Triple therapy versus dual-antiplatelet therapy for dolichoectatic vertebrobasilar fusiform aneurysms treated with flow diverters.

BACKGROUND: Dolichoectatic vertebrobasilar fusiform aneurysms (DVBFAs) have poor natural history when left untreated and high morbimortality when treated with microsurgery. Flow diversion (FD) with dual-antiplatelet therapy (DAPT) is feasible but carries high risk of perforator occlusion and progression of brainstem compression. Elaborate antithrombotic strategies are needed to preserve perforator patency while vessel remodeling occurs. We compared triple therapy (TT (DAPT plus oral anticoagulation)) and DAPT alone in patients with DVBFAs treated with FD. METHODS: Retrospective comparison of DAPT and TT in patients with DVBFAs treated with FD at eight US centers. RESULTS: The groups (DAPT=13, TT=14) were similar in age, sex, clinical presentation, baseline disability, and aneurysm characteristics. Radial access use was significantly higher in the TT group (71.4% vs 15.3%; P=0.006). Median number of flow diverters and adjunctive coiling use were non-different between groups. Acute ischemic stroke rate during the oral anticoagulation period was lower in the TT group than the DAPT group (7.1% vs 30.8%; P=0.167). Modified Rankin Scale score decline was significantly lower in the TT group (7.1% vs 69.2%; P=0.001). Overall rates of hemorrhagic complications (TT, 28.6% vs DAPT, 7.7%; P=0.162) and complete occlusion (TT, 25% vs DAPT, 54.4%; P=0.213) were non-different between the groups. Rate of moderate-to-severe disability at last follow-up was significantly lower in the TT group (21.4% vs 76.9%; P=0.007). CONCLUSIONS: Patients with DVBFAs treated with FD in the TT group had fewer ischemic strokes, less symptom progression, and overall better outcomes at last follow-up than similar patients in the DAPT group.

Neuroophthalmological manifestations of congenital aqueductal stenosis.

OBJECTIVE: Congenital aqueductal stenosis (CAS) is a common etiology of hydrocephalus that occurs in a subset of infants and may be linked to an increased incidence of ophthalmological abnormalities and delayed developmental milestones. Although hydrocephalus is common and widely studied, sparse literature exists on patients with isolated (no identifiable genetic link) CAS along with analysis of ophthalmological manifestations. In this study, the authors sought to describe the ophthalmological abnormalities and delayed developmental milestones of patients with isolated CAS. METHODS: Data of patients with CAS were prospectively entered and monitored in a surgical database maintained by the Department of Neurological Surgery at Children's Hospital of Pittsburgh from January 2005 to October 2016. Patients with a family history of congenital hydrocephalus, positive testing for genetic forms of aqueductal stenosis, other congenital abnormalities suggesting an underlying genetic syndrome, and stenosis/obstruction due to secondary causes were excluded from this study. Prenatal and perinatal history, CSF diversion history, and a variety of outcomes, including ophthalmological deficits and developmental milestones, were collected and analyzed. RESULTS: A total of 41 patients with isolated CAS were identified, with a mean follow-up duration of 6 years. Among that cohort, 26 patients (63.4%) developed neuroophthalmological complications, which were further stratified. Fourteen patients (34.1%) developed strabismus and 11 (26.8%) developed astigmatism, and 1 patient (2.4%) with papilledema was recorded. Among patients with ophthalmological abnormalities, 76.9% had delayed developmental milestones (p = 0.045). CONCLUSIONS: Patients with CAS were found to have increased risk of ophthalmological abnormalities requiring correction, along with an increased risk of delayed developmental milestones. Importantly, there was a significant correlation between the development of ophthalmological abnormalities and delayed developmental milestones that was independent of CSF diversion history. Larger patient cohort studies are required to explore whether earlier development of hydrocephalus, as is the case in CAS, causes elevated rates of neurological and ophthalmological complications, and if earlier CSF diversion correlates with improved outcomes.

Monitoring for Chemotherapy-Related Cardiotoxicity in the Form of Left Ventricular Systolic Dysfunction: A Review of Current Recommendations.

