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T Christoffersen

Publications and source records attributed to T Christoffersen.

At least 37 records · Page 2Linked to original sources
PubMed1995

Dexamethasone inversely regulates DNA synthesis and phosphoenolpyruvate carboxykinase mRNA levels in cultured rat hepatocytes: interactions with insulin, glucagon, and transforming growth factor beta 1.

In hepatocytes, glucocorticoids control the expression of several genes and exert significant, but complex, regulation of the proliferation. To shed more light on the growth responses to glucocorticoids in these cells, we treated adult rat hepatocytes in primary culture with dexamethasone, in various combinations with other hormones (insulin, glucagon, transforming growth factor beta 1 (TGF beta 1)), and examined the relationship between the effects on the DNA synthesis and the mRNA level of phosphoenolpyruvate carboxykinase, a gene typically expressed in differentiated hepatocytes. Insulin exhibited the previously observed suppressing effect on the glucocorticoid-induced phosphoenolpyruvate carboxykinase mRNA level, and also reversed growth-inhibitory effects of the glucocorticoid. Dexamethasone and glucagon (via cAMP) acted strongly synergistically both in enhancing the phosphoenolpyruvate carboxykinase expression and inhibiting the growth, the inhibitory effect of glucagon on DNA synthesis being totally dependent on dexamethasone. The effects of dexamethasone plus glucagon on both the phosphoenolpyruvate carboxykinase mRNA abundance and the DNA synthesis were partially counteracted by insulin. Dexamethasone is permissive for a promoting effect of TGF beta 1 on phosphoenolpyruvate carboxykinase expression, and was found to increase the maximal inhibitory effect of (but reduced the sensitivity to) TGF beta 1 on the DNA synthesis. The results indicate that there is an inverse glucocorticoid-induced regulation of the DNA synthesis and the expression of a liver-typical gene.

Animals↗
PubMed1995

Glaucoma screening with oculokinetic perimetry in general practice: is its specificity acceptable?

The main aim of the study was to estimate the specificity of oculokinetic perimetry (OKP) for glaucoma case-finding in general practice. The visual fields of 185 consecutive patients aged 40 years or more were screened with OKP in one general practice. Test specificity was 94%. The OKP test was abnormal in 17 patients. At follow-up 6 of these patients had glaucoma or were glaucoma suspects. Three of the remaining 11 patients had cataract. Eight OKP-positive patients had no eye disease. In 96 of the patients results of OKP were compared with Bjerrum campimetry, which revealed one possibly false-negative OKP test. Ten patients with previously diagnosed glaucoma were also examined with OKP. All 10 patients were identified by the OKP test. In 80 of the patients OKP was performed twice, supervised by two different observers. The proportion of agreement for normal tests was very high: 0.96 (95% CI: 0.91-1.0). The proportion of agreement for abnormal tests was 0.79 (95% CI: 0.57-1.0). The OKP test may be useful in glaucoma case-finding in general practice. However, the proportion of false-positive tests seems to be too high for OKP to be used alone in mass screening.

Adult↗
PubMed1994

Elevated glucose concentrations inhibit DNA synthesis and expression of c-myc in cultured hepatocytes.

Glucose depressed DNA synthesis in rat hepatocytes in primary culture. As compared to controls cultured with 5.6 mM glucose, maximal (> or = 75%) inhibition was obtained at 20-30 mM, and half-maximal effect at 10-15 mM. Comparison of D- and L-glucose showed that the effect was specific for the D-form. Maximal inhibition required the presence of glucose during the first 24 hours of culture. The expression of the c-myc gene was reduced when the hepatocytes were cultured in the presence of elevated glucose. The responses to epidermal growth factor, insulin and vasopressin, in terms of percentual stimulation of DNA synthesis, were qualitatively similar at 5.6 and 16.8 mM glucose, while glucagon stimulated more strongly when the glucose concentration was increased; glucagon at concentrations > or = 1 nM reversed the inhibition by glucose. 8-Br-cAMP mimicked the effect of glucagon. These results suggest that an increase in the level of glucose depresses hepatocyte DNA synthesis. The effect is associated with lowered expression of the c-myc gene and is counteracted by cAMP.

Adenylyl Cyclases↗
PubMed1994

Stimulation of hepatocyte DNA synthesis by prostaglandin E2 and prostaglandin F2 alpha: additivity with the effect of norepinephrine, and synergism with epidermal growth factor.

