Medicine (Austin & Northern Health) - Research Publications
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ItemAn Integrated Multi-Omic Network Analysis Identifies Seizure-Associated Dysregulated Pathways in the GAERS Model of Absence Epilepsy(MDPI, 2022-06-01)Absence epilepsy syndromes are part of the genetic generalized epilepsies, the pathogenesis of which remains poorly understood, although a polygenic architecture is presumed. Current focus on single molecule or gene identification to elucidate epileptogenic drivers is unable to fully capture the complex dysfunctional interactions occurring at a genetic/proteomic/metabolomic level. Here, we employ a multi-omic, network-based approach to characterize the molecular signature associated with absence epilepsy-like phenotype seen in a well validated rat model of genetic generalized epilepsy with absence seizures. Electroencephalographic and behavioral data was collected from Genetic Absence Epilepsy Rats from Strasbourg (GAERS, n = 6) and non-epileptic controls (NEC, n = 6), followed by proteomic and metabolomic profiling of the cortical and thalamic tissue of rats from both groups. The general framework of weighted correlation network analysis (WGCNA) was used to identify groups of highly correlated proteins and metabolites, which were then functionally annotated through joint pathway enrichment analysis. In both brain regions a large protein-metabolite module was found to be highly associated with the GAERS strain, absence seizures and associated anxiety and depressive-like phenotype. Quantitative pathway analysis indicated enrichment in oxidative pathways and a downregulation of the lysine degradation pathway in both brain regions. GSTM1 and ALDH2 were identified as central regulatory hubs of the seizure-associated module in the somatosensory cortex and thalamus, respectively. These enzymes are involved in lysine degradation and play important roles in maintaining oxidative balance. We conclude that the dysregulated pathways identified in the seizure-associated module may be involved in the aetiology and maintenance of absence seizure activity. This dysregulated activity could potentially be modulated by targeting one or both central regulatory hubs.
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ItemCommon risk variants for epilepsy are enriched in families previously targeted for rare monogenic variant discovery.(Elsevier BV, 2022-07)BACKGROUND: The epilepsies are highly heritable conditions that commonly follow complex inheritance. While monogenic causes have been identified in rare familial epilepsies, most familial epilepsies remain unsolved. We aimed to determine (1) whether common genetic variation contributes to familial epilepsy risk, and (2) whether that genetic risk is enriched in familial compared with non-familial (sporadic) epilepsies. METHODS: Using common variants derived from the largest epilepsy genome-wide association study, we calculated polygenic risk scores (PRS) for patients with familial epilepsy (n = 1,818 from 1,181 families), their unaffected relatives (n = 771), sporadic patients (n = 1,182), and population controls (n = 15,929). We also calculated separate PRS for genetic generalised epilepsy (GGE) and focal epilepsy. Statistical analyses used mixed-effects regression models to account for familial relatedness, sex, and ancestry. FINDINGS: Patients with familial epilepsies had higher epilepsy PRS compared to population controls (OR 1·20, padj = 5×10-9), sporadic patients (OR 1·11, padj = 0.008), and their own unaffected relatives (OR 1·12, padj = 0.01). The top 1% of the PRS distribution was enriched 3.8-fold for individuals with familial epilepsy when compared to the lowest decile (padj = 5×10-11). Familial PRS enrichment was consistent across epilepsy type; overall, polygenic risk was greatest for the GGE clinical group. There was no significant PRS difference in familial cases with established rare variant genetic etiologies compared to unsolved familial cases. INTERPRETATION: The aggregate effects of common genetic variants, measured as polygenic risk scores, play an important role in explaining why some families develop epilepsy, why specific family members are affected while their relatives are not, and why families manifest specific epilepsy types. Polygenic risk contributes to the complex inheritance of the epilepsies, including in individuals with a known genetic etiology. FUNDING: National Health and Medical Research Council of Australia, National Institutes of Health, American Academy of Neurology, Thomas B and Jeannette E Laws McCabe Fund, Mirowski Family Foundation.
