Allergic asthma induced in rhesus monkeys by house dust mite (Dermatophagoides farinae)

To establish whether allergic asthma could be induced experimentally in a nonhuman primate using a common human allergen, three female rhesus monkeys (Macaca mulatta) were sensitized with house dust mite (Dermatophagoides farinae) allergen (HDMA) by subcutaneous injection, followed by four intranasal sensitizations, and exposure to allergen aerosol 3 hours per day, 3 days per week for up to 13 weeks. Before aerosol challenge, all three monkeys skin-tested positive for HDMA. During aerosol challenge with HDMA, sensitized monkeys exhibited cough and rapid shallow breathing and increased airway resistance, which was reversed by albuterol aerosol treatment. Compared to nonsensitized monkeys, there was a fourfold reduction in the dose of histamine aerosol necessary to produce a 150% increase in airway resistance in sensitized monkeys. After aerosol challenge, serum levels of histamine were elevated in sensitized monkeys. Sensitized monkeys exhibited increased levels of HDMA-specific IgE in serum, numbers of eosinophils and exfoliated cells within lavage, and elevated CD25 expression on circulating CD4(+) lymphocytes. Intrapulmonary bronchi of sensitized monkeys had focal mucus cell hyperplasia, interstitial infiltrates of eosinophils, and thickening of the basement membrane zone. We conclude that a model of allergic asthma can be induced in rhesus monkeys using a protocol consisting of subcutaneous injection, intranasal instillation, and aerosol challenge with HDMA.     

Synaptophysin is an autoantigen in paraneoplastic neuropathy

Paraneoplastic neurological syndromes (PNS) are often associated with antineuronal autoantibodies and many of them could be identified in the recent years. However, there are still new antineuronal binding patterns with yet unidentified autoantigens. We here describe a new autoantibody associated with paraneoplastic sensorimotor and autonomic neuropathy in a patient with small cell lung cancer. In indirect immunofluorescence test, the patient's serum colocalised with the synaptic protein synaptophysin in the cerebellum and myenteric plexus of the gut. Immunoblotting showed a 38 kDa reactivity, which is also the molecular weight of synaptophysin. Therefore a Western Blot with recombinant synaptophysin has been used and revealed reactivity of the serum against synaptophysin. In patients with non-paraneoplastic neuropathies or healthy controls, anti-synaptophysin autoantibodies were not detectable. In 20 SCLC patients without neurological syndromes, two patients had low-titer anti-synaptophysin autoantibodies. The patient's serum and IgG fraction showed cytotoxicity to primary cultured myenteric plexus neurons. We conclude that synaptophysin is an autoantigen in paraneoplastic neurological syndromes.     

Time course of VCAM-1 and ICAM-1 in CSF in patients with basal ganglia haemorrhage

OBJECTIVES: In a pilot study we found a correlation of the clinical outcome with adhesion molecule (AM) concentrations in ventricular cerebrospinal fluid (CSF) but not in serum in patients with intracerebral haemorrhage. We now determined the time course of AM concentration in CSF and serum after basal ganglia haemorrhage (BGH) in order to further uncover pathogenetic mechanisms. MATERIALS AND METHODS: We included 11 patients with acute BGH and ventricular tamponade in which an extraventricular drainage had been applied to treat ventricular ballonade. Paired CSF and serum samples were obtained within 8 h after onset of BGH, as well as on the consecutive days 2, 4, 6, and 8, respectively. The concentrations of soluble ICAM-1 (sICAM-1) and VCAM-1 (sVCAM-1) in CSF and serum were measured by enzyme-linked immunosorbent assay. Moreover, we determined blood volume and perifocal oedema by a semi-automated planimetry technique from initial cranial computed tomography scans. RESULTS: sICAM-1 and sVCAM-1 levels in CSF were highest within the first hours after onset of BGH, then decreased significantly (P < 0.005 and <0.05, respectively) on day 2 and slightly increased thereafter. Furthermore, BGH volume was significantly correlated with the concentrations of sICAM-1 (r = 0.63, P < 0.05) and sVCAM-1 (r = 0.66, P < 0.05) in ventricular CSF but not in serum. CONCLUSIONS: Our results might indicate that the local inflammatory reaction is pronounced early after onset of BGH and appears to be restricted to the central nervous system. Moreover, AM concentrations measured early after BGH onset correlated stronger with radiological and clinical data than follow-up measurements.     

