Abstract: Diamond-Blackfan anemia (DBA) is a rare, congenital, pure red blood cell aplasia owing to gene defects affecting the function of ribosomal proteins, essential for erythroid maturation. Iron overload is a serious complication of chronic transfusions, which may lead to cardiac toxicity and endothelial damage. We report a case of pulmonary embolism, observed after viper bite in a transfusion-dependent child with DBA without known inherited thrombophilic factors. Embolic events are uncommon after viper bites, which they usually cause consumption coagulopathy, resulting in hypocoagulable state. DBA has not been earlier correlated with thrombotic episodes. In our patient, we suggest an iron overload-induced hypercoagulability state, which in the presence of a procoagulant substance lead to the development of a thromboembolic event.
Abstract: Viral meningitis is characterized by cerebrospinal fluid (CSF) lymphocyte pleocytosis, although neutrophils may predominate in the early phase. The T helper 1 (Th1)/Th2 cytokine balance and expression of adhesion molecules seem to be involved in the CSF chemotaxis. We aimed to determine expression of cytokines and adhesion molecules in enteroviral meningitis. We investigated the serum and CSF levels of adhesion molecules (E-selectin, L-selectin, vascular cell adhesion molecule-1 [VCAM-1], and intracellular adhesion molecule-1 [ICAM-1]) and cytokines (interleukin-12 [IL-12] and IL-4) in 105 children during an outbreak of enteroviral meningitis. Diagnosis was confirmed with positive polymerase chain reaction (PCR) and/or serology for echovirus or Coxsackie virus, and matched with control subjects for clinical features but with negative PCR and/or serology. Apart from VCAM-1, the CSF levels of all investigated inflammatory molecules were significantly increased. In serum, sL-selectin and ICAM-1 levels were significantly higher than control subjects. Serum and CSF L-selectin, serum VCAM-1, and CSF IL-12 were all observed to be expressed in significantly higher levels in the neutrophil-dominant subgroup (72% had duration of symptoms <24 h) than in the lymphocyte-dominant group (87.5% had duration of symptoms >24 h). Serum and CSF ICAM-1 was found at significantly higher levels in the latter group. Evolving expression of adhesion molecules and cytokines indicates a shift from Th1 to Th2 immune responses as infection progresses.
Abstract: The adipocytokines leptin and adiponectin represent a critical link between metabolism, immunity and chronic inflammation. A chronic vascular inflammatory state plays an important role in the pathophysiology of thalassaemia. We aimed to analyze the levels of these adipocytokines and determine any possible correlations with disease severity or vascular inflammation markers in beta-thalassaemia.
Abstract: We present the case of an 11-year-old obese girl who presented with idiopathic intracranial hypertension affecting first the lateral abducens nerve. She received acetazolamide, but 5 days later she developed lateral, peripheral facial palsy. Imaging evaluation was normal, which primarily excluded cerebral venous thrombosis and sustained the initial diagnosis. Despite some complicating factors (obesity, elevated intracranial pressure), prednisolone was administered for a short-term period to counteract the facial palsy. Ophthalmological residuals resolved within almost 1.5 months, while facial palsy receded after 4 months. Peripheral facial palsy is an extremely rare, but not unknown condition in idiopathic intracranial hypertension. As a symptom, it should be investigated thoroughly, primarily to exclude cerebral venous sinus thrombosis, before it can be attributed to idiopathic intracranial hypertension. As far as treatment is concerned, corticosteroids can be added to the initial treatment with acetazolamide, without worsening already elevated intracranial hypertension or ophthalmologic findings.
Abstract: The quality of life of patients with sickle cell disease in developed countries has improved significantly over the past two decades. Currently available measures to prevent the painful crises and the complications of the disease include the use of penicillin prophylaxis, antipneumonococcal vaccine, folate administration, chronic red cell transfusions in patients with cerebrovascular disease, iron chelating agents, fetal hemoglobin-enhancing agents, such as hydroxyurea, decitabine and butyrate, drugs that augment the endogenous nitric oxide levels and agents that restore red cell dehydration. Sickle cell patients show a broad phenotypic expression and a great variability in treatment response. Genetic association studies, which attempt to link polymorphisms with certain disease phenotypes and drug response, are taking the first steps in aiding individualized therapy in sickle cell patients in order to enhance efficacy and reduce toxicity.
