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Biomedical subjects

A M Holm

Publications and source records attributed to A M Holm.

At least 19 recordsLinked to original sources
PubMed2006

Polyclonal expansion of large granular lymphocytes in common variable immunodeficiency - association with neutropenia.

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency disease, characterized by low levels of circulating immunoglobulins and recurrent bacterial infections, particularly of the respiratory tract. T cell dysfunction is often present, and lymphoproliferative and autoimmune disorders as well as haematological cytopenias are frequently observed. In this study, we report a polyclonal expansion of large granular lymphocytes (LGL) in a substantial proportion of CVID patients, associated with splenomegaly, increased numbers of CD8(+) T cells, inverted CD4 : CD8 T cell ratios and neutropenia. CVID patients who had both increased numbers of LGL and granulocytopenia had elevated levels of soluble Fas ligand (sFasL). Our observations indicate that CVID may be added to the list of inflammatory diseases associated with increased numbers of LGL. Furthermore, our findings suggest common pathogenic mechanisms of granulocytopenia in CVID and lymphoproliferative disease of granular lymphocytes.

Adult↗
PubMed2005

Common variable immunodeficiency and the complement system; low mannose-binding lectin levels are associated with bronchiectasis.

The importance of the innate immune system, including mannose-binding lectin and the complement system, in common variable immunodeficiency is unclear. The objective of this study was to evaluate mannose-binding lectin and the complement system in relation to clinical and immunological parameters in patients with common variable immunodeficiency. Circulating levels of mannose-binding lectin, complement components, complement activation products and functional capacity of complement pathways were correlated to clinical features within 71 patients and compared with 30 healthy controls. The main findings were; the patients had signs of increased complement activation significantly associated with signs of autoimmunity and immunological hyperactivity; there were no signs of deficiencies of the classical and alternative complement pathways in the patient group; the prevalence of lectin pathway deficiency was the same in patients and controls, but patients with increased frequency of lower respiratory tract infections or bronchiectasis had lower capacity of the lectin pathway than patients without these features (P = 0.002 and 0.004, respectively); the serum concentration of mannose-binding lectin was inversely correlated to the frequency of lower respiratory tract infections (P = 0.002) and bronchiectasis (P = 0.01). We conclude that patients with common variable immunodeficiency have no increased frequency of complement deficiencies but signs of increased complement activation. Our findings suggest that mannose-binding lectin and the lectin complement pathway may protect against lower respiratory tract infection and bronhiectasis in patients with common variable immunodeficiency.

Adult↗
PubMed2004

Stimulation of toll-like receptor 2 in mononuclear cells from HIV-infected patients induces chemokine responses: possible pathogenic consequences.

Toll-like receptor 2 (TLR2) stimulation in monocytes may contribute to enhanced inflammation and viral replication in HIV infection. In the present study we examined if TLR2 stimulation could modulate chemokine responses in peripheral blood mononuclear cells (PBMC) from HIV-infected patients and healthy controls. Our main findings were, with similar qualitative patterns in both healthy controls and HIV-infected patients: (1) TLR2 stimulation induced up-regulation of several chemokines at the mRNA level as well as increased protein levels of macrophage inflammatory protein (MIP)-1alpha, interleukin (IL)-8 and regulated on activation, normal T cell expressed and secreted (RANTES); (2) TLR2 stimulation induced enhanced protein expression of CCR5 (a receptor for MIP-1alpha and RANTES) on monocytes; (3) In vitro stimulation with RANTES induced release of MIP-1alpha, MCP-1, IL-8 and interferon-gamma from PBMC. While increased levels of beta-chemokines possibly have antiviral effects, TLR2 stimulation may also promote a chemokine-driven inflammatory loop, potentially contributing to the immunopathogenesis of HIV infection.

Adult↗
PubMed2004

Gene expression analysis of peripheral T cells in a subgroup of common variable immunodeficiency shows predominance of CCR7(-) effector-memory T cells.

Common variable immunodeficiency (CVID) represents a heterogeneous group of antibody deficiency syndromes, characterized by defective antibody production in which T cell deficiency may play a pathogenic role. A subgroup of CVID patients has impaired in vitro T cell proliferation. Using microarray analyses of T cells from these patients, we found a gene expression pattern different from healthy controls and patients with X-linked agammaglobulinaemia. The profile of the differentially expressed genes suggests enhanced cytotoxic effector functions, antigen experienced or chronically activated T cells and a predominance of CCR7(-) T cells. Further experiments using flow cytometry revealed a striking predominance of CCR7(-) T cells in a subgroup of CVID patients, and an association with impaired T cell proliferation. Our observations indicate that a predominance of CCR7(-) T cells with effector-memory cell features and with reduced proliferative capacity may characterize a subgroup of CVID.

