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Biomedical subjects

J Palmblad

Publications and source records attributed to J Palmblad.

At least 55 records · Page 3Linked to original sources
PubMed1997

Dose-dependent enhancements by interferon-gamma on functional responses of neutrophils from chronic granulomatous disease patients.

Interferon-gamma (IFN-gamma) is recommended as prophylaxis against infections in patients with chronic granulomatous disease (CGD). However, since the optimal dose, the dosing interval, and the mechanisms of action are not well-defined, we studied the effects on CGD neutrophil (PMN) functions ex vivo of interferon-gamma (IFN-gamma). Evaluations were made on oxidative capacity, measured by superoxide anion production and chemiluminescence after stimulation with f-met-leu-phe (f-MLP) or phorbol-myristate-acetate, the killing of Aspergillus fumigatus hyphae (assessed as conversion of the tetrazolium salt MTT to formazan), and on the expression of Fc gammaRI receptor (CD64). After randomization, 9 CGD patients (4 with gp91phox, 3 with p47phox, 1 with p67phox deficiency and 1 with unspecified CGD) were given IFN-gamma, either 50 or 100 microg/m2 subcutaneously on 2 consecutive days after double blinded randomization. Furthermore, one female hyperlyonized X-linked carrier with a CGD phenotype was also studied separately after IFN-gamma treatment. Evaluations were made the day before and on days 1, 3, 8, and 18 after IFN-gamma administration. The killing of A fumigatus hyphae, being close to zero before IFN-gamma, was enhanced on day 3, being 36% higher than pretreatment values in the high-dose CGD group and 17% in the low-dose group. The expression of Fc gammaRI on PMN increased 3.7-fold in the high-dose and 2.3-fold in the low-dose CGD group, being maximal on day 1. Oxidative functions were raised in only selected patients represented by different subtypes of CGD. The hyperlyonized carrier of X-linked CGD responded to IFN-gamma with more enhanced oxidative responses and Aspergillus killing of her PMNs than the other patients. This study suggests that a higher dose of IFN-gamma than currently recommended confers transient enhancements of certain PMN functions in CGD patients.

Adolescent↗
PubMed1997

Mutations in the granulocyte colony-stimulating factor receptor gene in patients with severe congenital neutropenia.

Previously, nonsense mutations in the gene encoding the granulocyte colony-stimulating factor receptor (G-CSF-R) have been described in three patients with severe congenital neutropenia (SCN) (Proc Natl Acad Sci USA 1994; 91: 4480; New Engl J Med 1995; 333: 487). The mutations resulted in the truncation of the carboxy-terminal region of G-CSF-R essential for transduction of maturation signals. Two of these patients developed acute myeloblastic leukemia (AML). We present the results of a search among 20 additional cases of congenital neutropenia (CN) and SCN for the presence of mutations in the cytoplasmic domain of G-CSF-R. This series includes patients with familial and nonfamilial forms of CN and SCN. Mutations in the G-CSF-R gene were found in two new SCN cases. These mutations were nonsense mutations, located in the same cytoplasmic region of G-CSF-R as those found earlier, resulting in the truncation of the C-terminus. Both of these patients developed AML. None of the other patients showed clinical symptoms or cytogenetic features indicative of AML or progression to leukemia. The analysis in this extended series of patients thus has revealed five SCN cases with G-CSF-R mutations, four of whom developed AML. These results add support to the notion that mutations in the G-CSF-R gene, affecting the maturation signaling function of the receptor, define a distinct subgroup of SCN with increased susceptibilty to AML.

Adolescent↗
PubMed1997

Low circulating leptin levels in protein-energy malnourished chronically ill elderly patients.

OBJECTIVE: To evaluate serum leptin, a fat cell-derived protein, levels in relation to the malnutrition often observed in chronic disease. DESIGN: A comparison of circulating leptin concentrations in malnourished chronically ill elderly and in age-matched controls. SETTING: A university-affiliated teaching hospital in Stockholm, Sweden. SUBJECTS: Nineteen protein-energy malnourished elderly patients (74 +/- 1 years) with various chronic nonmalignant diseases and 18 healthy controls (72 +/- 1 years). MAIN OUTCOME MEASURES: Serum leptin levels measured by radioimmunoassay technique, nutritional status as expressed by body mass index (kg m[-2]), triceps skin fold, arm muscle circumference and serum albumin, and serum orosomucoid concentrations indicating inflammatory status. RESULTS: Patients and controls displayed body mass indexes of 17.4 +/- 0.7 and 25.0 +/- 1.1 (P < 0.001), respectively. Triceps skin fold (TSF) measurements revealed a pronounced fat depletion in the patients, being 8.5 +/- 0.9 and 22.3 +/- 1.5 mm (P < 0.001) in female and 6.1 +/- 0.7 and 10.8 +/- 0.8 mm (P < 0.001) in male patients and controls, respectively. Patient serum leptin concentrations were less than half of the corresponding concentrations in the controls, 4.3 +/- 1.1 and 9.3 +/- 1.3 ng mL(-1)(P < 0.01), respectively. The highest leptin concentrations were registered in female controls, 12.1 +/- 1.6 ng mL(-1). The serum leptin levels in the controls correlated with TSF (r = 0.74: P < 0.001). No such correlation was found in the patients. CONCLUSIONS: Serum leptin levels were low and did not seem to be directly associated with fat and muscle depletion in elderly patients with chronic illness, whereas they appeared to be positively correlated to body fat in healthy elderly.

