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Different marine invertebrates have different tubular or vesicular systems within their locomotor muscle fibres. The siphonophores Chelophyes, Abylopsis and Muggeia have invaginated tubules which are the morphological equivalent of the vertebrate invaginated tubular system, but lack a sarcoplasmic reticulum. In Chelophyes the previous suggestion that Ca2+ channels in the extensive invaginated tubule system allow ingress of Ca2+ is shown to be incorrect. Contraction of the swimming muscles in Chelophyes is not blocked by 20 μM ryanodine, nor is it induced by 10 mM caffeine, hence intracellular Ca2+ stores appear absent. Contraction is, however, maintained by replacement of the greater part of the usual external Na+ by Li+ or by or N-methyl-D-glucamine, although action potentials can still be evoked. Hence we conclude that following contraction, internal Ca2+ is reduced by a Na/Ca2+ exchange mechanism.

Intramembrane charge movement in skeletal muscle cells has been proposed to underlie the process leading to Ca release from the sarcoplasmic reticulum. A number of recent studies suggest that the dihydropyridine receptor located in the transverse-tubular membrane is responsible for the generation of intramembrane charge movement. The skeletal muscle cell of the mutant mouse with “Muscular Dysgenesis” is characterized by absence of excitation-contraction coupling. Here we investigated the charge movement in freshly dissociated skeletal muscle cells from dysgenic mice. In 9 out of 34 dysgenic mouse cells the charge movement was completely absent, in the remaining cells the charge movement was never more than 30 % of control. The amount of maximum charge movement (Qmax) in mutant muscle cells was less than 30 % of Qmax in normal muscle. Nifedipine, a dihydropyridine derivative, reduced the amount of charge movement in normal muscle cells but it was less effective on charge movement in mutant muscle cells. We conclude that there is an alteration of nifedipine-sensitive charge movement in the skeletal muscle cells from the mutant mice.

Behavioural assessments were made of mutant mice lacking histamine H1 receptors to reveal the function of H1 receptors in the behaviour of mice. Exploratory behaviour of mice in a new environment was examined to discover whether the absence of H1 receptors in mice affects actions relating to their emotions. The H1 receptor-deficient mice showed a significant decrease in ambulation in an open field and on an activity wheel. Cognitive functions and anxiety were examined using passive avoidance response test and the elevated plus-maze test, respectively. The passive avoidance test did not show any change in latency. The elevated plus-maze test revealed that the transfer latency of the mutant mice was significantly prolonged, indicating that H1 receptors are partly associated with the control of anxiety. Aggressive behaviour was examined by a resident-intruder aggression test. When confronted with an intruder, the mutant mice attacked the intruder significantly slower and less frequently than did wild-type mice after a six-month isolation period. A formalin test and a forced swimming test were used to evaluate the nociceptive response and depressive or despairing state, respectively, of both groups. The mutant mice showed a significant decrease of nociceptive response in the late phase without affecting the early phase. There was no significant difference in the forced swimming test between the two groups. The brain content of monoamines and their metabolites was measured in the H1 receptor null and wild-type mice. The turnover rate of 5-hydroxytryptamine defined by the ratio of 5-hydroxyindoleacetic acid and 5-hydroxytryptamine was significantly increased in the cerebral cortex and hippocampus of H1 receptor null mice. These results support the previous pharmacological findings that histamine modulates various neurophysiological functions such as locomotor activity, emotion, memory and learning, nociception and aggressive behaviour through H1 receptors.

The objective of this study was to examine the experience of spouses caregiving for their spouse with Parkinson's disease (PD) and to determine whether their experiences differed by stage of disease. By using a cross-sectional design and mail questionnaire data from 380 spouse caregivers across 23 sites of the Parkinson Study Group, key caregiver variables were examined by stage of PD. Three categories of variables--caregiver role strain (10 measures), caregiver situation (four measures), and caregiver characteristics (four measures)--were analyzed by using t tests with Bonferroni correction. Specific types and amounts of role strain accumulated as the disease progressed, and they differed significantly between stages (p0.05). In the caregiving situation, the mean number of caregiving tasks tripled by stage 4/5. Negative changes in lifestyle plus decreases in predictability in caregivers' lives increased significantly in late-stage disease (p0.05). Caregiver characteristics of physical health and preparedness did not significantly differ across stages of disease. Depression was significantly higher by stage 4/5. Mutuality, the positive quality of the relationship as perceived by the caregiving spouse, declined beginning at stage 2. Caregiver strain is experienced across all stages of PD and accumulates significantly as the disease progresses. This study defines types and amounts of strain by stage of disease, which will be helpful in designing formal intervention trials to provide more effective help for spouse caregivers.

To study magnetic states in ferrimagnetic Fe-oxides, we have measured magnetic circular x-ray dichroism at K-edge of 3d-transition metal. The observed dichroic signals are separately assigned to the contribution come from 3d-cation in tetrahedral or octahedral sites. We discuss the magnetic states of 3d-metal ion in terms of local enviroment.

