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Several studies have shown a relation between hyperhomocysteinaemia and arterial vascular disease. We looked at the association between hyperhomocysteinaemia and venous thrombosis which could be clinically important as hyperhomocysteinaemia is easily corrected by vitamin supplementation. We studied 185 patients with a history of recurrent venous thrombosis and 220 controls from the general population. Homocysteine concentrations were measured before and 6 h after oral methionine loading. We defined hyperhomocysteinaemia as the homocysteine concentration above the fasting or the postmethionine value found for the 90th percentile of the controls. Of the 185 patients with recurrent thrombosis, 46 (25%) had fasting homocysteine concentrations above the 90th percentile or the controls (odds ratio is 3·1 [1·8-5·5]). After adjustment for age, sex, and menopausal status the odds ratio was 2·0 (1·5-2·7). Similar results were found for the post-methionine value (unadjusted odds ratio 3·1 [1·7-5·5], adjusted 2·6 [1·9-3·5]). Hyperhomocysteinaemia is a common risk factor for recurrent venous thrombosis and can lead to a two-fold or three-fold increase in risk.

Fluorescence in situ hybridization (FISH) is a powerful tool for detection of numerical and structural chromosomal aberrations. We have compared conventional banding techniques and FISH for the detection of monosomy 7 (-7) and trisomy 8 (+8) in 89 patients with myeloid malignancies. Of these patients, 21 had -7, 30 had +8, four had both, and 34 had no aberrations or aberrations other than -7 or +8 as assessed by banding techniques. Sequential samples were available in 23 patients. Alphoid DNA probes specific for chromosomes no. 7 and 8 were used for FISH. As controls, 10 normal bone marrow (BM) samples were hybridized with the chromosomes no. 7 and 8 probes, and in addition all tumor samples were hybridized with a chromosome no. 1 specific probe. The cut-off value for -7 was 18% one-spot cells, and for +8 was 3% three-spot cells. FISH analysis of 44 samples with -7 or +8, and at least 10 metaphases evaluated, showed that the proportions of aberrant metaphase cells mirrored the interphase clone sizes. Most samples with nonclonal metaphase aberrations, including those with only a few metaphases, had increased numbers of aberrant interphase cells: 20% to 80% for -7, and 3% to 43% for +8. Interphase cytogenetics of the 34 samples without -7 or +8 did not show significant cell populations with -7 or +8. In four patients, -7 or +8 could not be confirmed by FISH due to additional structural aberrations, marker chromosomes, or wrongly interpreted banding results. As FISH will be used more and more in cytogenetic diagnosis, clinical follow-up, and therapy monitoring, it will be necessary to standardize FISH procedures and supplement the Standing Committee on Human Cytogenetic Nomenclature (ISCN) definitions of a clone with criteria specifically for in situ hybridization.

Interstitial deletions of the long arm of chromosome 5 are among the most characteristic abnormalities observed in myeloid disorders. To assess the lineage involvement of peripheral blood cells from patients with a 5q--anomaly, purified neutrophils, monocytes, T lymphocytes, and B lymphocytes were analyzed for loss of heterozygosity using six different highly polymorphic mininucleotide and dinucleotide (CA) repeat sequences from the 5q31 to 5q33 region. Ten patients were screened by polymerase chain reaction (PCR) amplification and proved to be informative for at least one marker. Six patients showed a complete or partial disappearance of an allele in myeloid cells, whereas cells of lymphoid lineages exhibited full heterozygosity. The other patients displayed no allelic loss, indicating that the informative markers were located outside the deleted chromosomal segments. In addition, three female patients who were also polymorphic for the BstXI site in the PGK- 1 gene were analyzed for the methylation status of this gene. Clonality of hematopoiesis, as determined by non-random X-chromosome inactivation, followed the same cell pattern as the 5q-specific allelic losses. In conclusion, using tumor-specific and clonal markers, we have demonstrated that the 5q- anomaly is restricted to cells of myeloid origin, leaving lymphoid cells unaffected.

Bone marrow cells of four patients with t(1;7) and myelodysplasia or acute myeloid leukemia were analyzed using nonradioactive in situ hydridisation. As probes, centromeric alphoid DNA sequences of chromosomes 1 and 7, a satellite DNA probe for 1q12, and chromosome-specific libraries of chromosomes 1 and 7 were used. The breakpoints of the t(1;7)(p11;p11) as determined by banding analysis could be studied more accurately, and the recently proposed designation t(1;7)(cen;cen) was confirmed in all four cases. Colocalization of alphoid DNA sequences of chromosomes 1 and 7 by double target in situ hybridisation was demonstrated in metaphase cells and also in interphase nuclei. The in situ hybridisation method described is applicable for the screening of peripheral blood cells or archival material.

