Review: Roles for astrocytes in epilepsy: insights from malformations of cortical development.

Malformations of cortical development (MCDs), such as cortical dysplasia and tuberous sclerosis complex, are common causes of intractable epilepsy, especially in paediatric patients. Recently, mounting evidence points to a common pathology of these disorders. Hyperactivation of mammalian target of rapamycin (mTOR) has been proposed as a central mechanism in most, if not all, MCDs. The transition from mTOR hyperactivation and cellular abnormalities to large-scale functional changes and seizure is, however, not fully understood. In this article we set out to review currently available information regarding MCD pathology, focusing on glial cells - especially astrocytes - and their interactions with the brain vascular system. A large body of evidence points to these elements as potential targets in MCD. Here, we attempt to provide a review of this evidence and propose some hypotheses regarding the possible chain of events linking primary glial dysfunction and epilepsy. We focus on extracellular matrix remodelling, blood-brain barrier leakage and failure of astrocyte-dependent removal of extracellular debris. We posit that the failure of these systems results in a chronically pro-inflammatory environment, maintaining local astrocytes in a state of gliosis, with increased susceptibility to seizures as a consequence.

Polymorphisms in genes of the BAFF/APRIL system may constitute risk factors of B-CLL--a preliminary study on a Polish population.

The association of single-nucleotide polymorphisms (SNPs) of B-cell activating factor (BAFF)/a proliferation-inducing ligand (APRIL) system with B-cell chronic lymphocytic leukemia (B-CLL) have been suggested, therefore, we investigated 20 SNPs of BAFF, APRIL, BAFF-R, transmembrane activator and calcium modulator and cyclophilin-ligand interactor (TACI), B-cell maturation antigen (BCMA) genes and the risk and outcome of B-CLL in 187 patients and 296 healthy subjects as well as ligand-receptor gene × gene interactions. Although the obtained P-values for all 20 SNPs did not reach statistical significance for this study (α = 0.003), the high value of the global chi-squared statistic (χ(2) df = 38 = 52.65; P = 0.0586), and obtained values of odds ratio indicate that rs9514828 (BAFF), rs3803800 (APRIL) and rs4985726 (TACI) may be associated with the risk of B-CLL. We observed that the B-CLL patients with the genotype rs9514828CT/rs11570136AA were diagnosed with the disease 12 years later than the whole group of patients in this study.

KIR/HLA gene combinations influence susceptibility to B-cell chronic lymphocytic leukemia and the clinical course of disease.

The aim of this study was to analyze the association between gene polymorphisms of killer-cell immunoglobulin-like receptors (KIRs) and their human leukocyte antigen (HLA) ligands and susceptibility to B-cell chronic lymphocytic leukemia (B-CLL) and the clinical course of disease. The distribution of individual KIR genes in 197 B-CLL patients and 200 controls was similar, except for a tendency for lower frequencies of the KIR2DS3 and KIR2DL5 genes among B-CLL patients (26.9% vs 35.5%, P = 0.06, 46.2% vs 55.5%, P = 0.06). The associations between KIR2DS3 and B-CLL reached statistical significance in women (P = 0.05). Moreover, we found a trend toward a lower frequency of genotypes with the presence of five or six activating KIR genes in B-CLL patients compared to controls (20.8% vs 29.0%, P = 0.06), and a significantly higher frequency of individuals possessing genotypes with a prevalence of inhibitory over activating KIR genes (ratio < 0.71) among B-CLL patients (P = 0.04). The HLA-Bw4 specificity was significantly reduced among B-CLL patients (48.7% vs 63.0%, P = 0.005), which resulted from a decreased frequency of HLA-Bw4(Thr80) (21.6% vs 32.0%, P = 0.02). Moreover, among HLA-Bw4-positive individuals, progression-free survival (PFS) tended to be higher in the presence of KIR3DS1 (77% ± 9% vs 39% ± 13%, P = 0.07). However, in B-CLL patients, the presence of HLA-C2 was associated with decreased PFS (49% ± 9% vs 75% ± 7%, P = 0.02), and among HLA-C2-positive patients, the probability of PFS was significantly reduced in the absence of KIR2DS1 (34% ± 11% vs 77% ± 7%, P = 0.007). Our results indicate that the pattern of inhibitory/activating KIR genes, together with their HLA ligands, is associated with susceptibility to B-CLL and affects the clinical course of this disease.

