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Biomedical subjects

M M Hansen

Publications and source records attributed to M M Hansen.

At least 19 recordsLinked to original sources

Microsatellite and mitochondrial DNA polymorphism reveals life-history dependent interbreeding between hatchery and wild brown trout (Salmo trutta L.).

The effects of stocking hatchery trout into wild populations were studied in a Danish river, using microsatellite and mitochondrial DNA (mtDNA) markers. Baseline samples were taken from hatchery trout and wild trout assumed to be unaffected by previous stocking. Also, samples were taken from resident and sea trout from a stocked section of the river. Genetic differentiation between the hatchery strain and the local wild population was modest (microsatellite FST = 0.06). Using assignment tests, more than 90% of individuals from the baseline samples were classified correctly. Assignment tests involving samples from the stocked river section suggested that the contribution by hatchery trout was low among sea trout (< 7%), but high (46%) among resident trout. Hybrid index analysis and a high percentage of mtDNA haplotypes specific to indigenous trout observed among resident trout that were assigned to the hatchery strain suggested that interbreeding took place between hatchery and wild trout. The latter result also indicated that male hatchery trout contributed more to interbreeding than females. We suggest that stronger selection acts against stocked hatchery trout that become anadromous compared to hatchery trout that become resident. As most resident trout are males this could also explain why gene flow from hatchery to wild trout appeared to be male biased. The results show that even despite modest differentiation at neutral loci domesticated trout may still perform worse than local populations and it is important to be aware of differential survival and reproductive success both between life-history types and between sexes.

Animals↗

Synthesis and anticonvulsant activity of 3-aryl-5H-2,3-benzodiazephine AMPA antagonists.

A novel series of 3-aryl-5H-2,3-benzodiazepines with N-3 aromatic substituents has been synthesized. Good in vivo anticonvulsant activity of the new compounds has been demonstrated employing the maximal electroshock seizure test in mice. Evaluation of a subset of the compounds in the cortical wedge assay confirmed the new structures to be AMPA antagonists.

Animals↗

Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors.

As part of our ongoing research program aimed at the identification of highly potent, selective, and systemically active agonists for group II metabotropic glutamate (mGlu) receptors, we have prepared novel heterobicyclic amino acids (-)-2-oxa-4-aminobicyclo[3.1. 0]hexane-4,6-dicarboxylate (LY379268, (-)-9) and (-)-2-thia-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY389795, (-)-10). Compounds (-)-9 and (-)-10 are structurally related to our previously described nanomolar potency group II mGlu receptor agonist, (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740 monohydrate, 5), with the C4-methylene unit of 5 being replaced with either an oxygen atom (as in (-)-9) or a sulfur atom (as in (-)-10). Compounds (-)-9 and (-)-10 potently and stereospecifically displaced specific binding of the mGlu2/3 receptor antagonist ([3H]LY341495) in rat cerebral cortical homogenates, displaying IC50 values of 15 +/- 4 and 8.4 +/- 0.8 nM, respectively, while having no effect up to 100 000 nM on radioligand binding to the glutamate recognition site on NMDA, AMPA, or kainate receptors. Compounds (-)-9 and (-)-10 also potently displaced [3H]LY341495 binding from membranes expressing recombinant human group II mGlu receptor subtypes: (-)-9, Ki = 14.1 +/- 1.4 nM at mGlu2 and 5.8 +/- 0.64 nM at mGlu3; (-)-10, Ki = 40.6 +/- 3.7 nM at mGlu2 and 4.7 +/- 1.2 nM at mGlu3. Evaluation of the functional effects of (-)-9 and (-)-10 on second-messenger responses in nonneuronal cells expressing human mGlu receptor subtypes demonstrated each to be a highly potent agonist for group II mGlu receptors: (-)-9, EC50 = 2.69 +/- 0.26 nM at mGlu2 and 4.58 +/- 0.04 nM at mGlu3; (-)-10, EC50 = 3.91 +/- 0.81 nM at mGlu2 and 7.63 +/- 2. 08 nM at mGlu3. In contrast, neither compound (up to 10 000 nM) displayed either agonist or antagonist activity in cells expressing recombinant human mGlu1a, mGlu5a, mGlu4a, or mGlu7a receptors. The agonist effects of (-)-9 and (-)-10 at group II mGlu receptors were not totally specific, however, as mGlu6 agonist activity was observed at high nanomolar concentrations for (-)-9 (EC50 = 401 +/- 46 nM) and at micromolar concentrations (EC50 = 2 430 +/- 600 nM) for (-)-10; furthermore, each activated mGlu8 receptors at micromolar concentrations (EC50 = 1 690 +/- 130 and 7 340 +/- 2 720 nM, respectively). Intraperitoneal administration of either (-)-9 or (-)-10 in the mouse resulted in a dose-related blockade of limbic seizure activity produced by the nonselective group I/group II mGluR agonist (1S,3R)-ACPD ((-)-9 ED50 = 19 mg/kg, (-)-10 ED50 = 14 mg/kg), indicating that these molecules effectively cross the blood-brain barrier following systemic administration and suppress group I mGluR-mediated limbic excitation. Thus, heterobicyclic amino acids (-)-9 and (-)-10 are novel pharmacological tools useful for exploring the functions of mGlu receptors in vitro and in vivo.

