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Biomedical subjects

U Johansson

Publications and source records attributed to U Johansson.

At least 55 records · Page 3Linked to original sources
PubMed1995

Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. Stockholm Breast Cancer Study Group.

BACKGROUND: Tamoxifen is being increasingly used for the treatment of breast cancer and is undergoing study for the primary prevention of breast cancer. However, concerns have been raised that the drug may increase the incidence of new primary malignancies, such as endometrial, liver, and colorectal cancers. PURPOSE: Our goal was to assess the carcinogenic risks associated with long-term use of tamoxifen in women with early stage breast cancer. METHODS: The incidence of new primary cancers among 2729 women participants of the Stockholm Trial was determined at a median follow-up of 9 years. In this trial, after primary surgery, postmenopausal patients aged less than 71 years with unilateral invasive breast cancer were randomly allocated to receive either 2 years of adjuvant tamoxifen (40 mg daily) or no adjuvant endocrine therapy. Information on second cancers was obtained by retrospective linkage to the Swedish Cancer Registry. To increase statistical power, a joint analysis of the incidence of endometrial and gastrointestinal cancers was performed in the following three major studies in Scandinavia evaluating adjuvant tamoxifen therapy: the Stockholm Trial, the Danish Breast Cancer Group Trial, and the South-Swedish Trial. These studies included a total of 4914 patients with a median follow-up of 8-9 years. All P values were calculated from two-tailed tests of statistical significance. RESULTS: In the Stockholm Trial, there was a statistically significant (P = .008) reduction in the incidence of second primary cancers in the contralateral breast among the tamoxifen-treated patients. However, there was a nearly sixfold increase in endometrial cancers (P < .001) and a threefold increase in gastrointestinal cancers in the tamoxifen-treated patients. The results of the joint studies showed a statistically significant increase in endometrial cancers among the tamoxifen-treated patients (relative risk [RR] = 4.1; 95% confidence interval [CI] = 1.9-8.9). There was also an excess of gastrointestinal cancers associated with tamoxifen. Most of this excess involved colorectal cancers (RR = 1.9; 95% CI = 1.1-3.3) and stomach cancer (RR = 3.2; 95% CI = 0.9-11.7). There was no substantial increase in any other type of gastrointestinal cancer (e.g., liver cancer) among the tamoxifen-treated patients. CONCLUSION: The endometrium and gastrointestinal organs may be target sites for tamoxifen-induced carcinogenesis in humans. IMPLICATIONS: The increased incidence of colorectal and stomach cancers reported here should be regarded as tentative until supported by long-term data from a larger number of tamoxifen trials. Also, appropriate surveillance of cancer incidence is warranted for the protection of participants enrolled in current tamoxifen chemoprevention trials.

Aged↗
PubMed1995

TP53 mutations and breast cancer prognosis: particularly poor survival rates for cases with mutations in the zinc-binding domains.

Acquired mutations in TP53 as well as immunohistochemically detectable protein expression have been implicated as prognostic factors for breast cancer. We have evaluated the relationship between mutations detected in 119 breast tumours and various clinicohistopathological indices, stratifying the mutations according to the functional domains as defined by the recent elucidation of the crystal structure of the protein. Patients with missense mutations located in regions encoding parts of the protein involved in zinc-binding had significantly decreased disease-free and overall survival relative to patients whose tumours had mutations in other domains. These results indicate that these biochemically defined domains also have biological relevance in terms of breast cancer disease course, and suggest that some mutations in TP53, more than others, can contribute to the development of clinically more aggressive and perhaps treatment resistant breast tumours. When confirmed, this will be of potential importance in predicting the clinical behaviour of breast cancer and its responsiveness to therapy.

Adult↗
PubMed1995

Murine mercury-induced autoimmunity: the role of T-helper cells.