Adipose Tissue↗
PubMed1997

Enhanced generation of interleukins 1 beta and 6 may contribute to the cachexia of chronic disease.

The cachexia of disease may be promoted by proinflammatory cytokines, eg, interleukin (IL) 1 beta, tumor necrosis factor alpha (TNF-alpha), and IL-6. These, as well as some antiinflammatory cytokines, eg, IL-1 receptor antagonist (IL-1ra), IL-10, and transforming growth factor beta 1 (TGF-beta 1), were analyzed in serum (IL-6, IL-1ra, IL-10, TGF-beta 1) and stimulated blood monocytes (IL-1 beta, TNF alpha, IL-6) obtained from elderly patients with protein-energy malnutrition (PEM). Twenty-one uninfected malnourished patients aged 75 +/- 1 y (mean +/- SD), with a body mass index (BMI; in kg/m2) of 17.2 +/- 0.5 and various noncancer disorders, and 22 healthy matched control subjects aged 72 +/- 1 y, with a BMI of 25.4 +/- 0.7 (significantly different from patients, P < 0.001), were included. Fifteen patients and their corresponding control subjects were reexamined 3 mo later. Isolated monocytes were stimulated with lipopolysaccharide (LPS) and concentrations of IL-1 beta, TNF-alpha, and IL-6 were determined. Serum concentrations of IL-6, IL-1ra, IL-10, TGF-beta 1, and acute-phase reactants were analyzed. Serum concentrations of orosomucoid and IL-6 were higher in the malnourished subjects than in the control subjects (1.14 +/- 0.1 compared with 0.8 +/- 0.3 g/L, P < 0.001; and 5 ng/L compared with undetectable concentrations, P < 0.01, respectively). Higher generation of IL-1 beta (2.7-fold; P < 0.05) and IL-6 (3.7-fold; P < 0.05) was found in monocytes from patients with PEM relative to the control subjects when monocytes were stimulated with 0.1 microgram LPS/L. Monocyte TNF generation and serum concentrations of IL-10, IL-1ra, and TGF-beta 1 did not differ. Similar results were obtained at follow-up. IL-1ra was negatively correlated with delayed cutaneous hypersensitivity (r = -0.34, P < 0.05). We conclude that enhanced generation of proinflammatory cytokines such as IL-6 and IL-1 beta in malnourished patients may contribute to the PEM often encountered in chronic nonmalignant disorders.

Aged↗
PubMed1996

Disturbed interaction of p21-rac with mutated p67-phox causes chronic granulomatous disease.

Chronic granulomatous disease (CGD) is characterized by the failure of phagocytic leukocytes to generate superoxide, needed for the intracellular killing of microorganisms. This is caused by mutations in any one of the four subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In a rare, autosomal recessive form of CGD, a 67-kD cytosolic component of this enzyme (p67-phox) is missing. We here report on a patient with a mutation in the p67-phox gene that leads to expression of a nonfunctional p67-phox protein. The purified granulocytes of this patient failed to produce superoxide and contained about half of the normal amount of p67-phox. Analysis of the cDNA and genomic DNA of this patient showed that the patient is a compound heterozygote for a triplet nucleotide deletion in the p67-phox gene, predicting an in-frame deletion of lysine 58 in the p67-phox protein and a larger deletion of 11-13 kb in the other allele. Interestingly, the 58Lys deletion in p67-phox disrupts the interaction with p21-rac1, a ras-related protein involved in the activation of the NADPH oxidase. In contrast to normal neutrophils, in which p47-phox and p67-phox translocate to the plasma membrane upon cell activation, the cells of the patient did not show this translocation, indicating that an interaction between p67-phox and p21-rac1 is essential for translocation of these cytosolic proteins and activation of the NADPH oxidase. Moreover, this CGD patient represents the first case of disease caused by a disturbed binding of a ras-related protein to its target protein.

