Polychlorinated biphenyl exposure and corticosterone levels in seven polar seabird species.

The role of polychlorinated biphenyls (PCBs) on exposure-related endocrine effects has been poorly investigated in wild birds. This is the case for stress hormones including corticosterone (CORT). Some studies have suggested that environmental exposure to PCBs and altered CORT secretion might be associated. Here we investigated the relationships between blood PCB concentrations and circulating CORT levels in seven free-ranging polar seabird species occupying different trophic positions, and hence covering a wide range of PCB exposure. Blood ∑7PCB concentrations (range: 61-115,632 ng/g lw) were positively associated to baseline or stress-induced CORT levels in three species and negatively associated to stress-induced CORT levels in one species. Global analysis suggests that in males, baseline CORT levels generally increase with increasing blood ∑7PCB concentrations, whereas stress-induced CORT levels decrease when reaching high blood ∑7PCB concentrations. This study suggests that the nature of the PCB-CORT relationships may depend on the level of PCB exposure.

Prognostic markers for detection of coexistent carcinoma in high-risk endometrial hyperplasia.

OBJECTIVES: Reliable predictive uterus-sparing methods are crucial for treatment decisions among women who wish to preserve fertility and for seriously ill patients for whom surgery is hazardous. Thus, prediction of myoinvasive carcinoma by objective histomorphometry (4C-rule) and subjective diagnosis (endometrial intraepithelial neoplasia, EIN) were investigated in high-risk endometrial biopsies. PATIENTS AND METHODS: A total of 45 patients retrospectively diagnosed with high-risk hyperplasia, of whom ten were found to have concurrent carcinoma, were investigated. The histomorphometric 4C-rule and the EIN classification system were used for outcome prediction. RESULTS: Myoinvasive disease was predicted with a sensitivity of 87% and a specificity of 79% by using 4C-rule assessment. The sensitivity and specificity of the EIN classification to predict coexistent carcinoma or not was 50% and 97%, respectively. CONCLUSION: Six out of the seven reported cases with myoinvasion were correctly diagnosed with the 4C-rule assessment. In contrast, only three out of the seven myoinvasive cases were diagnosed as cancer using the EIN approach.

Basal metabolic rate: heritability and genetic correlations with morphological traits in the zebra finch.

Studies of genetic variation in metabolic traits have so far not focused on birds. In our study population of captive zebra finches we found evidence for a significant heritable genetic component in basal metabolic rate (BMR). Heritability of all morphological traits investigated (body mass, head length, tars length and wing length) was significantly larger than zero. All traits were positively phenotypically correlated. Eight of 10 genetic correlations presented in this study differed significantly from zero, all being positive, suggesting the possibility of correlated responses to any selection acting on the traits. When conditioned on the genetic variance in body mass, the heritability of BMR was reduced from 25% to 4%. Hence, our results indicate that genetic changes in BMR through directional selection are possible, but the potential for adaptation independent of body mass may be limited.

Does food shortage delay development of homeothermy in European shag nestlings (Phalacrocorax aristotelis)?

Nestlings seem to face a trade-off between reducing the basal level of energy metabolism, as an energy-saving response, and maintaining thermogenic capacity during temporal food shortage. In the present study we examined developmental responses to short-term diet restriction of 12-16 day old nestling European shags kept under laboratory conditions and tested whether temporal food shortage delay the development of homeothermy. During food shortage the European shag nestlings substantially reduced basal level of energy metabolism, resulting in significant energy savings. The reduction in basal level of energy metabolism corresponded with a reduction in peak metabolic rate. At the same time, the low peak metabolic rate of diet-restricted nestlings was offset by a lower mass-specific minimal thermal conductance, and an increased mass-specific absolute scope. Consequently, the insulation and the portion of peak metabolic rate available for regulatory thermogenesis seemed to develop normally, as expected from age, during the period of food shortage. Further, the degree of homeothermy, measured as the index of homeothermy, was not significantly lower in diet-restricted nestlings compared to controls at the same age. We conclude that temporal food shortage did not significantly delay the development of homeothermy in the European shag nestlings despite substantial reductions in basal level of energy metabolism and peak metabolic rate.

