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Biomedical subjects

J Fehr

Publications and source records attributed to J Fehr.

At least 37 records · Page 2Linked to original sources
PubMed2000

Establishment and characterization of an arsenic-sensitive monoblastic leukaemia cell line (SigM5).

Few human monoblastic cell lines have been characterized to date. We have established the SigM5 cell line from a patient with acute monoblastic leukaemia (FAB M5a). Original leukaemic cells had a karyotype of 47,XY,+8, whereas the cell line showed a stemline clone of 81,XX,Y,Y,1,4,6,7,+8,+8,9,10,10,11,13,16,19[cp], with a minor sideline also present. Cytochemical staining was strongly positive with alpha-naphthylbutyrate acetate esterase, particulate positive with Sudan black and weakly positive for myeloperoxidase. Cells were positive for CD13, CD15, CD18, CD23, CD33, CD38, CD45, CD68 and myeloperoxidase. CD14 expression was 3-15%. SigM5 constitutively secreted interleukin (IL)-2, IL-8, IL-10, tumour necrosis factor (TNF)-alpha, ferritin, lysozyme, N-elastase and neopterin upon stimulation with interferon (IFN)-gamma. Cells expressed the proinflammatory mediator macrophage migration inhibitory factor (MIF). All NADPH oxidase subunits were constitutively present, but nitroblue tetrazolium reduction was only detectable upon activation with IFN-gamma. SigM5 monoblasts were sensitive to arsenic trioxide (As2O3) previously not described to induce apoptosis in monoblastic cells. Differing considerably in morphology, immunophenotype and sensitivity to arsenics from the widely used cell lines U937, HL-60 and THP-1, SigM5 is a new monoblastic cell line useful for studying leukaemogenesis, monocyte differentiation and tumour cell susceptibility to arsenic compounds.

Antineoplastic Agents↗
PubMed1999

Impaired liver function and retroviral activity are risk factors contributing to HIV-associated thrombocytopenia. Swiss HIV Cohort Study.

OBJECTIVE: To investigate the relationship between thrombopoetin (TPO) serum levels and HIV-associated thrombocytopenia. DESIGN AND METHODS: The relationship between TPO levels and severity of HIV-associated thrombocytopenia was investigated. Thirty-eight patients (19 patients with 30-96x10(9) platelets/l and 19 patients with <10x10(9) platelets/l) were matched with 38 HIV-positive non-thrombocytopenic patients (>150x10(9) platelets/l). RESULTS: HIV-positive patients with normal platelet counts had a median TPO serum level of 137 pg/ml. Patients with 30-96x10(9) platelets/l had decreased TPO levels with a median of 90 pg/ml (P = 0.016), and were more likely to have elevated serum aspartate-transferase levels (P<0.001) and hepatomegaly by palpation or ultrasound imaging (P = 0.005). The median TPO serum level of HIV-infected patients with severe thrombocytopenia was 110 pg/ml (non-significant). All patients with severe thrombocytopenia were positive for antibodies against hepatitis B virus core antigen, compared with 80% of HIV-infected persons without thrombocytopenia. Patients with severe thrombocytopenia were more likely to have high HIV replication compared to patients with normal platelet counts (P = 0.02), and reduction of plasma HIV-1 RNA levels was associated with increasing platelet counts. Severe thrombocytopenia was not associated with liver disease. CONCLUSIONS: Liver disease predisposes for low TPO serum levels and mild thrombocytopenia. High retroviral activity predisposes for severe, immune thrombocytopenic purpura-like thrombocytopenia. At least two distinct categories of severe HIV-associated thrombocytopenia exist, one responsive to antiretroviral treatment and one non-responsive to antiretroviral treatment.

Adult↗
PubMed1999

[Diagnosis of vitamin B12 deficiency: only apparently child's play].

We performed a systematic literature search for diagnostic criteria in establishing cobalamin deficiency. The diagnostic procedure is particularly uncertain in elderly patients with neurological symptoms and in cases with borderline cobalamin values. In any patient with suspected cobalamin deficiency we recommend analysing a full blood count and determining cobalamin concentration in a serum sample. Particularly in elderly patients and cases with neurological symptoms presenting borderline cobalamin values and no abnormalities in the blood count, we recommend further investigation with methylmalonic acid, homocystein and Schilling test. These additional tests should make it possible to decide whether to recommend lifelong substitution with cobalamin. Various cobalamin assays, Schilling test, food cobalamin test, gastroscopic evaluation and the problems surrounding these assays in the elderly are discussed. Our own experience with methylmalonic acid, homocystein determination and food cobalamin test did not reveal a simple diagnostic procedure in such cases. We conclude that there is still no "gold standard" for diagnostic procedure in the special cases mentioned.

