Astrocyte TNFR2 is required for CXCL12-mediated regulation of oligodendrocyte progenitor proliferation and differentiation within the adult CNS.

Multiple sclerosis (MS) is characterized by episodes of inflammatory demyelination with progressive failure of remyelination. Prior studies using murine models of MS indicate that remyelination within the adult central nervous system (CNS) requires the expression and activity of TNFR2 and CXCR4 by oligodendrocyte progenitor cells (OPCs), promoting their proliferation and differentiation into mature oligodendrocytes. Here, we extend these studies by examining the role of TNFR2 in the expression of the CXCR4 ligand, CXCL12, within the corpus callosum (CC) during cuprizone (CPZ) intoxication and by demonstrating that lentiviral-mediated gene delivery of CXCL12 to the demyelinated CC improves OPC proliferation and myelin expression during remyelination. Activated astrocytes and microglia express both TNFR1 and TNFR2 within the demyelinated CC. However, CPZ intoxicated TNFR2-/- mice exhibit loss of up-regulation of CXCL12 in astrocytes with concomitant decreases in numbers of CXCR4+ NG2+ OPCs within the CC. While CXCR4 antagonism does not affect OPC migration from subventricular zones into the CC, it decreases their proliferation and differentiation within the CC. Stereotactic delivery of lentivirus expressing CXCL12 protein into the CC of acutely demyelinated TNFR2-/- mice increases OPC proliferation and expression of myelin. In contrast, chronically demyelinated wild-type mice, which exhibit significant loss of astrocytes and OPCs, are unable to be rescued via CXCL12 lentivirus alone but instead required engraftment of CXCL12-expressing astrocytes for increased myelin expression. Our results show that TNFR2 activation induces CXCL12 expression in the demyelinated CC via autocrine signaling specifically within astrocytes, which promotes OPC proliferation and differentiation. In addition, gene delivery of critical pro-myelinating proteins might be a feasible approach for the treatment of remyelination failure in MS.

A case for less workup in near hanging.

BACKGROUND: No guidelines exist for the evaluation of patients after near hanging. Most patients receive a comprehensive workup, regardless of examination. We hypothesize that patients with a normal neurologic examination, without major signs or symptoms suggestive of injury, require no additional workup. METHODS: We reviewed medical charts of adult trauma patients who presented to a Level I trauma center between 1995 and 2013 after an isolated near-hanging episode. Demographics, Glasgow Coma Scale (GCS) score, imaging, and management were collected. Patients were stratified by neurologic examination into normal (GCS score = 15) and abnormal (GCS score <15) groups. Comparison between the groups was completed using univariate analyses. RESULTS: One hundred twenty-five patients presented after near hanging: 42 (33.6%) had abnormal GCS score, and 83 (66.4%) were normal. Among the normal patients, seven patients (8.5%) reported cervical spine tenderness; these patients also had abnormal examination findings including dysphagia, dysphonia, stridor, or crepitus. The normal group underwent 133 computed tomography scans and seven magnetic resonance imaging scans, with only two injuries identified: C5 facet fracture and a low-grade vertebral artery dissection. Neither injury required intervention. In patients with normal GCS score, cervical spine tenderness and at least one significant examination finding were 100% sensitive and 79% specific for identifying an underlying injury. CONCLUSION: Patient with normal GCS score, without signs and symptoms of injury, are unnecessarily receiving extensive diagnostic imaging. Imaging should be reserved for patients with cervical spine tenderness and dysphagia, dysphonia, stridor, and/or crepitus without the fear of incomplete workup. All patients with signs of additional trauma or decreased GCS score should be studied based on preexisting protocols. LEVEL OF EVIDENCE: Therapeutic/care management study, level V.

An analysis of omitting biliary tract imaging in 668 subjects admitted to an acute care surgery service with biochemical evidence of choledocholithiasis.

BACKGROUND: No consensus exists for the timing and utility of biliary imaging in patients with preoperative concern for choledocholithiasis. METHODS: Admissions to an acute care surgery service with evidence of choledocholithiasis undergoing same-admission cholecystectomy without preoperative or intraoperative imaging were identified. One-way analysis of variance on the log-transformed outcomes, with the Tukey-Kramer multiple comparison procedure, were used to compare means between groups. RESULTS: A total of 668 patients with elevated but downtrending liver enzymes underwent cholecystectomy without preoperative or intraoperative imaging. Thirty-eight patients (5.7%) had postoperative biliary imaging, of whom 22 (3.3%) had definite choledocholithiasis. One case of postoperative cholangitis occurred which required readmission and endoscopic retrograde cholangiopancreatography with no long-term morbidity. Presenting liver enzymes were significantly higher in the group found to have retained stones postoperatively than those without retained stones. CONCLUSIONS: Patients presenting with biochemical evidence of choledocholithiasis who downtrend preoperatively can be safely managed by cholecystectomy with omission of biliary tract imaging.

Establishing benchmarks for the management of elevated liver enzymes and/or dilated biliary trees in an urban safety net hospital: analysis of 915 subjects.

BACKGROUND: The push for public reporting of outcomes necessitates relevant benchmarks for disease states across different settings. This study establishes benchmarks for choledocholithiasis management in a safety net hospital setting. METHODS: We reviewed all patients admitted to our acute care surgery service with biochemical evidence of choledocholithiasis who underwent same-admission cholecystectomy (CCY) between July 2012 and December 2013. RESULTS: During this 18-month period, 915 patients were admitted with biochemical evidence of choledocholithiasis. Descriptive statistics for the cohort are provided, which include a 51% rate of obesity and 95% rate of pathologic cholecystitis. Conversion rates of 4% and complication rates of 6% were found. The majority had a CCY without biliary imaging (n = 630, 68.9%). CONCLUSIONS: Relevant benchmarks are characterized, and results of a practice pattern of omitting pre- or intraoperative biliary tree imaging are described. These findings serve as a first benchmark of choledocholithiasis management for urban safety net hospitals.