Previous data obtained in vivo and in vitro suggest that both prostaglandins (PGs) and catecholamines may have a role in promoting hepatocyte proliferation, and PGE2 and PGF2 alpha have also been implicated as mediators of the mitogenic actions of epidermal growth factor (EGF) (and transforming growth factor alpha [TGF alpha]). We have studied the effects of PGs and norepinephrine on DNA synthesis in serum-free primary cultures of rat hepatocytes, and compared the PG effects with those of norepinephrine. PGE2, PGF2 alpha, PGD2, and the synthetic analog dimethyl-PGE2 markedly enhanced the DNA synthesis. A more quantitative analysis of the effects of PGE2 and PGF2 alpha on the DNA synthesis, in the presence and absence of EGF, indicated that these PGs interacted in an essentially multiplicative manner with the effect of EGF. The effects of PGE2 and PGF2 alpha showed almost complete additivity with the stimulation of DNA synthesis produced by maximally effective concentrations of norepinephrine. The data suggest a) that PGE2 and PGF2 alpha facilitate and synergize with, rather than mediate, the actions of EGF in hepatocytes, and b) that this effect of the PGs occurs by mechanisms that are at least partly distinct from those of norepinephrine.

Animals↗
PubMed1994

Transforming growth factor beta 1 increases the phosphoenolpyruvate carboxykinase mRNA level in cultured rat hepatocytes.

Transforming growth factor beta 1 (TGF beta 1) elevated the phosphoenolpyruvate carboxykinase (PEPCK) mRNA abundance in primary cultures of rat hepatocytes. Although this increase was not as large as the rise in PEPCK gene expression induced by the cAMP-elevating agents glucagon or isoproterenol, the effect of TGF beta 1 was several-fold and concentration-dependent, with ED50 at about 2.5 pM, which is in the same concentration range as the previously found growth-inhibitory effect of TGF beta. The data show that the level of mRNA for PEPCK, an enzyme typically expressed in the liver, can be regulated in the same direction by TGF beta 1 and cAMP.

Animals↗
PubMed1993

Long-term inhibitory effect of cAMP on beta-adrenoceptor acquisition and nonselective attenuation of adenylyl cyclase in hepatocytes.

Long-term effects of cAMP on the surface expression of beta-adrenoceptors and adenylyl cyclase activity were investigated in primary cultures of rat hepatocytes. beta-Adrenoceptor density and catecholamine-responsive adenylyl cyclase activity increased during culturing in a biphasic manner, with a plateau of 10-20 h duration occurring approximately 10 h after plating. Treatment of hepatocyte cultures with 8-bromo-cAMP during the plateau period did not affect the density of beta-adrenoceptors. In contrast, addition of 8-bromo-cAMP, 8-chlorophenylthio-cAMP, forskolin or glucagon during a period of active recruitment of surface beta-adrenoceptors resulted in a suppression of the acquisition of beta-adrenoceptors. In both experimental situations there was a partial decrease in hormone-stimulated and basal adenylyl cyclase activity. The results suggest that cAMP exerts at least two types of long-term regulation of adenylyl cyclase in hepatocytes: a suppressive effect on beta-adrenoceptor acquisition, and a partial, nonselective decrease in adenylyl cyclase activity not involving beta-adrenoceptor down-regulation.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1993

Tonometry in the general practice setting (I): Tono-Pen compared to Goldman applanation tonometry.

Intraocular pressure was measured in 132 consecutive patients over the age of 20 in a general practice with two general practitioners (GP). Tono-Pen tonometry was compared to Goldmann applantation tonometry in a masked, randomized design. Also, agreement between Tono-Pen measurements by the GPs and the ophthalmologist was estimated. Both mean difference between Tono-Pen and Goldmann applantation measurements and mean differences between Tono-Pen readings made by GPs and ophthalmologist were less than 1 mmHg. Ninety-five percent limits of agreement between the two methods were approximately -4.5 mmHg and 5.5 mmHg, and between observers approximately -4 mmHg and 5 mmHg. The Tono-Pen was agreeable both to patients and physicians. The GPs made as accurate measurements as the ophthalmologist. The wide limits of agreement are clinically much more important than the small differences between means. Random variation was much greater than systematic variation. Wide limits of agreement will apply to all known methods of clinical tonometry.

Adult↗
PubMed1993

Tonometry in the general practice setting (II): Which cut-off point for referral--for which patients?

