[Portal vein thrombosis associated with a myeloproliferative disorder, prothrombin G20210A mutation, antiphospholipid syndrome, with repermeation during anticoagulant therapy]. / Thrombose portale récente régressive sous anticoagulants secondaire à un syndrome myéloprolifératif latent, une mutation G20210A du gène de la prothrombine et un syndrome des antiphospholipides.

Portal vein thrombosis, except in hepatocellular carcinoma and severe cirrhosis, is due to one or several prothrombotic disorders with or without a local precipitating factor. We report a case of a portal and splenic vein thrombosis, without cavernoma and varices which occurred in a 72-year-old man with abdominal pain and weakness. Three prothrombotic states including latent myeloproliferative disorder, antiphospholipid syndrome, and factor II G202101 mutation, were observed. Anticoagulant treatment resulted in complete repermeation of the portal and splenic veins without a hemorrhagic event. This illustrates that several prothrombotic states may occur in a single patient with portal vein thrombosis. Early anticoagulant therapy, in recent portal vein thrombosis, can result in repermeation.

Endogenous ABA maintains shoot growth in tomato independently of effects on plant water balance: evidence for an interaction with ethylene.

To examine whether the reduced shoot growth of abscisic acid (ABA)-deficient mutants of tomato is independent of effects on plant water balance, flacca and notabilis were grown under controlled-humidity conditions so that their leaf water potentials were equal to or higher than those of well-watered wild-type plants throughout development. Most parameters of shoot growth remained markedly impaired and root growth was also greatly reduced. Additional experiments with flacca showed that shoot growth substantially recovered when wild-type levels of ABA were restored by treatment with exogenous ABA, even though improvement in leaf water potential was prevented. The ability of applied ABA to increase growth was greatest for leaf expansion, which was restored by 75%. The ethylene evolution rate of growing leaves was doubled in flacca compared to the wild type and treatment with silver thiosulphate to inhibit ethylene action partially restored shoot growth. The results demonstrate that normal levels of endogenous ABA are required to maintain shoot development, particularly leaf expansion, in well-watered tomato plants, independently of effects on plant water balance. The impairment of shoot growth caused by ABA deficiency is at least partly attributable to ethylene.

[Efficacity of treatment with lamivudine in two patients with severe reactivation of hepatitis B after withdrawal of chemotherapy]. / Efficacité du traitement par lamivudine chez deux malades ayant eu une réactivation sévère d'une hépatite B induite par l'arrêt d'un traitement chimiothérapique.

Reactivation of chronic infection is a serious complication during and especially after the withdrawal of cancer chemotherapy in hepatitis B virus carriers. Mortality is high, ranging from 4 to 20%. We report two cases of severe reactivation, after withdrawal of chemotherapy for chronic lymphocytic leukemia in one case and for a bladder tumor in the other. Recovery occurred with lamivudine therapy. Morbidity and mortality are common in these cases, especially when intensive chemotherapy and/or chronic hepatitis and/or precore mutants viruses are involved. Although lamivudine seems to be effective in these cases, prophylactic use has not been clearly defined and must be evaluated.

Abscisic acid accumulation maintains maize primary root elongation at low water potentials by restricting ethylene production.

Previous work showed that primary root elongation in maize (Zea mays L.) seedlings at low water potentials (psi(w)) requires the accumulation of abscisic acid (ABA) (R.E. Sharp, Y. Wu, G.S. Voetberg, I.N. Saab, M.E. LeNoble [1994] J Exp Bot 45: 1743-1751). The objective of the present study was to determine whether the inhibition of elongation in ABA-deficient roots is attributable to ethylene. At a psi(w) of -1.6 MPa, inhibition of root elongation in dark-grown seedlings treated with fluridone to impose ABA deficiency was largely prevented with two inhibitors of ethylene synthesis (aminooxyacetic acid and aminoethoxyvinylglycine) and one inhibitor of ethylene action (silver thiosulfate). The fluridone treatment caused an increase in the rate of ethylene evolution from intact seedlings. This effect was completely prevented with aminooxyacetic acid and also when ABA was supplied at a concentration that restored the ABA content of the root elongation zone and the root elongation rate. Consistent results were obtained when ABA deficiency was imposed using the vp5 mutant. Both fluridone-treated and vp5 roots exhibited additional morphological symptoms of excess ethylene. The results demonstrate that an important role of ABA accumulation in the maintenance of root elongation at low psi(w) is to restrict ethylene production.

