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Central to the pathology of malaria disease are the repeated cycles of parasite invasion and destruction of human erythrocytes. In Plasmodium falciparum, the most virulent species causing malaria, erythrocyte invasion involves several specific receptor-ligand interactions that direct the pathway used to invade the host cell, with parasites varying in their dependency on these different pathways. Gene disruption of a key invasion ligand in the 3D7 parasite strain, the P. falciparum reticulocyte binding-like homolog 2b (PfRh2b), resulted in the parasite invading via a novel pathway. Here, we show results that suggest the molecular basis for this novel pathway is not due to a molecular switch but is instead mediated by the redeployment of machinery already present in the parent parasite but masked by the dominant role of PfRh2b. This would suggest that interactions directing invasion are organized hierarchically, where silencing of dominant invasion ligands reveal underlying alternative pathways. This provides wild parasites with the ability to adapt to immune-mediated selection or polymorphism in erythrocyte receptors and has implications for the use of invasion-related molecules in candidate vaccines.

Down syndrome (DS) individuals suffer mental retardation with further cognitive decline and early onset Alzheimer's disease. To understand how trisomy 21 causes these neurological abnormalities we investigated changes in gene expression networks combined with a systematic cell lineage analysis of adult neurogenesis using the Ts1Cje mouse model of DS. We demonstrated down regulation of a number of key genes involved in proliferation and cell cycle progression including Mcm7, Brca2, Prim1, Cenpo and Aurka in trisomic neurospheres. We found that trisomy did not affect the number of adult neural stem cells but resulted in reduced numbers of neural progenitors and neuroblasts. Analysis of differentiating adult Ts1Cje neural progenitors showed a severe reduction in numbers of neurons produced with a tendency for less elaborate neurites, whilst the numbers of astrocytes was increased. We have shown that trisomy affects a number of elements of adult neurogenesis likely to result in a progressive pathogenesis and consequently providing the potential for the development of therapies to slow progression of, or even ameliorate the neuronal deficits suffered by DS individuals.

Background The Ts1Cje mouse model of Down syndrome (DS) has partial triplication of mouse chromosome 16 (MMU16), which is partially homologous to human chromosome 21. These mice develop various neuropathological features identified in DS individuals. We analysed the effect of partial triplication of the MMU16 segment on global gene expression in the cerebral cortex, cerebellum and hippocampus of Ts1Cje mice at 4 time-points: postnatal day (P)1, P15, P30 and P84. Results Gene expression profiling identified a total of 317 differentially expressed genes (DEGs), selected from various spatiotemporal comparisons, between Ts1Cje and disomic mice. A total of 201 DEGs were identified from the cerebellum, 129 from the hippocampus and 40 from the cerebral cortex. Of these, only 18 DEGs were identified as common to all three brain regions and 15 were located in the triplicated segment. We validated 8 selected DEGs from the cerebral cortex ( Brwd1 , Donson , Erdr1 , Ifnar1 , Itgb8 , Itsn1 , Mrps6 and Tmem50b ), 18 DEGs from the cerebellum ( Atp5o , Brwd1 , Donson , Dopey2 , Erdr1 , Hmgn1 , Ifnar1 , Ifnar2 , Ifngr2 , Itgb8 , Itsn1 , Mrps6 , Paxbp1 , Son , Stat1 , Tbata, Tmem50b and Wrb ) and 11 DEGs from the hippocampus ( Atp5o , Brwd1 , Cbr1 , Donson , Erdr1 , Itgb8 , Itsn1 , Morc3 , Son , Tmem50b and Wrb ). Functional clustering analysis of the 317 DEGs identified interferon-related signal transduction as the most significantly dysregulated pathway in Ts1Cje postnatal brain development. RT-qPCR and western blotting analysis showed both Ifnar1 and Stat1 were over-expressed in P84 Ts1Cje cerebral cortex and cerebellum as compared to wild type littermates. Conclusions These findings suggest over-expression of interferon receptor may lead to over-stimulation of Jak-Stat signaling pathway which may contribute to the neuropathology in Ts1Cje or DS brain. The role of interferon mediated activation or inhibition of signal transduction including Jak-Stat signaling pathway has been well characterized in various biological processes and disease models including DS but information pertaining to the role of this pathway in the development and function of the Ts1Cje or DS brain remains scarce and warrants further investigation.

