Smooth Muscle Hyperplasia due to ACTA2/MYH11 Mutations: Identification of Novel Pathology and Pathways Leading to Aneurysms and Diverse Vascular Occlusive Diseases

Missense mutations in smooth muscle cell (SMC) specific ACTA2 (á-actin) and MYH11 (â-myosin heavy chain) cause diffuse and diverse vascular diseases, including thoracic aortic aneurysms and dissections (TAAD) and early onset coronary artery disease and stroke. The mechanism by which these mutations lead to dilatation of some arteries but occlusion of others is unknown. We hypothesized that the mutations act through two distinct mechanisms to cause varied vascular diseases: a loss of function, leading to decreased SMC contraction and aneurysms, and a gain of function, leading to increased SMC proliferation and occlusive disease. To test this hypothesis, ACTA2 mutant SMCs and myofibroblasts were assessed and found to not form á-actin filaments whereas control cells did, suggesting a dominant negative effect of ACTA2 mutations on filament formation. A loss of á-actin filaments would be predicted to cause decreased SMC contractility. Histological examination of vascular tissues from patients revealed SMC hyperplasia leading to arterial stenosis and occlusion, supporting a gain of function associated with the mutant gene. Furthermore, ACTA2 mutant SMCs and myofibroblasts proliferated more rapidly in static culture than control cells (p<0.05). We also determined that Acta2-/- mice have ascending aortic aneurysms. Histological examination revealed aortic medial SMC hyperplasia, but minimal features of medial degeneration. Acta2-/- SMCs proliferated more rapidly in culture than wildtype (p<0.05), and microarray analysis of Acta2-/- SMCs revealed increased expression of Actg2, 15 collagen genes, and multiple focal adhesion genes. Acta2-/- SMCs showed altered localization of vinculin and zyxin and increased phosphorylated focal adhesion kinase (FAK) in focal adhesions. A specific FAK inhibitor decreased Acta2-/- SMC proliferation to levels equal to wildtype SMCs (p<0.05), suggesting that FAK activation leads to the increased proliferation. We have described a unique pathology associated with ACTA2 and MYH11 mutations, as well as an aneurysm phenotype in Acta2-/- mice. Additionally, we identified a novel pathogenic pathway for vascular occlusive disease due to loss of SMC contractile filaments, alterations in focal adhesions, and activation of FAK signaling in SMCs with ACTA2 mutations.

Serum IL-6: a candidate biomarker for intracranial pressure elevation following isolated traumatic brain injury.

BACKGROUND: Increased intracranial pressure (ICP) is a serious, life-threatening, secondary event following traumatic brain injury (TBI). In many cases, ICP rises in a delayed fashion, reaching a maximal level 48-96 hours after the initial insult. While pressure catheters can be implanted to monitor ICP, there is no clinically proven method for determining a patient's risk for developing this pathology. METHODS: In the present study, we employed antibody array and Luminex-based screening methods to interrogate the levels of inflammatory cytokines in the serum of healthy volunteers and in severe TBI patients (GCS RESULTS: Consistent with previous reports, we observed sustained increases in IL-6 levels in TBI patients irrespective of their ICP status. However, the group of patients who subsequently experienced ICP >or= 25 mm Hg had significantly higher IL-6 levels within the first 17 hours of injury as compared to the patients whose ICP remained 128 pg/ml correctly identified 85% of isolated TBI patients who subsequently developed elevated ICP, and values between these cut-off values correctly identified 75% of all patients whose ICP remained CONCLUSIONS: Our results suggest that serum IL-6 can be used for the differential diagnosis of elevated ICP in isolated TBI.

Characterization of the inflammatory cells in ascending thoracic aortic aneurysms in patients with Marfan syndrome, familial thoracic aortic aneurysms, and sporadic aneurysms.

