Multipole polaron in the devil's staircase of CeSb.

Rare-earth intermetallic compounds exhibit rich phenomena induced by the interplay between localized f orbitals and conduction electrons. However, since the energy scale of the crystal-electric-field splitting is only a few millielectronvolts, the nature of the mobile electrons accompanied by collective crystal-electric-field excitations has not been unveiled. Here, we examine the low-energy electronic structures of CeSb through the anomalous magnetostructural transitions below the Néel temperature, ~17 K, termed the 'devil's staircase', using laser angle-resolved photoemission, Raman and neutron scattering spectroscopies. We report another type of electron-boson coupling between mobile electrons and quadrupole crystal-electric-field excitations of the 4f orbitals, which renormalizes the Sb 5p band prominently, yielding a kink at a very low energy (~7 meV). This coupling strength is strong and exhibits anomalous step-like enhancement during the devil's staircase transition, unveiling a new type of quasiparticle, named the 'multipole polaron', comprising a mobile electron dressed with a cloud of the quadrupole crystal-electric-field polarization.

Systemic delivery of IL-10 by an AAV vector prevents vascular remodeling and end-organ damage in stroke-prone spontaneously hypertensive rat.

Interleukin-10 (IL-10) ameliorates various T-helper type 1 cell-mediated chronic inflammatory diseases. Although the therapeutic benefits of IL-10 include antiatherosclerotic effects, pathophysiological effects of IL-10 on vascular remodeling in hypertension have not yet been elucidated. These studies were designed to determine whether sustained IL-10 expression, mediated by an adeno-associated virus (AAV) vector, prevents vascular remodeling and target-organ damage in the stroke-prone spontaneously hypertensive rat (SHR-SP)-an animal model of malignant hypertension. A single intramuscular injection of an AAV1 vector encoding rat IL-10 introduced long-term IL-10 expression. These IL-10-transduced rats had decreased stroke episodes and proteinuria, resulting in improved survival. Histological examination revealed a reduced level of deleterious vascular remodeling of resistance vessels in the brain and kidney of these rats. Immunohistochemical analysis indicated that IL-10 inhibited the enhanced renal transforming growth factor-beta expression and perivascular infiltration of monocytes/macrophages and nuclear factor-kappaB-positive cells normally observed in the SHR-SP. Four weeks after IL-10 vector injection, systolic blood pressure significantly decreased and this effect persisted for several months. Overall, AAV vector-mediated systemic IL-10 expression prevented vascular remodeling and inflammatory lesions of target organs in the SHR-SP. This approach provides significant insights into the prevention strategy of disease onset with unknown genetic predisposition or intractable polygenic disorders.

Chromosomal mapping of genes controlling development, histological grade, depth of invasion, and size of rat stomach carcinomas.

Rat stomach cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) are widely used as a model of differentiated-type human stomach cancers. ACI/N (ACT) rats are susceptible and BUF/Nac (BUF) rats are resistant to MNNG-induced stomach carcinogenesis, and the presence of an autosomal gene with a dominant BUF allele has been suggested. In this study, we performed a carcinogenicity test by giving MNNG in drinking water to 117 male ACI x (ACIxBUF)F1 backcross rats. Each of 100 effective rats was diagnosed for its "carcinoma development" and when it was bearing stomach carcinoma(s), for histological grade, depth of invasion, and size and number of tumors. Carcinoma development was diagnosed based both on the age of the rat and on the presence of stomach carcinoma(s). Linkage analysis was performed with the genotypes of 161 loci, covering 1637 cM of the rat genome. Contrary to our original expectations, the most influential gene was the one on chromosome (chr.) 15, Gastric cancer susceptibility gene 1 (Gcs1), which confers susceptibility to stomach carcinogenesis (LOD, 3.8) with a dominant BUF allele by promoting conversion from adenomas to carcinomas. Two resistance genes on chr. 4 and chr. 3, Gastric cancer resistance gene 1 (Gcr1) and Gcr2, were shown to confer dominant resistance (LOD, 2.7 and 2.6, respectively). Gcs1, Gcr1, and Gcr2 exerted additive effects on the development of stomach carcinomas. A gene on chr. 16, Gcr3, was indicated to reduce the depth of invasion (LOD, 2.2) and sizes of tumors (LOD, 1.9). No linkage was obtained using the number of tumors. These findings show that the coordinate effect of a susceptibility gene, Gcs1, and two resistance genes, Gcr1 and Gcr2, is responsible for the development of MNNG-induced stomach carcinomas and that Gcr3 is responsible for the growth of a stomach carcinoma, reflected in the depth of invasion and in the tumor size.