Biological Transport↗
PubMed1996

Biphasic effect of ATP on neutrophil functions mediated by P2U and adenosine A2A receptors.

In agreement with previous findings, the oxidative burst induced by fMet-Leu-Phe (fMLP) in polymorphonuclear neutrophils was enhanced by adenosine triphosphate (ATP) and uridine 5'-triphosphate (UTP), although these nucleotides were inactive as agonists per se. However, the enhancement by ATP was rapidly reversed to an inhibition by prolonged incubation. Adenosine diphosphate (ADP) was always inhibitory. Inhibition mediated by ATP coincided with its conversion into ADP, adenosine monophosphate (AMP), and adenosine. In addition, the inhibitory effects of ATP and ADP on the oxidative burst were virtually abolished by 9-chloro-2-(2-furanyl)-5,6-dihydro-[1,2,4]-triazolo[1,5] quinazolin-5-imine monomethanesulfonate (CGS 15943), a nonselective adenosine receptor antagonist, whereas the priming effect of ATP was antagonized by adenosine. Both ATP and UTP showed a similar potency in activating elastase release, intracellular inositol-(1,4,5)-triphosphate (IP3) formation and an increase in cytosolic calcium. Neither ATP nor UTP affected the initial rise in cytosolic calcium induced by fMLP, but did enhance the secondary calcium increase. When added simultaneously with fMLP, ADP and adenosine abolished this second calcium peak without influencing the first. These results indicate that purine and pyrimidine nucleotides acting on P2U-like receptors, which are coupled to the IP3 pathway, can increase calcium, release elastase, and enhance the oxidative burst induced by chemo-kines. Adenosine formed by hydrolysis from ATP and ADP, by contrast, reduces the oxidative bursts and the influx of extracellular calcium induced by fMLP.

Adenosine↗
PubMed1996

In vitro effects of ethanol on polymorphonuclear leukocyte membrane receptor expression and mobility.

The hampered inflammation and host defense seen in alcoholics may be due to impairment of functional responses of neutrophil polymorphonuclear leukocytes (PMN). We have shown that ethanol inhibits the oxidative metabolism of PMN induced by surface receptor dependent stimuli, such as N-formyl-methionyl-leucyl-phenylalanine (fMLP) and opsonized zymosan. Because the unresponsiveness might be due to reduced numbers of surface receptors, we assessed the expression of CR1, Fc-gamma, and fMLP receptors as well as membrane fluidity after treatment of PMN with ethanol in vitro. Ethanol impaired the induced expression of CR1 and fMLP receptors to 71% and 51% of control, respectively, but did not affect the resting level of CR1 nor Fc-gamma receptor expression. Furthermore, the mobility of cell membrane glycoconjugates was increased by ethanol. However, phagocytosis, a functional response dependent on membrane rheology, was unaffected. Because the results indicated an effect of ethanol on mobilization of receptors from intracellular stores, we assessed lactoferrin release, which was reduced to 59%. Thus, ethanol appeared to hamper the upregulation of PMN surface receptors or functional subsets of those stored in granules. Ethanol also increased the mobility of the cell membrane. These reactions were accompanied by reductions in the functional responses mediated by either class of receptors.

Cells, Cultured↗
PubMed1996

Inhibition of neutrophil-dependent cytotoxicity for human endothelial cells by antirheumatic drugs.

Because polymorphonuclear (PMN) neutrophils are major effector cells in vasculitides, we assessed whether disease-modifying antirheumatic drugs impaired the ability of human PMNs to lyse human umbilical vein endothelial cells (HUVECs) in vitro. HUVECs were grown to confluence and labeled with chromium 51. PMNs, stimuli, and antirheumatic drugs were added stepwise, and the release of 51Cr was subsequently assessed. Lipoxin A4 (LXA4) and the oligopeptide fMLP, activating PMNs by surface receptors, conferred highly significant cytolysis that was dose-dependently reduced when auranofin, gold sodium aurothiomalate (GSTM), and sulfasalazine and its metabolites sulfapyridine and 5-ASA were added to the assay system. This protection remained, but with stimulus- and drug-specific variations, when either PMNs or HUVECs alone were treated with drugs before washings and PMN activation. In contrast, methotrexate did not protect HUVECs. Cytotoxicity conferred by the ionophore A23187 was inhibited by auranofin and GSTM only. Likewise, when HUVEC cytolysis was induced by two major cytotoxic mechanisms of PMNs, exogenous H2O2, or PMN lysates, auranofin and GSTM hampered lysis significantly. Thus in this in vitro model of vasculitis, auranofin, GSTM, sulfasalazine, sulfapyridine, and 5-ASA--but not methotrexate--dose-dependently reduced the PMN-dependent endothelial cell damage by effects on the PMNs as well as effects on the HUVECs.