OBJECTIVE: This study sought to characterize the inflammatory infiltrate in ascending thoracic aortic aneurysm in patients with Marfan syndrome, familial thoracic aortic aneurysm, or nonfamilial thoracic aortic aneurysm. BACKGROUND: Thoracic aortic aneurysms are associated with a pathologic lesion termed "medial degeneration," which is described as a noninflammatory lesion. Thoracic aortic aneurysms are a complication of Marfan syndrome and can be inherited in an autosomal dominant manner of familial thoracic aortic aneurysm. METHODS: Full aortic segments were collected from patients undergoing elective repair with Marfan syndrome (n = 5), familial thoracic aortic aneurysm (n = 6), and thoracic aortic aneurysms (n = 9), along with control aortas (n = 5). Immunohistochemistry staining was performed using antibodies directed against markers of lymphocytes and macrophages. Real-time polymerase chain reaction analysis was performed to quantify the expression level of the T-cell receptor beta-chain variable region gene. RESULTS: Immunohistochemistry of thoracic aortic aneurysm aortas demonstrated that the media and adventitia from Marfan syndrome, familial thoracic aortic aneurysm, and sporadic cases had increased numbers of T lymphocytes and macrophages when compared with control aortas. The number of T cells and macrophages in the aortic media of the aneurysm correlated inversely with the patient's age at the time of prophylactic surgical repair of the aorta. T-cell receptor profiling indicated a similar clonal nature of the T cells in the aortic wall in a majority of aneurysms, whether the patient had Marfan syndrome, familial thoracic aortic aneurysm, or sporadic disease. CONCLUSION: These results indicate that the infiltration of inflammatory cells contributes to the pathogenesis of thoracic aortic aneurysms. Superantigen-driven stimulation of T lymphocytes in the aortic tissues of patients with thoracic aortic aneurysms may contribute to the initial immune response.

Intracranial EEG reveals a time- and frequency-specific role for the right inferior frontal gyrus and primary motor cortex in stopping initiated responses.

Inappropriate response tendencies may be stopped via a specific fronto/basal ganglia/primary motor cortical network. We sought to characterize the functional role of two regions in this putative stopping network, the right inferior frontal gyrus (IFG) and the primary motor cortex (M1), using electocorticography from subdural electrodes in four patients while they performed a stop-signal task. On each trial, a motor response was initiated, and on a minority of trials a stop signal instructed the patient to try to stop the response. For each patient, there was a greater right IFG response in the beta frequency band ( approximately 16 Hz) for successful versus unsuccessful stop trials. This finding adds to evidence for a functional network for stopping because changes in beta frequency activity have also been observed in the basal ganglia in association with behavioral stopping. In addition, the right IFG response occurred 100-250 ms after the stop signal, a time range consistent with a putative inhibitory control process rather than with stop-signal processing or feedback regarding success. A downstream target of inhibitory control is M1. In each patient, there was alpha/beta band desynchronization in M1 for stop trials. However, the degree of desynchronization in M1 was less for successfully than unsuccessfully stopped trials. This reduced desynchronization on successful stop trials could relate to increased GABA inhibition in M1. Together with other findings, the results suggest that behavioral stopping is implemented via synchronized activity in the beta frequency band in a right IFG/basal ganglia network, with downstream effects on M1.

Severe aortic and arterial aneurysms associated with a TGFBR2 mutation.

BACKGROUND: A 24-year-old man presented with previously diagnosed Marfan's syndrome. Since the age of 9 years, he had undergone eight cardiovascular procedures to treat rapidly progressive aneurysms, dissection and tortuous vascular disease involving the aortic root and arch, the thoracoabdominal aorta, and brachiocephalic, vertebral, internal thoracic and superior mesenteric arteries. Throughout this extensive series of cardiovascular surgical repairs, he recovered without stroke, paraplegia or renal impairment. INVESTIGATIONS: CT scans, arteriogram, genetic mutation screening of transforming growth factor beta receptors 1 and 2. DIAGNOSIS: Diffuse and rapidly progressing vascular disease in a patient who met the diagnostic criteria for Marfan's syndrome, but was later rediagnosed with Loeys-Dietz syndrome. Genetic testing also revealed a de novo mutation in transforming growth factor beta receptor 2. MANAGEMENT: Regular cardiovascular surveillance for aneurysms and dissections, and aggressive surgical treatment of vascular disease.