Amino Acids↗

Autoimmunity and extranodal lymphocytic infiltrates in lymphoproliferative disorders.

OBJECTIVE: To examine the relationship between autoimmunity and extranodal lymphocytic infiltrates in different lymphoproliferative disorders with immunoglobulin alterations. SUBJECTS AND DESIGN: A clinical review combined with a retrospective cohort study of 380 patients, 28 with monoclonal gammopathy of undetermined significance, three with common variable immunodeficiency, 147 with chronic lymphocytic leukaemia, 57 with Waldenström's macroglobulinaemia and 145 with non-Hodgkin's malignant lymphoma. SETTING: A university hospital and The State Serum Institute in Copenhagen. INTERVENTION: Clinical examination of each patient with special attention to chronic inflammatory and autoimmune manifestations. Biopsies were taken from non-infectious infiltrates, some of which were additionally tested with PCR analysis for gene rearrangements. Serological screening with a test battery for various autoantibodies was used in combination with techniques for the detection of M-components and monoclonal B-cell proliferation. MAIN OUTCOME MEASURES: Clinical and/or serological autoimmune manifestations, M-component and other immunoglobulin alterations, and inflammatory tissue changes were studied in patients with chronic inflammatory, polyclonal or oligoclonal pseudolymphomas and in monoclonal, malignant extranodal lymphomas. RESULTS: In 380 consecutive patients, 49 (12.9%) had extranodal manifestations, of whom 47 also had autoimmune manifestations. Nearly half of the 47 patients had more than one autoimmune manifestation. There was a strong correlation between clinical signs and corresponding autoantibodies such as anti-SSA and -SSB antibodies in Sjögren's syndrome (10 cases), antithyroid peroxidase antibodies in thyroiditis and Graves' disease (10 cases), and parietal cell antibodies in gastric ulcers with maltoma (12 cases). Clinical and serological signs of autoimmunity correlated strongly with female sex (34, 72% women; and 13, 28% men) and with immunoglobulin alterations. CONCLUSIONS: To our knowledge this is the first systematic review of B-lymphoproliferative and autoimmune disorders indicating that pseudolymphoma and malignant lymphomas, including maltomas, may develop in the context of a permanent autoantigenic drive.

Aged↗

Long-term efficacy of humalog in subjects with Type 1 diabetes mellitus.