Modeling Reality: How Computers Mirror Life covers a wide range of modern subjects in complex systems, suitable not only for undergraduate students who want to learn about modelling `reality' by using computer simulations, but also for researchers who want to learn something about subjects outside of their majors and need a simple guide. Readers are not required to have specialized training before they start the book. Each chapter is organized so as to train the reader to grasp the essential idea of simulating phenomena and guide him/her towards more advanced areas. The topics presented in this textbook fall into two categories. The first is at graduate level, namely probability, statistics, information theory, graph theory, and the Turing machine, which are standard topics in the course of information science and information engineering departments. The second addresses more advanced topics, namely cellular automata, deterministic chaos, fractals, game theory, neural networks, and genetic algorithms. Several topics included here (neural networks, game theory, information processing, etc) are now some of the main subjects of statistical mechanics, and many papers related to these interdisciplinary fields are published in Journal of Physics A: Mathematical and General, so readers of this journal will be familiar with the subject areas of this book. However, each area is restricted to an elementary level and if readers wish to know more about the topics they are interested in, they will need more advanced books. For example, on neural networks, the text deals with the back-propagation algorithm for perceptron learning. Nowadays, however, this is a rather old topic, so the reader might well choose, for example, Introduction to the Theory of Neural Computation by J Hertz et al (Perseus books, 1991) or Statistical Physics of Spin Glasses and Information Processing by H Nishimori (Oxford University Press, 2001) for further reading. Nevertheless, this book is worthwhile for the aforementioned readership as the 25 sample programs provided on an accompanying CD enhance the learning experience.

A Rutherford flat cable composed of sixteen 0.8-mm-diameter Nb3 Sn strands with CuNb-reinforced stabilizers (CuNb/Nb3Sn) has been developed for use as an outsert for a 47-T hybrid magnet. To guarantee the safety of the magnet in the event of a quench, the low residual resistance ratio characteristic of arc-melted-in-situ CuNb composite had to be improved upon, and to obtain high electric conductivity, a new CuNb fabrication method using a Nb rod was attempted. The thermal runaway characteristics of chemical vapor deposition- YBa2Cu3O7-δ (Y123) coated-conductor tapes with varying Cu stabilizer thicknesses were measured in magnetic fields of up to 10 T at temperatures ranging from 17 to 60 K. It was found that the ratio of the thermal runaway over-current to the critical current decreases as temperature decreases and that thermal runaway occurs just above the critical current level at 5 K. The properties of a cryogen-free, 20-T superconducting outsert for a 47-T hybrid magnet utilizing CuNb/Nb3Sn Rutherford flat cables and Y123 tapes and having a room temperature bore of 400 mm were investigated.

The nuclear activity of Rel/NFkappaB transcription factors is tightly regulated from the cytoplasmic compartment by an inhibitory subunit called IkappaBalpha. IkappaBalpha is rapidly phosphorylated and degraded in response to the stimulation through tumor necrosis factor alpha (TNFalpha) receptor, interleukin-1 receptor or CD40. To explore the molecular mechanisms of signal-induced depletion of IkappaBalpha, we have delineated the domain in IkappaBalpha that is required for TNFalpha-induced phosphorylation and rapid degradation of IkappaBalpha. In contrast to the previous reports, the PEST-like sequences, which are present in the carboxyl-terminal region of IkappaBalpha, are demonstrated here to be dispensable for TNFalpha-induced degradation but could be required for signal-independent degradation, as in the case of Cactus, Drosophila homologue of IkappaB. Furthermore, the ankyrin repeats, which are essential for forming a complex with Rel and RelA, are required for TNFalpha-induced degradation suggesting that the putative IkappaB protease could interact with IkappaBalpha in complex with RelA or could recognize the structure of ankyrin repeats. Our data also indicate that neither the ankyrin repeats nor the PEST-like sequences, are essential for TNFalpha-induced phosphorylation.

The design and implementation of the transport layer of a native ATM (asynchronous tranfer mode) protocol stack and its embedding into an overall architecture that provides end-to-end quality of service (QOS) is presented. Within this architecture, the typical transport functionalities are enlarged with QOS monitoring and adaptation mechanisms. A QOS-based API (application programming interface) is proposed that shields application programmers from the complexity of QOS management and control. Both unicast and multicast connections supporting interactive multimedia applications are considered.

Nitric oxide is an important vasodilator formed in many tissues, including the vascular endothelium. Because of the relationship between nitric oxide and basal vascular tone, genes regulating nitric oxide have been suggested as candidate genes involved with the development of hypertension. At least three isoforms of nitric oxide synthase have been identified. Two of the isoforms, endothelial and inducible nitric oxide synthase, may have particular importance in hypertension. The gene coding for endothelial nitric oxide synthase on chromosome 7 has been cloned. Polymorphic dinucleotide repeats within this nitric oxide synthase gene were used to test for linkage to hypertension in 259 hypertensive siblings from 112 Utah hypertensive sibships. The resulting 194 sibpairs shared 108 alleles identical by state compared to the expected 108.1 alleles shared as estimated from CEPH allele frequencies. After weighting for different sibship sizes, there was only a 3.9% excess allele sharing (P = 0.21). Allele sharing in more severe hypertensive sibpairs (either two antihypertensive medications or an unmedicated diastolic blood pressure (BP) of 100 mm Hg or higher) showed a 6% excess over expected sharing of alleles (P = 0.28). There was no difference between male and female sibpair sharing of alleles (5.2% vs 7.8%, respectively, both not significant). Therefore, there was no evidence that the gene for endothelial nitric oxide synthase was linked to hypertension in these sibpairs.

