Metallothionein-I/II expression associates with the astrocyte DNA damage response and not Alzheimer-type pathology in the ageing brain

Oxidative stress and oxidative DNA damage are early features of mild cognitive impairment and Alzheimer’s disease (AD), occurring before the formation of classical AD neuropathology, and resulting from an imbalance between pro- and anti-oxidants. Astrocytes play a major neuroprotective role, producing high levels of anti-oxidants including metallothionein-I and –II (MT-I/II). In the present study we characterized the immunoreactive profile of MT-I/II in the temporal cortex of the Cognitive Function and Ageing Study (CFAS) aging population-representative neuropathology cohort, and examined H2O2-modulation of MT transcription by human astrocytes. MT-I/II is primarily expressed by astrocytes in the aging brain, but is also associated with pyramidal neurons in a small proportion of cases. Astrocyte expression of MT-I/II does not correlate with Alzheimer-type pathology (Aβ plaques and neurofibrillary tangles) but does relate to astrocyte oxidative DNA damage (rs= 0.312, p= 0.006) and the astrocyte response to oxidative DNA damage in vivo (rs= 0.238, p= 0.04), and MT gene expression is significantly induced in human astrocytes response to oxidative stress in vitro (p=0.01). In contrast, neuronal MT-I/II does not relate to oxidative DNA damage or the neuronal DNA damage response, but is significantly higher in cases with high levels of local tangle pathology (p=0.007). As MT-I/II is neuroprotective against oxidative stress, modulation of MT-I/II expression is a potential therapeutic target to treat the onset and progression of cognitive impairment

Psychosocial Assessment of Candidates for Transplantation (PACT) Score Identifies High Risk Patients in Pediatric Renal Transplantation

Background: Currently, there is no standardized approach for determining psychosocial readiness in pediatric transplantation. We examined the utility of the Psychosocial Assessment of Candidates for Transplantation (PACT) to identify pediatric kidney transplant recipients at risk for adverse clinical outcomes.Methods: Kidney transplant patients <21-years-old transplanted at Duke University Medical Center between 2005 and 2015 underwent psychosocial assessment by a social worker with either PACT or unstructured interview, which were used to determine transplant candidacy. PACT assessed candidates on a scale of 0 (poor candidate) to 4 (excellent candidate) in areas of social support, psychological health, lifestyle factors, and understanding. Demographics and clinical outcomes were analyzed by presence or absence of PACT and further characterized by high (≥3) and low (≤2) scores.Results: Of 54 pediatric patients, 25 (46.3%) patients underwent pre-transplant evaluation utilizing PACT, while 29 (53.7%) were not evaluated with PACT. Patients assessed with PACT had a significantly lower percentage of acute rejection (16.0 vs. 55.2%, p = 0.007). After adjusting for HLA mismatch, a pre-transplant PACT score was persistently associated with lower odds of acute rejection (Odds Ratio 0.119, 95% Confidence Interval 0.027–0.52, p = 0.005). In PACT subsection analysis, the lack of family availability (OR 0.08, 95% CI 0.01–0.97, p = 0.047) and risk for psychopathology (OR 0.34, 95% CI 0.13–0.87, p = 0.025) were associated with a low PACT score and post-transplant non-adherence.Conclusions: Our study highlights the importance of standardized psychosocial assessments and the potential use of PACT in risk stratifying pre-transplant candidates

Routine cervical screening by primary HPV testing: early findings in the renewed National Cervical Screening Program

Objectives: To report human papillomavirus (HPV) testing patterns and rates of oncogenic HPV‐positivity for specimens submitted during the first 6 months after the National Cervical Screening Program switched from cytology‐ to primary HPV‐based screening. Design, participants: Retrospective cross‐sectional review of 195 606 specimens submitted for HPV testing, 1 December 2017 – 31 May 2018. Setting: Large community‐based general pathology laboratory in metropolitan Sydney. Main outcome measures: Prevalence of oncogenic HPV types (all, HPV16/18, non‐HPV16/18) by reason for HPV test (primary screening, non‐screening); for oncogenic HPV‐positive women in the age band recommended for primary HPV screening (25–74 years), prevalence of cytologic abnormality and rates of 12‐month follow‐up and colposcopy recommendations. Results: 195 606 samples were received: 157 700 (80.6%) for primary screening, 37 906 (19.4%) for non‐screening tests. Oncogenic HPV was detected in 8.1% of screening tests (95% CI, 7.9–8.2%) and 20.9% of non‐screening tests (95% CI, 20.5–21.3%); 35.5% (95% CI, 34.7–36.4%) of women of recommended screening age with positive oncogenic HPV screening test results also had a cytologic abnormality. The proportion of HPV16/18‐positive samples with high grade abnormality was 15.3% (95% CI, 14.2–16.6%); for samples positive for other oncogenic HPV types, the proportion was 6.3% (95% CI, 5.8–6.8%). Repeat HPV testing after 12 months was recommended for 5.4% (95% CI, 5.3–5.5%) and direct colposcopy for 2.6% (95% CI, 2.5–2.7%) of screened women aged 25–74 years. Conclusions: High grade cytologic abnormalities were more common in women positive for HPV16/18, supporting their higher risk classification. Colposcopy referral rates were higher than during primary cytology‐based testing, as predicted by clinical trial and modelling data. The prevalence of HPV was much higher in non‐screening than in primary screening samples. Our findings indicate the renewed program is performing as expected during the initial HPV screening round