AIMS: To evaluate the long-term effectiveness of Humalog insulin in lowering post meal glucose excursions. METHODS: Twenty young subjects with Type 1 diabetes mellitus (DM) who had received insulin-lispro (Humalog) for a least 1 year (mean +/- SD 1.8+/-1.6 years) were studied on two occasions, 3-14 days apart. They consumed a similar breakfast consisting of 450-600 kCal having fasted overnight. The same amount of human soluble Humulin Regular or Humalog insulin was given 10 min before the meal in a randomized, double-blind fashion. RESULTS: Postprandial glucose excursions at 30, 60, and 120 min were significantly lower (P<0.001, ANCOVA) when subjects received Humalog as compared to human soluble insulin. Serum-free insulin levels were significantly higher (P<0.001, ANOVA) at 30 and 60 min when subjects received Humalog as compared with human soluble insulin. Humalog antibody levels after up to 5.4 years of receiving Humalog insulin were not elevated beyond the values at 1 year. CONCLUSIONS: We conclude that Humalog insulin is effective in lowering postprandial glucose excursions even after up to 5.4 years of treatment.

Adult↗

Pharmacoeconomic considerations in treating patients with acute leukaemia.

Whereas individual cost-effectiveness analyses of new agents for acute leukaemia should be performed in target populations, any meaningful pharmacoeconomic evaluation of treatment options for this condition should include the many types of costs and outcomes in unselected, representative groups of patients. Both direct costs (e.g. costs for medication and hospitalisation) and indirect costs (e.g. lost productivity costs and reduced quality of life) are important parameters to assess, as are the costs of chronic adverse effects, research and development costs for new agents, and costs of procedure-related deaths. Complete remission, cure and survival are the 'success' response criteria for acute leukaemia treatments, in addition to prolonged life with acceptable quality of life for patients with incurable acute leukaemia. Death is 'failure', caused either by resistant disease (relapse and progressive disease) inspite of optimal chemotherapy or, sometimes, by insufficient treatment. All of these parameters should be taken into account when a pharmacoeconomic evaluation is performed (either for administrative or scientific purposes) in order to ensure a comprehensive and reliable background for the evaluation in question. Treatment of acute leukaemia is expensive with a total cost of about $US3000 per patient per day during the induction. Although 80% of children with acute leukaemia are cured, only less than 50% of adults are cured. Thus, a great cost is associated with death during treatment and only optimal medical treatment with full-scale combination chemotherapy and full supportive treatment can keep the number of deaths to a minimum.

Acute Disease↗

GM-CSF treatment in patients with B-chronic lymphocytic leukemia.

The effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the number of granulocytes in peripheral blood and myeloid cells in the bone marrow were studied in seven patients with chronic lymphocytic leukemia (CLL). The neutrophil count in the peripheral blood rose by a median of 193% (range 142-980%), p = 0.02, and the increase persisted for more than 2 weeks after discontinuation of the treatment. The percentage of myeloid cells in bone marrow increased by 166% (range--57-1800%). In neutropenic CLL patients with recurrent infections GM-CSF treatment may constitute a new treatment modality.

Aged↗

BEAM+autologous stem cell transplantation in malignant lymphoma: 100 consecutive transplants in a single centre. Efficacy, toxicity and engraftment in relation to stem-cell source and previous treatment.

One hundred consecutive patients with malignant lymphoma treated with high-dose chemotherapy and autologous stem cell transplantation, followed at least 1 yr post-transplant, are reported, 68 with non-Hodgkin's lymphoma and 32 with Hodgkin's disease. At transplant, 23 patients were in first remission, 69 in later chemosensitive disease and 8 were chemotherapy resistant. Based on previous treatment and stem-cell source, the patients were subdivided into 3 cohorts: BMT1: bone-marrow harvest and transplant after > or =3 treatment regimens (38 patients); BMT2: bone marrow harvest and transplant after less than 3 treatment regimens (24 patients); PBSCT: peripheral-blood stem cell transplant (38 patients, 5 of these with CD34+ cell selected PBSC). The 4-yr survival and progression-free survival of all patients was 45 and 40%, respectively. Forty-one patients have died, 27 of lymphoma, evenly distributed in the cohorts. Fourteen treatment-related deaths occurred, 13 of these in the BMT1 cohort, significantly more than in the other cohorts (p=0.001). In univariate survival analysis cohort, age, disease status at transplant and number of previous treatment regimens were significant. In multivariate survival analysis cohort, age and sex were independently significant, women having a shorter survival. The patients transplanted with unselected PBSC had significantly shorter duration of pancytopenia and hospital stay than the otherwise comparable BMT2 patients, but their progression-free survival was identical. We confirm that high-dose therapy with autologous stem cell transplant from blood or bone marrow in not-too-heavily pretreated patients is a safe procedure but will cure only half the patients.