Cardiotoxicity is a well-established complication of multiple cancer therapeutics, and the one of the most prominent effects that limits the use of these agents is in the form of left ventricular dysfunction, otherwise known as chemotherapy-induced cardiomyopathy (CIMP). Because CIMP can worsen patient outcomes and interfere with a patient's life-saving cancer treatments, it is important to implement a monitoring strategy for patients undergoing potentially cardiotoxic treatments. Efforts have been made by multiple societies to provide recommendations for screening and monitoring for CIMP in at-risk patients, with slight variations between guideline documents and expert consensuses. Most of the recommendations for monitoring for CIMP are specific to anthracyclines and the human epidermal growth factor receptor 2-antagonist trastuzumab, with very limited guidance for other cardiotoxic agents such as Tyr kinase inhibitors and proteasome inhibitors, which we cover in this article. Echocardiography remains the mainstay for imaging surveillance because of its safety profile and widespread availability, but the accuracy of cardiac magnetic resonance imaging (CMR) makes it an important modality when there are discrepancies in left ventricular ejection fraction assessment. Subclinical cardiotoxicity may be detected using laboratory biomarkers such as cardiac troponin and brain natriuretic peptide as well as myocardial deformation (strain) imaging by echocardiography or CMR. Specific recommendations for timing and frequency of laboratory biomarker assessment remain up for debate, but myocardial deformation imaging should be performed with every echocardiogram or CMR assessment. Future studies are needed to evaluate the efficacy of established surveillance recommendations and to develop specific recommendations for novel cancer therapeutics.

Bortezomib-Induced Reversible Cardiomyopathy: Recovered With Guideline-Directed Medical Therapy.

Bortezomib (BTZ) is a proteasome inhibitor (PI) used for the treatment of several hematologic malignancies, including multiple myeloma (MM), and various lymphomas including mantle cell lymphoma (MCL). It acts via disruption of the ubiquitin-proteasome pathway which plays a major role in regulating cell cycle and inhibiting synthesis of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB). The ubiquitin-proteasome pathway is also important in maintaining the integral signaling in cardiac myocytes. By inhibiting this system, BTZ induces cellular apoptosis in cancer cells, and possibly the cardiomyocytes. BTZ-induced cardiotoxicity in monotherapy and combination treatments is not well described in the literature. We observed a series of three patients who developed cardiotoxicity after treatment with BTZ. All patients had echocardiograms every 3 months until recovery to assess ejection fraction (EF) and global longitudinal strain (GLS). Two of the patients had a cardiac MRI (CMR) conducted during follow-up to assess for late gadolinium enhancement (LGE).  The median age of our patients was 55 years (range 37-74). Two of them had MM, while one patient had MCL. Table 1 demonstrates patient demographics, past medical histories, and the cumulative dose and duration of BTZ therapy. Of the three patients, only one had a heart failure exacerbation at diagnosis. The other two patients were diagnosed with asymptomatic left ventricular systolic dysfunction on routine pre-transplant echocardiograms. Most importantly, all three patients had improvement or normalization of cardiac function with discontinuation of BTZ and initiation of guideline-directed medical therapy (GDMT) for heart failure. The median duration to recovery was 5 months (range 3-13). One patient had underlying non-compaction cardiomyopathy, and although EF did not normalize, it recovered to his previous baseline. All 3 patients had improvement in GLS. Two patients underwent CMRI at the time of cardiomyopathy diagnosis and neither of them had any late gadolinium enhancement. Since there was no routine pre-treatment echocardiogram, using the GLS trend to detect subclinical cardiac dysfunction was not possible. This case series demonstrates that BTZ-induced cardiomyopathy is potentially reversible with discontinuation of the drug and early initiation of GDMT. Further studies are needed to determine the ideal surveillance strategy for BTZ-induced cardiomyopathy.

More expansive horizons: a review of endovascular therapy for patients with low NIHSS scores.