Adult↗
PubMed2004

Adipogenic and orexigenic effects of the ghrelin-receptor ligand tabimorelin are diminished in leptin-signalling-deficient ZDF rats.

OBJECTIVE: The aim was to investigate the possible interactions of the two peripheral hormones, leptin and ghrelin, that regulate the energy balance in opposite directions. METHODS: Leptin-receptor mutated Zucker diabetic fatty (ZDF) and lean control rats were treated with the ghrelin-receptor ligand, tabimorelin (50 mg/kg p.o.) for 18 days, and the effects on body weight, food intake and body composition were investigated. The level of expression of anabolic and catabolic neuropeptides and their receptors in the hypothalamic area were analysed by in situ hybridization. RESULTS: Tabimorelin treatment induced hyperphagia and adiposity (increased total fat mass and gain in body weight) in lean control rats, while these parameters were not increased in ZDF rats. Treatment with tabimorelin of lean control rats increased hypothalamic mRNA expression of the anabolic neuropeptide Y (NPY) mRNA and decreased hypothalamic expression of the catabolic peptide pro-opiomelanocortin (POMC) mRNA. In ZDF rats, the expression of POMC mRNA was not affected by treatment with tabimorelin, whereas NPY mRNA expression was increased in the hypothalamic arcuate nucleus. CONCLUSION: This shows that tabimorelin-induced adiposity and hyperphagia in lean control rats are correlated with increased hypothalamic NPY mRNA and decreased POMC mRNA expression. The elimination of tabimorelin-induced adiposity and hyperphagia in ZDF rats may be due to lack of POMC mRNA downregulation. In conclusion, we suggest that ghrelin-receptor ligands exert their adipogenic and orexigenic effects via hypothalamic mechanisms that are dependent on intact leptin-receptor signalling.

Adipose Tissue↗
PubMed2002

Occurrence and clinical presentation of systemic pneumococcal infections in an unselected population in Oslo, Norway, between 1993 and 1997.

In order to describe the clinical and microbiological manifestations of systemic pneumococcal infection in an unselected urban population, 147 cases that occurred in the period 1993-1997 were retrospectively reviewed. An unexpected finding was that gastrointestinal symptoms were remarkably common. All pneumococcal isolates were fully susceptible to penicillin. The 7-valent conjugated vaccine covered 71% of those under 2 years of age, but only 21% of those 15-65 years of age were covered. Although the case fatality rate was 17%, the rate of early fatality due to systemic pneumococcal infection was unchanged compared with data published in the era before antibiotics. This study emphasizes the importance of continuing efforts to prevent systemic pneumococcal infections.

Adolescent↗
PubMed2000

ACE-inhibition promotes apoptosis after balloon injury of rat carotid arteries.

OBJECTIVE: Angiotensin II stimulates vascular smooth muscle cell (VSMC) growth, and is considered to be an important mediator of intimal thickening after vascular injury. Recent evidence has indicated that VSMC apoptosis plays a major role in the response to balloon injury, and we therefore examined the effect of angiotensin converting enzyme (ACE)-inhibition on VSMC apoptosis and vascular lesion formation in the rat model of balloon injury. METHODS: Male Sprague-Dawley rats were subjected to carotid artery balloon injury and randomised to a standard diet or a diet supplemented with 1 mg/ml captopril in the drinking water. Animals were sacrificed 2 and 14 days after injury for assessment of apoptosis and proliferation by in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL) and proliferating cell nuclear antigen (PCNA) immunohistochemistry, respectively. At 14 days post injury, vessel cross-sections were subjected to microscopic morphometry and total cell numbers were determined. RESULTS: At 2 days after balloon injury, captopril-treated animals displayed a significant increase in the percentage of TUNEL-positive VSMCs in the medial area (12 +/- 4% vs. 1 +/- 1%; P < 0.05) as compared to controls. This increase in early apoptosis was associated with decreased intimal cellularity 14 days post injury (238 +/- 47 cells/cross-section vs. 449 +/- 75 cells/cross-section; P < 0.05), and a reduction of neointimal formation (0.13 +/- 0.02 mm2 vs. 0.23 +/- 0.04 mm2; P < 0.05). The fraction of PCNA-positive VSMCs per cross-section 2 or 14 days after injury was not significantly altered by captopril administration. CONCLUSION: Captopril inhibits neointimal formation in the rat model of arterial injury by mechanisms involving induction of VSMC apoptosis.

