Tariquidar-induced P-glycoprotein inhibition at the rat blood-brain barrier studied with (R)-11C-verapamil and PET.

The multidrug efflux transporter P-glycoprotein (P-gp) is expressed in high concentrations at the blood-brain barrier (BBB) and is believed to be implicated in resistance to central nervous system drugs. We used small-animal PET and (R)-11C-verapamil together with tariquidar, a new-generation P-gp modulator, to study the functional activity of P-gp at the BBB of rats. To enable a comparison with human PET data, we performed kinetic modeling to estimate the rate constants of radiotracer transport across the rat BBB. METHODS: A group of 7 Wistar Unilever rats underwent paired (R)-11C-verapamil PET scans at an interval of 3 h: 1 baseline scan and 1 scan after intravenous injection of tariquidar (15 mg/kg, n = 5) or vehicle (n = 2). RESULTS: After tariquidar administration, the distribution volume (DV) of (R)-11C-verapamil was 12-fold higher than baseline (3.68 +/- 0.81 vs. 0.30 +/- 0.08; P = 0.0007, paired t test), whereas the DVs were essentially the same when only vehicle was administered. The increase in DV could be attributed mainly to an increased influx rate constant (K1) of (R)-11C-verapamil into the brain, which was about 8-fold higher after tariquidar. A dose-response assessment with tariquidar provided an estimated half-maximum effect dose of 8.4 +/- 9.5 mg/kg. CONCLUSION: Our data demonstrate that (R)-11C-verapamil PET combined with tariquidar administration is a promising approach to measure P-gp function at the BBB.     

Schwangerschaft. Fehlgeburt. Geburt. Kindesmord

Ohne Zusammenfassung     

Arthrodesis for chronic static scapholunate dissociation: a prospective study in 12 patients.

Twelve patients had limited arthrodesis between the scaphoid and the lunate for chronic static scapholunate dissociation using internal plate osteosynthesis. The median time between the injury and surgery was 50 months (range 9-180). They were followed up for a year postoperatively. Preoperative symptoms were pain, functional impairment, and restricted movement. During operation the scapholunate interosseous ligament was completely torn and the scaphoid malrotated in all patients. The range of motion was measured preoperatively and postoperatively, and the unaffected side used for control. For all patients except one postoperative extension, flexion, and radial deviation had considerably decreased. However, supination increased in seven of 12 patients postoperatively and so did pronation in seven of 12 patients. One patient (case 12) had an improved range of motion postoperatively in all directions. The mean grip strength was 76% of the unaffected side preoperatively, and has increased to 85% postoperatively. We found that bone healing was rare and most arthrodeses healed by a fibrous union. We found no correlation with preoperative arthrosis and clinical outcome. One patient had retired from work before operation because of back pain and one because of age. Two patients had taken early retirement because of wrist pain, and one patient was still on sick-leave at the follow-up a year postoperatively. Five patients returned to full-time work and two patients to part-time work. Four patients were on long-term sick-leave preoperatively and three of them returned to their previous occupations. Analysis of the patients' subjective outcome (including pain and functional scores) showed overall satisfaction, and objective data show that scapholunate arthrodesis for chronic static scapholunate dissociation provides substantial improvement over the preoperative condition.     

Detection of IgA class antibody to hepatitis E virus in serum samples from patients with hepatitis E virus infection

A newly developed assay for IgA class antibody to hepatitis E virus (IgA anti-HEV) was used to study 145 serum samples collected during an outbreak of an enterically transmitted hepatitis that occurred in 3 villages in the lower Shebeli region of Southern Somalia between January, 1988 and November, 1989. A total of 52.4% of the afflicted patients were found positive for IgA anti-HEV, and 73.1% of these were also positive for IgM. Both antibodies disappeared during the convalescence period. Similar results were also seen in serum obtained from sporadic cases of acute waterborne hepatitis in Pakistan. © 1993 Wiley-Liss, Inc.     

