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Biomedical subjects

O Eriksson

Publications and source records attributed to O Eriksson.

At least 163 records · Page 9Linked to original sources

Endotoxemia in chronic renal failure.

In the past years dialyzers have been improved, and consequently pyrogenic reactions have become rare. However, some patients in our dialysis unit have shown symptoms during hemodialysis which we suspected could be caused by endotoxins. These patients, as well as controls without similar symptoms, had elevated levels of circulating endotoxin. We therefore measured endotoxin in blood from patients with chronic renal failure and different kinds of treatment. Serum samples were analyzed with a sensitive method described in the literature, using a chromogenic substrate and Limulus amebocyte lysate. In patients on hemodialysis (mean +/- SEM) the endotoxin value in samples taken immediately before dialysis was 40 +/- 4.7 ng/l and significantly elevated (p less than 0.001) compared with the endotoxin value (7 +/- 0.6 ng/l) found in the healthy reference group. Increased endotoxin levels were also seen in patients on hemofiltration (19 +/- 7.5 ng/l) and in patients with conservative treatment and various degrees of renal insufficiency (17 +/- 2.5 ng/l). Patients on peritoneal dialysis and renal-transplanted patients had levels not different from the controls. The mechanism behind endotoxemia in uremia is unknown but may partly be explained by reduced endotoxin elimination due to impaired liver macrophage function. The differences in endotoxin levels in patients on peritoneal or hemodialysis treatment may reflect that extracorporeal circulation enhances endotoxin entrance to the circulation and/or that endotoxin clearance is dependent on the dialysis regimen.

Adolescent↗

Some effects of metolazone on electrolyte transport.

Metolazone action was studied 1) in vitro on isolated operculum of Fundulus heteroclitus (active chloride transport) using an Ussing chamber (metolazone conc 500 microM) and in vivo 2) using the modified Sperber technique in the hen (metolazone infusion rate 0.75-1.2 micrograms/kg/min) and 3) in healthy volunteers using clearance techniques (metolazone infusion rate 10 mg/h). Metolazone reduced (p less than 0.05) short circuit current potential differences with 20% from average control values (p less than 0.05), while direct current resistance was unchanged. This is comparable to thiazide but much lower than loop diuretic effects. True tubular excretion fraction of metolazone before and after novobiocin (2.7 mumol/kg/min coinfusion averaged 14.1 and 4.5%, resp. (p less than 0.01; n = 8). Thus metolazone is partly eliminated by renal tubular secretion. However, the diuretic effect (sodium, chloride and potassium excretion)--and clearances of Cr51-EDTA and I125-Na-o-iodohippurate--were symmetrical, i.e. independent of metolazone urinary excretion rate, as previously shown for thiazides. Renal clearance of metolazone in healthy volunteers. (HPLC-method) averaged 173 +/- 20 ml/min (n = 8). Probenecid (1 g iv.) significantly reduced the renal clearance of metolazone to 33 +/- 7 ml/min and potassium excretion with maximum 30%, while diuretic and saluretic effects were significantly increased with maximum 30%. Thus, also in humans the diuretic effect of metolazone is not coupled to the urinary excretion rate of the drug, but suggests that its diuretic effect is elicited primarily from the peritubular side of the nephron. Probenecid apparently dissociates sodium from potassium excretion effects of metolazone. This implies a luminal, sodium-independent kaliuretic effect of the drug.

Adult↗

Effects of growth hormone substitution on mental performance in adults with growth hormone deficiency: a pilot study.

Five patients ages 22 to 36 years with growth hormone deficiency received substitution with native human growth hormone and biosynthetic methionyl human growth hormone, 8 IU i.m. three times weekly, for two separate 4-week periods. Before and at the end of each treatment period, five psychometric tests evaluating cognitive functions were performed. The results suggest a beneficial effect of growth hormone on certain cognitive functions. The results were similar for the two hGH preparations.

Adult↗

Chloride transport inhibition by various types of loop diuretics in fish opercular epithelium.