A tonometry study comparing Tono-Pen with Goldmann applanation tonometry in a general practice setting revealed four cases of ocular hypertension in 132 patients. Two of the 4 patients required further ophthalmological care after referral. None of these patients, but 4 patients with no ocular hypertension, would have been referred for follow-up if referral had been made on the basis of the single reading made by the general practitioner. Tonometry readings are subject to considerable random variation, and the implications for a cut-off policy in general practice is discussed. Associations between ocular hypertension and known risk factors are weak and offer limited help in selecting asymptomatic patients for measurement. Systematic screening should not be a routine. The cut-off point should be kept low to avoid false reassurance of glaucoma patients, possibly as low as 17 mmHg. Multiple measurements may limit the number of referrals if the readings remain low.

Adult↗
PubMed1993

Injury to the cornea due to fish bile.

A retrospective study of 207 patients with chemical eye injuries in northern Norway revealed that fish bile was the causal agent in 14%. Fish bile caused superficial corneal erosions in 28 of 29 cases. All but one of the patients were professional fishermen or fish industry workers. In one case delayed medical care led to serious corneal opacity. Provided that there was immediate and abundant rinsing of the affected eye and good medical care, the prognosis of fish bile injuries was fairly good. The mechanisms for corneal damage due to fish bile are not clear.

Adult↗
PubMed1992

Inhibition of hepatocyte DNA synthesis by transforming growth factor beta 1 and cyclic AMP: effect immediately before the G1/S border.

Previous studies have shown that both transforming growth factor beta (TGF-beta) and cyclic AMP (cAMP) inhibit hepatocyte DNA synthesis. While cAMP (in addition to being stimulatory in G0/early G1) exerts its inhibition on hepatocytes late in G1, the point where TGF-beta inhibits has not been precisely defined. We have now examined further the inhibitory effects of cAMP and TGF-beta 1 on DNA synthesis in primary rat hepatocyte cultures and, in particular, tried to determine where in the prereplicative period the cells are sensitive to these agents. Although a transient exposure to TGF-beta 1 (but not glucagon) during the first hours of the cell culturing led to inhibition of DNA synthesis, the cells were more sensitive at a point late in G1, where they also were inhibited by cAMP. Thus, exposure to TGF-beta 1, glucagon, or the cAMP analogue 8-chlorophenylthio-cAMP at a time when there was a continuous recruitment of cells to S phase strongly decreased the rate of S-phase entry. For both TGF-beta 1 and cAMP the inhibition was established within 1-2 h, the lag time being indistinguishable for the two agents. No evidence was found for a synergism between TGF-beta 1 and cAMP. Treatment with TGF-beta 1 did not detectably alter basal or glucagon-stimulated cAMP concentrations. The results suggest that in hepatocytes there is a process immediately before the G1/S border which is sensitive to both TGF-beta 1 and cAMP and which appears to represent a major point of inhibition.

Animals↗
PubMed1992

Stimulatory and inhibitory effects of catecholamines on DNA synthesis in primary rat hepatocyte cultures: role of alpha 1- and beta-adrenergic mechanisms.

Previous studies suggest that catecholamines may be involved in the regulation of liver growth. Considerable evidence implicates alpha 1-adrenergic mechanisms in the initiation of hepatocyte proliferation, while the role of beta-adrenoceptors is less clear. We have examined further the adrenergic regulation of hepatocyte DNA synthesis, using primary monolayer cultures. In hepatocytes that were also treated with epidermal growth factor and insulin, epinephrine or norepinephrine added early after the seeding strongly accelerated the rate of S phase entry. The beta-adrenergic agonist isoproterenol and the alpha-adrenergic agonist phenylephrine also stimulated the DNA synthesis, but were less efficient than epinephrine and norepinephrine. Experiments with the alpha 1-receptor blocker prazosine and the beta-receptor blocker timolol showed that the stimulatory effect of norepinephrine consisted of both an alpha 1- and a beta-adrenergic component. The alpha 1-component was most prominent in terms of maximal response at high concentrations of the agonist, but the beta-component contributed significantly and predominated at low concentrations (less than 0.1 microM) of norepinephrine. At later stages (about 40 h) of culturing norepinephrine strongly but reversibly inhibited the cells, acting at a point late in the G1 phase. This inhibition was mimicked by isoproterenol and abolished by timolol but was unaffected by prazosine, suggesting a beta-adrenoceptor-mediated effect. The results confirm the alpha 1-adrenoceptor-mediated stimulatory effect, but also show that beta-adrenoceptors may contribute to the growth stimulation by catecholamines. Furthermore, catecholamines, via beta-adrenoceptors and cyclic AMP, inhibit the G1-S transition, and may thus play a role in the termination of hepatic proliferation.

