[Paradigm shift of German medicine by introduction of nurse practicioners. Does it make sense in view of experience in the United Kingdom?]. / Paradigmenwechsel in der deutschen Medizin durch die Substitution ärztlicher Leistungen. Sinn oder Unsinn angesichts der Erfahrungen in Großbritannien?

Germany wants to introduce some models to allow nurses to work in medical roles. Although hospital nurses worked hard during the last couple of years to concentrate on pure patient care and to detach themselves from medicine, a short additional training of 6-12 months duration is planned to allow them to work independently in well defined areas of medicine (high blood pressure, wound care, dementia, diabetes). However, success of such models has only been tested in a few studies. Study results and experience with such models in the UK - where these developments are much more advanced - are not only positive. Generally, work of nurses in medical roles does not make patient care less expensive and doctor´s work less onerous. The benefit lies more in an add-on effect to doctor´s care. Therefore, a close scientific surveillance of such models must be guaranteed and results must be considered without any kind of ideology.

Defective p56Lck activity in T cells from an adult patient with idiopathic CD4+ lymphocytopenia.

Idiopathic CD4(+) lymphocytopenia (ICL) is defined by a stable loss of CD4(+) T cells in the absence of any known cause of immune deficiency. This syndrome is still of undetermined origin. It affects adult patients, some of them displaying opportunistic infections similar to HIV-infected subjects. The hypothesis that the cellular immune defect may be due to biochemical failures of the CD3-TCR pathway is investigated here in a patient associating a severe selective CD4(+) lymphocytopenia with an increased CD8(+) T cell count discovered in the course of a cryptococcal meningitidis. A 40% reduction of T cell proliferation to CD3-TCR stimulation is observed only in the CD4(+) subpopulation. The early CD3-induced protein tyrosine phosphorylations are conserved in both CD4(+) and CD8(+) subsets, and the levels of the T cell protein tyrosine kinases p56(Lck), p59(Fyn) and ZAP-70 are normal. However, we find a 50% reduction of p56(Lck) kinase activity in the patient's T cells compared to a healthy control donor. p59(Fyn) activity does not appear to be altered. Nevertheless, we do not find any genetic abnormality of p56(Lck). These results thus suggest that a defect of an unknown protein regulating p56(Lck) activity takes place in this patient's T cells. Taken together, these findings reveal p56(Lck) alteration in ICL and confirm the critical role of this kinase in the maintenance of the peripheral CD4(+) T cell subpopulation.

Comparison of subcutaneous and intravenous interleukin-2 in asymptomatic HIV-1 infection: a randomised controlled trial. ANRS 048 study group.

BACKGROUND: Intermittent interleukin-2 therapy for HIV-1 by continuous intravenous infusion leads to sustained increase of CD4 T cells. This method of administration is, however, inconvenient and has limiting toxic effects. We did a randomised study to compare safety and efficacy of antiviral treatment alone or combined with various interleukin-2 regimens in HIV-1-infected patients. METHODS: 94 symptom-free patients, naïve to antiretroviral treatment, with CD4-T-cell counts of 250-550 cells/microL at baseline were randomly assigned zidovudine and didanosine alone (n=26) or combined with interleukin-2 administered intravenously (12 million IU/day, n=22) or subcutaneously (3 million IU/m2 twice daily, n=24) for 5 days, or were given polyethylene-glycol-modified (PEG) interleukin-2 (2 million IU/m2 intravenous bolus, n=22) administered every 2 months from week 2 to week 50 (seven cycles). Safety and immunological and virological results were monitored until week 56. FINDINGS: CD4-T-cell count increased to higher than baseline by a mean of 564 cells/microL (subcutaneous group), 676 cells/microL (intravenous group), 105 cells/microL (PEG group), and 55 cells/microL (antiretroviral-therapy group, p=0.0001). 68% and 77% of patients in the subcutaneous and intravenous groups, respectively, achieved an 80% increase of CD4 T cells (p<0.001). In these two groups, 50% of patients restored a CD4/CD8-T-cell ratio of more than 1. The groups did not differ significantly for changes in plasma HIV-1 RNA loads throughout the study. The duration of common side-effects of interleukin-2 was shorter in the subcutaneous group, which enabled outpatient treatment. Naïve and memory CD4 T cells, CD28 expression on CD4 and CD8 T cells, and restoration of in-vitro proliferative response to mitogens and recall antigens increased in the intravenous and subcutaneous groups. INTERPRETATION: Subcutaneous interleukin-2 is a convenient regimen that, as well as intravenous therapy, improves immunological function in HIV-1-infected patients receiving two nucleosides. Larger studies are needed to show whether immunological improvements translate into clinical benefit.

