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The effects of fasting for 7 days were investigated in 13 patients with rheumatoid arthritis (RA) in comparison with a control regimen in a cross-over trial. The effects of fasting on clinical performance and blood neutrophil functions... more
The effects of fasting for 7 days were investigated in 13 patients with rheumatoid arthritis (RA) in comparison with a control regimen in a cross-over trial. The effects of fasting on clinical performance and blood neutrophil functions were studied. During fasting, with a mean weight loss of 5.1 kg, clinical inflammation in the joints and the erythrocyte sedimentation rate (ESR)
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Total parentenal nutrition (TPN) has been associated with an increased incidence of infection. To assess the hypothesis that TPN, and in particular one of its constituents, the fat emulsion Intralipid, might impair host defense, we... more
Total parentenal nutrition (TPN) has been associated with an increased incidence of infection. To assess the hypothesis that TPN, and in particular one of its constituents, the fat emulsion Intralipid, might impair host defense, we investigated in vitro migration, bactericidal functions, and chemiluminescence of the neutnophil granulocyte in four patients with Crohn's disease, given TPN for up to 12 wk.
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ABSTRACT Endometrial regrowth is associated with intense angiogenesis, for which vascular endothelial growth factor-A (VEGF-A) is an important regulator. However, the expression of other members of the VEGF family is less well documented.... more
ABSTRACT Endometrial regrowth is associated with intense angiogenesis, for which vascular endothelial growth factor-A (VEGF-A) is an important regulator. However, the expression of other members of the VEGF family is less well documented. The aim of this study was to localize members of the VEGF family (VEGF-A, -B and -C), and their receptors (VEGFR1, 2 and 3) in human endometrial blood vessels. Endometrial biopsies collected from four healthy and fertile women were used for immunohistochemistry assessments. Co-localization of VEGF-family proteins with CD34 stained endothelial structures was determined by image analysis. We demonstrate here the marked expression of VEGF-A as well as VEGFR2 and 3 in capillaries. Arterioles expressed VEGF-B, VEGFR1, 2, and 3 moderately and VEGF-A variably. Venules expressed only VEGFR3 markedly. In contrast, VEGF-C was not expressed in the arterioles, but moderately in the capillaries and weakly in the venules. VEGF-B was expressed in all blood vessels; however, VEGF-B was weakly expressed in capillaries and arterioles and moderately expressed in venules and arterioles. Thus, expression of VEGF-A. B and C and VEGF receptors 1-3 in endometrial blood vessels indicates a highly structured involvement of VEGF in the regulation of angiogenesis in the human endometrium.
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We conducted a nonrandomized prospective phase II study of thalidomide in anemic patients with myelofibrosis with myeloid metaplasia (MMM), with or without preceding polycythemia vera or essential thrombocythemia, with a primary aim to... more
We conducted a nonrandomized prospective phase II study of thalidomide in anemic patients with myelofibrosis with myeloid metaplasia (MMM), with or without preceding polycythemia vera or essential thrombocythemia, with a primary aim to improve anemia. Thalidomide was given in escalating doses with a target dose of 800 mg daily, but the median dose of thalidomide that was actually tolerated was 400 mg daily. Fifteen patients were entered into the study and 14 were evaluable for response. Five of 14 (36%) patients discontinued thalidomide before 3 mo because of side effects, and none of these five patients had a response at the time when thalidomide was stopped. When evaluated after 3 mo of therapy, none of the remaining nine patients exhibited a discernible clinical response. Three patients showed progressive disease defined as > 50% increase in the need for red cell transfusions. Treatment was poorly tolerated, with all patients reporting side effects of thalidomide, the most pro...
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The superoxide-forming nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase of human phagocytes comprises membrane-bound and cytosolic proteins, which, upon cell activation, assemble on the plasma membrane to form the... more
The superoxide-forming nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase of human phagocytes comprises membrane-bound and cytosolic proteins, which, upon cell activation, assemble on the plasma membrane to form the active enzyme. Patients with chronic granulomatous disease (CGD) are defective in one of the phagocyte oxidase (phox) components, p47-phox or p67-phox, which reside in the cytosol of resting phagocytes, or gp91-phox or p22-phox, which constitute the membrane-bound cytochrome b(558). In four X-linked CGD patients we have identified novel missense mutations in CYBB, the gene encoding gp91-phox. These mutations were associated with normal amounts of nonfunctional cytochrome b(558) in the patients' neutrophils. In phorbol-myristate-stimulated neutrophils and in a cell-free translocation assay with neutrophil membranes and cytosol, the association of p47-phox and p67-phox with the membrane fraction of the cells with Cys369-->Arg, Gly408-->Glu, and G...
