Regulation of the Ca2+ Channel CaV1.2 Supports Spatial Memory and Its Flexibility and LTD.

Widespread release of norepinephrine (NE) throughout the forebrain fosters learning and memory via adrenergic receptor (AR) signaling, but the molecular mechanisms are largely unknown. The ß2 AR and its downstream effectors, the trimeric stimulatory Gs-protein, adenylyl cyclase (AC), and the cAMP-dependent protein kinase A (PKA), form a unique signaling complex with the L-type Ca2+ channel (LTCC) CaV1.2. Phosphorylation of CaV1.2 by PKA on Ser1928 is required for the upregulation of Ca2+ influx on ß2 AR stimulation and long-term potentiation induced by prolonged theta-tetanus (PTT-LTP) but not LTP induced by two 1-s-long 100-Hz tetani. However, the function of Ser1928 phosphorylation in vivo is unknown. Here, we show that S1928A knock-in (KI) mice of both sexes, which lack PTT-LTP, express deficiencies during initial consolidation of spatial memory. Especially striking is the effect of this mutation on cognitive flexibility as tested by reversal learning. Mechanistically, long-term depression (LTD) has been implicated in reversal learning. It is abrogated in male and female S1928A knock-in mice and by ß2 AR antagonists and peptides that displace ß2 AR from CaV1.2. This work identifies CaV1.2 as a critical molecular locus that regulates synaptic plasticity, spatial memory and its reversal, and LTD.SIGNIFICANCE STATEMENT We show that phosphorylation of the Ca2+ channel CaV1.2 on Ser1928 is important for consolidation of spatial memory and especially its reversal, and long-term depression (LTD). Identification of Ser1928 as critical for LTD and reversal learning supports the model that LTD underlies flexibility of reference memory.

Effects of TRAM-34 and minocycline on neuroinflammation caused by diabetic ketoacidosis in a rat model.

INTRODUCTION: Diabetic ketoacidosis (DKA) causes acute and chronic neuroinflammation that may contribute to cognitive decline in patients with type 1 diabetes. We evaluated the effects of agents that reduce neuroinflammation (triarylmethane-34 (TRAM-34) and minocycline) during and after DKA in a rat model. RESEARCH DESIGN AND METHODS: Juvenile rats with DKA were treated with insulin and saline, either alone or in combination with TRAM-34 (40 mg/kg intraperitoneally twice daily for 3 days, then daily for 4 days) or minocycline (45 mg/kg intraperitoneally daily for 7 days). We compared cytokine and chemokine concentrations in brain tissue lysates during DKA among the three treatment groups and in normal controls and diabetic controls (n=9-15/group). We also compared brain inflammatory mediator levels in these same groups in adult diabetic rats that were treated for DKA as juveniles. RESULTS: Brain tissue concentrations of chemokine (C-C) motif ligand (CCL)3, CCL5 and interferon (IFNγ) were increased during acute DKA, as were brain cytokine composite scores. Both treatments reduced brain inflammatory mediator levels during acute DKA. TRAM-34 predominantly reduced chemokine concentrations (chemokine (C-X-C) motif ligand (CXCL-1), CCL5) whereas minocycline had broader effects, (reducing CXCL-1, tumor necrosis factor (TNFα), IFNγ, interleukin (IL) 2, IL-10 and IL-17A). Brain inflammatory mediator levels were elevated in adult rats that had DKA as juveniles, compared with adult diabetic rats without previous DKA, however, neither TRAM-34 nor minocycline treatment reduced these levels. CONCLUSIONS: These data demonstrate that both TRAM-34 and minocycline reduce acute neuroinflammation during DKA, however, treatment with these agents for 1 week after DKA does not reduce long-term neuroinflammation.

Heart block and cardiac embolization of fractured inferior vena cava filter.

