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Biomedical subjects

D Zucman

Publications and source records attributed to D Zucman.

16 recordsLinked to original sources
PubMed2005

Pulmonary manifestations of multicentric Castleman's disease in HIV infection: a clinical, biological and radiological study.

The aim of the present study was to report clinical, radiological and bronchoalveolar lavage (BAL) findings in patients with pulmonary manifestations of HIV-associated multicentric Castleman's disease (MCD). This was a retrospective study of 12 patients with histologically proven MCD. Clinical manifestations were as follows: dyspnoea (nine out of 12 cases), cough (n = 10), bilateral crackles (n = 10), together with high fever, malaise, peripheral lymphadenopathy (n = 12), and hepatosplenomegaly (n = 10). Two patients developed acute respiratory distress syndrome. Chest radiographs and computed tomography scans showed reticular (n = 7) and/or nodular (n = 7) interstitial patterns, with mediastinal lymphadenopathy (n = 9), and bilateral pleural effusion (n = 3). Fibreoptic endoscopy was normal in all cases. BAL analysis showed hypercellularity (n = 6) and/or lymphocytosis (n = 6), and human herpesvirus-8 DNA was detected in two out of two cases. Specific stains and cultures for pathogens were negative. All patients received etoposide and/or vinblastine, and improved after 2-4 days. Relapses were frequent (50 attacks in 12 patients). Six patients developed a non-Hodgkin's lymphoma, and five died. In conclusion, the pulmonary manifestation of HIV-related multicentric Castleman's disease is an acute reticulo-nodular interstitial pneumonitis, associated with severe systemic symptoms and peripheral lymphadenopathy. In bronchoalveolar lavage fluid, cellularity is not specific and human herpesvirus-8 DNA is detected. The clinical course is specific due to a rapid onset and regression, frequent relapses and a high occurrence of non-Hodgkin's lymphoma.

Adult↗
PubMed2003

[HHV 8 positive Castleman's disease and auto-immune neutropenia in 2 HIV-infected patients].

INTRODUCTION: Castleman's disease (CD) is a polyclonal lymphoplasmacytic and vascular proliferation prominent in lymphoid tissues, associated to Human Herpesvirus 8 (HHV-8) in Human Immunodeficiency Virus (HIV)-infected patients. The presence of autoimmune stigmates is frequent. EXEGESIS: We report two cases of neutropenia secondary to IgG neutrophil autoantibodies, indeterminate specificity, occurring in two HIV-infected patients with CD HHV-8+, treated by vinblastine since several years. The neutropenia was associated to other biologic stigmates of autoimmunity and the evolution has been complicated by several infections. Granulocyte-colony stimulating factor (G-CSF) and polyvalent immunoglobulin permitted a transient and low increase of neutrophila in one case. CONCLUSION: Auto-immune neutropenia in CD is rare and difficult to treat in our cases. This evolution is independent of relapse of CD. The immunoglobulin and G-CSF may be transitory effective.

Antineoplastic Agents, Phytogenic↗
PubMed2002

[Castleman's disease in patients infected with HIV].

PURPOSE: Castleman's disease is a polyclonal lymphoplasmacytic and vascular proliferation prominant in lymphoid tissues. It is associated with lymph node enlargement, hepatosplenomegaly and fever. This manifestations could be secondary to hyperproduction of interleukin 6. The prognosis is poor. The opportunistic infections which are characteristic of severe HIV infection worsen the prognosis. Prolonged monochemotherapy with vinblastine or etoposide can control Castleman's disease. CURRENT KNOWLEDGE AND KEY POINTS: Recent advances in human herpesvirus 8 (HHV8) knowledge and its predominance in the forms which are linked to the HIV seropositivity have partly explained the clinical manifestations of Castleman's disease. Indeed, HHV8 produce an homologous interleukin 6, the vIL-6, responsible for lymphoplasmacytic proliferation. The presence of other homologues of human cytokines produced by HHV8 could contribute to lymphoplasmacytosis and to endothelial proliferation. FUTURE AND PROSPECTS: Taking into account this viral origin, alpha interferon could be an alternative in forms which are less progressive. However, antiviral therapy against HHV8 or HIV and the immunitary restoration do not have any influence on the evolution of Castleman's disease, contrary to opportunistic infections.

