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

`Whose Shoes?` Can an educational board game engage Ugandan men in pregnancy and childbirth?

Background Men can play a significant role in reducing maternal morbidity and mortality in low-income countries. Maternal health programmes are increasingly looking for innovative interventions to engage men to help improve health outcomes for pregnant women. Educational board games offer a unique approach to present health information where learning is reinforced through group discussions supporting peer-to-peer interactions. Methods A qualitative study with men from Uganda currently living in the UK on their views of an educational board game. Men were purposively sampled to play a board game and participate in a focus group discussion. The pilot study explored perceptions on whether a board game was relevant as a health promotional tool in maternal health prior to implementation in Uganda. Results The results of the pilot study were promising; participants reported the use of visual aids and messages were easy to understand and enhanced change in perspective. Men in this study were receptive on the use of board games as a health promotional tool and recommended its use in rural Uganda. Conclusions This study provides preliminary data on the relevancy and efficacy of using board games in maternal health. Key messages from the focus group appeared to be that the board game is more than acceptable to fathers and that it needs to be adapted to the local context to make it suitable for men in rural Uganda

Costs and advance directives at the end of life: a case of the ‘Coaching Older Adults and Carers to have their preferences Heard (COACH)’ trial

Background Total costs associated with care for older people nearing the end of life and the cost variations related with end of life care decisions are not well documented in the literature. Healthcare utilisation and associated health care costs for a group of older Australians who entered Transition Care following an acute hospital admission were calculated. Costs were differentiated according to a number of health care decisions and outcomes including advance directives (ADs). Methods Study participants were drawn from the Coaching Older Adults and Carers to have their preferences Heard (COACH) trial funded by the Australian National Health and Medical Research Council. Data collected included total health care costs, the type of (and when) ADs were completed and the place of death. Two-step endogenous treatment-regression models were employed to test the relationship between costs and a number of variables including completion of ADs. Results The trial recruited 230 older adults with mean age 84 years. At the end of the trial, 53 had died and 80 had completed ADs. Total healthcare costs were higher for younger participants and those who had died. No statistically significant association was found between costs and completion of ADs. Conclusion For our frail study population, the completion of ADs did not have an effect on health care utilisation and costs. Further research is needed to substantiate these findings in larger and more diverse clinical cohorts of older people

Interventional hepatic ApoC-III knockdown improves atherosclerotic plaque stability and remodeling upon triglyceride lowering

Apolipoprotein C-III (apoC-III) is a critical regulator of triglyceride metabolism and correlates positively with hypertriglyceridemia and cardiovascular disease (CVD). It remains unclear if therapeutic apoC-III lowering reduces CVD risk and if the CVD correlation depends on the lipid-lowering or antiinflammatory properties. We determined the impact of interventional apoC-III lowering on atherogenesis using an apoC-III antisense oligonucleotide (ASO) in 2 hypertriglyceridemic mouse models where the intervention lowers plasma triglycerides and in a third lipid-refractory model. On a high-cholesterol Western diet apoC-III ASO treatment did not alter atherosclerotic lesion size but did attenuate advanced and unstable plaque development in the triglyceride-responsive mouse models. No lesion size or composition improvement was observed with apoC-III ASO in the lipid-refractory mice. To circumvent confounding effects of continuous high-cholesterol feeding, we tested the impact of interventional apoC-III lowering when switching to a cholesterol-poor diet after 12 weeks of Western diet. In this diet switch regimen, apoC-III ASO treatment significantly reduced plasma triglycerides, atherosclerotic lesion progression, and necrotic core area and increased fibrous cap thickness in lipid-responsive mice. Again, apoC-III ASO treatment did not alter triglyceride levels, lesion development, and lesion composition in lipid-refractory mice after the diet switch. Our findings suggest that interventional apoC-III lowering might be an effective strategy to reduce atherosclerosis lesion size and improve plaque stability when lipid lowering is achieved

The impact of religion on changes in end-of-life practices in European intensive care units: a comparative analysis over 16 years.

PURPOSE Religious beliefs affect end-of-life practices in intensive care units (ICUs). Changes over time in end-of-life practices were not investigated regarding religions. METHODS Twenty-two European ICUs (3 regions: Northern, Central, and Southern Europe) participated in both Ethicus-1 (years 1999-2000) and Ethicus-2 studies (years 2015-2016). Data of ICU patients who died or had limitations of life-sustaining therapy were analysed regarding changes in end-of-life practices and patient/physician religious affiliations. Frequencies, timing of decision-making, and religious affiliations of physicians/patients were compared using the same definitions. RESULTS In total, 4592 adult ICU patients (n = 2807 Ethicus-1, n = 1785 Ethicus-2) were analysed. In both studies, patient and physician religious affiliations were mostly Catholic, Greek Orthodox, Jewish, Protestant, or unknown. Treating physicians (but not patients) commonly reported no religious affiliation (18%). Distribution of end-of-life practices with respect to religion and geographical regions were comparable between the two studies. Withholding [n = 1143 (40.7%) Ethicus-1 and n = 892 (50%) Ethicus-2] and withdrawing [n = 695 (24.8%) Ethicus-1 and n = 692 (38.8%) Ethicus-2] were most commonly decided. No significant changes in end-of-life practices were observed for any religion over 16 years. The number of end-of-life discussions with patients/ families/ physicians increased, while mortality and time until first decision decreased. CONCLUSIONS Changes in end-of-life practices observed over 16 years appear unrelated to religious affiliations of ICU patients or their treating physicians, but the effects of religiosity and/or culture could not be assessed. Shorter time until decision in the ICU and increased numbers of patient and family discussions may indicate increased awareness of the importance of end-of-life decision-making in the ICU

