Homeostatic chemokines increase survival of B-chronic lymphocytic leukemia cells through inactivation of transcription factor FOXO3a.

B-chronic lymphocytic leukemia (B-CLL) cell is characterized by the accumulation of long-lived CD5+ B lymphocytes, whose survival in vivo is in part dependent on exogenous factors such as cytokines and/or extracellular matrix proteins. Homeostatic chemokines are critical mediators of lymphoid cell trafficking. However, how they function in cell signaling and survival remains ill-defined. In this study, we have investigated the role of the homeostatic chemokines, CXCL12, CCL21, CCL19 and CXCL13, in B-CLL cell survival. Using primary leukemic cells isolated from 26 patients, we observed that each chemokine enhances cell survival. Chemokines induced the phosphorylation of ERK1/2 and p90RSK, and of Akt and its effectors GSK3 and FOXO3a. Consistently, inhibitors against mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase inhibited chemokine-induced survival. Moreover, using a constitutively active mutated form of FOXO3a or siRNAs against FOXO3a in transfection experiments performed in primary B-CLL cells, we directly demonstrated the critical role of FOXO3a in both spontaneous and chemokine-induced B-CLL cell survival. Overall, our data support the notion that homeostatic chemokines contribute to B-CLL resistance to cell death through inactivation of the transcription factor FOXO3a, which may represent a novel therapeutic target in this hematopoietic malignancy.

A survey of the signaling pathways involved in megakaryocytic differentiation of the human K562 leukemia cell line by molecular and c-DNA array analysis.

The K562 cell line serves as a model to study the molecular mechanisms associated with leukemia differentiation. We show here that cotreatment of K562 cells with PMA and low doses of SB202190 (SB), an inhibitor of the p38 MAPK pathway, induced a majority of cells to differentiate towards the megakaryocytic lineage. Electronic microscopy analysis showed that K562 cells treated with PMA+SB exhibited characteristic features of physiological megakaryocytic differentiation including the presence of vacuoles and demarcation membranes. Differentiation was also accompanied by a net increase in megakaryocytic markers and a reduction of erythroid markers, especially when both effectors were present. PMA effect was selectively mediated by new PKC isoforms. Differentiation of K562 cells by the combination of PMA and SB required Erk1/2 activation, a threshold of JNK activation and p38 MAPK inhibition. Interestingly, higher concentrations of SB, which drastically activated JNK, blocked megakaryocytic differentiation, and considerably increased cell death in the presence of PMA. c-DNA microarray membranes and PCR analysis allow us to identify a set of genes modulated during PMA-induced K562 cell differentiation. Several gene families identified in our screening, including ephrins receptors and some angiogenic factors, had never been reported so far to be regulated during megakaryocytic differentiation.

Adherence to HAART in French HIV-infected injecting drug users: the contribution of buprenorphine drug maintenance treatment. The Manif 2000 study group.

OBJECTIVES: To assess adherence to highly active antiretroviral therapies (HAART) in a cohort of French patients infected by HIV through injection drug use (IDU), and the impact on adherence of buprenorphine ambulatory drug maintenance treatment (DMT) which has been widely introduced since 1996. DESIGN: Adherence assessment at first visit after initiation of HAART in the MANIF2000 cohort study. METHODS: Patient's face-to-face and self-administered questionnaires. Univariate and logistic regression adjusted odds ratios (OR) to compare characteristics of non-adherent versus adherent patients. RESULTS: Of the 164 patients, 34.8% took less than 80% of the prescribed HAART doses during the previous week. Decrease in viral load titres after initiation of HAART was significantly lower among non-adherent patients. After adjustment by logistic regression, non-adherence was associated with younger age, alcohol consumption, frequency of negative life-events during the prior 6 months and active drug use. However, IDU in buprenorphine DMT reached higher levels of adherence (78.1%) than ex-IDU (65.5%), although this difference did not reach statistical significance. CONCLUSION: Prescription of buprenorphine DMT may increase adherence to HAART among HIV-infected opiate-dependent patients. Reducing the negative impact of stressful life-events through psychosocial interventions should be considered, even for those who have stopped using drugs.