Castleman Disease↗
PubMed2001

Treatment intensification with abacavir in HIV-infected patients with at least 12 weeks previous lamivudine/zidovudine treatment.

OBJECTIVES: To demonstrate that lamivudine and zidovudine, given separately (lamivudine/zidovudine) or as a single combination tablet (Combivir), had equivalent efficacy. To evaluate the safety and antiretroviral activity of intensification with abacavir in patients treated with lamivudine/zidovudine for > or = 12 weeks. DESIGN: A 12-week, equivalence study of lamivudine/ zidovudine versus Combivir. Patients who completed this study could enter a 48-week, intensification study of Combivir plus abacavir. METHODS: In the equivalence study, treatment-naive patients were assessed for HIV-1 RNA, CD4 cell count and genotype. The same assessments plus phenotype were made in the intensification study. Serious adverse events were recorded in the equivalence study and all adverse events in the intensification study. RESULTS: Lamivudine/zidovudine (n=40) and Combivir (n=35) gave equivalent reductions in plasma HIV-1 RNA levels at week 12. An identical proportion of patients (74%) in each treatment group harboured virus with the M184V mutation after 12 weeks. Fifty-two patients entered the intensification study and 44 completed 48 weeks of treatment. At the time of intensification with abacavir, all 35 patients with evaluable isolates harboured HIV-1 containing M184V. Addition of abacavir to Combivir led to further decreases in plasma HIV-1 RNA and increases in CD4 cell counts compared with the start of intensification (P<0.001 at week 48). After 48 weeks of triple therapy, multi-nucleoside resistance mutations at codons 69 and 151 were not detected in any patients. All treatment regimens were generally well tolerated. CONCLUSION: Lamivudine/zidovudine and Combivir have equivalent antiretroviral activity over 12 weeks. Adding abacavir to Combivir can be a safe and effective therapeutic option for patients, including those harbouring virus with the M184V mutation.

Administration, Oral↗
PubMed2000

Long-term efficacy on Kaposi's sarcoma of highly active antiretroviral therapy in a cohort of HIV-positive patients. CISIH 92. Centre d'information et de soins de l'immunodéficience humaine.

OBJECTIVE: To assess the efficacy of highly active antiretroviral treatment (HAART) on AIDS-Kaposi's sarcoma (KS). DESIGN: Prospective cohort of patients followed for 24 months. SETTING: Four referral hospitals of the West Paris metropolitan area. PATIENTS/INTERVENTION: Thirty-nine AIDS-KS patients, 42 +/- 9 years old, who began HAART (HIV-protease inhibitor and two nucleoside analogues) between March and December 1996, were enrolled. One was lost to follow-up at month 12. MAIN OUTCOME MEASURES: KS response, using criteria of the AIDS clinical trials group (ACTG), CD4 cell counts, and plasma HIV-RNA, assessed every 6 months. ACTG TIS staging of KS. RESULTS: Eighteen patients had T1 KS and 21 T0 KS. One patient died from KS at month 6. KS improved progressively, with complete and partial response rates of 46% and 28% at month 24, respectively. Only six patients were still receiving systemic KS therapy at month 24. Complete response was observed in 10 of the 19 patients without systemic KS therapy at inclusion. Patients with complete response at month 24 had higher CD4 cell counts than others (465 +/- 343 versus 185 +/- 167 x 10(6)/l; P < 0.01), but the proportion of patients with HIV-1 RNA < 500 copies/ml was not significantly different. An increase in CD4 cell counts from inclusion to month 12 of > 150 x 10(6)/l [odds ratio (OR), 13.4; 95% confidence interval (CI), 2-82] and T0 KS at inclusion: [OR, 7; 95% CI, 1.1-42] were predictive of complete response at month 24. CONCLUSIONS: HAART appears to have prolonged efficacy on AIDS-KS, even without specific KS therapy, and this effect appears to be linked to the restoration of immune function.