Acute myocardial infarction (AMI) associated with left main coronary artery (LMCA) occlusion frequently results in poor prognosis because of the extensive area at risk with anterolateral wall involvement. Early diagnosis and subsequent treatment are essential to rescue these patients. In the current study, we retrospectively compared ECG findings in patients with LMCA occlusion, to those with proximal coronary artery occlusion. Of the 1880 patients undergoing coronary angiography within 24 hours of onset of AMI, 25 patients had LMCA occlusion. ECG findings on admission in these patients were compared to those in 30 consecutive patients with proximal coronary artery occlusion. Patients with previous AMI, left ventricular hypertrophy, or ⩾ 75% stenosis in non-infarct arteries were excluded from this study. Patients with right bundle branch block (RBBB) were included, but those with left bundle branch block were excluded because of the difficulty of diagnosing AMI. ST elevation or depression was considered present if ST deviation was ⩾ 0.1 mV. Left anterior fascicular block (LAFB) was defined by the mean QRS axis deviated to the left < 30° in the frontal plane. The culprit lesion was determined by coronary angiography and confirmed later by two cardiologists who were not aware of any ECG findings. Data …

We measured the time evolution of voltage and temperature of a CVD-Y123 coated conductor monolayer coil with Cu stabilizer under the cryocooled condition. The thermal runaway occurred locally at operate currents of 1.05-1.3 at 38 K and 1-10 T. In this case, the hot spot originated from the inhomogeneity of was observed. The thermal runaway generated from different parts of the tape at high and low fields at 38 K, respectively. This is due to the different heating behavior related to the distribution. The critical heating power of the thermal runaway obtained in this study were about 30 mW at 38 K and 10 T. It weakly depends on magnetic filed but is independent to the temperature. The analysis suggests that the cooling condition for the transient phenomena such as the thermal runaway is poor.

Internally reinforced Nb3Sn strands with CuNb-reinforcing stabilizer have been developed for realizing a compact high-field superconducting magnet. The Rutherford flat cables composed of sixteen strands were made with a 0.8 mm diameter CuNb/Nb3Sn strand. The designed critical current of the CuNb/Nb3Sn Rutherford flat cable is Ic = 1890 A at 13 T and 4.2 K in case of an ordinary heat-treatment at 670 for 96 h, which is two times higher than an operation current desired for safety margin. In addition, mechanical characteristics for CVD-processed YBa2Cu3O7 (YBCO) coated-conductor tapes were measured at 4.2 K in fields up to 18 T. It was found that YBCO tape exhibits the irreversible strain 0.5% and the irreversible stress 1140 MPa for the critical current at 4.2 K and 18 T for B//c. The cabling-and-react+prebending-processed CuNb/Nb3Sn Rutherford flat cables and CVD-processed YBCO tapes will be used as a react-and-wind method for the development of a 20 T superconducting magnet with a wide room temperature bore. We design a 20 T-440 mm warm-bore superconducting magnet consisting of YBCO inner coils, middle coils, and NbTi outer coils, which has the coil parameters of inner diameter 480 mm, outer diameter 1283 mm, and coil height 1302 mm. Since the coil inductance is estimated to be 232 H, the magnetic stored energy is 94 MJ at an operation current 900 A. An energy-saving 47 T hybrid magnet can be constructed in combination with a wide-bore 20 T superconducting outsert and a 15 MW-27 T water-cooled resistive insert.

Lecithin:cholesterol acyltransferase (LCAT) is a plasma enzyme that catalyzes esterification of plasma lipoprotein unesterified cholesterol, and plays a central role in maintaining reverse cholesterol transport through action with high density lipoprotein (HDL) and Cholesterol ester transfer protein (CETP). Cloned cDNA sequence of LCAT, consisted of about 1400 base pair which codes 416 amino acids, revealed high content of alpha-helix and beta-sheet, identity of amino acid sequence with various lipases, and putative structure of catalytic sites and mechanism of enzymatic action is proposed. Close relationship between location of gene mutation and severity of clinical and biochemical characteristics revealed by gene analysis in patients of LCAT deficiency and Fish eye disease is summarized.

