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Biomedical subjects

S B Christensen

Publications and source records attributed to S B Christensen.

18 recordsLinked to original sources
PubMed1992

Toxicodynamics of tumour promoters of mouse skin. III. Specific binding of the tumour promoter thapsigargin as measured by the cold-acetone filter assay.

A method is described for measuring rapid, specific, and saturable binding of the skin irritant and tumour-promoting secretagogue thapsigargin (sesquiterpene lactone) to the microsomal fraction from mouse brain. Employing the tritium-labelled compound its apparent dissociation constant, Kd, and the maximal amount of binding Bmax are shown to be 9.8 nM and 1.9 pmol/mg protein respectively. Such a Kd for thapsigargin is similar to (a) its IC50 value for inhibiting Ca2+ uptake in the microsomal fraction from rat brain and (b) its EC50 values for inducing a rise in the cytoplasmic Ca2+ concentration of human platelets and histamine release from rat peritoneal mast cells. A positive correlation is found between the binding affinities of thapsigargin, thapsitranstagin, and trilobolide, their potencies as secretagogues and their lipophilicities. This correlation does not extend to the skin-irritant activities of the compounds thus emphasizing that their mechanism of action is unlike that of 12-O-tetradecanoylphorbol 13-acetate.

Animals↗
PubMed1992

The molluscicidal activity of coumarins from Ethulia conyzoides and of dicumarol.

The molluscicidal principles of Ethulia conyzoides were identified as ethuliacoumarin A (1) and isoethuliacoumarin A (2). Ethuliacoumarin A possessed an LC90 between 19 and 23.5 ppm depending on the age of the snail against Biomphalaria glabrata, and between 12 and 15 ppm against Bulinus truncatus. In addition, ethuliacoumarin A was found to be cercaricidal at 25 ppm and ovicidal. Ethuliacoumarin has the structural requirements considered essential for anticoagulant activity. Consequently the anticoagulant dicumarol (4) was tested and found to be molluscicidal in the range from 2.5 to 10 ppm. In contrast, the coumarin anticoagulant warfarin (3) did not show molluscicidal activity.

Animals↗
PubMed1992

Comparison of the effects of thapsigargin and BAY K 8644 on spontaneous mechanical activity in rat portal vein and contractile responses of rat cardiac muscle.

The effect of thapsigargin, 10(-9)-10(-6) M, and Bay K 8644, 10(-9)-10(-7) M, was studied on isolated portal veins and cardiac muscles from rats. In rat portal veins thapsigargin induced a concentration dependent increase in the amplitude of the spontaneous mechanical activity without increasing the frequency of spontaneous activity. Thapsigargin was less effective than Bay K 8644 in increasing the amplitude of the mechanical activity. In contrast to thapsigargin Bay K 8644, 10(-6) M increases the frequency of the mechanical activity. Atropine, 10(-6) M, and phentolamine, 10(-6) M, had no effect on the thapsigargin and Bay K 8644 induced increase in mechanical activity. Nitrendipine, 10(-6) M, totally abolished the mechanical response in preparations stimulated by thapsigargin and Bay K 8644. In rat atrial and papillary muscles Bay K 8644 increases the frequency in right atrium and tension in both atrial and papillary muscles. Thapsigargin was without effect on the frequency and tension in the cardial preparations. In conclusion, thapsigargin increases the amplitude of spontaneous activity in rat portal veins. In contrast to Bay K 8644 thapsigargin was less effective in increasing the amplitude and had no effect on the frequency of spontaneous activity; furthermore, thapsigargin was without effect on cardiac muscles. The results support the view that an endoplasmatic Ca2(+)-pump sensitive to thapsigargin is of importance for spontaneous activity in portal veins while such pump is of minor importance for contractile activity in cardiac muscles.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

Relationship between agonist- and thapsigargin-sensitive calcium pools in adrenal glomerulosa cells. Thapsigargin-induced Ca2+ mobilization and entry.

