Novel pharmacological targets based on receptor heteromers

Studies performed in the last 10 years have provided solid evidence indicating that G-protein-coupled receptors are expressed on the plasma membrane as homo and heterodimers. The first consequence of this fact is that homo and heterodimers are the true targets of natural (hormones, neurotransmitters) and synthetic drugs. Furthermore a given receptor in a heteromer may display a different functional and/or pharmacological profile than the same receptor characterized as monomer or as homodimer. Recent evidence indicates that receptor heteromers are sensors that lead to a fine-tuning in neurotransmission or hormone regulation; mainly this is achieved by a modification of the signaling pathways activated via a given receptor when it is forming a given heteromer. Quite often antagonists display variable affinities when a given receptor is expressed with different heteromeric partners. This fact should be taken into account in the development of new drugs. Finally it should be pointed out that radioligand binding data has to be analyzed by a model that considers receptors as dimers and not as monomers. This model provides a novel approach to characterize drugs interacting with the orthosteric center (agonists/antagonists) or with allosteric centers (allosteric regulators).     

Health care professionals: what do they know about organ donation?

BACKGROUND: Although donor detection is influenced by the legal system and family refusal, underreporting due to erroneous knowledge of donation criteria and a lack of familiarity with the procedure among medical professionals is also a contributing factor. OBJECTIVE: To investigate the outlook of critical health professionals participating in our postgraduate courses (2001 to 2006) about organ donation. METHODS: We administered an in-depth survey, evaluating attitudes, knowledge, roles, and experiences related to organ and tissue donation and transplantation, to 350 participants before and after the postgraduate courses. RESULTS: We collected 690 surveys from 350 attendees. In the first survey, 280 (80%) of them showed a positive attitude toward organ donation, 210 (60%) toward tissue donation, and 24 (7%) declared lack of knowledge about the subject. Only 175 (50%) had relatives who had donated organs. Sixty-three participants (18%) believed brain death is not equivalent to death, 176 (50%) claimed a lack of adequate training in this area, and 211 (60%) felt uncomfortable approaching families for donation. Only 88 (25%) were able to state the percentage of people receiving an organ in Spain, and 36 (10%) reported the correct number. After the course, the participants declared progress in attitudes toward and comfort levels with donation. Furthermore, family refusal in our hospital decreased from 33% to 8% to 11%. CONCLUSION: Continuous training of health care professionals about transplant, the legal system, and communication skills are crucial for successful organ and tissue donation.     

Participation in the CCRI(II)-K2.H-3 comparison and study of the new TDCR-LS counter with 6 CPMs

The “conventional” TDCR system was used for standardization of the tritiated water in the frame of the international comparison organized by CCRI(II).The prototype of the new TDCR realized at LNHB with three CPMs (Ivan et al., 2008) was improved by constructing at IFIN-HH, a system containing six channel photomultiplier tubes arranged symmetrically in a new optical chamber. The system was tested by measuring various pure beta emitters and for comparative measurements of tritiated water for validation studies.     

In Vivo Effects of Dexmedetomidine on Laser-Doppler Flow and Pial Arteriolar Diameter

Background: The alpha2 -adrenergic agonist dexmedetomidine alters global cerebral blood flow (CBF). However, few studies have investigated the action of dexmedetomidine on the cerebral microcirculation. This investigation examined the effects of dexmedetomidine on (1) regional CBF in the rat cerebral cortex using laser-Doppler flowmetry and (2) on pial arteriolar diameter.

Methods: Halothane-anesthetized rats were fitted with instruments to measure CBF as determined by laser-Doppler flow (CBFldf) or to measure pial arteriolar diameter by preparing a cranial hollow deepened until a translucent plate of skull remained, thereby maintaining the integrity of the cranial vault. In both groups, 20 micro gram/kg dexmedetomidine was infused intravenously. Thirty minutes later, the mean arterial pressure was restored to control values with an infusion of phenylephrine (0.5 to 5 micro gram/kg/min).

Results: Administration of dexmedetomidine was associated with decreases in end-tidal and arterial carbon dioxide. The CBFldf and pial arteriolar diameter were measured during normocapnia (controlled carbon dioxide) and during dexmedetomidine-induced hypocapnia. Intravenous administration of dexmedetomidine significantly decreased systemic arterial pressure concurrent with a decrease in CBFldf (22% in normocapnic animals, 36% in hypocapnic animals). Restoration of mean arterial pressure increased CBFldf in normocapnic but not in hypocapnic animals. Similarly, dexmedetomidine significantly reduced pial vessel diameter in both normocapnic (9%) and hypocapnic animals (17%). However, vessel diameters remained decreased in the normocapnic and hypocapnic animals after the mean arterial pressure was restored.     

SPECT of serotonin transporters using 123I-ADAM: optimal imaging time after bolus injection and long-term test-retest in healthy volunteers.