Effect of indinavir and higher CD4+ T-cell count on viral load response after 6 months of highly active antiretroviral therapy.

This retrospective, unmasked chart review was undertaken to determine which HIV-infected patients receiving protease inhibitors (PIs) for the first time were most likely to experience a decrease in plasma viral load (PVL) and which factors were associated with a PVL < 500 copies/mL below the detectable limits after 6 months. A total of 308 patients aged > 15 years with a PVL > 500 copies/mL received therapy that included a PI in addition to other antiretroviral therapies (128 patients, saquinavir hard-gel capsule 600 mg TID; 107 patients, indinavir 800 mg TID; and 73 patients, ritonavir 600 mg BID). The choice of drug was at individual clinicians' discretion. Patients were followed for a median of 10 (range, 6 to 21) months. Of the 128 patients who received saquinavir, 45% were switched to another PI (33%, indinavir; 12%, ritonavir). Seventy percent of the 73 patients initially given ritonavir were switched (45%, indinavir; 25%, saquinavir), as were 23% of the 107 patients initially given indinavir (15%, saquinavir; 8%, ritonavir). A total of 34.1% (n = 105) of patients achieved a PVL < 500 copies/mL; in 51.6%, PVL decreased > 0.5 log copies/mL. In this subgroup, both treatment-naive patients and those who were receiving a new combination of antiretroviral therapy when they started PI treatment had a more pronounced decline in PVL (P < 0.001). After adjustment by logistic regression analysis for age, sex, mode of transmission, and duration of highly active antiretroviral therapy (HAART), CD4+ cell count and initial type of PI received were independently associated with PVL < 500 copies/mL. In the present study, the treatment success rate was low (34.1%) compared with rates observed in randomized, controlled trials. A higher CD4+ cell count and use of indinavir at the initiation of HAART are associated with a better viral load response.

Cutaneous T-cell lymphoma in association with a monoclonal gammopathy.

Monoclonal gammopathies and other abnormalities of immunoglobulin production may characterize or frequently be associated with B-cell lymphoproliferative disorders. We describe a patient with a T-cell cutaneous lymphoma, expressed clinically as Sézary's syndrome, in association with an immunoglobulin A type kappa M-component monoclonal gammopathy. No evidence for the coincident presence of a malignant plasma dyscrasia was found. This clinical association may lend clinical support to the concept that Sézary's syndrome is a T-helper-cell malignant proliferation. A colonic carcinoma was also present, possibly representing a second manifestation of a functionally abnormal cellular immune system.

Mycosis fungoides associated with Mediterranean lymphoma.

Mycosis fungoides was observed in a 71-year-old male with Mediterranean lymphoma, a B-cell malignancy. It is proposed that this association is not incidental since hypergammaglobulinaemia and even monoclonal gammopathies have repeatedly been described in cutaneous T-cell lymphomas. Mediterranean lymphoma might have resulted from (a) helper cell activities of tumor T-lymphocytes, (b) common antigenic stimuli, or (c) deranged T-B cooperation due to concomitant mycosis fungoides.

[Evaluation of the activities and value of allergo-anesthetic consultation at the University Hospital Center of Nice 1985-1991]. / Bilan d'activité et intérêt d'une consultation d'allergo-anesthésie au CHU de Nice de 1985 à 1991.