The interstitial lung disease multidisciplinary meeting: A position statement from the Thoracic Society of Australia and New Zealand and the Lung Foundation Australia

Interstitial lung diseases (ILD) are a diverse group of pulmonary diseases for which accurate diagnosis is critical for optimal treatment outcomes. Diagnosis of ILD can be challenging and a multidisciplinary approach is recommended in international guidelines. The purpose of this position paper is to review the evidence for the use of the multidisciplinary meeting (MDM) in ILD and suggest an approach to its governance and constitution, in an attempt to provide a standard methodology that could be applied across Australia and New Zealand. This position paper is endorsed by the Thoracic Society of Australia and New Zealand (TSANZ) and the Lung Foundation Australia (LFA)

Type 2 diabetes mellitus-associated transcriptome alterations in cortical neurones and associated neurovascular unit cells in the ageing brain.

Type 2 diabetes mellitus (T2D), characterised by peripheral insulin resistance, is a risk factor for dementia. In addition to its contribution to small and large vessel disease, T2D may directly damage cells of the brain neurovascular unit. In this study, we investigated the transcriptomic changes in cortical neurones, and associated astrocytes and endothelial cells of the neurovascular unit, in the ageing brain. Neurone, astrocyte, and endothelial cell-enriched mRNA, obtained by immuno-laser capture microdissection of temporal cortex (Brodmann area 21/22) from 6 cases with self-reported T2D in the Cognitive Function and Ageing Study neuropathology cohort, and an equal number of age and sex-matched controls, was assessed by microarray analysis. Integrated Molecular Pathway Level Analysis was performed using the Kyoto Encyclopaedia of Genes and Genomes database on significantly differentially expressed genes, defined as P < 0.05 and fold-change ± 1.2. Hub genes identified from Weighted Gene Co-expression Network Analysis were validated in neurones using the NanoString nCounter platform. The expression and cellular localisation of proteins encoded by selected candidate genes were confirmed by immunohistochemistry. 912, 2202, and 1227 genes were significantly differentially expressed between cases with self-reported T2D and controls in neurones, astrocytes, and endothelial cells respectively. Changes in cortical neurones included alterations in insulin and other signalling pathways, cell cycle, cellular senescence, inflammatory mediators, and components of the mitochondrial respiratory electron transport chain. Impaired insulin signalling was shared by neurovascular unit cells with, additionally, apoptotic pathway changes in astrocytes and dysregulation of advanced glycation end-product signalling in endothelial cells. Transcriptomic analysis identified changes in key cellular pathways associated with T2D that may contribute to neuronal damage and dysfunction. These effects on brain cells potentially contribute to a diabetic dementia, and may provide novel approaches for therapeutic intervention

Advanced Glycation End Product Formation in Human Cerebral Cortex Increases With Alzheimer-Type Neuropathologic Changes but Is Not Independently Associated With Dementia in a Population-Derived Aging Brain Cohort.

Diabetes mellitus is a risk factor for dementia, and nonenzymatic glycosylation of macromolecules results in formation of advanced glycation end-products (AGEs). We determined the variation in AGE formation in brains from the Cognitive Function and Ageing Study population-representative neuropathology cohort. AGEs were measured on temporal neocortex by enzyme-linked immunosorbent assay (ELISA) and cell-type specific expression on neurons, astrocytes and endothelium was detected by immunohistochemistry and assessed semiquantitatively. Fifteen percent of the cohort had self-reported diabetes, which was not significantly associated with dementia status at death or neuropathology measures. AGEs were expressed on neurons, astrocytes and endothelium and overall expression showed a positively skewed distribution in the population. AGE measures were not significantly associated with dementia. AGE measured by ELISA increased with Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neurofibrillary tangle score (p = 0.03) and Thal Aβ phase (p = 0.04), while AGE expression on neurons (and astrocytes), detected immunohistochemically, increased with increasing Braak tangle stage (p < 0.001), CERAD tangle score (p = 0.002), and neuritic plaques (p = 0.01). Measures of AGE did not show significant associations with cerebral amyloid angiopathy, microinfarcts or neuroinflammation. In conclusion, AGE expression increases with Alzheimer's neuropathology, particular later stages but is not independently associated with dementia. AGE formation is likely to be important for impaired brain cell function in aging and Alzheimer's

Diagnosis and management of idiopathic pulmonary fibrosis: Thoracic Society of Australia and New Zealand and Lung Foundation Australia position statements summary

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease associated with debilitating symptoms of dyspnoea and cough, resulting in respiratory failure, impaired quality of life and ultimately death. Diagnosing IPF can be challenging, as it often shares many features with other interstitial lung diseases. In this article, we summarise recent joint position statements on the diagnosis and management of IPF from the Thoracic Society of Australia and New Zealand and Lung Foundation Australia, specifically tailored for physicians across Australia and New Zealand. Main suggestions: A comprehensive multidisciplinary team meeting is suggested to establish a prompt and precise IPF diagnosis. Antifibrotic therapies should be considered to slow disease progression. However, enthusiasm should be tempered by the lack of evidence in many IPF subgroups, particularly the broader disease severity spectrum. Non-pharmacological interventions including pulmonary rehabilitation, supplemental oxygen, appropriate treatment of comorbidities and disease-related symptoms remain crucial to optimal management. Despite recent advances, IPF remains a fatal disease and suitable patients should be referred for lung transplantation assessment