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ItemStandards for practical intravenous rapid drug desensitization & delabeling: A WAO committee statement.(Elsevier BV, 2022-06)Drug hypersensitivity reactions (DHRs) to intravenous drugs can be severe and might leave patients and doctors in a difficult position where an essential treatment or intervention has to be suspended. Even if virtually any intravenous medication can potentially trigger a life-threatening DHR, chemotherapeutics, biologics, and antibiotics are amongst the intravenous drugs most frequently involved in these reactions. Admittedly, suspending such treatments may negatively impact the survival outcomes or the quality of life of affected patients. Delabeling pathways and rapid drug desensitization (RDD) can help reactive patients stay on first-choice therapies instead of turning to less efficacious, less cost-effective, or more toxic alternatives. However, these are high-complexity and high-risk techniques, which usually need expert teams and allergy-specific techniques (skin testing, in vitro testing, drug provocation testing) to ensure safety, an accurate diagnosis, and personalized management. Unfortunately, there are significant inequalities within and among countries in access to allergy departments with the necessary expertise and resources to offer these techniques and tackle these DHRs optimally. The main objective of this consensus document is to create a great benefit for patients worldwide by aiding allergists to expand the scope of their practice and support them with evidence, data, and experience from leading groups from around the globe. This statement of the Drug Hypersensitivity Committee of the World Allergy Organization (WAO) aims to be a comprehensive practical guide on the technical aspects of implementing acute-onset intravenous hypersensitivity delabeling and RDD for a wide range of drugs. Thus, the manuscript does not only focus on clinical pathways. Instead, it also provides guidance on topics usually left unaddressed, namely, internal validation, continuous quality improvement, creating a healthy multidisciplinary environment, and redesigning care (including a specific supplemental section on a real-life example of how to design a dedicated space that can combine basic and complex diagnostic and therapeutic techniques in allergy).
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ItemChildren at onset of type 1 diabetes show altered N-glycosylation of plasma proteins and IgG(SPRINGER, 2022-05-27)AIMS/HYPOTHESIS: Individual variation in plasma N-glycosylation has mainly been studied in the context of diabetes complications, and its role in type 1 diabetes onset is largely unknown. Our aims were to undertake a detailed characterisation of the plasma and IgG N-glycomes in patients with recent onset type 1 diabetes, and to evaluate their discriminative potential in risk assessment. METHODS: In the first part of the study, plasma and IgG N-glycans were chromatographically analysed in a study population from the DanDiabKids registry, comprising 1917 children and adolescents (0.6-19.1 years) who were newly diagnosed with type 1 diabetes. A follow-up study compared the results for 188 of these participants with those for their 244 unaffected siblings. Correlation of N-glycan abundance with the levels and number of various autoantibodies (against IA-2, GAD, ZnT8R, ZnT8W), as well as with sex and age at diagnosis, were estimated by using general linear modelling. A disease predictive model was built using logistic mixed-model elastic net regression, and evaluated using a 10-fold cross-validation. RESULTS: Our study showed that onset of type 1 diabetes was associated with an increase in the proportion of plasma and IgG high-mannose and bisecting GlcNAc structures, a decrease in monogalactosylation, and an increase in IgG disialylation. ZnT8R autoantibody levels were associated with higher IgG digalactosylated glycan with bisecting GlcNAc. Finally, an increase in the number of autoantibodies (which is a better predictor of progression to overt diabetes than the level of any individual antibody) was accompanied by a decrease in the proportions of some of the highly branched plasma N-glycans. Models including age, sex and N-glycans yielded notable discriminative power between children with type 1 diabetes and their healthy siblings, with AUCs of 0.915 and 0.869 for addition of plasma and IgG N-glycans, respectively. CONCLUSIONS/INTERPRETATION: We defined N-glycan changes accompanying onset of type 1 diabetes, and developed a predictive model based on N-glycan profiles that could have valuable potential in risk assessment. Increasing the power of tests to identify individuals at risk of disease development would be a considerable asset for type 1 diabetes prevention trials.