The malaria parasite, Plasmodium falciparum, exploits multiple ligand-receptor interactions, called invasion pathways, to invade the host erythrocyte. Strains of P. falciparum vary in their dependency on sialated red cell receptors for invasion. We show that switching from sialic acid-dependent to -independent invasion is reversible and depends on parasite ligand use. Expression of P. falciparum reticulocyte-binding like homolog 4 (PfRh4) correlates with sialic acid-independent invasion, and PfRh4 is essential for switching invasion pathways. Differential activation of PfRh4 represents a previously unknown mechanism to switch invasion pathways and provides P. falciparum with exquisite adaptability in the face of erythrocyte receptor polymorphisms and host immune responses.

Background and aimsSARS-CoV-2 and consequent pandemic has presented unique challenges. Beyond the direct COVID-related mortality in those with liver disease, we sought to determine the effect of lockdown on people with liver disease in Scotland. The effect of lockdown on those with alcohol-related disease is of interest; and whether there were associated implications for a change in alcohol intake and consequent presentations with decompensated disease.MethodsWe performed a retrospective analysis of patients admitted to seven Scottish hospitals with a history of liver disease between 1 April and 30 April 2020 and compared across the same time in 2017, 2018 and 2019. We also repeated an intermediate assessment based on a single centre to examine for delayed effects between 1 April and 31 July 2020.ResultsWe found that results and outcomes for patients admitted in 2020 were similar to those in previous years in terms of morbidity, mortality, and length of stay. In the Scotland-wide cohort: admission MELD (Model for End-stage Liver Disease) (16 (12–22) vs 15 (12–19); p=0.141), inpatient mortality ((10.9% vs 8.6%); p=0.499) and length of stay (8 days (4–15) vs 7 days (4–13); p=0.140). In the Edinburgh cohort: admission MELD (17 (12–23) vs 17 (13–21); p=0.805), inpatient mortality ((13.7% vs 10.1%; p=0.373) and length of stay (7 days (4–14) vs 7 days (3.5–14); p=0.525)).ConclusionThis assessment of immediate and medium-term lockdown impacts on those with chronic liver disease suggested a minimal effect on the presentation of decompensated liver disease to secondary care.

Chronic microbial infections are associated with fibrotic and inflammatory reactions known as granulomas showing similarities to wound-healing and tissue repair processes. We have previously mapped three leishmaniasis susceptibility loci, designated Imr1, -2, and -3, which exert their effect independently of T cell immune responses. Here, we show that the wound repair response is critically important for the rapid cure in murine cutaneous leishmaniasis caused by Leishmania major. Mice congenic for leishmaniasis resistance loci, which cured their lesions more rapidly than their susceptible parents, also expressed differentially genes involved in tissue repair, laid down more ordered collagen fibers, and healed punch biopsy wounds more rapidly. Fibroblast monolayers from these mice repaired in vitro wounds faster, and this process was accelerated by supernatants from infected macrophages. Because these effects are independent of T cell-mediated immunity, we conclude that the rate of wound healing is likely to be an important component of innate immunity involved in resistance to cutaneous leishmaniasis.

