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Significant evidence suggests that misfolded alpha‐synuclein (aSyn), a major component of Lewy bodies, propagates in a prion‐like manner contributing to disease progression in Parkinson's disease (PD) and other synucleinopathies. In fact, timed inoculation of M83 hemizygous mice with recombinant human aSyn preformed fibrils (PFF) has shown symptomatic deficits after substantial spreading of pathogenic alpha‐synuclein, as detected by markers for the phosphorylation of S129 of aSyn. However, whether accumulated toxicity impact human‐relevant cognitive and structural neuroanatomical measures is not fully understood. Here we performed a single unilateral striatal PFF injection in M83 hemizygous mice, and using two assays with translational potential, ex vivo magnetic resonance imaging (MRI) and touchscreen testing, we examined the combined neuroanatomical and behavioral impact of aSyn propagation. In PFF‐injected mice, we observed widespread atrophy in bilateral regions that project to or receive input from the injection site using MRI. We also identified early deficits in reversal learning prior to the emergence of motor symptoms. Our findings highlight a network of regions with related cellular correlates of pathology that follow the progression of aSyn spreading, and that affect brain areas relevant for reversal learning. Our experiments suggest that M83 hemizygous mice injected with human PFF provides a model to understand how misfolded aSyn affects human‐relevant pre‐clinical measures and suggest that these pre‐clinical biomarkers could be used to detect early toxicity of aSyn and provide better translational measures between mice and human disease. [ABSTRACT FROM AUTHOR]

An editorial is presented on proper allergy documentation into an electronic health record (EHR) playing a key role in patient safety. Topics include utilizing codified allergy information within clinical decision support allowing for safety alerts notifying clinicians to the potential for harm with the administration of certain medications; and large integrated health system fortifying the EHR due to the lack of native functionality.

BACKGROUND: Asparaginase agents are vital in the treatment of acute lymphoblastic leukemia (ALL) and can be delivered via an intravenous (IV) or intramuscular (IM) injection. Hypersensitivity reaction (HSR) rates with these agents are common, multifactorial, and treatment-altering. The specific route of asparaginase administration may lead to disparate rates of HSRs and other adverse events in pediatric patients with ALL. OBJECTIVE: To analyze the role of administration route in the incidence and severity of adverse events in pediatric patients receiving asparaginase therapy. METHODS: This single-center, retrospective analysis evaluated patients receiving pegaspargase or Erwinia asparaginase from January 1, 2008, through September 30, 2015. The primary outcome measured the incidence of HSRs with IV or IM pegaspargase and IV or IM Erwinia asparaginase. Secondary outcomes included the potential role of administration route on the timing and rate of adverse drug events. RESULTS: A total of 368 patients received pegaspargase during the study period. Of this group, 199 received only IV pegaspargase, 138 received only IM pegaspargase, and 31 received both IV and IM pegaspargase. Overall, HSRs occurred in 18.6% of patients who received IV administration and 13.8% who received IM administration (P = .241). Among patients who received both routes during ALL treatment, 9.7% had an HSR. A total of 43 (76.8%) patients had an HSR during the consolidation phase of therapy. A total of 517 Erwinia asparaginase doses were administered, and only 1 patient had an HSR. We found increased antiemetic use in 28 (36.4%) of 77 IV Erwinia asparaginase doses compared with only 28 (6.4%) of 440 IM doses (P <.001). CONCLUSION: Our findings showed no significant difference in HSR rates between patients receiving IV pegaspargase and those receiving IM pegaspargase. Hypersensitivity resulting from Erwinia asparaginase were infrequent, and IV Erwinia asparaginase administration displayed more emetogenicity than the traditional IM route. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Patients with ulcerative colitis (UC) are at increased risk for developing colorectal cancer (CRC). Surveillance in this at-risk population remains challenging. We assessed the methylation status of genes in the non-neoplastic mucosa of UC–CRC patients and controls to identify potential biomarkers of CRC.METHODS:We evaluated the methylation status of 10 genes (p16, p14, runt-related transcript factor-3 (RUNX3), cyclooxygenase-2 (COX-2), E-cadherin, methylated-in-tumor-1 (MINT1), MINT31, HPP1, estrogen receptor, SLC5A8) in UC–CRC tumors and non-neoplastic sections from both UC–CRC cases and UC controls (n=114 for each) using methylation-specific PCR.RESULTS:Amplification was successful for 96 UC controls, 83 tumors, and 66 non-adjacent, non-neoplastic samples. The prevalence of methylation was significantly greater in UC–CRC tumors for p16, RUNX3, MINT1, MINT31, and HPP1. Methylation of COX-2 and E-cadherin was greater in UC controls than in tumors. Univariate testing of these genes using non-adjacent, non-neoplastic sections from UC–CRC cases indicated that associations between p16, RUNX3, MINT1, MINT31, E-cadherin, and COX-2 and UC–CRC remained significant. In multivariable analysis of the six genes, only RUNX3, MINT1, and COX-2 remained significantly associated with the UC–CRC cases (odds ratio=12.6, 9.0, and 0.2, respectively). The results remained unaffected by the presence of PSC or severity of inflammation. Logistic regression modeling with the three genes showed interactions that increased the odds ratio for each gene.CONCLUSIONS:RUNX3, MINT1, and COX-2 are potential biomarkers for detecting the presence of CRC in patients with UC. These genes should be evaluated as biomarkers for colorectal dysplasia. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Ulcerative colitis (UC) is characterized by chronic recurrent mucosal inflammation. Genetic studies in UC have indicated linkage to chromosome 6 in the region of the tumor necrosis factor-alpha (TNF-α) gene, a potent proinflammatory cytokine. TNF-α production is influenced by multiple factors including the type of immune cell and its level of activation. However, several single nucleotide polymorphisms (SNP) in the promoter region of TNF-α have been correlated with either increased or decreased production, indicating that regulation of TNF-α is in part genetic. Because UC patients are at increased risk for developing colorectal cancer (CRC), we investigated if there was an association between SNPs in the promoter of the TNF-α gene and UC-CRC. METHODS: DNA was extracted from formalin-fixed, paraffin-embedded tissue from 114 UC-CRC cases and 114 UC-no CRC controls. Controls were frequency matched on duration and extent of colitis, age, ethnicity, and gender. All 228 tissue samples were analyzed for five TNF-α promoter polymorphisms (−238[G→A], −308[G→A], −857[C→T], −863[C→A], and −1031[T→C]) using PCR and sequencing. RESULTS: The −308(G→A) SNP was significantly associated with UC-CRC cases at both the allele and genotype level ( P < 0.0001). No other SNPs were significantly associated with UC-CRC. CONCLUSION: We report a novel finding of a strong association between the −308(G→A) SNP and UC-CRC. Complete elucidation of the mechanism of UC-CRC carcinogenesis will require investigation of other genes involved in modulating inflammation, but our results suggest that some UC patients may have additional genetic predispositions toward developing UC-CRC. [ABSTRACT FROM AUTHOR]