While the landmark 2015 stroke trials demonstrated that endovascular therapy (EVT) was superior to medical management for the treatment of acute ischemic stroke due to large vessel occlusion, the efficacy of EVT for patients presenting with a low NIHSS score remains undetermined. We conducted a review of the EVT low National Institutes of Health Stroke Scale (NIHSS) stroke literature, identifying 24 quantitative and six qualitative publications. Details of study designs and outcome were extracted and critically discussed.All identified qualitative studies were retrospective. There was significant study design heterogeneity, with 18 unique study designs between the 24 identified quantitative manuscripts. Study investigations included low NIHSS EVT feasibility (n=6), EVT versus best medical management (BMM; n=10), EVT versus intravenous therapy (IVT, n=3), and low NIHSS score versus high NIHSS score (n=3). From single-arm EVT feasibility studies, the reported ranges of modified Thrombolysis in Cerebral Infarction and symptomatic intracranial hemorrhage were 78-97% and 0-10%, respectively. The EVT versus BMM literature had heterogeneous results with 40% reporting benefit with EVT and 60% reporting neutral findings. None of the studies comparing EVT with IVT reported a difference between the two revascularization therapies. The four identified meta-analyses had incongruent inclusion criteria and conflicting results. Two randomized trials are currently investigating EVT in patients with a low NIHSS score. Selected meta-analyses do suggest a potential benefit of EVT over BMM; however, current and future randomized clinical trials will better elucidate the efficacy of EVT in this patient population.

Ballast and NeuronMax in stroke thrombectomy.

BACKGROUND: Comparative evaluation of long sheath performance in stroke thrombectomy has not been performed. OBJECTIVE: To review an initial experience with the new Ballast 6F long sheath compared with the NeuronMax, to evaluate comparative benchmarks in trackability, navigability, and procedural outcomes. METHODS: A prospectively maintained thrombectomy database was evaluated over a 6-month period to compare procedural and angiographic results between a cohort of patients treated with the historical institutional standard long sheath (NeuronMax) and another with the new Ballast long sheath via a transfemoral approach. RESULTS: Of 156 stroke thrombectomy cases, 69 were performed using NeuronMax and 40 using Ballast via a transfemoral approach; the remainder of cases employed alternative long sheaths or were performed via initial radial access. There was no significant difference in patient age, medical history, baseline National Institutes of Health Stroke Scale score, Alberta Stroke Program Early CT Score, arch type, tissue plasminogen activator use, and clot location between the two groups. Single-pass case frequency (41% for NeuronMax vs 44% for Ballast, p=0.84), and final successful revascularization (TICI 2b or greater) were similar between the two cohorts (91% vs 98%, p=0.42). Good 90-day outcome (modified Rankin Scale score 0-2) was also similar (33% for NeuronMax, 43% for Ballast, p=0.41). Excluding tandem occlusions, mean procedural time was 31 min for NeuronMax and 25 min for Ballast (p=0.09). Puncture to long sheath access and angiography in the base target vessel was faster for Ballast than NeuronMax (6.5 min vs 9.2 min, p=0.04). CONCLUSION: Among a cohort of practitioners with historical, preferential experience with NeuronMax for stroke thrombectomy, faster procedural times were achieved with Ballast with similar final angiographic results.

Incorporation of transradial approach in neuroendovascular procedures: defining benchmarks for rates of complications and conversion to femoral access.

BACKGROUND: The transradial approach (TRA) has gained increasing popularity for neuroendovascular procedures. However, the experience with TRA in neuroangiography is still in early stages in most centers, and the safety and feasibility of this approach have not been well established. The purpose of this study is to report the safety and feasibility of TRA for neuroendovascular procedures. METHODS: We reviewed charts from six institutions in the USA to include consecutive patients who underwent diagnostic or interventional neuroendovascular procedures through TRA from July 2018 to July 2019. Collected data included baseline characteristics, procedural variables, complications, and whether there was a crossover to transfemoral access. RESULTS: A total of 2203 patients were included in the study (age 56.1±15.2, 60.8% women). Of these, 1697 (77%) patients underwent diagnostic procedures and 506 (23%) underwent interventional procedures. Successfully completed procedures included aneurysm coiling (n=97), flow diversion (n=89), stent-assisted coiling (n=57), balloon-assisted coiling (n=19), and stroke thrombectomy (n=76). Crossover to femoral access was required in 114 (5.2%). There were no major complications related to the radial access site. Minor complications related to access site were seen in 14 (0.6%) patients. CONCLUSION: In this early stage of transforming to the 'radial-first' approach for neuroendovascular procedures, TRA was safe with low complication rates for both diagnostic and interventional procedures. A wide range of procedures were completed successfully using TRA.

