Transport of manganese via the olfactory pathway in rats: dosage dependency of the uptake and subcellular distribution of the metal in the olfactory epithelium and the brain

The dosage dependency of the uptake of Mn from the olfactory epithelium via olfactory neurons into the brain was studied after intranasal administration of the metal in rats. The results indicate that the Mn transport is saturable both regarding the uptake into the olfactory epithelium and the transfer to the olfactory bulb. Further, our data indicate that Mn moves relatively freely from the olfactory bulb to the olfactory cortex at an amount dependent on the level of influx into the bulb. The transport to the rest of the brain was related to the amounts in the olfactory bulb and the olfactory cortex, but the relative proportion reaching this area increased with increasing doses. Cell fractionations showed that the Mn was present both in the cytosol and in association with various cell constituents. Gel filtrations of the cytosol on a Superdex 30 column showed that about 20% of the Mn in the brain and about 3% in the olfactory epithelium was eluted together with high-molecular-weight materials (MW > 10,000), whereas the rest was eluted in the total volume and may represent unbound metal. It is likely that the metal has been loosely associated with protein(s) or other constituents at the application to the column, but that this association is too loose to be retained during the passage through the column. Our results show that the olfactory neurons provide a pathway with a considerable capacity to transport Mn into the brain. We propose that the neurotoxicity of inhaled Mn is related to an uptake via this route.     

What is the price of perfection? The hidden costs of using detailed assessment instruments to measure alcohol consumption

OBJECTIVE: This article describes results from a study investigating the effects of using long assessment instruments on attrition rates in mailed-out surveys. METHOD: Participants were randomly assigned to receive one of two versions of a mailed-out survey; one version incorporated a detailed assessment of drinking using the Timeline Follow back method (TLFB; n = 46) and the other employed a brief graduated frequency measure of alcohol consumption (n = 49). RESULTS: 29% fewer respondents who received the TLFB returned any of their survey materials as compared to those respondents who received just the graduated frequency measure (22% vs 51%). CONCLUSIONS: In some situations, e.g., mailed-out surveys, employing detailed survey instruments may not be justified as the increased respondent burden may result in increased attrition rates.     

Energy metabolism in the involuting mammary gland

A strong and coordinated upregulation of the glycolytic, glutaminolytic and pentose phosphate pathway enzymes occurs during the onset of lactation in the normal mouse mammary gland. Induction of apoptosis by removing the pups led to an inactivation of the same enzymes with different time courses. While the ATP-consuming glycolytic 6-phosphofructo 1-kinase and mitochondrial bound hexokinase still remained high on days one and two of involution, the ATP-regenerating pyruvate kinase was immediately reduced. The enzymes of the pentose phosphate and glutaminolytic pathway were inactivated on the first two days of involution. In accordance with such an inactivation of the enzymes ATP, GTP, UTP, ADP, NAD NADH and lactate concentrations decreased. The synthetic product of UTP, UDP-N-acetylglucosamine, increased. AMP was found in the milk, not in the epithelial cells. The inactivation of the enzymes was caused by partial proteolysis or by a loss of the intact proteins from the cytosol without signs of proteolysis.     

A cortisol suppression dose-response comparison of budesonide in controlled ileal release capsules with prednisolone

AIM: To assess the systemic effect of oral budesonide, given as Entocort controlled ileal release capsules, over a dose range of 3-15 mg/day, compared with that of a moderate dose (20 mg/day) of prednisolone. METHODS: Twenty four healthy subjects were given 3, 9 or 15 mg budesonide or 20 mg prednisolone once daily, or 4.5 mg budesonide b.d., or placebo for 5 days in a randomized, double-blind crossover study. The area under the curve (AUC) of plasma cortisol concentration and the amount of cortisol excreted in the urine were monitored. RESULTS: Both plasma and urine cortisol suppression showed a dose-response for the daily doses of budesonide. Prednisolone, 20 mg, suppressed plasma cortisol (AUC) statistically significantly more than 15 mg budesonide (P = 0.014), and 3 mg budesonide statistically significantly more than placebo (P = 0.010). No difference in AUC was detected between 9 mg and 4.5 mg budesonide b.d. Similar results for budesonide vs. placebo were obtained from urine cortisol excretion data. However, prednisolone affected urine cortisol less than it affected plasma cortisol. CONCLUSION: After 5 days of administration, budesonide controlled ileal release capsules, in both clinical (9 mg/day) and high doses (15 mg/day), affected plasma cortisol less than a moderate (20 mg/day) dose of prednisolone.     

