[Increased clinical use of growth factors].
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Genetic Therapy↗
Biomedical subjects
G Holm
Publications and source records attributed to G Holm.
Fixed versus response-adapted MOPP/ABVD chemotherapy in Hodgkin's disease. A prospective randomized trial.
BACKGROUND: The optimal number of chemotherapy courses in responding patients with advanced-stage Hodgkin's disease (HD) is unknown. PATIENTS AND METHODS: With minimizing chemotherapy and thereby reducing late complications as the objective, patients with advanced HD were randomized to receive either 4 full MOPP/ABVD courses or treatment up to complete remission (CR). Forty-seven patients were given the fixed (FT) and 41 patients the individual treatment (IT). The two groups were balanced according to age, histopathology and sex, although stage IVB dominated in the IT group (20 vs. 8). RESULTS: Sixty-six of 88 patients (75%) achieved CR. No difference between the two treatment groups in the proportion of stage IVB patients was seen when those achieving CR, i.e., the efficacy population were compared. The mean number of single chemotherapy courses given was 3.7 of MOPP and 3.5 of ABVD in the FT group, compared to 2.6 of MOPP and 2.5 of ABVD in the IT group (p < 0.001). The predicted progression-free survival at 10 years was 81% in the FT and 68% on the IT arm, respectively (p < 0.05). No statistically significant difference in cause-specific 10 year survival was observed (82% and 83%, respectively; p = 0.18). Long-standing CRs were achieved following minimal chemotherapy. CONCLUSIONS: Since there are no available methods to identify long-term disease-free survivors among CR patients following a limited induction treatment, we suggest that the policy of giving 3-4 full MOPP/ABVD courses should continue. The price for such an approach is the overtreatment of a subset of already cured patients.
Adolescent↗
Idiotype-specific T cells in multiple myeloma stage I: an evaluation by four different functional tests.
Idiotype-specific T cells were characterized in patients with multiple myeloma stage I by analysing idiotype-induced DNA synthesis (3H-thymidine incorporation), IL-2 and IFN-gamma production at the single cell level (ELISPOT) (in vitro tests) and delayed type hypersensitivity (DTH) skin reaction (in vivo test). In seven out of eight patients at least one of the four tests was positive. In five patients three or more tests were positive. One patient was negative in all four tests. Six patients had both IL-2 and IFN-gamma-secreting cells and three of them also a DTH response. Furthermore, those three patients with a proliferative response also had IL-2 and IFN-gamma-secreting cells induced by the idiotype. The data indicate that part of the idiotype-specific T cell fraction belongs to the CD4 Th1 cell population. Whether CD8-specific T cells also were present could not be ruled out. The present study provides further support for the existence of idiotype-specific T cells in multiple myeloma. Such cells might be an important target for an immune-mediated therapeutic approach.
Aged↗
Immunopathogenesis and immunotherapy in rheumatoid arthritis: an area in transition.
In years to come, new therapeutic modalities for the treatment of chronic arthritis will be launched for general clinical use. These therapies, until today only used in clinical studies, are based on knowledge obtained from animal models of chronic arthritis. This knowledge not only ushers therapeutic use in humans: in many settings, the animal studies have proven to be irreplacable tools to get insights into the pathogenesis of chronic arthritis. Rheumatoid arthritis (RA) shows a strong linkage of susceptibility to a certain epitope common to some HLA-DR beta chains; this immunogenetic linkage is the strongest evidence for specific, T-cell dependent immunity in the pathogenesis of the disease. Despite intense efforts, no unequivocal proofs of T-cell specificity or oligoclonality have been found in RA. Therapeutic efforts directed against T-cells or T-cell functions have also at the best showed partial effects. As compared to the local production of T-cell cytokines in the joint, monokine production is abundant. Therapies aimed at neutralizing the effects of the cartilage-devastating monokine TNF-a have showed remarkable results in small clinical trials. The possibility of increasing the presence of the regulatory cytokines IL-4, IL-10 and TGF-beta has also been explored, but only in animal studies. Immunology has also shed light on the mode of action of the commonly used 'disease modifying' drugs, and combinations of such drugs have shown increased potentials in recent clinical studies. The possibility of combining traditional anti-arthritic drugs with recent immunological tools seem promising for the future. This review discusses recent advances in the understanding of pathogenesis and delineate new therapeutic approaches for chronic arthritis from the point of view of the immunologically oriented clinician.