[Amifostine: current and future applications in cytoprotection]. / Amifostine: applications actuelles et perspectives en cytoprotection.

Originally developed against the effects of ionizing radiations, amifostine is an organic thiophosphate compound shown able to selectively protect normal tissues against cytotoxic agents in cellular and animal models, without protecting tumor tissues. Amifostine is a prodrug which is dephosphorylated into its active metabolite, a free thiol derivative, by membrane alkaline phosphatase of the target issue. This unique metabolism supports its cellular selectivity and its preferential uptake by normal tissues. In phase II clinical trials, a decreased toxicity has been demonstrated in patients given alkylating agents; however, reduction of the response has not been observed. On the basis of these results, a prospective, randomized, phase III study has been conducted in patients with ovarian carcinoma receiving a combination of cisplatinum and cyclophosphamide. A significant decrease in hematologic, renal and neurologic toxicity was observed in the amifostine-treated patients compared with the control group, and response rates did not significantly differ between the two groups. Insufficient or emerging data are only available for other applications, including either in vitro manipulation of hematopoietic grafts or in vivo treatment of non-Hodgkin's lymphoma, head and neck carcinoma, non-small cell lung cancer and radioprotection. No data are yet available in regard to the potential protective effects of amifostine against mutagenicity and cancerogenicity of both chemo- and radiotherapy.

Expression of elastase and fibrin in venous leg ulcer biopsies: a pilot study of pentoxifylline versus placebo.

The pathogenesis of venous leg ulcers is based on the leakage of fibrinogen leading to a pericapillary fibrin cuff and plugging of capillaries by white blood cells. On the basis of a previous work, we had assumed that the key event in the pathogenesis of venous leg ulcers is related to inflammation generated by activated white blood cells that accumulate under unrelieved blood pressure, because in ulcer biopsies we had detected the presence of tumor necrosis factor-alpha (TNF-alpha) in intracapillary monocytes, elastase in the polymorphonuclear leukocytes near the vessels, and a pericapillary undegraded fibrin cuff causing a diffusion barrier to oxygen. This concept was developed because TNF-alpha synthesized by activated monocytes is responsible for many deleterious effects. It has a potent mitogenic effect on fibroblasts, leading to new collagen deposition and angiogenesis, it induces an increase in collagenase production, it acts through upregulation of an intracellular adhesion molecule (ICAM-1), leading to leukocyte sequestration and consequently a release of toxic metabolites by the polymorphonuclear cells, an early step in chronic inflammation, it activates the coagulation pathway via a marked increase in monocyte-associated tissue factor (TF) procoagulant activity, and it inhibits fibrinolysis by promoting the release of PAI-1, contributing to undegraded fibrin deposition. Therefore, we were interested in evaluating, in patients with venous leg ulcers, the effect of pentoxifylline administered at 1,200 mg daily (versus placebo) for 2-months, as this drug induces a decrease in TNF-alpha synthesis and also blocks its activity. This pilot assay was performed in blind. Evolution of several parameters in ulcer biopsies are analyzed: TNF-alpha, intact fibrin, fibrin degradation products, ICAM-1, TF, and elastase. Pentoxifylline administration induced a decrease of local elastase and of fibrin deposit. These results support the hypothesis that accumulation of activated leukocytes is the key event in venous leg ulcers.

Effect of pentoxifylline on apoptosis of cultured cells.

Apoptosis or programmed cell death (PCD) was measured in two human cell models by flow cytometric analysis. Blood neutrophils underwent spontaneous apoptosis in short-term culture. Pentoxifylline (PTX) inhibited spontaneous neutrophil PCD. We confirmed that granulocyte/macrophage colony-stimulating factor (GM-CSF) inhibited apoptosis of polymorphonuclear neutrophils. Treatment with both GM-CSF and PTX did not increase the inhibition of PCD by either GM-CSF or PTX alone. Because apoptosis could be due to the accumulation of H2O2 in the culture medium, and because PTX has been described to reduce peroxide production, we studied the effect of adding catalase to the medium. Catalase reduced the neutrophil apoptosis and this effect was cumulative with the effect of PTX. Camptothecin, an inhibitor of topoisomerase I, induces a block in the S-phase of the cell cycle followed by apoptosis of the U937 cell line. This drug-induced apoptosis was partially inhibited by PTX, whereas the S-phase cell block was not affected. In conclusion, PTX was found to inhibit apoptosis in two different human cell types. In neutrophils, this effect appears to occur regardless of the inhibition of phosphodiesterase activity and inhibition of H2O2 release.

