Biomedical subjects
Publications and source records attributed to K Konstantopoulos.
Amyloid nephropathy was the presenting symptom in a case of Familial Mediterranean Fever (FMF). As recent progress in molecular pathology permits the detection of asymptomatic FMF individuals, it is suggested that relevant cases of renal amyloidosis should be tested for FMF mutations.
The HLA-A and -B antigens of 99 Greek patients with transfusion dependent homozygous beta thalassaemia were determined. The HLA antigen distribution in thalassaemic patients with a severe transfusion siderosis and in patients without signs of siderosis were compared to that of 400 healthy unrelated controls from the same population. There is an increase of HLA-B 14 antigen in both groups of thalassaemics as compared with the controls. No significant difference exists in the distribution of all the other HLA antigens between the two sub-groups of thalassaemics or with the controls.
A patient is presented having simultaneously chronic lymphocytic leukemia with a monoclonal B-lymphocyte population and mycosis fungoides with atypical T-cell population in the skin lesion and in the enlarged lymphoid nodes confirmed by detailed phenotyping.
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BACKGROUND AND OBJECTIVE: Excessive hemosiderosis is the main reason for the multi-organ failure observed in multitransfused patients. Deferiprone (1,2-dimethyl-3-hydroxy-pyridine-4-one, L1) is an orally active iron chelator mainly excreted via urine. We conducted a study in order to determine the efficacy and safety of L1 in Greek thalassemic patients. DESIGN AND METHODS: A group of 11 thalassaemic patients entered the study; L1, the Cipla formulation for deferiprone, at a daily dose of 75-100 mg/kg bw t.i.d. was used. After giving informed consent all patients were subjected to clinical examination and biological tests. RESULTS: All patients tolerated the L1 well; there were no significant side effects (except for slight gastrointestinal disturbances for the first days). The net urinary iron excretion ranged from 6.96 to 26.1 mg/24h. Serum ferritin declined within 4-6 months in most of the patients. INTERPRETATION AND CONCLUSIONS: The results suggest that L1 is a rather safe drug which decreases iron overload without causing any considerable side-effects in Greek thalassemics.
Micrococcus luteus was repeatedly isolated in blood cultures during a prolonged feverish syndrome in a patient who presented with multiple hepatic abscesses as well. In contrast to the literature, this case is not related to prosthetic devices; an untreated limb wound may have been the site of microbial entry.
Cytogenetic analysis was performed in 60 patients with primary myelodysplastic syndromes--diagnosed, treated, and followed in our department. In 41 cases, the presence of the NRAS mutation was also evaluated. The aim of this study was to evaluate the prognostic value of chromosomal abnormalities and NRAS mutation. The median age of the patients was 67 years (18-88 years), and the French-American-British classification was as follows: refractory anemia 26, refractory anemia with ring sideroblasts 4, refractory anemia with excess of blast cells 15, refractory anemia with excess of blast cells in transformation 3, and chronic myelomonocytic leukemia 12. Survival analysis was performed for the patients with a normal (n = 35), an abnormal (n = 25) karyotype and with a single (n = 15) or multiple (n = 10) cytogenetic abnormalities. Abnormal karyotypes were detected in 25 of the 60 patients (41.6%). Fifteen of these patients had a single and 10 had two or more lesions. The median survival of the patients with a normal (33.1 months) and with an abnormal (36.5 months) karyotype was not significantly different. Patients with multiple lesions had a reduced median survival compared with patients with single anomalies (19.2 versus 39.7 months, p = 0.5). Patients with an abnormal karyotype progressed to acute leukemia more frequently compared with patients without lesions (36 versus 28.6%, p = 0.5). NRAS mutation was detected in 2 of 10 CMMoL patients studied and in none of the 31 patients with other types of myelodysplastic syndrome. Marrow blasts more than 10% significantly affected survival.
Adhesion and stabilization of circulating tumor cells to endothelial cells in target blood vessels play an important role in the complex process of metastasis. We examined the cell surface receptors involved in the liver-metastatic adhesive interactions of murine RAW117 large-cell lymphoma cells to unstimulated hepatic sinusoidal endothelial cells (HSE) under physiological flow conditions. Flow cytometric analysis indicated that VCAM-1, ICAM-1 and PECAM-1 are constitutively expressed on the surfaces of both HSE and RAW117 cells. However, monoclonal antibody (mAb) blockade studies showed that ICAM-1 and PECAM-1 affected neither the attachment nor the stabilization step of the adhesion of RAW117 cells to HSE cell monolayers under flow. In contrast, RAW117 cells required a significantly lower shear stress to establish adhesion to HSE cells when VCAM-1 receptors on HSE cells were blocked with mAb. Furthermore, the presence of the anti-VCAM-1 mAb significantly decreased the extent of adhesion compared to that of the control, without affecting adherent cell stabilization times. Blocking the alpha4 integrin subunits present mainly on RAW117 cells produced similar results to those previously observed with anti-VCAM-1 mAb. Although constitutively present mainly on the surfaces of RAW117 cells, MAdCAM-1 and beta7 integrin subunit do not appear to play a role in either the arrest or stabilization of RAW117 cells on HSE cell monolayers. However, blocking the beta1 integrin subunit on the RAW117-H10 cells reduced adhesion to the same extent as anti-alpha4 and anti-VCAM-1 treatments. These observations suggest that an interaction of integrin alpha4/beta1 on RAW117 cells with liver endothelial VCAM-1 occurs during the early stages of the adhesion process and may be important in liver metastasis.