(123)I-ADAM (2-([2-([dimethylamino]methyl)phenyl]thio)-5-(123)I-iodophenylamine) has been recently proposed as a new serotonin transporter (SERT) ligand for SPECT. The objective of this study was to characterize (123)I-ADAM in healthy volunteers. (123)I-ADAM distribution in the normal brain, pseudoequilibrium interval after a single injection, normal specific uptake values, and long-term test-retest variability and reliability were investigated. METHODS: Ten healthy volunteers underwent 2 SPECT sessions under the same conditions 47.6 +/- 24.0 d apart. Scans were sequentially acquired from the time of (123)I-ADAM intravenous injection up to 12 h after injection. Regions of interest (ROIs) for cerebellum (C), midbrain, thalamus, striatum, mesial temporal region, and cortex were drawn on MR images and pasted to corresponding SPECT slices after coregistration. Specific uptake ratios (SURs) at pseudoequilibrium and the simplified reference tissue model (SRTM) methods were used for quantification. SURs were obtained as ([region - C]/C) at each time point. Test-retest variability and reliability (intraclass correlation coefficient [ICC]) were calculated. RESULTS: The highest (123)I-ADAM specific uptake was found in the midbrain and thalamus, followed by the striatum and mesial temporal region. Quantification results using SUR and SRTM were correlated with R = 0.93 (test) and R = 0.94 (retest). SURs remained stable in all regions from 4 to 6 h after injection. Using SUR, test-retest variability/ICC were 13% +/- 11%/0.74 in midbrain, 16% +/- 13%/0.63 in thalamus, 19% +/- 18%/0.62 in striatum, and 22% +/- 19%/0.05 in mesial temporal region. CONCLUSION: (123)I-ADAM accumulates in cerebral regions with high known SERT density. The optimal imaging time for (123)I-ADAM SPECT quantification is suggested to be from 4 to 6 h after a single injection. Long-term test-retest variability and reliability found in the midbrain are comparable to that reported with other (123)I-labeled SPECT ligands. These results support the use of (123)I-ADAM SPECT for SERT imaging after a single injection in humans.     

Squamous cell carcinoma of the renal pelvis presenting as duodenal obstruction

A 78-year-old woman with duodenal obstruction was studied with plai addominal X-rays, barium examination ultrasonography, CT, and incisional biopsy. The pathologic report revealed an infiltrating squamous cell carcinoma of the renal pelvis, Palliative gastroenterostomy was performed.     

Hemostatic effect of platelet von Willebrand factor.

In type III von Willebrand disease (vWD) patients, the bleeding time was only partially corrected or not modified after cryoprecipitate infusion, although the levels and the multimeric structure of plasma von Willebrand factor (vWF) were normal. However, the adhesion of normal platelets on the vessel wall subendothelium in the presence of postinfusion patient plasma improved more significantly than the bleeding time. These results suggest a role of the vWF released from normal platelets which is absent in type III vWD platelets. In 5 patients transfusion of normal platelet concentrates performed 1 h after cryoprecipitate infusion without modification of the bleeding time (> 30 min) normalized this parameter, and platelet adhesion to the subendothelium elicited a marked improvement. These last results confirm the suggestion that platelet vWF plays an important 'in vivo' role in the hemostatic process, particularly in patients suffering from severe vWD.     

Recombinant alpha-2b-interferon may restore natural-killer activity in patients with B-chronic lymphocytic leukemia.

In nine patients with CLL treated with chlorambucil followed by alpha-2b-interferon (alpha 2b-IFN), T, B and natural killer (NK) cells and NK activity were studied before entering the study, after chlorambucil treatment, and after administration of alpha 2b-IFN. When considered as a whole, basal NK activity was lower in CLL patients than in controls (21.0% +/- 10.9 versus 40.2% +/- 17.4, p less than 0.001); however, when considered individually, four out of nine patients had normal NK activity at diagnosis. Chlorambucil did not increase global NK activity (21.7% +/- 7.1), whereas alpha 2b-IFN did so (44.3% +/- 19.1). After alpha 2b-IFN only one of seven patients studied had low NK activity. Previously increased absolute counts of CD2+, CD4+, CD8+, CD16+, CD57+ lymphocytes were reversed with chlorambucil treatment to normal levels, while after this therapy CD11b+ and CD19+ cells decreased without reaching normal values. During alpha 2b-IFN therapy, an increase up to normal levels in the percentage of CD16+ (2.7% +/- 3.4 versus 7.7% +/- 6.5, p = 0.04) and CD57+ (3.0% +/- 3.0 versus 8.1% +/- 6.2, p = 0.020) lymphocytes was observed whereas the absolute number of CD19+ B-cells further decreased (5.2 x 10(9)/l +/- 2.5 vs 3.8 x 10(9)/l +/- 2.3), albeit not significantly.     

HLA antigens in spanish type 1 diabetic population. correlations with clinical,biological and autoimmune markers

Summary The HLA haplotype and its relationships with clinical, biological and immunological parameters were analyzed in a group of 87 Spanish type I diabetic patients at the clinical onset of the disease. The frequency of HLA-B18, DR3 and DR4 antigens was significantly increased whereas DR2, DR5 and DR7 were decreased in comparison with 189 healthy unrelated controls without family history of diabetes. DR3 showed a maximum relative risk for diabetes (5.5) whereas DR4 had a lower one (4.0). HLA-DR4 patients were younger at the time of diagnosis than DR4 negative (16.7vs 21.4 years). We found no statistically significant relationship between HLA antigens and the other variables studied including the presence of islet cell antibodies, complement fixing islet cell antibodies, insulin autoantibodies, organ-specific antibodies, fasting and maximal glucagon stimulated C-peptide levels, initial glycemia and glycosylated hemoglobin.