Treatment of mixed cryoglobulinemia with recombinant interferon alpha and adjuvant therapies. A prospective study on 20 patients.

In order to evaluate the efficacy of interferon alpha (IFNa) in mixed cryoglobulinemia (MC), a prospective multicenter clinical trial was conduced in April 1992. It consisted of treating 20 clinically symptomatic MC patients with IFNa for 26 weeks. Hepatitis C virus (HCV) infection was detected in 16 patients. A complete or partial clinical remission was obtained in 12 patients (60%). Eleven of these 12 responders (91.6%) experienced a clinical relapse less than 12 months after the end of therapy. Side effects were noted in 10 patients (50%). It was concluded that subcutaneously administered IFNa does not provide long-term remission.

Profound and possibly primary "idiopathic CD4+ T lymphocytopenia" in a patient with fungal infections.

A profound and long-lasting reduction in circulating CD4+ T lymphocytes (< 80/microliters) was found in a 37-year-old man (without known risk factors for HIV infection) presenting with recurrent oral candidiasis who subsequently developed cryptococcal meningitis. Infection with HIV was ruled out by serological and virological studies. In vitro and in vivo cell-mediated immunity was severely impaired. Abnormal phenotypic patterns of both CD4+ and CD8+ cells were consistently observed. A systematic family survey revealed in some of his asymptomatic relatives several immunological abnormalities which may point to a genetically based primary immunodeficiency disorder.

Splenectomy is safe and effective in human immunodeficiency virus-related immune thrombocytopenia.

Sixty-eight patients, followed in a prospective cohort study of 185 human immunodeficiency virus (HIV)-infected patients with severe immune thrombocytopenia (platelets < 50 x 10(9)/L), underwent splenectomy, 2 to 41 months (median: 10 months) after immune thrombocytopenic purpura (ITP) was diagnosed. The mean platelet count increased from 18 x 10(9)/L to 223 x 10(9)/L with a persistent increase in 56 (82%). It also led to a significant increase of the mean CD4 cell count from 475 x 10(6)/L to 725 x 10(6)/L within a mean delay of 10 months. In the whole cohort, with a mean follow-up of 63 months (range, 6 to 126), the 5-year estimated rate for progression to acquired immunodeficiency syndrome (AIDS) was 23% (95% confidence interval [CI], 15% to 31%) and the AIDS-free survival was 69% (95% CI, 61% to 77%). To investigate the potential impact of splenectomy, a Cox's multiple regression model was used; as splenectomy was not randomly assigned, it was incorporated as a time-dependent covariate. After adjustment on the CD4 cell count, no statistically significant differences were observed between the splenectomized and the nonsplenectomized patients: AIDS progression rate (P = 0.23), survival (P = 0.64) and AIDS-free survival (P = 0.72) were not influenced by splenectomy. Splenectomy is both effective and safe in the treatment of severe, refractory ITP associated with HIV infection.

Role of granulocyte-macrophage colony-stimulating factor, interleukin-3 and interleukin-5 in the eosinophilia associated with T cell lymphoma.