Genetically mercury-susceptible (H-2s) mice in which the nude (athymic) mutation had been introduced, and euthymic (H-2s) mice treated with anti-CD4 monoclonal antibodies were used to determine the importance of T-helper (CD4+) cells for induction of autoimmunity by mercury, and to study the possibility of using anti-CD4 MAb for treatment of manifest autoimmunity. SJL/N and (A.SW x SJL-nu) F1 x SJL-nu BC (H-2s) mice homozygous for the nude mutation (nu/nu) were treated with 10 mg HgCl2/litre drinking water for 6 weeks. These mice developed neither the antinucleolar antibodies (ANoA) nor the systemic immune-complex (IC) deposits seen in mercury-treated littermates heterozygous for the nude mutation (nu/+). The nu/nu mice showed a significant and substantial reduction of splenocytes with pan-T-(CD3+), T-helper-(CD4+) and T-cytotoxic/suppressor (CD8+) markers, which was accompanied by a severe reduction of the proliferative response to Concanavalin A. Euthymic SJL/N mice given an initial intravenous (i.v.) injection of 100 micrograms anti-CD4 MAb (clone GK 1.5, rat IgG2b), followed by 6 weeks treatment with 100 micrograms anti-CD4 MAb intraperitoneally (i.p.) every third day in combination with 10 mg HgCl2/litre drinking water, did not develop ANoA or systemic IC-deposits. These features were seen in controls i.p. injected with rat IgG2b and given HgCl2 in the drinking water. The anti-CD4 MAb-treated mice showed very few CD4+ splenocytes, but a significant increase of CD8+ cells and severely impaired T-cell function. The possibility of treating longstanding autoimmune conditions with anti-CD4 MAb was examined by giving euthymic SJL mice HgCl2 for 3 months, followed by a mercury-free interval of 3 months and finally 7 weekly injections of 1 mg anti-CD4 MAb. This therapy caused a severe reduction of CD4+ cells, but there was no decline in the ANoA titre. In conclusion, induction of systemic autoimmunity by mercury was strictly dependent on T cells, specifically T-helper (CD4+) cells, and mercury-induced ANoA persisted for a long time after stopping mercury treatment. At this late stage, the autoimmune condition was no longer amenable for anti-CD4 MAb therapy.

Animals↗
PubMed1994

Lipofuscin-induced autofluorescence of living neonatal rat cardiomyocytes in culture.

Lipofuscin-specific autofluorescence of living, cultured rat neonatal myocardial myocytes was studied with respect to intensity and spectral characteristics. The autofluorescence emission spectrum changed over time indicating continuously ongoing intramolecular reorganisation of the pigment. Moreover, as compared with formaldehyde-fixed material native lipofuscin produced a considerable red-shifted autofluorescence, indicating formaldehyde-induced molecular modification or quenching of certain parts of the spectrum. The relationship between oxidative stress and lipofuscinogenesis was confirmed because the rate of lipofuscin accumulation was increased when cells were grown at increasing ambient oxygen concentrations.

Animals↗
PubMed1994

Splanchnic and peripheral glucose metabolism in cirrhosis.

The effects of glucose and insulin administration on splanchnic and leg exchange of glucose were investigated in seven patients with cirrhosis and six sex- and age-matched healthy controls using the catheter technique. After a basal period, glucose infusion (1 mg.kg-1.min-1) was given for 45 min, followed by a 2-h euglycemic insulin clamp (1 mU.kg-1.min-1). In the basal state insulin levels were significantly higher in patients than in controls (25 +/- 4 vs. 7 +/- 2 microU/ml). Net splanchnic glucose output tended to be lower in patients than in controls (0.50 +/- 0.16 vs 0.73 +/- 0.11 mmol/min nonsignificant), as did leg glucose uptake (0.06 +/- 0.01 vs 0.08 +/- 0.02 mmol/min, non-significant). Glucose infusion resulted in a significant rise in leg glucose uptake, while net splanchnic glucose output decreased in both groups. During the euglycemic insulin clamp, insulin concentrations rose to 110 +/- 10 and 80 +/- 8 microU/ml in patients and controls, respectively. C-peptide concentrations decreased in the healthy controls but were unchanged from the basal level in patients with cirrhosis. Glucose disposal during the last half hour of the clamp was 1.12 +/- 0.08 and 3.19 +/- 0.04 mmol/min in patients and controls, respectively (p < 0.001). Glucose was taken up by the splanchnic region in both groups but this uptake was significantly greater in patients than in controls (0.42 +/- 0.05 vs. 0.25 +/- 0.06 mmol/min, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Adverse immunological effects and autoimmunity induced by dental amalgam and alloy in mice.

