[Home medical care from our hospital].

From April, 1996 to March, 1999, our hospital provided home medical care on a 24-hour basis for fifty patients with advanced or terminal cancer. Eventually, twenty-four patients died at home and twenty-six in the hospital. Stability of health status, the presence of willing and able caregivers, as well as a greater number of house-calls are suggested factors in facilitating a death at home. However, the patients who died in the hospital were obliged to readmit themselves until the time of death due to caregivers' reasons such as fatigue, emotional stress and/or health problems. In addition to timely availability and accessibility of respite care, psychosocial support for family caregivers by liaison nurses remains an issue to be solved in future.

A novel protein containing Cdc10/SWI6 motifs regulates expression of mRNA encoding catecholamine biosynthesizing enzymes.

Catecholaminergic (dopaminergic, noradrenergic, and adrenergic) transmitter phenotypes require the cooperative actions of four biosynthetic enzymes: tyrosine hydroxylase, aromatic L-amino acid decarboxylase, dopamine beta-hydroxylase, and phenylethanolamine N-methyltransferase. Mechanisms that control expression of these enzymes in a transmitter phenotype-specific manner, however, are poorly understood. Here, we provide evidence that overexpression of a novel cdc10/SWI6 motif-containing protein, V-1, elicits the coordinate up-regulation of tyrosine hydroxylase, aromatic L-amino acid decarboxylase, and dopamine beta-hydroxylase mRNAs in the neuronal cell line PC12D, and as a result, catecholamine levels are increased. Furthermore, V-1 is strongly expressed in the cytoplasm of rat chromaffin cells of adrenal medulla. Thus, V-1 may act as a cytoplasmic protein/protein adapter and be involved in control of the catecholaminergic phenotype expression via an intracellular pathway signaling to the nucleus.

Radiation dosimetry for indium-111-pentetreotide.

UNLABELLED: We present radiation dose estimates for 111In-pentetreotide. METHODS: Kinetic data were gathered in 10 subjects at two different sites. A compartmental model was used to fit the data, including retention, in three major organs and excretion. RESULTS: The data were consistent for the subjects at both sites. The organ receiving the highest dose was the kidneys (0.52 mGy/MBq); the effective dose equivalent was 0.1 mSv/MBq, and the effective dose was 0.073 mSv/MBq. CONCLUSION: The results of this study provide the basis for evaluation of radiation safety of this drug.

Increased level of neurokinin-1 tachykinin receptor gene expression during early postnatal development of rat brain.

Substance P is known to elicit diverse actions via activating multiple subtypes of tachykinin receptors, and these actions appear to be involved not only in synaptic transmission but also in synaptic plasticity during development of the mammalian central nervous system. The availability of sensitive quantitation of individual tachykinin receptor subtypes is crucial for elucidating the physiological function specifically mediated by activation of a particular receptor subtype. We thus attempted to develop an assay to determine the level of messenger RNA molecule encoding the neurokinin-1-type tachykinin receptor and apply it for assessment of developmental changes in the neurokinin-1 receptor gene expression in the rat brain to explore the role of tachykinin receptors during ontogeny. The assay was designed to use a competitive reverse transcription-polymerase chain reaction co-amplifying endogenous neurokinin-1 receptor messenger RNA and internal standard, which enabled specific quantification of the number of neurokinin-1 receptor transcripts, ranging from 3.1 x 10(3) to 1.3 x 10(5) molecules/microgram total RNA. The levels of neurokinin-1 receptor gene expression were examined in three different brain regions of the rat aged 0-56 days after birth. The order of neurokinin-1 receptor messenger RNA expression was hippocampus > cerebral cortex > > cerebellum at all ages examined except postnatal day 0, where its expression was more abundant in the cerebral cortex than in the hippocampus. From postnatal day 3 onward, the hippocampus contained 140-160% of the cortical levels. Although the tachykinin receptor expression in the cerebellum was too low to be accurately assessed by conventional techniques, our assay enabled us to determine the amount of cerebellar neurokinin-1 receptor messenger RNA that changed in the range 7-23% of the cortical level during postnatal development. A prominent feature revealed by this assay is that the neurokinin-1 receptor gene expression in the rat brain is developmentally regulated. The hippocampus displayed a transient peak of neurokinin-1 receptor messenger RNA at postnatal day 3 and a subsequent gradual decrease. In the cerebral cortex, the amount of the message was highest at birth, and was followed by a moderate decrease during postnatal development. At 56 days after birth, the expression levels in both brain regions were down-regulated to approximately 50% of their maximal levels. The transitory pattern of gene expression was also observed in the cerebellum. The results of this study demonstrate that the reverse transcription-polymerase chain reaction-based assay is useful to quantitate precisely the neurokinin-1 tachykinin receptor message in limited tissue samples derived from discrete brain regions. Together with previous findings, the increased level of neurokinin-1 receptor messenger RNA expression in immature rat brain shown by the present analysis suggests that the neurokinin-1-type tachykinin receptor may play a role in the synaptic plasticity associated with morphological and functional development of the mammalian CNS.