AIDS-Related Opportunistic Infections↗
PubMed2000

The VIRGO study: nevirapine, didanosine and stavudine combination therapy in antiretroviral-naive HIV-1-infected adults.

The virological and immunological efficacy of the triple regimen containing nevirapine (once or twice daily), didanosine (once daily) and stavudine, in antiretroviral-naive patients infected with HIV-1, was evaluated in an open-label, prospective, non-randomized, multi-centre, 52-week study. The first 60 patients (VIRGO I) received nevirapine as the standard dose, 200 mg twice daily; the subsequent 40 patients (VIRGO II) received nevirapine at a dose of 400 mg once daily. All patients received 400 mg of didanosine once daily and 40 mg of stavudine twice daily, adjusted for body weight. At baseline, the median CD4 cell count and plasma viral load (pVL) were 414 cells/mm3 and 4.59 log10 copies/ml in VIRGO I, and 412 cells/mm3 and 4.87 log10 copies/ml in VIRGO II. Using an intent-to-treat, 'non-completer equals failure', analysis, 78% (95% CI, 68-88%) of patients in VIRGO I and 68% (95% CI, 53-83%) of those in VIRGO II had a pVL <500 copies/ml at 24 weeks; the proportions achieving a pVL of <50 copies/ml were 62% (95% CI, 50-74%) and 50% (95% CI, 35-65%), respectively. The week 24 median CD4 cell count increase was 168 cells/mm3 (VIRGO I) and 139 cells/mm3 (VIRGO II). At week 52, 39/45 (87%) of VIRGO I patients had pVL <500 copies/ml and 30/45 (67%) <50 copies/ml. Of the 100 patients, 44 experienced grade 2 to 4 adverse events; 20 permanently discontinued study medication because of an adverse event. Combination therapy with the three reverse transcriptase (RT) inhibitors stavudine, once-daily didanosine and either once- or twice-daily nevirapine could be considered as an alternative option for first-line antiretroviral therapy.

Adult↗
PubMed1999

Interpretation of high levels of HIV-1 RNA in the cerebrospinal fluid (CSF) using amplicor HIV-1 monitor test.

A retrospective study of 19 cerebrospinal fluid (CSF) specimens from 14 HIV-positive subjects with subacute encephalopathy, neuropathy, or unexplained peripheral myelopathy was done comparatively with plasma specimens collected on the same day and tested in the same run as the corresponding CSF specimen. A single patient had a high HIV RNA level in CSF as compared to plasma (CSF/plasma ratio > 10), which seemed correlated with the clinical course. Further studies are needed to confirm that a high CSF/plasma HIV RNA ratio is associated with greater symptom severity.

HIV Infections↗
PubMed1999

Stavudine, didanosine and nevirapine in antiretroviral-naive HIV-1-infected patients.

In an ongoing, open-label, non-comparative study, the safety and efficacy of nevirapine/stavudine/didanosine were evaluated in 100 antiretroviral-naive adults with CD4 cell counts > or = 200 cells/mm3 and plasma HIV-1 RNA (pVL) > or = 5000 copies/ml. Sixty patients received nevirapine twice daily (VIRGO I) and 40 received nevirapine once daily (VIRGO II); all patients received didanosine once a day. After median follow-ups of 44 weeks in VIRGO I and 30 weeks in VIRGO II, the following virological results were observed (ongoing study): an intent-to-treat, non-completer equals failure analysis at week 24 showed the proportions of patients with pVL <500 copies/ml were 78% in VIRGO I (60% <50 copies/ml) and 75% in VIRGO II. An on-treatment analysis at week 52 showed 80% of patients with a pVL <500 copies/ml and 59% with <50 copies/ml in VIRGO I. The mean CD4 cell count increase was +171 cells/mm3 at week 24 and +218 cells/mm3 at week 52 in VIRGO I and +158 cells/mm3 at week 24 in VIRGO II. Cutaneous rash (grades 1 to 3) occurred in 24% of patients leading to nevirapine discontinuation in eight of 24 patients. Five other patients discontinued therapy during the first 24 weeks because of hepatic cytolysis, peripheral neuropathy or biological pancreatitis. The nevirapine/stavudine/didanosine combination is a convenient and safe regimen, with rapid and potent immunological and antiviral effects sustained over 12 months.