The relationships between agonist-sensitive calcium pools and those discharged by the Ca(2+)-ATPase inhibitor thapsigargin were studied in intact bovine adrenal glomerulosa cells and a subcellular adrenocortical membrane fraction. In Fura-2-loaded glomerulosa cells, angiotensin II (AII) stimulated a rapid increase in cytoplasmic Ca2+ concentration ([Ca2+]i) followed by a smaller plateau phase that was dependent on extra-cellular Ca2+. In such cells thapsigargin caused a sustained and dose-dependent increase in [Ca2+]i which was diminished in Ca(2+)-deficient medium. The contribution of an influx component to the thapsigargin-induced [Ca2+]i response was demonstrated by measurement of 45Ca influx rate in glomerulosa cells. Thapsigargin-induced Ca2+ entry was significantly less than that evoked by AII, and its kinetics were similar to those of the concomitant increase in [Ca2+]i. The rate of emptying of the agonist-responsive Ca2+ pool after thapsigargin treatment, as indicated by the progressive decrease in the size of the AII-induced Ca2+ transient, showed a rapid initial (t1/2 = 1.7 min) component that accounted for about 80% of the response and a slowly decreasing phase with t1/2 = 112 min. The latter thapsigargin-resistant component was abolished by the removal of extracellular Ca2+. Pretreatment with AII dose-dependently attenuated but did not abolish the subsequent Ca2+ response to thapsigargin and also increased the rate of the Ca2+ rise induced by thapsigargin. In bovine adrenocortical microsomes, thapsigargin inhibited the ATP-dependent filling of Ca2+ pools and caused a dose-dependent rise in extravesicular Ca2+ levels when added to previously loaded microsomes. The thapsigargin-releasable Ca2+ pool in adrenal microsomes was larger than the inositol 1,4,5-trisphosphate (Ins(1,4,5)P3)-sensitive Ca2+ pool but only slightly greater than the GTP-releasable pool. Ins(1,4,5)P3-induced Ca2+ release was reduced markedly when ATP-dependent Ca2+ loading of the microsomes was prevented by prior addition of thapsigargin. However, the subsequent Ca2+ response to Ins(1,4,5)P3 was consistently better preserved after the addition of thapsigargin to microsomes preloaded with Ca2+. This difference suggests that although Ca2+ uptake by the Ins(1,4,5)P3-responsive pool is also sensitive to thapsigargin, once filled, this pool shows a slower passive leakage than other thapsigargin-sensitive pools. These findings indicate that thapsigargin increases [Ca2+]i by inhibiting Ca2+ uptake into multiple intracellular Ca2+ pools and by also promoting entry of extracellular Ca2+.(ABSTRACT TRUNCATED AT 400 WORDS)

Angiotensin II↗
PubMed1991

Cyclic AMP- and inositol phosphate-independent inhibition of Ca2+ influx by cholera toxin in CD3-stimulated Jurkat T cells. A study with a cholera toxin-resistant cell variant and the Ca2+ endoplasmic reticulum-ATPase inhibitor thapsigargin.

In this report, we describe a Jurkat cell variant, termed JCT8, the selection of which is based upon its resistance to cell-growth inhibition mediated by the holotoxin of Vibrio cholerae, cholera toxin (CT). JCT8 cells exhibit normal cAMP production in response to various cAMP inducers, including CT, together with conserved ADP ribosylation in vitro of G-protein Gs alpha by the A subunit of the toxin. However, after a 4-h pretreatment with CT, JCT8 cells have a conserved expression of cell-surface CD3 molecules. These effects are in contrast to those elicited by the toxin in long term PGE2-desensitized Jurkat cells, which remain as sensitive as the wild type to the inhibitory action of CT on cell growth and CD3 cell-surface expression, despite poor responsiveness to CT with regard to cAMP production. In JCT8 cells, Ca2+ mobilization induced via the CD3/TCR is maintained after CT treatment contrasting with its complete suppression in the wild-type and in the PGE2-desensitized cells. However, as in the other cell types, CT still suppresses Ca2+ influx in JCT8 cells. Increase in inositol phosphates by CD3 stimulation of JCT8 cells, including of inositol 1,4,5-triphosphate (I(1,4,5)P3), is only partially antagonized by CT. This suggests either that in JCT8 cells there is a different susceptibility of Ca2+ mobilization and influx to partial inhibition by CT of CD3-triggered phospholipase C (PLC)-induced phosphoinositide hydrolysis or that an additional and PLC-independent suppressive effect of the toxin on Ca2+ influx may exist. To investigate this particular point further, we use Thapsigargin, a Ca(2+)-endoplasmic reticulum ATPase inhibitor that can mobilize in human T lymphocytes I(1,4,5)P3-dependent intracellular Ca2+ pools by a PLC-independent pathway. We demonstrate that the Ca2+ influx triggered in the wild-type Jurkat cells or in JCT8 cells by Thapsigargin is antagonized by CT. The present data are therefore consistent with the idea that CT specifically impairs in the Jurkat T cell model the entry of Ca2+ from extracellular spaces by a mechanism independent not only from cAMP but also in part from inhibition by the toxin of phosphoinositide hydrolysis.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1991