The chemerin knockout rat reveals chemerin dependence in female, but not male, experimental hypertension

Measures of the adipokine chemerin are elevated in multiple cardiovascular diseases, including hypertension, but little mechanistic work has been done to implicate chemerin as being causative in such diseases. The chemerin knockout (KO) rat was created to test the hypothesis that removal of chemerin would reduce pressure in the normal and hypertensive state. Western analyses confirmed loss of chemerin in the plasma and tissues of the KO vs. wild‐type (WT) rats. Chemerin concentration in plasma and tissues was lower in WT females than in WT males, as determined by Western analysis. Conscious male and female KO rats had modest differences in baseline measures vs. the WT that included systolic, diastolic, mean arterial and pulse pressures, and heart rate, all measured telemetrically. The mineralocorticoid deoxycorticosterone acetate (DOCA) and salt water, combined with uninephrectomy as a hypertensive stimulus, elevated mean and systolic blood pressures of the male KO higher than the male WT. By contrast, all pressures in the female KO were lower than their WT throughout DOCA‐salt treatment. These results revealed an unexpected sex difference in chemerin expression and the ability of chemerin to modify blood pressure in response to a hypertensive challenge.—Watts, S. W., Darios, E. S., Mullick, A. E., Garver, H., Saunders, T. L., Hughes, E. D., Filipiak, W. E., Zeidler, M. G., McMullen, N., Sinal, C. J., Kumar, R. K., Ferland, D. J., Fink, G. D. The chemerin knockout rat reveals chemerin dependence in female, but not male, experimental hypertension. FASEB J. 32, 6596–6614 (2018). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154357/1/fsb2fj201800479.pd

Genetic Control of Susceptibility to Infection with Candida albicans in Mice

Candida albicans is an opportunistic pathogen that causes acute disseminated infections in immunocompromised hosts, representing an important cause of morbidity and mortality in these patients. To study the genetic control of susceptibility to disseminated C. albicans in mice, we phenotyped a group of 23 phylogenetically distant inbred strains for susceptibility to infection as measured by extent of fungal replication in the kidney 48 hours following infection. Susceptibility was strongly associated with the loss-of-function mutant complement component 5 (C5/Hc) allele, which is known to be inherited by approximately 40% of inbred strains. Our survey identified 2 discordant strains, AKR/J (C5-deficient, resistant) and SM/J (C5-sufficient, susceptible), suggesting that additional genetic effects may control response to systemic candidiasis in these strains. Haplotype association mapping in the 23 strains using high density SNP maps revealed several putative loci regulating the extent of C. albicans replication, amongst which the most significant were C5 (P value = 2.43×10−11) and a novel effect on distal chromosome 11 (P value = 7.63×10−9). Compared to other C5-deficient strains, infected AKR/J strain displays a reduced fungal burden in the brain, heart and kidney, and increased survival, concomitant with uniquely high levels of serum IFNγ. C5-independent genetic effects were further investigated by linkage analysis in an [A/JxAKR/J]F2 cross (n = 158) where the mutant Hc allele is fixed. These studies identified a chromosome 11 locus (Carg4, Candida albicans resistance gene 4; LOD = 4.59), and a chromosome 8 locus (Carg3; LOD = 3.95), both initially detected by haplotype association mapping. Alleles at both loci were inherited in a co-dominant manner. Our results verify the important effect of C5-deficiency in inbred mouse strains, and further identify two novel loci, Carg3 and Carg4, which regulate resistance to C. albicans infection in a C5-independent manner

Casting a Wide Net: HIV Drug Resistance Monitoring in Pre-Exposure Prophylaxis Seroconverters in the Global Evaluation of Microbicide Sensitivity Project

Background: Evidence of HIV drug resistance (HIVDR) in individuals using oral pre-exposure prophylaxis (PrEP) who acquire HIV is limited to clinical trials and case studies. More data are needed to understand the risk of HIVDR with oral PrEP during PrEP rollout. Mechanisms to collect these data vary, and are dependent on cost, scale of PrEP distribution, and in-country infrastructure for the identification, collection, and testing of samples from PrEP seroconverters. / Methods: The Global Evaluation of Microbicide Sensitivity (GEMS) project, in collaboration with country stakeholders, initiated HIVDR monitoring among new HIV seroconverters with prior PrEP use in Eswatini, Kenya, South Africa, and Zimbabwe. Standalone protocols were developed to assess HIVDR among a national sample of PrEP users. In addition, HIVDR testing was incorporated into existing demonstration projects for key populations. / Lessons learned: Countries are supportive of conducting a timelimited evaluation of HIVDR during the early stages of PrEP rollout. As PrEP rollout expands, the need for long-term HIVDR monitoring with PrEP will need to be balanced with maintaining national HIV drug resistance surveillance for pretreatment and acquired drug resistance. Laboratory capacity is a common obstacle to setting up a monitoring system. / Conclusions: Establishing HIV resistance monitoring within PrEP programs is feasible. Approaches to drug resistance monitoring may evolve as the PrEP programs mature and expand. The methods and implementation support offered by GEMS assisted countries in developing methods to monitor for drug resistance that best fit their PrEP program needs and resources