Transradial versus transfemoral approaches for diagnostic cerebral angiography: a prospective, single-center, non-inferiority comparative effectiveness study.

BACKGROUND: Interventional cardiology produced level 1 evidence recommending radial artery-first for coronary angiography given lower vascular complications. Neuroendovascular surgeons have not widely adopted the transradial approach. This prospective, single center, non-inferiority comparative effectiveness study aims to compare the transradial and transfemoral approaches for diagnostic cerebral angiography with respect to efficacy, safety and patient satisfaction. METHODS: Consecutive patients presenting for diagnostic cerebral angiography were selected to undergo right radial or femoral access based on date of presentation. Primary outcome was ability to answer the predefined diagnostic goal of the cerebral angiogram using the initial access site and was assessed with a non-inferiority design. Secondary outcomes included technical success per vessel, complications, procedure times and patient satisfaction. RESULTS: A total of 312 patients were enrolled, 158 and 154 for right radial and femoral access, respectively. The diagnostic goal of the angiogram was achieved in 152 of 154 (99%) patients who underwent attempted femoral access compared with 153 of 158 (97%) patients who underwent radial access, confirming non-inferiority of the transradial approach. Secondary outcomes showed equivalent technical success by vessel, no major complications, and similar frequency of minor complications between the two approaches. In-room time was similar between approaches, though post-procedure recovery room time was significantly shorter for transradial patients. Patient satisfaction results significantly favored the radial approach. CONCLUSIONS: In patients undergoing diagnostic cerebral angiography, transfemoral and transradial access achieve procedural goals with similar effectiveness and safety, though patients strongly prefer the radial approach. Findings support consideration of adopting a radial-first strategy for diagnostic cerebral angiography.

Successful reperfusion, rather than number of passes, predicts clinical outcome after mechanical thrombectomy.

INTRODUCTION: For patients undergoing mechanical thrombectomy, numerous (>3) thrombectomy passes may be harmful. However, non-recanalization leads to poor outcomes. For patients requiring multiple thrombectomy passes to achieve reperfusion, it remains unclear if the risk/benefit ratio favors recanalization. OBJECTIVE: To test the hypothesis that the benefits afforded by successful reperfusion outweigh the risk conveyed by the numerous passes required. METHODS: We retrospectively reviewed prospectively collected data for patients presenting to a comprehensive stroke center with anterior circulation large vessel occlusion (ACLVO) and undergoing thrombectomy requiring more than one pass over 24 months. We stratified patients into three groups: group 1 (successful reperfusion in 2-3 passes), group 2 (successful reperfusion in ≥4 passes), and group 3 (unsuccessful reperfusion). RESULTS: 250 patients with ACLVO constituted the study cohort. Despite similar demographics, group 2 patients had better clinical outcomes than those in group 3 at 24 hours (National Institutes of Health Stroke Scale (NIHSS) score 13.5 vs 19.1, p<0.001) and at 90 days (modified Rankin Scale score 0-2 rates of 31.1% vs 0.0%, p=0.006) On multivariate logistic regression analysis, age (p=0.034), Alberta Stroke Program Early CT Score (p<0.01), NIHSS score (p=0.02), and parenchymal hematoma type 2 (p=0.015) were significant predictors of functional independence among those who achieved successful reperfusion, but the number of passes required did not predict outcome for these patients (p=0.74). CONCLUSION: Patients who achieve successful reperfusion after many passes have better clinical outcomes than those who do not, despite the number of passes and procedural time required. The number of passes required to achieve successful reperfusion beyond the first pass is not a predictor of functional independence.

Maturing institutional experience with the transradial approach for diagnostic cerebral arteriography: overcoming the learning curve.