The incidence of recurrence and hypothyroidism following treatment with antithyroid drugs, surgery or radioiodine in all patients with thyrotoxicosis in Malmö during the period 1970-1974.

The incidence of recurrence and of hypothyroidism was determined in all new patients treated for thyrotoxicosis during the period 1970-1974 in an unselected, well-defined urban population. A total of 309 patients were followed up for a median time period of 108 (1-192) months. There was a cumulative incidence of 51% recurrence in patients who were treated with antithyroid drugs for Graves' thyrotoxicosis, whereas after surgery or radioiodine treatment there were few recurrences, but 32% and 78% cumulative incidences of hypothyroidism. There were no recurrences after surgery or radioiodine treatment in patients with toxic multinodular goitre or solitary toxic adenoma, but 29% and 40% cumulative incidences of hypothyroidism following radioiodine treatment. Late hypothyroidism occurred after surgery for Graves' thyrotoxicosis, and in all groups treated with radioiodine. Thus it is advisable that all patients with Graves' thyrotoxicosis, regardless of treatment, and all patients with toxic multinodular goitre or solitary toxic adenoma treated with radioiodine, should be followed up for many years, and probably for life.

Adolescent↗
PubMed1991

Thapsigargin-induced increase in cytoplasmic Ca2+ concentration and aldosterone production in rat adrenal glomerulosa cells: interaction with potassium and angiotensin-II.

Thapsigargin (Tg), a microsomal Ca2+ pump inhibitor, dose-dependently increases the cytoplasmic Ca2+ concentration and aldosterone production without having any striking effect on the formation of inositol phosphates in isolated rat adrenal glomerulosa cells. The interaction of Tg with the major Ca2(+)-mediated stimuli of glomerulosa cells on aldosterone production was also examined. The effects of Tg and the Ca2(+)-mobilizing angiotensin-II (AII) were additive. The aldosterone production stimulatory effect of potassium, which induces Ca2+ influx via voltage-operated Ca2+ channels, was potentiated by Tg. The positive interaction between Tg and potassium on aldosterone production raises the possibility that stimuli generating Ca2+ signal by depleting intracellular Ca2+ stores, such as Tg or AII, enhance the response of the cell to depolarization. Such an interaction between AII and potassium may have an important role in the physiological control of aldosterone production.

Aldosterone↗
PubMed1991

The influence of different degrees of chronic lymphocytic thyroiditis on thyroid function after surgery for benign, non-toxic goitre.

Of 220 patients, surgically treated for benign, non-toxic goitre with unilateral procedures during a six-year period, 201 could be followed up, on average, 8 years postoperatively. Twenty-four patients were treated with thyroxine immediately postoperatively ("recurrence prophylaxis"); in the other patients thyroxine was only given in cases of hypothyroidism (significant increase of S-TSH). Occurrence of lymphoid infiltration in the removed lobe was subjectively quantified according to a five point scale. Five of the 15 patients with pronounced inflammation developed hypothyroidism whereas 5 of the 137 patients without inflammation had hypothyroidism (p less than 0.05). There was a significant difference in S-TSH postoperatively between patients with no or, only a slight degree of, chronic inflammation, and patients with pronounced inflammation. This study indicates that histologic grading of lymphocytic infiltration in the thyroid gland may be useful for predicting the risk of postoperative hypothyroidism.