Animals↗
Antibodies against endothelial cells and cardiolipin in young patients with peripheral atherosclerotic disease.
OBJECTIVES: To investigate the prevalence of anticardiolipin and antiendothelial cell antibodies in patients operated on for atherosclerotic peripheral vascular disease before 50 years of age. The hypothesis to be tested was whether antibodies associated with an immune/inflammatory damage to the vascular wall were associated also with early atherosclerosis. DESIGN: A case-control study. SETTING: Departments of surgery and an immunological research laboratory, and routine laboratories of two tertiary referral hospitals. SUBJECTS: All patients operated for atherosclerotic peripheral vascular disease before 50 years of age. Sixty-two patients (33 males, 29 females), and 67 age- and sex-matched controls participated. The diagnosis of atherosclerosis was made on the basis of the clinical presentation and angiographic visualization of the diseased vasculature. MAIN OUTCOME MEASURES: Subjects were compared for the prevalence of anticardiolipin and antiendothelial cell antibodies, altered serum lipoprotein levels, smoking, diabetes, hypertension, and signs of inflammation. RESULTS: Antibodies against endothelial cells and cardiolipin were found in 12.9 and 14.5% of the patients, respectively, which was higher than observed in the control group (P < 0.05). Sixty per cent of patients with antibodies were females. Conventional risk factors were more often noted in the patient group. However, patients with antibodies against endothelial cell and/or cardiolipin had a lower prevalence of hyperlipidaemia/dyslipidaemia when compared to patients without these antibodies (P < 0.05). CONCLUSIONS: Antibodies against endothelial cells and cardiolipin are present in a subset of patients with clinical and angiographic diagnosis of severe premature atherosclerotic peripheral vascular disease. The lower occurrence of hyperlipidaemia/dyslipidaemia in patients with autoantibodies, in comparison to patients without the antibodies, suggests that these antibodies have a role in vascular damage.
Adult↗
C4 null alleles in a Swedish population.
The distribution of C4 null alleles (C4Q0) was studied in a Swedish population comprising 410 male individuals from Stockholm County and Uppsala City. The prevalances of homozygous C4A*Q0 and C4B*Q0 determined by analysing the gene products in serum were 5.0 and 5.6%, respectively, in the Stockholm population and 4.0% each in the Uppsala population. These values are higher than those previously reported from other Caucasian populations. The finding reflects a different genetic composition of the Swedish population and may have relevance to the disease spectrum in this population as compared to other Caucasian populations.
Adult↗
Association between circulating immune complexes, complement C4 null alleles, and myocardial infarction before age 45 years.
One hundred patients who had survived a myocardial infarction before the age of 45 years and 90 age- and sex-matched healthy individuals were investigated for circulating immune complexes (CICs) and the presence of complement C4 null alleles (C4Q0). CICs were found in increased concentrations in 20% of patients and 6.7% of control subjects. Patients and control subjects had the same prevalence of C4Q0. CICs were present in all patients and in 36% of the control subjects homozygous for C4Q0. Patients and control subjects heterozygous for C4Q0 had CICs in 71% and 0%, respectively. The high prevalence and a high concentration of CICs were particularly associated with C4A*Q0. Patients homozygous for C4A*Q0 had concentrations of LDL that were lower than found in other patients. The increased concentration of CICs associated with genetic deficiencies of the complement factor C4 might thus be an additional etiological factor for the development of chronic vascular damage and premature myocardial infarction.
Adult↗
Growth hormone secretion after testosterone administration to men with visceral obesity.