Research Interests: Human Genetics, Humans, Sequence alignment, Electron Transfer, Blood, and 14 moreInfant, Enzyme, NADPH oxidase, Clinical Sciences, Neutrophils, Cytochrome B, Protein Secondary Structure Prediction, Amino Acid Sequence, Amino Acid Substitution Rates, Cell free System, Reference Values, Plasma Membrane, Superoxides, and Respiratory Burst
... Drug-Induced Neutropenia-A Survey for Stockholm 1973-1978 Per Arneborn and Jan Palmblad From the Department of Infectious Diseases, Roslugstull's Hospital, and Department of Medicine IV, Siidersjukhuset, Stockholm, Sweden ...... more
... Drug-Induced Neutropenia-A Survey for Stockholm 1973-1978 Per Arneborn and Jan Palmblad From the Department of Infectious Diseases, Roslugstull's Hospital, and Department of Medicine IV, Siidersjukhuset, Stockholm, Sweden ... In earlier Arta Med Scand 212 Page 4. ...
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We studied the effects of leukotrienes on in vitro functions of neutrophil polymorphonuclear (PMN) granulocytes. Leukotriene B4 (LTB4) evoked a stimulated and directed migration of neutrophils under agarose with an optimum concentration... more
We studied the effects of leukotrienes on in vitro functions of neutrophil polymorphonuclear (PMN) granulocytes. Leukotriene B4 (LTB4) evoked a stimulated and directed migration of neutrophils under agarose with an optimum concentration of 10(-6)M, whereas two nonenzymatically formed isomers (compounds I and II) induced this response at 10(-5)M. Leukotriene C4 (LTC4) and 5-hydroxyeicosate-traenoic acid (5-HETE) did not affect this PMN migration. At the same optimum concentrations, LTB4 and compounds I and II augmented PMN adherence to nylon fibers. The chemotactic and adherence responses were of the same magnitude as with formal-Met-Leu-Phe (fMLP) at 10(-7)M. None of the leukotrienes influenced the spontaneous or phagocytosis-associated chemiluminescence or the ability to kill Staphylococcus aures. The cyclooxygenase inhibitor, indomethacin, inhibited only partly the fMLP-induced migration at high concentrations and stimulated migration at 2.5 x 10(-7)M, suggesting that arachidonic ...
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77 unselected adult patients with acute myeloblastic leukaemia (AML), including practically all AML patients from an area with 1.9 million inhabitants, were randomized for either (1) 5 days pretreatment with 1-asparaginase and... more
77 unselected adult patients with acute myeloblastic leukaemia (AML), including practically all AML patients from an area with 1.9 million inhabitants, were randomized for either (1) 5 days pretreatment with 1-asparaginase and prednisolone followed by a combination of rubidomycin and cytosine arabinoside (ARAP), or (2) treatment with a combination of rubidomycin, cytosine arabinoside and prednisolone without 1-asparaginase pretreatment (RAP). Complete remission was induced with ARAP in 12 patients (31%) and with RAP in 13 patients (34%). Thus pretreatment with 1-asparaginase did not improve the therapeutic response. The overall remission frequency was significantly higher below the age of 60; 50% compared to 13% above this age. Side-effects such as liver dysfunction, nausea and vomiting were more common in patients pretreated with 1-asparaginase. Sterilization of the gut did not improve the remission frequency with either regime.
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A case of visceral leishmaniasis is presented, where a pre-existing polycythemia vera obscured signs of the infection.