Abstract: Over the last few years, increased evidence has supported the role of iron dysregulation in the pathogenesis of multiple sclerosis (MS), as iron is essential for myelin formation and oxidative phosphorylation. We studied indices of iron metabolism, such as serum iron, ferritin, transferrin and soluble transferrin receptor (sTFR) levels in 27 MS patients. Seven patients had chronic progressive active disease (CP-A), six had chronic progressive stable (CP-S), ten had relapsing remitting active (RR-A) and four had relapsing-remitting stable (RR-S) disease. sTFR levels were found to be significantly higher in CP-A (P = 0.021) and RR-A (P < 0.004) patients than in controls. sTFR levels were also elevated in CP-S patients but did not reach significance (P = 0.064). sTFR values in RR-S patients were comparable to those found in controls (P = 0.31). Ferritin levels were significantly elevated only in CP-A patients (P < 0.002). Patients of the CP group had significantly higher ferritin values than the RR patients (P < 0.004). Haemoglobin values as well as iron and transferrin levels were within normal limits in all patients. In conclusion, the increased serum sTFR and ferritin levels in nonanaemic MS patients with active disease reflect the increased iron turnover. The mild elevation of sTFR levels in CP-S patients may indicate active inflammation with ongoing oxidative damage that is not detectable by history or examination.
Abstract: Interleukin-5 contributes both in eosinophilopoiesis and neural development. Serum interleukin-5 levels were measured with enzyme-linked immunosorbent assay technique in 68 children with epilepsy receiving sodium valproate monotherapy and compared with the levels of 60 healthy controls and 14 children with epilepsy receiving carbamazepine. Eosinophilia was observed in 35.3% of children receiving valproate. Interleukin-5 in valproate users was significantly higher compared with children receiving carbamazepine and controls. Valproate users who exhibited eosinophilia had higher interleukin-5 levels compared with those without eosinophilia. However, the interleukin-5 level was also elevated, although to a lesser degree, in children without eosinophilia. The majority of valproate responders had high interleukin-5 levels. A positive correlation between interleukin-5 levels and the eosinophil count was also noted. We postulate that valproate contributes to the pathogenesis of eosinophilia, probably inducing interleukin-5 production. The finding that serum interleukin-5 was significantly elevated in valproate responders and even in valproate users without eosinophilia suggests that the increase in interleukin-5 might represent one of valproate's antiepileptic mechanisms.
Abstract: Brucellosis is characterized by chronicity and relapses despite efficacious treatment. Cytokines and especially the Th1/Th2 balance may be involved in the susceptibility or resistance to the Brucella species. In order to identify predictors of treatment outcome, we measured the pre and posttreatment levels of serum interleukin-2 (IL-2) and soluble IL-2 receptor alpha (sIL-2Ralpha) in 20 children with brucellosis. All children were treated for 6 weeks and three of them (15%) presented with a relapse at 2, 3 and 8 months after treatment had ended.
Abstract: The most common single genetic disorder and a major public health issue in Greece and other Mediterranean countries is beta-thalassemia. Current therapeutic approaches for homozygous beta-thalassemia entail blood transfusions and iron chelation therapy with deferoxamine or deferiprone for preventing tissue hemosiderosis. Recently, much effort has focused on various inducers of fetal hemoglobin (HbF) such as recombinant human erythropoietin (rHuEPO), especially in beta-thalassemia intermedia. Ten adult patients, 5 with beta-thalassemia major and 5 with beta-thalassemia intermedia, received 150 IU/kg rHuEPO (epoetin-alpha) subcutaneously three times a week. Seven patients were transfused every 14-30 days and 3 with beta-thalassemia intermedia were only occasionally transfused. The minimum duration of treatment was 12 weeks in order to define if there was any response. Transfusion intervals were modified according to the rHuEPO response to maintain stable Hb values. Lower transfusion requirements were observed in 5 patients after rHuEPO treatment (p = 0.028). In the 3 non-transfused patients, Hb values increased, and the patients are still being treated and followed up for a period ranging from 14 weeks to 2 years. Two patients with thalassemia major discontinued treatment after 12 weeks, as they did not achieve any response regarding transfusion requirements or Hb values. Pretreatment serum transferrin receptor levels were higher than in controls (p < 0.001) and significantly increased following rHuEPO treatment (p = 0.027). Patients had higher serum endothelin-3, sICAM-1 and sE-selectin values before rHuEPO treatment compared to controls (p < 0.001, p < 0.001 and p = 0.016, respectively), but these values were not altered during treatment. HbF values presented a slight, non-significant increase. rHuEPO treatment has a beneficial effect in transfusion-dependent beta-thalassemia patients. Although a slight increase in HbF levels was observed, other possible mechanisms are probably involved. None of our patients experienced thrombotic complications and a rise in blood pressure.
Abstract: Abnormal adhesion of red blood cells to the endothelium and the production of cytokines and vasoactive substances, such as endothelin-1 contribute to the pathogenesis of microvascular occlusion in sickle cell disease (SCD), even during the steady state. Endothelin-3 (ET-3) is a vasoconstrictive agent, which has not yet been studied in SCD.