Aging↗
PubMed1999

[Comparison of a D-dimer rapid-test with a plasma-immunoassay for diagnosis of venous thrombosis or pulmonary embolism in a medical emergency unit].

The level of D-dimer in the blood reflects the level of lysed, cross-linked fibrin, and is useful in the diagnosis of clinically suspected deep venous thrombosis and pulmonary embolism. We compared two assays for the measurement of D-dimer levels, the whole-blood immunoassay SimpliRED which can be performed in two minutes, and the plasma immunoassay NycoCard. D-dimer levels were determined with these two techniques in 100 patients. With clinically suspected deep vein thrombosis and positive D-dimer levels a compression ultrasonography using a colour coded Duplex instrument, or a phlebography were done. For clinically suspected pulmonary embolism a ventilation/perfusion scan was done in patients with normal x-ray. Patients with radiographic abnormalities were investigated with spiral computed tomography or pulmonary arteriography. When both assays showed negative results a diagnostic procedure was only done if there was a high clinical suspicion for thromboembolism. Both assays showed a correct positive result in seven of the eight diagnosed thromboembolic events and one false negative result each. The SimpliRED assay exhibited a sensitivity of 87.5% and a specificity of 61%, the negative predictive value was 98.3%, positive predictive value 15.9%. The NycoCard assay displayed also a sensitivity of 87.5%, specificity was lower with 39.6%, the negative predictive value was 97.4%, positive predictive value 10.7%. The SimpliRED assay can be a valuable tool when laboratory facilities for a plasma immunoassay are not accessible. The negative predictive value is very high, therefore this test is considered to be helpful for excluding a thromboembolic event.

Adult↗
PubMed1999

Cloning of the hereditary hemochromatosis gene: implications for pathogenesis, diagnosis, and screening.

Hereditary hemochromatosis (HH) is one of the most common genetic disorders affecting populations of European ancestry. It is characterized by an inappropriately high iron absorption that leads to iron overload preferentially in the parenchymal organs. Although the severity of the phenotype can be modified by a number of factors, it is clear that most homozygotes will eventually become symptomatic. Clinical manifestations are often nonspecific and easily overlooked. Untreated HH can be associated with substantial morbidity and mortality. Diagnosis in the pre-cirrhotic stage, however, results in normal life expectancy. Early diagnosis and the initiation of phlebotomy therapy are therefore keys to preventing complications related to iron overload. The recent isolation of a strong candidate gene for hemochromatosis has the potential to allow for genetic diagnosis and screening in the near future. This exciting finding is likely not only to change clinical practice but also to yield new insights into the poorly understood pathophysiology of the disease.

Cloning, Molecular↗
PubMed1998

Inhibition of leukocyte emigration induced during the systemic inflammatory reaction in vivo is not due to IL-8.

In keeping with the multistep model of leukocyte-endothelial cell interaction, stimulation of endothelium by cytokines or endotoxin (LPS) in vitro leads to selectin/integrin-mediated neutrophil adhesion, followed by neutrophil endothelial transmigration. The i.p. injection of LPS in vivo induces a systemic inflammatory reaction in a mouse model with generalized activation of both endothelial cells (up-regulation of adhesion molecules ICAM-1, VCAM-1, E-selectin) and neutrophils (up-regulation of Mac-1). However, no intravascular endothelial adhesion or tissue emigration of neutrophils can be observed. Even more importantly, the in vivo emigration of polymorphonuclear cells at sites of a local inflammatory reaction (IL-8, TNF, LPS) is totally inhibited when the mice are pretreated systemically with LPS, although the neutrophils respond fully to a rechallenge with LPS ex vivo, and endothelial adhesion molecules are further up-regulated locally. The systemic application of TNF also caused a total inhibition of neutrophil emigration. However, while anti-TNF mAb abrogated the inhibitory activity induced by TNF, they had no effect on systemic LPS. The systemic application of IL-8 did not inhibit neutrophil emigration, nor did the pretreatment of mice with anti-IL-8 mAb before the systemic application of LPS abrogate the inhibitory activity induced by LPS. Therefore, the putative inhibitor of neutrophil emigration, which may be of great physiologic importance, as it prevents in vivo the generalized emigration of activated neutrophils, most likely is not IL-8.