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We have studied effects of two partially purified human leukocyte (alpha) interferon (IFN) preparations (PIF-A and PIF-B) and a highly purified fibroblast (beta) IFN on the functional activity of normal human neutrophils (PMNs). In vitro,... more
We have studied effects of two partially purified human leukocyte (alpha) interferon (IFN) preparations (PIF-A and PIF-B) and a highly purified fibroblast (beta) IFN on the functional activity of normal human neutrophils (PMNs). In vitro, PIF-B conferred a significant and dose-dependent enhancement of chemiluminescence (CL) induced both by phagocytosis and a soluble stimulus, f-Met-Leu-Phe, and decreased killing of Staph. aureus. In contrast, PIF-A caused only a slight inhibition of bactericidal activity and had no effects on CL. beta-IFN had no effects on either bactericidal activity or CL. Migration under agarose was decreased with all of the IFN but phagocytosis and release of enzymes was not affected. PMNs from seven patients treated with PIF-A for multiple myeloma exhibited increased CL responses but no other PMN functions were affected. The findings that human IFN preparations affect PMN functions indicate that high-dose IFN therapy of immunocompromised patients should be carefully evaluated for the possibility of increased infectious complications.
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We prospectively tested the hypothesis that prevention of herpes simplex virus infection with acyclovir might also reduce the incidence of bacterial infections in adult patients with acute leukaemia. During the first induction therapy a... more
We prospectively tested the hypothesis that prevention of herpes simplex virus infection with acyclovir might also reduce the incidence of bacterial infections in adult patients with acute leukaemia. During the first induction therapy a double-blind, randomized and placebo-controlled study was undertaken. Fifty-two patients were treated with 200 mg acyclovir orally four times daily throughout the induction period, whereas 55 patients received placebo. The groups were comparable with regard to age, cytotoxic chemotherapy and duration of neutropenia. Bacteraemias were significantly fewer in the acyclovir group (20 versus 41 episodes; P = 0.007). The number of isolated microorganisms causing bacterial or fungal infections was also lower during acyclovir prophylaxis (52 isolates, versus 93 isolates; P = 0.02). There was no significant difference between the groups with regard to the number of clinically documented infections or fevers of unknown origin. Herpes simplex virus isolations occurred only in the placebo group (P = 0.001). Thus, oral acyclovir prophylaxis was associated with reductions of all microbiologically documented infections suggesting that prevention of herpes simplex virus reactivation in acute leukaemia patients may reduce the occurrence of other infections.
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ABSTRACT Auranofln, a new anti-arthritic oral gold compound, was studied with regard to its effects on the functions of the neutrophil polymorphonuclear (PMN) granulocyte. Firstly, human PMNs were preincubated in vitro with auranofln in... more
ABSTRACT Auranofln, a new anti-arthritic oral gold compound, was studied with regard to its effects on the functions of the neutrophil polymorphonuclear (PMN) granulocyte. Firstly, human PMNs were preincubated in vitro with auranofln in concentrations ranging from 1-4 µ;g/ml, whereafter PMN functions in vitro were assayed. Following such exposure, PMN adherence to nylon fibres was significantly increased and this enhancement was most pronounced at the lower auranofln concentrations (p
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We studied the efficacy of ceftazidime as initial monotherapy in 82 adult patients with acute leukemia who developed 123 febrile episodes during induction chemotherapy. 88% of the patients survived their febrile episode(s), whereas 10%... more
We studied the efficacy of ceftazidime as initial monotherapy in 82 adult patients with acute leukemia who developed 123 febrile episodes during induction chemotherapy. 88% of the patients survived their febrile episode(s), whereas 10% died of infection. When assessed at 72 h after initiation of treatment (early evaluation), 43/123 episodes (35%) had been successfully treated with ceftazidime. These 43 favourable responses were seen in 15/47 (32%) microbiologically documented infections, 20/46 (43%) clinically defined infections, and 8/30 (27%) fever of unknown origin (FUO). At the resolution of fever (late evaluation) 115 episodes were evaluable, and 48% had responded successfully to ceftazidime. Successful treatment was most frequently observed in FUO, 18/29 (62%). In contrast, only 19/44 (43%) microbiologically documented infections and 18/42 (43%) clinically defined infections were cured during ceftazidime treatment. In bacteremia the response rate was only 8/26 (31%). Thus, this study shows that although ceftazidime can be safely used for initial empirical monotherapy in neutropenic leukemia patients, the need for therapy modification is high and few patients with serious infections are cured with ceftazidime alone.
