Transdermal nitroglycerin in patients with subarachnoid hemorrhage

Delayed ischemic neurological deficit (DIND) following cerebral vasospasm remains a cause for high morbidity and mortality in patients with subarachnoid hemorrhage (SAH). There is experimental and clinical evidence of positive effects of nitric oxide (NO) donors on cerebral vasospasm. We therefore analysed the effect of transdermal nitroglycerin in patients with SAH measuring transcranial Doppler velocities (TCD), cerebral blood flow (CBF) and DIND. Nitroglycerin was used in a target dose of 14 microg/kg/h. TCD assessment was performed daily. CBF measurements were done using the perfusion CT-technique. Blood pressure, volume intake and vasopressor administration, were registered. Nine patients were randomly assigned either to the nitroglycerin group (N-group) and eight patients in the control group (C-group). Mean TCD values in the extracranial portion of the internal carotid artery (ICA) were lower in the N-group (p<0.005). Mean TCD in the middle cerebral arteries (MCA) showed no difference. The Lindegaard ratio was higher in the N-group (p<0.04). CBF in the N-group was higher than in the C-group (p<0.03). Even though nitroglycerin reduces blood pressure and lowers ICA TCD-values and increases the Lindegaard ratio, a higher CBF was measured in the N-group. Thus, nitroglycerin influences the cerebral vascular tone and increases CBF. SAH therapy with nitroglycerin is possible without increasing the risk of DIND. The exact timing of onset, duration and reduction of nitroglycerin administration in respect to the appearance of vasospasm may have a strong impact on the success of such a therapy.

Cerebral revascularization model in a swine

The purpose of this study was to analyze the suitability of the cerebral vasculature of the pig regarding a revascularization procedure. In two 60 kg pigs the femoral artery was exposed and canulated for selective angiography and interventional procedures. After the angiography, the pigs were brought to the animal OR for craniotomy and analysis of the intracranial cerebral arteries and the surgical exposure of the carotid arteries under the microscope. Angiography demonstrated the presence of a true internal-, external carotid artery and vertebral arteries. Both the vertebral and internal carotid arteries are feeding a rete mirabilis both at the cranial base and the cranio-cervical junction. At these sites further advancement of the angiography catheter was not possible. Out of these rete mirabilis, an intracranial carotid artery and an intracranial vertebral artery were formed, respectively. The intracranial cerebral vessels were of the dimension of 1 mm and less. The extracranial portion of the internal carotid artery was 2.5 mm of diameter. From these findings, we conclude that a direct cerebral revascularization procedure of the intracranial vessels is not possible in the swine. However, a global revascularization procedure on the extracranial portion of the internal carotid artery is thus feasible, both using a low- and high-flow anastamosis technique.

Cholesterol granuloma of the petrous apex: benefit of computer-aided surgery

The following is an analysis of the role of computer aided surgery by infralabyrinthine-subcochlear approach to the petrous apex for cholesterol granulomas with hearing preservation. In a retrospective case review from 1996 to 2008 six patients were analysed in our tertiary referral centre, otorhinolaryngology outpatient clinic. Excellent intraoperative localisation of the carotid artery, facial nerve and the entrance into the cholesterol cyst of the bone by means of the navigation system was seen. Additionally, the operation time decreased from an initial 4 h down to 2 h. The application of computer-aided surgery allows intraoperative monitoring of the position of the tip of the microsurgical instruments in case of a rare disease and in the delicate area of the petrous apex giving a high security level.

Injuring potential of drinking glasses

At a party of a sports club, an argument started between two groups of young men, in the course of which one of the persons involved threw a beer glass hitting a young man of the other group, who collapsed with a profusely bleeding wound. Although resuscitation measures were initiated immediately, the victim died at the scene due to exsanguination from the completely severed left external carotid artery in combination with the aspiration of blood. Tests with drinking glasses thrown at a skull-neck model suggested that an undamaged beer glass thrown at the head of the victim could not cause the fatal injuries on the neck because of its splintering behaviour. In fact, it seemed that the beer glass had been damaged prior to throwing it and that its sharp edges perforated the skin on hitting the neck.

