Search PubMed⌕ Search

Biomedical subjects

J Palmblad

Publications and source records attributed to J Palmblad.

At least 19 recordsLinked to original sources
PubMed2006

Assignment of the gene locus for severe congenital neutropenia to chromosome 1q22 in the original Kostmann family from Northern Sweden.

Autosomal recessive severe congenital neutropenia (SCN) or Kostmann syndrome is characterised by reduced neutrophil counts and subsequent recurrent bacterial infections. The disease was originally described in a large consanguineous pedigree from Northern Sweden. A genome-wide autozygosity scan was initiated on samples from four individuals in the original pedigree using high density single nucleotide polymorphism (SNP) genotyping arrays in order to map the disease locus. Thirty candidate regions were identified and the ascertainment of samples from two additional patients confirmed a single haplotype with significant association to the disorder (p<0.01) on chromosome 1q22. One affected individual from the original Kostmann pedigree was confirmed as a phenocopy. The minimal haplotype shared by affected individuals spans a candidate region of 1.2 Mb, containing several potential candidate genes.

Chromosome Mapping↗
PubMed2006

ESPEN Guidelines on Enteral Nutrition: Geriatrics.

Nutritional intake is often compromised in elderly, multimorbid patients. Enteral nutrition (EN) by means of oral nutritional supplements (ONS) and tube feeding (TF) offers the possibility to increase or to insure nutrient intake in case of insufficient oral food intake. The present guideline is intended to give evidence-based recommendations for the use of ONS and TF in geriatric patients. It was developed by an interdisciplinary expert group in accordance with officially accepted standards and is based on all relevant publications since 1985. The guideline was discussed and accepted in a consensus conference. EN by means of ONS is recommended for geriatric patients at nutritional risk, in case of multimorbidity and frailty, and following orthopaedic-surgical procedures. In elderly people at risk of undernutrition ONS improve nutritional status and reduce mortality. After orthopaedic-surgery ONS reduce unfavourable outcome. TF is clearly indicated in patients with neurologic dysphagia. In contrast, TF is not indicated in final disease states, including final dementia, and in order to facilitate patient care. Altogether, it is strongly recommended not to wait until severe undernutrition has developed, but to start EN therapy early, as soon as a nutritional risk becomes apparent.

Aged↗
PubMed2006

Successful renal transplantation in patients with chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a genetic disease caused by structural mutations in the enzyme NADPH oxidase that results in severe immunodeficiency. End-stage renal disease occurs in this patient population, and is often attributed to the necessary use of nephrotoxic anti-infectives. In this report, we present the experiences of two centers in transplantation of three patients with CGD: one transplanted with CGD, one cured of his CGD with bone marrow transplantation who subsequently underwent kidney transplantation and one that received a kidney transplant prior to being cured of CGD via a sequential peripheral blood stem cell transplant (SCT). All three recipients have enjoyed excellent outcomes. Their courses demonstrate the absolute requirements for a multidisciplinary and compulsive approach before, during and after transplantation. These case reports also highlight the unexpectedly benign effects of immunosuppressive therapy in this patient population.

Adult↗
PubMed2004

Characterization of blood vessels in bone marrow from patients with chronic myeloid leukemia and polycythemia vera.

Angiogenesis is a feature of hematological malignancies which may provide prognostic information. However, there is, as yet, no established marker for leukemia-associated vessels in bone marrow. In this study, immunohistochemical stainings for von Willebrand factor (vWf), CD34, Tie-2, angiomodulin, glycodelin, cycloxygenase-2 (Cox-2) and endoglin were compared in order to identify the bone marrow vasculature. Chronic myeloid leukemia (CML), a disease displaying intense angiogenesis, and polycythemia vera (PV), a disease with a low microvascular density (MVD), were studied, as well as normal bone marrow. Only vWf, CD34 and Tie-2 stained the bone marrow endothelium. Although more vessels were stained for vWf than for CD34, there was no evidence that vWf stained more disease-associated vessels. In double staining, Tie-2 co-localized with CD34, but vessels staining only for Tie-2 were also found. However, the number of Tie-2-positive vessels did not correlate to either the MVD or the disease. Angiomodulin, glycodelin, Cox-2 and endoglin did not stain vessel-like structures. In conclusion, estimating the MVD by means of CD34 staining appears to be the most reliable method, but none of the tested molecules qualified as a specific marker for leukemia-associated vessels in the bone marrow.

Aged↗
PubMed2004

Interactions between lipoxin A4, the stable analogue 16-phenoxy-lipoxin A4 and leukotriene B4 in cytokine generation by human monocytes.