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Previous studies have shown that the small-bowel shunt operation for morbid obesity may be followed by signs of enhanced cell-mediated immunity and polymorphonuclear (PMN) granulocyte bactericidal capacity. In the present study seven... more
Previous studies have shown that the small-bowel shunt operation for morbid obesity may be followed by signs of enhanced cell-mediated immunity and polymorphonuclear (PMN) granulocyte bactericidal capacity. In the present study seven patients, operated 4 months--4.5 years previously and exhibiting postoperative arthralgias, arthritis, and/or skin rashes, were investigated with regard to their PMN adherence and bactericidal capacity and plasma levels of complement factors 3 and 4 (C3 and C4). There patients showed a decreased PMN bactericidal capacity compared both with 10 other shunt-operated patients without skin and joint symptoms and with healthy controls, whereas PMN adherence was lower than for the non-symptomatic patients but similar to that of the controls. Two patients had C3 levels above the reference value; all had normal C4 values. Thus, a small-bowel shunt operation for obesity, complicated by skin and joint symptoms, might be associated with decreased PMN bactericidal capacity.
Research Interests: Obesity, Cell Adhesion, Humans, Female, Male, and 6 moreArthritis, Clinical Sciences, Middle Aged, Neutrophils, Adult, and Small Intestine
We evaluated whether various alkylglycerols would initiate a functional response of human neutrophils or modify responses induced by a formyl peptide (fMLP) in vitro. We found that platelet activating factor (PAF) was the most potent with... more
We evaluated whether various alkylglycerols would initiate a functional response of human neutrophils or modify responses induced by a formyl peptide (fMLP) in vitro. We found that platelet activating factor (PAF) was the most potent with regard to the ability to produce an oxidative response (assessed by cytochrome c reduction and/or chemiluminescence), followed by ET-16-OCH3. Lyso-PAF, ET-18-OCH3, batyl- and chimyl alcohols exhibited only a weak activity. PAF was also the most efficient lipid conferring a rise of intracellular calcium concentrations ([Ca2+]i). ET-16-OCH3, ET-18-OCH3 and lysoPAF were less potent, although maximal [Ca2+]i levels were similar to that of 0.1 mumol/l fMLP. The kinetics of the calcium responses were highly specific for each ether lipid. When neutrophils had been treated with PAF or ET-18-OCH3 and were subsequently stimulated by fMLP, enhancement of the oxidative response was noted. Thus, this study shows that there was an association between the ability of an alkylglycerol to initiate oxidative and calcium responses, indicating strict structure-activity relationships for these lipids.
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Four different functions of the immune defence were studied in six men undergoing open-heart surgery with cardiopulmonary bypass (CPB). Pre-operatively, a few hours after and three days after surgery the following tests were performed:... more
Four different functions of the immune defence were studied in six men undergoing open-heart surgery with cardiopulmonary bypass (CPB). Pre-operatively, a few hours after and three days after surgery the following tests were performed: (I) in vivo phagocytic and metabolic functions of the reticuloendothelial system (RES), (II) haemolytic activity of blood monocytes, (III) nitroblue tetrazolium (NBT) reduction by granulocytes, and (IV) bactericidal capacity of granulocytes. Compared to the pre-operative values, the RES functions were unchanged postoperatively, whereas there was a significant increase in the haemolytic activity of monocytes and in the NBT reduction of granulocytes. The capacity of the granulocytes to kill bacteria was normal a few hours after surgery, but significantly increased on day 3. No infectious complications occurred and all patients recovered uneventfully. These results suggest that, at the present time, open-heart surgery under CPB is accompanied by an increased activity of granulocytes and monocytes in the early postoperative period.