Hypertriglyceridemia is common among individuals with noninsulin-dependent diabetes mellitus (NIDDM), and heterozygous lipoprotein lipase (LPL) mutations may result in the syndrome of familial hypertriglyceridemia and low levels of high density lipoprotein (HDL) cholesterol. To test the hypothesis that heterozygous LPL mutations predispose to the hypertriglyceridemia and low HDL cholesterol levels observed among members of familial NIDDM families, we examined 36 members and 3 unrelated spouses selected from members of 20 pedigrees for triglyceride levels exceeding the age- and sex-specific 95th percentile. Eighteen pedigree members and 2 spouses were diabetic. LPL exons 1-9 were screened by single strand conformation polymorphism analysis. Six different variants were detected in exons 2, 3, 4, 8, and 9, including 4 (exons 3, 4, and 8) silent nucleotide substitutions. A common nonsense mutation (exon 9; Ser--Ter) was present in 2 pedigrees, and a missense mutation (exon 2; Asp--Asn) was also present in members of 2 pedigrees. Analysis of members of these families suggested an association of the exon 2 variant with hypertriglyceridemia, although this trend was no longer significant when individuals with diabetes were excluded from the analysis. The variant enzyme was not present among 83 random control individuals, and when expressed in COS-1 cells, it was similar to the wild type with respect to specific activity, heparin binding, and heat stability. Our data suggest that coding region mutations of the LPL gene cannot account for the elevated triglyceride and low HDL levels noted in diabetic individuals and their relatives in most NIDDM pedigrees, but the exon 2 Asn variant may contribute to the hypertriglyceridemia in some families.

Summary The lungs of rabbits experimentally infected with Dirofilaria immitis were examined histopathologically, to compare the changes with those seen in human pulmonary dirofilariasis. Eight rabbits were infected subcutaneously with two to eight immature worms to induce pulmonary dirofilariasis. Obstructive changes, similar to those reported in human pulmonary dirofilariasis, were observed in the blood vessels surrounding the worms. A form of arteritis, similar to occlusive arteritis, and periarteritis were also observed in the lungs of the rabbits. These results suggest that experimentally induced dirofilariasis in the rabbit is a useful animal model for human pulmonary dirofilariasis.

Lipoprotein lipase (LPL) binds with high affinity to the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) and promotes binding, uptake, and degradation of normal triglyceride-rich lipoproteins in a process mediated by LRP (Chappell, D. A., Fry, G. L., Naknitx, M.A., Muhonen, L. E., Pladet, M. W., Iverius, P-H., and Strickland, D. K. (1993) J. Biol. Chem. 268, 14168-14175). To localize the portion of LPL that is responsible for interacting with LRP, fragments of LPL were expressed in bacteria. A fragment of human LPL containing the COOH-terminal domain (residues 313-448, designated LPLC) which lacks the catalytic site was able to bind to LRP. Purified LRP bound specifically to microtiter wells coated with LPL or LPLC with KD values of 2.8 and 5 nM, respectively. The effects of several mutations of LPLC were tested. Mutation of Lys407 to Ala reduced the affinity of LPLC for LRP by approximately 10-fold. Like native LPL, LPLC prevented the binding of activated alpha 2-macroglobulin and the 39-kDa receptor-associated protein to LRP and inhibited the internalization and degradation of activated alpha 2-macroglobulin and receptor-associated protein in cultured fibroblasts. LPLC also bound to 125I-labeled human normal triglyceride-rich lipoproteins and promoted their binding to purified LRP and to cultured cells. Mutation of Trp393 and Trp394 to Ala completely abolished the ability of LPLC to bind to lipoproteins, but had little effect on its interaction with LRP. These data indicate that the COOH-terminal domain of LPL may function both in binding lipoproteins and mediating their interaction with LRP.

A non-selective cation channel was found in primary cultured porcine coronary artery smooth muscle cells. In patch-clamp studies in the cell-attached mode, this channel was activated by bath application of genistein, a specific inhibitor of tyrosine kinase, but not by daidzein, which is similar in structure to genistein but has no inhibitory effect on tyrosine kinase. This channel discriminated poorly between Na+ and K+ (permeability ratio PNa/PK = 1.03), and also transported Ca2+. The single-channel conductance measured with a pipette solution containing 150 mM Na+ was 139 +/- 24 pS (mean +/- SD, n = 5), and that for the inward current measured with 100 mM Ca2+ solution was 25 +/- 9 pS (n = 3). This non-selective cation channel was also activated by staurosporine, a non-specific protein kinase inhibitor, but not by H-7, an inhibitor of protein serine/threonine kinase. These results suggest that the activity of the non-selective cation channel is negatively regulated by tyrosine kinase activity, and thus a decrease of the enzyme activity in porcine coronary artery smooth muscle cells may result in membrane depolarization and Ca2+ entry.

Basophils play a major role in allergic reactions-particularly in late phase reactions-by releasing histamine and other mediators of inflammation. Although transmembrane ion fluxes are thought to play an important role in the modulation of histamine release, little is known about ion pathways through the basophil membrane. We thus studied human basophils from normal subjects (n = 25 cells) with the patch-clamp method. We observed that IgE-dependent activation of human basophils led to the opening of non selective cation channels with a 20pS conductance. This was obtained when the patch pipette was applied onto the cell surface and sealed onto it in order to measure transmembrane currents on a small surface of intact basophils (cell-attached configuration). Non selective channels with the same 20pS conductance were also observed when a membrane patch was detached from basophil and its inner side placed in a Ca(2+)-containing medium (inside-out configuration). These data are a first contribution of the patch-clamp method in the understanding of ion movements in human basophils.