The energy economy of the arctic-breeding Kittiwake (Rissa tridactyla): a review.

The present paper reviews recent studies on changes in body mass, body composition and rates of energy expenditure during the breeding season in the black-legged Kittiwake (Rissa tridactyla) on Svalbard (79 degrees N). The main characteristic of the energy budget is a pronounced decrease in body mass as well as basal metabolic rate (BMR) after the eggs have hatched. While most internal organs lose mass in direct proportion to the general decrease in body mass, the liver and kidney masses decrease to a disproportionately greater extent. Since both the liver and the kidney have high intrinsic metabolic rates, these results support an earlier notion that the reduction in body mass is an adaptation to reduce maintenance costs. Alternatively, the reduced BMR is due to a decrease in energy uptake from the gastrointestinal tract, thereby ensuring that undigested food is ready to be regurgitated to the chicks. At the end of the chick-rearing period, the field metabolic rate (FMR) reaches its highest level, probably due to an increased workload associated with chick feeding. This occurs at a time of low body mass and BMR. A pronounced increase in the metabolic scope (FMR/BMR) during the latter part of the chick-rearing period demonstrates that BMR and FMR may change independently of each other and that the ratio FMR/BMR may not be a good measure of energy stress.

Individual variation in field metabolic rate of kittiwakes (Rissa tridactyla) during the chick-rearing period.

Field metabolic rate (FMR), using the doubly labelled water (DLW) method, was measured in free-ranging adult kittiwakes (Rissa tridactyla) early and late in the chick-rearing period at Svalbard, Norway. Individual variation in FMR was analysed by comparing FMR with body mass, sex, nest attendance, chick age, brood size, and basal metabolic rate (BMR). Mean FMR of kittiwakes during the chick-rearing period was 27.0+/-0.9 (SE) W kg(-1), while the individual variation (calculated as coefficient of variation [CV]) in FMR was 24%. Sex, time spent away from the nest, age of the chicks, and brood size contributed significantly to FMR and explained 65% of the variation in FMR. The FMR increased by 32% from early until late in the chick-rearing period. This occurred simultaneously with an increase in the time spent away from the nest. In 15 of 20 pairs, one of the mates had 15% or higher (mean of the 15 pairs, 22%+/-8%) FMR (W kg(-1)) than their partner, even though the mates spent equal amounts of time away from the nest. This indicates an intrapair conflict in FMR. The variation in total FMR of pairs was 40% less than the individual variation, and total FMR of pairs increased with age of the chicks. This indicates that the mates adjust their energy expenditure within a relatively constant FMR determined by the energy needs of the chicks. Individual variation in FMR could not be explained by variation in body mass or BMR. BMR measured late in the chick-rearing period was 26% lower than previous measurements of BMR from the prebreeding and incubation periods. The increase in FMR and simultaneous decrease in BMR caused a 40% increase in metabolic intensity (FMR/BMR) of kittiwakes during the chick-rearing period. It is suggested that the metabolic intensity is not a proper measure of the metabolic load in seabirds.

Sex hormone binding globulin stimulates female sexual receptivity.

Sex hormone binding globulin (SHBG) is found in the brain and acts directly on plasma membrane-associated receptors in the prostate gland. Infusing SHBG into the medial preoptic area or medial basal hypothalamus of female rats increases their female sexual receptivity. SHBG, SHBG plus estradiol (SHBG-E), and SHBG-E plus oxytocin all significantly increased female sexual receptivity over vehicle or estradiol plus oxytocin infused controls, as measured by lordosis quotients and receptivity scores, at 40, and 90 min after their infusions into the medial preoptic area. When infused into the medial basal hypothalamus, SHBG-E plus oxytocin resulted in significantly increased sexual receptivity 20 and 40 min after infusion when compared to its estradiol plus oxytocin control group. SHBG produced in the brain may be released endogenously to have immediate effects on reproductive physiology and behavior.