Antirheumatic Agents↗
PubMed1996

[Chronic neutropenia].

Chronic severe neutropenia can now be successfully treated with G-CSF (granulocyte colony stimulating factor). The granulocyte count is often normalised and the frequency of infections dramatically reduced. However, the congenital form of the disease has been observed to be associated with a substantial risk of acute leukaemia and osteoporosis, although it is not known whether this risk is intrinsic to the disease or related to the treatment. To improve the knowledge of the natural history of the disease and the benefits and risk of treatment, an international registry has been established. The authors of the article, who are Nordic liaison physicians for the registry, urge all those caring for patients with chronic neutropenia to contact them for discussions as to the inclusion of their patients into the register.

Bone Marrow Transplantation↗
PubMed1995

1-O-hexadecyl-2-metoxy-glycero-3-phosphatidylcholine--a methoxy ether lipid inhibiting platelet activating factor-induced platelet aggregation and neutrophil oxidative metabolism.

Whether or not two alkylglycerols could initiate a functional response in human platelets or modify responses induced by platelet activating factor (PAF) was evaluated. It was found that 1-100 microM 1-O-hexadecyl-2-metoxy-glycero-3-phosphatidylcholine (Et-16-OCH3) induced platelet aggregation but 1-O-hexadecyl-sn-glycerol (chimyl alcohol; CA) did not. Et-16-OCH3-induced platelet aggregation was abolished by pretreatment with the PAF receptor antagonist WEB 2086. While CA had no effect on platelet aggregation induced by PAF, pretreatment with Et-16-OCH3 (0.1 microM or higher) significantly inhibited platelet aggregation induced by PAF, but had no effect on aggregation caused by ADP, thrombin or phorbol myristate acetate (PMA). A receptor binding study using radiolabelled [3H]WEB 2086 showed that Et-16-OCH3 exerts its actions through interaction with the PAF receptor. Moreover, Et-16-OCH3 inhibited neutrophil chemiluminescence responses induced by PAF, but not reactions to PMA or a formyl peptide. Finally, 1 microM Et-16-OCH3 induced a rise in the intracellular calcium concentration in platelets equal to that induced by PAF and also had an calcium ionophore-like effect at 100 microM. Thus, this study shows that Et-16-OCH3 is both a potent inducer of platelet aggregation and an inhibitor of PAF-induced platelet aggregation and neutrophil chemiluminescence, through interaction with the PAF receptor.

Azepines↗
PubMed1995

Development and characterization of essential fatty acid deficiency in human endothelial cells in culture.

We induced an essential fatty acid deficiency (EFAD) in human umbilical vein endothelial cells by culture in medium with 20% (vol/vol) delipidated fetal calf serum. EFAD, reflected by decreased cellular linoleic acid (18:2 omega 6) and arachidonic acid (20:4 omega 6) and emergence of the oleic acid derivative 5,8,11-eicosatrienoic acid (20:3 omega 9; Mead's acid), was evident after 1 week of culture and became pronounced after 2 weeks. Beyond that time point, control cells (cultured in 20% normal fetal calf serum) grew deficient of 18:2 omega 6, and EFAD cells died. 18:2 omega 6 addition to EFAD cells resulted in dose-dependent increases of 18:2 omega 6 and 20:4 omega 6. 20:4 omega 6 or 5,8,11,14,17-eicosapentaenoic acid (20:5 omega 3) additions resulted in normalization of these acids, and conversion of 20:5 omega 3 to 4,7,10,13,16,19-docosahexaenoic acid (22:6 omega 3) was noted. Agonist-induced increases in concentrations of prostacycline (prostaglandin I2; PGI2) and cytosolic Ca2+, [Ca2+]i, were reduced in EFAD cells and not restored by 18:2 omega 6 or 20:4 omega 6 additions. Change of the medium in EFAD cultures 1 day before the experiments decreased 20:3 omega 9 and normalized the PGI2 production and [Ca2+]i changes, whereas addition of 20:3 omega 9 to control cells impaired the [Ca2+]i response, indicating a suppressive effect of 20:3 omega 9. Thus, EFAD in endothelial cells is associated with abnormalities of eicosanoid and second-messenger production partly attributable to 20:3 omega 9 accumulation. Moreover, the gradual emergence of 18:2 omega 6 deficiency in regularly grown control cells underlines the need for careful analysis of fatty acids in long-term cell cultures.

