mGlu1 tonically regulates levels of calcium-permeable AMPA receptors in cultured nucleus accumbens neurons through retinoic acid signaling and protein translation.

In several brain regions, ongoing metabotropic glutamate receptor 1 (mGlu1) transmission has been shown to tonically suppress synaptic levels of Ca2+ -permeable AMPA receptors (CP-AMPARs) while pharmacological activation of mGlu1 removes CP-AMPARs from these synapses. Consistent with this, we previously showed in nucleus accumbens (NAc) medium spiny neurons (MSNs) that reduced mGlu1 tone enables and mGlu1 positive allosteric modulation reverses the elevation of CP-AMPAR levels in the NAc that underlies enhanced cocaine craving in the "incubation of craving" rat model of addiction. To better understand mGlu1/CP-AMPAR interactions, we used a NAc/prefrontal cortex co-culture system in which NAc MSNs express high CP-AMPAR levels, providing an in vitro model for NAc MSNs after the incubation of cocaine craving. The non-specific group I orthosteric agonist dihydroxyphenylglycine (10 min) decreased cell surface GluA1 but not GluA2, indicating CP-AMPAR internalization. This was prevented by mGlu1 (LY367385) or mGlu5 (MTEP) blockade. However, a selective role for mGlu1 emerged in studies of long-term antagonist treatment. Thus, LY367385 (24 hr) increased surface GluA1 without affecting GluA2, whereas MTEP (24 hr) had no effect. In hippocampal neurons, scaling up of CP-AMPARs can occur through a mechanism requiring retinoic acid (RA) signaling and new GluA1 synthesis. Consistent with this, the LY367385-induced increase in surface GluA1 was blocked by anisomycin (translation inhibitor) or 4-(diethylamino)-benzaldehyde (RA synthesis inhibitor). Thus, mGlu1 transmission tonically suppresses cell surface CP-AMPAR levels, and decreasing mGlu1 tone increases surface CP-AMPARs via RA signaling and protein translation. These results identify a novel mechanism for homeostatic plasticity in NAc MSNs.

A Rare Case of Esophageal Carcinoma Cuniculatum Palliated by Esophageal and Endobronchial Stenting.

Carcinoma cuniculatum is a rare variant of well-differentiated squamous cell carcinoma. To date, there are less than 30 cases of esophageal carcinoma cuniculatum reported. It is frequently a diagnostic challenge: A definitive diagnosis typically cannot be made before esophagectomy. We present a uniquely aggressive case of esophageal carcinoma cuniculatum complicated by a bronchoesophageal fistula and successfully palliated with dual esophageal and endobronchial stenting.

Impact of technique on cushing disease outcome using strict remission criteria.

BACKGROUND: Cushing disease (CD) constitutes a challenging condition for the pituitary surgeon. Given the variety of factors affecting outcomes in CD, it is uncertain whether the newer endoscopic technique improves the results of surgery. METHODS: A review was conducted of CD cases at our institution between 2000 and 2010. Analysis was done to: determine if surgical technique had an effect on outcome, identify the predictors of outcome and provide details of failed cases. Remission was defined as normal postoperative 24-hour urinary free cortisol (24-h UFC), suppression of morning serum cortisol to <50 nmol/L after 1mg of dexamethasone or being dependent on steroid replacement. RESULTS: Forty-two patients met our inclusion criteria. Average follow-up period was 33 months. There were 15 macroadenomas and 27 microadenomas. Seventeen patients had an endoscopic transsphenoidal surgery and twenty-five patients had a microscopic transsphenoidal procedure. Long-term overall remission was achieved in 26 (62%) patients. There was no significant difference in remission rates between the two techniques (p value 0.757). Patient's subjective symptomatic improvement and drop of morning serum cortisol in the postoperative period to less than 100 nmol/L correlated with long-term remission (p value 0.0031 and 0.0101, respectively) while repeat surgery was the only predictor of the lack of postoperative remission (p value 0.0008). CONCLUSIONS: Revision surgery predicted poor remission rate for CD. Within the power of our study size, there was no difference in outcome between the endoscopic and microscopic approaches. Surgical outcomes should be reviewed in association with remission criteria used in a study.

Case Report: Culture-negative Prosthetic Valve Endocarditis.

