Recent Publications by CFE Educators

Dendritic spines undergo the processes of formation, maturation, and pruning during development. Molecular mechanisms controlling spine maturation and pruning remain largely unknown. The gene for brain-derived neurotrophic factor (BDNF) produces two pools of mRNA, with either a short or long 3' untranslated region (3' UTR). Our previous results show that short 3' UTR Bdnf mRNA is restricted to cell bodies, whereas long 3' UTR Bdnf mRNA is also trafficked to dendrites for local translation. Mutant mice lacking long 3' UTR Bdnf mRNA display normal spines at 3 weeks of age, but thinner and denser spines in adults compared to wild-type littermates. These observations suggest that BDNF translated from long 3' UTR Bdnf mRNA, likely in dendrites, is required for spine maturation and pruning. In this study, using rat hippocampal neuronal cultures, we found that knocking down long 3' UTR Bdnf mRNA blocked spine head enlargement and spine elimination, whereas overexpressing long 3' UTR Bdnf mRNA had the opposite effect. The effect of long 3' UTR Bdnf mRNA on spine head enlargement and spine elimination was diminished by a human single-nucleotide polymorphism (SNP, rs712442) in its 3' UTR that inhibited dendritic localization of Bdnf mRNA. Furthermore, we found that overexpression of either Bdnf mRNA increased spine density at earlier time points. Spine morphological alterations were associated with corresponding changes in density, size, and function of synapses. These results indicate that somatically synthesized BDNF promotes spine formation, whereas dendritically synthesized BDNF is a key regulator of spine head growth and spine pruning.

OBJECTIVE

Trauma and infection have been postulated as "triggers" for hemorrhage from underlying brain vascular lesions (arteriovenous malformations, cavernous malformations, and aneurysms) in pediatric hemorrhagic stroke. We decided to perform an association study examining these environmental risk factors.

METHODS

In this case-control study nested within the cohort of 2.3 million children enrolled in a Northern California integrated health plan (1993-2004), we identified childhood hemorrhagic stroke cases through electronic searches of diagnostic and radiology databases, confirmed through chart review. Three age- and facility-matched controls per case were randomly selected from the study population. Exposure variables were measured using medical records documented before stroke diagnosis. Main outcome measure was hemorrhagic stroke.

RESULTS

Of 132 childhood, non-neonatal hemorrhagic stroke cases, 65 had underlying vascular lesions: 34 arteriovenous malformations, 16 cavernous malformations, and 15 aneurysms. A documented exposure to head and neck trauma in the prior 12 weeks was present in 3 cases (4.6%) with underlying vascular lesions, compared with no controls (p 0.015). However, all 3 vascular lesions were aneurysms, and traumatic pseudoaneurysms were possible. Recent minor infection (prior 4 weeks) was present in 5 cases (7.7%) and 9 controls (4.6%) (p = 0.34).

CONCLUSIONS

Our observed association between trauma and hemorrhagic stroke with a vascular lesion may be explained by traumatic pseudoaneurysms. Neither recent head or neck trauma nor infection appeared to be a "trigger" for pediatric hemorrhagic stroke due to underlying vascular malformations.

Matrix metalloproteinases (MMPs) are zinc dependent endopeptidases that can be released from neurons in an activity dependent manner to play a role in varied forms of learning and memory. MMP inhibitors impair hippocampal long term potentiation (LTP), spatial memory, and behavioral correlates of drug addiction. Since MMPs are thought to influence LTP through a β1 integrin dependent mechanism, it has been suggested that these enzymes cleave specific substrates to generate integrin binding ligands. In previously published work, we have shown that neuronal activity stimulates rapid MMP dependent shedding of intercellular adhesion molecule-5 (ICAM-5), a synaptic adhesion molecule expressed on dendrites of the telencephalon. We have also shown that the ICAM-5 ectodomain can interact with β1 integrins to stimulate integrin dependent phosphorylation of cofilin, an event that occurs with dendritic spine maturation and LTP. In the current study, we investigate the potential for the ICAM-5 ectodomain to stimulate changes in α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR) dependent glutamatergic transmission. Single cell recordings show that the ICAM-5 ectodomain stimulates an increase in the frequency, but not the amplitude, of AMPA mini excitatory post synaptic currents (mEPSCs). With biotinylation and precipitation assays, we also show that the ICAM-5 ectodomain stimulates an increase in membrane levels of GluA1, but not GluA2, AMPAR subunits. In addition, we observe an ICAM-5 associated increase in GluA1 phosphorylation at serine 845. Concomitantly, ICAM-5 affects an increase in GluA1 surface staining along dendrites without affecting an increase in dendritic spine number. Together these data are consistent with the possibility that soluble ICAM-5 increases glutamatergic transmission and that post-synaptic changes, including increased phosphorylation and dendritic insertion of GluA1, could contribute. We suggest that future studies are warranted to determine whether ICAM-5 is one of a select group of synaptic CAMs whose shedding contributes to MMP dependent effects on learning and memory.