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Research Interests: Calcium, Rheumatoid Arthritis, Multidisciplinary, Signal Transduction, Humans, and 13 moreEndothelial Cells, Nitric oxide, Immune modulation, Inflammatory disease, Lipopolysaccharides, Endothelial cell, Tumor necrosis factor-alpha, Protein Expression, Protein isoforms, Tumor Necrosis Factor–α (TNF), Nitrites, Intracellular Calcium, and Interleukin
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Since the essential fatty acid linoleic acid is the precursor of arachidonic acid and thus of leukotrine B4 (LTB4), essential fatty acid deficiency (EFAD) may result in decreased synthesis of this stimulator of neutrophil granulocyte... more
Since the essential fatty acid linoleic acid is the precursor of arachidonic acid and thus of leukotrine B4 (LTB4), essential fatty acid deficiency (EFAD) may result in decreased synthesis of this stimulator of neutrophil granulocyte functions. Peritoneal and blood neutrophils from rats fed a diet with only 0.3% of energy requirements as linoleic acid and exhibiting biochemical evidence of EFAD showed substantial functional impairments compared to neutrophils from rats maintained on a diet with 3% of the energy requirement as linoleic acid. Oxidative burst activation (assessed by chemiluminescence), chemotaxis and aggregation were impaired upon stimulation with formylpeptides or the ionophore A23187. In contrast, these functions were intact on stimulation with exogenous LTB4. Chemiluminescence was slightly but not significantly enhanced in EFAD rat neutrophils compared to controls when stimulated with phorbol myristate acetate (PMA). There were no differences between EFAD and control peritoneal neutrophils in the number of f-met-leu-phe (fMLP) receptors, or in their affinity for the ligand, assessed with fML(3H)P. The fraction of responding cells also were similar, assessed with dichlorofluorescein diacetate fluorescence. Moreover, the endogeneous LTB4 production in response to A23187 or fMLP was decreased by 57.7% and 63.5%, respectively, in EFAD peritoneal neutrophils. Thus, EFAD was associated with reductions of LTB4 production and neutrophil responsiveness to A23187 and formylpeptides but not to LTB4 or PMA, which supports the hypothesis that endogeneous LTB4 may contribute to the activation of neutrophil functions involved in inflammation and host defense.
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The International Prognostic Scoring System (IPSS), based on the number of cytopenias, percentage of bone marrow blasts and cytogenetics, is an important prognostic tool for patients with myelodysplastic syndrome (MDS). In addition,... more
The International Prognostic Scoring System (IPSS), based on the number of cytopenias, percentage of bone marrow blasts and cytogenetics, is an important prognostic tool for patients with myelodysplastic syndrome (MDS). In addition, factors such as high bone marrow cellularity and lactate dehydrogenase levels have been associated with an adverse outcome, spontaneously and after chemotherapy. Recently, increased bone marrow angiogenesis, measured as, e.g. microvascular density (MVD), was reported to be more intense in high-risk than in low-risk MDS. To assess the prognostic role of MVD in MDS, a cohort of 56 patients, thoroughly investigated for various clinical and morphological parameters, were followed-up for survival > or =60 months after the diagnostic analysis. As a group MDS patients had higher MVD compared to healthy controls (p<0.02). The highest median MVD value was observed in the RAEB group, but there was no overall significant difference between the FAB groups. No significant correlations were observed between MVD and peripheral blood counts, bone marrow cellularity, percentage of bone marrow blasts and CD34 positive cells, apoptotic index (TUNEL), proliferation index (MIB-1), erythroid index, FAB group and IPSS score. MVD was not correlated to overall survival. In contrast, bone marrow blast count <5%, low or normal cellularity, as well as a high erythroid index, indicated a favorable survival. Thus, our data do not support an important prognostic role of angiogenesis, reflected by microvessel density, in the myelodysplastic syndromes.
Research Interests: Leukemia, Apoptosis, Humans, Myelodysplastic Syndrome, Female, and 16 moreMale, Bone marrow, Risk factors, Clinical Sciences, Aged, Middle Aged, Adult, Prognosis, Risk Factors, Indexation, Cell Proliferation, Lactate dehydrogenase, Low Risk, Overall Survival, Predictive value of tests, and Cohort Studies
Several laser procedures, extracorporeal lithotripsies (ESWL), and high-velocity missile trauma generate pressure transients that are transmitted through the tissues. Despite several publications demonstrating shock wave-induced tissue... more
Several laser procedures, extracorporeal lithotripsies (ESWL), and high-velocity missile trauma generate pressure transients that are transmitted through the tissues. Despite several publications demonstrating shock wave-induced tissue injury, little is known about its pathophysiology. This study introduces an in vitro model for studying shock wave effects on endothelial cell (EC) monolayers. A Nd:YAG laser-driven flyer-plate technique was used to generate shock waves. Physical characteristics were determined with a pressure transducer, a high-speed video camera, and sequential photography. Biological effects were studied with phase contrast and lightfield microscopy, computerized morphometry, immunocytochemistry, spectrophotometry, and enzyme-linked immunosorbent assay (ELISA). The shock waves generated were highly reproducible. Cavitation was verified and quantified, and its extent could be varied in the vials. Exposed cultures exhibited areas with cell membrane damage and cell detachment. Release of LD was elevated (P < 0.01) in exposed vials. The EC lesions were larger (>P < 0.01) in cultures submitted to high vs. low extent of cavitation. The flyer-plate model can be used to subject cell monolayers to defined and reproducible shock waves causing immediate cell injury similar to the previously reported vascular lesions associated with ESWL, pulsed lasers, and blast trauma. With the flyer-plate model, such lesions may be further studied on the cellular and subcellular levels.