BACKGROUND: Despite growing interest in the transradial approach for neurovascular procedures, prospective data about the learning curve for neurointerventionalists adopting this approach are limited. METHODS: A subsequent prospective series of 50 consecutive right transradial diagnostic cerebral arteriograms was compared with our initial institutional experience using a procedural staging system. The primary outcome was the ability to achieve the predefined procedural goals using the radial approach. Secondary outcomes included the technical ability to access and inject each supraaortic artery of interest and the incidence of complications. RESULTS: The primary outcome was achieved in 49 patients (98%) compared with 88% in the initial series (p=0.05). One stage 2 failure (2%) occurred. Crossover to the transfemoral approach occurred in one patient (2%) compared with 8% in the initial series (p=0.16). All supraaortic arteries of interest were accessed and injected with success rates between 93% and 100%. There were no major complications and two minor complications. CONCLUSION: Neurointerventionalists can overcome the right transradial learning curve and achieve high success rates and low crossover rates after performing 30-50 cases.

A prospective study of the transradial approach for diagnostic cerebral arteriography.

BACKGROUND: The transradial approach for cardiac catheterization is associated with improved patient safety and satisfaction in comparison with the transfemoral approach. Prospective data for the transradial approach for cerebral arteriography are lacking. OBJECTIVE: To carry out a prospective study of consecutive patients undergoing transradial cerebral arteriography at our institution to evaluate the safety, feasibility, and limitations of this approach. METHODS: Consecutive patients referred for diagnostic cerebral arteriography at an institution with minimal transradial experience were enrolled until 50 right transradial diagnostic cerebral arteriograms were obtained. A procedural staging system was developed and goals of angiography were defined before each procedure. The primary outcome was the ability to achieve the predefined goals using the transradial approach. Secondary outcomes included the technical ability to access and inject each supra-aortic artery of interest and the incidence of complications. RESULTS: A total of 65 patients were screened; 15 were excluded owing to contraindications and 50 underwent attempted right transradial cerebral arteriography. The primary outcome was achieved in 44 patients (88%). Failures occurred at stage 1 (n=3, 6%), stage 2 (n=1, 2%), stage 3a (n=1, 2%), and stage 3b (n=1, 2%). Crossover to the transfemoral approach occurred in four patients (8%) and the procedure was terminated in two patients (4%). All supra-aortic arteries of interest were accessed and injected, with success rates between 89% and 100% with the exception of the left vertebral artery (successful in 59%). There were no major complications and five minor complications. CONCLUSION: Neurointerventionalists attempting the transradial approach can expect to achieve moderate early success and a low complication rate.

High Prevalence of Clinically Important Echocardiographic Abnormalities in Patients with a Normal Electrocardiogram Referred for Transthoracic Echocardiography.

BACKGROUND: Normal electrocardiographic (ECG) results have been reported to be associated with a low prevalence of structural heart disease and thus may preclude the need for transthoracic echocardiographic (TTE) imaging. The goal of this study was to determine the prevalence of important TTE abnormalities in patients with a normal ECG referred for TTE imaging. METHODS: Consecutive electrocardiograms over 6 months were reviewed. Patients with a normal ECG who underwent TTE imaging within 30 days formed the study group. TTE indication and appropriateness designation were determined. TTE findings were noted, including a composite, "major TTE abnormalities" (Maj TTE ABNs). RESULTS: Of 26,254 electrocardiograms reviewed, 3,955 (15%) were normal, 522 with qualifying TTE studies. Maj TTE ABNs were common (27%). The most common TTE indication was signs or symptoms of congestive heart failure (17%), 35% of which had Maj TTE ABNs. Two echocardiographic indications were found to have significantly fewer of Maj TTE ABNs: palpitations (4%, P < .01) and preoperative evaluation before noncardiac surgery (6%, P < .01). A majority of TTE studies were appropriate (76%), with only 14% rarely appropriate. Maj TTE ABNs were less common in rarely appropriate compared with appropriate TTE studies (13% vs 30%, P < .01), with a very low prevalence of Maj TTE ABNs in outpatient rarely appropriate TTE studies (4%). CONCLUSIONS: Clinically important TTE abnormalities in patients with a normal ECG are common, suggesting that normal ECG results should not routinely preclude TTE imaging to identify structural heart disease. However, recognition of common clinical indications and application of the appropriate use criteria may identify patients with a normal ECG in whom TTE imaging is of very low yield.

Evaluation of Occipitocervical Arthrodesis Rates with Screw-based Fixation and Osteoinductive Fusion Adjuncts.

