Evaluation of the impact of nasal colonization with methicillin-resistant Staphylococcus aureus on left ventricular assist device infections.

In this retrospective cohort study, we evaluated the predictive value of methicillin-resistant Staphylococcus aureus (MRSA) nasal swabs for the development of MRSA infections in patients with left ventricular assist devices. In 106 patients, the MRSA nasal swab had a negative predictive value of 92.9% demonstrating a potential role in antibiotic de-escalation.

Intravenous insulin for the management of non-emergent hyperglycemia in the emergency department.

PURPOSE: There is currently no consensus regarding the necessity of emergency department (ED) glucose reduction to manage hyperglycemia in patients presenting without a hyperglycemic emergency. Known consequences of intravenous (IV) insulin administration include hypoglycemia, hypokalemia, and increased ED length of stay. The primary objective of this study was to assess the impact of IV regular insulin on glucose reduction and ED length of stay in patients presenting to the ED with non-emergent hyperglycemia. Secondary objectives included the characterization of potential adverse events. METHODS: This was a retrospective, observational study of patients ≥18 years who received IV regular insulin and were discharged from the ED at a large academic Trauma Center. Univariate and multivariable regression analyses were utilized to determine if an association existed between IV insulin administration and blood glucose as well as ED length of stay. RESULTS: A total of 405 patients were included in the analysis. An insulin dose >5 units was associated with a greater reduction in blood glucose (difference = 37.4 mg/dL; p < .001) but no difference in ED length of stay relative to ≤5 units. Furthermore, 7.9% of patients developed hypokalemia and 0.4% developed hypoglycemia. CONCLUSION: The use of >5 units of IV regular insulin for the management of isolated hyperglycemia in the ED was associated with a modest reduction in blood glucose and no difference in ED length of stay compared with those that received ≤5 units. However, use of IV insulin for this purpose resulted in a 7.9% occurrence of hypokalemia.

TREM2 function impedes tau seeding in neuritic plaques.

Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been associated with increased risk for sporadic, late-onset Alzheimer's disease. Here we show that germline knockout of Trem2 or the TREM2R47H variant reduces microgliosis around amyloid-ß plaques and facilitates the seeding and spreading of neuritic plaque tau aggregates. These findings demonstrate a key role for TREM2 and microglia in limiting the development of peri-plaque tau pathologies.

TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy.

Variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) were recently found to increase the risk for developing Alzheimer's disease (AD). In the brain, TREM2 is predominately expressed on microglia, and its association with AD adds to increasing evidence implicating a role for the innate immune system in AD initiation and progression. Thus far, studies have found TREM2 is protective in the response to amyloid pathology while variants leading to a loss of TREM2 function impair microglial signaling and are deleterious. However, the potential role of TREM2 in the context of tau pathology has not yet been characterized. In this study, we crossed Trem2+/+ (T2+/+) and Trem2-/- (T2-/-) mice to the PS19 human tau transgenic line (PS) to investigate whether loss of TREM2 function affected tau pathology, the microglial response to tau pathology, or neurodegeneration. Strikingly, by 9 mo of age, T2-/-PS mice exhibited significantly less brain atrophy as quantified by ventricular enlargement and preserved cortical volume in the entorhinal and piriform regions compared with T2+/+PS mice. However, no TREM2-dependent differences were observed for phosphorylated tau staining or insoluble tau levels. Rather, T2-/-PS mice exhibited significantly reduced microgliosis in the hippocampus and piriform cortex compared with T2+/+PS mice. Gene expression analyses and immunostaining revealed microglial activation was significantly attenuated in T2-/-PS mice, and there were lower levels of inflammatory cytokines and astrogliosis. These unexpected findings suggest that impairing microglial TREM2 signaling reduces neuroinflammation and is protective against neurodegeneration in the setting of pure tauopathy.

AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy.

Tauopathies are characterized by the progressive accumulation of hyperphosphorylated, aggregated forms of tau. Our laboratory has previously demonstrated that passive immunization with an anti-tau antibody, HJ8.5, decreased accumulation of pathological tau in a human P301S tau-expressing transgenic (P301S-tg) mouse model of frontotemporal dementia/tauopathy. To investigate whether the Fc domain of HJ8.5 is required for the therapeutic effect, we engineered single-chain variable fragments (scFvs) derived from HJ8.5 with variable linker lengths, all specific to human tau. Based on different binding properties, we selected two anti-tau scFvs and tested their efficacy in vivo by adeno-associated virus-mediated gene transfer to the brain of P301S-tg mice. The scFvs significantly reduced levels of hyperphosphorylated, aggregated tau in brain tissue of P301S-tg mice, associated with a decrease in detergent-soluble tau species. Interestingly, these mice showed substantial levels of scFvs in the cerebrospinal fluid without significant effects on total extracellular tau levels. Therefore, our study provides a novel strategy for anti-tau immunotherapeutics that potentially limits a detrimental proinflammatory response.

The Effects of Peripheral and Central High Insulin on Brain Insulin Signaling and Amyloid-ß in Young and Old APP/PS1 Mice.

Hyperinsulinemia is a risk factor for late-onset Alzheimer's disease (AD). In vitro experiments describe potential connections between insulin, insulin signaling, and amyloid-ß (Aß), but in vivo experiments are needed to validate these relationships under physiological conditions. First, we performed hyperinsulinemic-euglycemic clamps with concurrent hippocampal microdialysis in young, awake, behaving APPswe/PS1dE9 transgenic mice. Both a postprandial and supraphysiological insulin clamp significantly increased interstitial fluid (ISF) and plasma Aß compared with controls. We could detect no increase in brain, ISF, or CSF insulin or brain insulin signaling in response to peripheral hyperinsulinemia, despite detecting increased signaling in the muscle. Next, we delivered insulin directly into the hippocampus of young APP/PS1 mice via reverse microdialysis. Brain tissue insulin and insulin signaling was dose-dependently increased, but ISF Aß was unchanged by central insulin administration. Finally, to determine whether peripheral and central high insulin has differential effects in the presence of significant amyloid pathology, we repeated these experiments in older APP/PS1 mice with significant amyloid plaque burden. Postprandial insulin clamps increased ISF and plasma Aß, whereas direct delivery of insulin to the hippocampus significantly increased tissue insulin and insulin signaling, with no effect on Aß in old mice. These results suggest that the brain is still responsive to insulin in the presence of amyloid pathology but increased insulin signaling does not acutely modulate Aß in vivo before or after the onset of amyloid pathology. Peripheral hyperinsulinemia modestly increases ISF and plasma Aß in young and old mice, independent of neuronal insulin signaling. SIGNIFICANCE STATEMENT: The transportation of insulin from blood to brain is a saturable process relevant to understanding the link between hyperinsulinemia and AD. In vitro experiments have found direct connections between high insulin and extracellular Aß, but these mechanisms presume that peripheral high insulin elevates brain insulin significantly. We found that physiological hyperinsulinemia in awake, behaving mice does not increase CNS insulin to an appreciable level yet modestly increases extracellular Aß. We also found that the brain of aged APP/PS1 mice was not insulin resistant, contrary to the current state of the literature. These results further elucidate the relationship between insulin, the brain, and AD and its conflicting roles as both a risk factor and potential treatment.