Duration and degree of cyclosporin induced P-glycoprotein inhibition in the rat blood-brain barrier can be studied with PET

Active efflux transporters in the blood-brain barrier lower the brain concentrations of many drug molecules and endogenous substances and thus affect their central action. The objective of this investigation was to study the dynamics of the entire inhibition process of the efflux transporter P-glycoprotein (P-gp), using positron emission tomography (PET). The P-gp marker [(11)C]verapamil was administered to anesthetized rats as an i.v. bolus dose followed by graded infusions via a computerized pump system to obtain a steady-state concentration of [(11)C]verapamil in brain. The P-gp modulator cyclosporin A (CsA) (3, 10 and 25 mg/kg) was administered as a short bolus injection 30 min after the start of the [(11)C]verapamil infusion. The CsA pharmacokinetics was studied in whole blood in a parallel group of rats. The CsA blood concentrations were used as input to model P-gp inhibition. The inhibition of P-gp was observed as a rapid increase in brain concentrations of [(11)C]verapamil, with a maximum after 5, 7.5 and 17.5 min for the respective doses. The respective increases in maximal [(11)C]verapamil concentrations were 1.5, 2.5 and 4 times the baseline concentration. A model in which CsA inhibited P-gp by decreasing the transport of [(11)C]verapamil out from the brain resulted in the best fit. Our data suggest that it is not the CsA concentration in blood, but rather the CsA concentration in an effect compartment, probably the endothelial cells of the blood-brain barrier that is responsible for the inhibition of P-gp.     

The central circulation in congestive heart failure non-invasively evaluated with dynamic positron emission tomography

BACKGROUND: Positron emission tomography (PET) with [15O]-H2O-PET (WAT-PET) or [11C]-acetate (AC-PET) quantifies myocardial perfusion and oxidative metabolism, but routine clinical use is hampered by the need for additional investigations to assess cardiac performance. OBJECTIVE: To apply classical tracer kinetics to dynamic PET could provide important haemodynamic parameters. METHODS: First-pass PET data were used with indicator dilution techniques to measure stroke volume index (SVI). Early pulmonary retention of [11C]-acetate was converted to standard uptake values (SUV) (Lung(AC-SUV)). Regional lung water (rLW) content was computed from the WAT-PET scan at equilibrium. PET was compared with radionuclide angiography and echocardiography in patients with ischaemic cardiomyopathy with New York Heart Association class II (n = 10) or III (n = 18) congestive heart failure. Elderly male volunteers without heart disease (n = 11) underwent AC-PET as controls. RESULTS: SVI with both tracers correlated in patients (r = 0.91, P<0.001, estimated standard error = 4 ml m(-2)) and with left ventricular ejection fraction (both tracers r>0.6, P<0.001). SVI was significantly different between all groups (ANOVA: P<0.001). Lung(AC-SUV) correlated with rLW (r = 0.78, P<0.001) and both were elevated in severe heart failure (P<0.05 for both). Elevated Lung(AC-SUV) was associated with a restrictive left ventricular (LV) filling pattern by Doppler echocardiography. CONCLUSION: Dynamic PET with first-pass analysis and tracers of myocardial perfusion enables quantification of the haemodynamic consequences of LV systolic and diastolic dysfunctions in ischaemic cardiomyopathy and could be useful in the evaluation of the central circulation in heart failure.     

Social anxiety and self-consciousness in binge eating disorder: associations with eating disorder psychopathology

ObjectiveResearch has consistently shown that anxiety disorders are common among individuals with eating disorders. Although social phobia has been found to be highly associated with eating disorders, less is known about social anxiety in individuals with binge eating disorder (BED). The present study examined associations between social anxiety and self-consciousness with body mass index (BMI) and eating disorder psychopathology in BED.MethodsParticipants were 113 overweight or obese treatment-seeking men and women with BED. Participants were administered semistructural diagnostic clinical interviews and completed a battery of self-report measures.ResultsSocial anxiety was positively and significantly correlated with shape and weight concerns and binge eating frequency. After accounting for depressive levels, social anxiety and self-consciousness accounted for significant variance in eating, shape, and weight concerns and overall eating disorder global severity scores (Eating Disorder Examination). Social anxiety also accounted for significant variance in binge eating frequency after covarying for depressive levels. Social anxiety and self-consciousness were not significantly associated with BMI or dietary restraint.DiscussionOur findings suggest that greater social anxiety and heightened self-consciousness are associated with greater eating disorder psychopathology, most notably with greater shape and weight concerns and binge eating frequency in patients with BED. Social anxiety and self-consciousness do not appear to be merely functions of excess weight, and future research should examine whether they contribute to the maintenance of binge eating and associated eating disorder psychopathology.     