Estrogen-stimulated endothelial repair requires osteopontin

OBJECTIVE: Estradiol (E(2)) is known to accelerate reendothelialization and thus prevent intimal thickening and in-stent restenosis after angioplasty. Transplantation experiments with ERalpha(-/-) mice have previously shown that E(2) acts through local and bone marrow cell compartments to enhance endothelial healing. However, the downstream mechanisms induced by E(2) to mediate endothelial repair are still poorly understood. METHODS AND RESULTS: We show here that after endovascular carotid artery injury, E(2)-enhanced endothelial repair is lost in osteopontin-deficient mice (OPN(-/-)). Transplantation of OPN(-/-) bone marrow into wild-type lethally irradiated mice, and vice versa, suggested that osteopontin plays a crucial role in both the local and the bone marrow actions of E(2). In the vascular compartment, using transgenic mice expressing doxycyclin regulatable-osteopontin, we show that endothelial cell specific osteopontin overexpression mimics E(2)-enhanced endothelial cell migration and proliferation in the regenerating endothelium. In the bone marrow cell compartment, we demonstrate that E(2) enhances bone marrow-derived mononuclear cell adhesion to regenerating endothelium in vivo, and that this effect is dependent on osteopontin. CONCLUSIONS: We demonstrate here that E(2) acceleration of the endothelial repair requires osteopontin, both for bone marrow-derived cell recruitment and for endothelial cell migration and proliferation.

Whole-body vibration dosage alters leg blood flow

The effect of whole-body vibration dosage on leg blood flow was investigated. Nine healthy young adult males completed a set of 14 random vibration and non-vibration exercise bouts whilst squatting on a Galileo 900 plate. Six vibration frequencies ranging from 5 to 30 Hz (5 Hz increments) were used in combination with a 2.5 mm and 4.5 mm amplitude to produce twelve 1-min vibration bouts. Subjects also completed two 1-min bouts where no vibration was applied. Systolic and diastolic diameters of the common femoral artery and blood cell velocity were measured by an echo Doppler ultrasound in a standing or rest condition prior to the bouts and during and after each bout. Repeated measures MANOVAs were used in the statistical analysis. Compared with the standing condition, the exercise bouts produced a four-fold increase in mean blood cell velocity (P<0.001) and a two-fold increase in peak blood cell velocity (P<0.001). Compared to the non-vibration bouts, frequencies of 10-30 Hz increased mean blood cell velocity by approximately 33% (P<0.01) whereas 20-30 Hz increased peak blood cell velocity by approximately 27% (P<0.01). Amplitude was additive to frequency but only achieved significance at 30 Hz (P<0.05). Compared with the standing condition, squatting alone produced significant increases in mean and peak blood cell velocity (P<0.001). The results show leg blood flow increased during the squat or non-vibration bouts and systematically increased with frequency in the vibration bouts.

Chronic critical leg ischemia: revascularization of the isolated popliteal segment in comparison with femoro-distal bypass

Several patients with chronic critical limb ischemia show angiographically an isolated popliteal segment (IPS) and a single calf vessel (SCV) with no direct communication to the former. In this situation a bypass can be inserted from the common femoral artery to the IPS or to the SCV. The results of 73 bypass procedures--40 to an isolated popliteal segment and 33 to a single calf vessel for limb salvage--were prospectively evaluated. Eighty percent of the grafts were performed with an autogenous saphenous vein (ASV), the rest with a thin wall polytetrafluoroethylene (PTFE) prosthesis. The mean age of our patients was 75 years and many suffered from cardiovascular disease. The operative mortality rate was 3% and the mean postoperative survival 32 months. Three year patency and limb salvage rates for ASV grafts was 83% and 87% (IPS) respectively 77% and 76% (MCV); for PTFE grafts 58% and 88% (IPS) respectively 17% and 50% (MCV). There was no significant difference found in patency and limb salvage rates of the two procedures if the graft was an autogenous saphenous vein (p > 0.05). The PTFE prosthesis was only suitable for grafts inserted to the isolated popliteal segment.

Effects of obesity on endothelium-dependent reactivity during acute nitric oxide synthase inhibition: modulatory role of endothelin.

This study investigated vascular reactivity in response to acetylcholine, in the presence of acute inhibition of nitric oxide synthase, in the carotid artery and aorta of obese C57Bl6/J mice fed on a high-fat diet for 30 weeks, and of control mice. A subgroup of obese animals was also treated with the ET(A) receptor antagonist darusentan (50 mg x kg(-1) x day(-1)). In vascular rings from control animals, acetylcholine caused endothelium-dependent contractions in the carotid artery, but not in the aorta. In vascular rings from obese mice, contractility to acetylcholine was also evident in the aorta, and that in the carotid artery was increased compared with control mice. ET(A) receptor blockade by darusentan treatment of the obese mice prevented enhanced vasoconstriction to acetylcholine, resulting in mild vasodilatation. Thus obesity increases endothelium-dependent vasoconstriction in the absence of endothelial nitric oxide. This effect can be completely prevented by chronic ET(A) receptor blockade, suggesting that endothelin modulates increased endothelium-dependent vasoconstriction in obesity.