BACKGROUND: Prosthetic valve endocarditis can be difficult to diagnose and cause significant morbidity and mortality, especially when no culture data are available to guide therapy. Transthoracic and transesophageal echocardiograms, the studies of choice for initial endocarditis evaluation, can be less reliable due to artifact and post-surgical changes. Some less common forms of endocarditis may be difficult to culture and, due to their fastidious nature, may delay the identification of causative organisms. Given the lack of directed antimicrobial treatment, culturenegative prosthetic valve endocarditis is specifically difficult. A wide differential diagnosis is critical to make a timely diagnosis and initiate treatment. CASE PRESENTATION: We present a case of a patient presenting with dyspnea which was found to have culture-negative endocarditis requiring mitral and aortic valve replacement that ultimately was complicated with culture-negative prosthetic valve endocarditis. Identifying a culprit organism made appropriate and timely antimicrobial treatment difficult, ultimately resulting in the patient dying from endocarditis complications. CONCLUSION: A high index of suspicion is needed when managing infective endocarditis, especially when prosthetic valves are involved. Diagnostic accuracy of cultures and echocardiography may be reduced when dealing with prosthetic valve endocarditis; thus, alternative methods of diagnosis may be required to make a timely diagnosis of causative organisms.

Racial Differences in the Utilization of Guideline-Recommended and Life-Sustaining Procedures During Hospitalizations for Out-of-Hospital Cardiac Arrest.

BACKGROUND: Racial and ethnic minorities are at risk for disparities in quality of care after out-of-hospital cardiopulmonary arrest (OHCA). As such, we examined associations between race and ethnicity and use of guideline-recommended and life-sustaining procedures during hospitalizations for OHCA. METHODS: This was a retrospective study of hospitalizations for OHCA in all acute-care, non-federal California hospitals from 2009 to 2011. Associations between the use of (1) guideline-recommended procedures (cardiac catheterization for ventricular fibrillation/tachycardia, therapeutic hypothermia), (2) life-sustaining procedures (percutaneous endoscopic gastrostomy (PEG)/tracheostomy, renal replacement therapy (RRT)), and (3) palliative care and race/ethnicity were examined using hierarchical logistic regression analysis. RESULTS: Among 51,198 hospitalizations for OHCA, unadjusted rates of cardiac catheterization were 34.9% in Whites, 19.8% in Blacks, 27.2% in Hispanics, and 30.9% in Asians (P < 0.01). Rates of therapeutic hypothermia were 2.3% in Whites, 1.1% in Blacks, 1.3% in Hispanics, and 1.9% in Asians (P < 0.01). Rates of PEG/tracheostomy and RRT were 2.2% and 9.8% in Whites, 5.7% and 19.9% in Blacks, 4.2% and 19.9% in Hispanics, and 3.4% and 18.2% in Asians, respectively (P < 0.01). Rates of palliative care were 14.8% in Whites, 9.6% in Blacks, 10.1% in Hispanics, and 14.3% in Asians (P < 0.01). Differences in utilization of procedures persisted after adjustment for patient and hospital-related factors. CONCLUSION: Racial and ethnic minorities are less likely to receive guideline-recommended interventions and palliative care, and more likely to receive life-sustaining treatments following OHCA. These findings suggest that significant disparities exist in medical care after OHCA.

Correction to: Racial Differences in the Utilization of Guideline-Recommended and Life-Sustaining Procedures During Hospitalizations for Out-of-Hospital Cardiac Arrest.

There was an error in Fig. 1 as published in this article, and the Hemodialysis and Palliative Care titles in the figure are reversed.

Trafficking of calcium-permeable and calcium-impermeable AMPA receptors in nucleus accumbens medium spiny neurons co-cultured with prefrontal cortex neurons.

AMPA receptor (AMPAR) transmission onto medium spiny neurons (MSNs) of the adult rat nucleus accumbens (NAc) is normally dominated by GluA2-containing, Ca2+-impermeable AMPAR (CI-AMPARs). However, GluA2-lacking, Ca2+-permeable AMPA receptors (CP-AMPARs) accumulate after prolonged withdrawal from extended-access cocaine self-administration and thereafter their activation is required for the intensified (incubated) cue-induced cocaine craving that characterizes prolonged withdrawal from such regimens. These findings suggest the existence of mechanisms in NAc MSNs that differentially regulate CI-AMPARs and CP-AMPARs. Here, we compared trafficking of GluA1A2 CI-AMPARs and homomeric GluA1 CP-AMPARs using immunocytochemical assays in cultured NAc MSNs plated with prefrontal cortical neurons to restore excitatory inputs. We began by evaluating constitutive internalization of surface receptors and found that this occurs more rapidly for CP-AMPARs. Next, we studied receptor insertion into the membrane; combined with past results, the present findings suggest that activation of protein kinase A accelerates insertion of both CP-AMPARs and CI-AMPARs. We also studied constitutive cycling (net loss of receptors from the membrane under conditions where internalization and recycling are both occurring). Interestingly, although CP-AMPARs exhibit faster constitutive internalization, they cycle at similar rates as CI-AMPARs, suggesting faster reinsertion of CP-AMPARs. In studies of synaptic scaling, long-term (24 h) activity blockade increased surface expression and cycling rates of CI-AMPARs but not CP-AMPARs, whereas long-term increases in activity produced more pronounced scaling down of CI-AMPARs than CP-AMPARs but did not alter receptor cycling. These findings can be used to evaluate and generate hypotheses regarding AMPAR plasticity in the rat NAc following cocaine exposure.

