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Biomedical subjects

L G Larsson

Publications and source records attributed to L G Larsson.

At least 37 records · Page 2Linked to original sources
PubMed1998

(R)-(+)-2-[[[3-(Morpholinomethyl)-2H-chromen-8-yl]oxy]methyl] morpholine methanesulfonate: a new selective rat 5-hydroxytryptamine1B receptor antagonist.

In the search for new 5-hydroxytryptamine (5-HT) receptor antagonists it was found that the compound (R)-(+)-2-[[[3-(morpholinomethyl)-2H-chromen-8-yl]oxy] methyl] morpholine methanesulfonate, (R)-25, is a selective rat 5-hydroxytryptamine1B (r5-HT1B) receptor antagonist. The binding profile showed a 13-fold preference for r5-HT1B (Ki = 47 +/- 5 nM; n = 3) vs bovine 5-HT1B (Ki = 630 nM; n = 1) receptors. The compound had very low affinity for other monoaminergic receptors examined. The r5-HT1B receptor antagonism was demonstrated by the potentiation of the K+-stimulated release of [3H]-5-HT from superfused rat brain slices in vitro, an effect that was antagonized by addition of 5-HT to the superfusion fluid. (R)-25 at 20 mg/kg sc enhanced the 5-HT turnover in four rat brain regions (hypothalamus, hippocampus, striatum, and frontal cortex) with about 40% measured as the 5-HTP accumulation after decarboxylase inhibition with 3-hydroxybenzylhydrazine. At 3 mg/kg sc (R)-25 produced a significant increase in the number of wet dog shakes in rats, a 5-HT2A/5-HT2C response that was abolished by depletion of 5-HT after pretreatment with the tryptophan hydroxylase inhibitor p-chlorophenylalanine. These observations show that (R)-25, by inhibiting terminal r5-HT1B autoreceptors, increases the 5-HT turnover and the synaptic concentration of 5-HT.

Animals↗
PubMed1998

Differential regional antagonism of 8-OH-DPAT-induced decrease in serotonin synthesis by two 5-HT1A receptor antagonists.

The effects of two 5-HT1A receptor antagonists, (R)-3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2 H-1-benzopyran-5-carboxamide hydrogen (2 R,3 R)-tartrate monohydrate (NAD-299) and N-(2-(1-(2-methoxyphenyl)-piperazinyl))ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY-100635) on the decrease in 5-hydroxytryptophan (5-HTP) accumulation evoked by (RS)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene (8-OH-DPAT) in rats treated with the decarboxylase inhibitor, 3-hydroxyphenylhydrazine (NSD 1015) were studied in four rat brain regions: hippocampus, hypothalamus, striatum and frontal cortex. Dose-response studies revealed differential effects of both antagonists in the areas examined. Both antagonists were significantly more potent in antagonising the effect of 0.30 and 0.76 micromol/kg s.c. 8-OH-DPAT in hippocampus than in hypothalamus, striatum and frontal cortex in mentioned order. This order of potency was the opposite to that found for 8-OH-DPAT in decreasing the 5-HTP accumulation. Since previous studies by others have indicated that the reserve of somatodendritic 5-HT1A receptors is greater in dorsal raphe nucleus innervating frontal cortex and striatum than in median raphe nucleus which mainly innervates hippocampus, the observed different regional potency of the two 5-HT1A receptor antagonists may be explained by this difference in the 5-HT1A receptor reserve.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

Are symptoms of obstructive sleep apnoea syndrome related to bronchitic symptoms or lung function impairment? Report from the Obstructive Lung Disease in Northern Sweden Study.