OBJECTIVE: A 66-year-old man underwent a placement of an inferior vena cava filter before a gastric surgery 9 years prior, presented to the emergency room with a complete atrioventricular block. Chest x-ray and transthoracic echocardiogram showed struts migrating to right ventricle with tricuspid regurgitation. Cardiothoracic surgery was consulted and declined an open surgical intervention due to the location of the embolized fragments and the patient's overall condition. It was also felt that the fragments had migrated chronically and were adhered to the cardiac structures. METHODS: The patient underwent a dual-chamber permanent pacemaker implantation. Post-implant fluoroscopy showed no displacement of the inferior vena cava filter struts due to the pacemaker leads indicating that the filter fracture had likely been a chronic process. RESULTS: This case highlights a rare combination of complications related to inferior vena cava filter fractures and the importance of assessing for such fractures in chronic placements. Inferior vena cava filter placement for a duration greater than 1 month can be associated with filter fractures and strut migration which may lead to, although rare, serious or fatal complications such as complete atrioventricular conduction system disruption and valvular damage including significant tricuspid regurgitation. CONCLUSIONS: Assessing for inferior vena cava filter fractures in chronic filter placement is important to avoid such complications. When possible, retrieval of the filter should be considered in all patients outside the acute setting in order to avoid filter-related complications. Filter retrieval rates remain low even when a retrievable filter is in place and the patient no longer has a contraindication to anticoagulation.

Pocket salvage in patients with infected device pocket and limited vascular access: a viable last resort?

This case study describes a pocket salvage procedure in a patient with a device pocket infection and limited vascular access. This case report also provides a literature review of recent studies addressing the success of pocket salvage procedures in patients not showing any signs of systemic infection.

A rapid, safe, and low-cost technique for the induction of mild therapeutic hypothermia in post-cardiac arrest patients.

AIM OF STUDY: The benefits of inducing mild therapeutic hypothermia (MTH) in cardiac arrest patients are well established. Timing and speed of induction have been related to improved outcomes in several animal trials and one human study. We report the results of an easily implemented, rapid, safe, and low-cost protocol for the induction of MTH. METHODS: All in-hospital cardiac arrest (IHCA) and out-of-hospital cardiac arrest (OHCA) patients admitted to an intensive care unit meeting inclusion criteria were cooled using a combination modality of rapid, cold saline infusion (CSI), evaporative surface cooling, and ice water gastric lavage. Cooling tasks were performed with a primary emphasis on speed. The main endpoints were the time intervals between return of spontaneous circulation (ROSC), initiation of hypothermia (IH), and achievement of target temperature (TT). RESULTS: 65 patients underwent MTH during a 3-year period. All patients reached target temperature. Median ROSC-TT was 134min. Median ROSC-IH was 68min. Median IH-TT was 60min. IH-TT cooling rate was 2.6°C/h. Complications were similar to that of other large trials. 31% of this mixed population of IHCA and OHCA patients recovered to a Pittsburgh cerebral performance score (CPC) of 1 or 2. CONCLUSION: A protocol using a combination of core and surface cooling modalities was rapid, safe, and low cost in achieving MTH. The cooling rate of 2.6°C/h was superior to most published protocols. This method uses readily available equipment and reduces the need for costly commercial devices.

Management of ventricular tachycardia in patients with structural heart disease.

Patients with structural heart disease and ventricular tachycardia (VT) can be difficult to manage clinically. Many treatment options are available, but no single approach can be applied to every patient. This review aims to discuss the current options available for the management of this population. VT can be associated with cardiomyopathy of any etiology, both ischemic and nonischemic. Antiarrhythmic drugs have not been shown to decrease mortality in this patient population, but they can help reduce episodes. While the advent of the implantable cardioverter-defibrillator has revolutionized the treatment of VT, patients with recurrent shocks for VT have high morbidity and mortality. The development of catheter ablation over the past few decades has greatly aided the ability to control VT in these patients. The approach to patients with VT and structural heart disease is multifaceted. Often, a combination of therapeutic techniques is required to obtain the best result.

Robust replication of genotype-phenotype associations across multiple diseases in an electronic medical record.