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Omega-3 fatty acids, e.g., dokosahexaenoic acid (DHA) and eikosapentaenoic acid (EPA), ameliorate inflammatory reactions by various mechanisms, but the role of prostaglandins remains unclear. Our aim was to determine if dietary... more
Omega-3 fatty acids, e.g., dokosahexaenoic acid (DHA) and eikosapentaenoic acid (EPA), ameliorate inflammatory reactions by various mechanisms, but the role of prostaglandins remains unclear. Our aim was to determine if dietary supplementation with a DHA-rich fish oil influenced the release of PGF(2alpha) from peripheral blood mononuclear cells (PBMC). In the OmegAD study, 174 Alzheimer disease patients received either 1.7 g DHA plus 0.6 g EPA or a placebo daily for six months. PBMCs from the 21 (9 on fish oil and 12 on placebo) first-randomized patients were stimulated with either lipopolysaccharide (LPS) or phytohemagglutinin (PHA) before and after 6 months. Our results showed that plasma concentrations of DHA and EPA increased significantly at 6 months in the omega-3 group. PGF(2alpha) release from LPS- (but not from PHA-) stimulated PBMC was significantly diminished in this group; no change was noted in the placebo group. PGF(2alpha) changes correlated inversely with changes in plasma DHA and EPA. Decreased IL-6 and IL-1(beta) levels correlated with decreased PGF(2alpha) levels. The stimulus-specific PGF(2alpha) release from PBMC after 6 months of oral supplementation with the DHA-rich fish oil might be one event related to reduced inflammatory reactions associated with omega-3 fatty acid intake.
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During the 10-year period 1976-1985, a total of 154 cases of blood dyscrasia were reported in Sweden which were evaluated as having a probable or possible causal relationship with trimethoprim-sulphamethoxazole (T-SM). There were 61 cases... more
During the 10-year period 1976-1985, a total of 154 cases of blood dyscrasia were reported in Sweden which were evaluated as having a probable or possible causal relationship with trimethoprim-sulphamethoxazole (T-SM). There were 61 cases of leucopenia (of which 16 had agranulocytosis), 28 cases of thrombocytopenia, and two of non-haemolytic anaemia. There were also 32 cases of bicytopenia and 31 cases of tricytopenia. The median age varied from 38 years in the leucopenia group to 81 years in those with tricytopenia. The overall fatality rate was 17%, ranging from 2% in the group with mild leucopenia to 52% in the group with tricytopenia. In relation to sales and prescription data, the overall incidence of reported T-SM blood dyscrasias was 5.3 per million defined daily doses, and among out-patients the incidence was one case per 18,000 prescriptions. Thus the overall incidence of any blood reaction to T-SM appears to be low. In relation to prescription data, elderly people were overrepresented among the serious reactions.
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A 53-year male patient, treated for rheumatoid arthritis with sulphasalazine, developed a total agranulocytosis. When this state had prevailed for at least 10 d no bone marrow granulocyte progenitor cells were detectable. Intravenous... more
A 53-year male patient, treated for rheumatoid arthritis with sulphasalazine, developed a total agranulocytosis. When this state had prevailed for at least 10 d no bone marrow granulocyte progenitor cells were detectable. Intravenous GM-CSF treatment was initiated 5 d later, and the patient recovered within the next 6 d. GM-CSF treatment for severe agranulocytosis deserves further investigation.