Anti-HIV Agents↗
PubMed1996

[Double kidney-total pancreas transplantation with bladder reimplantation. 25 cases].

Twenty five double kidney-pancreas transplantations were performed according to the total pancreas transplantation technique with drainage of exocrine secretions into the bladder via a vesicoduodenostomy. 72% of kidney-pancreas grafts were functional at one year and 59% were functional at four years. The authors observed a slightly higher rejection rate (0.56 versus 0.34) and a higher incidence of urinary tract infection (60% versus 35%) following double pancreas and renal transplantation than after isolated renal transplantation. Complications were rare: two venous thromboses and two cases of urethritis requiring of rediversion of the duodenum into the intestine. These good results, comparable to those reported in the international registry, reflect the value of the pancreatic and renal transplantation technique using a total pancreas drained into the bladder. It would probably be preferable to transplant patients earlier, when chronic renal failure secondary to insulin-dependent diabetes induces end-stage renal failure and the need for haemodialysis.

Adolescent↗
PubMed1995

Pentamidine-induced derangements of glucose homeostasis. Determinant roles of renal failure and drug accumulation. A study of 128 patients.

OBJECTIVE: To assess the prevalence, presentation, and risk factors of pentamidine-induced dysglycemia. RESEARCH DESIGN AND METHODS: Blood glucose values were screened in 244 consecutive immunocompromised patients with Pneumocystis carinii pneumonia: 116 being treated with cotrimoxazole and 128 others with pentamidine. RESULTS: Two cotrimoxazole patients developed diabetes as a result of necrotizing pancreatitis (1.7%); the others remained euglycemic. Forty-eight pentamidine-treated patients (38.5%) developed severe glucose homeostasis disorders: hypoglycemia in 7, hypoglycemia and then diabetes in 18, and diabetes alone in 23 (P < 0.001 vs. the cotrimoxazole group). Hypoglycemia was early, sudden, often recurrent, and life-threatening, associated with inappropriately high insulin levels in plasma; the B-cell response to stimuli was poor. Of the 41 diabetic patients, 26 required insulin therapy; their plasma C-peptide levels were lower than normal, and the B-cell secretory responses to stimuli were poor. Islet cell antibodies, insulin antibodies, and insulitis were not detected. The pentamidine-treated dysglycemic patients differed from their euglycemic counterparts by higher pentamidine doses (P < 0.001), higher plasma creatinine levels (P < 0.001), and more severe anoxia (P < 0.05) and shock (P < 0.001). Most of them had received pentamidine mesylate parenterally (n = 36; 75%); six others received the isethionate salt and six exclusively pentamidine aerosols. CONCLUSIONS: Pentamidine-induced dysglycemic accidents are primarily due to inappropriate insulin release and toxicity to the islet B-cells. Drug accumulation due to excessive doses, iterative courses, and/or renal impairment is the determining risk factor.

AIDS-Related Opportunistic Infections↗
PubMed1991

Neurosteroids: biosynthesis, metabolism and function of pregnenolone and dehydroepiandrosterone in the brain.

