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Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-β pathway that is essential for TGF-β signal transmission. SMAD3 mutations lead to increased aortic expression of several key players in the TGF-β pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-β pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis. [ABSTRACT FROM AUTHOR]

van Noord D, Biermann K, Moons L M G, Pattynama P M T, Verhagen H J M, Kuipers E J & Mensink P B F (2010) Histopathology 57, 615-621 Histological changes in patients with chronic upper gastrointestinal ischaemia Aims: Diagnosing chronic upper gastrointestinal ischaemia (CUGI) remains a challenge in clinical practice. Histological examination of biopsy material currently plays no role in the diagnosis of transient CUGI, as little is known about gastrointestinal histology in these patients. The aim of this study was to investigate upper gastrointestinal histology in patients with well-defined CUGI. Methods and results: Consecutive patients suspected of CUGI were included prospectively and underwent a diagnostic work-up existing of upper endoscopy, gastrointestinal tonometry and computed tomography (CT) or magnetic resonance (MR) angiography. Results were discussed in a multidisciplinary team and a consensus diagnosis was made. Endoscopic biopsy samples were taken from the descending duodenum, gastric antrum and corpus, and scored using the Sydney, Vienna, Chiu, Marsh and Operative Link for Gastritis Assessment (OLGA) classifications. Gastropathy was scored present or absent. Seventy-nine patients were analysed in 8 months. CUGI was diagnosed in 41 patients (52%): 36 males, mean age 60 (17-86) years. Prevalence of gastropathy was significantly higher in patients with ischaemia ( P = 0.025). No other differences were found between patients with and without ischaemia. Conclusions: Histological examination of biopsy samples plays no definitive role in diagnosing CUGI, but the presence of histological signs of reactive gastropathy can be used to support the clinical diagnosis of ischaemia. [ABSTRACT FROM AUTHOR]

Background: Little is known about the efficacy and safety of renal artery stenting in patients with atherosclerotic renal artery stenosis (ARAS) and impaired renal function. Objective: To determine the efficacy and safety of stent placement in patients with ARAS and impaired renal function. Design: Randomized clinical trial. Randomization was centralized and computer generated, and allocation was assigned by e-mail. Patients, providers, and persons who assessed outcomes were not blinded to treatment assignment. Setting: 10 European medical centers. Participants: 140 patients with creatinine clearance less than 80 mL/min per 1.73 m2 and ARAS of 50% or greater. Intervention: Stent placement and medical treatment (64 patients) or medical treatment only (76 patients). Medical treatment consisted of antihypertensive treatment, a statin, and aspirin. Measurements: The primary end point was a 20% or greater decrease in creatinine clearance. Secondary end points included safety and cardiovascular morbidity and mortality. Results: Forty-six of 64 patients assigned to stent placement had the procedure. Ten of the 64 patients (16%) in the stent placement group and 16 patients (22%) in the medication group reached the primary end point (hazard ratio, 0.73 [95% CI, 0.33 to 1.61]). Serious complications occurred in the stent group, including 2 procedure-related deaths (3%), 1 late death secondary to an infected hematoma, and 1 patient who required dialysis secondary to cholesterol embolism. The groups did not differ for other secondary end points. Limitation: Many patients were falsely identified as having renal artery stenosis greater than 50% by noninvasive imaging and did not ultimately require stenting. Conclusion: Stent placement with medical treatment had no clear effect on progression of impaired renal function but led to a small number of significant procedure-related complications. The study findings favor a conservative approach to patients with ARAS, focused on cardiovascular risk factor management and avoiding stenting. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the pressure gradient and degree of flow reduction associated with embolus protection filters for carotid stenting in an in vitro experiment. Methods: Three filter devices with a perforated membrane design and one wire mesh type filter were tested. At a pressure of 70 mmHg, the flow reduction and pressure gradient were measured in a 5-mm tube using blood-mimicking fluid. Results: The pressure gradient in the wire mesh filter was 1.65±0.49 mmHg (95% CI 1.32 to 1.86). The mean pressure gradient in the perforated membrane filters was 6.88±2.62 mmHg (95% CI 6.22 to 7.55, p<0.0001). There was also a significant correlation between pressure gradient and flow reduction (r=-0.77, p<0.01). Conclusion: Embolic protection filters cause a pressure gradient and obstruct blood flow. This effect is marked in perforated membrane filters and almost absent in the wire mesh filter. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the pattern of catecholamine response in patients undergoing carotid endarterectomy (CEA) or carotid artery stenting (CAS). Methods: Adrenaline, noradrenaline, and renin levels were measured at 5 time points in 12 patients undergoing 13 CEAs (1 bilateral) and 13 patients undergoing unilateral CAS. Arterial blood samples were taken at the following time points: (1) after induction in CEA patients or 5 minutes following first contrast injection in CAS patients, (2) 5 minutes following ICA clamp release in surgical patients or deflation of the balloon in the CAS cohort, (3) 60 minutes following ICA clamp release in surgical patients or deflation of the balloon in the CAS cohort, and (4) 24 hours following the procedure. Intraoperative blood pressure and heart rate were recorded using radial arterial monitoring. Changes in adrenaline, noradrenaline, and renin levels are expressed as ratios versus baseline. Results: Patterns of adrenaline and noradrenaline release were significantly different in patients undergoing CAS and CEA, with much higher and more variable surges of adrenaline and noradrenaline occurring in CEA patients. Adrenaline and noradrenaline levels increased significantly over baseline following carotid artery clamping in patients undergoing CEA (noradrenaline ratio before clamping: 1.54±1.25, 24 hours after unclamping: 8.38±16.35 [p<0.001]; adrenaline ratio before clamping: 1.12±0.49, 60 minutes after unclamping: 17.59±19.14 [p<0.001]). Conversely, in patients undergoing CAS, catecholamine levels remained unchanged (noradrenaline ratio before dilation: 0.96±0.23, 24 hours after the procedure: 0.92±0.32 [p=NS]; adrenaline ratio before dilation: 0.83±0.33, 60 minutes after balloon deflation: 0.56±0.32 [p=NS]). Conclusions: CAS is associated with a significantly less marked catecholamine response than CEA, which may reflect down-regulation of the sympathetic nervous... [ABSTRACT FROM AUTHOR]