Erucylphosphocholine: pharmacokinetics, biodistribution and CNS-accumulation in the rat after intravenous administration

The clinical use of alkylphosphocholines (APC) in cancer patients is restricted because of the high gastrointestinal toxicity and the need for oral administration. Therefore we evaluated the clinical pharmacology of erucylphosphocholine (ErPC), the first derivative of the APC family suitable for intravenous administration with strong antineoplastic activity, in vitro and in vivo in rats. The pharmacokinetic parameters after a single intravenous dose of 40 mg/kg were calculated using a two-compartment model: C_max= 1.6 ± 0.3 μmol/ml, T_1/2α= 0.18 ± 0.09 h, T_1/2β= 3.3 ± 0.88 h, clearance = 9.7 ± 1.2 ml/h, AUC = 2.5 ± 0.3 μmol/ml per h and Vss = 40.4 ± 7.9 ml. Biodistribution studies were performed after repeated ErPC administration at different doses. Intravenous injections of 20 mg/kg given at intervals of 48 h for up to 4 weeks were well tolerated. Neither clinical evaluation nor laboratory parameters (haematology and clinical chemistry) revealed toxic side effects. In contrast, higher doses of ErPC (40 mg/kg per 48 h) led to weight loss. After 2 and 4 weeks of therapy with 20 mg/kg per 48 h a high ErPC accumulation was found in the adrenal glands, small intestine and brain. The brain to serum concentration ratios averaged 2.1 after 2 weeks and 4.5 after 4 weeks. Significant leucocytosis and thrombocytosis were observed after 4 weeks of ErPC treatment. The findings suggest that ErPC is a suitable candidate for clinical trials. In particular, owing to the high accumulation in brain tissue, ErPC is a potential agent for chemotherapy against malignant brain tumours. Received: 4 January 1999 / Accepted: 6 May 1999     

Feasibility and validity of transcranial duplex sonography in patients with acute stroke

OBJECTIVES: To evaluate in a prospective multicentre setting the feasibility of transcranial colour coded duplex sonography (TCCS) for examination of the middle cerebral artery (MCA) in patients with acute hemispheric stroke, and to assess the validity of sonographic findings in a subgroup of patients who also had a correlative angiographic examination. METHODS: TCCS was performed in 58 consecutive patients within six hours of the onset of a moderate to severe hemispheric stroke. Ultrasound contrast agent (Levovist) was applied if necessary. Thirty two patients also had computed tomography angiography (n=13), magnetic resonance angiography (n=18), or digital subtraction angiography (n=1). In 14 of these patients, both the sonographic and corresponding angiographic examination were performed within six hours of stroke onset (mean time difference between TCCS and angiography 0.8 hours). Eighteen patients, in whom angiography was carried out more than 24 hours after stroke onset, had a follow up TCCS for method comparison (mean time difference 6.1 hours). RESULTS: Initial unenhanced TCCS performed 3.4 (SD 1.2) hours after the onset of symptoms depicted the symptomatic MCA mainstem in 32 patients (55%) (13 occlusions, one stenosis, 18 patent arteries). After signal enhancement, MCA status could be determined in 54 patients (93%) (p<0.05), showing an occlusion in 25, a stenosis in two, and a patent artery in 27 patients. In 31 of the 32 patients who had correlative angiography, TCCS and angiography produced the same diagnosis of the symptomatic MCA (10 occlusions, three stenoses, 18 patent arteries); TCCS was inconclusive in the remaining one. CONCLUSION: TCCS is a feasible, fast, and valid non-invasive bedside method for evaluating the MCA in an acute stroke setting, particularly when contrast enhancement is applied. It may be a valuable and cost effective alternative to computed tomography and magnetic resonance angiography in future stroke trials.     