Isolated opercular epithelia of killifish (Fundulus heteroclitus), mounted in an Ussing chamber, were used to study the effects of various diuretics on chloride transport, measured as short-circuit current (SCC). The acidic 'loop' diuretics, ethacrynic acid and azosemide, and the basic 'loop' diuretics, muzolimine and MK 447, reduced SCC and exhibited similar dose-effect curves, with EC50s for SCC of 64, 17, greater than 500 and 224 microM, respectively. The alkaline diuretic tizolemide (HOE 740) and the p-COOH-analogue of sulphanilamide were inactive, suggesting that the chloruretic effects of these agents are of a thiazide type. The method can thus discriminate between the effects of loop and thiazide types of diuretics, but not between those of structurally highly different 'loop' diuretics of an acidic and basic nature. Monomethylation of the SO2NH2 group of bumetanide had no effect on the activity of this agent whereas dimethylation reduced it fourfold. The (-)enantiomers of the 'loop' diuretics indacrinone and ozolinone were four and greater than 100 times more active, respectively, than the (+)forms. These results are in accordance with those obtained for the same drugs in the mammalian kidney, and point to the presence of a highly specific binding site for these diuretics. Attempts were also made to explore the prerequisites for binding of the loop diuretic to the active site. Pretreatment of the opercular epithelium with an alpha-L-fucose-binding lectin did not prevent the inhibitory actions of furosemide and indacrinone. Probenecid and (+)ozolinone, both of which block organic anion transport, did not prevent the effects of bumetanide and (-)ozolinone.

Animals↗

Inhibitory effects of chemically-different 'loop' diuretics on chloride transport across the bullfrog cornea.

Frog (Rana catesbeiana) corneas were mounted in an Ussing chamber, modified to facilitate dissection and to avoid edge damage to the epithelial tissue during mounting and measurements. When bathed in Conway solution of pH 7.4 the corneas displayed highly stable electrical properties, with a transepithelial potential difference (PD) of 16.6 +/- 1.O mV and a short-circuit current (SCC) of 10.3 +/- 0.8 microA cm-2. The DC resistance was 2.0 +/- 0.15 k omega X cm2 (mean +/- SE, n = 45). An increase in the intracellular cyclic AMP level induced by prostaglandin E2 and by 3-isobutyl-1-methylxanthine (IBMX) resulted in an increase in SCC. Ortho-vanadate, an inhibitor of Na+-K+-ATPase, reduced SCC. The acidic loop diuretics furosemide, bumetanide and the levorotatory form of indacrinone (MK-196) reduced SCC by about 50% at concentrations of 500, 100 and 46 microM, respectively. The (-)form of MK-196 was four times more active than the (+)form. Dimethylation of the SO2NH2 group reduced the activity of bumetanide. The basic diuretics muzolimine (Bay G 2821) and MK-447, were found, similarly, to reduce SCC by about 50% at concentrations of 500 microM. In view of their 'high ceiling' type of saluretic effects in whole animals, these basic agents should therefore be classified as 'loop' diuretics. The effects of these structurally highly different 'loop' diuretics are similar in epithelia which secrete (cornea) and in those which absorb (the renal thick ascending limb of Henle's loop; TALH) chloride ions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Oxidation of tricyclic antidepressant drugs, debrisoquine and 7-ethoxyresorufin, by human liver preparations.

Data obtained from human studies in vivo show that the dispositions of the tricyclic antidepressant drugs desmethylimipramine (DMI) and nortriptyline are related to the debrisoquine hydroxylation phenotype. To obtain insight into the enzymic mechanisms behind this, the metabolism of debrisoquine and antidepressant drugs by human liver preparations have been studied. The 2-hydroxylation of DMI in vitro correlates with the 4-hydroxylation of debrisoquine among various livers (rs = 0.90). Debrisoquine inhibits DMI hydroxylation competitively, and DMI inhibits debrisoquine hydroxylation, suggesting that DMI hydroxylation is catalysed by the debrisoquine hydroxylase in human liver. By monitoring the hydroxylation of DMI in various fractions during separation and purification of cytochrome P-450 from human liver microsomes we have purified a cytochrome P-450 which efficiently hydroxylates this drug. The apparently electrophoretically homogeneous enzyme had a molecular weight of 51,500 and hydroxylated DMI and debrisoquine at rates of up to 0.95 and 0.45 nmol/min . nmol P-450, respectively. This is probably the major debrisoquine hydroxylating cytochrome P-450 in man. Nortriptyline 10-hydroxylation correlates strongly (r = 0.96) with debrisoquine hydroxylation in human liver microsomes. Nortriptyline inhibits DMI-hydroxylation competitively, and the drug also inhibits the 4-hydroxylation of debrisoquine. Thus it is probable that nortriptyline is hydroxylated by debrisoquine hydroxylase. Imipramine N-demethylation did not correlate significantly (P greater than 0.1) with debrisoquine hydroxylation among microsomes from nine livers. However, if a liver from a subject, which was a poor metabolizer of debrisoquine in vivo, was included, a correlation was obtained (r = 0.79, P less than 0.01, N = 10). Imipramine demethylation also correlated with DMI-hydroxylation only if the 'poor metabolizer' liver was included (r = 0.75, P less than 0.05, N = 10). Debrisoquine inhibited imipramine demethylation competitively. The data indicate that imipramine can interact with debrisoquine- and DMI-hydroxylase, but it is uncertain if this enzyme plays an important quantitative role in its demethylation. Ethoxyresorufin O-deethylation correlated with DMI hydroxylation (r = 0.80) in human liver preparations, and DMI inhibited the former reaction in what is probably a mixed competitive-non-competitive inhibition. Liver preparations from a subject who was a poor oxidizer of debrisoquine both in vivo and in vitro had unusually low capacity to metabolize ethoxyresorufin. Thus ethoxyresorufin, at least partly, seems to interact with an enzyme that can metabolize DMI in human liver.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