Metabolic syndrome increases the prevalence of spine osteoarthritis.

OBJECTIVE: To determine whether the prevalence of severe spinal osteoarthritis (OA) increases with the number of metabolic syndrome (MetS) risk factors. METHODS: Data from a single surgeon's high volume, spine surgery practice were reviewed. Severe OA was defined as degenerative spondylolisthesis or cervical or lumbar stenosis causing neurologically based symptoms and early OA as lumbar and cervical spondylosis causing axial pain only. Logistic regression modeling was used to determine the odds (adjusted for age and sex) of having severe spine OA with more numerous MetS risk factors. RESULTS: Severe spinal OA was identified in 839/1502 patients (55.9%) and early OA in the remaining 663 individuals (44.1%). The overall prevalence of MetS was 30/1502 (2.0%): 26/839 (3.1%) in the severe OA group and 4/663 (0.6%) in the early OA group (P = 0.001). Presence of all four MetS risk factors was associated with almost quadruple the odds of having severe OA as compared with absence of risk factors (OR 3.9 [1.4-11.6], P < 0.01). CONCLUSION: The components of MetS are more prevalent in subjects with severe spinal OA than in those with spondylosis causing axial pain. Future study of the association between MetS and the incidence of OA is required.

Risk prediction models for mortality in community-acquired pneumonia: a systematic review.

BACKGROUND: Several models have been developed to predict the risk of mortality in community-acquired pneumonia (CAP). This study aims to systematically identify and evaluate the performance of published risk prediction models for CAP. METHODS: We searched MEDLINE, EMBASE, and Cochrane library in November 2011 for initial derivation and validation studies for models which predict pneumonia mortality. We aimed to present the comparative usefulness of their mortality prediction. RESULTS: We identified 20 different published risk prediction models for mortality in CAP. Four models relied on clinical variables that could be assessed in community settings, with the two validated models BTS1 and CRB-65 showing fairly similar balanced accuracy levels (0.77 and 0.72, resp.), while CRB-65 had AUROC of 0.78. Nine models required laboratory tests in addition to clinical variables, and the best performance levels amongst the validated models were those of CURB and CURB-65 (balanced accuracy 0.73 and 0.71, resp.), with CURB-65 having an AUROC of 0.79. The PSI (AUROC 0.82) was the only validated model with good discriminative ability among the four that relied on clinical, laboratorial, and radiological variables. CONCLUSIONS: There is no convincing evidence that other risk prediction models improve upon the well-established CURB-65 and PSI models.

Chest x-ray as a screening tool for blunt thoracic trauma in children.

BACKGROUND: With the increasing use of thoracic computed tomography (CT) to screen for injuries in pediatric blunt thoracic trauma (BTT), we determined whether chest x-ray (CXR) and other clinical and epidemiologic variables could be used to predict significant thoracic injuries, to inform the selective use of CT in pediatric BTT. We further queried if these were discrepant from factors associated with the decision to obtain a thoracic CT. METHODS: This retrospective cohort study included cases of BTT from three Level I pediatric trauma centers between April 1999 and March 2008. Pre-CT epidemiologic, clinical, and radiologic variables associated with CT findings of any thoracic injury or a significant thoracic injury as well as the decision to obtain a thoracic CT were determined using logistic regression. RESULTS: Of 425 patients, 40% patients had a significant thoracic injury, 49% had nonsignificant thoracic injury, and 11% had no thoracic injury at all. Presence of hydrothorax and/or pneumothorax on CXR significantly increased the likelihood of significant chest injury visualized by CT (adjusted odds ratio 10.8; 95% confidence interval, 6.5-18), as did the presence of isolated subcutaneous emphysema (adjusted odds ratio, 19.8; 95% confidence interval, 2.3-168). Although a normal CXR finding was not statistically associated with a reduced risk of significant thoracic injury, 8 of the 9 cases with normal CXR findings and significant injuries involved occult pneumothoraces or hemothoraces not requiring intervention. Converse to features suggesting increased risk of significant injury, the decision to obtain a thoracic CT was only associated with later period in the study and obtaining a CT scan of another body region. CONCLUSION: CXR can be used to screen for significant thoracic injuries and direct the selective use of thoracic CT in pediatric BTT. Prospective studies are needed to validate these findings and develop guidelines that include CXR to define indications for thoracic CT in pediatric BTT. LEVEL OF EVIDENCE: Prognostic study, level III.