Lipoxins display both stimulatory and inhibitory actions with leucocytes that are cell-type dependent. We tested whether lipoxin A4 (LXA4) and its stable synthetic analogue 16-phenoxy-17-18,19,20-tetranor-lipoxin-A4 (16-phe-LXA4) modulated the ability of human blood monocytes (MO) to express mRNA and proteins for interleukin-1beta (IL-1beta), IL-6 and IL-1 receptor antagonist (IL-1Ra) in vitro and compared their actions with lipopolysaccharide (LPS) and leukotriene B4 (LTB4). 16-phe-LXA4, LPS and LTB4, but not LXA4, induced gene expression of IL-1beta in MO. IL-1beta protein synthesis increased by LPS (1500-fold), LTB4 (280-fold) and 16-phe-LXA4 (30-fold). Although the IL-1Ra gene was constitutively activated, mRNA concentration not affected by any of the stimulants, IL-Ra protein synthesis was increased by LPS (with 74%), 16-phe-LXA4 (35%) and LTB4 (20%), but not by LXA4. Each of these stimuli upregulated the IL-6 gene. Increases of IL-6 protein were 3000-fold for LPS, threefold for 16-phe-LXA4, eightfold for LXA(4 and) twofold for LTB4. Prior exposure of MO to 16-phe-LXA4, but not LXA4, reduced LTB4 induced synthesis of IL-1beta with 66%, IL-6 with 20% and IL-1Ra with 29%. Thus, a stable LXA analogue, that resists rapid inactivation by monocytes, displays novel actions in cytokine generation, intimately involved in the regulation of inflammation.

Cytokines↗
PubMed2004

Activation of human umbilical vein endothelial cells leads to relocation and release of high-mobility group box chromosomal protein 1.

The nuclear protein high-mobility group box chromosomal protein 1 (HMGB1) was recently described to act as a pro-inflammatory cytokine and as a late mediator of severe sepsis and septic shock. The protein is released from monocytes in response to endotoxin and activates monocytes and endothelial cells through nuclear factor kappa B. We have previously demonstrated that the B-box of HMGB1 mediates a pro-inflammatory effect on endothelial cells including the upregulation of cell-adhesion molecules and release of interleukin (IL)-8 and granulocyte colony-stimulating factor. Here, we report that HMGB1 is released from human umbilical vein endothelial cells (HUVEC) in response to lipopolysaccharide (LPS) and tumour necrosis factor (TNF)-alpha. A nuclear relocation of HMGB1 to the cytoplasm was seen at 4 h. Subsequently, high amounts of HMGB1 could be seen in the supernatants from stimulated cells after 16 h. It was also observed that the pro-inflammatory activity of HMGB1 is sensitive to dexamethasone. Interestingly, the HMGB1-induced TNF-alpha release from monocytes could be inhibited by either the A-box of the protein or the p38 inhibitor CNI-1493, but neither had any inhibitory effects on the HMGB1-dependent upregulation of cell-adhesion molecules on HUVEC. Altogether, these results suggest that HUVEC may be an important source of HMGB1 secretion in response to systemic infection and that endothelial cells and monocytes may use different signalling pathways.

Cell Adhesion↗
PubMed2002

Expression of the vascular endothelial growth factor (VEGF) family in human endometrial blood vessels.

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.

Adult↗
PubMed2002

Negligible clinical effects of thalidomide in patients with myelofibrosis with myeloid metaplasia.

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 prominent being fatigue documented in 80% of patients. Two patients died while on study, one from acute myelogenous leukemia and one from pneumonia. We conclude that thalidomide given in doses employed in the treatment of multiple myeloma gives no clinically relevant hematological effects in advanced MMM and is hampered by a very high incidence of side effects.

Adult↗
PubMed2001

[New observations support the significance of angiogenesis in myeloma].

Angiogenesis appears to be a prominent feature of many hematological disorders, in particular multiple myeloma. The remissions achieved when treating patients with advanced myeloma with the angiostatic drug thalidomide suggested that the disease might be angiogenesis-dependent. However, the mechanisms for the beneficial effect of thalidomide are, at this time, rather unclear, and may involve other effects beside angiostasis. Nonetheless, these and other observations have spurred an interest in angiogenesis that might lead to new concepts and treatment modalities. Here, an update concerning angiogenesis and multiple myeloma is presented.

Angiogenesis Inhibitors↗
PubMed2001

Activity of the leukocyte NADPH oxidase in whole neutrophils and cell-free neutrophil preparations stimulated with long-chain polyunsaturated fatty acids.