To investigate whether the high prevalence of symptoms related to obstructive sleep apnoea syndrome (OSAS) in a bronchitic cohort is correlated with the bronchitic symptoms or lung function impairment we examined two cohorts with bronchitic symptoms (n = 357 and 82) and a reference group who had reported no respiratory symptoms in a previous survey in 1986 (n = 140). The study was a part of the Obstructive Lung Disease in Northern Sweden Study and included clinical examination and lung function tests. Although lung function measured as FEV1 percentage predicted was correlated with bronchitic symptoms we found that bronchitic symptoms and body mass index but not lung function impairment were correlated with symptoms related to obstructive sleep apnoea. According to our findings it was the various bronchitic symptoms such as longstanding cough, wheezing, sputum production and chronic productive cough that were correlated with OSAS symptoms. This might be due to increased upper airway swelling or increased upper airway resistance, and lung function impairment does not seem to be responsible for the high prevalence of symptoms related to obstructive sleep apnoea in this bronchitic cohort.

Body Mass Index↗
PubMed1997

Analysis of the DNA-binding activities of Myc/Max/Mad network complexes during induced differentiation of U-937 monoblasts and F9 teratocarcinoma cells.

The bHLHZip protein Max interacts with both the Myc and Mad family proteins forming heterodimers which specifically bind certain E-box DNA recognition sequences, thereby regulating transcription. Whereas Myc proteins actively promote cell proliferation, Mad complexes have the opposite function. Although the main regulation of this network seems to be the control of myc- and mad family gene expression, regulation at the level of DNA-binding and transactivation may also be in operation. Few studies on the DNA-binding activity of native Myc:Max or Max:Mad complexes have been reported mainly due to technical difficulties. To overcome these problems we have developed a specific and sensitive solid phase DNA-binding assay based on partial purification of native Myc, Max and Mad1 complexes by immunological methods. Using this technique we report that the DNA-binding activity of c-Myc-containing complexes is reduced during induced differentiation of U-937 monoblasts and F9 embryonic teratocarcinoma cells. In contrast, the DNA-binding of Mad1-containing complexes increases during monocytic differentiation. In general, the DNA-binding activity of c-Myc and Mad1 correlate with their expression. However, our studies of early kinetics of TPA-induced differentiation of U-937 cells as well as of late events during F9 differentiation suggest that post-translational regulation of Myc and Max DNA-binding may also occur. The solid phase DNA-binding assay may thus provide a tool to study the regulation of DNA-binding in more detail.

Animals↗
PubMed1997

Symptoms related to snoring and sleep apnoea in subjects with chronic bronchitis: report from the Obstructive Lung Disease in Northern Sweden Study.

To assess the relationship between chronic bronchitis and obstructive sleep apnoea, a postal survey was performed. A postal questionnaire was sent to 523 subjects identified as having chronic bronchitis or long-standing cough and sputum production in the Obstructive Lung Disease in Northern Sweden Study I (OLIN I). In 1986-88, all 6610 adults born in 1919-20, 1934-35 and 1949-50 living in representative areas in Northern Sweden were screened for airway diseases according to different methods. A random sample of healthy adults identified in the screening were chosen as references (n = 625). Subjects were asked about a variety of airway symptoms, smoking habits and symptoms related to obstructive sleep apnoea syndrome (OSAS). In the bronchitic group, 20% did not report bronchitic symptoms in the present study, and 26% of the formerly healthy reference group reported at least one bronchitic symptom in the present study. Snoring, apnoea and liability to 'nod off' during activity were much more common in the bronchitic group in both men and women, and most common in men, as expected. Snoring was reported by 29% of the men in the bronchitic group and by 14% in the reference group. In women, the corresponding figures were 14 and 8%, respectively, and for apnoea, the figures were 25 vs. 11% in men and 6 vs. 4% in women. The prevalence of OSAS symptoms was similar in subjects with attacks of breathlessness, long-standing cough, sputum production and recurrent wheezing. Bronchitic symptoms may influence quality of sleep and contribute to daytime tiredness, but this does not fully explain the high prevalence of snoring and apnoea reported by subjects in this cohort. This study indicates a positive correlation between chronic bronchitis and OSAS, but sleep studies are required to confirm this.

Adult↗
PubMed1997

Updated overview of the Swedish Randomized Trials on Breast Cancer Screening with Mammography: age group 40-49 at randomization.