Adult↗

[Campath-1H--a monoclonal antibody for treatment of non-Hodgkin's and chronic lymphatic leukemia].

Treatment with antibodies in patients with lymphoproliferative diseases was, until recently, limited to phase I studies due to limited response or subsequent development of anti-globulin response. The introduction of the hybridoma technique during the 1970s facilitated large scale production of antibodies, including the development of the Campath rat-antibodies. The epitope was launched against CD52, a glycoprotein present in large amounts on the surface of lymphocytes, and the primary use was in-vitro depletion of bone marrow from allogeneic bone marrow transplantation donors. The development of the human Campath-1H antibody was successful in 1988, leading to minimized anti-globulin response when used in vivo, and large multi-center studies were initiated. In this study we present an overview of the preclinical and clinical experiences with Campath-1H, including data from patients treated with the antibody in our clinic.

Aged↗

Subcutaneous lesions and bacteraemia due to Stenotrophomonas maltophilia in three leukaemic patients with neutropenia.

Subcutaneous lesions were seen in three of 13 neutropenia patients who had Stenotrophomonas (Xanthomonas) maltophilia bacteraemia. The characteristic clinical presentation resembled leukaemic infiltrates, and were different from deep ulcers or subcutaneous nodules caused by Pseudomonas aeruginosa. The three patients had acute leukaemia and were treated with intensive combination chemotherapy. All had previously been treated with broad-spectrum antibiotics, and each patient recovered after proper combination antibiotic treatment given according to sensitivity testing.

Adult↗

[Chronic lymphatic leukemia. Peroral cladribine as primary treatment].

Ten patients with newly diagnosed B-chronic lymphocytic leukaemia were treated with cladribin orally for five days every four weeks with a median of four series. This is the first reported clinical study where a purine analogue is administered orally. The tumour reducing effect was fast. Eight out of 10 patients responded with a partial or clinical complete remission. Two of these were in molecular biological complete remission. With an observation time of 22 months we have seen no serious side effects so far. A randomized study (including a long term follow up) between chlorambucil, fludarabin and cladribin is needed to clarify the future role of cladribin in B-CLL treatment.

Aged↗

[Autologous stem cell transplantation. From bone marrow to selected blood stem cells: 100 consecutive procedures at a single center].

One hundred consecutive autologous stem cell transplants are reported: Non-Hodgkin's lymphoma 51 cases, Hodgkin's disease 27 cases, acute leukaemia 14 cases, multiple myeloma seven cases and chronic myeloid leukaemia one case. Most patients were in their second or later remission. The overall three-year survival for all patients was 60% and the three-year disease-free survival was 50% for lymphoma patients and 30% for acute leukaemia patients. The dominant source of stem cells was bone marrow during 1993, but from 1994 it has been peripheral blood, now totalling 33 cases. There were 12 toxic deaths, all among patients who were heavily treated before bone marrow harvest and transplantation. The patients transplanted with blood stem cells had significantly shorter duration of pancytopenia, and hospital stay, but their disease-free survival was not longer than that of a comparable group of bone marrow transplanted patients. Six patients were transplanted with purified CD34+ cells (selected by avidity column (Ceprate (R)), and had duration of thrombocytopenia and hospital stay similar to the patients transplanted with unmanipulated blood stem cells, but slightly longer duration of neutropenia. We conclude that high-dose therapy with autologous stem cell transplantation in not too heavily pretreated patients is a safe procedure irrespective of the source of stem cells.