Angioplasty, Balloon↗
PubMed2000

Apoptosis and formation of peroxynitrite in the lungs of patients with obliterative bronchiolitis.

BACKGROUND: Obliterative bronchiolitis (OB) is the principal long-term complication of lung and heart-lung transplantation. OB is characterized histologically by inflammation, epithelial cell loss, fibrosis, and obliteration of the terminal airways. The contribution of apoptosis and peroxynitrite formation in OB was examined and assessed whether immunohistochemical markers of these reactions in transbronchial biopsy specimens were predictive of OB development. METHODS: Pulmonary tissue samples from lung transplant recipients with OB (n = 5) or without OB (control group; n = 7) were investigated by in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) and nitrotyrosine immunohistochemistry. Furthermore, TUNEL and nitrotyrosine expression was compared between matched transbronchial biopsy specimens from the two patient groups. RESULTS: Sections with active OB displayed a significantly increased number of TUNEL-positive epithelial cells and macrophages compared with very little TUNEL in control specimens. TUNEL was almost absent in inactive OB. Nitrotyrosine was detected in all samples of pulmonary tissue, but nitrotyrosine expression was more intense in patients with active OB. There was no apparent temporospatial correlation of TUNEL and nitrotyrosine expression, and in matched transbronchial specimens, these immunohistochemical markers failed to identify patients with imminent risk of developing OB. CONCLUSIONS: Apoptosis contributes to the pathophysiology of active OB but is apparently not directly paralleled by tissue peroxynitrite formation. In transbronchial biopsy specimens, markers of apoptosis and peroxynitrite formation are not valid predictors of OB and more studies are required to deliniate the role of these mechanisms in pulmonary allograft rejection.

Apoptosis↗
PubMed2000

Effects of L-arginine on vascular smooth muscle cell proliferation and apoptosis after balloon injury.

Nitric oxide (NO) inhibits neointimal formation in experimental models of restenosis, but the mechanisms have not been fully elucidated. This study examined whether the beneficial effect of L-arginine, the physiological NO precursor, was associated with alteration of the apoptotic and proliferative activities of vascular smooth muscle cells (VSMCs) in the vessel wall after arterial injury. Balloon injury was performed in the rat carotid-artery injury model. Rats were treated with L-arginine (2.25% in the drinking water) or normal drinking water, and sacrificed at 1, 2 and 14 days postinjury. Apoptosis was assessed by terminal deoxynucleotidyl transferase mediated dUTP-biotin nick-end labeling (TUNEL), and proliferation by proliferating cell nuclear antigen (PCNA) immunohistochemistry. Treatment with L-arginine increased the luminal area at 14 days postinjury (0.26 +/- 0.03 mm2 vs 0.14 +/- 0.04 mm2; p < 0.05), and this effect was attributable to a reduction in neointimal formation (0.11 +/- 0.03 mm2 vs 0.23 +/- 0.04 mm2; p < 0.05), while L-arginine did not affect vascular remodeling, as indicated by the total vessel area. The decreased neointimal area at 14 days after balloon injury contained a reduced percentage of TUNEL positive (0.1 +/- 0.1% vs 2.0 +/- 0.6%; p < 0.05), and PCNA positive (13.0 +/- 2.6% vs 27.2 +/- 5.9%; p < 0.05) nuclei, respectively. L-arginine did not influence the apoptotic or proliferative activities of VSMCs at earlier time points postinjury. The favourable effect of L-arginine in the rat model of arterial injury is associated with inhibition of VSMC proliferative activity in the vessel wall and is not explained by increased VSMC apoptosis.

Angioplasty, Balloon↗
PubMed1999

Aminoguanidine induces constrictive vascular remodeling and inhibits smooth muscle cell death after balloon injury.

We examined the effects of aminoguanidine, an inhibitor of inducible nitric oxide synthase, in the rat model of balloon injury. Arteries were assessed by histomorphometry, and vascular smooth muscle cell death and proliferation were examined 24 h and 14 days after balloon injury by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) of fragmented DNA and expression of proliferating cell nuclear antigen, respectively. Aminoguanidine decreased the luminal area 14 days after balloon injury (0.19+/-0.04 mm2 vs. 0.35+/-0.02 mmr2; P < 0.005), and this effect was attributable to reduction of the total vessel area, i.e., constrictive vascular remodeling (0.42+/-0.03 mm2 vs. 0.55+/-0.03 mm2; P < 0.005). At 24 h after injury, the percentage of TUNEL-positive cells in the medial layer was reduced by aminoguanidine (2.0+/-1.0% vs. 17.3+/-5.4%; P < 0.05), and the percentage of proliferating cells was increased (18.4+/-5.5% vs. 4.9+/-2.2%; P < 0.05). Aminoguanidine did not influence the density of VSMC nuclei in the injured artery wall, systemic blood pressure or endothelium-dependent vasorelaxation. We conclude, that in the rat model of balloon injury, aminoguanidine induces luminal loss by constrictive vascular remodeling in association with reduced early VSMC death and increased proliferation.