Monitoring cerebral oxygenation during balloon occlusion with multichannel NIRS

We report on oxygenation changes noninvasively recorded by multichannel continuous-wave near infrared spectroscopy (CW-NIRS) during endovascular neuroradiologic interventions requiring temporary balloon occlusion of arteries supplying the cerebral circulation. Digital subtraction angiography (DSA) provides reference data on the site, timing, and effectiveness of the flow stagnation as well as on the amount and direction of collateral circulation. This setting allows us to relate CW-NIRS findings to brain specific perfusion changes. We focused our analysis on the transition from normal perfusion to vessel occlusion, i.e., before hypoxia becomes clinically apparent. The localization of the maximal response correlated either with the core (occlusion of the middle cerebral artery) or with the watershed areas (occlusion of the internal carotid artery) of the respective vascular territories. In one patient with clinically and angiographically confirmed insufficient collateral flow during carotid artery occlusion, the total hemoglobin concentration became significantly asymmetric, with decreased values in the ipsilateral watershed area and contralaterally increased values. Multichannel CW-NIRS monitoring might serve as an objective and early predictive marker of critical perfusion changes during interventions-to prevent hypoxic damage of the brain. It also might provide valuable human reference data on oxygenation changes as they typically occur during acute stroke.

First Clinical Experience With Celt ACD(®) : A Femoral Arterial Puncture Closure Device

Introduction This prospective nonrandomized study compared the safety and efficacy of a novel arterial closure device (ACD) in common femoral artery procedures to that of the FDA submitted historical manual pressure control group, who underwent either a diagnostic angiogram (DA) or a percutaneous coronary intervention (PCI) procedure. Methods and Results A total of 55 patients were enrolled in this study of the novel ACD. Of the 55 patients, 39 were enrolled in the DA group and 16 were enrolled in the PCI group. Six patients were excluded. A device was deployed in 49 patients. Time to hemostasis (TTH), time to ambulation (TTA), device function, and device-related vascular complications were measured. In the device group, the TTH for the combined DA and PCI patients was 32 seconds (0.54 ± 0.93 minutes), significantly lower when compared with 16.0 ± 12.2 minutes (P < 0.0001) for the control group. Overall major vascular complication rate did not differ significantly, device group (1/49) and the historical control group (1/217). TTA in the combined PCI and DA device group was 226.4 ± 231.9 at the German site (site ambulation policy). In the Irish site, the average TTA in the PCI group was 187 minutes (n = 8) and 85 minutes (n = 14) in the DA group. Conclusion The Celt ACD® device is safe, effective, and significantly decreases the TTH compared to manual pressure and has a low vascular complications rate. The device may be effective in early ambulation and discharge of patients postcoronary intervention procedures.

Intravenous mesenchymal stem cell therapy for traumatic brain injury.

OBJECT: Cell therapy has shown preclinical promise in the treatment of many diseases, and its application is being translated to the clinical arena. Intravenous mesenchymal stem cell (MSC) therapy has been shown to improve functional recovery after traumatic brain injury (TBI). Herein, the authors report on their attempts to reproduce such observations, including detailed characterizations of the MSC population, non-bromodeoxyuridine-based cell labeling, macroscopic and microscopic cell tracking, quantification of cells traversing the pulmonary microvasculature, and well-validated measurement of motor and cognitive function recovery. METHODS: Rat MSCs were isolated, expanded in vitro, immunophenotyped, and labeled. Four million MSCs were intravenously infused into Sprague-Dawley rats 24 hours after receiving a moderate, unilateral controlled cortical impact TBI. Infrared macroscopic cell tracking was used to identify cell distribution. Immunohistochemical analysis of brain and lung tissues 48 hours and 2 weeks postinfusion revealed transplanted cells in these locations, and these cells were quantified. Intraarterial blood sampling and flow cytometry were used to quantify the number of transplanted cells reaching the arterial circulation. Motor and cognitive behavioral testing was performed to evaluate functional recovery. RESULTS: At 48 hours post-MSC infusion, the majority of cells were localized to the lungs. Between 1.5 and 3.7% of the infused cells were estimated to traverse the lungs and reach the arterial circulation, 0.295% reached the carotid artery, and a very small percentage reached the cerebral parenchyma (0.0005%) and remained there. Almost no cells were identified in the brain tissue at 2 weeks postinfusion. No motor or cognitive functional improvements in recovery were identified. CONCLUSIONS: The intravenous infusion of MSCs appeared neither to result in significant acute or prolonged cerebral engraftment of cells nor to modify the recovery of motor or cognitive function. Less than 4% of the infused cells were likely to traverse the pulmonary microvasculature and reach the arterial circulation, a phenomenon termed the "pulmonary first-pass effect," which may limit the efficacy of this therapeutic approach. The data in this study contradict the findings of previous reports and highlight the potential shortcomings of acute, single-dose, intravenous MSC therapy for TBI.