Action potentials in Aplysia MA1 neurons are known to produce inhibitory junction potentials (IJPs) in muscle cells in a specific portion (mm block) of the buccal musculature. These IJPs are reversibly blocked by curare (d-TC), suggesting that the transmitter is acetylcholine (ACh) and the receptor is a cholinergic ACh receptor. Muscle fibres were enzymatically dissociated from the mm portion, and whole cell patch clamp was performed onto those fibres to study the ionic mechanism associated with the ACh reception. The results revealed that the ACh receptor is associated with a Cl- channel.

Binding to heparan sulfate governs many aspects of the physiological action and regulation of the lipolytic enzyme, lipoprotein lipase (LPL). In an attempt to identify the structural determinants which mediate this interaction, basic residues in three segments of the primary sequence of human LPL (residues 147-151, 279-282, and 292-304) were replaced with alanine, either singly or in various combinations, and variant proteins were subjected to affinity chromatography on heparin-Superose. Five basic residues in two distinct segments of the primary sequence were critical determinants of the high affinity for heparin manifested by the active enzyme (R279, K280, R282, K296, R297). By contrast, no such evidence could be detected for basic residues in the first cluster (K147, K148) or for other basic residues in the third cluster (K292, R294, K304), while the evidence for K300 was unresolved. The conformation of this heparin-binding domain can be inferred by reference to the three-dimensional structure of the homologous enzyme, pancreatic lipase (Winkler, F. K., D'Arcy, A., and Hunziker, W. (1990) Nature 343, 771-774). Affinity of the active enzyme for heparin could not be reduced below a threshold, suggesting that other heparin-binding determinants exist elsewhere in the molecule, as supported by recently published evidence (Davis, R. C., Wong, H., Nikazy, J., Wang, K., Han, Q., and Schotz, M. C. (1992) J. Biol. Chem. 267, 21499-21504).

FUT-175 (6-amidino-2-naphthyl p-guanidinobenzoate dimethane-sulphonate), a potent serine protease inhibitor, has been reported to inhibit complement activity in vitro, and especially the classical complement pathway effectively. In the present study, we examined the inhibitory effect of FUT-175 on the classical complement pathway components by hemolytic assay using purified human complement components. As a result, 50% inhibition of the C1 protease activity for classical C3 convertase formation and for C2 was obtained with 3.0 x 10(-8) M and 7.0 x 10(-8) M of FUT-175, respectively. FUT-175 did not inhibit the C2 protease activity at all. We then administered FUT-175 to 5 glomerulonephritic patients with hypocomplementemia and proteinuria in order to assess the clinical effectiveness of this drug. When FUT-175 was administered intravenously and continuously at a rate of 0.1 to 0.2 mg/kg/hr for 2 weeks, the urinary protein excretion decreased significantly from 2.9 +/- 0.8 to 1.4 +/- 0.5 g/day (P0.025). In these patients, some of the serum complement markers (serum C3, C4 level and the hemolytic activity via the classical complement pathway (CH50)) were increased after FUT-175 administration. The above findings suggests that FUT-175 can exert beneficial effects on glomerulonephritis with hypocomplementemia by inhibiting complement activation.

The ATP-sensitive K+ channel (KATP channel) and the Ca(2+)-activated K+ channel (KCa channel) were active in cell-attached and excised inside-out patch configurations in cultured smooth muscle cells of the porcine coronary artery. Vasopressin activated the KCa channel (240 pS) when it was applied in the bath in the cell-attached patch mode presumably because of an increase in intracellular Ca2+, but it had no direct effect on the KCa channel. However, vasopressin directly blocked the KATP channel from outside the cell membranes in a concentration-dependent manner in both outside-out and cell-attached patch configurations; the K(+)-channel opener, nicorandil, reversed this effect. The KATP channel (30 pS) was highly active in the intact cell-attached patch configuration when the pipette contained a physiological concentration of Ca2+, suggesting that this channel may control the resting membrane potential. (The block might produce depolarization of the cells and might result in the contraction of smooth muscle cells.) These observations suggest that the KATP channel may play a role, at least in part, in controlling the contraction of smooth muscle cells of the coronary artery and that the control of vascular tone by vasopressin may be related to its ability to block the KATP channel.

The mode of action of the pyrethroid insecticide deltamethrin on inexcitable embryonic cultured cockroach neurones has been investigated using the patchclamp technique. Whole-cell recordings of the current induced by step depolarizations of the cell membrane showed that concentrations of deltamethrin ranging from 10−8 to 5x10−6moll-− induced a small tetrodotoxin (TTX)-sensitive inward current that peaked at around + 10 mV and reversed at around +60 mV. The activation and inactivation kinetics of this current were much slower than those of the axonal sodium current in this same species and were relatively insensitive to membrane potential. Steady-state inactivation was almost absent. Single-channel activity associated with the action of the insecticide was analyzed using the cell-attached configuration. Three distinct patterns of activity were found: (1) discrete single-channel events of relatively short duration, (2) long events of comparatively small amplitude and (3) complex bursts made up of a succession of openings and closings to several levels. These three patterns were analyzed quantitatively using specially designed programs. The first pattern of activity could be seen in most patches. It consisted of short (1-lOms) rectangular events of comparatively small amplitude (1.5pA at rest) and very low open time probability (around 0.001). The current-voltage relationship of these small events was linear over the voltage range studied and the (extrapolated) reversal potential approximated ENa. The second pattern of activity was observed less frequently. The channels could stay open for very long periods (up to several seconds) and occasionally flickered between two or more levels. The third pattern of activity was observed in many patches. During the burst, which could last from a few milliseconds to a few hundred milliseconds, the singlechannel current jumped almost continuously between several levels (up to 7 or 8). The size of the different (single-channel) current levels was the same for the three patterns of activity. Furthermore, these levels corresponded to multiples of the same minimum level (around 1 pA at the resting potential). These results suggest that deltamethrin activates several states of one or several populations of sodium channels.