Visceral obesity in men has been reported to be characterized by low testosterone (T) and insulin-like growth factor I (IGF-I) concentrations, the latter suggesting a relative growth hormone (GH) deficiency. Since T and GH-secretions are interrelated, men with visceral obesity were substituted with T for 14 days, and diurnal secretion pattern of GH as well as IGF-I concentrations, and metabolic variables were followed. Visceral obese men were characterized by a decreased total GH secretion and diminished peak amplitude, size, and number. T-substitution was followed by elevation of IGF-I levels. The IGF-I increase correlated with the elevation of T-concentration, and was most pronounced in men with the lowest concentrations of free T from the outset. There were no detectable changes in total quantity, amplitude, size or number of peaks of GH secretion. Glucose, chlolesterol and triglycerides as well as diastolic blood pressure decreased. There were no changes in thyroid or hematology variables. T-substitution of visceral obese men is followed by an elevation of IGF-I concentrations. It is suggested that this might be due either to minor, non-detectable increases in GH secretion, or to direct effects of T on IGF-I concentrations. The regulatory mechanisms by which T-administration are leading to metabolic and anthropometric improvements, might be direct effects of T, with or without mediation via GH secretion.
Abdominal Fat↗
Anti-idiotypic B lymphocytes in patients with monoclonal gammopathies.
The prevalence of peripheral blood B cells secreting antibodies reacting with the F(ab')2 fragment of monoclonal IgG was studied in five patients with multiple myeloma (MM), nine patients with monoclonal gammopathy of undetermined significance (MGUS) and six healthy controls. An enzyme-linked immunospot assay allowed direct visualization of antibody producing B cells. All patients had B cells producing antibodies to autologous or allogeneic monoclonal IgG. Autoreactive cells were found more frequently than alloreactive cells in seven out of nine patients with MGUS and three out of four patients with MM. The same frequency of alloreactive cells in the patient groups was detected in healthy individuals. These findings show the existence of B cells producing anti-idiotypic antibodies which could be a part of an idiotypic network in monoclonal gammopathies.
Aged↗
Treatment of myasthenia gravis with anti-CD4 antibody: improvement correlates to decreased T-cell autoreactivity.
We treated a patient with severe myasthenia gravis with a chimeric (murine/human) anti-CD4 monoclonal antibody (cM-T412) for 7 days and followed the therapeutic effect by standardized muscle function tests, single-fiber electromyography, and immunologic examinations of disease-specific B- and T-cell functions. Clinical and electrophysiologic improvement began within 4 days, lasted for 3 months, and was maximal between days 16 and 58. The CD4+ lymphocytes decreased to a minimum of 80 cells per microliters of peripheral blood, recovered slowly during the first year of follow-up, and did not correlate with changes in disease severity. T-cell stimulation by human acetylcholine receptor was abolished by the treatment but became detectable at the time of worsening of symptoms. The concentration of acetylcholine receptor antibodies in serum was not decreased by the treatment. The results suggest that anti-CD4 antibody administration could be effective in the treatment of severe myasthenia gravis and indicate that acetylcholine receptor-specific T lymphocytes might contribute to the disturbed neuromuscular transmission in the disease.
Antibodies↗
Smoking as an additional risk for tooth loss.
Epidemiological studies have shown that loss of teeth is associated with increasing age. This was explained as the result of the action of microorganisms which, as components of dental plaque, destroyed the tooth by causing caries or periodontitis. Routine prevention programs therefore concentrated on removal of plaque, resulting in good oral hygiene. Despite good oral hygiene some individuals developed periodontitis. Studies have indicated that smoking may be a risk factor for this disease. This study was undertaken to determine whether or not smoking is also a risk factor for tooth loss. A total of 273 individuals were followed for 10 years, during which 93 individuals lost a total of 260 teeth. Younger individuals and especially males smoking more than 15 cigarettes a day were found to have the highest relative risk of losing teeth (4.55 and 3.18 respectively). In the younger age groups the proportional attributable risk was also highest; 78% for smokers smoking more than 15 cigarettes a day. The combination of a high plaque score and smoking was, together with age, the strongest predictor of tooth loss. The findings of this study suggest that smokers, especially those in the age group < 50 years, are a high risk group for tooth loss.