Murine cerebellar neurons express a novel gene encoding a protein related to cell cycle control and cell fate determination proteins.

We cloned cDNAs of a novel protein (designated V-1) that has been identified from among the developmentally regulated proteins in the rat cerebellum. Protein sequencing analysis (Taoka, M., Yamakuni, T., Song, S.-Y., Yamakawa, Y., Seta, K., Okuyama, T., and Isobe, T. (1992) Eur. J. Biochem. 207, 615-620) and cDNA sequence analysis revealed that the V-1 protein consists of 117 amino acids and contains 2.5 contiguous repeats of the cdc10/SWI6 motif, which was originally found in the products of the cell cycle control genes of yeasts and the cell fate determination genes in Drosophila and Caenorhabditis elegans. In situ hybridization histochemistry revealed that the expression of the V-1 gene is transiently increased in postmigratory granule cells during postnatal rat cerebellar development and thereafter is markedly suppressed, whereas Purkinje cells constitutively express V-1 mRNA. In contrast, cerebellar granule cells of the staggerer mutant mouse continue to express the V-1 gene even when the granule cells of the normal mouse have ceased to express the V-1 gene, suggesting that the expression of the V-1 gene in granule cells is regulated through the interaction with Purkinje cells. On the basis of these results, we postulate that the V-1 protein has a potential role in the differentiation of granule cells.

Comparison of the effects of ioversol and other contrast media on the blood-brain barrier.

Little information is available concerning the neurotoxicity of ioversol injected in animals. The effects of ioversol and other contrast media as well as vehicle control on the blood-brain barrier (BBB) were examined by injection into the left carotid artery of Mongolian gerbils 1 min prior to the i.v. injection of [8-14C]dopamine. The animals were sacrificed 1 min after the i.v. injection to prepare the frontal brain sections following the stereotaxic atlas. No uptake of the labeled substance was observed when the vehicle control and ioversol were used, suggesting that exposure to ioversol does not damage the BBB. Both meglumine sodium amidotrizoate and iohexol caused damage to the BBB, as shown in the cerebral cortex, brain stem, and hippocampus sections in the left semisphere. Iopaidol induced a much less but significant effect. Our results suggest that ioversol is an useful contrast medium.

Inverse dose-rate effect of DNA breaks and inactivation of transforming activity induced by tritiated water and 60Co gamma-rays.

When an aqueous solution of plasmid DNA at a constant low concentration of 5 micrograms/cm3 was irradiated with 60Co gamma-rays, D37 dose of single-strand breaks was decreased from 18 Gy at a dose-rate of 6.77 Gy/h of acute irradiation to 2.3 Gy at a dose-rate of 0.00212 Gy/h. Or G value was increased from 0.0010 to 0.0081. Similar dose-rate dependency of D37 dose and G value were also found when the plasmid DNA solution was treated with various concentrations of tritiated water at various dose-rates, ranging from 5.13 Gy/h to 0.000118 Gy/h. RBE of tritium beta-rays for single-strand breaks was ranged from 0.3 to 0.5 in a wide range of dose-rates. When the DNA solution was saturated with argon to remove oxygen, the dose-rate dependency of gamma-rays was abolished and that of tritium beta-rays was significantly suppressed. When the DNA solution in air was kept at 4 degrees C for 50 h or 25 days after acute irradiation, the G value of DNA breaks was the same as that kept at -20 degrees C for the same period, but much lower than that of the solution irradiated for the same period at a lower dose-rate to give the same total doses. This shows that the inverse dose-rate effect could not be induced from the different exposure periods but from continuous irradiation of different dose-rates. The inverse dose-rate effect for inactivation of transforming activity of DNA irradiated with tritiated water was also observed in the range from 0.0588 Gy/h to 0.00118 Gy/h.