A combination of nifedipine (40 mg twice daily) plus carteolol (10 mg twice daily) was compared with nifedipine monotherapy in ten patients with essential hypertension. Ambulatory blood pressure (BP) monitoring over 24 hours and treadmill exercise testing were performed before treatment with nifedipine (but after the placebo period), after four weeks of nifedipine treatment, and after four weeks of nifedipine+carteolol combination therapy. At the end of nifedipine monotherapy, 24-hour average ambulatory BP, minimum ambulatory BP during sleep, maximum ambulatory BP, and casual BP all decreased significantly (P less than 0.01). However, the standard deviation (SD) of the ambulatory BP was not affected. The change in systolic BP response to treadmill exercise increased. After a four-week period of nifedipine+carteolol combination therapy, average ambulatory BP and maximum ambulatory BP were further decreased (P less than 0.01). The SD of the ambulatory BP and the change in BP response to exercise were significantly decreased (P less than 0.01), but the minimum ambulatory BP was not affected. These findings suggest that nifedipine and carteolol differ in their influence on diurnal BP variation and on exercise-induced BP elevation. Carteolol may mainly attenuate stress-induced BP elevation and have little influence on nocturnal BP decline. In contrast, nifedipine may affect the BP profile uniformly over the entire day. Nifedipine+carteolol combination therapy may be superior to nifedipine monotherapy because carteolol has a minimal effect on nocturnal BP and decreases stress-induced BP elevation.

High performance and high uniformity are required for superconducting wires and cables to be used for recently planned accelerators such as SSC (Collider and High Energy Booster), RHIC and LHC. These wires and cables have been developed by Furukawa Electric to have high critical current densities in spite of fine NbTi filaments and, at the same time, to have high dimensional, mechanical and electrical uniformity. On the other hand, realization of the long piece length of the wire is the one of the most crucial requirement for the economical process. The problem of the wire breakage originates from various causes. In this paper, we analyze the problem from the viewpoint of wire structures such as wire diameter, matrix ratio, filament diameter, filament spacing and so on, based on our much experience with fabrication of accelerator wires and other wires having similar structure.

Intramembrane charge movement and Ca2+ release from sarcoplasmic reticulum was studied in foetal skeletal muscle cells from normal and mutant mice with 'muscular dysgenesis' (mdg/mdg). It was shown that: 1) unlike normal myotubes, in dysgenic myotubes membrane depolarization did not evoke calcium release from the sarcoplasmic reticulum; 2) when all ionic currents are pharmacologically suppressed, membrane depolarization produced an asymmetric intramembrane charge movement in both normal and dysgenic myotubes. The relationship between the membrane potential and the amount of charge movement in these muscles could be expressed by a two-state Boltzmann equation; 3) the maximum amount of charge movement associated with depolarization (Qon max) in normal and in dysgenic myotubes was 6.3 +/- 1.4 nC/microF (n = 6) and 1.7 +/- 0.3 nC/microF (n = 6) respectively; 4) nifedipine (1-20 microM) applied to the bath reduced Qon max by about 40% in normal muscle cells. In contrast, the drug had no significant effect on the charge movement of dysgenic myotubes; and 5) the amount of nifedipine-resistant charge movement in normal and in dysgenic myotubes was 3.5 nC/microF (n = 3) and 1.7 nC/microF 1 maximum (n = 3), respectively.

Na+ and K+ are the major extra- and intracellular cations, respectively. We have thus studied the role of these ions on human basophil histamine release by modifying their transmembrane gradients or by increasing membrane ion fluxes using ionophores. 1) When external Na+ (reduced to 4 mM) was replaced by the nonpermeating Na+ substitute N-methyl-D-glucamine, the release of histamine was enhanced in 2 mM Ca2+ (from 37.5 +/- 8.0% in 140 mM Na+ to 68.5 +/- 9.1% in low Na+) and became possible in the presence of low Ca2+ (at 1 microM Ca2+: from 0.6 +/- 0.7% in 140 mM Na+ to 36.2 +/- 8.0% in low Na+); moreover, in low Na+, the release of histamine became partly independent on Ca2+ influx. 2) Increasing the Na+ influx with the cation channel-forming gramicidin D inhibited the release of histamine by 33.2 +/- 13.6% (n = 6) in an external Na(+)-dependent manner. 3) Decreasing K+ efflux using K+ channel blockers (4-aminopyridine, quinine, sparteine) inhibited histamine release in a dose-response manner. 4) The K+ ionophore valinomycin, which increases K+ efflux, slightly enhanced IgE-mediated histamine release when used alone, whereas it potentiated the release of histamine from leukocytes previously treated with 4-aminopyridine by 57.0 +/- 18.6% (n = 7). 5) Decreasing K+ efflux by increasing external K+ inhibited IgE-mediated release in a similar manner as Na+ did. The inhibitory effects of Na+ and high K+ were not additive, thus suggesting that both cations inhibited the release by a common mechanism. In conclusion 1) our data evidence that histamine release from human basophils is inhibited by Na+ influx and potentiated by K+ efflux; 2) they suggest that K+ channels are present on the basophil membrane and that Na+ and K+ fluxes act on histamine release most probably via modulation of membrane potential.

