Expression and Differential Responsiveness of Central Nervous System Glial Cell Populations to the Acute Phase Protein Serum Amyloid A

Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves hepatic production of acute-phase proteins, including serum amyloid A (SAA). Extrahepatically, SAA immunoreactivity is found in axonal myelin sheaths of cortex in Alzheimer's disease and multiple sclerosis (MS), although its cellular origin is unclear. We examined the responses of cultured rat cortical astrocytes, microglia and oligodendrocyte precursor cells (OPCs) to master pro-inflammatory cytokine tumour necrosis factor (TNF)-\u3b1 and lipopolysaccaride (LPS). TNF-\u3b1 time-dependently increased Saa1 (but not Saa3) mRNA expression in purified microglia, enriched astrocytes, and OPCs (as did LPS for microglia and astrocytes). Astrocytes depleted of microglia were markedly less responsive to TNF-\u3b1 and LPS, even after re-addition of microglia. Microglia and enriched astrocytes showed complementary Saa1 expression profiles following TNF-\u3b1 or LPS challenge, being higher in microglia with TNF-\u3b1 and higher in astrocytes with LPS. Recombinant human apo-SAA stimulated production of both inflammatory mediators and its own mRNA in microglia and enriched, but not microglia-depleted astrocytes. Co-ultramicronized palmitoylethanolamide/luteolin, an established anti-inflammatory/neuroprotective agent, reduced Saa1 expression in OPCs subjected to TNF-\u3b1 treatment. These last data, together with past findings suggest that co-ultramicronized palmitoylethanolamide/luteolin may be a novel approach in the treatment of inflammatory demyelinating disorders like MS

Treatment effects may remain the same even when trial participants differed from the target population

Objective RCTs have been criticised for lacking external validity. We assessed whether a trial in people with type I diabetes mellitus (T1DM) mirrored the wider population, and applied sample-weighting methods to assess the impact of differences on our trial's findings. Study design and setting The REPOSE trial was nested within a large UK cohort capturing demographic, clinical and quality of life (QoL) data for people with T1DM undergoing structured diabetes-specific education. We firstly assessed whether our RCT participants were comparable to this cohort using propensity score modelling. Following this we re-weighted the trial population to better match the wider cohort and re-estimated the treatment effect. Results Trial participants differed from the cohort in regards to sex, weight, HbA1c and also QoL and satisfaction with current treatment. Nevertheless, the treatment effects derived from alternative model weightings were similar to that of the original RCT. Conclusions Our RCT participants differed in composition to the wider population but the original findings were unaffected by sampling adjustments. We encourage investigators take steps to address criticisms of generalisability, but doing so is problematic: external data, even if available, may contain limited information and analyses can be susceptible to model misspecification

Heart Failure and Multimorbidity in Australian General Practice

Background: Heart failure (HF) is a serious condition that mostly affects older people. Despite the ageing population experiencing an increased prevalence of many chronic conditions, current guidelines focus on isolated management of HF. Objective: To describe the burden of multimorbidity in patients with HF being managed in general practice in Australia. Design: Data from the Bettering the Evaluation And Care of Health (BEACH) programme were used to determine (i) the prevalence of HF, (ii) the number of co-existing long-term conditions, and (iii) the most common disease combinations in patients with HF. The study was undertaken over fifteen, 5-week recording periods between November 2012 and March 2016. Results: The dataset included a total of 25,790 general practitioner (GP) encounters with patients aged ≥45 years, collected by 1,445 GPs. HF had been diagnosed in 1,119 of these patients, a prevalence of 4.34% (95% confidence interval [CI] 3.99–4.68) among patients at GP encounters, and 2.08% (95% CI 1.87–2.29) when applied to the general Australian population overall. HF rarely occurred in isolation, with 99.1% of patients having at least one and 53.4% having six or more other chronic illnesses. The most common pair of comorbidities among active patients with HF was hypertension and osteoarthritis (43.4%). Conclusion: Overall, one in every 20−25 GP encounters with patients aged ≥45 years in Australia is with a patient with HF. Multimorbidity is a typical presentation among this patient group and guidelines for general practice must take this into account.Journal of Comorbidity 2017;7(1):44–4