Dental amalgam fillings are the most important source of mercury exposure in the general population, but their potential to cause systemic health consequences is disputed. In this study, inbred mice genetically susceptible to mercury-induced immune aberrations were used to examine whether dental amalgam may interfere with the immune system and cause autoimmunity. Female SJL/N mice were implanted in the peritoneal cavity with 8-100 mg silver amalgam or silver alloy for 10 weeks or 6 months. Chronic hyperimmunoglobulinemia, serum IgG autoantibodies targeting the nucleolar protein fibrillarin, and systemic immune-complex deposits developed in a time- and dose-dependent manner after implantation of amalgam or alloy. Splenocytes from mice implanted with amalgam or alloy showed an increased expression of class II molecules. The functional capacity of splenic T and B cells was affected in a dose-dependent way: 10 weeks of low-dose and 6 months of high-dose amalgam implantation strongly increased mitogen-induced T and B cell proliferation, whereas 10 weeks of high-dose implantation decreased the proliferation. Not only mercury but also silver accumulated in the spleen and kidneys after amalgam implantation. In conclusion, dental amalgam implantation in a physiological body milieu causes chronic stimulation of the immune system with induction of systemic autoimmunity in genetically sensitive mice. Implantation of silver alloy not containing mercury also induced autoimmunity, suggesting that other elements, especially silver, have the potential to induce autoimmunity in genetically susceptible vertebrates. Accumulation of heavy metals, from dental amalgam and other sources, may lower the threshold of an individual metal to elicit immunological aberrations. We hypothesize that under appropriate conditions of genetic susceptibility and adequate body burden, heavy metal exposure from dental amalgam may contribute to immunological aberrations, which could lead to overt autoimmunity.

Animals↗
PubMed1994

Insulin action on glucose transport in isolated skeletal muscle from patients with liver cirrhosis.

Insulin resistance, associated with liver cirrhosis, has been suggested to be localized in skeletal muscle. We used an in vitro incubation technique to determine insulin action on glucose transport in skeletal muscle obtained from seven patients with clinically stable alcoholic cirrhosis and seven healthy age- and sex-matched individuals. In addition, a euglycemic-hyperinsulinemic clamp procedure was performed to assess whole-body insulin-mediated glucose uptake. Insulin-mediated peripheral glucose utilization was 40% lower (p < 0.05) in the cirrhotic patients than in the healthy individuals. Intact skeletal muscle from the vastus lateralis portion of the quadriceps femoris muscle was obtained from each study participant. Thereafter, smaller skeletal muscle strips (approximately 18 mg) were dissected free and incubated in vitro to assess the rate of non-insulin- and insulin-stimulated 3-O-methylglucose transport. Insulin increased the rate of 3-O-methylglucose transport in a dose-dependent manner, with a maximal response observed in the presence of 200 microU/ml in skeletal muscle obtained from the cirrhotic patients and healthy individuals. The dose-response curve for insulin-stimulated 3-O-methylglucose transport did not differ between the groups. Furthermore, muscle glycogen content of needle biopsy specimens was comparable in the two groups. In conclusion, the present group of patients, with liver cirrhosis on an alcoholic basis, had a normal insulin-stimulated capacity for glucose transport at the cellular level irrespective of the degree of whole-body insulin resistance. The mechanism for the divergence between the in vivo and in vitro responses to insulin remains to be elucidated.

3-O-Methylglucose↗
PubMed1993

Neonatal exposure to DDT induces increased susceptibility to pyrethroid (bioallethrin) exposure at adult age.--Changes in cholinergic muscarinic receptor and behavioural variables.