Endotoxin-induced suppression of erythropoiesis: the role of erythropoietin and a heme synthesis stimulating factor

The regulation of erythropoiesis is primarily controlled by erythropoietin (Ep). Recently, however, other factors that both stimulate and inhibit erythropoiesis have been reported. Using an in vitro liquid culture of bone marrow cells, a factor in normal mouse serum was demonstrated that markedly stimulated heme synthesis by marrow erythroid cells. In this study, the role of this heme synthesis stimulating factor (HSF) and Ep in the erythropoietic suppression caused by endotoxin administration to mice was examined. Although HSF levels did not alter appreciably after endotoxin injection, marrow erythroid cells from these animals became unresponsive to the factor. This could be reversed if Ep was added to the culture in vitro or if the hormone was injected into the mice 18 hr prior to harvesting the marrow. This marrow erythroid cell response is identical to that seen in animals in whom Ep levels are markedly reduced, such as that found in exhypoxic polycythemia, and suggest a decrease in the hormone following endotoxin administration. Additional studies demonstrated that when Ep was injected into mice 6 hr after endotoxin administration, an increase in femoral erythroid colony-forming units (CFU-E), proerythroblast number, and 59 Fe incorporation into femoral marrow cells could be demonstrated. These findings, together with the marrow erythroid cell response to the hormone, suggest that the mechanism for suppression of erythropoiesis after endotoxin injection is a reduction in the level of circulating Ep.     

Therapy of patients with human T-cell lymphotrophic virus I-induced adult T-cell leukemia with anti-Tac, a monoclonal antibody to the receptor for interleukin-2

Human T-cell lymphotropic virus I (HTLV-I)-induced adult T-cell leukemia (ATL) cells constitutively express interleukin-2 (IL-2) receptors identified by the anti-Tac monoclonal antibody (MoAb), whereas normal resting cells do not. This observation provided the scientific basis for a trial of intravenous anti-Tac in the treatment of nine patients with ATL. The patients did not suffer untoward reactions and did not have a reduction in the normal formed elements of the blood, and only one of the nine produced antibodies to the anti-Tac MoAb. Three patients had transient mixed, partial, or complete remissions lasting from 1 to more than 8 months after anti-Tac therapy, as assessed by routine hematologic tests, immunofluorescence analysis of circulating cells, and molecular genetic analysis of HTLV-I provirus integration and of the T-cell receptor gene rearrangement. The precise mechanism of the antitumor effects is unclear; however, the use of a MoAb that prevents the interaction of IL-2 with its receptor on ATL cells provides a rational approach for the treatment of this malignancy.     

Electron Probe X-Ray Microanalysis of Residual Bodies in Aged Cultured Human Glial Cells

Secondary lysosomes of the residual body type are frequent in nondividing cells from phase III cultures of human glial cells. These organelles have previously been shown to be analogous to lipofuscin granules of postmitotic cells in vivo. Most recent studies favor the assumption that residual bodies mainly result from incomplete degradation within the lysosomal vacuome of endogenous cellular components such as mitochondria and endoplasmic reticulum. Since iron occurs in several metalloenzymes produced by such organelles, it should then be possible to demonstrate accumulated iron within residual bodies. X-ray dispersive analysis of sectioned biological material is often hampered by diffusion and dissolution during preparation, as well as by too low a concentration of the elements. In this study we cultured glial cells on Formvar-coated gold grids and studied them unsectioned, after brief glutaraldehyde fixation and freeze-drying, in a transmission electron microscope at 100 kV in TEM and STEM mode. It was then possible to demonstrate iron in residual bodies of aged cells, presumably because the type of preparation utilized does not permit much dissolution.     

Fragile X syndrome in mildly mentally retarded children in a Northern Swedish county. A prevalence study

In an extensive etiological study of an unselected series of mildly mentally retarded children (MMR) (IQ 50–70) born 1959–1970 in a northern Swedish county, 5 of 110 boys (4.5%) and none of 61 girls had a fragile site on the distal end of the X-chromosome (Fra Xq 28). Consequently fragile X was seen in 2.9% of the total series of 171 children. In a combined series of severe and mild mental retardation, the incidence of the fragile X syndrome was calculated to be 1:3000 in the county of Vasterbotten. Next to trisomy 21 the fragile X syndrome was the most common single identified cause of MMR in boys. A cytogenetic investigation using special cultural conditions and banding techniques should be performed in cases of mental retardation of unclear etiology and in possible female carriers.