Animals↗
PubMed1998

Aplastic anemia rescued by exhaustion of cytokine-secreting CD8+ T cells in persistent infection with lymphocytic choriomeningitis virus.

Aplastic anemia may be associated with persistent viral infections that result from failure of the immune system to control virus. To evaluate the effects on hematopoiesis exerted by sustained viral replication in the presence of activated T cells, blood values and bone marrow (BM) function were analyzed in chronic infection with lymphocytic choriomeningitis virus (LCMV) in perforin-deficient (P0/0) mice. These mice exhibit a vigorous T cell response, but are unable to eliminate the virus. Within 14 d after infection, a progressive pancytopenia developed that eventually was lethal due to agranulocytosis and thrombocytopenia correlating with an increasing loss of morphologically differentiated, pluripotent, and committed progenitors in the BM. This hematopoietic disease caused by a noncytopathic chronic virus infection was prevented by depletion of CD8+, but not of CD4+, T cells and accelerated by increasing the frequency of LCMV-specific CD8+ T cells in T cell receptor (TCR) transgenic (tg) mice. LCMV and CD8+ T cells were found only transiently in the BM of infected wild-type mice. In contrast, increased numbers of CD8+ T cells and LCMV persisted at high levels in antigen-presenting cells of infected P0/0 and P0/0 x TCR tg mice. No cognate interaction between the TCR and hematopoietic progenitors presenting either LCMV-derived or self-antigens on the major histocompatibility complex was found, but damage to hematopoiesis was due to excessive secretion and action of tumor necrosis factor (TNF)/lymphotoxin (LT)-alpha and interferon (IFN)-gamma produced by CD8+ T cells. This was studied in double-knockout mice that were genetically deficient in perforin and TNF receptor type 1. Compared with P0/0 mice, these mice had identical T cell compartments and T cell responses to LCMV, yet they survived LCMV infection and became life-long virus carriers. The numbers of hematopoietic precursors in the BM were increased compared with P0/0 mice after LCMV infection, although transient blood disease was still noticed. This residual disease activity was found to depend on IFN-gamma-producing LCMV-specific T cells and the time point of hematopoietic recovery paralleled disappearance of these virus-specific, IFN-gamma-producing CD8+ T cells. Thus, in the absence of IFN-gamma and/or TNF/LT-alpha, exhaustion of virus-specific T cells was not hampered.

Anemia, Aplastic↗
PubMed1997

[Castleman's disease--a rare cause of a febrile state with lymphadenopathy].

HISTORY AND CLINICAL FINDINGS: A 26-year-old man had a prolonged fever, 10 kg weight loss and generalized lymphadenopathy, first diagnosed as a malignant lymphoma. On admission he was febrile and in a markedly reduced physical condition. Submandibular, angular, cubital and inguinal lymph nodes were slightly enlarged bilaterally. INVESTIGATIONS: Serology and blood cultures were negative. Sonography and computed tomography showed enlarged lymph nodes in the neck, mediastinum, axillae, retroperitoneum and mesentery. Biopsies of lymph nodes and bone marrow revealed changes characteristic of Castleman's disease. TREATMENT AND COURSE: Prednisone was administered, 20 mg daily for 20 days, the dose gradually reduced over 4 months. The fever ceased after 14 days and the patients's working capacity was fully restored after 7 weeks. CONCLUSION: In a case of prolonged fever of unknown cause Castleman's disease should be included in the differential diagnosis. It at first consists of polyclonal lymphatic proliferation. But transformation to malignant lymphoma and systemic Kaposi's sarcoma have been described in the disease's generalized form.

Adult↗
PubMed1997

Virus-induced transient bone marrow aplasia: major role of interferon-alpha/beta during acute infection with the noncytopathic lymphocytic choriomeningitis virus.