The purpose of this overview is to estimate more precisely the long-term effect of mammography screening by adding four more years of follow-up to women aged 40-49 years in the four Swedish trials on mammography screening. Data from the four, trials were merged and linked to the Swedish Cancer and Cause of Death Register for 1958-1993 and 1951-1993 respectively to identify date of breast cancer diagnosis and cause and date of death. The invited and control groups comprised 48,569 and 40,247 women respectively. At the December 1993 follow-up, 602 and 482 breast cancer cases were identified in the two groups respectively, of which 104 and 111 had breast cancer as the underlying cause of death. This corresponds to a relative risk (RR) of 0.77 (95% CI: 0.59-1.01) for the two groups. In the 40-44 age group at randomization, 94% of breast cancer patients in the study and 89% in the control group were diagnosed before the age of 50; however, among breast cancer deaths in this age group, only two in the invited and five in the control group died after age 50. At follow-up of women 40-44 years at randomization 208 women in the invited and 184 in the control group were reported to the Cancer registry with breast cancer. Out of these 195 (94%) and 163 (89%) respectively were reported before the age of 50. Further, the relative risk for the age group 40-44 years at randomization by age at follow-up was 1.11, 0.51 and 0.46 for the age groups 45-49, 50-54, and 55-59 at follow-up. This study shows a 23% reduction in the breast cancer mortality in women 40-49 years at randomization achieved from a median trial time of 7.0 years, a median follow-up time of 12.8 years, and a screening interval of 18-24 months. Almost all of the effect in the 40-44 year age group at randomization was due to screening before the age of 50.

Adult↗
PubMed1997

Controversies in screening with mammography.

Screening with mammography in order to detect early curable breast cancer has been widely used during the last 2-3 decades. Especially an overview of 4 randomised trials in Sweden has shown a convincing short-term relative reduction of the breast cancer mortality while the long-term absolute effect on this mortality has been impossible to study due to screening of the control groups after some years. There is, however, rather general consensus about the value of screening in women above 50 years of age whereas screening in the age group 40-49 is still controversial due to the low rate of mammographically demonstrable cancers and the high rate of recalls for supplementary mammography, clinical examinations and biopsies in relation to cancers found. Recent follow-up of the pooled Swedish randomised trials have shown an about 20% almost significant reduction of the breast cancer mortality in women aged 40-49 at randomisation but the design of these trials does not allow an adequate estimation of the extra benefit obtained by starting periodical screening at age 40 instead of at age 50. The author proposes that screening in the age group 40-49 should be regarded as experimental and subject to proper randomised trials of a type on-going in UK and planned within UICC.

Adult↗
PubMed1997

The pharmacological characterization of a novel selective 5-hydroxytryptamine1A receptor antagonist, NAD-299.

The pharmacological properties of a novel selective 5-hydroxytryptamine1A (5-HT1A) receptor antagonist, NAD-299 [(R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate] were examined in vitro and in vivo and compared with the reference 5-HT1A receptor antagonist, WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)piperazin-yl))ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride]. The new compound had high affinity for 5-HT1A receptors in vitro with a Ki value of 0.6 nM. The only other receptors for which NAD-299 had affinity less than 1 microM were alpha-1 and beta adrenoceptors with Ki values of 260 and 340 nM, respectively. Thus, the selectivity of NAD-299 for 5-HT1A receptors was more than 400 times. WAY-100635 had considerably higher affinity than NAD-299 for alpha-1 adrenoceptors (Ki = 45 nM) and dopamine D2 and D3 receptors (Ki = 79 and 67 nM, respectively). Like WAY-100635, NAD-299 competitively blocked 5-HT-induced inhibition of vasoactive intestinal peptide-stimulated cAMP production in GH4ZD10 cells and had no intrinsic activity. Both compounds were therefore 5-HT1A receptor antagonists in vitro and also behaved as such in in vivo experiments. Thus, they competitively antagonized the 8-hydroxy-2-(di-n-propylamino)tetralin-induced 5-HT behavioral effects, hypothermia, corticosterone secretion and inhibition of passive avoidance behavior without causing any actions of their own. The effective dose of NAD-299 varied between 0.03 and 0.35 micromol/kg s.c., depending on the test and the dose of 8-hydroxy-2-(di-n-propylamino)tetralin.