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BACKGROUND: After activation, platelets adhere to neutrophils via P-selectin and beta2-integrin. The molecular mechanisms and adhesion events in whole blood exposed to venous levels of hydrodynamic shear in the absence of exogenous activation remain unknown. METHODS AND RESULTS: Whole blood was sheared at approximately 100 s(-1). The kinetics of neutrophil-platelet adhesion and neutrophil aggregation were measured in real time by flow cytometry. P-selectin was upregulated to the platelet surface in response to shear and was the primary factor mediating neutrophil-platelet adhesion. The extent of neutrophil aggregation increased linearly with platelet adhesion to neutrophils. Blocking either P-selectin, its glycoprotein ligand PSGL-1, or both simultaneously by preincubation with a monoclonal antibody resulted in equivalent inhibition of neutrophil-platelet adhesion (approximately 30%) and neutrophil aggregation (approximately 70%). The residual amount of neutrophil adhesion was blocked with anti-CD11b/CD18. Treatment of blood with prostacyclin analogue ZK36374, which raises cAMP levels in platelets, blocked P-selectin upregulation and neutrophil aggregation to baseline. Complete abrogation of platelet-neutrophil adhesion required both ZK36374 and anti-CD18. Electron microscopic observations of fixed blood specimens revealed that platelets augmented neutrophil aggregation both by forming bridges between neutrophils and through contact-mediated activation. CONCLUSIONS: The results are consistent with a model in which venous levels of shear support platelet adherence to neutrophils via P-selectin binding PSGL-1. This interaction alone is sufficient to mediate neutrophil aggregation. Abrogation of platelet adhesion and aggregation requires blocking Mac-1 in addition to PSGL-1 or P-selectin. The described mechanisms are likely of key importance in the pathogenesis and progression of thrombotic disorders that are exacerbated by leukocyte-platelet aggregation.
Cellular interactions play a key role in diverse biological processes within the cardiovascular system. Targeting of leukocytes to sites of inflammation is viewed as a multistage process of sequential involvement of distinct adhesion molecules on the leukocyte and endothelial cell (EC) surface that is dictated by the local fluid dynamic environment. For neutrophils, the initial contact and rolling along the vessel wall are mediated primarily by selecting. Subsequent firm adhesion requires activation of neutrophil P, integrins and binding to their ligand ICAM-1 on the EC surface. The final step of this cascade of events includes neutrophil transmigration to extravascular tissue space. The neutrophil model of emigration in inflammation has been extended and refined to account for monocyte and T cell interactions with ECs. Platelet adhesion to thrombogenic surfaces (i.e. immobilized von Willebrand factor) under flow follows the general principles of leukocyte extravasation. More specifically, platelet glycoprotein (GP) Ib alpha appears to mediate an initial selectin-like tethering platelet-vWf interaction, followed by alpha II beta beta 3 integrin activation and firm adhesion. Some of the signaling mechanisms associated with cellular interactions in inflammatory and thrombotic processes are discussed. These basic principles are also discussed in the context of tissue engineering research.
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The case of a 29-year-old woman with aplastic anaemia in remission who relapsed during pregnancy is reported here. Following successful Caesarean delivery, spontaneous remission was obtained and the patient remains well thereafter. Pathogenetic and therapeutic aspects of this rare complication of pregnancy are discussed.
Myelofibrosis is not frequent in systemic lupus erythematosus (SLE). A review in the literature reveals that the co-incidence is rather rare since there are only a few papers reporting this combination. The female patient described hereby, presented with thrombocytopenia; following investigation, the diagnosis of SLE was established and bone marrow examination revealed an increase of marrow reticulin. Treatment with steroids reversed both thrombocytopenia and bone marrow fibrosis.