Production of proinflammatory cytokines and cytokines involved in the TH1/TH2 balance is modulated by pentoxifylline.

The modulation of cytokine release induced by pentoxifylline (PTX) has recently been demonstrated not to be restricted solely to tumor necrosis factor (TNF)-alpha. This prompted us to study the influence of PTX on a larger spectrum of cytokines with proinflammatory actions [TNF-alpha, interleukin-6, (IL)-6, IL-1 beta, IL-8] or with implied actions in the TH1 (IL-2, IFN-gamma)/TH2 (IL-10) balance. The IL-1RA was also explored. This work was performed using a whole-blood model in which cytokine production is measured after stimulation by lipopolysaccharide (LPS) (25 micrograms/ml) and phytohemagglutinin (PHA) (5 micrograms/ml) in 1:10 diluted whole blood. The stimulation test was performed in blood from healthy controls and from septic patients (without septic shock) in the presence or absence of PTX at 10(-6), 10(-5), 10(-4), or 10(-3) M. In controls and septic patients, at a 10(-4) M PTX concentration the production of IL-2 is strongly diminished (26-32% of the basal level), followed by diminution of IFN-gamma (30-40%). As expected, of the proinflammatory cytokines TNF was the most strongly suppressed (50% of baseline) followed by IL-1 (about 80% of basal production). Finally, IL-10 was also influenced by PTX (65% of baseline). At 10(-4) M, IL-1RA and IL-6 were unaffected by PTX. Taken altogether, our data demonstrate that PTX possesses a much broader spectrum of activity on cytokine production than was initially described, and it appears to be a potential and promising immunotherapeutic agent.

Inhibitors of phosphodiesterase (pentoxifylline, trequinsin) inhibit apical and subcellular matrix expression of tissue factor in cultured human endothelial cells.

Exposure of endothelial cells (ECs) to thrombin or cytokines leads to major changes in their biochemical properties, which confer procoagulant activities. Stimulated ECs express the procoagulant glycoprotein tissue factor (TF). Although some TF is expressed on the apical surface of the cells, most is deposited as a cryptic pool in the subendothelial matrix. This matrix-associated TF may play a role in thromboembolic complications associated with alterations in the integrity of the EC monolayer. We have measured TF activity on the surface and in the subcellular matrix of human saphenous vein ECs in culture, by assaying the TF-dependent formation of activated factor X in the presence of factor VII. The subcellular matrix was prepared by exposure of ECs to ammonium hydroxide. Incubation of ECs for 4 h with 1 U/ml human thrombin induced TF expression on the apical cell surface and in the matrix. Activity in the matrix was 4.1 +/- 0.5 times greater than on the cell surface. Pentoxifylline inhibited the expression of TF both on the cell surface and in the matrix. The EC50 was on the order of 3.9 mM in both cases. No signs of cell toxicity were observed at this concentration of pentoxifylline. Similar effects were obtained with trequinsin (HL 725), a phosphodiesterase inhibitor, with an EC50 of 40 microM. This suggests that an increase in cAMP may be involved in the mechanism of action of pentoxifylline. Inhibition of TF deposition in the matrix may be important in the prevention of thromboembolic episodes in conditions where ECs either retract or are removed by major injury.

Leukocyte activation study during occlusive arterial disease of the lower limb: effect of pentoxifylline infusion.

Granulocytes play a significant role in vascular diseases. The mechanisms of neutrophil-mediated vascular injury include their increased endothelial adhesion and activation with release of inflammatory mediators. Pentoxifylline (PTX) has a well-demonstrated ability to act on the activated neutrophils. It increases chemotaxis and decreases their adherence to endothelial cells, oxidative burst, and enzyme release. In this preliminary study, we investigated the effects of PTX on ischemia-induced changes in polymorphonuclear neutrophils (PMN) activation and cytokine release. A double-blind, randomized, placebo-controlled trial was carried out in 14 patients (age range 46-86 years) suffering from critical ischemia, as defined by the European Consensus Document, or subacute ischemia due to occlusive arterial disease of the lower limb. Femoral and antecubital venous blood samples on the side of the ischemic leg were obtained from patients immediately before (TO) and after infusion (T24) of PTX or placebo. PMN activation was evaluated by study of cell migration, beta 2 integrin expression (CD11b/ CD18), oxidative burst, and elastase release. Inflammation proteins were analyzed, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL-6), C-reactive protein (CRP), and fibrinogen. Before treatment, our results demonstrate an important activation in both femoral and antecubital venous blood. PMN activation markers, cytokine release, and other inflammation proteins were significantly increased compared with normal subjects. In the experimental group there was no significant difference between femoral and antecubital venous blood. Six patients received PTX infusion and seven patients were in the placebo group. The effect of PTX was evaluated after 24 h of treatment (1,200 mg). In the PTX group the following variables were improved compared with the placebo group: CD11b expression on PMNs, elastase released from PMNs, fibrinogen, CRP, TNF-alpha, and IL6 in plasma. These preliminary results should be interpreted with caution because of the small sample size. Further trials may contribute to more complete understanding.