We studied two patients with a leukaemic T cell lymphoma who presented with a marked increase in blood eosinophilia. To investigate the mechanism of the eosinophilia, supernatants of peripheral blood cells containing more than 80% lymphoma cells were tested by biological assays for the presence of colony stimulating factors (CSF). In one case supernatants stimulated the growth of granulocyte-macrophage (GM), erythroid and eosinophil colonies. These effects were neutralized by anti-GM-CSF antibodies; anti-IL5 antibodies slightly decreased eosinophil colony formation. Supernatants derived from the second patient cells stimulated the same lineages. Neutralizing experiments demonstrated that in addition to GM-CSF it contained interleukin 3 (IL-3) and interleukin 5 (IL-5). In agreement with the biological data, RNA studies using the polymerase chain reaction showed that cells from the first patient expressed GM-CSF transcripts; IL-5 transcripts were also detected in very low amounts. GM-CSF, IL-3 and IL-5 transcripts were detected in cells from the second patient. Thus eosinophilia associated with some T cell lymphoma is likely due to secretion of different combinations of cytokines by malignant cells.

[Heavy chain diseases]. / Maladies des chaînes lourdes.

Heavy chain diseases (HCD) are immunoproliferative disorders characterized by the production of monoclonal immunoglobulin molecules composed of deleted heavy chains devoid of light chains. The diagnosis is established by immunoelectrophoresis (possibly combined to immunoselection) or immunofixation. The clinicopathologic features of gamma HCD are heterogenous, often somewhat similar to macroglobulinemia. Some patients show no evidence of underlying malignant lymphoproliferation. Autoimmune disorders are frequent. mu HCD is rare and often presents as chronic lymphocytic leukemia with hepatosplenomegaly and vacuolated plasma cells on bone marrow smears. Alpha chain disease is the most frequent. In its usual digestive form, the clinicopathologic pattern is uniform. The main clinical features are chronic diarrhea and severe malabsorption syndrome. At the initial stage, there is a diffuse lymphoplasmocytic infiltration of the small intestine and mesenteric nodes, sometimes reversible after treatment by antibiotics alone. At the terminal stage, a malignant lymphoma, often of immunoblastic type, occurs. The natural history and epidemiology of alpha HCD should provide insights into the pathogenesis of malignant lymphoid proliferations.

CD8 lymphocytosis and pseudotumoral splenomegaly in HIV infection.

Three patients infected with human immunodeficiency virus (HIV) presented with pseudotumoral splenomegaly, CD8 lymphocytosis (3.5-5.1 x 10(9)/l), and hypergammaglobulinaemia. Spleen and bone marrow showed diffuse CD8 lymphocyte and plasma-cell infiltration. Amplification of the T-cell-receptor gamma chain gene did not reveal any clonal T-cell population. Phenotypic analysis showed a predominance of CD8/CD57 suppressor T cells with expression of activation markers (DR and CD38). No cytotoxic T lymphocytes specific for HIV could be detected. The three patients shared the HLA haplotype A1, B8, DR3. The association with this haplotype suggests a genetically determined host immune response to HIV.

Infection of megakaryocytes by human immunodeficiency virus in seropositive patients with immune thrombocytopenic purpura.

Twenty-one human immunodeficiency virus (HIV)-positive patients, including 11 acquired immunodeficiency syndrome (AIDS)-free patients with immune thrombocytopenic purpura (ITP), were studied to determine whether the megakaryocytic/platelet lineage was infected by HIV. Because purification of platelets did not reach a level sufficient for unequivocal results by the polymerase chain reaction, in situ hybridization was thus performed. Purified marrow megakaryocytes (MK) from 10 HIV-infected ITP patients were studied using a 35S HIV riboprobe, antisense of an HIV ENV sequence. HIV transcripts were clearly detected in MK from five of these 10 patients, although heterogeneity among MK was observed. In three of these five cases, small amounts of HIV glycoproteins were detected in MK by means of immunofluorescence. In addition anti-HIV antibodies could be eluted from platelets of all patients. In contrast, HIV transcripts were not detected in MK derived from colony-forming units-MK (CFU-MK) cultured in suspension, suggesting either that MK are infected by HIV during terminal differentiation or that HIV-infected CFU-MK are unable to differentiate in vitro. In conclusion, this study suggests that HIV infection of MK may be implicated in the pathogenesis of thrombocytopenia of HIV-positive patients.