Paraneoplastic neurological syndromes in patients with carcinoid

Background: Paraneoplastic neurological syndromes (PNS) are mainly associated with small‐cell lung cancer, gynaecological tumours and lymphomas. Few studies report the association of neurological syndromes with a carcinoid, the majority being a serotonin‐related myopathy. We report four patients with a PNS associated with carcinoid. Patients and results: The clinical syndromes were sensory neuropathy, limbic encephalitis, myelopathy and brain stem encephalitis. Two patients had antineuronal autoantibodies (one anti‐Hu, one anti‐Yo), one patient had antinuclear antibodies, and one patient had no autoantibodies. For two of the carcinoids, expression of HuD in the tumour could be demonstrated. Conclusion: This study demonstrates that carcinoids can also be associated with classical antineuronal antibody‐associated PNS.     

On the Applicability of the Coarse Grained Coupled CFD-DEM Model to Predict the Heat Transfer During the Fluidized Bed Drying of Pharmaceutical Granules

Pharmaceutical Research - Fluidized bed dryer often used in the pharmaceutical industry for drying of wet granules. Coupled computational fluid dynamics (CFD) – discrete element method (DEM)...     

Dislocation of the Third Ventricle Due to Space-Occupying Stroke Evaluated by Transcranial Duplex Sonography

Transcranial color-coded duplex sonography is a recently introduced method for visualizing (1) the blood flow velocity of the basal cerebral arteries and (2) the brain parenchyma as an acoustic impedance image. Dislocation of the third ventricle due to space-occupying stroke is an important clinical marker. This study evaluated the dislocation of the third ventricle from the brain midline by transcranial duplex sonography in 10 healthy volunteers. The mean dislocation was 0.2 ± 0.3 mm. Eighteen stroke patients were investigated within 12 hours by both duplex sonography and computed tomography (CT) and the dislocation of the third ventricle was measured. Correlation between the two methods was high (r = 0.87, N = 27). Twelve stroke patients divided into three subgroups according to the extent of the space-occupying effects of the lesion were followed for 3 weeks. The increase and decrease of the dislocation of the third ventricle over the time were monitored. In conclusion, transcranial duplex sonography is a reliable tool to monitor dislocation of the third ventricle due to space-occupying stroke.     

In vitro evaluation of the sinus sagittalis superior thrombosis model in the rat using 3D micro- and nanocomputed tomography

Introduction

Thrombosis of the cerebral veins and sinus are common causes of stroke. Animal models help us to understand the underlying pathophysiology of this condition. Therefore, the purpose of our study was to evaluate a well-established model for sinus sagittalis (SSS) thrombosis using micro- and nanocomputed tomography (CT) imaging.

Methods

SSS thrombosis was performed in four rats. After contrast perfusion, brains were isolated and scanned using micro-CT at (8 µm)³ voxel size to generate 3D images of the cerebral vasculature. For more detailed information on vascular perfusion territories, nano-CT imaging was performed to investigate the boundary layer of contrast-enhanced vessels and the occluded veins. The venous and arterial vascular volume fraction and gray scale measurements were obtained in the SSS thrombosis group and compared to controls. The significance of differences in vascular volume fraction and gray scale measurements was tested with analysis of variance. Results were complemented with histology.

Results

Micro-CT proved to accurately visualize and differentiate vascular occlusion territories performed in the SSS thrombosis model. Moreover, 3D micro-CT provided quantitative information on arterial and venous vascular volume fraction. Micro-CT imaging enables a total 3D visualization of complications (ventricle rupture) in the SSS thrombosis model. We established gray scale measurements by which focal cerebral ischemia could be radiographically categorized (p?<?0.001).

Conclusions

Using nano-CT, the interface of contrast-perfused and occluded veins can be visualized. Micro-CT is feasible for analysis and differentiation of perfusion territories in an animal model of focal cerebral ischemia.