Fish oils are known for their anti-inflammatory effects. In this paper we investigated the influence of eicosapentaenoic acid and docosahexaenoic acid (omega-3 fatty acids), as well as docosapentaenoic acid, a metabolic product of omega-3 fatty acid metabolism, on O2(-)-production catalyzed by the NADPH oxidase in whole neutrophils and in a cell-free system consisting of neutrophil membranes and cytosol. As a standard we used arachidonic acid (an omega-6 fatty acid) found in a high proportion in the Western diet, and known as an effective activator of the oxidase in both systems. Our data show that with omega-3 fatty acids, the O2(-)-production in both systems is reduced as compared to the effect of arachidonic acid. The effects are more pronounced with increasing carbon chain length and increasing numbers of double bonds. Our results suggest another mechanism besides the inhibition of eicosanoid and cytokine production to explain the beneficial effects of fish oils in reducing inflammation.

Adult↗
PubMed2001

Non-immune chronic idiopathic neutropenia of adult: an overview.

There is strong evidence that non-immune chronic idiopathic neutropenia of adult is a cytokine-mediated syndrome characterized by (a) neutropenia of varying degree associated with a low number of lineage-specific CD34+ cells and increased production of inhibitors of hematopoiesis, including transforming growth factor-beta1 and tumor necrosis factor-alpha; (b) lymphopenia due to selective loss of primed/memory T-cells and NK cells; (c) increased splenic volume on ultrasonography in 48.1% of patients; (d) osteopenia and/or osteoporosis in 60.0% of patients; (e) anemia, mostly of the type of anemia of chronic disease, in 15.6% of patients; (f) features of chronic antigenic stimulation, including increased proportion of bone marrow plasma cells, increased serum levels of IgG1 and/or IgA, increased frequency of monoclonal gammopathy of undetermined significance, increased frequency of antinuclear antibodies with specific reactivity, and increased serum levels of circulating immune complexes; and (g) increased concentrations of a variety of macrophage-derived pro-inflammatory cytokines and chemokines capable of affecting bone metabolism, bone marrow function, and leukocyte trafficking. All these findings are suggestive of the existence of an unrecognized low-grade chronic inflammatory process which may be involved in the pathogenesis of the disorder. Neutropenia in these patients is probably the result of a combination of at least three factors, reduced neutrophil production in bone marrow, enhanced neutrophil extravasation, and increased sequestration and/or extravasation of neutrophils into the spleen.

Adult↗
PubMed2001

Chronic mild neutropenia in adults: relation to IgG3 deficiency and infection susceptibility.

OBJECTIVES: Chronic mild neutropenias (NP, i.e. absolute neutrophil blood counts/ANC/0.5-1.5 x 10(9) L(-1)) are accompanied by a variable infection susceptibility, which may or may not be as a result of concomitant conditions. Here, we assessed whether such patients also displayed an immunoglobulin deficiency and if this condition contributed to infection proneness. DESIGN, SETTING AND SUBJECTS: Thirty consecutive adult Caucasian patients with chronic mild NP were followed at one university hospital for up to 28 years. Comparisons were made with 49 IgG3 deficiency patients at an immunodeficiency clinic. MAIN OUTCOME MEASURES: Recorded infections, ANC and serum immunoglobulin levels; flow cytometry assessments of blood lymphocyte subsets and tests for autoimmunity were run to determine neutropenia subtypes. RESULTS: Forty per cent of the NP patients were treated for severe or recurrent infections. The mean IgG3 value for the NP patients was significantly lower than for healthy controls (P < 0.005) and 33% of the patients displayed IgG3 values below the reference values (i.e. below 0.21 g L(-1)), and an additional 13% had IgG3 values within the range others consider low (0.21-0.41 g L(-1)). Unexpectedly, neutropenic IgG3 deficiency patients exhibited less infection proneness than those with normal IgG3 values (P=0.03). Patients with autoimmune, large granular lymphocyte-associated or idiopathic NP had IgG3 deficiency in 63, 44 and 38%, respectively. In addition, none of IgG3 deficiency patients followed at the immunodeficiency clinic displayed neutropenia. CONCLUSION: IgG3 deficiency is common amongst chronic mild neutropenia patients, particularly in those with autoimmune background, but contributes not significantly to infection susceptibility.

Adult↗
PubMed2001

Acute and chronic neutropenias. What is new?

Recently, some of the mechanisms and consequences in the severe chronic neutropenias (e.g. the neutrophil elastase gene mutations and the risk to progress to myelodysplasia and acute leukaemia) and in drug-induced agranulocytosis (e.g. the apoptosis-inducing ability of metabolites of clozapine) have been elucidated, and new aspects of autoimmune and the large granular lymphocyte syndrome were described (e.g. aberrant elaboration of Fas-ligand causing neutrophil apoptosis). Investigations of the mild to moderate chronic neutropenias have shown the significance of interactions between the myeloid development and the immune network (e.g. relations to immunoglobulin aberrations). Granulocyte-colony stimulation factor (G-CSF) is widely used in patients with severe chronic neutropenia, however, its use in other conditions is mostly based on anecdotal evidence. In addition, immune modulating regimens, such as metothrexate, ciclosporine and monoclonal antibodies, are increasingly employed for the autoimmune neutropenias.