Animals↗
PubMed1992

Regulation of surface expression of high-affinity receptors for epidermal growth factor (EGF) in hepatocytes by hormones, differentiating agents, and phorbol ester.

Freshly isolated adult rat hepatocytes exhibit a nonhomogeneous population of epidermal growth factor (EGF) receptors with about 10,000 high-affinity binding sites (Kd 20 pM) and about 200,000 low-affinity sites (Kd 600 pM) per cell. With culturing as primary monolayers under conditions where the cells show a marked increase in the sensitivity to the growth-stimulatory effect of EGF, a gradual reduction in the number of EGF receptors and an almost complete loss of high-affinity EGF receptors is seen. Insulin, which promotes growth of hepatocytes in concert with EGF, enhances the down-regulation of these high-affinity receptors. The differentiating (and growth-inhibitory) agent n-butyrate counteracts this down-regulation and preserves the high-affinity receptors. This effect of butyrate is synergistic with the glucocorticoid agent dexamethasone. Another differentiating agent, dimethylsulfoxide (DMSO), also counteracts the down-regulation of high-affinity EGF receptors. Moreover, the tumor promoter, tetradecanoylphorbol acetate (TPA), down-regulates the EGF receptor. This effect is particularly evident when studying the high-affinity receptors up-regulated by prior treatment with butyrate plus dexamethasone. Taken together these results provide strong support for the notion that an inverse relationship exists between expression of high-affinity EGF binding and responsiveness to growth activation by EGF.

Animals↗
PubMed1992

Growth-regulatory effects of glucagon, insulin, and epidermal growth factor in cultured hepatocytes. Temporal aspects and evidence for bidirectional control by cyclic AMP.

Data presented indicate that in hepatocytes insulin and glucagon promote growth by acting in a relatively early part of the prereplicative period (G0 or early G1) whereas cells (if pretreated with insulin) become more sensitive to EGF at the later stages, ie, nearer the S phase entry. The data indicate that at least two effects of glucagon (cAMP) on hepatocyte proliferation exist; in addition to a growth-promoting modulation early in the prereplicative period, there is also an inhibitory effect of glucagon (as well as other cAMP-elevating agents) that is exerted at a point shortly before the G1-to-S transition. Because both effects occur dose-dependently in the normal range of glucagon concentrations in portal blood, it is conceivable that glucagon/cAMP is involved both when liver growth is initiated and terminated.

Animals↗
PubMed1991

[P pills and risk of cancer].

The article summarizes present knowledge on the relationship between use of oral contraceptives use and the risk of hormone dependent cancers. The authors conclude that, at present, this knowledge does not warrant a change in current prescription practice.

Adult↗
PubMed1990

Amiloride inhibits constitutive internalization and increases the surface number of epidermal growth factor receptors in intact rat hepatocytes.

In previous experiments the surface expression of epidermal growth factor (EGF) receptors in freshly isolated rat hepatocytes varied temperature- and time-dependently and was depleted by monensin and cycloheximide in a way suggesting that a subpopulation of these receptors are subject to constitutive cycling (Gladhaug and Christoffersen; 1988). We here report the finding that pretreatment of the hepatocytes with amiloride exerts marked effects on cellular EGF receptor movements. After 2 h incubation with 1 mM amiloride, the receptor level was approximately 270,000 sites/cell surface vs. 140,000 in the untreated cell, with no change in receptor affinity. Amiloride thus stabilized the surface EGF receptor pool at an elevated level. In cells pretreated with amiloride for 60 min, the relative endocytosis decreased from about 2.6 EGF molecules internalized per receptor during 15 min endocytosis in untreated cells to about 1.5 molecules/receptor in amiloride-treated cells. These results suggest that amiloride causes an accumulation of EGF receptors at the hepatocyte surface due to inhibition of constitutive receptor internalization. In addition, it was found that in amiloride-treated hepatocytes the phorbol ester TPA strongly inhibited high-affinity EGF binding without affecting the total surface receptor number. In control cells, TPA did not consistently affect binding. Pretreatment with amiloride prevented surface EGF receptor depletion induced by cycloheximide and puromycin, but it did not significantly inhibit surface receptor depletion caused by monensin. Although the underlying mechanism of the amiloride effect on intracellular receptor trafficking is not clear, the results provide further evidence for a continuous, ligand-independent EGF receptor cycling pathway in hepatocytes.

Amiloride↗