Raised plasma concentrations of 3-methoxy-4-hydroxyphenylethyleneglycol in cirrhotic patients with or without hepatic encephalopathy.

We measured the plasma concentration of a centrally derived noradrenaline (NA) metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), in 20 cirrhotic patients (eight with (group A) and 12 without (group B) hepatic encephalopathy (HE] and in 14 age matched healthy subjects to study if the central NA metabolism would be altered in liver cirrhosis patients, particularly in those with HE. The mean (SEM) plasma MHPG concentrations in the patient groups, group A (74.9 (8.6) pmol/l) and B (54.8 (7.2) pmol/l), were significantly (p less than 0.01) greater than in the control group (22.3 (2.0) pmol/l), and that in group A was significantly (p less than 0.05) greater than in group B. The plasma concentration of MHPG observed in these study subjects (n = 34) correlated (rs = 0.77, p less than 0.01) more strongly with the ratio of plasma catecholamine precursor amino acids (tyrosine and phenylalanine) to other neutral amino acids (tryptophan, leucine, isoleucine, and valine) known to compete with catecholamine precursor amino acids for uptake into the brain than with plasma concentration of tyrosine plus phenylalanine alone (rs = 0.63, p less than 0.01). In addition, the mean plasma MHPG concentrations measured in another group of eight cirrhotic patients (group C) during HE (79.3 (10.6) pmol/l) was significantly (p less than 0.01) greater than that measured after the recovery from HE (47.2 (5.2) pmol/l). The results suggest that the central NA metabolism may be altered in patients with liver cirrhosis, particularly in those with HE, and that the derangement in the central NA metabolism may be associated not only with an increase in plasma catecholamine precursor amino acids but also with a decrease in branched chain amino acids.

Plasma catecholamine concentrations during a 72-hour aminophylline infusion in children with acute asthma.

To explore the possibility that theophylline may act through adrenomedullary secretion of catecholamines, we examined the time courses of plasma norepinephrine (NE), epinephrine (E), and theophylline concentrations and peak expiratory flow (PEF) in nine children with an acute exacerbation of asthma receiving a 72-hour constant infusion of aminophylline. These measurements were made before (baseline) and at 2, 24, 48, and 72 hours after the infusion began. Plasma theophylline concentrations were kept constant in a near midpoint therapeutic range (mean +/- SEM, 14.1 +/- 1.3 to 16.1 +/- 1.1 micrograms/ml) during the 24- to 72-hour infusion periods. Compared with the respective baseline values (383.8 +/- 56.0 and 67.6 +/- 11.8 pg/ml for NE and E), the following postinfusion plasma catecholamines reached statistically significant difference: 664.0 +/- 125.1 pg/ml for NE at 24 hours (p less than 0.05), and 214.9 +/- 57.8, 233.7 +/- 82.2, and 137.6 +/- 39.4 pg/ml for E at 2, 24, and 48 hours (p less than 0.01). Despite the fact that similar plasma theophylline concentrations were maintained, plasma E, which peaked at 24 hours after dose, returned toward the baseline at the end of infusion (99.7 +/- 24.1 pg/ml), whereas this trend was not observed for NE. The postinfusion PEF increased (p less than 0.01) in a stepwise fashion, compared with the baseline, as the infusion progressed. The change in PEF correlated significantly (p less than 0.002) with plasma theophylline concentrations but not with the increase in plasma E from the baseline. Theophylline concentrations did not correlate with the increase in plasma NE or E from the baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

Simultaneous determination of four monoamine metabolites and serotonin in cerebrospinal fluid by "high-performance" liquid chromatography with electrochemical detection; application for patients with Alzheimer's disease.

We describe an optimized, sensitive assay procedure for simultaneously determining 3-methoxy-4-hydroxyphenylglycol, 3,4-dihydroxyphenylacetic acid, and serotonin in human lumbar cerebrospinal fluid. The assay is based on liquid chromatography with an electrochemical detection system equipped with a newly developed, highly sensitive graphite electrode. Before assay, samples are deproteinized with perchloric acid, 0.2 mol/L. The within- and between-day CVs were less than 2.5% and 6.7%, respectively, for all compounds. The lower limits of detection for 3-methoxy-4-hydroxyphenylglycol and 3,4-dihydroxyphenylacetic acid were 0.5 pg and for the other three analytes 1.5 pg per injection. Preliminary data on monoaminergic metabolites by the current assay showed that concentrations of dopaminergic and serotonergic metabolites were significantly (P less than 0.05) lower in patients with Alzheimer's disease than in the age-matched controls. In addition, the concentration of 3,4-dihydroxyphenylacetic acid correlated significantly (P less than 0.01) with that of homovanillic acid, suggesting that monitoring either of these metabolites in cerebrospinal fluid can be used as an index of central dopaminergic activity.