Acute Disease↗
PubMed2001

Human umbilical vein endothelial cells generate leukotriene C4 via microsomal glutathione S-transferase type 2 and express the CysLT(1) receptor.

Certain immunocompetent myeloid cells, such as eosinophils, basophils and mast cells, have a large capacity to synthesize the potent proinflammatory and spasmogenic mediator leukotriene (LT) C4 via a specific microsomal glutathione S-transferase (MGST) termed LTC4 synthase (LTC4S). Here, we report that MGST2, a distant homologue of LTC4S, is abundantly expressed in Human umbilical vein endothelial cells (HUVEC) and converts LTA4 into a single product, LTC4. Thus, using Northern blot, RT-PCR, Western blot, and enzyme activity assays, we show that MGST2 is the main, if not the only, enzyme that converts LTA4 into LTC4 in membrane preparations of HUVEC. In fact, we failed to detect any expression of LTC4S, MGST1 or MGST3 in these cells, indicating that MGST2 is a critical enzyme for transcellular LTC4 biosynthesis in the vascular wall. Unlike LTC4S, MGST2 prefers the naturally occurring free acid of LTA4 over the methyl ester as substrate and is also susceptible to product inhibition with an IC50 of about 1 microM for LTC4. Moreover, HUVEC were found to express the CysLT1 receptor in line with a paracrine and autocrine role for cysteinyl-leukotrienes in endothelial cell function.

Blotting, Northern↗
PubMed2001

Angiogenesis research: guidelines for translation to clinical application.

Angiogenesis research is being translated to the clinic. Certain guidelines may facilitate this effort. Recruitment of endothelial cells by a tumor is an early event in angiogenesis, a process regulated at genetic and epigenetic levels. The microvascular endothelial cell has become an important second target in cancer therapy. Angiogenesis inhibitors are either "direct" or "indirect" and their optimal dosing depends on a different logic than conventional chemotherapy. Conversely, antiangiogenic scheduling of chemotherapy can by-pass drug resistance. Like all solid tumors, hematologic malignancies are angiogenesis-dependent. Further, angiogenesis is modulated by proteins and cells from the hematopoietic and hemostatic systems. Clinical testing of angiogenesis inhibitors has accentuated the need for surrogate markers of tumor angiogenesis activity. Microvessel density, so valuable as a prognostic indicator of metastatic risk, cannot determine efficacy of an angiogenesis inhibitor. In the future, angiogenesis inhibitors may be added to chemotherapy or to radiotherapy, or to other modalities. Also, combinations of angiogenesis inhibitors may be administered together.

Angiogenesis Inhibitors↗
PubMed2000

No effect of carvedilol on nitric oxide generation in phagocytes but modulation of production of superoxide ions.

Since carvedilol has been claimed to possess antioxidative effects, this drug might affect functional responses, including nitric oxide (NO) generation, of polymorphonuclear neutrophils (PMN) and macrophages. When we assessed the effects of carvedilol on PMN responses in vitro, we observed that carvedilol dose dependently modulated generation of superoxide ions by NADPH oxidase when induced by the formylpeptide formyl-methionyl-leucyl-phenylalanine (fMLP) or the phorbol ester phorbol myristate acetate. This effect was not coupled to diminished phospholipase C activity. In contrast to the effect on NADPH oxidase, neither the fMLP-elicited NO generation by PMN nor the response of the murine macrophage cell line J774 to lipopolysaccharide was affected. There was no evidence from cell-free assay systems that carvedilol is a scavenger for superoxide ions or NO. Moreover, carvedilol did not affect other reactions dependent on NO, e.g. spontaneous or fMLP-stimulated PMN migration or lipoxin A(4)-, fMLP-, or A23187-induced neutrophil cytotoxicity for human umbilical vein endothelial cells. Thus, these effects point to the possibility that carvedilol modulates the NADPH oxidase of PMN but leaves the nitric oxide synthase of phagocytes intact.

Animals↗
PubMed2000

[New discoveries explain how smoking accelerates atherosclerosis].

Although it is well known that cigarette smoking is a risk factor for the development of atherosclerosis, facts have been scarce concerning mechanisms for the effects of smoke on the blood vessel wall. New findings show that endothelial cells are activated by substances found in smoke, so that leukocytes adhere to and interact with them. Among such substances platelet activating factor and nitric oxide have attracted recent attention. This paper reviews hypotheses concerning these reactions.

Animals↗