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Arachidonic acid is metabolized in neutrophils by lipoxygenase to leukotrienes, which are suggested to play a central role in inflammation. The antirheumatic drug auranofin (4 micrograms/ml) was found not to inhibit neutrophil production... more
Arachidonic acid is metabolized in neutrophils by lipoxygenase to leukotrienes, which are suggested to play a central role in inflammation. The antirheumatic drug auranofin (4 micrograms/ml) was found not to inhibit neutrophil production of the lipoxygenase products 5-HETE-, 15-HETE and LTB4, in vitro when stimulated with the calcium ionophore A23187. Auranofin, however, modulated neutrophil aggregation, enzyme release and chemotaxis induced by LTB4. The results suggest that auranofin may exert some of its antirheumatic effects through affecting neutrophil responses to leukotrienes.
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ABSTRACT Beside the inability to produce superoxide ions, neutrophils (PMN) from chronic granulomatous disease (CGD) patients show other functional defects, e.g. abnormal membrane potential reactions. We observed that PMN from a female... more
ABSTRACT Beside the inability to produce superoxide ions, neutrophils (PMN) from chronic granulomatous disease (CGD) patients show other functional defects, e.g. abnormal membrane potential reactions. We observed that PMN from a female CGD carrier, with a discrete mutation in one allele of the pg91(phox) gene and exhibiting extreme lyonization, showed a consistently and remarkably delayed PMN cytosolic calcium response to the tripeptide fMLP or leukotriene B4 (LTB4). In keeping with results from other CGD patients, membrane potential changes were abnormal, whereas chemotaxis and adherence was normal. Since phospholipase D-generated metabolites are important for calcium transients we examined the generation of phosphatidic acid, but found that to be normal. A male CGD patient with pg91(phox) deficiency exhibited a trend toward prolongation of this calcium response, whereas two other CGD patients (one with p47 and one with 67(phox) deficiencies) had normal calcium transients. Thus, our finding points to a defect of the stimulus response coupling for fMLP and LTB4, which is supposed to be characteristic for this patient or a subset of CGD patients.
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Research Interests: Stem Cells, Immunohistochemistry, Stem Cell, Human, real time PCR, and 20 moreCaesarean Section, Cell Differentiation, Pregnancy, Humans, Endothelial Cells, Mice, Female, Animals, Male, Animal Model, Human reproduction, Bone Marrow Transplantation, Donor, Adult, Endothelial cell, Cesarean Section, Utero, Endometrium, Blood Vessel, and Hematopoietic Stem Cell Transplantation
Chronic granulomatous disease (CGD) is an inherited immunodeficiency caused by defects in any of four genes encoding components of the leukocyte nicotinamide dinucleotide phosphate, reduced (NADPH) oxidase. One of these is the autosomal... more
Chronic granulomatous disease (CGD) is an inherited immunodeficiency caused by defects in any of four genes encoding components of the leukocyte nicotinamide dinucleotide phosphate, reduced (NADPH) oxidase. One of these is the autosomal neutrophil cytosolic factor 1 (NCF1) gene encoding the p47phoxprotein. Most (>97%) CGD patients without p47phox (A47° CGD) are homozygotes for one particular mutation in NCF1, a GT deletion in exon 2. This is due to recombination events between NCF1 and its two pseudogenes (ψNCF1) that contain this GT deletion. We have previously set up a gene-scan method to establish the ratio of NCF1 genes and pseudogenes. With this method we now found, in three CGD families patients with the normal number of two intact NCF1 genes (and four ψNCF1 genes) and in six CGD families, patients with one intact NCF1 gene (and five ψNCF1 genes). All patients lacked p47phox protein expression. These results indicate that other mutations were present in their NCF1 gene than the GT deletion. To identify these mutations, we designed PCR primers to specifically amplify the cDNA or parts of the genomic DNA from NCF1 but not from the ψNCF1 genes. We found point mutations in NCF1 in eight families. In another family, we found a 2,860-bp deletion starting in intron 2 and ending in intron 5. In six families the patients were compound heterozygotes for the GT deletion and one of these other mutations; in two families the patients had a homozygous missense mutation; and in one family the patient was a compound heterozygote for a splice defect and a nonsense mutation. Family members with either the GT deletion or one of these other mutations were identified as carriers. This knowledge was used in one of the families for prenatal diagnosis. Hum Mutat 27(12), 1218–1229, 2006. © 2006 Wiley-Liss, Inc.