Large-scale DNA databanks linked to electronic medical record (EMR) systems have been proposed as an approach for rapidly generating large, diverse cohorts for discovery and replication of genotype-phenotype associations. However, the extent to which such resources are capable of delivering on this promise is unknown. We studied whether an EMR-linked DNA biorepository can be used to detect known genotype-phenotype associations for five diseases. Twenty-one SNPs previously implicated as common variants predisposing to atrial fibrillation, Crohn disease, multiple sclerosis, rheumatoid arthritis, or type 2 diabetes were successfully genotyped in 9483 samples accrued over 4 mo into BioVU, the Vanderbilt University Medical Center DNA biobank. Previously reported odds ratios (OR(PR)) ranged from 1.14 to 2.36. For each phenotype, natural language processing techniques and billing-code queries were used to identify cases (n = 70-698) and controls (n = 808-3818) from deidentified health records. Each of the 21 tests of association yielded point estimates in the expected direction. Previous genotype-phenotype associations were replicated (p < 0.05) in 8/14 cases when the OR(PR) was > 1.25, and in 0/7 with lower OR(PR). Statistically significant associations were detected in all analyses that were adequately powered. In each of the five diseases studied, at least one previously reported association was replicated. These data demonstrate that phenotypes representing clinical diagnoses can be extracted from EMR systems, and they support the use of DNA resources coupled to EMR systems as tools for rapid generation of large data sets required for replication of associations found in research cohorts and for discovery in genome science.

Recovery following propofol-associated brugada electrocardiogram.

Brugada syndrome is a genetic disorder associated with an increased risk of sudden cardiac death that has typical electrocardiographic (ECG) patterns. Recently, there have been reports of Brugada ECG patterns seen in critically ill patients who received propofol,(1) and this pattern was associated with a very high imminent mortality. We report a case in which a critically ill patient developed a Brugada ECG pattern following high-dose propofol infusion. Once the ECG pattern was recognized, the propofol was discontinued and the ECG pattern resolved, and the patient was discharged home with no arrhythmic sequelae.

Comparison of findings on stress myocardial perfusion imaging in men with versus without erectile dysfunction and without prior heart disease.

Erectile dysfunction (ED) has been associated with a future risk of myocardial infarction, yet the findings on stress testing in men with ED and without previous coronary artery disease are unknown. Stress myocardial perfusion single-photon emission computed tomographic imaging (MPI) allows detection of coronary artery disease and predicts cardiovascular prognosis. Our goal was to determine the association between ED and findings at stress MPI testing in men without previous coronary artery disease. Five hundred seventy-five men without previous coronary artery disease referred for stress MPI were prospectively screened for ED with the validated International Index of Erectile Function. ED was present in 46% of subjects, and ED was associated with more mild (summed stress score >or=4) and severe (summed stress score >8) coronary artery disease and with more composite high-risk stress MPI findings (summed stress score >8, left ventricular ejection fraction <40%, transient ischemic dilation). In patients referred for exercise, ED was associated with a lower Duke treadmill score. On multivariate analysis, ED was found to be an independent predictor of a summed stress score >or=4, a summed stress score >8, and composite high-risk MPI findings. In conclusion, in men without known coronary artery disease referred for stress MPI testing, ED is associated with adverse prognostic indicators at MPI testing including coronary artery disease and high-risk MPI findings.

Atrial fibrillation after aortic arch repair requiring deep hypothermic circulatory arrest: incidence, clinical outcome, and clinical predictors.

OBJECTIVE: To delineate the incidence, outcome impact, and clinical predictors of atrial fibrillation (AF) after adult aortic arch repair requiring deep hypothermic circulatory arrest (AAR-DHCA) AIMS: To determine the incidence of AF after AAR-DHCA, to determine whether AF after AAR-DHCA affects mortality or stay in the intensive care unit (ICU), to determine multivariate predictors for AF after AAR-DHCA, and to determine whether aprotinin protects against AF after AAR-DHCA. STUDY DESIGN: Retrospective and observational. STUDY SETTING: Single large university hospital. PARTICIPANTS: All adults undergoing AAR-DHCA in 2000 and 2001. MAIN RESULTS: The cohort size was 144. Antifibrinolytic exposure was 100%, aprotinin 66% and aminocaproic acid 34%. The incidence of AF was 34.0%. AF was not significantly associated with increased mortality or prolonged ICU stay. Advanced age was a multivariate risk factor for AF. Lower temperature nadir during DHCA was protective against postoperative AF. Aprotinin had no demonstrable effect on AF after AAR-DHCA. CONCLUSIONS: AF after AAR-DHCA is common but does not independently increase mortality or ICU stay. The risk of AF after AAR-DHCA increases with age but decreases with the degree of hypothermia during DHCA. Aprotinin does not appear to affect the risk of AF after AAR-DHCA.