AN EPIDEMIOLOGIC CASE-CONTROL ANALYSIS OF CHILDHOOD INTRACRANIAL AND SPINAL CORD TUMORS IN RELATION TO PATERNAL OCCUPATION AT BIRTH (BRAIN, CANCER)

Epidemiologic case-control studies of small groups of childhood nervous system tumor patients have suggested that parental employment in occupations with exposure to hydrocarbons is a risk factor for disease. The main focus of this case-control study was to assess the paternal occupation at the time of birth of offspring who later developed childhood intracranial and spinal tumors. All children under 15 years of age dying of such tumors in Texas, during the period 1964-1980, were selected as cases. Disease and demographic data were abstracted from death certificates. The birth certificate for each child of the final group of 499 cases was located and parental occupation information, as well as demographic and obstetric data, were collected. The comparison group consisted of a random sample from all Texas live births with the same birth year, race and sex distribution as the cases.^ The paternal occupations were categorized into broad classifications of those involving hydrocarbon exposure versus those that did not, based on the occupation criteria used in the previous studies. Odds ratios did not indicate any increased risk associated with general paternal hydrocarbon exposure in the workplace. In prior studies, increased risk estimates were detected with narrower groups of occupations involving exposure to hydrocarbon materials. The data from this study were classified according to these groups, and again, no increased risks were indicated except for a statistically insignificant but elevated odds ratio for fathers who were paper and pulp mill workers.^ Odds ratios were calculated for specific occupations and industries previously implicated as risk factors. Significantly associated odds ratios (OR) were detected for electricians (OR = 3.5), especially those working for construction companies (OR = 10.0), for employment in the printing occupations (OR = 4.5), particularly graphic arts workers (OR = 21.9), and in the electronics and electronic machinery industries (OR = 3.5). Analysis of the petroleum refining and chemical industries, which were not found in previous study populations, revealed significantly elevated odds ratios of 3.0 for occupations with probable heavy exposure to chemicals and petroleum compounds and 10.0 for salesmen of chemical products. ^

Development, implementation, and evaluation of a structured reporting web tool for abdominal aortic aneurysms

BACKGROUND The majority of radiological reports are lacking a standard structure. Even within a specialized area of radiology, each report has its individual structure with regards to details and order, often containing too much of non-relevant information the referring physician is not interested in. For gathering relevant clinical key parameters in an efficient way or to support long-term therapy monitoring, structured reporting might be advantageous. OBJECTIVE Despite of new technologies in medical information systems, medical reporting is still not dynamic. To improve the quality of communication in radiology reports, a new structured reporting system was developed for abdominal aortic aneurysms (AAA), intended to enhance professional communication by providing the pertinent clinical information in a predefined standard. METHODS Actual state analysis was performed within the departments of radiology and vascular surgery by developing a Technology Acceptance Model. The SWOT (strengths, weaknesses, opportunities, and threats) analysis focused on optimization of the radiology reporting of patients with AAA. Definition of clinical parameters was achieved by interviewing experienced clinicians in radiology and vascular surgery. For evaluation, a focus group (4 radiologists) looked at the reports of 16 patients. The usability and reliability of the method was validated in a real-world test environment in the field of radiology. RESULTS A Web-based application for radiological "structured reporting" (SR) was successfully standardized for AAA. Its organization comprises three main categories: characteristics of pathology and adjacent anatomy, measurements, and additional findings. Using different graphical widgets (eg, drop-down menus) in each category facilitate predefined data entries. Measurement parameters shown in a diagram can be defined for clinical monitoring and be adducted for quick adjudications. Figures for optional use to guide and standardize the reporting are embedded. Analysis of variance shows decreased average time required with SR to obtain a radiological report compared to free-text reporting (P=.0001). Questionnaire responses confirm a high acceptance rate by the user. CONCLUSIONS The new SR system may support efficient radiological reporting for initial diagnosis and follow-up for AAA. Perceived advantages of our SR platform are ease of use, which may lead to more accurate decision support. The new system is open to communicate not only with clinical partners but also with Radiology Information and Hospital Information Systems.