Background: Helical computed tomography (CT) is a readily available tool for diagnosing pulmonary embolism (PE); however, its role in the management of patients with clinically suspected PE has not been fully established.Objective: To determine the effectiveness and safety of using helical CT of the pulmonary arteries as the primary diagnostic test in patients with suspected PE.Design: Multicenter, prospective clinical outcome study.Setting: Two academic hospitals and one large teaching hospital in the Netherlands.Patients: 510 consecutive inpatients and outpatients with clinically suspected PE followed for 3 months.Interventions: Patients underwent helical CT of the pulmonary arteries within 24 hours after presenting with signs and symptoms of PE. If CT results were normal or inconclusive, compression ultrasonography was performed on the same day as CT and repeated on days 4 and 7 if findings on the first compression ultrasonography were normal. When CT or compression ultrasonography results were positive for thromboembolism, anticoagulation was started. Anticoagulation was not started when results of CT were negative for PE or indicated an alternative diagnosis that explained the clinical signs and symptoms, or when results on serial compression ultrasonography were normal.Measurements: Patients received instructions to report any symptoms or signs of PE or deep venous thrombosis (DVT) during the 3-month follow-up period. The authors performed compression ultrasonography or phlebography for suspected DVT and pulmonary angiography for suspected PE.Results: Computed tomography identified PE in 124 of 510 patients (24.3%) and an alternative diagnosis in 130 patients (25.5%); CT scans were normal in 248 patients (48.6%). The CT scan could not be interpreted in 8 patients (1.6%) and was not obtained in 2. Compression ultrasonography revealed DVT in 2 patients at the first examination; findings on repeated compression ultrasonography at days 4 and 7 were normal. Mortality in the patients with normal helical CT scans was 4.1% (10 of 246 patients). No patients in this group died of fatal PE, 1 patient developed nonfatal PE, and venous thromboembolism occurred in 0.4% of these patients (95% CI, 0% to 2.2%). In the patients with alternative diagnoses, 1 patient had DVT on objective testing during follow-up. Mortality in this group was 21.5% (28 of 130 patients); in 1 of these patients, PE could not be confidently ruled out as a contributing cause of death. Venous thromboembolism occurred in 1.5% of these patients (CI, 0.2% to 5.6%).Conclusions: In patients with suspected PE, helical CT can be used safely as the primary diagnostic test to rule out PE. Serial compression ultrasonography has limited additional value. [ABSTRACT FROM AUTHOR]