Image cytometry in malignancy grading of breast cancer. Results in a prospective study with seven years of follow-up.

A fully automated system for image cytometry is presented. In combination with a special tumor sampling procedure, the system proved able to record with high reproducibility a large number of tumor cell population descriptors of high prognostic significance in a prospective study of breast cancer. These included the degree of abnormality of DNA distribution (strongly correlated with the proliferative rate) and some descriptors of shape and texture (strongly correlated with the grading system for breast cancer suggested by the World Health Organization). While the extreme complexity of a true malignancy grading system for breast cancer is underlined, the results of this study indicate that its creation is a possibility, given sufficient effort by interdisciplinary teams using modern sophisticated analytical techniques.

Breast Neoplasms↗

A program for logistic prediction modelling.

A computer program has been developed that can be used for analysing a binary outcome variable and a set of regressors of type interval with a logistic (i.e. nonlinear) model.

Biometry↗

The use of isolated fish opercular epithelium as a model tissue for studying intrinsic activities of loop diuretics.

Isolated opercular epithelia of killifish (Fundulus heteroclitus) were mounted in an Ussing chamber. The epithelia displayed a transepithelial electrical potential difference (PD) of 10.6 +/- 0.3 mV (sea-water side negative) and a short-circuit current (SCC) of 72.1 +/- 2.1 microA cm-2. The electrical resistance was 160 +/- 3 omega cm2 (mean +/- SE, n = 269). The unidirectional flux of 36Cl from blood side to sea-water side compared well with the SCC. No net flux of 22Na or 24Na across the epithelium was observed. Raising of cyclic AMP levels by theophylline, 3-isobutyl-I-methyl-xanthine, isoprenaline and forskolin, increased SCC and PD. Prostaglandins PGE2 and to some extent PGF2 alpha inhibited SCC and PD. Inhibition of Na+-K+-ATPase by ouabain and orthovanadate reduced SCC and PD. Pretreatment of the epithelium with the stilbene disulphonic acid (DIDS) did not prevent the action of orthovanadate. Different types of diuretics were tested, but only the loop diuretics bumetanide, piretanide, and furosemide, rapidly and strongly inhibited PD and SCC and unidirectional 36Cl serosal to mucosal flux. Dose-response curves for these agents were parallel and EC50 values for effects on SCC were 40, 52, and 295 microM, respectively. The same relative activities of these diuretics have been seen in the renal thick ascending limb of Henle's loop (TALH). It is concluded that the killifish opercular skin responds to hormonal stimuli and various pharmacological agents in a manner similar to that of mammalian renal TALH. It should therefore be a useful model for studies of the modes of action and the structure-activity relationships of diuretics which act by inhibition of chloride transport or Na+-K+-ATPase activity.

Action Potentials↗

Effects of fine-needle aspiration and other biopsy procedures on tumor dissemination in mice.

Using five syngeneic tumor-host systems in mice, we studied the influence of fine-needle aspiration biopsy, incisional biopsy, and excisional biopsy on tumor death rates. Guided by results from pilot studies a very strict test protocol was developed which made possible a comparison between the tumor systems in spite of their differences in tumor growth rates and dissemination patterns. The compiled results from the experiments did not reveal any differences in tumor death rates, neither between the test groups and their controls, nor between the three biopsy methods: fine-needle aspiration biopsy, incisional biopsy, and excisional biopsy. Additional experiments confirmed, however, earlier observations that tumor cell seeding and tumor outgrowth by way of the aspiration needle track may occur under extreme test conditions.