Renal dysfunction after thoracic aortic surgery requiring deep hypothermic circulatory arrest: definition, incidence, and clinical predictors.

OBJECTIVE: The purpose of this study was to evaluate renal dysfunction (RD) after thoracic aortic surgery (TAS) requiring deep hypothermic circulatory arrest (DHCA), to determine the influence of definition on RD after TAS-DHCA, to determine univariate predictors of RD after TAS-DHCA, and to determine multivariate predictors for RD TAS-DHCA. RD was defined in 3 ways: (1) >25% reduction in creatinine clearance, (2) >50% increase in serum creatinine, and (3) >50% increase in serum creatinine with an abnormal peak serum creatinine (>1.3 mg/dL for men and >1.0 mg/dL for women). STUDY DESIGN: Retrospective and observational. STUDY SETTING: Single large university hospital. PARTICIPANTS: All adults requiring TAS-DHCA in 2000 and 2001. MAIN RESULTS: The cohort size was 144. Antifibrinolytic exposure was 100%: aprotinin 66% and aminocaproic acid 34%. The incidence of RD TAS-DHCA was 22.9% to 38.2%, depending on the definition. The incidence of renal replacement therapy was 2.8%. Multivariate predictors for RD after TAS-DHCA were sepsis, aprotinin exposure, preoperative hypertension, age, and donor exposures. CONCLUSIONS: Although RD after TAS-DHCA varies substantially because of definition, it is still very common. Its multivariate predictors merit further focused research to enhance perioperative protection of the kidney.

Clinical predictors for prolonged intensive care unit stay in adults undergoing thoracic aortic surgery requiring deep hypothermic circulatory arrest.

OBJECTIVE: The purpose of this study was to describe clinical predictors for prolonged length of stay in the intensive care unit (PLOS-ICU) after adult thoracic aortic surgery requiring standardized deep hypothermic circulatory arrest (DHCA); and to determine the incidence of PLOS-ICU after DHCA, univariate predictors for PLOS-ICU, and multivariate predictors for PLOS-ICU. STUDY DESIGN: A retrospective and observational study. PLOS-ICU was defined as longer than 5 days in the ICU. STUDY SETTING: Cardiothoracic operating rooms and the ICU. PARTICIPANTS: All adults requiring thoracic aortic repair with DHCA INTERVENTIONS: None. MAIN RESULTS: The cohort size was 144. The incidence of PLOS-ICU was 27.8%. The mortality rate was 11.1%. Univariate predictors for PLOS-ICU were age, stroke, DHCA duration, vasopressor dependence >72 hours, mediastinal re-exploration for bleeding, and renal dysfunction. Multivariate predictors for PLOS-ICU were stroke, vasopressor dependence >72 hours, and renal dysfunction. CONCLUSIONS: PLOS-ICU after DHCA is common. The identified multivariate predictors merit further hypothesis-driven research to enhance perioperative protection of the brain, kidney, and cardiovascular system.

Clinical predictors for mortality in adults undergoing thoracic aortic surgery requiring deep hypothermic circulatory arrest.