Ordinal patterns in epileptic brains: Analysis of intracranial EEG and simultaneous EEG-fMRI

Epileptic seizures are associated with high behavioral stereotypy of the patients. In the EEG of epilepsy patients characteristic signal patterns can be found during and between seizures. Here we use ordinal patterns to analyze EEGs of epilepsy patients and quantify the degree of signal determinism. Besides relative signal redundancy and the fraction of forbidden patterns we introduce the fraction of under-represented patterns as a new measure. Using the logistic map, parameter scans are performed to explore the sensitivity of the measures to signal determinism. Thereafter, application is made to two types of EEGs recorded in two epilepsy patients. Intracranial EEG shows pronounced determinism peaks during seizures. Finally, we demonstrate that ordinal patterns may be useful for improving analysis of non-invasive simultaneous EEG-fMRI.

The role of diameter versus volume as the best prognostic measurement of abdominal aortic aneurysms

Accurate measurement of abdominal aortic aneurysms is necessary to predict rupture risk and, more recently, to follow aneurysm sac behavior following endovascular repair. Up until this point, aneurysm diameter has been the most common measurement utilized for these purposes. Although aneurysm diameter is predictive of rupture, accurate measurement is hindered by such factors as aortic tortuosity and interobserver variability, and it does not account for variations in morphology such as saccular aneurysms. Additionally, decreases in aneurysm diameter do not completely describe the somewhat complex remodeling seen following endovascular repair of aortic aneurysms. Measurement of aneurysm volume has the advantage of describing aneurysm morphology in a multidimensional fashion, but it has not been readily available or easily measured until recently. This has changed with the introduction of commercially available software tools that permit quicker and easier to perform volume measurements. Whether it is time for volume to replace, or compliment, diameter is the subject of the current debate.

Localization of Epileptogenic Zone on Pre-surgical Intracranial EEG Recordings: Toward a Validation of Quantitative Signal Analysis Approaches

In patients diagnosed with pharmaco-resistant epilepsy, cerebral areas responsible for seizure generation can be defined by performing implantation of intracranial electrodes. The identification of the epileptogenic zone (EZ) is based on visual inspection of the intracranial electroencephalogram (IEEG) performed by highly qualified neurophysiologists. New computer-based quantitative EEG analyses have been developed in collaboration with the signal analysis community to expedite EZ detection. The aim of the present report is to compare different signal analysis approaches developed in four different European laboratories working in close collaboration with four European Epilepsy Centers. Computer-based signal analysis methods were retrospectively applied to IEEG recordings performed in four patients undergoing pre-surgical exploration of pharmaco-resistant epilepsy. The four methods elaborated by the different teams to identify the EZ are based either on frequency analysis, on nonlinear signal analysis, on connectivity measures or on statistical parametric mapping of epileptogenicity indices. All methods converge on the identification of EZ in patients that present with fast activity at seizure onset. When traditional visual inspection was not successful in detecting EZ on IEEG, the different signal analysis methods produced highly discordant results. Quantitative analysis of IEEG recordings complement clinical evaluation by contributing to the study of epileptogenic networks during seizures. We demonstrate that the degree of sensitivity of different computer-based methods to detect the EZ in respect to visual EEG inspection depends on the specific seizure pattern.