Life-threatening accident during anesthesia scarcely happen but the consequences may be dramatic. We report our experience of an allergo-anesthesia consultation created since 1985 in Nice hospital. 452 patients have been investigated: 1) 109 for life-threatening anaphylactic and anaphylactoid drug reactions. They have been investigated by: skin tests intradermal reactions (IDR) and prick tests with substances used during anesthesia (drugs and latex) and for all the muscle relaxants; the radioabsorbent test (RAST) for the muscles relaxants, propofol and latex; the human basophilic degranulation test (HBDT) for all the other drugs. We used the imputability decision table to classify the reactions. When anaphylaxis diagnosis was established (14) an "allergy card" was given to patients which identified the drugs to which they had a positive reaction. 62 patients have presented an anaphylaxis: 57 due to muscle relaxants (37 due to suxamethonium), 4 to latex and 1 to a gelatin. Patients were subsequently contacted and 50 of the 58 have responded. 18 of these patients have received 22 new anesthesias. Without exception, the advises to avoid a drug have been followed, 17 patients have a positive reaction to a muscle relaxant. In four of these, another muscle relaxant (skin test negative) was used without any trouble. For the other 13 who had shown a cross reactivity, all the muscle relaxants had been rejected and another anesthetic technique have been used: local anesthesia (3 cases), epidural (2 cases) associated or not with narcotics (propofol, midazolam), general anesthesia (propofol, midazolam, droperidol, phenoperidine). These drugs were all skin test negative.(ABSTRACT TRUNCATED AT 250 WORDS)

[Hemostasis anomalies and human immunodeficiency virus infection]. / Anomalies de l'hémostase et infection par le virus de l'immunodéficience humaine.

Because hemostasis disorder in HIV infected patients are frequent and have clinical effects, they have aroused the interest of internal medicine. Such anomalies are not yet clearly defined and include various parameters. Thrombocytopenia which is the most widespread and the best documented manifestation, whether of peripheral origin by immunological platelet destruction or of central origin by a shortage in platelet production, responds well to medical treatment, especially to zidovudine. The circulating anti-coagulants frequently observed in HIV infected patients, whether anti-phospholipid antibodies or anti-cardiolipines are mostly asymptomatic. Other coagulation disorders (affection of the inhibitory system or fibrinolysis) are rarely observed and generally have no clinical incidence. Apart from thrombocytopenias and thrombotic thrombocytopenic purpura the incidence of clinical signs (thrombotic or hemorrhagic accidents) in HIV infected patients is not higher than in an HIV-free population and respond to the same treatment.

[Kaposi disease and sex hormones: apropos of a case, review of the literature]. / Maladie de Kaposi et hormones sexuelles: à propos d'une observation, revue de la littérature.

The authors report one case of AIDS-related-like Kaposi's sarcoma (KS) in a 59-year-old bisexual man without HIV-1 and HIV-2 infection. KS developed while the patient was receiving both androgen and steroid therapy for aplastic anemia, and regressed after their simultaneous interruption, despite the persistence of aplastic anemia. The authors discuss the etiology of KS in the patient, with a special regard to a putative role of the androgen therapy. The authors examine the arguments of the literature, probably underestimated, that may suggest a role of sex hormones in the pathogenesis of KS.

[Systemic complications of beta-blocking eyedrops. Apropos of 6 cases]. / Accidents systémiques des bêta-bloquants en collyres. A propos de six observations.

Six cases of systemic reactions to topical treatment with beta-blocking eyedrops are reported, bradycardia and faintness due to an overdosage of ophthalmic timolol; decompensated heart failure one month after the prescription of carteolol eyedrops: bronchospasm after two weeks of treatment with metipranolol eyedrops; crippling Raynaud's phenomenon of otherwise unknown origin, which had begun with timolol eyedrops, continued with carteolol eyedrops and regressed after discontinuation of ophthalmic beta-blockers; aggravation of an anaphylactoid shock in a patient treated with ophthalmic timolol, and myocardial infarction possibly due to the abrupt withdrawal of timolol eyedrops. It cannot be overstressed that the rules governing the prescription of oral beta-blockers also apply to ophthalmic preparations of these drugs: respect of contra-indications, strict adherence to the dosage recommended, gradual drug withdrawal and regular supervision. Only controlled studies and long-term follow-up will be able to demonstrate differences in safety between the five beta-blockers commercialized as eyedrops in this country.

