Systemic immune challenge exacerbates neurodegeneration in a model of neurological lysosomal disease.

Mucopolysaccharidosis type IIIA (MPS IIIA) is a rare paediatric lysosomal storage disorder, caused by the progressive accumulation of heparan sulphate, resulting in neurocognitive decline and behavioural abnormalities. Anecdotal reports from paediatricians indicate a more severe neurodegeneration in MPS IIIA patients, following infection, suggesting inflammation as a potential driver of neuropathology. To test this hypothesis, we performed acute studies in which WT and MPS IIIA mice were challenged with the TLR3-dependent viral mimetic poly(I:C). The challenge with an acute high poly(I:C) dose exacerbated systemic and brain cytokine expression, especially IL-1ß in the hippocampus. This was accompanied by an increase in caspase-1 activity within the brain of MPS IIIA mice with concomitant loss of hippocampal GFAP and NeuN expression. Similar levels of cell damage, together with exacerbation of gliosis, were also observed in MPS IIIA mice following low chronic poly(I:C) dosing. While further investigation is warranted to fully understand the extent of IL-1ß involvement in MPS IIIA exacerbated neurodegeneration, our data robustly reinforces our previous findings, indicating IL-1ß as a pivotal catalyst for neuropathological processes in MPS IIIA.

Akt2 deficiency impairs Th17 differentiation, augments Th2 differentiation, and alters the peripheral response to immunization.

Akt1 and Akt2, isoforms of the serine threonine kinase Akt, are essential for T cell development. However, their role in peripheral T cell differentiation remains undefined. Using mice with germline deletions of either Akt1 or Akt2, we found that both isoforms are important for Th17 differentiation, although Akt2 loss had a greater impact than loss of Akt1. In contrast to defective IL-17 production, Akt2 -/- T cells exhibited enhanced IL-4 production in vitro under Th2 polarizing conditions. In vivo , Akt2 -/- mice displayed significantly diminished IL-17A and GM-CSF production following immunization with myelin oligodendrocyte glycoprotein (MOG). This dampened response was associated with further alterations in Th cell differentiation including decreased IFNγ production but preserved IL-4 production, and preferential expansion of regulatory T cells compared to non-regulatory CD4 T cells. Taken together, we identify Akt2 as an important signaling molecule in regulating peripheral CD4 T cell responses.

A comparison of changes in drug burden index between older inpatients who fell and people who have not fallen: A case-control study.

OBJECTIVE: Older inpatients who fall are often frail, with multiple co-morbidities and polypharmacy. Although the causes of falls are multifactorial, sedating and delirium-inducing drugs increase that risk. The aims were to determine whether people who fell had a change in their sedative and anticholinergic medication burden during an admission compared to people who did not fall. A secondary aim was to determine the factors associated with change in drug burden. METHODS: A retrospective, observational, case-control study of inpatients who fell. Two hundred consecutive people who fell were compared with 200 randomly selected people who had not fallen. Demographics, functional ability, frailty and cognition were recorded. For each patient, their total medications and anticholinergic and sedative burden were calculated on admission and on discharge, using the drug burden index (DBI). RESULTS: People who fell were more dependent and cognitively impaired than people who did not fallen. People who fell had a higher DBI on admission, than people who had not fall (mean: .69 vs .43, respectively, p < .001) and discharge (.66 vs .38, p < .001). For both cohorts, the DBI decreased between admission and discharge (-.03 and -.05), but neither were clinically significant. Higher total medications and a higher number DBI medications on admission were both associated with greater DBI changes (p = .003 and <.001, respectively). However, the presence (or absence) of cognitive impairment, dependency, frailty and single vs multiple falls were not significantly associated with DBI changes. CONCLUSIONS: In older people, DBI medications and falls are both common and have serious consequences, yet this study was unable to demonstrate any clinically relevant reduction in average DBI either in people who fell or people who had not fallen during a hospital admission.