Animals↗

Effects of standard diuretics and ortho-vanadate on sodium transport across isolated frog skin.

Frog (Rana temporaria) skins were studied in an Ussing type lucite chamber adapted to diminish tissue edge damage. The transepithelial electrical potential difference, short circuit current and direct current (DC) resistance of skins mounted in this chamber were 56, 20 and 24% higher, respectively, than those of skins mounted in a conventional chamber. Amiloride, triamterene, ouabain and ortho-vanadate inhibited short circuit current and net mucosal to serosal flux of 22Na. Amiloride and triamterene had rapid onsets of action and were effective only when administered to the mucosal (pond) side of the skin. Ouabain and ortho-vanadate had slower onsets of action and were effective only when administered to the serosal side of the skin. Steady state of effects of these drugs was not reached within the three-hour period of the experiments. The inhibitory effect of ortho-vanadate was blocked by adding a disulfonic stilbene derivative (DIDS) to the serosal side of the skin. Serosal prostaglandin E2 stimulated the short-circuit current and decreased the DC resistance. Thiazides, acetazolamide and loop diuretics had no effects on Na+ transport by frog skin. Thus, frog skin seems to be a useful model only in studies of the mode of action and the structure-activity relationship of diuretic which act by inhibiting sodium entry or Na+-K+-ATPase activity.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

Local tumour cell seeding by fine-needle aspiration biopsy. A semiquantitative study.

We have performed fine-needle biopsies from solid or ascites-growing mouse tumours. The biopsies were taken via striated muscle or the peritoneal cavity of healthy mice syngeneic with the tumours and the tumour-bearing animals. The incidence of tumour takes in these new mice were compared with the intramuscular or intraperitoneal transplantability of the tumours. In order to estimate more accurately the number of seeded cells, we also performed aspiration biopsy through the leg muscles of healthy animals into ascites-growing tumours labelled with 125IUDR. The resulting radioactivity in the leg muscle was compared with the radioactivity of the ascites tumour cells. The studies indicate that one may seed 10(3)-10(4) cells, and sometimes more, into the needle track with fine-needle aspiration biopsy from extremely cellular and dedifferentiated tumors.

Animals↗

Histopathological systems of breast cancer classification: reproducibility and clinical significance.

The inter- and intraobserver reproducibilities of the histopathological systems of breast cancer classification suggested by the World Health Organisation (WHO), the Armed Forces Institute of Pathology (AFIP) and Ackerman have been analysed. The reproducibilities of the three classification systems were only "fair" to "moderate" and no correlation with the five-year recurrence rate was found. Our results indicate that these classification systems are without biological significance and are useless for prognosis in the individual patient. When the tumours were classified according to degree of differentiation (high, moderate, low) or graded according to WHO (which includes both differentiation and nuclear atypia), however, there was a significant correlation with the five-year recurrence rate. Yet even such "reduced" subdivisions are of no value in judging prognosis for the individual patient at the time of diagnosis; rather, they are useful only in the follow-up analysis of groups of patients.

Breast Neoplasms↗

Increased incidence of cervical atypia in women with systemic lupus erythematosus treated with chemotherapy.

In a retrospective study we found that 19 of 80 women with systemic lupus erythematosus had atypical cervical smears as compared to only 9 of 80 age-matched women without the disease. This increased incidence occurred mainly among women receiving cytotoxic drugs. Cervical atypia in women with lupus was not morphologically different from cervical atypia in general. Possible mechanisms responsible for the increased incidence are discussed. It is concluded that women with lupus who receive chemotherapy should have cervical smears taken regularly.

Adult↗

Correlation between cytometric features and mitotic frequency in human breast carcinoma.

An evaluation of cytometric features of 142 human breast cancers was performed. Twenty-two cytometric features describing density, structure and shape were correlated with mitotic frequency and labeling index of some of the tumors and with the observed recurrence rate of the tumors within 3 years after removal of the breast. A new cytometric measure was also created by combining the four features most strongly correlated with mitotic frequency of the tumors. It was found that the variance of the nuclear area was the feature that was most strongly correlated with mitotic frequency and recurrence rate. No new cytometric measure created by combining the four features most strongly correlated with mitotic frequency, correlated as well as variance of nuclear area even though the four features were optimized by multiple regression analysis for their correlation with mitotic frequency.

Breast Neoplasms↗