Adult↗
Clinical improvement of myasthenia gravis by treatment with a chimeric anti-CD4 monoclonal antibody.
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Antibodies, Monoclonal↗
Androgen treatment of abdominally obese men.
Middle-aged men with abdominal obesity were treated in a double-blind study with moderate doses of transdermal preparations of testosterone (T), dihydrotestosterone (DHT), or placebo. This resulted in moderately elevated T concentrations and marked decreases in follicle stimulating and luteinizing hormones in the group treated with T, while the DHT group showed elevated DHT, markedly lower T values, and less diminution of gonadotropin concentrations. In the group treated with T visceral fat mass decreased (measured by computerized tomography) without significant changes in other depot fat regions. Lean body mass did not change. In the group treated with T, glucose disposal rate, measured with the euglycemic hyperinsulinemic clamp method, was markedly augmented. Plasma triglycerides, cholesterol, and fasting blood glucose concentrations as well as diastolic blood pressure decreased. There were no such changes in the DHT or placebo treatment groups. The men treated with T reported increased well-being and energy. In none of the groups did prostate volume, specific prostate antigen concentration, genito-urinary history, or urinary flow measurement change. It is suggested that supplementation of abdominal obese men with moderate doses of T might have several beneficial effects.
Abdominal Fat↗
Lymphocyte and granulocyte function in nutritionally depleted patients. The effect of 2 weeks of total parenteral nutrition.
Parenteral nutrition has been reported to restore impaired immune function in nutritionally depleted patients. Lymphocyte and granulocyte function were studied before and after 2 weeks of total parenteral nutrition (TPN) in 9 depleted patients, 5 with gastrointestinal cancer and 4 with benign gastrointestinal disorders. The ability of purified blood lymphocytes to incorporate (14)C-labelled thymidine spontaneously and following mitogenic and antigenic stimulation was studied. Before TPN spontaneous lymphocyte activity was significantly increased and mitogen and antigen responsiveness significantly decreased in comparison to healthy controls. These abnormalities were more pronounced in patients with malignant disorders while the remaining patients showed a moderate impairment. No improvement in lymphocyte capacity was observed following 2 weeks of TPN. Granulocyte function measured as chemotaxis, phagocytosis, NBT-reduction and bactericidal capacity did not differ significantly between patients and controls and no changes were seen following nutritional treatment. These findings support the concept that the underlying disease and/or other factors rather than the secondary nutritional depletion are the main reasons for immune impairment. Furthermore, no immunomodulating effects of lipid emulsions on lymphocyte and granulocyte function, under these experimental conditions, were apparent.
Journal Article↗
T-cell stimulation induced by idiotypes on monoclonal immunoglobulins in patients with monoclonal gammopathies.
The stimulation of peripheral blood mononuclear cells by purified autologous and/or allogeneic monoclonal IgG was studied in five patients with multiple myeloma (MM), nine patients with monoclonal gammopathy of undetermined significance (MGUS) and six healthy individuals. Single cells secreting IFN-gamma or IL-2 were identified using an enzyme-linked immunospot assay. Patients' cells were preferentially stimulated by autologous monoclonal IgG at low concentrations (1-100 pg/ml), while 100 ng/ml or higher stimulated T cells both from patients and, to a lesser degree, healthy individuals. This biphasic dose-response of T-cell stimulation by autologous monoclonal IgG was reproduced in all patients. The numbers of cells secreting IFN-gamma and IL-2 in response to allogeneic IgG were significantly lower than the numbers obtained using autologous IgG in patients with MM and MGUS. Cells from healthy individuals were stimulated by allogeneic monoclonal IgG, but to a lesser extent. The results of this study support the presence of idiotype-reactive T cells in patients with MM and MGUS and also may suggest a general but less pronounced T-cell reactivity to monoclonal IgG among these patients.
Aged↗
Effects of acute exercise on insulin and non-insulin-dependent glucose uptake in normal and moderately obese women.