[Human immunodeficiency virus (HIV), thrombopenia and pregnancy]. / Virus de l'immunodéficience humaine (V.I.H.), thrombopénie et grossesse.

Three cases of thrombocytopenia in pregnant women are described. Two of these patients had an AIDS-like illness and the third one had AIDS. This HIV-associated change occurred in 8% of the complications of a consecutive series of 38 pregnant women who were positive for the HIV antibody test in the course of one year. A link with HIV was established after eliminating idiopathic pregnancy thrombocytopenic purpura and after eliminating every other viral cause for the thrombocytopenia. The normal myelogram speaks in favour of a peripheral origin for the platelet destruction. Treatment consisted in administering immunoglobulins intravenously in a continuous transfusion in doses of 0.04 g/kg per day. The method was effective in two cases. Three cesareans were carried out. In two cases the recovery was uncomplicated and in the third case the haemorrhagic syndrome developed immediately after delivery. This patient died 35 days after delivery. Fetal scalp blood or fetal cord blood could not be taken in any of these three cases. The newborn did not have thrombocytopenia at birth, but they did have anti-IVF antibodies and one of them developed and AIDS-like syndrome. The time interval has not been long enough to assess the further development in the two other cases. The survivors are being followed up with a threefold assessment of the blood picture, the immunological state and the virology. This is being done on the two surviving mothers and the three infants.

[Disseminated Penicillium marneffei infection suggesting visceral leishmaniasis in an HIV infected patient]. / Infection à Penicillium marneffei évoquant une leishmaniose viscérale chez un patient infecté par le VIH.

BACKGROUND: Penicilliosis is a fungal infection caused by Penicillium marneffei. In Southeast Asia, this infection is common in HIV-infected patients but few cases have been reported in Europe. CASE REPORT: The patient lived in southern France. He had HIV infection and was immunocompromised. The clinical signs suggested visceral leishmaniasis. Iterative travels to Southeast Asia were reported leading to the diagnosis of P. marneffei infection. DISCUSSION: In southern France, imported penicilliosis marneffei may be misdiagnosed as visceral leishmaniasis.

[Observance during clinical trials in HIV infection. A discontinuity between patient history and trial logic]. / L'observance au cours des essais thérapeutiques dans l'infection à VIH. Une discontinuité entre l'histoire des patients et la logique des essais.

OBJECTIVES: Describe and analyze the processes which lead to patient compliance or non-compliance in HIV treatment trials and to develop a model for strategies aimed at improving compliance and facilitating inclusion (adherence) of these patients. METHOD: First, 12 members of the health care teams at two day care clinics (Internal medicine unit, Sainte-Marguerite Hospital, Marseille and Hematology unit, Cimiez Hospital, Nice) were interviewed. In addition, 40 patients involved in the Delta trial (known compliance in 22, non compliance in 7, trial refusal in 7 and eligibility in 5 who were not invited to participate) responded in semi-directive discussions. RESULTS: The physicians found that the responses were a priori in agreement with patient compliance for those who had participated. Physicians tended to introduce "unofficial" criteria to select patients on the basis of "psychosociological" patterns. Patient agreement to begin the trial or to refuse inclusion and their compliance to medical prescriptions depended in part on their personal opinion concerning AIDS treatment. Patients who presevered in following medical prescriptions in the long-term trial adapted their lifestyle to the new care system (participation in the trial) and discussed their "adaptation" with the physician. The importance of the patient-physician relationship is of prime importance in the behavior of compliant patients. CONCLUSION: A communication strategy, reinforcing patient adherence at inclusion and favoring compliance during the trial should be part of the "basic rules" for controlled regulation of compliance in clinical trials.

[Causes of hospitalization and death in the MANIF 2000 cohort, composed of HIV-infected patients contaminated by intravenous drug use, 1995-1999]. / Motifs d'hospitalisation et mortalité dans la cohorte MANIF 2000, composée de sujets infectés par le VIH et contaminés par usage de drogues en intraveineux, 1995-1999.