Development of high field dipole model magnets for future high energy accelerators has been carried out as a part of the cooperative accelerator program between CERN and KEK. A single aperture dipole model magnet was completed and tested. The magnet reached 8.0 T at 4.3 K and 9.87 T at 1.8 K. A twin aperture dipole model magnet with an identical coil design is being assembled. The development status and test results are described. >

The authors devised a new treatment strategy using continuous ambulatory hemofiltration (CAHF) in between short hemodialyses (short HD). For CAHF, a small wearable hemofilter (0.1 m2) was developed using a membrane permeable to low molecular weight proteins. During short HD, no body water was removed, but saline, equivalent to 3% body weight, was administered at a constant rate. During CAHF, 1 L of replacement fluid was administered intravenously after every meal to increase the replacement volume. Switch from the conventional to new strategy resulted in far more stable blood pressure during short HD, a decrease in time averaged body weight, and a decrease in a decrease in time averaged blood urea nitrogen and plasma beta 2-m levels.

A total of 38 cases of advanced rectal cancer (non-radiation group; 25 cases, radiation group; 13 cases) was studied in order to clarify the effect of preoperative radiation therapy (42.6 Gy) on lymph node metastases in rectal carcinoma. In all cases, microcarbon was submucosally injected into the rectal wall the day before operation in order to increase the number of removable lymph nodes from resected specimens as many as possible. By this method, the number of lymph nodes detected per specimen increased from 40 to 60. The incidence of lymph node metastases was 38.5% in radiation group and 64.0% in non-radiation group. The mean number of lymph nodes with metastases was 8.6 in non-radiation group, however, 2.8 in radiation group. With regard to the relationship between size and number of positive lymph nodes, especially in small lymph nodes measuring less than 3 mm, the incidence of metastases was 6.4% in non-radiation group, whereas 0% in radiation group. As a result, it was evident that preoperative radiation therapy in rectal cancer would reduce the number of positive lymph nodes significantly and the effect of radiation was prominent in small lymph nodes.

Twenty-nine patients with rectal carcinoma who were treated by surgery only and 27 patients who received adjuvant preoperative radiation (42.6 Gy) were subjects of the present study. The entire pelvis was radiated with the dose of 30.6 Gy, and the rest 12 Gy was delivered to the primary tumor. By injecting micro activated carbon into the submucosa of the rectum near the tumor, the number of the defection of removed lymph nodes in non-radiation as well as radiation group was markedly improved, 48.6 and 54.2 respectively. The rates of distal lymph nodes metastases in irradiated patients were 25.9% (n0 74.1%, n1 14.8%, n2 11.1%, n3 0%), whereas it was 51.7% in patients who had surgical resection only (n0 48.3%, n1 20.7%, n2 17.2%, n3 13.8%). The number of metastatic lymph nodes were fewer in irradiated patients. Histopathological study indicated that preoperative irradiation was effective on decreasing the quantity of metastatic lymph nodes.

Extracellular application of ATP transiently increases the cytosolic-free Ca++ concentration ([Ca++]i) in cultured smooth muscle cells of porcine coronary artery, and this activates large conductance Ca(++)-activated K (Kca) channels. In the present study effects of nitroglycerin (NG) and 4-aminopyridine (4-AP) on [Ca++]; and contraction were studied. 4-AP blocked Kca channels and enhanced the rise of [Ca++]i with oscillation, which led to contraction of the cells. NG activated the Kca channels of 300 picosiemens and inhibited 4-AP-induced contraction and oscillation of [Ca++]i. These results suggest that the vasorelaxant effect of NG involves hyperpolarization of the cell membrane by activating the Kca channels. NG also cause rapid decrease of [Ca++]i during the Ca(++)-mobilization by ATP in Ca-free solution. Similar effects were observed with cyclic GMP, suggesting that the effects of NG on the Kca channels and [Ca++]i were mediated by cyclic GMP.