5-Hydroxytryptophan↗
PubMed1996

An overview of the Swedish randomised mammography trials: total mortality pattern and the representivity of the study cohorts.

OBJECTIVES: To analyse the cause of death pattern in the cohorts of women included in the Swedish randomised mammography screening trials by comparing the groups of invited and control women both with each other and with the general population of Swedish women. SETTING: Since 1977 four randomised trials of mammography screening have been performed in Sweden: Malmö, Kopparberg and Ostergötland (the two county trial), Stockholm, and Gothenburg. DESIGN: Overview of four randomised mammography screening trials. RESULTS: The total numbers of deaths in the invited and control groups respectively were 15 695 and 11 887 corresponding to a relative risk (RR) of 1.00. There were no significant differences between the invited and control groups for cause-specific mortality, except for breast cancer. When the total mortality in the invited and the control groups was compared with that for Swedish women in general the standardised mortality ratio was close to 100. CONCLUSIONS: The cause of death pattern in the invited group was, except for breast cancer, very similar to that in the control group, showing that the groups were comparable. Similarly, the total mortality including breast cancer mortality in the control group was almost identical to that in Swedish women in general. The same was true, with the exception of breast cancer, for the invited group. These observations confirm that the trial cohorts are representative of Swedish women and indicate that the quantitative results from these trials may safely be generalised to the Swedish populations.

Adult↗
PubMed1996

The Swedish randomised mammography screening trials: analysis of their effect on the breast cancer related excess mortality.

OBJECTIVE: To apply an indirect method for estimation of the breast cancer related excess mortality in the Swedish randomised mammography screening trials. SETTING: Randomised trials on mammography screening have, in Sweden, been performed in the counties of Kopparberg (W) and Ostergötland (E), the so called WE study, and in the three largest cities in Sweden, Stockholm (southern part), Gothenburg, and Malmö. An overview of the trials was presented in the Lancet in 1993 and included 156,911 women in the invited group and 125,866 in the control group. METHODS: The excess mortality in the breast cancer subgroups was estimated by indirect standardisation using official national cause of death statistics according to Statistics Sweden as a reference. RESULTS: The estimated reduction of the breast cancer related mortality was 24% for the whole group (40-74 years at randomisation). The corresponding figures for the age groups 40-49, 50-59, and 60-69 years were 6%, 28%, and 34% respectively. CONCLUSION: The results are very similar to those presented earlier based on the traditional comparison of the breast cancer mortality in the invited and in the control group. This analysis further strengthens previous reports on a beneficial effect of mammography screening, which is especially pronounced in the age group 50-69.

Adult↗
PubMed1995

The hematopoietic transcription factor PU.1 is downregulated in human multiple myeloma cell lines.

PU.1 is a hematopoietic transcription factor belonging to the Ets-family. It is identical to the Spi-1 oncogene, which is implicated in spleen focus-forming virus-induced murine erythroleukemias. PU.1 seems to be required for early development of multiple hematopoietic lineages, but its expression in mature cells is preferentially observed in cells of the B-cell-and monocyte/macrophage-differentiation lineage. It binds the so-called Pu box, an important tissue-specific regulatory DNA element present in a number of genes expressed in these cell lineages. We have analyzed the expression and activity of PU.1 during human B-cell development using a panel of B-cell lines representing different stages of maturation, from early precursors to differentiated plasma cells. PU.1 mRNA expression and PU.1 DNA binding activity, as measured by Northern blot analysis and electrophoretic mobility shift assay, respectively, were evident in cell lines representing pro-B, pre-B, and mature B cells. We could also show Pu box-dependent transactivation of a reporter gene in transient transfections in these cell lines. In contrast, in a number of multiple myeloma cell lines, representing differentiated, plasma cell-like B cells, PU.1 DNA binding activity, mRNA expression, and Pu box-dependent transactivation were absent or detectable at a very low level. In lymphoblastoid cell lines, which exemplify an intermediate stage of B-cell differentiation, a reduced expression and activity were observed. The findings in the human multiple myeloma cell lines represent the first examples of B cells with downregulated PU.1 expression and apparently contradict observations in the murine system in which PU.1 is expressed and active in plasmacytoma cell lines. At present, it is unclear whether the lack of PU.1 expression and activity in human multiple myeloma cell lines represents a malignancy-associated defect in these cells or exemplifies a normal developmental regulation in terminally differentiated B cells.

