LPS- induced inflammation exacerbates phospho-tau pathology in rTg4510 mice.

Inflammation and microglial activation are associated with Alzheimer's disease (AD) pathology. Somewhat surprisingly, injection of a prototypical inflammatory agent, lipopolysaccharide (LPS) into brains of amyloid precursor protein (APP) transgenic mice clears some of the pre-existing amyloid deposits. It is less well understood how brain inflammation modulates tau pathology in the absence of Aß. These studies examined the role of LPS-induced inflammation on tau pathology. We used transgenic rTg4510 mice, which express the P301L mutation (4R0N TauP301L) and initiate tau pathology between 3-5 months of age. First, we found an age-dependent increase in several markers of microglial activation as these rTg4510 mice aged and tau tangles accumulated. LPS injections into the frontal cortex and hippocampus induced significant activation of CD45 and arginase 1 in rTg4510 and non-transgenic mice. In addition, activation of YM1 by LPS was exaggerated in transgenic mice relative to non-transgenic animals. Expression of Ser199/202 and phospho-tau Ser396 was increased in rTg4510 mice that received LPS compared to vehicle injections. However, the numbers of silver-positive neurons, implying presence of more pre- and mature tangles, was not significantly affected by LPS administration. These data suggest that inflammatory stimuli can facilitate tau phosphorylation. Coupled with prior results demonstrating clearance of Aß by similar LPS injections, these results suggest that brain inflammation may have opposing effects on amyloid and tau pathology, possibly explaining the failures (to date) of anti-inflammatory therapies in AD patients.

Epidemiology of pediatric buprenorphine and methadone exposures reported to the poison centers.

BACKGROUND: Buprenorphine prescriptions have increased dramatically within the United States, whereas methadone continues to be used widely. We investigated the trends and characteristics of buprenorphine and methadone exposures in the pediatric population. METHODS: We identified pediatric exposures to buprenorphine and methadone using the National Poison Data System from 2013 to 2016. We descriptively assessed characteristics of the exposures. Trends in exposures were evaluated using generalized linear mixed models. RESULTS: Pediatric buprenorphine exposures increased from 2013 (1097) to 2016 (1226) while methadone calls decreased (486 to 396). After adjusting for the random effects of the geographical region, the mean number of pediatric buprenorphine exposures (per 100,000 pediatric population) increased from 1.3 to 1.5 (P = .05). Conversely, the mean number of methadone exposures decreased from 0.6 to 0.4 (P = .03). Children aged ≤3 years constituted the highest percentage of both exposures. Unintentional exposures accounted for most of the buprenorphine (86.9%) and methadone (62.4%) exposures. Major clinical effects were demonstrated in 2.3% of buprenorphine exposures and were more frequent with methadone (13%). West Virginia and Maryland demonstrated the highest incidence of buprenorphine and methadone exposures, respectively. CONCLUSIONS: Pediatric buprenorphine exposures increased but demonstrated less severe effects compared to methadone exposures, which decreased during the study period.

Acute hypersensitivity reaction to Crotalidae polyvalent immune Fab (CroFab) as initial presentation of galactose-α-1,3-galactose (α-gal) allergy.

Crotalidae polyvalent immune Fab antivenom (CroFab), commonly used for the treatment of clinically significant North American crotalinae envenomation, is generally well-tolerated. A novel form of anaphylaxis due to an IgE antibody response to the mammalian oligosaccharide galactose-α-1,3-galactose (α-gal) has been established following red-meat consumption as well as IV administration of cetuximab, which contain the α-gal epitope. We present a case of α-gal allergy discovered after acute hypersensitivity reaction to FabAV. A 61-year-old healthy female was bitten on her left ankle by Agkistrodon contortrix. Given the patient's rapid progression of pain and swelling, she was given FabAV. During infusion of FabAV, she developed diffuse hives over her entire body and itching, but denied respiratory or gastrointestinal symptoms and her vital signs remained stable. The FabAV was immediately discontinued and she received intravenous diphenhydramine and famotidine with gradual resolution of symptoms. On further discussion, she denied a history of α-gal or papaya allergy but rarely ate red meat and endorsed sustaining frequent tick bites. Subsequent antibody testing was significant for an α-1,3-galactose IgE concentration of 45,000 U/L (normal <3500 U/L), confirming α-gal allergy. To our knowledge, this is the first report of FabAV hypersensitivity associated with an underlying α-gal allergy.

Computer navigation and distal femoral reconstruction in the oncologic patient.

OBJECTIVES: As adjuvant treatments for musculoskeletal malignancies improve expectations of preserved function increase. We questioned whether computer navigation for distal femoral reconstruction would improve outcomes. METHODS: Twenty oncology patients were reviewed after distal femoral reconstruction using navigation. Outcomes included local recurrence, implant revision, patient function, patellofemoral complications and leg-length inequality. RESULTS: Implant survivorship was 85% at 26 months. There were no local recurrences and 3 failures for aseptic loosening. Good functional outcomes were observed in remaining cases. CONCLUSION: Computer navigation for distal femoral reconstruction resulted in acceptable functional outcomes and implant survivorship. Reduced local recurrence were observed at intermediate follow-up. Level of Evidence: Level IV.

Aging enhances classical activation but mitigates alternative activation in the central nervous system.

The roles of microglia and macrophages during neuroinflammation and neurodegenerative diseases remain controversial. To date, at least 2 activations states have been suggested, consisting of a classical response (M1) and the alternative response (M2). Identifying selective biomarkers of microglia that representative their functional activation states may help elucidate disease course and enable a better understanding of repair mechanisms. Two cocktails containing either tumor necrosis factor (TNF)-α, interleukin (IL)-12, and IL-1ß (referred to as CKT-1) or IL-13 and IL-4 (referred to CKT-2) were injections into the hippocampus of mice aged 6, 12, or 24 months. Microarray analysis was performed on hippocampal tissue 3 days postinjection. Gene transcripts were compared between CKT-1 versus CKT-2 stimulator cocktails. Several selective transcripts expressed for the CKT-1 included CXCL13, haptoglobin, MARCO, and calgranulin B, whereas a smaller subset of genes was selectively induced by the CKT-2 and consisted of FIZZ1, IGF-1, and EAR 11. Importantly, selective transcripts were induced at all ages by CKT-1, whereas selective gene transcripts induced by CKT-2 decreased with age suggesting an age-related reduction in the IL-4/ IL-13 signaling pathway.