Enhanced Dopamine-Dependent Hippocampal Plasticity after Single MK-801 Application

Dopaminergic hyperfunction and N-methyl-D-aspartate receptor (NMDAR) hypofunction have both been implicated in psychosis. Dopamine-releasing drugs and NMDAR antagonists replicate symptoms associated with psychosis in healthy humans and exacerbate symptoms in patients with schizophrenia. Though hippocampal dysfunction contributes to psychosis, the impact of NMDAR hypofunction on hippocampal plasticity remains poorly understood. Here, we used an NMDAR antagonist rodent model of psychosis to investigate hippocampal long-term potentiation (LTP). We found that single systemic NMDAR antagonism results in a region-specific, presynaptic LTP at hippocampal CA1-subiculum synapses that is induced by activation of D1/D5 dopamine receptors and modulated by L-type voltage-gated Ca²⁺ channels. Thereby, our findings may provide a cellular mechanism how NMDAR antagonism can lead to an enhanced hippocampal output causing activation of the hippocampus-ventral tegmental area-loop and overdrive of the dopamine system.     

Direct videoscopic approach to the descending thoracic aorta for aortic arch endograft delivery: evaluation in a porcine model.

PURPOSE: To examine the feasibility of a direct videoscopic approach to the descending thoracic aorta for endograft delivery to the aortic arch. METHODS: A double purse-string suture was placed on the aorta of 3 pigs via a thoracoscopic approach. Subsequently, the aorta was cannulated in the center of the purse-string. A 22-F delivery catheter was advanced under fluoroscopic control over a guidewire via a trocar into the proximal aorta. After deployment of a tubular endograft, the catheter was withdrawn from the aorta while simultaneously tightening the purse-string suture, without aortic cross clamping. The outcome was evaluated by post implant angiography and autopsy results. RESULTS: The procedure was successfully completed in all animals, with a mean total procedure time of 126 minutes (range 118-137). Mean endograft implantation time from needle puncture to catheter extraction was 27 minutes (range 21-37). Hemostasis was obtained in all animals after withdrawal of the delivery catheter and tightening the purse-string suture. The mean blood loss was 143 mL (range 80-220). Autopsy proved all purse-string sutures to be adequately placed and all endografts deployed in the correct position. CONCLUSION: A direct videoscopic approach to the descending thoracic aorta proved a feasible technique for endograft delivery to the aortic arch in a porcine model.     

Frequency of major hemorrhage in patients treated with unfractionated intravenous heparin for deep venous thrombosis or pulmonary embolism: a study in routine clinical practice

BACKGROUND: The rate of major hemorrhage during the initial treatment with unfractionated heparin (UFH) in patients with deep venous thrombosis (DVT) and pulmonary embolism (PE) in routine clinical practice is understudied. In recent clinical trials an overall average of 3.8% was reported. However, the incidence of this complication in routine patient care might be higher owing to less strict patient selection and lack of standardization in the administration of heparin. We have determined major bleeding rates during heparin treatment for DVT or PE in routine practice and compared these rates with data from clinical trials. METHODS: Data on the occurrence of major hemorrhage were retrieved according to strict criteria from the records of patients who had received continuous intravenous UFH therapy to treat objectively documented DVT or PE in 3 hospitals. RESULTS: After exclusion of 29 patients because of lack of objective diagnosis of DVT or PE and 25 patients because of initial treatment with low-molecular-weight heparin, 424 consecutive patients were available for detailed analysis. Among them, 17 patients (4.0%; 95% confidence interval, 2.1%-5.9%) experienced major hemorrhage during UFH treatment, which in most patients occurred at the end of planned heparin therapy; one of the hemorrhages was fatal. Six patients (1.4%; 95% confidence interval, 0.3%-2.5%) developed clinically suspected recurrent venous thromboembolism (fatal in 1 case) during UFH treatment or within 7 days' cessation. CONCLUSIONS: Administration of continuous intravenous UFH in patients with DVT or PE in routine clinical practice leads to a major bleeding rate of 4.0%. This rate is comparable to the rate of major bleeding in patients who received UFH in clinical trials. Our findings are relevant to the discussion of major bleeding rates in patients with DVT and PE treated in daily clinical practice with subcutaneous low-molecular-weight heparin and newer antithrombotic drugs.     