OBJECTIVES: To investigate the effectiveness of exercise on the regulation of insulin sensitivity. METHODS: Eleven premenopausal women, with body fat mass from the normal range to moderate obesity, were examined with glucose clamp at 10 mmol/L glucose concentration to determine insulin-dependent and non-insulin-dependent (after somatostatin inhibition of endogenous insulin production) glucose uptake (= IDGU and NIDGU respectively) before and 24 hrs after a glycogen-decreasing exercise. RESULTS: IDGU, but not NIDGU, increased after exercise. The degree of increase of IDGU after exercise showed negative correlations with body mass index (borderline, significance), the waist to hip circumference ratio, fasting free testosterone and free fatty acid concentrations, as well as diastolic blood pressure (borderline significance), and a positive relationship to sex hormone binding globulin concentration and IDGU before exercise. CONCLUSION: It is concluded that only IDGU contributes to the augmentation of insulin sensitivity after a glycogen-decreasing exercise in women. Additionally, the increase of IDGU is less in abdominal obesity, and negatively dependent on free fatty acid concentrations, hyperandrogenism and hyperinsulinaemia, all putative pathogenetic factors for insulin resistance.
Adult↗
The morphology and metabolism of intraabdominal adipose tissue in men.
Mass, morphology, and metabolism of total adipose tissue and its subcutaneous, visceral, and retroperitoneal subcompartments were examined in 16 men with a wide variation of total body fat. Computerized tomography (CT) scans showed that the intraabdominal fat mass comprised approximately 20% of total fat mass. Visceral and retroperitoneal fat masses were approximately 80% and 20% of total intraabdominal fat mass, respectively. Enlargement of intraabdominal fat depots was due to a parallel adipocyte enlargement only. Direct significant correlations were found between these adipose tissue masses and blood glucose and plasma insulin levels, blood pressure, and liver function tests, while glucose disposal rate during euglycemic glucose clamp measurements at submaximal insulin concentrations (GDR), plasma testosterone, and sex hormone-binding globulin concentrations correlated negatively. The correlations for glucose, insulin, and GDR were strongest with visceral fat mass. Adipose tissue lipid uptake, measured after oral administration of labeled oleic acid in triglyceride, was approximately 50% higher in omental than in subcutaneous adipose tissues. Adipocytes from omental fat also showed a higher lipolytic sensitivity and responsiveness to catecholamines. Furthermore, these adipocytes were less sensitive to the antilipolytic effects of insulin. Both lipid uptake and lipolytic sensitivity and responsiveness showed strong correlations (r = 0.8 to 0.9) to blood glucose and plasma insulin concentrations and also to the GDR (negative), while no such correlations were found with lipid uptake in subcutaneous or retroperitoneal abdominal adipose tissues. Taken together, these results suggest a higher turnover of lipids in visceral than in the other fat depots, which is closely correlated to systemic insulin resistance and glucose metabolism in men.
Abdomen↗
Guar gum improves insulin sensitivity, blood lipids, blood pressure, and fibrinolysis in healthy men.
A double-blind, placebo-controlled, cross-over study was carried out in 25 healthy, nonobese middle-aged men to test the effect of guar gum on glucose and lipid metabolism, blood pressure, and fibrinolysis. Ten grams guar or placebo granulate was given three times a day for 6 wk with a 2-wk run-in before and a wash-out period after. Decreases in fasting blood glucose (P < 0.001), cholesterol (P < 0.001), triglycerides (P < 0.05), plasminogen activator inhibitor-1 activity (P < 0.01), systolic blood pressure (P < 0.01), and diastolic blood pressure (P < 0.001) were seen during guar treatment when compared with placebo. Insulin sensitivity, measured with the euglycemic-clamp technique, increased (P < 0.01), adipose tissue-glucose uptake measured in vitro increased (P < 0.001), and 24-h urinary excretion of sodium and potassium increased (P < 0.001) during guar treatment. Fasting plasma insulin, renin, aldosterone, and fibrinogen concentrations as well as skeletal-muscle electrolytes, urinary catecholamines, and body weight remained unaltered. These findings support a role for guar in the treatment of the metabolic syndrome in which insulin resistance seems to play a pivotal role.
Adipose Tissue↗