The effect of tolcapone on the pharmacokinetics of benserazide.

This study investigated the potential interaction between tolcapone, a catechol-O-methyltransferase (COMT) inhibitor, and the decarboxylase inhibitor, benserazide. In an open-labelled six-week study, patients with Parkinson's disease (PD), treated with levodopa/benserazide, were given tolcapone at 200 mg t.i.d. Blood samples for analysis of benserazide, its main active metabolite, trihydroxybenzylhydrazine, levodopa and 3-O- methyldopa (3-OMD) were collected immediately before and repeatedly after the first drug intake of the day at baseline and after 1-2 and 6 weeks of treatment. Furthermore, animal experiments were performed to determine the levels of benserazide and trihydroxybenzylhydrazine at doses for which safety had previously been established. It was shown that tolcapone can cause an increase in benserazide plasma concentrations and that this effect is dependent on the benserazide dose. When tolcapone was combined with 25 mg benserazide the elevation was small. Although the increase was more pronounced when tolcapone was combined with 50 mg benserazide, the levels were still substantially lower than concentrations causing toxicity in animals. The safety margin derived from this study, together with the absence of any organic toxic effects in clinical trials, show that the observed interaction between tolcapone and benserazide does not represent a safety concern for PD patients treated with this combination.

Conjugated estradiol increases female sexual receptivity in response to oxytocin infused into the medial preoptic area and medial basal hypothalamus.

The ovarian steroid estradiol (E) has been found to increase both receptor affinity and release of the neuropeptide oxytocin (OT) in plasma membrane preparations. Therefore, we hypothesized that E conjugated to bovine serum albumin at position 6 (E-6-BSA) would increase behavioral responsiveness to OT. Preliminary results showed that 200 ng/microl of E-6-BSA increased sexual receptivity slightly, but not significantly. Therefore, this dose was used as a subthreshold dose to test whether it would increase sexual responsiveness when infused in combination with 100 ng/microl OT. After recovery from cannula implantation surgery animals were injected with 0.5 microg E benzoate daily for 3 days before testing. On the fourth day, after a baseline preinfusion test rats were infused bilaterally with E-6-BSA alone or with OT, OT with BSA, or conjugated progesterone, luteinizing hormone-releasing hormone equimolar to OT alone, or with E-6-BSA or conjugated progesterone alone. When infused into either the medial preoptic area-anterior hypothalamus or the medial basal hypothalamus the combination of OT and E-6-BSA significantly increased sexual receptivity over receptivity after artificial cerebrospinal fluid control infusions. Neither bilateral infusions of OT in combination with conjugated progesterone nor E-6-BSA in combination with luteinizing hormone-releasing hormone enhanced sexual receptivity. Results presented here strongly support the conclusion that some of the effects that E has in sensitizing brain systems to the facilitating effects of OT occur at the membrane level in the medial preoptic area-anterior hypothalamus and medial basal hypothalamus.

Dental caries determinants in an adult Portuguese population and a comparison with Norwegian adults.

The present epidemiologic dental caries study indicates a high number of decayed surfaces (mean, 13.5 +/- 11.8 (SD)) in a Portuguese population of 30- to 39-year-olds from Porto. The most influential determinants for variation in carious surfaces were oral hygiene, gender, salivary buffer capacity, and missing teeth. By entering the most influential independent variables in a final multiple classification analysis, the total explained variance in carious surfaces was 27%. A comparison with results from a similar Norwegian dental health study showed that the biologic factors of importance for number of carious surfaces were the same, whereas the sociocultural determinants differed.

Prevalence and persistence of stomach ache and headache among children. Follow-up of a cohort of Norwegian children from 4 to 10 years of age.