Value of direct measurement of active renin concentrations in congenital adrenal hyperplasia due to 21-hydroxylase deficiency

In congenital adrenal hyperplasia (CAR) due to 21-hydroxylase deficiency, measurement of plasma renin activity (PRA) has been the method of choice in diagnosing salt loss and in monitoring adequacy of mineralocorticoid replacement therapy. Due to methodological problems in PRA determinations, direct immunoradiometric assays for the measurement of active renin concentration have been developed. We measured PRA and active renin concentrations simultaneously in 39 patients with CAH (30 salt-wasting, 9 simple virilizing) to evaluate the potential role of this new method in the management of this disease. PRA was determined with an enzymatic assay (sample volume: 2 × 1000 l plasma), active renin concentration with a direct immunoradiometric assay (sample volume: 2 × 200 l plasma or serum). We found a highly significant correlation between active renin and PRA in our patients (P < 0.001), as previously shown in healthy subjects. Active renin was as reliable as PRA to assess the quality of mineralocorticoid replacement.     

Partial models in fixed prosthodontics

In general there is consensus regarding the required criteria for crown- and bridge restorations. However, the variety in methods used for their fabrication is large. Textbooks and courses tend to advocate the use of full arch impressions without supplying objective data indicating better clinical behaviour of these restorations compared with the use of quadrant impressions. This article presents advantages, disadvantages, indication and essential steps when using quadrant models.     

The rate constant of photoinhibition, measured in lincomycin-treated leaves, is directly proportional to light intensity

Pumpkin leaves grown under high light (500-700 micromol of photons m-2.s-1) were illuminated under photon flux densities ranging from 6.5 to 1500 micromol.m-2.s-1 in the presence of lincomycin, an inhibitor of chloroplast protein synthesis. The illumination at all light intensities caused photoinhibition, measured as a decrease in the ratio of variable to maximum fluorescence. Loss of photosystem II (PSII) electron transfer activity correlated with the decrease in the fluorescence ratio. The rate constant of photoinhibition, determined from first-order fits, was directly proportional to photon flux density at all light intensities studied. The fluorescence ratio did not decrease if the leaves were illuminated in low light in the absence of lincomycin or incubated in darkness in the presence of lincomycin. The constancy of the quantum yield of photoinhibition under different photon flux densities strongly suggests that photoinhibition in vivo occurs by one dominant mechanism under all light intensities. This mechanism probably is not the acceptor side mechanism characterized in the anaerobic case in vitro. Furthermore, there was an excellent correlation between the loss of PSII activity and the loss of the D1 protein from thylakoid membranes under low light. At low light, photoinhibition occurs so slowly that inactive PSII centers with the D1 protein waiting to be degraded do not accumulate. The kinetic agreement between D1 protein degradation and the inactivation of PSII indicates that the turnover of the D1 protein depends on photoinhibition under both low and high light.     

Contractile effect of big endothelin-1 and its conversion to endothelin-1 in rabbit cerebral arteries

The effect of big endothelin-1 (big ET-1) and its conversion to endothelin-1 (ET-1) in rabbit cerebral arteries were examined. Big ET-1 and ET-1 induced concentration-dependent contractions in the basilar artery; ET-1 was approximately 8 times more potent than big ET-1. The metalloprotease inhibitor phosphoramidon (30 ol/1) almost abolished the contractile response to big ET-1, whereas the ET-1-induced contraction was unaffected. Removal of the endothelium did not attenuate the big ET-1-induced contraction. ET-1 was approximately 14 times more potent than endothelin-3 (ET-3) to elicit contraction. The contractions induced by big ET-1, ET-1 and ET-3 were all inhibited by the ET_A receptor antagonist BQ 123 (3 mol/l). The ET_B receptor antagonist IRL 1038 (3 mol/l) had no effect on the contractile responses to big ET-1 and ET 1, but produced a small inhibition of the ET-3-induced contraction. Formation of ET-1 was demonstrated in membrane fractions of cerebral arteries incubated with big ET-1 as measured by high pressure liquid chromatography followed by radioimmunoassay. These results suggest that externally applied big ET-1 is converted to ET-1 by a phosphoramidon-sensitive endothelin converting enzyme present in the vascular smooth muscle cells. The ET-1 formed subsequently mediates the big ET-1-induced contraction by activation of mainly ETA receptors, although a small contribution of ETB receptors cannot be excluded.     