Acute iron poisoning in adult female.

We report a case of a 27-year-old female with anemia, treated with high dose oral and parenteral iron therapy (within 20 days, the patient received a total dose of 4 g Fe+2 orally and 700 mg Fe+2 iv and im), and developed clinical manifestations characteristic of acute iron poisoning. Initial gastrointestinal symptoms and hypotension were followed by signs of mitochondrial toxicity: high leucocytosis, shock, multi-organ failure and disseminated intravascular coagulation. We discuss the difficulties in diagnosing acute iron poisoning. The initial low total iron blood capacity and high ferritin level, as well as the typical sequence of symptoms, supported the diagnosis. The patient avoided fatal consequences, probably due to the administration of iron doses over an extended period of time. However, cumulative effects led to the apparent iron toxicity. After 2 weeks of treatment, the patient was discharged from hospital in good condition. Human & Experimental Toxicology (2007) 26, 663-666.

Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study.

To assess the efficacy of an original DAC-7 regimen: daunorubicine (DNR) 60 mg/m2/day, days 1-3; cytarabine (AraC) 200 mg/m2/day, days 1-7; cladribine (2-CdA) 5 mg/m2/day, days 1-5, 400 untreated adult acute myeloid leukemia patients (including 63 with preceding myelodysplastic syndrome), aged 45 (16-60) years were randomized to either DAC-7 (n=200) or DA-7 (without 2-CdA, n=200). The overall CR rate equaled 72% for DAC-7 and 69% for DA-7 arm (P=NS). After a single course of DAC-7 induction, the CR rate equaled 64% and was significantly higher compared to 47% in the DA-7 arm (P=0.0009). Median hospitalization time during the induction was 7 days shorter for DAC-7 compared to the DA-7 group (33 vs 40 days, P=0.002). Toxicity was comparable in both groups. The probability of 3-year leukemia-free survival (LFS) for DAC-7 and DA-7 group equaled 43 and 34%, respectively (P=NS). There was a trend toward higher LFS rate for patients aged >40 years receiving DAC-7 compared with DA-7 regimen (44 vs 28%, P=0.05). This study proves that addition of 2-CdA increases antileukemic potency of DNR+AraC regimen, thus resulting in a higher CR rate after one induction cycle when compared to DA-7, without additional toxicity. It shortens hospitalization time and may improve long-term survival in patients aged >40 years.

[Pharmacologic therapy of bone tissue changes due to hematologic malignancies and bone metastasis]. / Farmakologiczne leczenie zmian kostnych w przebiegu nowotoworów hematologicznych i w przerzutach do kosci.

Haematologic malignancies and solid tumors are often complicated by the bone tissue destruction. Neoplastic osteolysis and/or osteosclerosis occurs together with the disturbances of calcium and phosphorus metabolism. This paper updates the possibilities of a modern specific pharmacologic treatment of bone and mineral homeostasis changes caused by neoplasms.

[Emperipolesis in megakaryocytes in patients with thrombocytosis in the course of myeloproliferative disorders]. / Emperipoleza w megakariocytach u chorych z nadplytkowoscia w przebiegu zespolu mieloproliferacyjnego.