Adenoma↗
PubMed1990

Ca2+ influx in human T lymphocytes is induced independently of inositol phosphate production by mobilization of intracellular Ca2+ stores. A study with the Ca2+ endoplasmic reticulum-ATPase inhibitor thapsigargin.

Thapsigargin (TG), a sesquiterpene lactone and non-phorbol 12-myristate 13-acetate tumor promoter, stimulates a rapid increase in intracellular free Ca2+ [( Ca2+]i) in human T lymphocytes clone P28. The [Ca2+]i response to TG is sustained in the presence of 1 mM extracellular Ca2+, while it becomes transient in Ca2(+)-free medium suggesting that TG activates both the release of Ca2+ from intracellular stores and the entry of Ca2+ from extracellular spaces. TG-induced Ca2+ influx is completely abolished after cell depolarization caused by increased extracellular concentrations of K+. The rise in [Ca2+]i stimulated by TG occurs in the absence of detectable production of inositol phosphates. Moreover, TG does not alter the early biochemical events of T cell activation triggered through the CD2 or the CD3 T cell antigens. Indeed, both inositol phosphate production and intracellular pH increase induced by specific monoclonal antibodies (mAb) remain unchanged after TG treatment. These data suggest that in human T lymphocytes TG releases Ca2+ from an intracellular pool by a mechanism which is independent of the phospholipase C metabolic pathway. Preincubation with TG of T cell clone P28 empties both the CD2 and the CD3-sensitive intracellular Ca2+ pool(s). Conversely, prestimulation of T cell clone P28 by CD3 or CD2-specific mAb inhibits the Ca2(+)-mobilizing effect of TG. Thus it appears that TG and CD2- or CD3-specific mAb mobilize Ca2+ from common Ca2+ pool(s). Taken together, these results demonstrate that Ca2+ influx in human T cells may be linked to mobilization of intracellular Ca2+ pools and by a mechanism independent of phosphoinositide hydrolysis. They further indicate that the release of intracellular Ca2+ pool(s) may play a major role in the opening of cell membrane Ca2+ channels observed during the CD2- or CD3-induced stimulation of human T lymphocytes.

Antibodies, Monoclonal↗
PubMed1979

A histochemical study of alkaline and acid phosphatase activity in osteoarthritic synovial membrane.

In order to determine the localization and activity of alkaline and acid phosphatase in the synovial membrane of osteoarthritic hip joints, enzymo-histochemical analyses were performed using Burstone's and Barka & Anderson's methods. Frozen sections of synovial biopsy material from 12 osteoarthritic and 6 control hip joints were studied. Alkaline phosphatase was found located in fibroblasts below the lining cells and in capillaries and precapillary arterioles. Acid phosphatase was seen in the lysosomes in the lining cells. Semiquantitative evaluation by means of initial time determination showed significantly greater activity in osteoarthritic synovia than in the control group. Whilst the increased activity of lysosomal enzymes is presumably implicated in the joint cartilage damage seen in osteoarthritis, the significance of elevated alkaline phosphatase levels is not yet clear.

Acid Phosphatase↗
PubMed1979

A histochemical study of alkaline and acid phosphatase activity in subchondral bone from osteoarthrotic human hips.

In order to analyze the presence of alkaline and acid phosphatase activity in osteoarthrotic subchondral bone frozen sections from 24 femoral heads were prepared for semiquantitative analysis, using the enzyme-histochemical methods described by Burstone and by Barka and Anderson. Different areas of the subchondral bone, viz. weight-bearing, nonweight-bearing and osteophytes as well as central regions were analyzed. Furthermore, the cartilagenous changes were determined by histological-histochemical grading. There were wide variations within the same femoral head with significantly greater activity of both alkaline and acid phosphatase in weight-bearing than in nonweight-bearing areas and in subchondral bone than in central regions. Osteophytes excluded, the enzyme activities correlated directly with the severity of the cartilage lesions. These enzyme activities presumably reflect the degree of bone regeneration and bone resorption respectively.