Changes in serum immunoglobulin patterns in adults with common variable immunodeficiency.

Striking variations of serum immunoglobulin class and IgG subclass levels were observed in five patients with common variable immunodeficiency. They occurred mainly in untreated patients or, in those patients who received substitutive therapy, could not be merely due to replacement. They result in major changes in the immunoglobulin deficiency patterns, such as a shift from profound hypoimmunoglobulinaemia to IgA/IgG2/IgG4 deficiency or to isolated IgG2 deficiency. These findings have practical implications for the diagnosis and management of patients with primary humoral immunodeficiency.

High dose chemoradiotherapy and autologous blood stem cell transplantation in multiple myeloma.

We report the results of peripheral blood stem cell (PBSC) collection performed after priming with a semi-intensive CHOP regimen in 70 patients with aggressive multiple myeloma (MM). Forty-one of the 44 previously untreated patients compared to 17 of the 26 patients with a refractory disease yielded stem cells enough for autotransplantation. Phenotypic and genotypic studies of collected mononuclear cells, even performed after depletion of monocytes and/or of T lymphocytes, did not reveal contamination by tumor plasma cells or clonal B cell precursors in any studied case. Forty-eight of the 58 patients with successful PBSC collection have been presently treated by high dose therapy followed by autologous blood stem cell transplantation (ABSCT). Among the 43 patients who received a regimen including total body irradiation, four died within six months after the autograft. All remainders responded and most often achieved an impressive tumor mass reduction. Ten relapsed and four died from disease progression. Nine to 70 months (median: 35 months) after blood stem cell collection, 29 patients are either in apparent complete remission or with a state of stable residual disease, most often minimal. Blood stem cell autograft was successful in all evaluable patients and the kinetic of hematologic recovery was roughly related to the amount of reinfused CFU-GM (2.1 to 50 x 10(4)/kg). Median delays for granulocytes greater than 500/mm3 and platelets greater than 25,000/mm3 were 15 days and 20 days, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Interleukin 6 dependence of spontaneous in vitro differentiation of B cells from patients with IgM gammapathy.

Blood B cells from eight patients with clonal lymphoid disorders characterized by monoclonal IgM secretion (four with malignant plasmacytic proliferation typical of Waldenström macroglobulinemia and four without overt lymphoid neoplasia) were found to spontaneously differentiate in vitro into plasma cells. In all instances, monoclonal plasma cells (8-45% of the cells) were generated from extensively purified B cells or T-cell-depleted peripheral blood mononuclear cells after a 7-day culture period, with a corresponding high rate of IgM secretion into the culture medium. This differentiation occurred in the absence of any cell proliferation process as measured by [3H]thymidine uptake at day 2 or 4. Normal B cells did not differentiate under the same experimental conditions. Detection of interleukin 6 (IL-6) bioactivity in all patients' B-cell culture supernatants as well as of IL-6 mRNA in freshly prepared, uncultured B cells in the two cases studied by in situ hybridization suggested that IL-6 secretion by B cells may play a role in this process. Moreover, in the four patients without overt lymphoid proliferation, B-cell differentiation was significantly inhibited (60-80%) in the presence of anti-IL-6 antibodies. In contrast, anti-IL-6 antibodies did not preclude the differentiation into plasma cells of B cells from the four patients with bona fide Waldenström macroglobulinemia. These results suggest a two-step pathogenesis for such human lymphoplasmacytic clonal proliferations, the initial stage being characterized by an IL-6-dependent autocrine differentiation pathway.