Results from a prospective cohort of 136 children, from 4 to 10 years of age, indicated that stomach ache was almost as prevalent among preschool children as children of school age. Headache was almost absent among 4-year-olds but prevalent at 10 years of age. Generally, early pain complaints were persistent. The co-occurrence of stomach ache and headache increased from 4% of children at 4 years of age to 20% when they reached 10 years of age.

Recombinant interferon-alpha combined with prednisone in metastatic renal cell carcinoma. Reduced toxicity without reduction of the response rate--a phase II study.

Five responses (lung metastases, three; lymph node metastases, two) were observed in 23 patients with metastatic renal cell carcinoma who received recombinant interferon-alpha-2A (IFN) 18 X 10(6) U in three intramuscular doses each week combined with oral prednisone (10 to 20 mg daily). The response duration was 4+, 4+, 9, 11+, and 15+ months. In general, the combination treatment of interferon and prednisone lead to a significant reduction of the subjective side effects (flu-like symptoms) as compared to a previous experience in patients treated with interferon only. Reduction of the interferon dose or discontinuation of IFN treatment was necessary in only two of 23 patients receiving IFN plus prednisone. Prednisone, however, had little effect on the hepatic toxicity often associated with high-dose IFN treatment. The subjective tolerability of a high dose of IFN is significantly increased if oral prednisone (10-20 mg) is given concomitantly in patients with metastatic renal cell carcinoma without reducing the response rate. Randomized trials will be necessary to confirm the efficacy of the IFN and prednisone combination. In addition, higher doses of IFN combined with prednisone should be evaluated in this malignancy.

Prediction of objective response to recombinant interferon-alpha with or without vinblastine in metastatic renal cell carcinoma.

Clinical, histopathological and DNA cytometric parameters were analyzed before treatment in 57 patients with metastatic renal cell carcinoma (RCC) with regard to their ability to predict objective response to treatment with interferon-alpha (IFN) with or without vinblastine (VB). No pretreatment factor could be identified which was correlated with response. Patients who had at least 30% size reduction of their indicator lesion(s) after 2 months and did not present with new visible metastases had a significantly higher chance to obtain objective response than those in whom this condition was not fulfilled. We suggest that interferon treatment (with or without VB) should be offered for 2 months to all patients with metastatic RCC who are to receive systemic therapy. If at least 30% tumour size reduction is observed at that time, the patient will most probably respond objectively. If the size reduction is less, IFN with or without VB is likely to be ineffective in terms of response achievement.

Recombinant interferon-alpha with or without vinblastine in metastatic renal carcinoma. Results of a randomised phase II study.

In a randomised phase II study, 5 of 24 patients with metastatic renal carcinoma responded to treatment with interferon (IFN) (Roferon A, Roche, Basle, Switzerland) (18 x 10(6) u i.m. 3 times/week). The combination of IFN with vinblastine (0.1 mg/kg every third week) yielded a response rate of 16% (4 of 25 patients). Three patients continue to show a response (2 complete, 1 partial) more than 20 months after cessation of treatment. Flu-like symptoms represented the major side effect and often led to modification or discontinuation of treatment. It was concluded that IFN is the treatment of choice in patients with metastatic renal carcinoma who are candidates for medical treatment. The significance of additional vinblastine is uncertain.

Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma.

Twenty patients with measurable metastatic renal cell carcinoma (RCC) were were treated with interferon alfa-2a (Roferon-A), 36 X 10(6)U intramuscularly 3 times weekly, alone (2 patients) or in combination with vinblastine, 0.10-0.15 mg/kg intravenously every 2 to 3 weeks. Objective responses in the lung, bone, liver, and lymph node metastases were seen in 6 of 18 evaluable patients. Dose reduction of interferon alfa-2a was necessary in 19 of the 20 patients due to intolerable flu-like side effects and fatigue. Bone marrow suppression and increase of gamma-GT represented the most often observed objective toxicity. The preliminary results of this combination treatment in RCC are promising and warrant randomized studies exploring the role of vinblastine. The dose of interferon alfa-2a should be reduced by 50% to avoid excessive toxicity and to maximize patient compliance.