Susceptibility-Weighted Imaging in Pediatric Arterial Ischemic Stroke: A Valuable Alternative for the Noninvasive Evaluation of Altered Cerebral Hemodynamics

BACKGROUND AND PURPOSE:SWI provides information about blood oxygenation levels in intracranial vessels. Prior reports have shown that SWI focusing on venous drainage can provide noninvasive information about the degree of brain perfusion in pediatric arterial ischemic stroke. We aimed to evaluate the influence of the SWI venous signal pattern in predicting stroke evolution and the development of malignant edema in a large cohort of children with arterial ischemic stroke.MATERIALS AND METHODS:A semiquantitative analysis of venous signal intensity on SWI and diffusion characteristics on DTI was performed in 16 vascular territories. The mismatch between areas with SWI-hypointense venous signal and restricted diffusion was correlated with stroke progression on follow-up. SWI-hyperintense signal was correlated with the development of malignant edema.RESULTS:We included 24 children with a confirmed diagnosis of pediatric arterial ischemic stroke. Follow-up images were available for 14/24 children. MCA stroke progression on follow-up was observed in 5/6 children, with 2/8 children without mismatch between areas of initial SWI hypointense venous signal and areas of restricted diffusion on DTI. This mismatch showed a statistically significant association (P = .03) for infarct progression. Postischemic malignant edema developed in 2/10 children with and 0/14 children without SWI-hyperintense venous signal on initial SWI (P = .07).CONCLUSIONS:SWI-DTI mismatch predicts stroke progression in pediatric arterial ischemic stroke. SWI-hyperintense signal is not useful for predicting the development of malignant edema. SWI should be routinely added to the neuroimaging diagnostic protocol of pediatric arterial ischemic stroke.

Acute arterial ischemic stroke (AIS) affects 2–5/100,000 children every year and is associated with high mortality and morbidity.¹ The mortality rate is estimated at 5%–13%, and moderate-to-severe neurologic deficits or epilepsy occur in >50% of children after AIS.^2,3 The Chest and American Heart Association guidelines support the use of anticoagulation in acute pediatric arterial ischemic stroke (PAIS) despite of the absence of large-scale clinical trials.^4,5 Antithrombotic therapy aims to prevent early propagation of the thrombus, inhibit the formation of new thrombus, and promote early recanalization to save hypoperfused tissue at risk of irreversible ischemic infarction. However, the diagnosis of PAIS should be made first, and tissue at risk for infarction should be detected. The diagnosis of PAIS is frequently delayed or missed.⁶ DWI/DTI is a highly sensitive MR imaging sequence in detecting early ischemic regions and is the diagnostic criterion standard for imaging acute PAIS.⁷ Neuroimaging techniques that allow early, reliable, noninvasive identification of potentially salvageable hypoperfused brain tissue—the so called ischemic penumbra—are imperative to guide treatment.SWI is a high-spatial-resolution, gradient-echo MR imaging sequence that accentuates the magnetic properties of various substances such as blood, blood products, nonheme iron, and calcification.⁸ In addition, SWI accentuates magnetic susceptibility differences between deoxygenated hemoglobin in the vessels and adjacent oxygenated tissues. A few previous reports have shown that SWI-hypointense signals in veins draining hypoperfused brain areas provide indirect evaluation of critically perfused tissue by focusing on venous drainage.^9–12 In addition, SWI-hyperintense signal was reported to detect regions of hyperperfusion and to be associated with an increased risk of developing postischemic malignant edema.¹³ SWI may consequently serve as a valuable alternative sequence to evaluate the hemodynamics of brain tissue in PAIS.The aims of this retrospective study were to evaluate the potential of acute SWI to identify potentially salvageable brain tissue and to predict the development of postischemic malignant edema in the largest cohort of PAIS reported so far, to our knowledge. We hypothesized that hypointense venous signal on acute SWI may identify brain tissue at risk of infarction progression by focusing on venous drainage and that the presence of SWI-hyperintense venous signal may predict the development of postischemic malignant edema.     