Abstract: Patients with ataxia-telangiectasia (A-T) and cancer are exposed to additional toxicity due to their underlying inability to repair chemotherapy-induced DNA damage. The authors report the development of osteosarcoma as a second neoplasia in a child with A-T who was treated, without being irradiated, for non-Hodgkin's lymphoma as a primary malignancy. This is the first report of osteosarcoma associated with A-T. The authors postulate that the mechanisms of carcinogenesis are common and independent of the different histopathology categories of these two neoplasias, and the underlying "canvas" of the A-T mutated gene was further triggered by chemotherapy, leading to the development of a second malignancy.
Abstract: Beta-Thalassemia is a common autosomal recessive disorder resulting from over 200 different mutations of the beta-globin genes. The spectrum of beta-thalassemia mutations in Greece has been previously described in the population of the capital city of Athens, or in beta-thalassemia patients having transfusion therapy. The aim of the present study was to identify the distribution of the most common beta-thalassemia mutations in the population of northwestern and central Greece.
Abstract: The Th1/Th2 cytokine balance seems to be involved in the susceptibility or resistance to Brucella infection, however the precise role of interleukins in human brucellosis has not been thoroughly explored.
Abstract: We report on a 28-year-old patient with transfusion-dependent beta-thalassemia major, who was treated effectively with recombinant human erythropoietin (rHuEpo). rHuEpo promotes the differentiation and proliferation of erythroid cells, induces the production of fetal hemoglobin (HbF), and could be useful in the treatment of some selected transfusion-dependent thalassemia patients. Prior to rHuEpo treatment, the patient was on a regular blood transfusion regimen. Splenectomy did not decrease the transfusion requirements. Additionally, red cell alloimmunization had developed; therefore, we decided to start rHuEpo treatment (Eprex, Jansen Cilag, Greece) in an attempt to improve his anemia and the quality of life. Our patient responded well to rHuEpo treatment and was able to extend the intervals between transfusions from 10-14 to 55-65 days and to sustain a pretransfusion hemoglobin level above 7 g/dl. HbF levels were slightly increased from 55% to 60-65%. Indicators of vascular endothelial activation [serum endothelin-3, intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin] were decreased during treatment. rHuEpo was well tolerated without complications. rHuEpo treatment seemed to have had a beneficial effect and to have improved the quality of life in beta-thalassemia major, although it did have a slight effect on HbF levels, suggesting other possible mechanisms of rHuEpo action.
Abstract: Endothelial activation and subclinical microvascular occlusions are an ongoing process during steady-state sickle cell disease, leading to interleukin production and an acute-phase response. Alpha-2-macroglobulin (alpha2M) is an acute-phase protein mainly regulated by interleukin-6 (IL-6). On the other hand, alpha2M acts as a carrier protein for IL-6 during inflammatory stress. The purpose of this study is to further assess the interactions between IL-6 and alpha2M as potent modulators of inflammatory reactions during the steady state of sickle cell disease. We measured alpha2M and IL-6 levels in 21 patients (12 male, 9 female; age range 12-44 years) in the steady state of sickle cell disease. Four patients had homozygous sickle cell anaemia and 17 had double heterozygous sickle cell/beta-thalassaemia. Diagnostic quantification of alpha2M was performed by rate nephelometry. Commercial enzyme immunoassay test kits were used for the quantitative measurement of IL-6. The alpha2M and IL-6 levels were compared to the values obtained from healthy volunteers. Mean values (+/- SD) of alpha2M and IL-6 were found to be significantly increased (p < 0.0005) in the patients (alpha2M: 337.2 +/- 104 mg/dl; IL-6: 4 +/- 2.1 pg/ml) compared to the healthy controls (alpha2M: 204.2 +/- 45.8 mg/dl; IL-6: 1.15 +/- 2.5 pg/ml). IL-6 values were positively correlated with alpha2M levels (r = 0.61, p < 0.01). We observed increased alpha2M and IL-6 levels in steady-state sickle cell disease and a positive correlation between these two inflammatory mediators. We suggest that alpha2M is a potent modulator of the inflammatory reaction and tissue repair mechanism during steady-state microvascular occlusions. Elucidating the role of alpha2M in sickle cell disease could lead to the development of novel strategies and therapies for preventing the harmful systemic or local effects of excess cytokine production.
Abstract: Sickle cell disease (SCD) is characterized by chronic hemolysis, frequent infections, and recurrent occlusions of microcirculation, which cause painful crises and result in chronic organ damage and failure. Occlusions of the microcirculation and infections are important factors that stimulate the production of cytokines and acute-phase proteins. Cytokines seem to be involved with several possible mechanisms in the pathogenesis of vasoocclusive phenomena in SCD: vascular endothelial activation, induction of red-cell adhesiveness to vascular endothelium, induction of neutrophil adhesiveness to endothelium, development of vascular intimal hyperplasia, platelet activation, endothelin-1 production, and dysregulation of endothelial apoptosis. Cytokines are also thought to be involved in the regulation of hemopoiesis, the inhibition of immune functions, and the development of growth deficits. Investigation of cytokines in SCD patients will elucidate the pathogenesis of the disease and its complications and may help in assessing disease severity and prognosis.