Intracranial meningiomas associated with cervical syringohydromyelia in a cat

Eine dreizehnjährige, weibliche, nicht kastrierte Hauskatze wurde zur chirurgischen Therapie eines multiplen Meningeoms in der Kleintierklinik des Tierspital Bern vorgestellt. Eine leichtgradige generalisierte Ataxie wurde beobachtet, die Propriozeption war generalisiert herabgesetzt und der Drohreflex war beidseitig reduziert. Es wurden eine prä- und eine postoperative Magnetrezonanztomographie durchgeführt. Drei supratentoriale extra-axiale Raumforderungen wurden diagnostiziert. Eine vierte Masse wurde infratentorial extra-axial über der linken zerebellären Hemisphere lokalisiert. Eine Herniation des kaudoventralen Kleinhirn (Vermis) von ungefähr einem Zentimeter Länge durch das Foramen magnum wurde beobachtet. Eine zervikale Syringohydromyelie wurde als Zufallsbefund diagnostiziert. Die Meningeome wurden durch 3 Kraniotomiestellen entfernt. Zwei Jahre nach der Operation ist die Katze normal. Anhand der vorhandenen Literatur wird die tumor-assoziierte Syringohydromyelie besprochen. Die Therapie der Syringohydromyelie sollte gegen den kausalen pathologischen Prozess (z.B. intrakranieller Tumor) für die Liquorzirkulationsstörung gerichtet sein.

Magnetic resonance imaging signs of presumed elevated intracranial pressure in dogs.

The aim of this study was to describe magnetic resonance imaging (MRI) findings associated with presumed elevated intracranial pressure (ICP) in dogs and to evaluate whether MRI could be used to discriminate between dogs with and without elevated ICP. Of 91 dogs that underwent cranial MRI examination, 18 (19.8%) were diagnosed with elevated ICP based on neurological examination, fundoscopy and transcranial Doppler ultrasonography. The MRI findings that showed the strongest association with elevated ICP were mass effect (odds ratio [OR], 78.5), caudal transtentorial herniation (OR, 72.0), subfalcine herniation (OR, 45.6), perilesional oedema (OR, 34.0), displacement of the lamina quadrigemina (OR, 27.7) and effacement of the cerebral sulci (OR, 27.1). The presence of any two or more of the following MRI findings identified elevated ICP with a sensitivity of 72% and a specificity of 96%: compression of the suprapineal recess, compression of the third ventricle, compression of the fourth ventricle, effacement of the cerebral sulci and caudal transposition of the lamina quadrigemina. In conclusion, there is an association between MRI findings and elevated ICP in dogs; therefore, MRI might be useful to discriminate between dogs with and without elevated ICP.

Intracranial Aneurysm Rupture Is Predicted by Measures of Solar Activity.

OBJECTIVE The cause precipitating intracranial aneurysm rupture remains unknown in many cases. It has been observed that aneurysm ruptures are clustered in time, but the trigger mechanism remains obscure. Because solar activity has been associated with cardiovascular mortality and morbidity, we decided to study its association to aneurysm rupture in the Swiss population. METHODS Patient data were extracted from the Swiss SOS database, at time of analysis covering 918 consecutive patients with angiography-proven aneurysmal subarachnoid hemorrhage treated at 7 Swiss neurovascular centers between January 1, 2009, and December 31, 2011. The daily rupture frequency (RF) was correlated to the absolute amount and the change in various parameters of interest representing continuous measurements of solar activity (radioflux [F10.7 index], solar proton flux, solar flare occurrence, planetary K-index/planetary A-index, Space Environment Services Center [SESC] sunspot number and sunspot area) using Poisson regression analysis. RESULTS During the period of interest, there were 517 days without recorded aneurysm rupture. There were 398, 139, 27, 12, 1, and 1 days with 1, 2, 3, 4, 5, and 6 ruptures per day. Poisson regression analysis demonstrated a significant correlation of F10.7 index and RF (incidence rate ratio [IRR] = 1.006303; standard error (SE) 0.0013201; 95% confidence interval (CI) 1.003719-1.008894; P < 0.001), according to which every 1-unit increase of the F10.7 index increased the count for an aneurysm to rupture by 0.63%. A likewise statistically significant relationship of both the SESC sunspot number (IRR 1.003413; SE 0.0007913; 95% CI 1.001864-1.004965; P < 0.001) and the sunspot area (IRR 1.000419; SE 0.0000866; 95% CI 1.000249-1.000589; P < 0.001) emerged. All other variables analyzed showed no significant correlation with RF. CONCLUSIONS We found greater radioflux, SESC sunspot number, and sunspot area to be associated with an increased count of aneurysm rupture. The clinical meaningfulness of this statistical association must be interpreted carefully and future studies are warranted to rule out a type-1 error.