HIV-related thrombocytopenia.

About 5-10% of HIV seropositive individuals, in all risk groups, develop a syndrome of immunological thrombocytopenic purpura (ITP). Despite the clear association between HIV infection and thrombocytopenia, the exact immune mechanism leading to the peripheral platelet destruction remains unclear. Whereas some data support the direct effect of autoantibodies to platelet constituents, other findings argue in favour of the deposition of immune complexes containing anti-HIV antibodies. Although viral components could not be detected in the immune complexes or on the platelet membrane, megakaryocytes were shown to contain viral RNA and there is some evidence for a direct or indirect role of HIV in the pathophysiology of this disorder. Steroids, intravenous high dose polyvalent immunoglobulin, anti-rhesus immunoglobulin, danazol and vincristine usually induce only a transient increase in platelet counts. Zidovudine was shown to provide a sustained response in 40-60% of the patients and appears to be the treatment of choice for HIV-related thrombocytopenia. Splenectomy has been effective in many cases with persistent, profound and symptomatic thrombocytopenia and, on a 4-year follow-up, does not influence the progression rate to AIDS or survival. Patients with thrombocytopenia are not at greater risk for the development of AIDS than seropositive non-thrombocytopenic patients. Thus, thrombocytopenia should not be viewed as a stage in the progression from asymptomatic infection to AIDS.

Immunological features of human immunodeficiency virus disease.

Infection with the human immunodeficiency viruses results in a profound immunosuppression responsible for most of the clinical features of AIDS. The virus devastates the immune system because its main target is the T4 lymphocyte, which is the key component for generating and regulating the immune response. The cellular receptor for HIV, the membrane glycoprotein CD4, is found mainly on the surface of this major subpopulation of T lymphocytes and also on many other cell types such as those of the monocyte/macrophage series. HIV can destroy CD4 cells by direct virus cytotoxicity and indirectly through the host response against HIV-infected cells or gp120-targeted cells. Cells of the macrophage lineage are generally not destroyed but serve as a reservoir of virus. HIV also causes functional impairment in T cells, B cells and monocytes. The virus can exist in latent or chronic form. The mechanisms of cellular destruction, viral persistence and conversion to a productive infection are being studied vigorously. Host factors that may affect clinical outcome and immunological markers that may predict progression of HIV disease are presently delineated. Prolonged serological latency may follow infection with HIV. Protective humoral and cell-mediated immune responses to HIV are either poor or not sustained. Recent results on HIV-specific cytotoxic T lymphocytes are of great interest. These cytotoxic cells, particularly those directed to gp120 targets, probably contribute to cellular damage. A central question regarding immunity to HIV is its beneficial versus deleterious effects, particularly in regard to the eventual development of an AIDS vaccine.

[Peripheral neuropathy and plasmocytic proliferations. Apropos of 17 cases]. / Neuropathie périphérique et proliférations plasmocytaires. A propos de 17 observations.

Seventeen cases of peripheral neuropathy with plasmocytic proliferation were grouped together to analyze the clinical manifestations and evolution of this association of symptoms. The plasmocytic proliferation was 5 times that of multiple myeloma, 9 times that of a solitary bone plasmacytoma and 3 times that of a solitary plasmacytoma. The follow-up lasted 1 to 18 years (mean, 8 years) for solitary plasmacytomas. Other cutaneous and endocrinological symptoms, organomegaly and edema were sometimes present. The evolution was relatively severe, except in 6 patients whose solitary plasmacytomas were successfully treated with radiation. Six patients died 2 to 8 years (mean, 5 years) after the onset of neuropathy as a result of a progression of the neuropathy and/or anasarca (4 cases), or acute leukemia (2 cases) abetted by long-term chemotherapy. The therapeutic approaches available, the nature of the plasmocytic proliferation and its association with the neuropathy and the other symptoms are discussed.