Stimulatory effect of thyroid hormone on RA-induced granulocytic differentiation in leukemic cells.

Retinoic acid, vitamin D3, and dexamethasone are known inducers of myeloid leukemic cell differentiation. Recent evidence indicates that these drugs mediate their biological effects through binding to a nuclear receptor which belongs to the steroid/thyroid hormone receptor superfamily. This paper shows that the ligands of the other receptors of this family, estrogens, progesterone, androgens and thyroid hormone, do not induce leukemic cell differentiation. However, thyroid hormone potentiates, by one order of magnitude, the dose-response effect of retinoic acid in HL-60 cells.

[Comparison of the antiemetic effectiveness of high-dose corticosteroids with synacthene in nausea induced by chemotherapy: results of a randomized study]. / Comparaison de l'efficacité anti-émétique de corticoïdes à fortes doses à celle du synacthène lors de nausées induites par la chimiothérapie: résultats d'une étude randomisée.

One hundred two patients submitted to intensive chemotherapy were included in a randomized study with cross over comparing for the second course two anti-emetics: tetracosactide (D1: 3 mg, D2 and D3: 2 mg/d) and methylprednisolone (D1: 240 mg, D2 and D3: 160 mg/d). Most patients presented with malignant lymphoma. All patients experienced nausea and emesis during first course of chemotherapy. Results were similar in both groups, respectively for tetracosactide and methylprednisolone: no nausea 37 versus 40%, less than 3 emesis 69% versus 73%. Secondary effects were observed in 5 and 8% of cases. Tetracosactide with a schedule of 7 mg for 3 days gives the same results than methylprednisolone 560 mg for 3 days in chemotherapy induced nausea and emesis prevention.

Malignant acanthosis nigricans associated with non-Hodgkin's lymphoma. Report of 2 cases.

Two cases of malignant acanthosis nigricans associated with non-Hodgkin's lymphoma are presented. A 61-year-old negro male with a diffuse large cell non-Hodgkin's lymphoma presented extensive acanthosis nigricans, pachydermatoglyphy and florid cutaneous papillomatosis. No viral particles were observed by electron microscopic studies of the wart-like lesions. Acanthosis nigricans disappeared under chemotherapy. The second case was a 21-year-old caucasian male with non T non B diffuse large cell non-Hodgkin's lymphoma. Very few cases of acanthosis nigricans associated with non-Hodgkin's lymphoma have been reported in the literature, since to our knowledge these two are only the fourth and fifth. Pachydermatoglyphy and florid cutaneous papillomatosis are markers of malignant acanthosis nigricans.

[Therapy of acute leukemia in the adult. Role of anthracyclines]. / Traitement des leucémies aiguës de l'adulte. Place des anthracyclines.

Anthracyclines chemotherapy has changed the outcome of adult acute leukemia. Daunomycin, Adriamycin and Zorubicine are the three main analog derivatives. In adult ALL, in randomized study, anthracyclines in induction regimen improve significantly the remission rate up to 80%. In AML, combination chemotherapy of Ara-C and anthracyclines is the standard induction regimen. In randomized study, Daunomycin has the same activity than adriamycin at the same dose with less toxicity. Comparison of Daunomycin: 60 mg/m2 X 3 d with Zorubicin: 120 mg/m2 X 3 d shows the same activity in association with Ara-C with less toxicity. In protocol 01 AM 81, Zorubicin has been used at the dose of 200 mg/m2 X 4 d in association with Ara-C: 200 mg/m2 X 5 d. 444 patients has been included in the study. The complete remission rate is 83% with a mortality rate of 7% and only 11% failure. Zorubicin allows intensification of induction regimen with similar or less toxicity than conventionnal regimens.