Effect of beta-adrenoceptor blockade on exercise-induced plasma catecholamine concentration-heart rate response relationship.

We examined the chronotropic and sympathoadrenal responses to a strenuous exercise in eight normal subjects receiving placebo and carteolol, a nonselective beta-adrenoceptor blocker. Plasma catecholamines were measured with high-performance liquid chromatography with electrochemical detection (HPLC-ECD). Mean plasma norepinephrine (NE) and epinephrine (E) concentrations attained at 0.5 and 2 min after exercise were significantly (p less than 0.001-0.05) greater in the carteolol trial than in the placebo trial and approached concentrations fairly similar to preexercise baseline values by 15 min after cessation of exercise in the two trials. The postexercise plasma NE and E concentration-chronotropic response relationships were shifted to the right in the carteolol as compared with the placebo phase. The maximal postexercise NE concentrations measured during the placebo trial correlated significantly with beta-adrenoceptor blockade (p less than 0.05, r = 0.74), whereas the relationship between E concentrations and beta-adrenoceptor blockade did not reach significant level in this small group of study subjects. The results suggest that beta-adrenoceptor blockade increases plasma concentrations of both NE and E during an earlier postexercise period and may cause a greater reflex sympathetic activation as compared with the adrenal response. However, the mechanism(s) remains unclear. Whether the exercise-induced NE rather than E would participate more predominantly in the chronotropic response to beta-adrenoceptor blockade requires further studies.

Disposition kinetics and dynamics of nicainoprol, a new antiarrhythmic agent, in humans.

Kinetics and resting and exercise-induced hemodynamic and ECG effects of nicainoprol, a new antiarrhythmic structurally resembling propafenone or propranolol, were investigated in eight healthy male subjects receiving a 1-hour infusion (100 mg) and oral dose (200 mg) in a randomized-crossover fashion. Nicainoprol in plasma and urine was determined by a specific HPLC assay. Plasma concentration-time data were fitted to a triexponential equation. Mean postinfusion kinetic data were: alpha-phase half-life = 3.1 minutes, beta-phase half-life = 106.6 minutes, and gamma-phase half-life = 12.4 hours; volume of central compartment = 0.114 L/kg; steady-state volume of distribution = 0.67 L/kg; total clearance = 3.6 ml/min/kg; and renal clearance = 0.56 ml/min/kg. Absolute bioavailability was approximately 70% and peak plasma drug concentration occurred 2.3 hours after oral administration. Interindividual variability in AUC was 1.6- and 2.4-fold after intravenous and oral administration, respectively. Cumulative fraction excreted unchanged in urine was approximately 15% and 9% of the dose after intravenous and oral administration, respectively. Resting heart rates were increased, whereas exercise-induced heart rates were unchanged after both doses. QRS durations were widened after both doses. PR and QTc intervals were prolonged during intravenous study. The results suggest that nicainoprol is an enzyme-limited or poorly extracted drug suitable for both intravenous and oral administration and devoid of beta-blocking action in humans, at least with doses tested in this study. Its ECG properties appear to be similar to those of class I antiarrhythmics.

Characterization of vasopressor response to sympathetic stimulation in the pithed rat: differential regulation of neuronally stimulated and blood-borne catecholamine-stimulated pressor responses in rats harboring pheochromocytoma.