The incorporation of other marrow cells into megakaryocytes, termed emperipolesis, has been studied in paraffin biopsy sections from 17 untreated patients with myeloproliferative disorders (MPDs). The group consisted of 12 females and 5 males, aged from 34 to 72 years (mean 51.3). Patients with essential thrombocythemia (ET)--9, chronic granulocytic leukemia (CGL)--4, polycythemia vera (PV)--3, and myelofibrosis (MF)--1 were included into the study. Clusters of large polyploid megakaryocytes were observed in anatomic relation to the marrow sinusoidal system. Emperipolesis has been scored as being present or absent per 100 megakaryocytes/slide. Cells found within megakaryocytes were mostly erythroblasts and mature granulocytes. The number of incorporated cells varied from 1 to 7 per one megakaryocyte. Considering the 17 patients with MPDs, emperipolesis was observed in a vast majority of those with ET(8/9) and PV(2/3), in some with CGL(1/4), but not in MF. The mechanism of megakaryocytic emperipolesis remains unclear. Adhesion molecules on megakaryocytes and incorporated cells may possible mediate the cell-to-cell interactions important for emperipolesis.

[Long-term (over 10-years) survival in Hodgkin's disease]. / Dlugotrwale (ponad 10-letnie) przezycie w chorobie Hodgkina.

61 patients with Hodgkin's disease, i.e., 40.9% of all HD pts hospitalized in the years 1970-1981 are more than 10 years survivors: 46 are alive and 15 died of underlying disease or its complications. The most important prognostic factor at diagnosis was clinical advancement and the form A or B of HD. Age and sex also influenced survival but to a lesser degree. Patients living in CCR were more likely to have MC histology than those with relapsing disease, who more often showed LD and LP type. Among 5 persons with second neoplasms four disclosed NS type of HD. No statistical differences in clinical prognostic factors were encountered between further alive and those who died after more than 10-yrs. Almost all patients were able to normally continue their familial and professional lives.

Structure-function analysis of vitamin D(2) analogs as potential inducers of leukemia differentiation and inhibitors of prostate cancer proliferation.

We characterized a structure-function relationships of four analogs of vitamin D(2) with extended and branched side-chains. We tested their ability to induce differentiation of human acute myeloid leukemia (AML) cells both in vitro and ex vivo. Our experiments on five human cell lines revealed substantial differences among tested analogs. Analogs with side-chains extended by one (PRI-1906) or two carbon units (PRI-1907) displayed similar or elevated cell-differentiating activity in comparison to 1,25-dihydroxyvitamin D(3) (1,25D), whereas further extending side-chain resulted in substantially lower biological activity (PRI-1908 and PRI-1909). Similar pattern of cell-differentiating activities to that observed in human cell lines has also been shown in blast cells isolated from patients diagnosed with AML. The ability of the analogs to activate expression of CYP24A1 gene has been studied in HL60 cell line. The analog PRI-1906 activated expression of CYP24A1 similarly to 1,25D, while PRI-1907 weaker than 1,25D. In addition, the analogs PRI-1906 and PRI-1907 were able to moderately inhibit proliferation and significantly activate expression of CYP24A1 mRNA in prostate cancer cells PC-3. Finally, we examined the molecular actions triggered by these analogs and found that their biological activity was related to their ability to induce expression and nuclear translocation of VDR and C/EBPß.

[Observation of D-dimer levels in serum of patients with acute leukemia]. / Obserwacja stezenia D-dimerów w surowicy u pacjentów chorych na ostre bialaczki.

The blood coagulation and fibrinolysis disorders are common complications observed in patients with acute leukemias, particularly in acute myelogenous leukemia. These abnormalities are mediated by thromboplastic substances released from the blast cells and the alteration of hemostatic properties of vascular endothelium. The plasma concentration of D-dimer (cross-linked fibrin degradation products), measured by enzyme immunoassay, using monoclonal antibodies, serves as a specific marker of the coagulation activation and fibrinolysis system. In our study, the plasma concentration of D-dimer was investigated in 142 patients with acute leukemia during clinical course--at the time of initial diagnosis, complete remission, relapse or in cases resistant to chemotherapy. It has been revealed that, at the time of initial diagnosis, the plasma level of D-dimer was elevated in most patients, irrespective of the type of acute leukemia. However, the initially elevated plasma concentration of D-dimer was significantly lower when complete remission had been achieved. Furthermore, in the majority of cases of relapse or resistance to chemotherapy, a further increase of plasma concentration of D-dimer is commonly observed.