Prospective, multicenter, single-arm study of mechanical thrombectomy using Solitaire Flow Restoration in acute ischemic stroke

BACKGROUND AND PURPOSE Mechanical thrombectomy using stent retriever devices have been advocated to increase revascularization in intracranial vessel occlusion. We present the results of a large prospective study on the use of the Solitaire Flow Restoration in patients with acute ischemic stroke. METHODS Solitaire Flow Restoration Thrombectomy for Acute Revascularization was an international, multicenter, prospective, single-arm study of Solitaire Flow Restoration thrombectomy in patients with large vessel anterior circulation strokes treated within 8 hours of symptom onset. Strict criteria for site selection were applied. The primary end point was the revascularization rate (thrombolysis in cerebral infarction ≥2b) of the occluded vessel as determined by an independent core laboratory. The secondary end point was the rate of good functional outcome (defined as 90-day modified Rankin scale, 0-2). RESULTS A total of 202 patients were enrolled across 14 comprehensive stroke centers in Europe, Canada, and Australia. The median age was 72 years, 60% were female patients. The median National Institute of Health Stroke Scale was 17. Most proximal intracranial occlusion was the internal carotid artery in 18%, and the middle cerebral artery in 82%. Successful revascularization was achieved in 79.2% of patients. Device and procedure-related severe adverse events were found in 7.4%. Favorable neurological outcome was found in 57.9%. The mortality rate was 6.9%. Any intracranial hemorrhagic transformation was found in 18.8% of patients, 1.5% were symptomatic. CONCLUSIONS In this single-arm study, treatment with the Solitaire Flow Restoration device in intracranial anterior circulation occlusions results in high rates of revascularization, low risk of clinically relevant procedural complications, and good clinical outcomes in combination with low mortality at 90 days. CLINICAL TRIAL REGISTRATION URL http://www.clinicaltrials.gov. Unique identifier: NCT01327989.

Thoracic aortic disease in tuberous sclerosis complex: molecular pathogenesis and potential therapies in Tsc2+/- mice.

Tuberous sclerosis complex (TSC) is a genetic disorder with pleiotropic manifestations caused by heterozygous mutations in either TSC1 or TSC2. One of the less investigated complications of TSC is the formation of aneurysms of the descending aorta, which are characterized on pathologic examination by smooth muscle cell (SMC) proliferation in the aortic media. SMCs were explanted from Tsc2(+/-) mice to investigate the pathogenesis of aortic aneurysms caused by TSC2 mutations. Tsc2(+/-) SMCs demonstrated increased phosphorylation of mammalian target of rapamycin (mTOR), S6 and p70S6K and increased proliferation rates compared with wild-type (WT) SMCs. Tsc2(+/-) SMCs also had reduced expression of SMC contractile proteins compared with WT SMCs. An inhibitor of mTOR signaling, rapamycin, decreased SMC proliferation and increased contractile protein expression in the Tsc2(+/-) SMCs to levels similar to WT SMCs. Exposure to alpha-elastin fragments also decreased proliferation of Tsc2(+/-) SMCs and increased levels of p27(kip1), but failed to increase expression of contractile proteins. In response to artery injury using a carotid artery ligation model, Tsc2(+/-) mice significantly increased neointima formation compared with the control mice, and the neointima formation was inhibited by treatment with rapamycin. These results demonstrate that Tsc2 haploinsufficiency in SMCs increases proliferation and decreases contractile protein expression and suggest that the increased proliferative potential of the mutant cells may be suppressed in vivo by interaction with elastin. These findings provide insights into the molecular pathogenesis of aortic disease in TSC patients and identify a potential therapeutic target for treatment of this complication of the disease.