The vasopressor response to sympathetic stimulation in the pithed rat was characterized both by analyzing the effects of chemical sympathectomy, adrenalectomy and selective antagonists on the vasopressor response and by measurement of changes in plasma concentrations of catecholamines. Stimulation of the spinal sympathetic outflow evoked a biphasic pressor response: an initial transient component was caused mainly by postganglionic sympathetic nerve stimulation (the direct response); a slowly developing secondary component was mediated predominantly by circulating catecholamines released from the adrenal medulla (the adrenal response). Parallel analysis of plasma catecholamines showed that the rise in epinephrine appeared to be closely related to this adrenal component. The pressor response in adrenalectomized rats was selectively blocked by prazosin but not by yohimbine; however, in sympathectomized rats, the pressor response was abolished by prazosin and yohimbine together but not by either drug given alone. These results suggest that the direct, neurogenic component is mediated mainly by alpha-1 adrenoceptors whereas the secondary, adrenally mediated response occurs by activation of both alpha-1 and alpha-2 adrenoceptors. Furthermore, the in vivo regulation of each component of the pressor response was studied in rats harboring pheochromocytoma (PHEO), a tumor causing marked elevations in endogenous catecholamine concentrations. In PHEO rats, the direct pressor response was found to be relatively intact but the adrenal response was blunted. Inasmuch as there was normal rise in plasma epinephrine to electrical stimulation in PHEO rats, the results suggest a differential regulation of neuronally stimulated and blood-borne catecholamine-mediated pressor responses in PHEO rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma monoaminergic metabolites and catecholamines in subarachnoid hemorrhage. Clinical implications.

We examined plasma catecholamines and monoaminergic metabolites (3-methoxy-4-hydroxyphenylethyleneglycol [MHPG], homovanillic acid [HVA], and 5-hydroxyindoleacetic acid) in patients with stroke successively up to three weeks after the initiation of symptoms. Plasma levels of free catecholamines were significantly elevated in patients with subarachnoid hemorrhage (SAH). However, no significant differences in plasma catecholamines were found when the patients with SAH were subdivided into noncomatose and comatose groups. In contrast, plasma HVA, MHPG, and 5-hydroxyindoleacetic acid levels in comatose patients with SAH significantly increased as compared not only with normal controls but also with noncomatose patients with SAH, and the peak levels of HVA and MHPG occurred within seven days poststroke. Such trends as observed in SAH were not observed in patients with cerebral hemorrhage. Our results suggest the usefulness of plasma monitoring of possibly centrally originating monoaminergic metabolites for predicting the degree of cerebral dysfunction in patients with SAH.

Effect of beta-adrenoceptor blockade on exercise-induced plasma catecholamine concentrations and their dissipation profile.

The time-course of plasma noradrenaline (NA) and adrenaline (A) concentrations and their dissipation profiles were examined concomitantly with heart rate changes after strenuous exercise in eight normal subjects receiving either placebo or carteolol, a beta-adrenoceptor blocker. Post-exercise NA concentrations declined with time in a biexponential manner, while A disappearance curves were apparently monophasic. Plasma NA concentrations and their peak value attained within 3 min after exercise were higher in the carteolol than in the placebo phase, whereas there were no significant differences in the first and second disappearance t1/2 between the two trials. The monoexponential t1/2 of A in the carteolol trial was significantly longer than in the placebo trial. Our results suggest that the dissipation profiles of catecholamines released by exercise appear to be affected by beta-adrenoceptor blockade.

Plasma 3-methoxy-4-hydroxyphenylethyleneglycol and homovanillic acid concentrations in patients with subarachnoid hemorrhage.

To ask if the determination of central-nervous-system-derived catecholamine metabolites in peripheral circulation could be a useful index of brain dysfunction after subarachnoid hemorrhage, 3-methoxy-4-hydroxyphenylethyleneglycol and homovanillic acid concentrations in plasma, together with those of free catecholamines (noradrenaline, adrenaline, and dopamine), were serially measured for up to 3 weeks after the initiation of symptoms in 23 patients with aneurysmal subarachnoid hemorrhage as compared to 17 healthy and 9 patient controls. Catecholamines and their metabolites were determined by using high-performance liquid chromatography with electrochemical detection. Plasma 3-methoxy-4-hydroxyphenylethyleneglycol concentrations were markedly elevated in subarachnoid hemorrhage patients with coma compared to those without, and the maximal concentrations observed in comatose patients never occurred in normal subjects or in patients with other neurological disorders. The mean maximal plasma concentrations of free catecholamines did not differ significantly between the comatose and noncomatose groups. Combining 3-methoxy-4-hydroxyphenylethyleneglycol with homovanillic acid level data more clearly discriminated between the comatose and noncomatose subarachnoid hemorrhage groups. The results suggest that plasma concentration of 3-methoxy-4-hydroxyphenylethyleneglycol, a major metabolite of brain noradrenaline, can be a prognostic discriminator for patients with subarachnoid hemorrhage and its discriminating power can be strengthened by combining it with homovanillic acid data.