This retrospective, observational study was performed on adult patients undergoing thoracic aortic surgery (ATAS) requiring standardized deep hypothermic circulatory arrest (DHCA) with following aims. (1). To determine the mortality rate after ATAS-DHCA (2). To determine univariate predictors for mortality after ATAS-DHCA (3). To determine multivariate predictors for mortality after ATAS-DHCA A total of 144 patients operated during 2000/2001 were included. The mortality rate was 11.1%. Univariate predictors for mortality after ATAS-DHCA were preoperative ejection fraction less than 40%, stroke, packed red blood cell transfusion within first 24 hours, sepsis, mediastinal re-exploration for bleeding within first 24 hours, and renal dysfunction. Multivariate predictors for mortality after ATAS-DHCA were sepsis (odds ratio 21.3:1; confidence interval 3.8-12.1; p=0.001), postoperative stroke (odds ratio 7.4:1; confidence interval 1.9-28.7; p=0.004) and mediastinal re-exploration within first 24 hours (odds ratio 7.7:1; confidence interval 1.3-45.1; p = 0.02) We conclude that mortality after ATAS-DHCA remains high. The identified multivariate predictors merit further hypothesis-driven intervention.

A randomized controlled clinical trial of real-time needle-guided ultrasound for internal jugular venous cannulation in a large university anesthesia department.

OBJECTIVE: The purpose of this study was to evaluate needle-guided ultrasound for internal jugular venous cannulation in a large university anesthesia department, to determine cumulative cannulation success by method, to determine first-pass cannulation success by method and operator, and to determine arterial puncture by method and operator. STUDY DESIGN: Prospective, observational, and randomized. Blinding was not possible. Cohort size was calculated for 80% power to detect a technique difference, with significance defined as p < 0.05. SETTING: Operating rooms of the Hospital of the University of Pennsylvania. PARTICIPANTS: Elective surgical patients requiring internal jugular venous cannulation. INTERVENTIONS: Cannulation of the internal jugular vein occurred by needle-guided ultrasound (NGU) or by ultrasound without a needle guide. MAIN RESULTS: Four hundred thirty-four procedures were studied in 429 patients. NGU significantly enhances cannulation success after first (68.9%-80.9%, p = 0.0054) and second (80.0%-93.1%, p = 0.0001) needle passes. Cumulative cannulation success by the seventh needle pass is 100%, regardless of technique. The needle-guide specifically improves first-pass success in the junior operator (65.6%-79.8%, p = 0.0144). Arterial puncture averages 4.2%, regardless of technique (p > 0.05) or operator (p > 0.05). CONCLUSIONS: Although the needle guide facilitates prompt cannulation with ultrasound in the novice operator, it offers no additional protection against arterial puncture. This may be because of a lack of control of needle depth rather than needle direction. A possible solution may be biplanar ultrasound for central venous cannulation.

The accuracy and completeness of data collected by prospective and retrospective methods.

OBJECTIVES: To describe and test a model that compares the accuracy of data gathered prospectively versus retrospectively among adult emergency department patients admitted with chest pain. METHODS: The authors developed a model of information flow from subject to medical record to the clinical study case report form, based on a literature review. To test this model, a bidirectional (prospective and retrospective) study was conducted, enrolling all eligible adult patients who were admitted with a chief complaint of chest pain. The authors interviewed patients in the emergency department to determine their chest pain history and established a prospective database; this was considered the criterion standard. Then, patient medical records were reviewed to determine the accuracy and completeness of the information available through a retrospective medical record review. RESULTS: The model described applies the concepts of reliability and validity to information passed on by the study subject, the clinician, and the medical record abstractor. This study was comprised of 104 subjects, of which 63% were men and the median age was 63 years. Subjects were uncertain of responses for 0-8% of questions and responded differently upon reinterview for subsets of questions 0-30% of the time. The sensitivity of the medical record for risk factors for coronary artery disease was 0.77 to 0.93. Among the 88 subjects (85%) who indicated that their chest pain was substernal or left chest, the medical record described this location in 44%. Timing of the chest pain was the most difficult item to accurately capture from the medical record. CONCLUSIONS: Information obtained retrospectively from the abstraction of medical records is measurably less accurate than information obtained prospectively from research subjects. For certain items, more than half of the information is not available. This loss of information is related to the data types included in the study and by the assumptions that a researcher performing a retrospective study makes about implied versus explicitly stated responses. A model of information flow that incorporates the concepts of reliability and validity can be used to measure some of the loss of information that occurs at each step along the way from subject to clinician to medical record abstractor.