We have recently reported that DDT and the pyrethroid bioallethrin cause similar changes in the brain muscarinic cholinergic receptors (MAChR) and behavioural disturbances in the neonatal and adult mouse when given to neonatal mice during the peak of rapid brain growth. In the present study the interaction between neonatal and adult exposure to DDT and bioallethrin, respectively, is explored. Ten-day-old NMRI mice received a single low oral dose of DDT (0.5 mg/kg body wt). At adult age (5 months) the mice received bioallethrin 0.7 mg/kg body wt./day per os for 7 days. Mice used as controls received a 20% fat emulsion vehicle. The spontaneous behavioural tests revealed significant differences, both in mice treated neonatally with DDT and receiving bioallethrin as adults and in mice receiving the vehicle as neonates and bioallethrin as adults, compared with their corresponding controls. However, the behavioural changes developed in mutually opposite directions. Significant changes in MAChR, assayed in the P2 fraction of the cerebral cortex by using the muscarinic antagonist, quinuclidinyl benzilate ([3H]QNB) and agonist carbachol, was only observed in animals receiving DDT as neonates and bioallethrin as adults. The present study indicates an increased susceptibility in the cholinergic muscarinic receptors and a different behaviour reaction in animals already exposed to DDT (at a physiologically relevant dose), when again exposed to a similar neurotoxic agent as adults.

Administration, Oral↗
PubMed1993

Influence of insulin on glucose metabolism and lipolysis in adipose tissue in situ in patients with liver cirrhosis.

The influence of insulin on lipolysis and glucose metabolism in abdominal adipose tissue was studied in situ with the microdialysis technique during a euglycaemic insulin clamp (1 mU kg-1 min-1) in nine cirrhotic patients and 10 controls. The cirrhotic patients displayed a 50% decrease in glucose utilization rate during the clamp (P < 0.001). Dialysate glucose levels decreased similarly by 20-30%., in patients and controls, which in the presence of unchanged local blood flow in the adipose tissue in response to insulin, is at hand with a glucose uptake into the adipocytes of similar magnitude in both groups. Before and during the clamp, the arterial and dialysate levels of glycerol were higher in the patients than in the control subjects (ANOVA P = 0.001 and 0.048 in arterial blood and dialysate, respectively). In relative terms, however, insulin induced a 70% reduction of arterial and dialysate glycerol in both groups. The concentrations of lactate and pyruvate in the dialysate and blood increased in a similar way in both groups during hyperinsulinaemia. The results suggest an increased rate of lipolysis in cirrhotic patients. Insulin cannot lower it to normal, although it is still capable of achieving a relative reduction. No explanation was found in the adipose tissue to the insulin resistance to whole-body glucose utilization that was noted in the patients with cirrhosis.

Adipose Tissue↗
PubMed1993

Round window membrane in serous and purulent otitis media. Structural study in the rat.

The rat was used as an animal model to reveal structural alterations in the round window membrane (RWM) during serous otitis media (SOM) and purulent otitis media (POM) over a 6-week period. Comparison of POM animals and control animals showed that the RWM in the former became almost six times as thick as that in controls, whereas that of SOM animals was twice as thick. The structural changes in the RWM in POM animals were confined mainly to the epithelium facing the middle ear cavity and the subepithelial space, which was invaded by inflammatory cells and exhibited dilated vessels. The normal flat epithelium was transformed via cuboidal cells to a cylindric epithelium containing both ciliated and goblet cells. In SOM animals, light microscopy revealed only minor changes in the RWM structure. Ultrastructurally, however, the connective tissue layer exhibited dense aggregations of collagen, increased numbers of fibroblasts, and, in one case, elastic fibers. This last phenomenon was not observed in either POM ears or normal ears. The study showed that various inflammatory conditions of the middle ear, both noninfectious (SOM) and infectious (POM), can cause different structural alterations of the RWM. These structural changes may influence passage through the RWM differently.

Animals↗
PubMed1992

Effect of insulin on human adipose tissue metabolism in situ. Interactions with beta-adrenoceptors.