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ItemFunctional correlates of clinical phenotype and severity in recurrent SCN2A variants(NATURE PORTFOLIO, 2022-05-30)In SCN2A-related disorders, there is an urgent demand to establish efficient methods for determining the gain- (GoF) or loss-of-function (LoF) character of variants, to identify suitable candidates for precision therapies. Here we classify clinical phenotypes of 179 individuals with 38 recurrent SCN2A variants as early-infantile or later-onset epilepsy, or intellectual disability/autism spectrum disorder (ID/ASD) and assess the functional impact of 13 variants using dynamic action potential clamp (DAPC) and voltage clamp. Results show that 36/38 variants are associated with only one phenotypic group (30 early-infantile, 5 later-onset, 1 ID/ASD). Unexpectedly, we revealed major differences in outcome severity between individuals with the same variant for 40% of early-infantile variants studied. DAPC was superior to voltage clamp in predicting the impact of mutations on neuronal excitability and confirmed GoF produces early-infantile phenotypes and LoF later-onset phenotypes. For one early-infantile variant, the co-expression of the α1 and β2 subunits of the Nav1.2 channel was needed to unveil functional impact, confirming the prediction of 3D molecular modeling. Neither DAPC nor voltage clamp reliably predicted phenotypic severity of early-infantile variants. Genotype, phenotypic group and DAPC are accurate predictors of the biophysical impact of SCN2A variants, but other approaches are needed to predict severity.
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ItemCirculating Soluble ACE2 Plays an Independent Role to Protect against Vascular Damage in Diabetic Mice(MDPI, 2022-05-01)Circulating levels of soluble ACE2 are increased by diabetes. Although this increase is associated with the presence and severity of cardiovascular disease, the specific role of soluble ACE2 in atherogenesis is unclear. Previous studies suggested that, like circulating ACE, soluble ACE2 plays a limited role in vascular homeostasis. To challenge this hypothesis, we aimed to selectively increase circulating ACE2 and measure its effects on angiotensin II dependent atherogenesis. Firstly, in Ace2/ApoE DKO mice, restoration of circulating ACE2 with recombinant murine soluble (rmACE219-613; 1 mg/kg/alternate day IP) reduced plaque accumulation in the aortic arch, suggesting that the phenotype may be driven as much by loss of soluble ACE2 as the reduction in local ACE2. Secondly, in diabetic ApoE KO mice, where activation of the renin angiotensin system drives accelerated atherosclerosis, rmACE219-613 also reduced plaque accumulation in the aorta after 6 weeks. Thirdly, to ensure consistent long-term delivery of soluble ACE2, an intramuscular injection was used to deliver a DNA minicircle encoding ACE219-613. This strategy efficiently increased circulating soluble ACE2 and reduced atherogenesis and albuminuria in diabetic ApoE KO mice followed for 10 weeks. We propose that soluble ACE2 has independent vasculoprotective effects. Future strategies that increase soluble ACE2 may reduce accelerated atherosclerosis in diabetes and other states in which the renin angiotensin system is upregulated.
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ItemMas-related G protein-coupled receptor type D antagonism improves portal hypertension in cirrhotic rats(JOHN WILEY & SONS LTD, 2022-05-20)Splanchnic vasodilatation contributes to the development and aggravation of portal hypertension (PHT). We previously demonstrated that in cirrhosis, angiotensin- mediates splanchnic vasodilatation through the Mas receptor (MasR). In this study, we investigated whether the recently characterized second receptor for angiotensin-(1-7), Mas-related G protein-coupled receptor type D (MrgD), contributes to splanchnic vasodilatation in cirrhotic and noncirrhotic PHT. Splanchnic vascular hemodynamic and portal pressure were determined in two rat models of cirrhotic PHT and a rat model with noncirrhotic PHT, treated with either MrgD blocker D-Pro7 -Ang-(1-7) (D-Pro) or MasR blocker A779. Gene and protein expression of MrgD and MasR were measured in splanchnic vessels and livers of cirrhotic and healthy rats and in patients with cirrhosis and healthy subjects. Mesenteric resistance vessels isolated from cirrhotic rats were used in myographs to study their vasodilatory properties. MrgD was up-regulated in cirrhotic splanchnic vessels but not in the liver. In cirrhotic rats, treatment with D-Pro but not A779 completely restored splanchnic vascular resistance to a healthy level, resulting in a 33% reduction in portal pressure. Mesenteric vessels pretreated with D-Pro but not with A779 failed to relax in response to acetylcholine. There was no splanchnic vascular MrgD or MasR up-regulation in noncirrhotic PHT; thus, receptor blockers had no effect on splanchnic hemodynamics. Conclusion: MrgD plays a major role in the development of cirrhotic PHT and is a promising target for the development of novel therapies to treat PHT in cirrhosis. Moreover, neither MrgD nor MasR contributes to noncirrhotic PHT.