OBJECTIVE: To describe the causes of hospitalization and mortality among the MANIF 2000 cohort study, composed of HIV-infected patients contaminated through intravenous drug use. METHOD: Data collection with a standardized questionnaires with clinical, biological, therapeutic and psycho-sociologic data on inclusion and every six months. Dates and causes of hospitalization and death were collected retrospectively by nurses from the hospital clinical records. Comparison were made using the chi(2) or Mann-Whitney tests with 5% significance threshold. RESULTS: The MANIF 2000 cohort study included, between October 1995 and June 1998, 467 patients with a median age of 33 years, 30% of whom were women. On inclusion, 42.2% were still injecting drugs (half of them were on substitution therapy), 10.5% had stopped injections of drugs, 32% exhibited more than 500CD4/mm(3) and 55.7% had not taken antiretroviral treatment. As of December 31(st) 1999, 21 patients had died, i.e. a mortality rate of 19% persons/years of follow-up (10-fold greater than that expected in the general population). Less than 5 deaths were due to HIV (n=4). Suicides and liver disease each represented the same number of deaths. Out of the 335 patients not having missed more than one follow-up throughout the 24 month period, 120 had been hospitalized at least once (n=223 hospitalizations), i.e., a hospitalization rate of 2.8 per 100 persons/month of follow-up. A quarter of hospitalizations were due to benign infections or stage B or C pathologies according to the 1993 classification of HIV infections and one hospitalization out of 5 was due to psychiatric problems (in majority depressive syndromes). Other predominant causes were worsening of general state of health, trauma, problems related to alcohol consumption, drugs abuse or hepatic decompensation. CONCLUSION: HIV-infected patients contaminated by intravenous drug use represent a particular population that cumulates many risk factors and which requires careful monitoring of co-morbidities such as hepatic and psychiatric diseases in order to avoid premature death.

[Hospital medical students: a population at risk for accidental exposure to blood]. / Les étudiants hospitaliers: une population à risque d'accidents d'exposition au sang (AES).

OBJECTIVE: Infections transmitted by blood such as viral hepatitis B and C or human immunodeficiency virus (HIV) are a true threat to health care workers. As medical students are exposed to accidental contamination during their hospital activities, we conducted a survey among medical students in Nice France to determine the frequency and circumstances of needle prick accidents and how the risk of blood exposure is managed. METHODS: A survey was conducted between December 1 and December 15, 1996 among second cycle medical students. An anonymous questionnaire was proposed to all students attending mandatory faculty classes. A blood-exposure accident was defined as a needle prick or a cut caused by another sharp object which occurred in the hospital. RESULTS: Among the 237 students enrolled in the classes, 200 (84%) responded to the survey. Among these, one-quarter had experienced a blood-exposure accident by needle prick. For students terminating their second cycle, this rate was 37%. In 58% of the cases, the accidents had occurred when the students were on duty (excepting hospital training courses). Blood drawing for gas measurements was the most frequent circumstance (44%). Only 39% of the students had declared the accident and 51% had had a serology control within 2 months. The serological status of the source patient was unknown to the students in nearly half the cases. Only one out of two students applied elementary safety measures systematically (gloves, not recapping the needle). Only 13% of the students stated they had received information about blood-exposure accidents and their prevention and less than 50% had a correct notion of the risk of hepatitis B and C and HIV transmission by needle pricks. CONCLUSION: The incidence of blood-exposure accidents in hospital medical students is high and probably underestimated by official statistics due to the low declaration rate. Measures should rapidly implemented to inform and train students on prevention. Our units are currently working with students, the medical faculty and the occupational medicine unit to reach these objectives.

[Visceral leishmaniasis associated with Wegener disease. Use of lipid complex amphotericin B and liposomal amphotericin B]. / Leishmaniose viscérale associée à une maladie de Wegener. Utilisation de l'amphotéricine B en complexes lipidiques et de l'amphotéricine B liposomale.