The hematologic consequences of infection with the noncytopathic lymphocytic choriomeningitis virus (LCMV) were studied in wild-type mice with inherent variations in their interferon (IFN)-alpha/beta responder ability and in mutant mice lacking alpha/beta (IFN-alpha/beta R0/0) or gamma IFN (IFN-gamma R0/0) receptors. During the first week of infection, wild type mice demonstrated a transient pancytopenia. Within a given genetic background, the extent of the blood cell abnormalities did not correlate with the virulence of the LCMV isolate but variations were detected between different mouse strains: they were found to depend on their IFN-alpha/beta responder phenotype. Whereas IFN-gamma R0/0 mice were comparable to wild-type mice, IFN-alpha/beta R0/0 mice exhibited unchanged peripheral blood values during acute LCMV infection. In parallel, the bone marrow (BM) cellularity, the pluripotential and committed progenitor compartments were up to 30-fold reduced in wild type and IFN-gamma R0/0, but remained unchanged in IFN-alpha/beta R0/0 mice. Viral titers in BM 3 d after LCMV infection were similar in these mice, but antigen localization was different. Viral antigen was predominantly confined to stromal BM in normal mice and IFN-gamma R0/0 knockouts, whereas, in IFN-alpha/beta R0/0 mice, LCMV was detected in > 90% of megakaryocytes and 10-15% of myeloid precursors, but not in erythroblasts Although IFN-alpha/beta efficiently prevented viral replication in potentially susceptible hematopoietic cells, even in overwhelming LCMV infection, unlimited virus multiplication in platelet and myeloid precursors in IFN-alpha/beta R0/0 mice did not interfere with the number of circulating blood cells. Natural killer (NK) cell expansion and activity in the BM was comparable on day 3 after infection in mutant and control mice. Adaptive immune responses did not play a major role because comparable kinetics of LCMV-induced pancytopenia and transient depletion of the pluripotential and committed progenitor compartments were observed in CD8(0/0) and CD4(0/0) mice, in mice depleted of NK cells, in lpr mice, and in perforin-deficient (P0/0) mice lacking lytic NK cells. Thus, the reversible depression of hematopoiesis during early LCMV infection was not mediated by LCMV-WE-specific cytotoxic T lymphocyte, cytolysis, or secreted IFN-gamma from virally induced NK cells but was a direct effect of IFN-alpha/beta.

Acute Disease↗
PubMed1997

The diagnostic value of the neutrophil left shift in predicting inflammatory and infectious disease.

The use of neutrophil left-shift parameters in the diagnosis of inflammatory and infective disease (ID) was evaluated. The level of C-reactive protein (CRP), currently the best quantitative parameter of inflammation, was used as the gold standard. Of 292 patients, 230 (79%) had a level of CRP of 1.0 mg/dL or greater and were classified as having inflammation, whereas 62 (21%) had normal levels. The neutrophil band count in each patient was determined by microscopic examination of 200 WBCs. The diagnostic value of the band count as an indicator for ID was evaluated in comparison to the WBC count, the neutrophil count, and the left-shift indicators of two automated hematologic analyzers, H*1 Technicon (Bayer Technicon Instruments, Tarrytown, NY) and Coulter MAX M (Coulter Electronics, Hialeah, Fla). When receiver operating characteristics were used, the band count was superior to the immature to total neutrophil count (I/T) ratio, the total WBC count, and the neutrophil count. The sensitivity and specificity in identifying ID at designated cutoff points were as follows: band count of 20% or greater of total WBC count (53% and 79%, respectively), I/T ratio of 0.25 or greater (59% and 63%), total WBC count of 9.6 x 10(6)/mL or greater (68% and 56%), and neutrophil count of 8.0 x 10(6)/mL or greater (60% and 58%). The performance of the H*1 Technicon left-shift flag was similar but slightly inferior to the band count (sensitivity, 44%; specificity, 79%), whereas the Coulter MAX M flags had a clearly higher sensitivity (79%) and lower specificity (53%). In addition, microscopic evaluation to determine the presence of reactive morphologic changes in neutrophils, such as toxic granules, Döhle bodies, and cytoplasmic vacuoles, had a high sensitivity (80%) but a low specificity (58%) in predicting ID. The diagnostic value of both microscopic and automated neutrophil left-shift parameters as indicators for ID is limited. Morphologic changes in neutrophils, however, either have a high specificity (band count) or a high sensitivity (toxic signs) in predicting ID and therefore may be a clinically useful tool.

Adolescent↗
PubMed1996

Estimation of the lower limits of manual and automated platelet counting.