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ItemNF-kappa B-inducing kinase (NIK) is activated in pancreatic beta-cells but does not contribute to the development of diabetes(SPRINGERNATURE, 2022-05-19)The transcription factor nuclear factor-κB (NF-κB) has a key role in the pathogenesis of diabetes and its complications. Although activation of the canonical NF-κB pathway in β-cells is generally deleterious, little is known about the role of the non-canonical NF-κB signalling and its main regulator, the NF-κB-inducing kinase (NIK), on pancreatic β-cell survival and function. Previous studies based on models of NIK overexpression in pancreatic islet cells showed that NIK induced either spontaneous β-cell death due to islet inflammation or glucose intolerance during diet-induced obesity (DIO) in mice. Therefore, NIK has been proposed as a potential target for diabetes therapy. However, no clear studies showed whether inhibition of NIK improves diabetes development. Here we show that genetic silencing of NIK in pancreatic β-cells neither modifies diabetes incidence nor inflammatory responses in a mouse model of immune-mediated diabetes. Moreover, NIK silencing in DIO mice did not influence body weight gain, nor glucose metabolism. In vitro studies corroborated the in vivo findings in terms of β-cell survival, function, and downstream gene regulation. Taken together, our data suggest that NIK activation is dispensable for the development of diabetes.
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ItemEffects of low-dose oral micronised progesterone on sleep, psychological distress, and breast development in transgender individuals undergoing feminising hormone therapy: a prospective controlled study(BIOSCIENTIFICA LTD, 2022-05-01)Objective: The role of micronised progesterone in hormone regimens for transgender individuals undergoing feminising hormone therapy remains uncertain. We aimed to determine the effect of oral micronised progesterone on sleep quality, psychological distress, and breast development in transgender individuals undergoing feminising hormone therapy. Design: Prospective case-control study. Twenty-three transgender individuals on stable oestradiol treatment newly commencing 100 mg oral progesterone (n = 23) and controls continuing standard care (n = 19) were assessed over 3 months. Methods: Pittsburgh Sleep Quality Index (PSQI), Kessler psychological distress scale (K10), and Tanner stage to assess breast development were assessed at 0 and 3 months. Non-parametric analysis of covariance was used to compare differences between groups. Results: Compared with controls over 3 months, there was no difference in PSQI (P = 0.35), K10 (P = 0.64), or Tanner stage (P = 0.42). There was no significant difference in the proportion of individuals with clinically significant improvement in PSQI (25% vs 22%, P = 0.84). One individual had a significant deterioration in psychological distress that improved following the cessation of progesterone. Conclusions: Low-dose progesterone was not associated with changes in sleep quality, psychological distress, or breast development over 3 months follow-up, though there was significant inter-individual variability. Larger, placebo-controlled trials are required to further evaluate different doses of progesterone in feminising hormone therapy regimens.
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ItemMedicines for long-term obesity management.(NPS MedicineWise, 2022-04)Obesity is always genetic or epigenetic in origin in an obesogenic environment. Dietary therapy is required for weight loss. Drugs to suppress hunger and increase satiety may assist while losing weight and are essential for most patients in the weight maintenance period. A combination of drugs may be needed. A personalised approach must be used when selecting the appropriate weight loss drug for the patient. This considers possible contraindications, the method of administration and adverse effects, and includes discussing the cost of the treatment. Several drugs do not have an approved indication in Australia for weight loss.