Abstract: Whereas beta-2-microglobulin (beta2M) has mainly been used as a prognostic factor in patients with lymphoproliferative disorders, some studies have reported the value of beta2M in myeloproliferative disorders (MPD). In order to investigate a potential role in the pathogenesis of MPD and to find a possible value as indicators in monitoring the course of the disease, we measured beta2M, TNF-alpha, IL-1alpha, IL-1beta, IL-2, sIL-2R, IL-6 and IL-10 in 55 patients with MPD, at diagnosis and during the course of the disease. In progressive disease and particularly when transformation to acute leukemia occurred, high levels of beta2M, IL-2 and sIL-2R were found in all patients; the elevation was progressive, which suggests a potential prognostic usefulness in the individual patient.
Abstract: To identify a possible acute phase response during the steady state of sickle cell disease, we estimated the serum alterations of acute phase proteins, beta2-microglobulin (beta2M), kappa and lambda light chains, interleukins (ILs) and tumor necrosis factor-alpha (TNFalpha) in 21 patients. Increased concentrations of C-reactive protein (CRP) were found in 5 patients, alpha-1-acid-glycoprotein (AGP) in 3, alpha-1-antitrypsin (AAT) in 8, ceruloplasmin (CER) in 2, alpha-2-macroglobulin (AMG) in 14 and decreased haptoglobin (HPT) and transferrin (TFR) in 11 and 9, respectively. Increased beta2M was found in 10 patients and kappa and lambda light chains in 11. IL-1beta, IL-2, IL-4, IL-10 and TNFalpha were not detected in any of the patients. However, significantly increased values of IL-6 and sIL-2r were found. This study has demonstrated increased serum levels of some of the acute phase proteins in patients during the steady state of sickle cell disease. This may be a result of a subclinical vaso-occlusion which in turn leads to a covert inflammatory response. Cytokines, and in particular IL-6, produced after this response, seem to be responsible for the high levels of acute phase proteins in the steady state of this disease.
Abstract: In order to investigate the possible existence of a prognostic factor for B cell chronic lymphocytic leukemia (B-CLL), we determined the serum levels of TNF-alpha, IL-1a, IL-1b, IL-2, sIL-2R, IL-6, IL-10 and beta-2M in 20 patients. We observed significant changes in sIL-2R and beta-2M levels, whereas in all stages of disease, TNF-alpha and other interleukins exhibited only mild changes. An excellent correlation between sIL-2R and beta-2M levels and disease activity wes reported. Patients with aggressive disease (Rai stages III and IV and Richter's syndrome) had increased levels. Patients who responded to therapy and with improved clinical status had decreased sIL-2R and beta-2M levels. However, patients with progressive disease and no response to therapy were associated with increased levels of sIL-2R and beta-2M. In conclusions, as serum levels of sIL-2R and beta-2M are increased in the aggressive stages of B-CLL, they may be used as reliable markers for monitoring B-CLL activity, showing response to treatment and early relapse and/or disease progression.
Abstract: Sudden cardiac death (SCD) has not been investigated separately in Greece. The aim of this study is to describe the epidemiological characteristics of people dying suddenly out of hospital in an area of Greece. In 1990, a population based study was started to detect the cases of people dying suddenly out of hospital (< 1 h after onset of acute symptoms or < 6 h after being seen alive) in a closed population in Northwest Greece (Ioannina area: 160,000 inhabitants). During a 3.5 year period, 283 potential cases aged 30-70 years were identified by monitoring the mortality in the emergency rooms of the two hospitals of the area, the coroner's office and the death certificates from the Government Department of Statistics. The diagnosis of SCD was established in 223 (183 men, 40 women; mean ages 59 and 61 years respectively) after visiting and interviewing the relatives and/or the family doctors within 12 days (range 1-28) after the death. SCD in the study accounts for 50% of all cardiovascular deaths and is the most common cause of death after neoplasia. The most common place of death was home (151 cases, 68%), and in 174 cases (78%) deaths occurred while the patients were relaxing or during routine activities. Prodromal symptoms were reported in 57 cases (26%). The time of day of death showed a circadian variation, with a peak in the late morning from 9:00 to 12:00. Ninety four (42%) had a prior history of heart disease. One hundred and ninety one cases (86%) occurred in the subgroup of age 50-70 years.(ABSTRACT TRUNCATED AT 250 WORDS)