Most evaluators of automated or manual methods for platelet counting focus on characteristics such as imprecision, linearity, and carry over. The limits of the analytical procedure are usually not assessed. The limits of the different techniques are neither discussed in the literature nor do manufacturers of analytical systems supply these data. A new procedure is presented to assess the performance of the manual as well as the automated platelet count. This procedure allows, with defined statistical confidence (eg, 95%), the determination of (1) the limit of platelet detection (LD) at which signals of platelets can be discriminated from the system noise; (2) the lower limit of quantification (LLQ), at which a certain imprecision is not surpassed; and (3) the power of definition (PD) that defines the number of values that can be discriminated in a certain interval. For each value, the PD allows calculation of the two adjacent (lower and higher) values that are significantly (P > or = 0.95) different. For the manual count, LD was found to be 1.6 x 10(9) plt/L and the LLQ 6.9 x 10(9) plt/L. For the automated count with the Technicon H1, LD was 4.3 x 10(9) plt/L and LLQ 13.8 x 10(9) plt/L (CVmax = 15%). The PD in the range 20 to 100 x 10(9) plt/L is 8 for the automated and 7 for the manual count.

Analysis of Variance↗
PubMed1996

Early diagnosis of low grade malignant lymphoma and chronic lymphocytic leukaemia. Verification of morphologically suspected malignancy in blood lymphocytes by flow cytometry.

According to international recommendations, the diagnosis of chronic lymphocytic leukaemia (CLL) is made on the grounds of persistent peripheral lymphocytosis or lymphocytic infiltration of the bone marrow. The appearance of morphologically atypical lymphocytes in low-grade malignant lymphoma (NHL) or CLL is easily overlooked, and is generally not regarded as a diagnostic criterion. We report 12 cases of CLL/NHL who were detected only by morphological screening of routine peripheral blood smears (83,400 blood smears). The diagnosis of CLL/NHL was not suggested by the patients' history, physical or other laboratory findings, and had not been contemplated by the physician in charge. Monoclonality of peripheral lymphocytes was confirmed by immunophenotyping and Southern blotting. The lymphoma was classified histologically according to the International Working Formulation (bone marrow biopsy). A monoclonal lymphatic population was not found by immunophenotyping in the blood of 11 patients whose lymphocytes were morphologically classified as activated-abnormal. However, 3 patients suspected to have NHL/CLL on morphological screening of blood smears had to be classified as benign after immunophenotyping. We conclude that morphological screening of routine blood smears is an inexpensive and easy additional screening method for CLL and low grade malignant NHL.

Aged↗
PubMed1996

HB Hinwil or beta 38(C4)Thr-->Asn: a new beta chain variant detected in a Swiss family.

This paper reports a new hemoglobin variant which was identified while investigating the cause of a mild erythrocytosis. The abnormal beta-globin chain was detected by reversed phase chromatography. Mutation mapping of the beta-globin gene by polymerase chain reaction and denaturing gradient gel electrophoresis followed by sequence analysis revealed a C-->A transversion at codon 38, predicting a Thr-->Asn substitution. Tryptic peptide mapping by liquid chromatography electrospray mass spectrometry, followed by conventional Edman peptide sequence analysis, confirmed the predicted amino acid substitution. In contrast to the only other known mutation at codon 38, Hb Hazebrouck (Thr-->Pro), this hemoglobin is stable and shows elevated oxygen affinity.

Amino Acid Sequence↗
PubMed1996

[Value of the blood picture and flow cytometry immunotyping in the early diagnosis of low-grade lymphoma].

Low-grade malignant non-Hodgkin lymphoma [NHL] and chronic lymphocytic leukemia [CLL] as its special form are slowly progressing malignancies which may present with lymphadenopathy, splenomegaly or, more rarely, hepatomegaly. The diagnosis is made by bone marrow or lymph node histology, while laboratory tests are relatively unspecific and may only hint towards the diagnosis. In contrast to high-grade malignant lymphoma, low-grade malignant NHL is often associated with the appearance of malignant lymphoma cells in peripheral blood. These malignant lymphocytes may be differentiated microscopically from normal lymphocytes, so that the diagnosis of NHL may be suspected not only because of clinical symptoms or lymphocytosis, which may present late in the natural history of the disease, but also on morphological grounds. Three types of low-grade malignant NHL cells may be recognized in peripheral blood: A mature appearing lymphocytic type with only slight alterations of the nucleus, a lymphoplasmocytic type, and a lymphocytic type with prominent alterations of the nucleus. The appearance of smudge cells and a monotony in lymphocyte morphology may serve as further diagnostic aids. Once the diagnosis has been suspected on morphological grounds, it may be verified in the case of B-cell lymphomas by flow cytometry. The clonality of T-cell lymphoproliferative disorders in addition has to be proven by demonstrating a clonal rearrangement of the T-cell receptor in Southern blots. An early diagnosis of low-grade malignant NHL may not only provide new insights into the natural history of monoclonal cytopathies but may also be of importance in the clinical management of patients.

Blood Cells↗