A negative rapid ELISA D-dimer test alone in outpatients with a low to moderate clinical probability (CP) on pulmonary embolism (PE) is predicted to safely exclude pulmonary embolism. The combination of a negative rapid ELISA D-dimer test and a low to moderate CP on PE followed by compression ultrasonography (CUS) for the detection of deep vein thrombosis (DVT) is safe and cost-effective as it reduces the need for noninvasive imaging techniques to about 50% to 60% of outpatients with suspected PE. A high probability ventilation- perfusion (VP) scan or a positive spiral CT consistent with PE and the detection of DVT by CUS are currently considered to be clear indications for anticoagulant treatment. Subsequent pulmonary angiography (PA) is the gold standard diagnostic strategy to exclude or diagnose PE in suspected outpatients with a negative CUS, a positive rapid ELISA D-dimer test, and a nondiagnostic VP scan or negative spiral CT to prevent overtreatment with anticoagulants. However, the willingness of clinicians and the availability of resources to perform PA is restricted, a fact that has provided an impetus for clinical investigators to search for alternative noninvasive strategies to exclude or detect venous thromboembolism (VTE). Serial CUS testing for the detection of DVT in patients with a low to moderate CP on PE and a nondiagnostic VP scan or negative spiral CT is predicted to be safe and will reduce the need for PA to less than 12% or even less than 5%. This noninvasive serial CUS strategy restricts the need for invasive PA to a minor group of patients (<5%) with the combination of a low CP on PE and high probability VP scan or the combination of a nondiagnostic VP scan or negative spiral CT and a high CP on PE. Prospective evaluations are warranted to implement and to validate the advantages and the disadvantages of the various combinations of noninvasive strategies and to compare serial CUS testing versus PA in randomized... [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To assess local control, overall survival, and toxicity of four-dimensional, risk-adapted stereotactic body radiotherapy (SBRT) delivered while tracking respiratory motion in patients with primary and metastatic lung cancer located in the central chest. Methods: Fifty-eight central lesions of 56 patients (39 with primary, 17 with metastatic tumors) were treated. Fifteen tumors located near the esophagus were treated with 6 fractions of 8Gy. Other tumors were treated according to the following dose escalation scheme: 5 fractions of 9Gy (n =6), then 5 fractions of 10Gy (n =15), and finally 5 fractions of 12Gy (n =22). Results: Dose constraints for critical structures were generally achieved; in 21 patients the coverage of the PTV was reduced below 95% to protect adjacent organs at risk. At a median follow-up of 23months, the actuarial 2-years local tumor control was 85% for tumors treated with a BED >100Gy compared to 60% for tumors treated with a BED ⩽100Gy. No grade 4 or 5 toxicity was observed. Acute grade 1–2 esophagitis was observed in 11% of patients. Conclusion: SBRT of central lung lesions can be safely delivered, with promising early tumor control in patients many of whom have severe comorbid conditions. [Copyright &y& Elsevier]

: PurposeHigh-precision external beam radiotherapy (EBRT) has been suggested as a potential alternative to endovascular brachytherapy for the treatment of coronary artery in-stent restenosis. The purpose of our study was to investigate and compare different options to define a smallest feasible target volume.: Methods and materialsThe cardiac motion of 17 coronary artery stents in 17 patients was studied by use of biplane conventional angiography, recorded during breath-hold. Each stent was reconstructed in three dimensions by use of biplane sets of frames covering an entire cardiac cycle. The volume traversed by the stent during the entire or part of the cardiac cycle was determined. Four options to define the stent-traversed volume (STV) as a target for high-precision EBRT were investigated.: ResultsThe mean STV during the entire cardiac cycle was 3.5 cm3; the STV represented less than 1% of the heart volume in all patients. The STV during the diastolic and systolic phase resulted in a mean reduction of 26.6% and 29.1%, respectively, compared with the STV during the entire cardiac cycle. The smallest STV, measured during a 160-ms interval within the cardiac cycle, resulted in a mean maximal reduction of 75.9% compared with the STV during the entire cardiac cycle.: ConclusionsThe STV during the entire cardiac cycle represents a small potential target volume for high-precision EBRT. A significant reduction of this target volume is possible in case of definition during a selected interval within the cardiac cycle. [Copyright &y& Elsevier]

Unlabelled: Gastroesophageal variceal bleeding in patients with cirrhosis is associated with significant morbidity and mortality, as well as a high rebleeding risk. Limited data are available on the role of transjugular intrahepatic portosystemic shunt (TIPS) with covered stents in patients receiving standard endoscopic, vasoactive, and antibiotic treatment. In this multicenter randomized trial, long-term endoscopic variceal ligation (EVL) or glue injection + β-blocker treatment was compared with TIPS placement in 72 patients with a first or second episode of gastric and/or esophageal variceal bleeding, after hemodynamic stabilization upon endoscopic, vasoactive, and antibiotic treatment. Randomization was stratified according to Child-Pugh score. Kaplan-Meier (event-free) survival estimates were used for the endpoints rebleeding, death, treatment failure, and hepatic encephalopathy. During a median follow-up of 23 months, 10 (29%) of 35 patients in the endoscopy + β-blocker group, as compared to 0 of 37 (0%) patients in the TIPS group, developed variceal rebleeding (P = 0.001). Mortality (TIPS 32% vs. endoscopy 26%; P = 0.418) and treatment failure (TIPS 38% vs. endoscopy 34%; P = 0.685) did not differ between groups. Early hepatic encephalopathy (within 1 year) was significantly more frequent in the TIPS group (35% vs. 14%; P = 0.035), but during long-term follow-up this difference diminished (38% vs. 23%; P = 0.121)., Conclusions: In unselected patients with cirrhosis, who underwent successful endoscopic hemostasis for variceal bleeding, covered TIPS was superior to EVL + β-blocker for reduction of variceal rebleeding, but did not improve survival. TIPS was associated with higher rates of early hepatic encephalopathy., (© 2015 by the American Association for the Study of Liver Diseases.)