Major clinical outcomes in adults undergoing thoracic aortic surgery requiring deep hypothermic circulatory arrest: quantification of organ-based perioperative outcome and detection of opportunities for perioperative intervention.

OBJECTIVE: The purpose of this study was to describe clinical outcome after adult thoracic aortic surgery requiring standardized deep hypothermic circulatory arrest (DHCA), to determine mortality and length of stay, neurologic outcome, cardiorespiratory outcome, and hemostatic and renal outcome after DHCA. DESIGN: Retrospective and observational. SETTING: Cardiothoracic operating rooms and intensive care unit (ICU). PARTICIPANTS: All adults requiring thoracic aortic repair with DHCA. INTERVENTIONS: None. The study was observational. MAIN RESULTS: The cohort size was 110. All patients received an antifibrinolytic. The mortality rate was 8.2%. The mean length of stay was 6.8 days (ICU) and 14.0 days (hospital). The incidence of stroke was 8.1% and postoperative delirium was 10.9%. The rate of postoperative atrial fibrillation was 43.6%; 19.1% required postoperative mechanical ventilation longer than 72 hours. Chest tube drainage was 931 mL for the first 24 hours. Postoperative dialysis was required in 1.8% of patients. Renal dysfunction occurred in 40% to 50% of patients, depending on the definition. CONCLUSIONS: The protocol for DHCA at the authors' institution is associated with superior or equivalent perioperative outcomes to those reported in the literature. This study identified the need for further quantification of the clinical outcomes after DHCA in order to prioritize outcome-based hypothesis-driven prospective intervention in DHCA.

Analysis of the interatrial septum by transesophageal echocardiography in adult cardiac surgical patients: anatomic variants and correlation with patent foramen ovale.

OBJECTIVES: The purpose of this study was to document the perioperative prevalence of anatomic variants of the interatrial septum (IAS), to classify atrial septal aneurysm based on mobility pattern, and to correlate anatomic variants of IAS with patent foramen ovale (PFO). DESIGN: A prospective observational study. SETTING: University hospital (single institution). PARTICIPANTS: Patients presenting for cardiac surgery requiring transesophageal echocardiography. INTERVENTIONS: Multiplane TEE in 2 atrial views with color-flow Doppler and contrast echocardiography with a provocative respiratory maneuver. MEASUREMENTS AND MAIN RESULTS: The cohort size was 206. PFO prevalence was 30.1%. The prevalence of IAS lipomatous hypertrophy was 43.2%, atrial septal flap (ASF) 43.2%, and atrial septal aneurysm (ASA) 28.6%. ASF and ASA were significantly ( p < 0.05) associated with PFO. Selected ASA subtypes are significantly associated with PFO ( p < 0.05). CONCLUSIONS: IAS anatomic variants are common in adult cardiac surgical patients undergoing multiplane TEE. The presence of ASF and ASA predicts enhanced PFO detection. ASA mobility patterns significantly correlate ( p < 0.05) with the presence of PFO.

Duration of symptoms and follow-up patterns of patients discharged from the emergency department after presenting with abdominal or flank pain.

BACKGROUND: Little is known about the duration of symptoms and follow-up patterns of patients seen in emergency departments for abdominal or flank pain. OBJECTIVE: We aimed to measure the duration of symptoms and follow-up rate of patients discharged home from the emergency department after presenting with non-traumatic abdominal or flank pain. METHODS: We conducted a single-centre, prospective descriptive study of adult patients who presented to our emergency department with non-traumatic abdominal or flank pain and were discharged from the emergency department. We gathered clinical data during the index emergency department visit and conducted telephone interviews of subjects 2-5 weeks later. RESULTS: We reached 63 of 90 subjects (70%). The median duration of pain was 3 days after the emergency department visit. During the follow-up period, only 41% had followed-up with their family physician or primary care provider, although an additional 21% had planned to. Persistence of symptoms was common in the 37% of subjects who did not follow-up. CONCLUSION: Of subjects discharged from the emergency department after visits for non-traumatic abdominal or flank pain, most improve within several days. Fewer than half follow-up with a family practitioner or a primary care provider. Emergency department revisits are uncommon and often for unrelated problems.