Although the existence of salt sensitivity in essential hypertensives has been well known, the precise mechanism(s) has not yet been elucidated. The aim of this study was to clarify the relation between the responses in blood pressure, extra- and intracellular cations and calcium-regulating hormones to oral NaCl loading in essential hypertensives. After oral NaCl loading, mean blood pressure, urinary excretions of calcium and magnesium, and PLT[Ca2+]i were significantly increased. [Ca2+]o and E[Mg]i were decreased. The changes (delta) in mean blood pressure by NaCl loading positively correlated with delta PLT[Ca2+]i and delta PTH, and negatively with delta[Ca2+]o and delta E[Mg]i. Delta PLT[Ca2+]i positively correlated with delta PTH and negatively with delta[Ca2+]o and delta E[Mg]i. From these results, the blood pressure response to oral NaCl loading is associated with the alternation of [Ca2+]i metabolism in which the changes in magnesium metabolism and calcium-regulating hormones may be involved.

A human beta-interferon (HuIFN-beta) gene inserted into a eukaryotic expression vector (pSV2IFN-beta) was entrapped in liposomes having positive charges on their surface. Liposome-mediated transfection of the gene into cultured glioma cells (U251-MG) resulted in the secretion of HuIFN-beta into the medium. The HuIFN-beta level in the culture medium of glioma cells reached 24 +/- 8 (mean +/- SD) IU/ml after 96 h of incubation, at which level the growth inhibitory effect on the cells was found to be greater than 40 times as compared with exogenously added HuIFN-beta. When the plasmid-containing liposomes were coupled with a monoclonal antibody (G-22 MCA) against glioma-associated antigen, the level of HuIFN-beta in the medium was 178 +/- 26 IU/ml, resulting in a 7-fold increase, and the growth inhibitory effect was further elevated. Since the addition of a monoclonal antibody against HuIFN-beta to the medium did not cause the cell growth to resume, the growth inhibitory effect on the cells seems to be ascribed to HuIFN-beta produced in the cells transfected with its gene. Accordingly, the specific delivery of the HuIFN-beta gene into glioma cells by the use of such liposomes might become a useful technique for gene therapy of malignant glioma.

We have investigated effects of monocyte colony-stimulating factor (M-CSF) on the uptake of acetylated low density lipoproteins (acetyl-LDL) and the activity of cholesterol esterification in human monocyte-derived macrophage. The cells were cultured with M-CSF for 10 days and then incubated with acetyl-LDL for 24 h. M-CSF (128 ng/ml) enhanced the uptake and degradation of 10 micrograms/ml of 125I-acetyl LDL 7.5-fold (n = 6) and the effect of M-CSF was dose-dependent at the concentrations of 0.5-32 ng/ml. The binding experiments at 4 degrees C demonstrated that the number of acetyl-LDL receptor was increased by the addition of M-CSF. Supporting this, ligand blotting analysis revealed a significant increase in a receptor protein for acetyl-LDL (240 kDa). Binding of LDL was also enhanced by M-CSF but less significantly than that of acetyl-LDL. Cellular cholesterol esterification in the presence of 10 micrograms/ml acetyl-LDL was enhanced 24.1-fold (n = 13) by 128 ng/ml M-CSF. It was evident that M-CSF enhanced cholesterol esterification to a greater extent than the cellular uptake of acetyl-LDL (24.1- versus 7.5-fold). Cholesterol esterification was also enhanced by the addition of granulocyte-macrophage colony-stimulating factor and interleukin 1. We conclude that M-CSF enhances the uptake of both acetyl-LDL and LDL by increasing their receptor number, and further enhances the process of cholesterol esterification, resulting in a remarkable increase in cholesterol esterification in macrophages. These findings strongly suggest the significant involvement of cytokines such as M-CSF in cholesterol metabolism of macrophages.

During the hemodialyses of eight patients with end-stage renal failure, who often had sudden-onset dialysis-induced hypotension, catecholamine (CA) levels were measured in the ultrafiltrate obtained by a mini-filter placed in series upstream of the dialyzer. The water evaporation rate from the skin (reflecting the perspiration rate) was also monitored. Results showed a temporary elevation in CA levels in the ultrafiltrate before hypotension occurred. This rise did not continue for long, returning to baseline when hypotension actually occurred. The temporary elevation may reflect transient compensation by the sympathetic nervous system for the decrease in vascular wall tension. It was also found that there was considerable water evaporation from the skin during hypotension. Because sweat gland activity is reflexively modulated by the baroreceptor, perspiration after a drop in blood pressure may reflect the normal diminiution in baroreceptor activity.

The percentage, absolute number and expression of Ia-antigen of macrophages (Mø) in peripheral blood cells (PBC) and splenocytes from Bio-Breeding/Worcester (BB/W) rats were evaluated. The percentage of Mø in PBC and splenocytes from BB/W rats was significantly higher than those in normal Wistar rats from Clea Japan Inc. (NW/C) and Charles River Japan Inc. (NW/CR). The percentage of Ia-positive Mø in PBC and splenocytes from BB/W rats was significantly increased compared with that in NW/C rats. On the other hand, there was no significant difference in the percentage of Ia-positive Mø of PBC between BB/W and NW/CR rats, and the percentage of Ia-positive Mø in the spleen from BB/W rats was significantly lower than those in NW/CR rats. Thus, the quantity of MHC class II molecules on circulating Mø is not related to the pathogenesis of diabetes mellitus in BB/W rats.