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This study identifies multiple pathways used by monocytes to adhere to 4-hour interleukin-1beta stimulated human umbilical vein endothelial cells under flow conditions. Physiologic shear stresses were simulated in a flow chamber with parallel plate geometry; quantitation of primary adhesion, secondary adhesion, and transmigration was performed using phase contrast videomicroscopy. Neuraminidase treatment of monocytes reduced primary interaction by 50%, whereas blocking L-selectin or very late antigen-4 showed significant but smaller effects (approximately 30% inhibition). However, a combined treatment against all three pathways was able to reduce interaction by 80%. Blocking beta2 and alpha4 integrin pathways together inhibited secondary/firm adhesion by 75%. Only 40% of firmly adherent monocytes transmigrated across the endothelial monolayer with significantly increased transmigration times when both beta2 and alpha4 integrins were blocked. These results demonstrate that monocytes can use multiple receptors to interact with endothelial cells at both primary and secondary adhesion stages, and that these pathways have to be blocked simultaneously for maximum inhibition.
This study demonstrates that endothelial P-selectin and vascular cell adhesion molecule 1 (VCAM-1), but not intercellular adhesion molecule 1 (ICAM-1), are capable of supporting extensive primary adhesion of T cells under flow. To address this issue, we used human umbilical vein endothelial cells (HUVECs) stimulated with histamine, interleukin-4 (IL-4), or interferon-gamma (IFN-gamma) that provide essentially a P-selectin, VCAM-1, or ICAM-1 surface, respectively, in a physiologically relevant cell type. Monoclonal antibody (mAb) blockade studies were carried out to confirm the specificity of these adhesive interactions and rule out a number of other potentially important adhesion molecules. Quantitation of adhesion showed that almost all of the interacting T cells rolled on histamine-stimulated HUVECs or CHO-P cell monolayers. In contrast, approximately 20% of the total interacting T cells with 24-h IL-4-treated HUVECs were firmly adherent. mAb blocking experiments revealed that T cell adhesion to IL-4-treated HUVECs is alpha 4-VCAM-1 dependent. Furthermore, mAb 4B9 directed against domain 1 of VCAM-1 eliminated adhesion, suggesting that alpha 4 integrins may not interact with either the alternatively spliced domain 4 of VCAM-1 or fibronectin in this process. At a wall shear stress of 2 dyn/cm2, the mean T cell rolling velocities were significantly lower on 24-h IL-4-activated HUVECs (10.2 +/- 2.6 microgm/s) compared with either CHO-P cells (15.6 +/- 3.1 microm/s) or histamine-stimulated HUVECs (16.6 +/- 6.1 microm/s). ICAM-1, expressed on the surface of 24-h IFN-gamma-activated HUVECs pretreated with an anti-VCAM-1 mAb to eliminate any VCAM-1-dependent contribution, did not support T cell adhesion under shear conditions. Together these data indicate that T cell primary adhesion can be mediate d by both endothelial P-selectin and VCAM-1 but not ICAM-1. alpha 4 integrins are highly versatile molecules, capable of initiating T cell rolling interactions and mediating firm arrest on activated endothelium.
The effects of intravenous Integrelin, an antagonist of platelet glycoprotein (GP) IIb-IIIa, were studied ex vivo in flow models of platelet adhesion/aggregation in patients undergoing angioplasty. Blood was collected from each patient before, during, and after a 24-h Integrelin infusion (0.75 micrograms/kg/min; plasma Integrelin levels, 312-759 ng/ml). The effects of Integrelin administered in vivo were evaluated by using two different models of platelet thrombus formation: (a) platelet adhesion onto von Willebrand factor (vWF)/collagen, followed by platelet aggregation, in a perfusion system; and (b) direct platelet aggregation induced by elevated levels of shear stress imposed by a cone-and-plate viscometer. Neither aspirin nor heparin, also given to the patients, affected platelet adhesion or aggregation in these flow models. In the perfusion studies, platelet adhesion to vWF/collagen I was not inhibited by in vivo Integrelin. In contrast, in each of the six patients studied by using blood collected after 45 min of Integrelin infusion, there was a decrease in the size of platelet aggregates compared with patient baseline samples. In the viscometer experiments, shear-induced platelet aggregation was reduced by 61-71% in samples collected 45 min into the Integrelin infusion (plasma Integrelin levels: 759 +/- 69 ng/ml) compared with baseline samples. Within 24-48 h after termination of the Integrelin, direct shear-induced platelet aggregation and platelet aggregation subsequent to adhesion returned to or near baseline in each of the patients studied. We conclude that Integrelin administered in vivo inhibits both platelet aggregation subsequent to initial platelet adhesion and direct shear-induced platelet aggregation under pathologic flowing conditions, After discontinuation of the drug, these inhibitory effects do not persist in vivo as long as the inhibitory effect on aggregation produced by c7E3 (the monoclonal antibody against GPIIb-IIIa).