Atypical and typical antipsychotic drug interactions with the dopamine D2 receptor

A model of the dopamine D2 receptor was used to study the receptor interactions of dopamine, the typical antipsychotics haloperidol and loxapine, and the atypical antipsychotics clozapine and melperone. The atypical antipsychotics interacted with the halogen atom of the ring system in the direction of the transmembrane helices (TMHs) 2, 3 and 7, while the typical had the corresponding halogen atom in the direction of TMH5. Molecular dynamics simulations indicated that the average helical displacement upon binding increased in the order: typical < atypical < dopamine. Upon binding, the atypical induced larger displacements into TMH5 than did the typical. The typical had stronger non-bonded interactions with the receptor than had the atypical, which is in agreement with the experimental observation that the atypical antipsychotic drugs dissociate faster from the receptor than the typical antipsychotic drugs.     

Sideroblastic anemia with markedly increased free erythrocyte protoporphyrin without dermal photosensitivity

A patient with idiopathic sideroblastic anemia and atypical clinical and biochemical findings is described. He had a greatly increased erythrocyte and plasma protoporphyrin, but normal urine and fecal porphyrins. The erythrocyte protoporphyrin had a fluorescence spectrum typical of free protoporphyrin, but caused no photosensitivity. Bone marrow metal chelatase activity was normal. There were no clinical signs of liver disease. The abnormal porphyrin metabolism in this patient is not known though a number of explanations are discussed.     

Influence of Plasma Proteins on Erythrocyte Morphology and Sedimentation

The influence of plasma proteins on erythrocytes was studied by interference microscopy, scanning electron microscopy (SEM), and by Westergren erythrocyte sedimentation rate (ESR). Albumin kept erythrocytes dispersed as discoid spheres. Fibrinogen seemed responsible for the rouleaux phenomenon, but needed the co-influence of an immunoglobulin to induce rouleaux type of aggregates and high ESR. IgG, IgA and IgM caused immunologic type of aggregates. Albumin acted synergistically with fibrinogen and immunoglobulins. Normal blood contained a network of rouleaux, which probably explained the low normal ESR. High ESR was either due to rouleaux type aggregates where fibrinogen was dominant, or immunologic type aggregates where IgG, IgA or IgM were dominant proteins. Cold agglutinin disease showed normal blood morphology and normal ESR at 37°C and immunologic type aggregates and high ESR at 25°C.     

The relationship between the erythrocyte sedimentation rate (ESR) and plasma proteins in clinical materials and models

The relationship between the erythrocyte sedimentation rate (ESR) and plasma proteins was studied within homogenous clinical material and in in vitro models. In acute phase reactions, fibrinogen was the likely cause of the ESR-elevation, but there were significant associations between the ESR and the concentrations of α₁-antitrypsin, C₃, haptoglobin and albumin. In chronic diseases, the ESR-elevation was probably caused by fibrinogen, mono- or polyclonal increase of IgG, IgA, IgM alone or in combinations. In multiple myeloma of the IgG and IgA subtypes, significant correlations were found between the ESR and the monoclonal proteins or between the ESR and the percentage of plasma cells in bone marrow. Model studies showed that the ESR increased linearly with the concentrations of fibrinogen or gammaglobulin (IgG) when these exceeded normal thresholds. The ESR was slightly decreased by increasing concentrations of albumin. Albumin had a synergistic effect on the ESR together with gammaglobulin, but not together with fibrinogen.     

Interaction between heparin and acetylsalicylic acid on gastric mucosal and skin bleeding in humans.

The haemorrhagic effect of unfractionated heparin and of the low molecular weight heparin, enoxaparin, on gastric mucosal bleeding induced by acetylsalicylic acid (ASA) and on skin bleeding induced by the Simplate technique was investigated in healthy human volunteers. Endoscopic estimation of gastric bleeding by visual analogue scores was more sensitive than biochemical quantitation of blood in the gastric washing by a modified HaemoQuant method. Contrary to what was expected, the ASA-induced gastric mucosal bleeding was not increased by heparin pretreatment, whereas heparin in combination with ASA, but not ASA alone, significantly increased the skin bleeding time. In the interaction with ASA, enoxaparin and unfractionated heparin appeared to act similarly.     

Revised standardization method of the one-stage prothrombin time

The revised ratio method which is recommended for standardization of the one-stage prothrombin time, presumes that identical regression lines exist between clotting times of abnormal and normal plasma. A modification is proposed which corrects for possible deviation of the mean clotting time of normal plasma from the regression line between clotting times of abnormal plasma. The modified revised ration method is theoretically preferable and does not need the restrictions in calibration which are recommended for the revised ratio method.     

Sequential flow cytometric analysis of cellular DNA-content in peripheral blood during treatment for acute leukaemia.

Sequential flow cytometric analysis (FCM) of relative nuclear DNA content per cell was done in peripheral blood of 12 patients during treatment for acute leukaemia. A marked increase of cells with S-phase DNA-content during the first hours of treatment was found in patients responding favorably to treatment. One patient with increase of 'S-phase cells' died before clinical improvement could be evaluated. However, lack of S-phase increase at one treatment cycle did not exclude a favorable response in the next. Two cases with probable aneuploid leukaemia showed gradual disappearance of abnormal cells during therapy. The value of FCM analysis of peripheral blood seems to be in predicting the response to treatment before clinical signs appear.     

A molecular model of a putative substrate releasing conformation of multidrug resistance protein 5 (MRP5)

The ATP-binding cassette (ABC) transporter multidrug resistance protein 5 (MRP5) contributes to the cellular export of organic anions, including guanosine 3'-5' cyclic monophosphate (cGMP). The structural knowledge of this protein is limited, and in lack of an MRP5 X-ray structure, a model of MRP5 was constructed based on the homology with the bacterial ABC transporter Sav1866 from Staphylococcus aureus, which has been crystallised in an outward-facing, substrate releasing conformation. Two putative binding sites were identified, and docking of cGMP indicated that TMHs 1-3, 6, 11 and 12 were in contact with the ligands in binding site 1, while TMHs 1, 3, 5-8 were in contact with the ligands in binding site 2. The proposed MRP5 model may be used for further experimental studies of the molecular structure and function of this member of the ABC-transporter superfamily.