BACKGROUND: Leishmaniasis in a patient with Wegenerís disease raises the problem of amphotericin toxicity further compromising the pre-existing renal disorder. CASE REPORT: An anemic patient treated for Wegenerís disease developed visceral leishmaniasis. This renal failure patient was treated with lipid complex amphotericin B and liposomal amphotericin B. We report outcome at 10 months follow-up. DISCUSSION: The new formulations of amphotericin B allow effective treatment of visceral leishmaniasis in renal failure patients. Long-lasting results are probably favored by the interruption of immuno-suppressive therapy.

[Bacillary epithelioid angiomatosis in AIDS. Two cases]. / Angiomatose épithélioïde bacillaire au cours du SIDA. Deux observations.

Bacillary angiomatosis is a newly recognized multisystem opportunistic infection seen in the human immunodeficiency virus infection. The disease is marked by papular and nodular vascular skin lesions that clinically resemble Kaposi's sarcoma. Histologically, the lesions are different and show clusters of bacteria showing the structure of Gram negative bacilli staining with Warthin-Starry stain. Transmission electron microscopy shows that the organisms (1 to 2 microns) have a trilamellar wall structure. Treatment with oral erythromycin (2 to 3 g a day) for 2 to 4 weeks rapidly leads to resolution.

[Prolonged survival in multiple myeloma. Characteristics of presentation and response to treatment of 73 patients who survived 5 years or longer]. / Survie prolongée au cours du myélome multiple. Caractéristiques de présentation et de réponse au traitement de 73 malades ayant vécu 5 ans ou plus.

Data concerning the presentation and response to treatment of 73 patients with multiple myeloma who survived for 5 years or more were reviewed. At the time of diagnosis, the proportion of patients with hypercalcaemia (4%), severe anaemia (9%), renal failure (10%) or high beta 2-microglobulin levels (25%) was low. Less than one-third of our patients belonged to a "high risk" group, as defined by the three classification systems adopted: the lowest percentage of such patients (18%) was observed with the Medical Research Council classification. In all patients, but even more in those with an initially aggressive disease (P less than 0.05), obtaining a plateau (70% of the cases) or even an optimal tumoral regression with complete disappearance of monoclonal immunoglobulin (26% of the cases) seems to be a highly favourable factor. The same applies, though to a lesser degree, to slow response to chemotherapy (18 months on average). In all responders whether the remission was maintained or not by chemotherapy seemed to have no influence on the frequency (70%) and delay of relapses (4 1/2 years on average from the time of diagnosis). The risk of secondary blood disease (2 AML 1, 1 AML4, 1 RAEB, 1 ASIA, four of which were directly responsible for death) after 4 years on average of chemotherapy must be taken into consideration.

Total genomic alteration as measured by SNP-array-based molecular karyotyping is predictive of overall survival in a cohort of MDS or AML patients treated with azacitidine.

Metaphase cytogenetics (MC) has a major role in the risk stratification of patients with myelodysplastic syndromes (MDSs) and can affect the choice of therapies. Azacitidine (AZA) has changed the outcome of patients with MDS or acute myeloid leukemia (AML) unfit for intensive chemotherapy. Identification of patients without the benefit of AZA would allow AZA combination or other drugs in first-line treatments. New whole-genome scanning technologies such as single nucleotide polymorphism microarray (SNP-A)-based molecular karyotyping (MK) improve the risk stratification in MDS and AML. Maintenance of genomic integrity is less than three megabases (Mbs) total disruption of the genome correlated with better overall survival (OS) in patients with lower-risk MDS. In this SNP-A study, we aimed at defining a cutoff value for total genomic copy number (CN) alterations (TGA) influencing the median OS in a cohort of 51 higher-risk MDS/AML patients treated with AZA. We observed that the relative risk of worse OS increased >100 Mb of TGA, as detected by SNP-A-based MK (8 and 15 months respectively, P=0.02). Our data suggest that precise measurement of TGA could provide predictive information in poor and very poor revised International Prognostic Scoring system (IPSS-R) patients treated with AZA.