Angioplasty, Balloon↗
PubMed1999

Pentoxifylline inhibits neointimal formation and stimulates constrictive vascular remodeling after arterial injury.

Pentoxifylline (PTX) is a phosphodiesterase inhibitor used in the treatment of peripheral vascular disease, and this agent can suppress inflammatory vascular damage. Inflammation has been implicated in vascular lesion formation, and we examined the effects of PTX in a model of arterial injury. Sprague-Dawley rats were treated with intraperitoneal PTX (75 mg/kg/day) or saline starting 3 days before carotid balloon injury, and killed 24 h or 14 days later. Carotid arteries were analyzed by cross-sectional morphometry, immunostaining for proliferating cell nuclear antigen (PCNA) and subjected to terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL). Moreover, the effects of PTX on vascular smooth-muscle cell (VSMC) migration and production of collagen types I, IV, and VI were examined in vitro. At 14 days after balloon injury, PTX reduced the neointimal area (0.074+/-0.001 vs. 0.172+/-0.003 mm2; p<0.001), media area (0.143+/-0.001 vs. 0.176+/-0.001 mm2; p<0.01), intima/media ratio (0.50+/-0.02 vs. 0.99+/-0.12; p<0.001), and total vessel area (0.601+/-0.010 vs. 0.744+/-0.011 mm2; p<0.01). The lumen area, PCNA expression, and TUNEL were similar in the two treatment groups, whereas the neointimal cell density was increased by PTX (3,476+/-504 cells/mm2 vs. 2,215+/-232 cells/mm2; p<0.05). In vitro, PTX inhibited VSMC production of collagen type I in a concentration-dependent manner and did not influence VSMC migration. We conclude that PTX inhibits neointimal formation and induces constrictive vascular remodeling in the rat model of balloon injury by mechanisms involving decreased VSMC collagen type I production.

Animals↗
PubMed1999

Apoptosis in acute pulmonary allograft rejection and cytomegalovirus infection.

Apoptosis is a form of programmed cell death, characterized by activation of endonucleases that cleave DNA into oligonucleosomal fragments, which can be identified by in situ terminal deoxyribonucleotide transferase-mediated dUTP nick-end labeling (TUNEL). This process has recently been implicated in cardiac and hepatic allograft rejection, and we investigated its contribution to acute pulmonary allograft rejection and cytomegalovirus (CMV) pneumonitis by in situ TUNEL of transbronchial biopsy specimens. In situ TUNEL was performed on 70 transbronchial biopsy samples collected from 25 pulmonary allograft recipients for diagnosis of acute rejection or CMV pneumonitis, and the number of apoptotic nuclei/mm2 was correlated with the rejection grade (International Society of Heart and Lung Transplantation classification). During acute pulmonary allograft rejection, apoptotic nuclei were demonstrated in pulmonary parenchymal cells and mononuclear infiltrating cells, and the number of apoptotic cells was positively correlated with the rejection grade. In addition, a marked increase in the density of apoptotic cells was found in pulmonary allografts with CMV pneumonitis. We conclude that apoptosis contributes to cell death during acute pulmonary allograft rejection and CMV infection.

Acute Disease↗
PubMed1998

[Pathophysiology of restenosis following percutaneous transluminal coronary angioplasty].

Symptomatic restenosis occurs in approximately 30-40% of patients after percutaneous transluminal coronary angioplasty (PTCA). Despite intensive research, the primary pathophysiological mediators have not been defined, and pharmacological therapy has not been effective in preventing restenosis. Restenosis is a multifactorial and sequential process, which is initiated by mechanical injury of the vessel wall, and involves neointima formation caused by the local proliferation of smooth muscle cells and production of an extracellular matrix, followed by vascular remodelling. Numerous mediators are involved in these processes, e.g., protooncogenes, growth factors, cytokines and nitric oxide. This review discusses the pathobiological mechanisms underlying coronary restenosis, and outlines the prospects for future therapy.