Radiation doses of yttrium-90 citrate and yttrium-90 EDTMP as determined via analogous yttrium-86 complexes and positron emission tomography

Yttrium-90 is used for palliative therapy for the treatment of skeletal metastases, but because it is a pure - emitter, data on the pharmacokinetics and radiation doses to metastases and unaffected organs are lacking. To obtain such data, the present study employed yttrium-86 as a substitute for⁹⁰Y, with detection by positron emission tomography (PET). The study compared the properties of two different⁸⁶Y complexes —⁸⁶y-citrate and⁸⁶Y -ethylene diamine tetramethylene phosphonate (EDTMP) — in ten patients with prostatic cancer who had developed multiple bone metastases (the ten patients being divided into two groups of five). Early dynamics were measured up to 1 h post injection (p.i.) over the liver region, followed by subsequent whole-body PET scans up to 3 days p.i. Absolute uptake data were determined for normal bone, bone metastases, liver and kidney. Radiation doses were calculated according to the MIRD recommendations. Based on the pharmacokinetic measurements of the distribution of the⁸⁶Y complexes, it was possible to calculate radiation doses for the bone metastases and the red bone marrow delivered by complexes containing⁹⁰Y. In 1 cm³ of bone metastasis, doses of 26±11 mGy/MBq and 18±2 mGy/MBq were determined per MBq of injected⁹⁰Y- citrate and⁹⁰Y- EDTMP, respectively. The doses to the bone marrow were 2.5±0.4 mGy/MBq for⁹⁰Y- citrate and 1.8±0.6 mGy/MBq for⁹⁰Y-EDTMP.⁸⁶Y and PET provide quantitative information applicable to the clinical use of⁹⁰Y. This method may also be useful for the design of other⁹⁰Y radiopharmaceuticals and for planning radiotherapy dosages.     

Uptake of iodine-123-α-methyl tyrosine by gliomas and non-neoplastic brain lesions

Using single-photon emission tomography (SPET), the radiopharmaceuticall,-3-iodine-123--methyl tyrosine (IMT) has been applied to the imaging of amino acid transport into brain tumours. It was the aim of this study to investigate whether IMT SPET is capable of differentiating between high-grade gliomas, low-grade gliomas and non-neoplastic brain lesions. To this end, IMT uptake was determined in 53 patients using the triple-headed SPET camera MULTISPECT 3. Twenty-eight of these subjects suffered from high-grade gliomas (WHO grade III or IV), 12 from low-grade gliomas (WHO grade II), and 13 from non-neoplastic brain lesions, including lesions after effective therapy of a glioma (five cases), infarctions (four cases), inflammatory lesions (three cases) and traumatic haematoma (one case). IMT uptake was significantly higher in high-grade gliomas than in low-grade gliomas and non-neoplastic lesions. IMT uptake by low-grade gliomas was not significantly different from that by non-neoplastic lesions. Diagnostic sensitivity and specificity were 71% and 83% for differentiating high-grade from low-grade gliomas, 82% and 100% for distinguishing high-grade gliomas from non-neoplastic lesions, and 50% and 100% for discriminating low-grade gliomas from non-neoplastic lesions. Analogously to positron emission tomography with radioactively labelled amino acids and fluorine-18 deoxyglucose, IMT SPET may aid in differentiating high-grade gliomas from histologically benign brain tumours and non-neoplastic brain lesions; it is of only limited value in differentiating between non-neoplastic lesions and histologically benign brain tumours.