The effects of insulin, and its interactions with catecholamines through beta-adrenoceptors, on human adipose tissue glucose utilization and lipolysis were investigated in vivo. Microdialysis of the extracellular compartment of abdominal subcutaneous adipose tissue was performed in healthy subjects of normal weight, before and during a 2-h hyperinsulinaemic (61 +/- 3 mU/l), euglycaemic clamp. The tissue was perfused with or without the beta-adrenergic agonist isoproterenol (10(-6) mol/l), and the tissue dialysate concentrations of glucose, glycerol (lipolysis index) lactate and pyruvate were determined. During the insulin infusion, glucose in adipose tissue decreased by 20% (p less than 0.001), despite arterial steady-state normoglycaemia. The concentrations of lactate and pyruvate increased gradually to a steady-state plateau of twice the basal level in adipose tissue and arterial blood. Insulin-induced suppression of glycerol (lipolysis index) was, if anything, more marked in adipose tissue than in plasma (65% vs 50% decrease from baseline levels, p less than 0.05). In situ perfusion of adipose tissue with isoproterenol, starting either at the beginning of the study period or at 45 min after initiation of the insulin infusion, resulted in marked and rapid elevations of all the investigated metabolites in the adipose tissue extracellular compartment (p less than 0.05-0.005). It is concluded that insulin action on glucose uptake and lipolysis in human adipose tissue in vivo is counteracted by beta-adrenoceptor stimulation. In contrast, insulin and beta-adrenoceptors have synergistic effects on non-oxidative glucose metabolism in human adipose tissue in situ.

Adipose Tissue↗
PubMed1992

Thermogenic response to intravenous nutrition in patients with cirrhosis.

Energy expenditure was determined using continuous indirect calorimetry in the basal state and during 3 h of total parenteral nutrition (TPN) in 8 patients with cirrhosis and 8 healthy volunteers. TPN consisted of glucose, fat and amino acids and had a glucose/fat ratio of 50:50. The infusion rate was set to provide energy corresponding to 62.5% of the individually measured 24-h resting energy expenditure. In the basal state energy expenditure was similar in patients and controls while the respiratory quotient (RQ) was lower in the patients (0.78 +/- 0.01 vs. 0.82 +/- 0.01, mean +/- SEM, p < 0.05). During TPN, energy expenditure increased progressively during the 3-h infusion period. The average rise in energy expenditure was similar in patients (19.1 +/- 1.2%) and in controls (21.4 +/- 1.6%, n.s.). The RQ rose in both groups, but more in the patients with cirrhosis. At the end of the study, RQ was higher in patients (0.89 +/- 0.01) than in controls (0.85 +/- 0.01, p < 0.05). It is concluded that the nutrient-induced rise in energy expenditure during TPN is not significantly different in patients with cirrhosis and control subjects. Furthermore, the results indicate that the increased fat utilization in overnight fasting cirrhotic patients is rapidly shifted to an augmented carbohydrate oxidation during TPN, possibly as a consequence of marked hyperinsulinemia.

Adult↗
PubMed1992

Phagolysosomal pH in alveolar macrophages.

We studied phagolysosomal pH in alveolar macrophages (AM) using fluorescein-labeled yeast (FYP) and silica particles (FSP) as probes. Fluorescence intensities from the ingested test particles were measured on populations of AM using fluorescence spectrometry and on individual phagolysosomes using fluorescence microscopy. Measurements were performed on rabbit AM, which had been incubated with FYP or FSP (in vitro procedure). We also instilled FYP or FSP via the trachea into rabbit lungs and after 1 day, 1 week, 1 month, and 3 months lavaged the lungs and measured the pH in AM (in vivo procedure). Phagolysosomal pH was independent of the number and size of the fluorescent particles. Measurements of populations of AM with fluorescence spectrometry and of individual phagolysosomes with fluorescence microscopy gave similar average pH. For the FYP, pH decreased during the first day after lavage both in the in vitro and the in vivo procedures. For the FSP, pH was unchanged during the same period. After 1 day pH was similar for both particles. Electron microscopy showed a larger number of lysosomes in contact with phagosomes and a higher percentage of vacuolated phagosomes for FYP than for FSP. In the in vivo procedure, pH was unchanged at least up to 1 month, and this pH was lower than that in the in vitro procedure. The difference was probably due to conditions at the time of phagocytosis. Particles retained in the lung parenchyma were within AM, and their location within the AM appeared unchanged from 1 week up to 3 months.

Animals↗
PubMed1992

A cross-sectional and longitudinal study of craniomandibular dysfunction in an elderly population.