Occipitocervical (OC) instability may be associated with neurologic impairment and even death. There is a paucity of research on the rate of arthrodesis utilizing modern screw-based constructs coupled with adjuvant osteoinductive agents. We reviewed our experience with OC constructs and compared the fusion rate, functional outcome, and rate of adverse events between recombinant human bone morphogenetic protein (BMP)-2, autologous iliac crest bone graft (ICBG), a combination of BMP and ICBG, and local bone autograft alone. We performed a retrospective cohort analysis of all adult admissions for operative treatment of OC instability utilizing segmental screw-based constructs for OC arthrodesis between January 2003 and September 2012. Data concerning demographic characteristics, diagnostic and procedural details, radiographic pathology, and clinical course were abstracted from medical records. The primary end point was evidence of stable fixation and osseous union on either dynamic lateral radiographs or computed tomography (CT) imaging at most recent follow-up. Secondary end points included functional outcome as determined by Nurick scale and Neck disability index (NDI) at ≥ 1year postoperation, as well as perioperative morbidity and mortality at 30 days and 3 months. During the study period, 94 patients (mean age: 62 ± 18 years) underwent OC fixation with segmental screw-based constructs. The four fusion adjunct cohorts analyzed included local autograft alone (32%), ICBG (41%), BMP (14%), or a combination of ICBG and BMP (14%). Notably, demineralized bone matrix was also used in 61% of cases overall, but its use did not differ significantly among the four cohorts (p = 0.28). Median radiographic follow-up was 6 months postoperatively (range: 1.5-54 months). Clinical outcomes were assessed at a median postoperative follow-up of 45 months (range: 12-87 months). Overall, radiographic evidence of arthrodesis was present in 83% of patients assessed and was not significantly different between adjunct cohorts (local autograft 92%, ICBG 77%, BMP 88%, and combination of ICBG and BMP 83%; p = 0.79). This finding persisted despite adjustment for age, pathology, number of levels instrumented, and attendant procedures. Importantly, neither the presence of arthrodesis nor fusion adjunct was significantly associated with functional outcome in both univariate and adjusted regression models. Additionally, perioperative adverse events occurred in 23% of cases and did not vary significantly in incidence or severity between fusion adjunct cohorts. We present a large series of patients treated for OC instability with rigid fixation utilizing modern segmental screw-based constructs. The use of adjuvant osteoinductive agents (BMP, ICBG, or a combination) produced equivalent rates of arthrodesis, functional outcome, and adverse events compared with use of local autograft alone.

Educational Resources "Over the Head" of Neurosurgical Patients: The Economic Impact of Inadequate Health Literacy.

BACKGROUND: Health literacy is the ability with which individuals can obtain, understand, and apply basic health information. Approximately 36% of Americans have basic or below basic health literacy skills. This low health literacy is particularly prevalent in neurosurgery, a growing field of medicine with considerable complexity and a patient population commonly affected with disease-related cognitive impairment. Consequences of poor patient understanding range from increased emergency department admissions rates to reduced adherence to preoperative medication instructions. Economic implications include increasing health care expenditures, decreasing access to health care, and decreasing quality of care. Health literacy costs the United States $106-236 billion per year. METHODS: Consequences of inadequate patient understanding vary widely. This article reviews and addresses the economic impact of the failure to address low health literacy in neurosurgery. RESULTS: Various groups have proposed techniques and devised outlines to improve health literacy, such as detailing principles targeting the underlying issues of health care illiteracy. The government, through legislation including the Affordable Care Act and the National Action Plan to Improve Health Literacy, has also shown its desire to remedy the effects of insufficient health literacy. CONCLUSIONS: Despite current efforts, further action is still needed. Health literacy is a key determinant in ensuring longevity and quality of life.

Giant pseudomeningocele causing urinary obstruction in a patient with Marfan syndrome.