B-Lymphocytes↗
PubMed1995

Time course of bromocriptine induced excitation in the rat: behavioural and biochemical studies.

The aim of the present study was to further investigate the behavioural and biochemical pharmacology of the directly acting dopamine (DA) receptor agonist bromocriptine (BRC). BRC produced an initial depression of locomotion followed after about an hour by a weak but significant locomotor stimulation. The stimulation was potentiated by concomitant administration of the D1 agonist SKF38393. Ex vivo biochemical determinations indicated that reductions in dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels occurred in the striatum after BRC injection without a significant change in DA levels, indicating a reduced DA turnover. An increase in 5-hydroxytryptamine (5HT) and 5-hydroxyindoleacetic acid (5HIAA) levels occurred in the striatum leading to a significant increase in turnover (i.e. ratio of 5HIAA to 5HT). Noradrenaline concentrations increased in the striatum. In the cortex, sharp falls in HVA and DOPAC levels without a corresponding change in DA were observed. While there was no significant change in noradrenaline levels in this brain region, an increase in 5HIAA, but not in 5HT, levels occurred. These changes indicate an increase in 5HT turnover (ratio of 5HIAA to 5HT). In vivo dialysis indicated that extracellular levels of DA, DOPAC and HVA in the striata of freely moving rats were sharply reduced for at least 6 h after injection. In vitro binding studies showed that BRC exhibited high (Ki values in low nanomolar range) affinities for DA D2A, D2B, D3, alpha 1 and alpha 2 adrenergic receptors together with unexpectedly high affinity (about 1 nM) for 5HT1A receptors. The data indicate that the initial behavioural depression and later locomotor stimulation induced by BRC are accompanied by a sharp monophasic fall in striatal extracellular DA levels as indicated by dialysis studies. Since the behavioural stimulation was augmented by concomitant D1 receptor stimulation, the data suggest that the reduced DA turnover is influencing the amount of DA available to stimulate postsynaptic D1 receptors. However, the biochemical studies indicated that BRC has a high affinity for 5HT1A receptors and affects the turnover of 5HT in the brain. Thus, the behavioural effects of BRC may depend not only on effects on the DA system but also on 5HT systems.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1995

Benefits and liabilities of hypermobility in the back pain disorders of industrial workers.

OBJECTIVES: Back pain disorders, sometimes called 'the nemesis of medicine and the albatross of industry', are ubiquitous, but have stubbornly defied diagnosis and treatment. Hypermobility syndrome, which is also very common, has been called 'an enigma of human physiology'. Both conditions have attracted wide attention and interest only recently. In an earlier study, we considered the benefits and liabilities of joint hypermobility by studying 660 musicians in the USA. In a parallel manner, the present study analysed the back pain disorders of 606 workers in a Swedish high-technology industrial plant in the context of spinal hypermobility. SUBJECTS AND METHODS: The 606 industrial workers were examined for spinal hypermobility using a standard protocol, and interviewed for work-related body-posture requirements and the low back, shoulder and neck pain disorders experienced by them. The data were analysed for associations between hypermobility and physical complaints as a whole, and by taking into account gender and body-postures at work. RESULTS: Twenty-six per cent (37) of 144 workers with hypermobility but only 14% (64) of 453 without hypermobility experienced back pain (P < 0.002). Among the 326 workers with sitting or standing jobs, 40% (29) of 71 with hypermobility had back pain, whereas only 12% (30) of the 255 without hypermobility experienced back pain (P < 0.001). The corresponding numbers with back pain for 235 in jobs with changing body-postures were 4.5% (3) of 66 with hypermobility and 14% (14) of 169 without hypermobility (P = 0.04). CONCLUSIONS: Hypermobility of the spine is an asset if the work requires change of body-posture, but a liability for those in a standing or sitting assignment. It reinforces a similar hypothesis proposed by Larsson et al.