BACKGROUND

Differentiated thyroid cancer (DTC) with distant metastases at presentation is uncommon; the prognosis of patients with this condition is more favorable than for other cancers. Demographic, clinical, and pathologic characteristics are described at a population level; factors associated with long-term disease-specific survival are identified.

METHODS

Patients were identified in the Surveillance, Epidemiology, and End Results (SEER) database between 1988 and 2009. They were divided into two groups: patients with distant metastases (met-DTC) and patients without distant metastases (DTC) at presentation. Data analyses were performed with chi square tests, ANOVA, Kaplan-Meier analysis, and binary logistic and Cox proportional hazards regression.

RESULTS

A total of 1,291 patients with met-DTC at diagnosis and 58,518 with DTC were included. The met-DTC rate was 2.2 %; compared to DTC, met-DTC patients were more often male (22.7 vs 41.3 %, respectively; p 0.001) and older (mean 48.8 vs 62.7 years; p 0.001). Patients with met-DTC were more likely not to have had surgery (23.3 vs 2.0 %; p 0.001) or to have received radiation therapy (RAI) (66.8 vs 46.5 %; p 0.001). Met-DTC tumors were larger (mean 41.0 vs 20.5 mm; p 0.001). Independent factors associated with distant metastases were male gender, older age, single status, black and "other" races, follicular and Hurthle cell histology, larger tumors, and positive regional lymph nodes. Disease-specific survival was lower for met-DTC; this has not improved over the past two decades (p = 0.494). Independent factors associated with mortality included patient age ≥ 45 years, single status, follicular and Hurthle cell histologies, tumor size >4 cm, and not receiving surgery and/or RAI.

CONCLUSIONS

Overall, met-DTC is uncommon. Given the lack of survival improvement observed over the last two decades, novel treatments should be pursued aggressively for this subset of patients.

Lymph node metastases in papillary thyroid cancer are a common occurrence; however, the management of clinically negative cervical lymph nodes remains controversial. Preoperative neck ultrasound mapping is crucial, and complete dissection of a nodal compartment is recommended for any metastatic lymph nodes. The role of prophylactic central neck dissection remains controversial. The BRAF V600E mutation is a common mutation in papillary thyroid cancer, and has been associated with more aggressive tumor behavior. Evaluating the BRAF status of tumors may have implications for treatment and surveillance. New areas of research continue to focus on risk stratification and identifying which patients benefit from a more aggressive treatment, such as prophylactic central lymphadenectomy and radioiodine ablation and more intense surveillance strategies.

Pain is a ubiquitous problem, affecting more than 100 million individuals in the United States chronically and many more in the acute setting. Up to three-quarters of patients presenting to the emergency department (ED) report pain as a key component of their reasons for requiring acute care. While pain management is a fundamental component of emergency medicine (EM), there are numerous attitudinal and structural barriers that have been identified to effectively providing pain control in the ED. Coupled with public demands and administrative mandates, concerns surrounding ED pain management have reached a crisis level that should be considered an ethical issue in the profession of EM. In this article, the authors propose an ethical framework based on a combination of virtue, narrative, and relationship theories that can be used to address the clinical dilemmas that arise in managing pain in ED patients.