Defective collagen biosynthesis in Marfan syndrome predisposes to dural defects such as dural ectasia, meningocele, and pseudomeningocele; thus, an increased index of suspicion for these conditions should be present in the clinical setting of Marfan syndrome. The authors describe a young woman with Marfan syndrome who was being treated with anticoagulants for a prosthetic heart valve and who presented with a spontaneous retroperitoneal hemorrhage requiring surgical evacuation. No CSF leak was encountered at surgery, but she developed progressively more severe positional headaches over the following year. She then experienced the sudden onset of acute urinary obstruction, at which time CT revealed a 17 × 15 × 13-cm presacral pseudomeningocele communicating with the thecal sac through a sacral bone defect. An anterior surgical approach was used for drainage of the pseudomeningocele as well as for primary closure of the dural defect with a bovine pericardial patch and autologous subcutaneous fat graft. After a short period of lumbar subarachnoid drainage of the CSF, the patient was able to resume normal activity without recurrent symptoms. To the authors' knowledge, such a pseudomeningocele in a patient with Marfan syndrome has been reported only twice, and this case features the largest pseudomeningocele to date. They also review the pertinent literature regarding presentation, diagnosis, and management of these lesions.

Organic dust augments nucleotide-binding oligomerization domain expression via an NF-{kappa}B pathway to negatively regulate inflammatory responses.

Nucleotide-binding oligomerization domain 2 (NOD2) is involved in innate immune responses to peptidoglycan degradation products. Peptidoglycans are important mediators of organic dust-induced airway diseases in exposed agriculture workers; however, the role of NOD2 in response to complex organic dust is unknown. Monocytes/macrophages were exposed to swine facility organic dust extract (ODE), whereupon NOD2 expression was evaluated by real-time PCR and Western blot. ODE induced significant NOD2 mRNA and protein expression at 24 and 48 h, respectively, which was mediated via a NF-κB signaling pathway as opposed to a TNF-α autocrine/paracrine mechanism. Specifically, NF-κB translocation increased rapidly following ODE stimulation as demonstrated by EMSA, and inhibition of the NF-κB pathway significantly reduced ODE-induced NOD2 expression. However, there was no significant reduction in ODE-induced NOD2 gene expression when TNF-α was inhibited or absent. Next, it was determined whether NOD2 regulated ODE-induced inflammatory cytokine production. Knockdown of NOD2 expression by small interfering RNA resulted in increased CXCL8 and IL-6, but not TNF-α production in response to ODE. Similarly, primary lung macrophages from NOD2 knockout mice demonstrated increased IL-6, CXCL1, and CXCL1, but not TNF-α, expression. Lastly, a higher degree of airway inflammation occurred in the absence of NOD2 following acute (single) and repetitive (3 wk) ODE exposure in an established in vivo murine model. In summary, ODE-induced NOD2 expression is directly dependent on NF-κB signaling, and NOD2 is a negative regulator of complex, organic dust-induced inflammatory cytokine/chemokine production in mononuclear phagocytes.

The cell cycle regulator phosphorylated retinoblastoma protein is associated with tau pathology in several tauopathies.

Retinoblastoma protein (pRb) is a ubiquitous 928-amino acid cell cycle regulatory molecule with diverse biologic activities. One critical function of pRb is the control of the G1-to-S phase checkpoint of the cell cycle. In the hypophosphorylated state, pRb suppresses the activity of E2F transcription factors thereby inhibiting transcription of cell cycle-promoting genes. On phosphorylation, primarily by cyclin-dependent kinases, phosphorylated pRb dissociates from E2F and permits cell cycle progression. We previously found phosphorylated pRb to be intimately associated with hyperphosphorylated tau-containing neurofibrillary tangles of Alzheimer disease (AD), the pathogenesis of which is believed to involve dysregulation of the cell cycle and marked neuronal death. Here, we used immunohistochemistry to investigate the presence of phosphorylated pRb in other distinct neurodegenerative diseases that share the common characteristic of hyperphosphorylated tau pathology and neuronal loss with AD.We found colocalized labeling of tau pathology and phosphorylated pRb in Pick disease and progressive supranuclear palsy (3 cases each), neurodegeneration with brain iron accumulation type 1 (2 cases), and Parkinson-amyotrophic lateral sclerosis of Guam, subacute sclerosing panencephalitis, frontotemporal dementia and Parkinsonism linked to chromosome 17, and dementia pugilistica (1 case each). These observations further implicate aberrant neuronal cell cycle progression in neurodegenerative diseases, particularly tauopathies, and suggest a novel target for therapeutic intervention.