Adolescent↗

The bone-marrow infiltration pattern in B-cell chronic lymphocytic leukemia is not an important prognostic factor. Danish CLL Study Group.

In a multicentre study of 635 consecutive newly diagnosed patients with B-CLL, the histological bone marrow (BM) specimens were reviewed independently by each of 3 pathologists and found evaluable for BM infiltration pattern in 575 patients, 404 of whom had a CD5+, mainly FMC7-, faint surface-membrane immunoglobulin (SIg) fluorescence-intensity ppenotype. In these 404 patients the following BM infiltration patterns were found: mixed nodular-interstitial (30%), moderate interstitial (44%), heavy interstitial (20%) and diffuse packed (6%). In univariate survival analysis, significant differences were found according to BM pattern (p < 0.05), the presence of nodules being a favorable prognostic sign. In multivariate survival analysis in a model including age, clinical stage, BM pattern, BM lymphocytosis, WBC and sex, only age and stage but not BM pattern or BM lymphocytosis had independent prognostic significance. In stage A, progression-free survival was significantly longer in patients with nodular than in patients with non-nodular bone-marrow pattern. The overall survival of these patients, however, did not differ, possibly owing to the prompt and prolonged treatment given to most patients at the time of progression to stage B or C. We conclude that in CD5+, SIg(faint), mainly FMC7-B-CLL, bone-marrow histology may predict unstable disease in early clinical stage but is not important for treatment decisions, when these are based on clinical stage.

Age Factors↗

Oral cladribine as primary therapy for patients with B-cell chronic lymphocytic leukemia.

PURPOSE: Purine analogs have wide potential indications in the treatment of hematologic malignancies, but intravenous administration has been required. We previously established that the oral bioavailability of cladribine is 50%. Our aim was to evaluate the efficacy and toxicity of oral cladribine to previously untreated patients with chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Sixty-three patients with symptomatic but previously untreated CLL received cladribine solution 10 mg/m2/d orally for 5 consecutive days in monthly courses. RESULTS: Complete remission (CR) was achieved in 24 patients (38%), and 23 patients (37%) had a partial response (PR). Most patients, including those in whom there was no remission (NR) achieved normal blood lymphocyte counts. Failure to meet response criteria was mostly due to thrombocytopenia. The median response duration was not reached at 2 years. The median survival time among 13 deceased patients was 322 days, whereas the median observation time of surviving patients is 760 days. The overall survival rate at 2 years is 82%. Response rate was associated with clinical stage. Grade III to IV infectious toxicity occurred in one third of patients. CONCLUSION: Orally administered cladribine is an effective and feasible therapy for CLL, and produces durable remissions in three quarters of the patients. However, significant toxicity may occur and further studies are required to assess long-term effects and quality-of-life aspects.

Administration, Oral↗

Salvage therapy with fludarabine in patients with progressive B-chronic lymphocytic leukemia.

Thirty patients with B-chronic lymphocytic leukemia, aged 45-82 years, were treated with fludarabine. CLL was diagnosed 8-120 months earlier. The patients had been exposed to a median of 3 different regimens before treatment with fludarabine, and all had progressive disease when they entered the study. Among the 30 patients, 1 had a metastatic carcinoma and 7 patients with WHO performance status 3 died before the second cycle of fludarabine treatment could be given. The remaining 22 patients were considered eligible for response evaluation. The response rate was 32% with 1 complete response and 6 partial responses. However, seven patients achieved stable disease and 8 progressed. The median survival for responders was 24 months and for non-responders 9 months. Response to treatment was correlated with low tumor burden and performance status. In a total of 94 treatment courses, 17 febrile episodes were registered in 10 patients. We conclude that treatment with fludarabine can be useful in patients with progressive and refractory disease.

Aged↗