The biology and mechanism of chemoresistance of brain metastases

Primary brain neoplasms and metastases to the brain are generally resistant to systemic chemotherapy. The purpose of theses studies was to determine the mechanism(s) for this resistance. We have developed a model to study the biology of brain metastasis by injecting metastatic K1735 melanoma cells into the carotid artery of syngeneic C3H/HeN or nude mice. The resulting brain lesions are produced in the parenchyma of the brain. Mice with subcutaneous or brain melanoma lesions were treated intravenously with doxorubicin (DXR) (7 mg/kg). The s.c. lesions regressed in most of the mice whereas no therapeutic benefits were produced in mice with brain metastases. The intravenous injection of sodium fluorescine revealed that the blood-brain barrier (BBB) is intact in and around brain metastases smaller than 0.2 mm$\sp2$ but not in larger lesions, implying that the BBB is not a major obstacle for chemotherapy of brain metastases.^ Western blot and FACS analyses revealed that K1735 melanoma brain metastases expressed high levels of P-glycoprotein (P-gp) as compared to s.c. tumors or in vitro cultures. Similarly, K1735 cells from brain metastases expressed higher levels of mdrl mRNA. This increased expression of mdrl was due to adaptation to the local brain environment. We base this conclusion on the results of two studies. First, K1735 cells from brain metastases cultured for 7 days lost the high mdrl expression. Second, in crossover experiments K1735 cells from s.c. tumors (low mdrl expression) implanted into the brain exhibited high levels of mdrl expression whereas cells from brain metastases implanted s.c. lost the high level mdrl expression.^ To investigate the mechanism by which the brain environment upregulates mdrl expression of the K1735 cells we first studied the regulation of P-gp in brain endothelial cells. Since astrocytes are closely linked with the BBB we cocultured brain endothelial cells for 3 days with astrocytes. These endothelial cells expressed high levels of mdrl mRNA and protein whereas endothelial cells cocultured with endothelial cells or fibroblasts did not. We next cocultured K1735 melanoma cells with astrocytes. Here again, astrocytes (but not fibroblasts or tumor cells) uprelated the mdrl expression in K1735 tumor cells. This upregulation inversely correlated with intracellular drug accumulation and sensitivity to DXR.^ The data conclude that the resistance of melanoma brain metastases to chemotherapy is not due to an intact BBB but to the upregulation of the mdrl gene by the organ microenvironment, i.e., the astrocytes. This epigenetic mediated resistance to chemotherapy has wide implications for the therapy of brain metastases. ^

Younger Stroke Patients With Large Pretreatment Diffusion-Weighted Imaging Lesions May Benefit From Endovascular Treatment.

BACKGROUND AND PURPOSE Lesion volume on diffusion-weighted magnetic resonance imaging (DWI) before acute stroke therapy is a predictor of outcome. Therefore, patients with large volumes are often excluded from therapy. The aim of this study was to analyze the impact of endovascular treatment in patients with large DWI lesion volumes (>70 mL). METHODS Three hundred seventy-two patients with middle cerebral or internal carotid artery occlusions examined with magnetic resonance imaging before treatment since 2004 were included. Baseline data and 3 months outcome were recorded prospectively. DWI lesion volumes were measured semiautomatically. RESULTS One hundred five patients had lesions >70 mL. Overall, the volume of DWI lesions was an independent predictor of unfavorable outcome, survival, and symptomatic intracerebral hemorrhage (P<0.001 each). In patients with DWI lesions >70 mL, 11 of 31 (35.5%) reached favorable outcome (modified Rankin scale score, 0-2) after thrombolysis in cerebral infarction 2b-3 reperfusion in contrast to 3 of 35 (8.6%) after thrombolysis in cerebral infarction 0-2a reperfusion (P=0.014). Reperfusion success, patient age, and DWI lesion volume were independent predictors of outcome in patients with DWI lesions >70 mL. Thirteen of 66 (19.7%) patients with lesions >70 mL had symptomatic intracerebral hemorrhage with a trend for reduced risk with avoidance of thrombolytic agents. CONCLUSIONS There was a growing risk for poor outcome and symptomatic intracerebral hemorrhage with increasing pretreatment DWI lesion volumes. Nevertheless, favorable outcome was achieved in every third patient with DWI lesions >70 mL after successful endovascular reperfusion, whereas after poor or failed reperfusion, outcome was favorable in only every 12th patient. Therefore, endovascular treatment might be considered in patients with large DWI lesions, especially in younger patients.