Phase I/II tolerability/pharmacokinetic study with one-hour intravenous infusion of doxifluiridine (5'-dFUrd) 3 g/m2 VS 5 g/m2 QD x 5 per month.

Eighteen patients with advanced solid cancer were treated with daily 5'-dFUrd infusions given over 1 h on days 1-5 of a 4-week cycle. Nine patients received 3 g/m2 5'-dFUrd daily and another nine patients 5 g/m2. One patient on 5 g/m2 5'-dFUrd was not fully evaluable for tolerability due to early death (progressive disease) 4 weeks after the first cycle. A total of 48 cycles was given. The gastrointestinal and hematological toxicity was generally mild (grade 1-2). Central neurotoxicity (ataxia, unsteadiness, diplopia, dysarthria, sometimes confusion) was observed in 7 of 8 patients on 5 g/m2 5'-dFUrd leading to premature discontinuation of treatment in 3 patients (after 2 cycles). Only 3 of the 9 patients in the 3 g/m2 group had slight signs of cerebellopathy. Typically, the reversible neurological side effects started at the end of the 2nd week of a cycle. The serum elimination kinetics of 5'-dFUrd and its metabolites 5-FU and 5'-dFUH2 have been investigated in the serum and showed very low intra- and interindividual variations. Peak concentrations of the 5'-dFUrd at the end of the infusion approximated 500 mumol/l and 1000 mumol/l for the 3 g/m2 and 5 g/m2 group, respectively. The peak of the serum 5-FU was reached at the same time, the ratio 5-FU/5'-dFUrd being around 10%. The elimination half-life time for 5-FU was protracted by a factor of 2-3 compared with the direct injection of 5-FU. Monthly infusion of 5'-dFUrd 5 mg/m2 per day on days 1-5 lead to an unacceptable frequency and degree of neurological toxicity. Similar infusions of 5'-dFUrd 3 g/m2 per day on days 1-5 were well tolerated.

On the therapeutic mechanism of Mg2+ in digitoxic arrhythmias and the role of cardiac glycosides in Mg depletion.

In 9 (of 17 attempted) experiments (8 aborted due to premature tissue death), transmembrane electrical activity was recorded from canine false tendons superfused with Mg-free Tyrode's solution to simulate hypomagnesemia. Oscillatory after-potentials (OAP) developed similar to those seen after exposure to 2 X 10(-7) M ouabain, a short-lasting (0.5-1 time the duration of an action potential) OAP that often reached threshold superimposed on a long-lasting (3-4 times as long as the short) OAP. Both forms of OAP were shown to be Ca2+-dependent, as both were prevented by 10(-7) M nifedipine, but only the short OAP were abolished by nifedipine once they had appeared, while high (5 mM = 10 times normal) Mg2+ both prevented and terminated short and long OAP in digitoxic preparations. Results suggest that cardiac glycosides may deplete Mg from the myocardium. The mechanism of the therapeutic action of Mg2+ in digitalis intoxication is discussed in light of its involvement in Ca2+ sequestration by the sarcoplasmic reticulum.

A mathematical model of parasystole and its application to clinical arrhythmias.

A ventricular parasystolic focus capable of generating manifest ectopic beats should not be totally insulated from the electrical events that accompany depolarization in the surrounding tissue; the intrinsic cycle length of the ectopic discharge may be modulated by electrotonic influences transmitted across the zone of "protection." To study the nature of the interaction, response patterns were examined in a mathematical model programmed to simulate an ectopic pacemaker protected, but not divorced from ventricular responses to the normal pacemaker. Computer runs covered a wide range of heart rates, and a wide range of magnitudes of the simulated electrotonic influence. Application of the results obtained in the model to published examples of complex arrhythmias revealed a remarkably close fit to many clinical examples. This findings suggests that many patterns attributed to a re-entrant "extrasystolic" rhythm may, in fact, represent the modulated activity of a parasystolic focus.