10 ohms were associated with a higher rate of conduction recovery (37% vs. 1.5%, P < 0.001). Likewise, patients with PV conduction recovery demonstrated during redo procedure (Group 1) had larger regions where ablation resulted in <10 ohm impedance decrease than patients without PV conduction recovery (Group 2) (21.9 ± 15.5 mm vs. 11.5 ± 2.1 mm, P < 0.01). CONCLUSION: Recovered PV conduction occurs predominantly in regions where adjacent ablation applications result in impedance decreases <10 ohms. Impedance-guided ablation strategies may improve durability of PVI.
Vascular actions of relaxin: nitric oxide and beyond
The peptide hormone relaxin regulates the essential maternal haemodynamic adaptations in early pregnancy through direct actions on the renal and systemic vasculature. These vascular actions of relaxin occur mainly through endothelium-derived NO-mediated vasodilator pathways and improvements in arterial compliance in small resistance-size arteries. This work catalysed a plethora of studies which revealed quite heterogeneous responses across the different regions of the vasculature, and also uncovered NO-independent mechanisms of relaxin action. In this review, we first describe the role of endogenous relaxin in maintaining normal vascular function, largely referring to work in pregnant and male relaxin-deficient animals. We then discuss the diversity of mechanisms mediating relaxin action in different vascular beds, including the involvement of prostanoids, VEGF, endothelium-derived hyperpolarisation and antioxidant activity in addition to the classic NO-mediated vasodilatory pathway. We conclude the review with current perspectives on the vascular remodelling capabilities of relaxin. LINKED ARTICLES: This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc.
Depression and anger in fathers of unsettled infants: A community cohort study
AIM: To examine the relationship between unsettled infant behaviour and fathers' depressive symptoms, cognitions surrounding infant sleep (anger, doubt), and personal sleep, in a community cohort. METHODS: Data were collected from 102 fathers of healthy infants at 4 weeks, 4 months and 6 months of age. Measures included father report of infant sleep and crying problems, depressive symptoms, cognitions about infant sleep and own sleep quality and quantity. Data were analysed using adjusted regression models. RESULTS: Sleep problems at 4 months of age were associated with increased depressive symptoms (adjusted mean difference 2.64 (1.27-4.00)), doubt (adjusted mean difference 1.82 (0.40-3.25)), anger (adjusted mean difference 1.86 (0.51-3.20)), poor personal sleep quantity (adjusted odds ratio (OR) 0.21; 95% confidence interval (CI) 0.09-0.51) and quality (adjusted OR 0.20; 95% CI 0.08-0.51); and at 6 months of age, with increased depressive symptoms (adjusted mean difference 2.56 (1.28-3.84)), anger (adjusted mean difference 1.63 (0.40-2.87)), poor personal sleep quantity (adjusted OR 0.14; 95% CI 0.05-0.38) and quality (adjusted OR 0.28; 95% CI 0.11-0.72). Infant cry problems at 4 months were associated with increased anger (adjusted mean difference 1.98 (0.60-3.36)) and doubt (adjusted mean difference 1.55 (0.05-3.05)); and at 6 months, with increased depressive symptoms (adjusted mean difference 3.04 (1.59-4.69)), anger (adjusted mean difference 2.73 (1.29-4.17)) and less personal sleep (adjusted OR 0.22; 95% CI 0.07-0.71). CONCLUSION: Fathers of unsettled infants reported greater anger towards their infant and increased depressive symptoms by 4 months infant age, with these symptoms persisting 2 months later. Evidence-based interventions are needed for these fathers.
Human glandular organoid formation in murine engineering chambers after collagenase digestion and flow cytometry isolation of normal human breast tissue single cells
Women with high mammographic density (MD) are at increased risk of breast cancer (BC) after adjustment for age and body mass index. We have developed a murine biochamber model in which both high MD (HMD) and low MD (LMD) tissue can be propagated. Here, we tested whether cells isolated by collagenase digestion and fluorescence-activated cell sorting (FACS) from normal breast can be reconstituted in our biochamber model, which would allow cell-specific manipulations to be tested. Fresh breast tissue was collected from women (n = 7) undergoing prophylactic mastectomy. The tissue underwent collagenase digestion overnight and, in some cases, additional FACS enrichment to obtain mature epithelial, luminal progenitor, mammary stem, and stromal cells. Cells were then transferred bilaterally into biochambers in SCID mice (n = 5-7) and incubated for 6 weeks, before harvesting for histological analyses, and immunohistochemical staining for cytokeratins (CK), vimentin, Ki-67, murine macrophages, and Cleaved Caspase-3. Biochambers inoculated with single cells after collagenase digestion or with flow cytometry contained glandular structures of human origin (human vimentin-positive), which expressed CK-14 and pan-CK, and were proliferating (Ki-67-positive). Glandular structures from the digested tissues were smaller than those in chambers seeded with finely chopped intact mammary tissue. Mouse macrophage infiltration was higher in the chambers arising from digested tissues. Pooled single cells and FACS fractionated cells were viable in the murine biochambers and formed proliferating glandular organoids of human origin. This is among the first report to demonstrate the success of formed human glandular organoids from isolated primary mammary cells in the murine biochamber model.
Cancer beliefs in ethnic minority populations: a review and meta-synthesis of qualitative studies
People from ethnic minorities often experience poorer cancer outcomes, possibly due to later presentation to healthcare and later diagnosis. We aimed to identify common cancer beliefs in minority populations in developed countries, which can affect symptom appraisal and help seeking for symptomatic cancer. Our systematic review found 15 relevant qualitative studies, located in the United Kingdom (six), United States (five), Australia (two) and Canada (two) of African, African-American, Asian, Arabic, Hispanic and Latino minority groups. We conducted a meta-synthesis that found specific emotional reactions to cancer, knowledge and beliefs and interactions with healthcare services as contributing factors in help seeking for a cancer diagnosis. These findings may be useful to inform the development of interventions to facilitate cancer diagnosis in minority populations.
Attitudes and barriers to providing dietary advice: perceptions of dental hygienists and oral health therapists
OBJECTIVES: Effective dietary counselling in a dental setting can significantly reduce the risk of oral disease. However, studies suggest that dental professionals are not instigating dietary advice on a regular basis, and there is a lack of current information of the barriers experienced that limit the delivery of dietary advice. The aim of this study was to investigate the current attitudes and practice behaviours of dental hygienists and oral health therapists in NSW, Australia, regarding dietary advice, and identify the barriers that limit its delivery. METHODS: A convenience sample of dental hygienists and oral health therapists were surveyed using a mail-out questionnaire. The questionnaire investigated the demographic data of participants, the attitudes and practice behaviours of participants, the perceived barriers and current dietary resources accessed by participants. RESULTS: Of 987 dental hygienists and oral health therapists, 426 participants responded. The study results suggest that many dental hygienists and oral health therapists have positive beliefs regarding the importance of dietary counselling. However, there are a multitude of barriers preventing the delivery of dietary advice; these include time, patient compliance, patient knowledge of nutrition topics, personal counselling skills and practitioners' knowledge of nutrition. CONCLUSION: Whilst dental hygienists and oral health therapists recognize the importance of diet and have positive attitudes towards providing dietary advice to patients, this study identified many barriers preventing implementation in practice. This information may be used to develop targeted strategies aimed at overcoming these barriers and improving behaviours.