Three cohorts of subjects in their 70s (born in 1901 to 1902, 1906 to 1907, and 1911 to 1912; n = 1,065) were investigated by means of questionnaires and clinical examination. The first cohort was followed to age 83 and the others to age 75. Symptoms of craniomandibular dysfunction were reported less frequently with increasing age. This was especially marked in men. Clinical signs of severe dysfunction were rare, and according to the Helkimo classification they tended to decrease with increasing age. The longitudinal results mainly confirmed the cross-sectional data. The results indicated that there is no increased risk of craniomandibular dysfunction with aging. On the contrary, awareness of such symptoms tended to decrease with aging.

Age Factors↗
PubMed1991

Phagolysosomal pH and location of particles in alveolar macrophages.

Fluorescein-labeled silica particles (FSP) were instilled into the tracheae of rabbits. Groups of four rabbits were killed after 24 hr, 1 week, 1 month, or 3 months and their lungs were lavaged. Phagolysosomal pH in the alveolar macrophages (AM) was measured using microscope fluorometry with FSP as a probe. Due to the marked decline of the fluorescence intensities from the FSP between 1 and 3 months after instillation, it was not possible to measure pH at 3 months, but the values from 24 hr, 1 week, and 1 month were quite similar, with group means of 4.8 and 4.9, respectively. Phagolysosomal pH in AM which phagocytized the FSP in vitro showed values about half a pH unit higher. AM from rabbits lavaged at 1 week had more lysosomes in contact with the FSP-containing phagolysosomes and a higher degree of vacuolization between the FSP and the phagolysosomal membrane than AM lavaged at 1 day. The location of the FSP in the AM appeared to be similar in rabbits lavaged after 1 week and 3 months. In histologic sections from the lungs the large majority of the FSP were within cells at all time points.

Animals↗
PubMed1991

Strain differences in the effect of mercury on murine cell-mediated immune reactions.

The effect of mercuric chloride on mitogen-induced DNA synthesis was investigated using lymphocytes from SJL and DBA mice, which are known to be susceptible and resistant to induction of autoimmunity by mercury, respectively. Treatment of SJL mice with 5 ppm mercuric chloride in their drinking-water for 2 wk resulted in a two- to three-fold increase of concanavalin A and lipopolysaccharide-induced thymidine incorporation in splenocytes. Mitogen-induced thymidine incorporation in splenocytes from identically treated DBA mice was not significantly different from that seen in controls. In vitro treatment of splenocytes from SJL mice with mercury caused a dose-dependent increase of concanavalin A-, lipopolysaccharide and phytohaemagglutinin-induced thymidine incorporation. This effect was optimal when 10(-7)-10(-8) M-mercuric chloride were added as a pulse 1 hr before the addition of mitogens, whereas higher and lower concentrations were less effective. The mitogen-induced DNA synthesis in splenocytes from DBA mice was either not affected by the addition of mercuric chloride or decreased by higher mercury concentrations. The addition of mercury to thymocytes from DBA and SJL mice caused a slight and moderate increase, respectively, in concanavalin A-induced thymidine incorporation.

Animals↗
PubMed1990

Sequential analysis of serum proteins in middle ear effusions. A study in rats with experimentally induced serous and purulent otitis media.

Two otomicroscopically well-defined types of otitis media (OM)--one culture-negative serous (SOM) and the other purulent (POM)--were induced in rats by mechanically obstructing the eustachian tube or by splitting the soft palate. Samples of middle ear effusions (MEE) produced and sera were characterized electrophoretically and immunochemically at 1, 2, 3, 4 and 6 weeks after inducing middle ear fluid. The levels of albumin, transferrin, IgG, IgG1, IgG2, IgM, IgA, and secretory IgA (S-IgA) were determined. All proteins increased 3- to 10-fold in the MEE of the SOM group, whereas the concentrations in the POM group were low. Concentrations of some of the MEE proteins were seen to increase during the course of SOM, while concentrations in the POM group appeared to diminish. The protein content of the MEE in SOM and POM changed dynamically during the observation period. These alterations differed between the two types of OM, reflecting the differing mechanisms that produce the MEE content. These findings indicate that sequential characterization of effusion material in animal OM models may elicit information which might allow staging of this complex disease clinically.

Albumins↗