Adolescent↗
PubMed1995

Determination of cause of death among breast cancer cases in the Swedish randomized mammography screening trials. A comparison between official statistics and validation by an endpoint committee.

Between 1976 and 1982, four randomized mammography screening trials started in five screening centres in Sweden, involving 282,777 women (156,911 invited and 125,866 controls) with the aim to study if invitation to screening reduced the breast cancer mortality. An overview of the trials was performed to reduce the confidence intervals for the relative risk estimates. All 1,296 deaths occurring in women with breast cancer detected after randomization were evaluated by an independent endpoint committee (EPC), consisting of four physicians who reviewed collected medical information that was blinded regarding mammography screening. If there was disagreement between the EPC members at the initial individual evaluation the final classification was made at consensus meetings. In only 6.9% (n = 89) of the cases was there disagreement as to whether breast cancer was or was not the underlying cause of death. It was also found that 'breast cancer as underlying cause of death' and 'breast cancer as underlying or contributory cause of death' according to Statistics Sweden resulted in relative risk estimates very similar to those based on the classification by the EPC. The study thus supports the use of official health statistics in the evaluation of randomized breast screening trials in Sweden.

Adult↗
PubMed1995

A cohort study with regard to the risk of haematological malignancies in patients treated with x-rays for benign lesions in the locomotor system. I. Epidemiological analyses.

Roentgen treatment for painful benign conditions in the locomotor system as arthrosis and spondylosis was in Sweden very common up to the beginning of the 1960s. The mode of treatment differed from the British ankylosing spondylitis series as smaller parts of the red bone marrow were exposed and smaller doses were applied. A cohort of 20,024 such patients treated 1950-1964 at two hospitals in northern Sweden was analysed with regard to the risk of haematological malignancies. Average factors for conversion of prescribed skin doses to mean absorbed red bone marrow doses were estimated on random samples of the different treatment sites and then applied on the cohort in its whole. The standard incidence ratio (SIR) for leukaemia was 1.18 (95% CI: 0.98-1.42) and the standard mortality ratio (SMR) 1.25 (0.99-1.45). In the highest dose group (mean absorbed red bone marrow dose > 0.5 Gy) the corresponding values were 1.40 (1.00-1.92) and 1.50 (1.08-2.04). In the mortality analysis also a slightly increased myeloma risk was noted with SMR = 1.20 (0.99-1.56). Extension of the cohort and nested case-control studies are under progress.

Adult↗
PubMed1995

A cohort study with regard to the risk of haematological malignancies in patients treated with x-rays for benign lesions in the locomotor system. II. Estimation of absorbed dose in the red bone marrow.

A cohort study with regard to the risk of haematological malignancies was performed on about 20,000 patients who in 1950-1964 received roentgen treatment for benign conditions in the locomotor system. In order to estimate the mean absorbed red bone marrow dose the treatments were classified as concerning 10 sites (cervical spine, thoracic spine, lumbar spine, sacral region, shoulder, hip, elbow, wrist, knee and ankle). The four last-mentioned sites do not normally contain red bone marrow in adults and their contribution to the mean absorbed dose was regarded as zero. For the other 6 sites random samples consisting of 30 patients for each site were drawn from the cohort. By use of the treatment records and data from the literature on some physical parameters and red bone marrow distribution in normal adult persons, average conversion factors were calculated by which the subscribed surface dose could be converted into mean absorbed dose in red bone marrow. These conversion factors were then applied on the whole cohort and used for stratification of it according to different levels of exposure.

Adult↗