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Biomedical subjects

J Fehr

Publications and source records attributed to J Fehr.

At least 19 recordsLinked to original sources
PubMed2002

In patients with deep-vein thrombosis elevated levels of factor VIII correlate only with von Willebrand factor but not other endothelial cell-derived coagulation and fibrinolysis proteins.

Several studies have shown that patients with venous thrombosis have elevated levels of factor VIII (FVIII) at an increased frequency. Most such patients also have high von Willebrand factor (vWF) levels. Since vWF is synthesized by the vascular endothelium, we hypothesized that elevated FVIII levels would also be associated with an increase of other endothelial cell-derived coagulation proteins suggesting perturbation of the endothelium. In 100 healthy individuals and 129 patients with venous thromboembolism, we have determined antigenic FVIII levels along with several endothelial proteins including vWF, soluble thrombomodulin (sTM), tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor 1 (PAI-1). Levels of FVIII, vWF, PAI-1 and t-PA were significantly increased in patients compared with the controls (FVIII, vWF, and PAI-1,P < 0.001; t-PA, P < 0.05). Levels of sTM, however, were higher in the controls than in the patients (P < 0.001). Whereas the FVIII levels correlated well with the vWF levels in the patients (correlation, 0.61; P < 0.001) and the controls (correlation, 0.70; P < 0.001), there was neither a relevant correlation between FVIII and sTM, PAI-1, and t-PA, nor between vWF and sTM, PAI-1, and t-PA in the patients and the controls. In conclusion, although levels of PAI-1 and t-PA can be found, on average, at increased levels in patients with thrombosis, FVIII levels correlate only with vWF but not other endothelial cell-derived coagulation and fibrinolysis proteins including sTM, PAI-1, and t-PA.

Adult↗
PubMed2001

Persistent polyclonal B-cell lymphocytosis is an expansion of functional IgD(+)CD27(+) memory B cells.

Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare disorder of unknown aetiology affecting predominantly young to middle-aged women. It is characterized by a polyclonal expansion of B cells, including typical binucleated lymphocytes, and is associated with the presence of the translocation t(14;18), involving the bcl-2 oncogene. The stage of differentiation of the B cells expanded in PPBL is not known. We analysed the immunophenotype of the expanded B-cell subset in five new patients with PPBL and found a large uniform expansion of a recently defined human memory B-cell population, IgD(+)CD27(+) memory B cells. After in vitro stimulation with interleukin 2 (IL-2) and Staphylococcus aureus Cowan strain I, B cells from PPBL patients produced high levels of IgM immunoglobulins, which is a characteristic feature of IgD(+)CD27(+) memory B cells. Using a quantitative real-time polymerase chain reaction method, we found a high frequency of the translocation t(14;18) in the range of 1000-3000 per 106 B cells in PPBL patients. In contrast, a much smaller number of cells with a t(14;18) was found in B cells from healthy individuals. Our finding that PPBL is an accumulation of memory B cells further suggests that chronic antigeneic stimulation plays an important part in the pathogenesis of this disorder. This IgD(+)CD27(+) memory B-cell population might harbour a certain number of 'physiological' t(14;18) translocations that increases as this population expands in PPBL patients and constitutes the majority of peripheral blood lymphocytes.

Adult↗
PubMed2001

Coagulation activation markers do not correlate with the clinical risk of thrombosis in pregnant women.

OBJECTIVE: Because coagulation activation markers have been shown to indicate an increased risk of thrombosis, we tested whether thrombin-antithrombin III complexes and D-dimers correlated with the risk assessment in pregnant women on the basis of clinical data. STUDY DESIGN: We divided a group of 261 pregnant women (305 pregnancies) into low- and high-risk groups according to the personal and family histories of thrombosis and the presence of a hereditary or an acquired thrombophilia. Women with a thrombotic event in the current pregnancy formed a separate group. All pregnancies with or without heparin therapy were closely monitored with thrombin-antithrombin III and D-dimer values for the entire course of the pregnancy. Retrospectively, the data were then correlated with the different groups and subgroups. RESULTS: The course of the mean thrombin-antithrombin III values of all 305 pregnancies was close to or slightly above the upper cutoff line, whereas the D-dimer values were well within the normal range. Independent of heparin, there was no difference in the course of the thrombin-antithrombin III and D-dimer values between the low- and high-risk groups. Only women with ongoing thrombosis during pregnancy had significantly higher thrombin-antithrombin III and D-dimer values with or without heparin therapy. Among those individuals with elevated thrombin-antithrombin III or D-dimer values, there were no specific, recognizable patients who had elevated markers more often than others. CONCLUSIONS: Thrombin-antithrombin III and D-dimer values do not correlate with a risk stratification assessed by clinical criteria. There are many women at low clinical risk who have elevated markers, and there are many women at very high clinical risk who have normal markers. Thus thromboprophylaxis would often be used inadequately if the indication were based on coagulation markers.