Angioplasty, Balloon, Coronary↗
PubMed1998

Hippocampal stimulation produces neuronal death in the immature brain.

We re-examined the proposed resistance of the immature brain to seizure-induced damage. In awake, freely moving rat pups, intermittent perforant path stimulation produced selective hippocampal cell loss and reduction in paired-pulse inhibition. During 16 h of stimulation, animals showed frequent wet dog shakes and hind-limb scratching movements but no convulsive motor activity. In situ end-labelling performed 2 h after the end of stimulation showed an intense band of positively-labelled eosinophilic cells with condensed profiles bilaterally in the dentate granule cell layer of stimulated animals. Control animals showed no in situ end-labelling positivity in the dentate gyrus. These cells were not observed 24 h later, suggestive of rapidly scavenged apoptotic cells. One day after the end of stimulation, many necrotic interneurons with eosinophilic cytoplasm and pyknotic nuclei were observed in the hilus of the stimulated dentate gyrus in all rats tested. Hippocampal pyramidal cells in CA1, CA3 and subiculum showed bilateral damage greater on the side of stimulation, and prepiriform cortex sustained bilateral symmetrical lesions. One month after perforant path stimulation, Cresyl Violet staining showed the number of large hilar interneurons (>15 microm) was reduced on the stimulated side (54.1 +/- 12.2) compared to the non-stimulated side (100.5 +/- 10.2 cells, P<0.01). Immunohistochemical analysis showed significant losses in somatostatin (8.5 +/- 1.6 stimulated side, 22.8 +/- 3.8 unstimulated side, P<0.05) and neuropeptide Y (12.8 +/- 3.2 stimulated side, 17.0 +/- 4.1 unstimulated side, P<0.05) immunoreactive cells in the stimulated hilus but no loss of parvalbumin-immunoreactive cells. Significant reductions in paired-pulse inhibition were found after stimulation but there was some return of inhibition by one month. These combined data demonstrate that the immature brain can incur damage as a result of prolonged seizure-like hippocampal activity mimicking status epilepticus in immature rats. The hippocampal damage produced by perforant path stimulation is associated with the immediate loss of physiological inhibition suggesting important modification of excitatory control in an extremely epileptogenic region of the brain.

Animals↗
PubMed1997

[Pneumococcal endocarditis of the tricuspid valve. A case report with review of the literature].

The incidence of invasive infections caused by Streptococcus pneumoniae has increased dramatically in Norway the last 5-10 years. We describe a patient with a pneumococcal endocarditis of the tricuspic valve who illustrates some of the diagnostic and therapeutic problems often connected with right-sided endocarditis. We also review literature on pneumococcal endocarditis. Since the introduction of antibiotics, the incidence of pneumococcal endocarditis has decreased significantly. The most important predisposition still seems to be alcoholism. Cases of pneumococcal endocarditis require prolonged and consistent antibiotic treatment. Rapid destruction of the valves is typical, and often demands surgical intervention at an early stage. So far no multiresistant pneumococci have been observed in Norway. The increased incidence of serious pneumococcal infections has recently made it necessary to recommend that pneumococcal vaccine be given on wider indications.

Endocarditis, Bacterial↗
PubMed1997

Is there an association between periodontal condition and HIV infection?

Individuals in Tanzania who have limited access to medical and dental treatment provide an opportunity to study the natural association between periodontal condition and HIV infection and the stage of infection. 119 HIV-infected adult individuals and 73 individuals with AIDS from the AIDS Clinical Trial Clinic at Muhimbili Medical Centre (MMC) in Dar-es-Salaam participated as cases. Mean age was 35.3 and 35.1 years, respectively. 156 individuals with a mean age of 28.3 years, confirmed as HIV-seronegative, served as controls. There were no significant differences in bleeding on probing, pocket formation or attachment loss among the HIV-seronegative individuals, HIV-seropositive and AIDS patients. We applied multiple logistic regression to calculate odds ratios for presence of periodontal conditions adjusting for age, gender and DMFT. Our odds ratios did not reveal any significant associations between bleeding on probing, pocket formation or attachment loss with regard to lymphocyte and CD4+ T-cell counts among the HIV-infected individuals and AIDS patients. When associations were investigated with regard to HIV-serostatus (HIV-seronegative, HIV-seropositive or AIDS), our adjusted odds ratios were insignificant, too. In fact, most odds ratios were close to 1. Thus, our study supports recent views that the presence, extent and severity of periodontal disease among HIV-infected individuals, may be less that hitherto thought.

Acquired Immunodeficiency Syndrome↗