Immunoglobulin Gene Rearrangement in Plasma Cell Dyscrasias: Detection of Small Clonal Cell Populations in Peripheral Blood and Bone Marrow

The bone marrow (BM) and peripheral blood (PB) samples of 71 patients with plasma cell dyscrasias were analysed by the Southern blot technique for the presence of clonal immunoglobulin (Ig) gene rearrangements. 53% of BM samples examined were archival material such as air dried BM slides or frozen trephine biopsies. The results were related to bone marrow plasmacytosis as determined by cytology and flow cytometry, and other clinical parameters. Clonal Ig gene rearrangements were found in BM samples of 45 (83%) of 54 MM patients and in 3 of 6 patients with monoclonal gammopathy of unknown significance (MGUS). Clonal cell populations in the PB were detected in 11 (30%) of 37 examined MM patients, but in none of the patients with MGUS or solitary plasmacytoma of bone. PB involvement was associated with progressive disease. Circulating monoclonal cells were significantly associated with higher M-protein levels (p 0.05). Thus, circulating clonal precursor cells are encountered more frequently in active MM.     

Is size-reducing ascending aortoplasty with external reinforcement an option in modern aortic surgery?

OBJECTIVE: Enlargement of the ascending aorta is often combined with valvular, coronary, or other cardiac diseases. Reduction aortoplasty can be an optional therapy; however, indications regarding the diameter of aorta, the history of dilatation (poststenosis, bicuspid aortic valve), or the intraoperative management (wall excision, reduction suture, external reinforcement) are not established. METHODS: In a retrospective study between 1997 and 2005, we investigated 531 patients operated for aneurysm or ectasia of the ascending aorta (diameter: 45-76mm). Of these, in 50 patients, size-reducing ascending aortoplasty was performed. External reinforcement with a non-coated dacron prosthesis was added in order to stabilize the aortic wall. RESULTS: Aortoplasty was associated with aortic valve replacement in 47 cases (35 mechanical vs 12 biological), subvalvular myectomy in 29 cases, and CABG in 13 cases. The procedure was performed with low hospital mortality (2%) and a low postoperative morbidity. Computertomographic and echocardiographic diameters were significantly smaller after reduction (55.8+/-9mm down to 40.51+/-6.2mm (CT), p<0.002; 54.1+/-6.7mm preoperatively down to 38.7+/-7.1mm (echocardiography), p<0.002), with stable performance in long-term follow-up (mean follow-up time: 70 months). CONCLUSIONS: As demonstrated in this study, size reduction of the ascending aorta using aortoplasty with external reinforcement is a safe procedure with excellent long-term results. It is a therapeutic option in modern aortic surgery in patients with poststenotic dilatation of the aorta without impairment of the sinotubular junction of the aortic valve and root.     

Precision of Image-Guided Radiotherapy (IGRT) in Six Degrees of Freedom and Limitations in Clinical Practice

PURPOSE: To evaluate the precision of image-guided radiotherapy (IGRT) using cone-beam computed tomography (CB-CT) for volume imaging and a robotic couch for correcting setup errors in six degrees of freedom. PATIENTS AND METHODS: 47 consecutive patients with 372 fractions were classified according to whether a patient fixation device was used (pat(fix): n = 28) or not (pat(non-fix): n = 19). Prior to treatment a CB-CT was acquired and translational and rotational setup errors were corrected online without an action level using a robotic couch (HexaPOD). A second CB-CT was acquired after the correction process and after treatment in 134 and 238 fractions, respectively. RESULTS: In 17 fractions (4.6%) rotational errors > 3 degrees exceeded the motion range of the HexaPOD. Errors (3D vector) after the correction process were significantly smaller for pat(fix) compared to pat(non-fix) (p < 0.001): 0.9 mm +/- 0.5 mm and 1.6 mm +/- 0.8 mm, respectively. For pat(non-fix) the correction of rotational errors resulted in displacements of the patients on the angled couch of 0.6 mm/1 degree. Intrafractional motion further decreased precision in pat(non-fix) but not in pat(fix). CONCLUSION: Very high precision in cranial and extracranial treatment of immobilized patients was demonstrated. Without application of adequate immobilization the correction of rotational errors and intrafractional patient motion significantly decreased the accuracy of the online correction protocol.     

Comparison of three different purification methods for the routine preparation of [11C] Metomidate.

PET with (R)-[O-methyl-11C] metomidate ([11C] MTO) is an attractive method for the characterisation of adrenal masses discriminating lesions of adrenal cortical origin from noncortical lesions. [11C] MTO was prepared by the reaction of [11C] methyliodide with the corresponding free acid. Three purification methods have been compared. The method of choice uses preparative HPLC with a ready-to-use weak acidic solvent.