Adolescent↗
PubMed2001

Familial persistent polyclonal B-cell lymphocytosis.

We report the occurrence of the syndrome of persistent polyclonal B-cell lymphocytosis in a brother and a sister. Both showed the morphological and immunophenotypic features of this rare disorder. In addition both had mild splenomegaly, increase of serum IgM and serological evidence of previous EBV infection. Of interest, two additional brothers had no evidence of PPBL but were indistinguishable in terms of HLA haplotype (HLA-DR7), smoking habits or evidence of EBV infection. These observations provide additional support for a genetic basis of the syndrome but suggest that pathogenic factors other than those known so far may be required for its full expression.

Antigens, Viral↗
PubMed2000

[Frequency of HFE gene mutations and genotype-phenotype correlations in patients with hereditary hemochromatosis in Switzerland].

Hereditary haemochromatosis is one of the most common genetic disorders affecting populations of European ancestry. Isolation of a strong candidate gene, the HFE gene, allows genetic diagnosis in a large number of cases. However, different mutation frequencies have been reported in hereditary haemochromatosis patient populations from various geographic regions. Such data and phenotype-genotype correlations from Swiss patients with hereditary haemochromatosis are lacking. The objective of our study was to determine the frequency of HFE gene mutations in Swiss patients with hereditary haemochromatosis and to describe the clinical phenotype of patients with either a homozygous C282Y mutation or compound heterozygotes. 71 patients with a clinical diagnosis of hereditary haemochromatosis were identified through a questionnaire sent to physicians caring for hereditary haemochromatosis patients. Pertinent clinical data, in particular those reflecting iron body stores, were collected. Genotyping for the C282Y and H63D mutation of the HFE gene was performed. In 90% of the cases a mutation of the HFE gene was found. 86% of the patients were homozygous for the C282Y mutation, 4% were compound heterozygotes for the C282Y and the H63D mutation. Patients with the homozygous C282Y mutation showed a broad phenotypic spectrum that could not be accounted for by age or sex differences only. Our results demonstrate that within the Swiss population genetic testing can also identify the vast majority of patients with hereditary haemochromatosis. However, the diagnosis is not ruled out by a negative genetic test. Furthermore, a broad phenotypic spectrum is associated with the homozygous C282Y mutation in Swiss hereditary haemochromatosis patients. The implications of these findings for planning of widespread genetic screening for hereditary haemochromatosis in the general population are discussed.

Adult↗
PubMed2000

[Reading speed in movement in the peripheral visual field].

BACKGROUND: Moving and distracting stimuli often occur in the peripheral visual field during visual tasks in daily life. Do they influence reading performance? METHOD: In 30 normal subjects with a normal visual acuity we investigated eye movements by electronystagmography (ENG) during silent reading of a standardized text. The 17 degrees-wide text was presented at a distance of 1 m, ENG was recorded bitemporally. Blinks were monitored via vertical ENG electrodes. For surrounding stimulation we presented a bar stimulus moving at 30 degrees/s. Three experimental conditions were compared: [1] no peripheral motion, [2] peripheral motion to the right, and [3] peripheral motion to the left. We quantitatively analyzed reading speed and blink frequency. RESULTS: Reading speed and blink frequency was nearly identical in the three experimental conditions, they differed by 1-8%. CONCLUSIONS: Although the full periphery was stimulated, and the moving stimulus was noticed by our subjects, reading was not affected by surrounding optokinetic stimulation. Attentive reading does not appear to be affected by visual motion in the periphery.

Adult↗
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↗