Abstract —Hyperhomocysteinemia is a risk factor for atherosclerosis and thrombosis and is inversely related to plasma folate and vitamin B12 levels. We assessed the effects of vitamin supplementation on plasma homocysteine levels in 89 patients with a history of recurrent venous thrombosis and 227 healthy volunteers. Patients and hyperhomocysteinemic (homocysteine level >16 μmol/L) volunteers were randomized to placebo or high-dose multivitamin supplements containing 5 mg folic acid, 0.4 mg hydroxycobalamin, and 50 mg pyridoxine. A subgroup of volunteers without hyperhomocysteinemia was also randomized into three additional regimens of 5 mg folic acid, 0.5 mg folic acid, or 0.4 mg hydroxycobalamin. Before and after the intervention period, blood samples were taken for measurements of homocysteine, folate, cobalamin, and pyridoxal-5′-phosphate levels. Supplementation with high-dose multivitamin preparations normalized plasma homocysteine levels (≤16 μmol/L) in 26 of 30 individuals compared with 7 of 30 in the placebo group. Also in normohomocysteinemic subjects, multivitamin supplementation strongly reduced homocysteine levels (median reduction, 30%; range, −22% to 55%). In this subgroup the effect of folic acid alone was similar to that of multivitamin: median reduction, 26%; range, −2% to 52% for 5 mg folic acid and 25%; range, −54% to 40% for 0.5 mg folic acid. Cobalamin supplementation had only a slight effect on homocysteine lowering (median reduction, 10%; range, −21% to 41%). Our study shows that combined vitamin supplementation reduces homocysteine levels effectively in patients with venous thrombosis and in healthy volunteers, either with or without hyperhomocysteinemia. Even supplementation with 0.5 mg of folic acid led to a substantial reduction of blood homocysteine levels.

This case report describes a patient with localized hyaline-vascular (H-V) type Castleman's disease with concomitant malignant B-cell lymphoma. Malignant lymphoma has been described in association with multicentric type Castleman's disease, but not in association with the localized H-V type. Evidence for a relation between the two lesions in this patient by means of histologic, flow-cytometric, cytogenetic and gene rearrangement studies was not found.

The effect of conservative treatment of aplastic anaemia was evaluated retrospectively in 40 patients. No significant beneficial effect was provided by long-term high-dose oxymethalone in 20 patients or by metenolone, adrenstonolone, or testosterone in 14 patients. Splenectomy gave no improvement in the majority of cases, although in some it decreased the transfusion requirement. Immunosuppressive treatment was successful in 1 patient with a positive LE phenomenon. Until a specific treatment becomes available, the possibility offered by alternative treatment, e.g. bone marrow transplantation, in cases with poor prognostic parameters should be considered.

Of the 14 patients with aplastic anaemia treated in our hospital with anti-thymocyte globulin (ATG), four were refractory to random platelets before therapy due to the presence of leucocyte antibodies. In contrast to the ten nonrefractory patients in whom no success was obtained, three of the four refractory patients showed haematological improvement after ATG. Additionally, two patients could be substituted again with random platelets. The other two hardly needed platelet-transfusions after ATG, and they were given HLA-compatible platelets. To determine the degree of immunosuppression, these four patients were tested for the presence of antibodies against leucocytes and two endemic viruses, i.e., mumps and rubella virus. Before ATG, all sera reacted with almost the whole leucocyte testpanel. After treatment, the leucocyte antibodies disappeared completely in three patients. In one patient there was no dramatic change. In all patients, however, the antibody-titre against the mumps and rubella viruses remained constant and there was only a slight decrease in total IgG content in the three "suppressed" patients. We conclude that it might be worthwhile to study systematically the selective immuno-suppressive effect of ATG.

A case report is presented of a 39-year-old woman suffering from a myelodysplastic syndrome, who developed a moderately severe stable diffuse intravascular coagulation (DIC) during an uneventful pregnancy. Intravenous administration of antithrombin III concentrate was attempted to combat the DIC. Improved survival of platelet transfusions, facilitating supportive care, suggested some therapeutic benefit. In contrast, only minimal effects on the results of the coagulation tests were observed.

The effect of conservative treatment of aplastic anaemia was evaluated retrospectively in 40 patients. No significant beneficial effect was provided by long-term high-dose oxymethalone in 20 patients

Two patients with polycythemia vera and an extra der(1)t(1;9) chromosome are reported. In one patient this was found as the sole abnormality. The other patient originally presented with trisomy 9 but later developed an extra der(1) during the further course of the disease with disappearance of the extra chromosome 9. In situ hybridization studies on this latter patient proved that the centromere of chromosome 1 was involved in the formation of the derivative chromosome.

A patient with acute myelomonocytic leukemia type M4, with a trisomy 22 as the only chromosomal abnormality is reported. All six previously published cases with this anomaly had acute myeloid leukemia. The subtype was AMMoL in five patients, and the subtype of the sixth one was not indicated.

Together with Dr. E. Gluckman (Hopital St. Louis, Paris) and Dr. B. Speck (Kanton Hospital, Basel) we have recently published a study, in which the effect of ATG on the clinical course of severe aplastic anemia was assessed [13]. Our conclusions were that: a) about half of the patients suffering from severe aplastic anemia improved significantly after 4 daily doses of ATG; b) it was unlikely that this apparent beneficial effect of ATG was due to patient selection in the sense that we had selected patients which without ATG treatment would have survived anyhow; c) it was possible that the ATG removed from the bone marrow T cells which interfered with the differentiation of the stem cells. A possibility which is strongly supported by in vitro studies by one of us [8] and others [1].

The factor VIII ratio was measured in 102 pregnant women (43 uncomplicated pregnancies, 19 with pre-eclampsia without fetal growth retardation, 8 pre-eclampsia complicated by fetal growth retardation, 12 with only fetal growth retardation and 20 with gestational diabetes). The pathological pregnancies showed a statistically significant elevation of the factor VIII ratio compared to the normal pregnancies. The group of pre-eclampsia complicated by fetal growth retardation showed the most marked increase of the factor VIII ratio. The results are discussed in relation to the hypothesis that the elevated factor VIII ratio is mainly due to the release of factor VIII antigen by various forms of vascular stress.