Pregnenolone (P) and dehydroepiandrosterone (D) accumulate in the brain as unconjugated steroids and their sulfate (S) and fatty acid (L) esters. The microsomal acyl-transferase activity is highest in immature (1-3 weeks old) male rats. The immunocytochemical and biochemical evidence for P biosynthesis by differentiated oligodendrocytes is reviewed. The importance of P synthesis for its brain accumulation is assessed by the intracysternal injection of the inhibitor aminoglutethimide. Primary glial cell cultures convert P to 20-OH-P, PL, progesterone, 5 alpha-pregnane-3,20-dione and 3 alpha-hydroxy-5 alpha-pregnane-20-one (Polone). Astroglial cell cultures also produce these metabolites, whereas neurons from 17-day mouse embryos only form 20-OH-P. P and D are converted to the corresponding 7 alpha-hydroxylated metabolites by a very active P-450 enzyme from rat brain microsomes. Several functions of neurosteroids are documented. P decreases in olfactory bulb of intact male rats exposed to the scent of estrous females. D inhibits the aggressive behavior of castrated male mice towards lactating female intruders. The D analog 3 beta-methyl-androst-5-en-17-one, which cannot be metabolized into sex steroids and is not demonstrably androgenic or estrogenic is at least as efficient as D. Both compounds elicit a marked decrease of PS in rat brain. The Cl- conductance of gamma-aminobutyric (GABAA) receptor is stimulated by GABA agonists, an effect which is enhanced by Polone and antagonized by PS. Thus, P metabolites in brain as well as steroids of extraencephalic sources may be involved physiologically in GABAA receptor function. The neurosteroids accumulated in brain may be precursors of sex steroid hormones and progesterone receptors have been localized in glial cells. P and D do not bind to any known intracellular receptor. A heat stable P binding protein has been found in brain cytosol with distinct ligand specificity. A binding component specific for steroids sulfates, including Polone S, DS and PS, in the order of decreasing affinity is localized in adult rat brain synaptosomal membranes. Its relationship to the GABAA receptor is under current investigation.

Animals↗
PubMedDate not supplied

AIDS-related Kaposi's sarcoma patients with visceral manifestations. Response to human chorionic gonadotropin preparations.

OBJECTIVE: In vitro cell culture studies and a murine model for human Kaposi's sarcoma (KS) have shown that human chorionic gonadotropin (hCG)-associated factor (HAF) isolated from commercial hCG preparations has antiproliferative and cell killing effects on neoplastic KS cells, without toxic effects on normal endothelial cells and lymphocytes. These findings prompted preliminary study of hCG preparations for patients with early-stage KS with skin lesions only and no known visceral involvement. Complete or partial regression of the skin lesions occurred after intralesional injections of hCG (hCG-Pregnyl, hCG-APL). The current study sought to extend these early observations to evaluation of the safety of hCG in acquired immunodeficiency syndrome (AIDS) KS patients with aggressive disease and visceral involvement. These patients present in a more advanced stage of the disease that is coupled with serious immunodeficiency. They commonly respond poorly to conventional chemotherapy and have a reduced median life expectancy of only 4 to 9 months. STUDY DESIGN/METHODS: After approval by the local institutional review boards, 13 patients with advanced AIDS-KS gave informed consent and were treated with hCG preparations. These hCG preparations are known to have antiproliferative activity in laboratory tests. Patients were monitored for tumor size by clinical evaluation, ultrasonography, radiography, respiratory functions, and endoscopic examination. Histologic examinations of biopsied tissues were used for studies of apoptosis using in situ hybridization techniques. The patients were also monitored for CD4+ T-cell numbers and human immunodeficiency virus type 1 (HIV-1) plasma viral load according to common clinical practice. RESULTS: Thirteen patients with advanced AIDS-KS and visceral KS were treated with hCG. Five of 13 (38%) patients had dramatic responses to therapy, and overall tolerance to the drug was excellent for all patients. Some hCG preparations also showed beneficial effects against HIV-associated markers. An accompanying decrease in viral load (plasma HIV-1 RNA) was observed in one patient, a dramatic increase in CD4+ cells occurred in another, and significant weight gain was seen in seven patients. CONCLUSIONS: These clinical observations suggest that patients with aggressive visceral forms of KS, usually indicative of an extremely poor prognosis and poor response to combined chemotherapy, can benefit from this new therapeutic approach. In some patients, these preparations also induce several other beneficial effects, such as weight gain, reduction in HIV-1 RNA load, or increase in the CD4+ T-cell count. Additional controlled clinical trials comparing this new therapeutic option with standard cytotoxic chemotherapy are needed. These trials should be extended to patients with KS not related to HIV-1 infection. Because we showed elsewhere that pure hCG had no effect on KS, identification and subsequent clinical use of the active molecules in hCG preparations is urgently needed.

AIDS-Related Opportunistic Infections↗