Acid Phosphatase↗
PubMed1977

Fractures of the neck of the talus.

One hundred and twenty-three patients with fracture of the neck of the talus were followed up over an average of 22 months. Ffity-four fractures were undisplaced, 53 associated with subtaler dislocation, and 16 associated with dislocation of the talus in both ankle joint and subtalar joint. Of the total 123 patients, 21% (26/123) developed avascular necrosis, 31% (38/123) developed talo-crural and 47% (58/123) subtalar osteoarthrosis. Fifteen per cent (18/123) of the fractures united with considerable deformity, and four per cent (5/123) exhibited non-union of the neck. Out of 63 patients with isolated fracture of the neck of the talus, 65% (41/63) reported moderate or severe complaints, and 52% (33/63) complained of functional disability often resulting in a change to lighter work. Even among the 54 undisplaced cases there were unexpected numbers of late sequelae, such as osteoarthrosis, subjective complaints and disablement.

Adolescent↗
PubMed1977

Fracture of the body of the talus.

Fifty-one patients with fracture of the body of the talus were seen at follow-up examination an average of 23 months after treatment. Osteonecrosis had developed in 8 out of 17 patients with displaced shearing or crush fractures of the trochlea. Malunion as well as subluxation predisposed to osteoarthrosis in the subtalar and talocrural joints. Thus, osteoarthrosis was present in 9 out of 21 patients without malunion, in 8 out of 16 patients with malunion, and in 11 out of 14 with malunion as well as subluxation. Judging from the nature of the complaints, the difficulties in rehabilitation, and the disability assessment, the prognosis was fairly grave, also after the small, usually non-displaced fractures of the posterior and lateral tubercles. Out of 20 patients with fractures of this type only 6 obtained almost complete relief from their symptoms, only 8 could go back to their previous work on a full-time basis, and 11 were assessed to be 10 per cent or more disabled. Fractures in the posterior and lateral tubercles must therefore be interpreted as links in more extensive injuries involving the subtalar joint and possibly the talocrural joint with associated injuries to articular cartilage, joint capsules, and ligaments.

Adolescent↗
PubMed1977

A histological demonstration of nerves in subchondral bone.

Several different staining procedures were carried out on decalcified histological sections from human femoral heads to demonstrate the nerves in subchondral bone. The femoral heads were obtained at surgery from patients with fractures of the femoral neck or osteoarthritic hip joints. The Bodian technique was found to be the most suitable. Serial sections were used in order to disclose the various sources of error. It was not possible to demonstrate nerves in the bone matrix, but they were easily seen in the subchondral bone marrow, after related to the vessels. A comparison of the fracture and osteoarthritic cases revealed an obvious difference; more nerves were seen in osteoarthritis. The method described is considered suitable for further study of the nerves in osteoarthritic femoral heads.

Bone Matrix↗
PubMed1977

Subtalar dislocation.

During the period from 1945 to 1972, 30 cases of subtalar dislocation were reported to the Directorate of Industrial Injuries Insurance in Denmark. The lesions were classified according to type of dislocation showing that the medial inward type predominated by far. According to the findings of the present investigation, the long-term prognosis seems to be more serious than has hitherto been assumed. X-ray and clinical examination disclosed that arthrosis of the subtalar joints was demonstrable in 19 patients. Six of these patients had pantalar arthrosis, the causative factor in two cases being avascular necrosis of the talus. Clinical examination showed that walking was associated with some degree of pain in 21 patients and 15 patients had a more or less pronounced limp.

Humans↗
PubMedDate not supplied

New proazulene guaianolides from Thapsia villosa.

Four new guaianolides 2-5 possessing the terpenoid skeleton of archangelolide [6] were isolated from a specimen of Thapsia villosa [chromosome number 2n = 66 (= 6x)]. Attempts to hydrolyze the natural products 2-6 yielded azulenes, mainly 7-acetyl-1,4-dimethylazulene [9].

Animals↗