During the first UK national coronavirus pandemic lockdown (Mar-Jul 2020), alcohol sales increased 30% in supermarkets. Surveys reported that 20% of people increased their alcohol consumption and numbers of high-risk drinkers increased by 13%. Post-lockdown, clinicians noted high numbers of alcohol-related liver disease (ArLD)-related admissions. We hypothesised that greater alcohol consumption in high-risk drinkers contributed to this increase. We conducted a national service evaluation to document the number and severity of unplanned ArLD hospital admissions pre- and post-lockdown.We performed a retrospective service evaluation in 28 UK hospitals of all unplanned admissions during a one-week period in August 2019 and the same period in August 2020. The protocol was approved by the lead site’s Clinical Audit Department and registered at participating sites. We applied a validated coding algorithm that more accurately identifies ArLD admissions than using only ArLD codes in the primary diagnosis.1 Eligible cases were manually reviewed and data extracted into a pre-designed collection tool. Data collected included demographics, diagnosis, alcohol use and liver disease severity scores, which were compared between evaluation periods.There was an 18% absolute increase in unplanned hospital admissions for patients with ArLD in the evaluation period in 2020 compared to 2019 (263 vs 223). Demographics were similar between the two periods (mean age 55; 37% female). In-hospital mortality was similar (9.0% vs 7.2%) and there were no differences between proportions of patients with complications of liver disease including variceal bleeding and alcoholic hepatitis. Patients in both evaluation periods had similar severity of liver disease with mean Child Pugh score of 8 and MELD 14. Those with alcoholic hepatitis had mean MELD 20 (SD 7.5) and discriminant function 90 (SD 70).In the post-lockdown period, there were more active alcohol drinkers (151 vs 196; 75% vs 68%) than pre-lockdown. Mean consumption per patient was higher (154 vs 127 units alcohol/week; p=0.02). More patients reported drinking spirits post- vs pre-lockdown (31% vs 22%; p=0.06).This national service evaluation demonstrates an increase in unplanned ArLD hospital admissions post-lockdown with patients reporting heavier alcohol use. Although there were no differences in clinical presentations or outcomes, these patients have advanced liver disease with high short-term mortality. These data suggest the pandemic has disproportionately affected high-risk drinkers and demonstrate the heavy burden of ArLD in the UK. There is an ongoing need to develop long-term strategies to improve these patients’ outcomes.ReferenceKallis, et al. Aliment Pharm Therap 2020;52:182–95.

IntroductionAcute liver failure (ALF) has a high short term mortality. Current prognostic models lack sensitivity. This study aimed to investigate the prognostic potential of iron metabolism in ALF.Methods528 patients admitted to a liver transplant unit with ALF were selected. Aetiology, outcome (spontaneously survived vs. death/transplant) and hepatic encephalopathy (HE) were recorded. Patients without the relevant iron indices recorded were excluded.ResultsParacetamol overdose (POD) patients (n=236) had a significantly higher transferrin if they survived (n=168) compared to those that died or were transplanted (n=68) (1.585 (1.363–1.918) vs. 1.285 (1.000–1.730) (p<0.001))In non-POD patients (n=88) the median transferrin was also significantly higher in those patients that survived (n=48) compared to those that died or were transplanted (n=40) (1.965 (1.435–2.375) vs. 1.455 (1.078–1.803) (p=0.001))In POD patients (n=246) the median ferritin was significantly higher in those who died or were transplanted (n=70) compared with survivors (n=176) (36,822(13,054–64,358) vs. 17,641 (5,120–42,895) (p=0.002)). There was no statistical difference in the non-POD group.Transferrin was significantly lower in POD patients with HE (n=143) compared to those that never developed HE (n=93) (1.420 (1.100–1.720) vs. 1.670 (1.400–1.990) (p<0.001)). Levels were also significantly lower in the non-POD group (1.500 (1.085–1.945) vs. 1.985 (1.445–2.365) (p=0.007)).Ferritin was significantly higher in POD patients with HE (n=146) compared to those who never developed HE (n=99). (24,828 (9,267–61,214) vs. 17,149 (3,153–37,994) (p=0.009)). There was no difference in the non-POD group.No significant results were found when comparing circulating iron levels and transferrin saturations.ROC curve analysis, however, showed that iron studies are poor at predicting survival in ALF. For example the area under the curve for transferrin to predict survival in POD patients was 0.662. To predict encephalopathy free course of disease in the same group of patients was 0.666.ConclusionsIron indices, specifically ferritin and transferrin, are significantly different in patients with ALF and relate to aetiology and outcome. However they are poor at predicting survival.