Calcium↗
PubMed1995

Rabbit polymorphonuclear granulocyte function during ethanol administration--migration and oxidative responses in a joint with immune complex synovitis.

Functional impairments of polymorphonuclear granulocytes (PMN) are believed to contribute to hampered inflammation and host defence in alcoholics. We studied effects of i.v. ethanol administration on PMN responses in rabbits during induction of a knee-joint synovitis. The synovitis conferred systemic effects, since chemiluminescent responses of peripheral blood PMN to opsonized zymosan and phorpbol myristate acetate (PMA) increased 6.4- and 17.9-fold, respectively. Chemiluminescent responses of synovial PMN were further amplified. This up-regulation was reduced to 33% in rabbits treated with ethanol when opsonized zymosan was used as the PMN stimulus; in contrast, PMA responses were unaffected. The appearance and migration of PMN to the synovitis joint were normal despite a blood ethanol concentration of 0.5%. Thus, ethanol impaired release of oxygen metabolites from PMN, but not the delivery of cells at an inflammatory site.

Animals↗
PubMed1995

Prevalence, genetics and clinical presentation of chronic granulomatous disease in Sweden.

To estimate the prevalence of chronic granulomatous disease (CGD) in Sweden, an inquiry asking for known and possible CGD cases was mailed to paediatric, internal medicine and infectious disease departments all over Sweden. The detected patients were characterized as to genetics and the clinical presentation. Twenty-one patients (belonging to 16 different families) were found, corresponding to a prevalence of approximately 1/450,000 individuals. The patients with X-linked disease, lacking a functional gp91phox protein (n = 12), comprised 57% and 43% of the patients had an autosomal recessive (AR) disease lacking p47phox (n = 7) or p67phox (n = 1), respectively. All unrelated patients with X-linked disease displayed different gene abnormalities such as point mutations predicting nonsense (n = 3), missense (n = 1) or splice site mutations (n = 2), but also a total deletion and a unique 40 base pair duplicature insertion. The patients with p47phox-deficiency showed a GT deletion at a GTGT tandem repeat, and the p67phox-deficient patient displayed a heterozygous in-frame deletion of AAG combined with a large deletion in the other allele. Three patients died during the study period, two from pseudomonas cepacia infections. Patients with X-linked disease had more frequent infections (mean of 1.7 per year), than the patients with AR inheritance (0.5 infections per year). The most common infections were dermal abscesses (n = 111), followed by lymphadenitis (n = 82) and pneumonias (n = 73). Inflammatory bowel disease-like symptoms, mimicking Crohn's disease of the colon, was seen in three CGD patients.

Adolescent↗
PubMed1995

Mechanisms for lipoxin A4-induced neutrophil-dependent cytotoxicity for human endothelial cells.

In a model of vasculitis we have evaluated mechanisms for how neutrophil polymorphonuclear granulocytes (PMNs) kill cultured human umbilical vein endothelial cells (HUVECs) in vitro (as release of chromium 51) in response to the double dioxygenation product of arachidonic acid, lipoxin A4 (LXA4) and to formyl-methionyl-leucyl-phenylalanine (fMLP). The cytolysis induced by LXA4 and fMLP was dose dependent, with maximum values at 100 nmol/L (which caused a 2.7-fold and 2.3-fold increases of 51Cr release, respectively, relative to buffer-treated controls). LXA4 also conferred a peak of cytotoxicity at 0.1 nmol/L (which caused a 2.2-fold increase in 51Cr release). Leukotriene B4, platelet activating factor (PAF), and zymosan-activated serum were inefficient. Phorbol myristate acetate caused the most prominent cytotoxicity, which was first evident at 1 mumol/L. The LXA4 effect was abrogated by superoxide dismutase, catalase, alpha 2-macroglobulin, and alpha 1-antitrypsin but not by mannitol. Addition of a monoclonal antibody (mAb) to CD18 also inhibited neutrophil-dependent cytotoxicity to LXA4 and fMLP. MAbs to intercellular adhesion molecule-1 or P-selectin blocked 100% and 52%, respectively, of the LXA4-induced cytotoxicity. Neutrophils from a patient with chronic granulomatous disease were incapable of mediating any cytotoxicity. The LXA4 effect was inhibited by the PAF receptor antagonist WEB-2086 and by treating neutrophils with pertussis toxin. Thus this novel effect of LXA4, as a potent promoter of neutrophil-mediated cytotoxicity for HUVECs, is a process dependent on PMN adhesion proteins, oxygen radicals, and proteases, and it is apparently associated with endogenous PAF expression and requires pertussis-sensitive G proteins.

Catalase↗