Influence of oxygen tension on the viscoelastic behavior of red blood cells in sickle cell disease

Although the rheological behavior of sickle cell suspensions and of hemoglobin S solutions is known to be strongly dependent on oxygen tension (PO2), little data exist concerning the influence of PO2 on the viscoelasticity of individual HbSS RBC. We have used micropipette aspiration techniques to test the deformation response of both HbSS and control HbAA RBC over a wide range of PO2 at 23 degrees C. Sickled, spiculed HbSS cells were present for PO2 approximately less than 35 mm Hg; for a number of these cells, the deformation response was essentially elastic and an effective membrane rigidity (EMR) was calculated. EMR increased with decreasing PO2 and was approximately 5 to 50 times higher than the equivalent rigidity of oxygenated HbSS RBC. In addition, the rate of membrane deformation was very slow for sickled cells; the half-time for the deformation process increased as PO2 was lowered and was about two orders of magnitude longer than the equivalent time for normal RBC. Other sickled cells exhibited plastic deformation when subjected to comparable deforming forces and experienced irreversible membrane deformation and budding. At all PO2 levels tested, some HbSS RBC remained as discocytes; these cells had normal membrane elasticity and membrane viscosity. Furthermore, changes in PO2 did not affect the membrane properties of HbAA RBC. Thus, gross abnormalities in the deformation response of HbSS RBC were only detected after morphological sickling had occurred. These abnormalities most likely arose from changes in the cytoplasmic HbS viscoelasticity and, if present in vivo, would be expected to impair the flow of HbSS cells in the microcirculation.     

Use of a water-soluble busulfan formulation--pharmacokinetic studies in a canine model

In a canine model we investigated the toxicity and pharmacokinetics of a water soluble busulfan preparation. Busulfan was dissolved in dimethylsulfoxide (DMSO) and administered either orally or intravenously in a single dose of 1 mg/kg. The application in either preparation was well tolerated. In seven dogs, peak levels in the range of 730 ng/mL to 1,000 ng/mL were measured after intravenous injection with an area under curve (AUC) of 75 ng.h/kg.mL to 146 ng.h/kg.mL. It was of note that even the oral administration of the same busulfan preparation resulted in AUC values in the same range as observed after parenteral application. The absorption rate of busulfan tablets in our model was as unpredictable as documented in clinical trials. On the basis of the present study, clinical trials using busulfan dissolved in DMSO given either intravenously or orally appear warranted. This approach should lead to predictable blood levels, reduced toxicity, and increased efficacy of busulfan-containing regimens.     

Expression and function of CD40 on Hodgkin and Reed-Sternberg cells and the possible relevance for Hodgkin's disease

CD40 was originally described as a B-cell-restricted antigen and was subsequently found to be a member of the tumor necrosis factor (TNF) receptor superfamily. CD40 is also expressed on dendritic cells, thymic epithelium, monocytes, and some carcinoma cell lines, and plays a critical role in cell contact-dependent activation. Primary and cultured Hodgkin and Reed-Sternberg (H-RS) cells, the presumed malignant cells of Hodgkin's disease (HD); were found to express high levels of cell surface CD40. We found that recombinant CD40 ligand (CD40L) induced interleukin-8 (IL-8) secretion and enhanced IL-6, TNF, and lymphotoxin-alpha (LT-alpha/TNF-beta) release from cultured H-RS cells. These cytokines play a significant role in the clinical presentation and pathology of HD, a tumor of cytokine-producing cells. CD40L had no mitogenic activity for HD-derived cell lines. In contrast, CD40L enhanced expression of costimulatory molecules intracellular adhesion molecule-T and B7-1 on cultured H-RS cells, both of which are overexpressed on primary H-RS cells. In addition, CD40L induced a 40% to 60% reduction of the expression of the HD-associated CD30 antigen, another member of the TNF receptor superfamily. Primary and cultured H- RS cells express not only CD30, but also CD40. CD40L has pleiotropic biologic activities on H-RS cells, and the CD40-CD40L interaction might be a critical element in the deregulated cytokine network and cell contact-dependent activation cascade typical for HD.