Population-based mapping of pulmonary adenoma susceptibility 1 locus.

Pulmonary adenoma susceptibility 1 (Pas1), the major locus affecting inherited predisposition to lung tumor development in mice, maps near the Kras2 gene. We previously reported a significant association between a KRAS2/RsaI polymorphism and the risk and prognosis of lung adenocarcinoma (ADCA) in the Italian population. In the present case-control study, we examined 269 lung ADCA patients, 121 squamous cell lung carcinoma patients, and 632 healthy individuals (general population controls) in the Japanese population with genetic markers spanning approximately 1200 kb in the KRAS2 region. Allele-specific oligonucleotide hybridization revealed the same KRAS2/RsaI polymorphism associated with risk and prognosis as in Italian lung ADCA patients; the polymorphism was significantly associated with clinical stage (P < 0.001) and survival rate (log rank = 0.0014), confirming the mapping of PAS1 and pointing to the role of this locus in human lung cancer.

Initial effects of the left ventricular repair by plication may not last long in a rat ischemic cardiomyopathy model.

BACKGROUND: Long term effects of left ventricle (LV) repair surgery (LVR) for ischemic cardiomyopathy are not well understood. METHODS AND RESULTS: Sixty-nine rats developed ischemic cardiomyopathy with large akinetic LV area 4 weeks after the left anterior descending artery was ligated. In a second surgery 4 weeks later, 33 rats underwent LVR by plication of the akinetic LV area (LVR group), and 36 underwent rethoracotomy alone (sham group). No medication was used in either group. All rats survived the second surgery. LV end-diastolic dimension as measured by echocardiography, LV fractional shortening, and the maximal end-systolic pressure-volume relationship (E(max)) as calculated from the data by catheter-tipped manometer and echocardiography improved in the LVR group after the second surgery, but LV end-diastolic dimension and E(max) gradually deteriorated as time passed. LV end-diastolic pressure improved 1 week after LVR but rose significantly 4 weeks after LVR. Brain natriuretic peptide mRNA was lower in the LVR group than in the sham group 1 week after LVR but not 4 weeks postoperatively. CONCLUSIONS: Initial improvement in LV function and neurohormonal status after LVR did not last for 4 weeks in this rat model when untreated medically. The mechanism of deterioration should be elucidated to improve long-term results of LVR.

Spontaneous healing of chyle leakage after lymphangiography.

We report a 34-year-old man with the complication of chylous ascites after retroperitoneal lymphadenectomy that was refractory to various conservative therapies. Because surgical treatment for chylous ascites was considered, lymphangiography was performed to identify the area of leakage of chyle, after which the chylous ascites spontaneously healed.

[Early and late results and problems of coronary artery bypass grafting in patients over 80-year-old].

This study evaluated the validity of coronary artery bypass grafting (CABG) in patients over 80-year-old investigating the early and late result, patient's opinion to the surgery, and change of activities of daily living scale. From July 1993 to September 2002, consecutive 94 patients over 80-year-old were performed CABG in our institution. The group consisted of 43 female patients, and mean age of 82.6 years. Of these patients, 36 were operated conventional CABG (CABG group) and 58 patients were operated with off-pump CABG (OPCAB) group. There were no significant differences between 2 groups in preoperative characteristics except for anemia and hypertension. Operative results, including mortality, number of distal anastomoses, operative time had no significant differences between 2 groups. But maximum CK-MB fraction was higher in CABG group. There were 4 operative deaths, indicating operative mortality was 4.3%. Late results showed overall survival rate at 3 years was 81.1% and cardiac event free survival rate at 3 years was 88.8%. Questionnaire revealed over 80% patients were satisfied with the surgery but less than 40% patients felt activities of daily living (ADL) scale was improved. Operative results of CABG in octogenarians were satisfied, but more efforts to remain patient's high ADL were mandatory.

Excess NF-κB induces ectopic odontogenesis in embryonic incisor epithelium.

Nuclear factor kappa B (NF-κB) signaling plays critical roles in many physiological and pathological processes, including regulating organogenesis. Down-regulation of NF-κB signaling during development results in hypohidrotic ectodermal dysplasia. The roles of NF-κB signaling in tooth development, however, are not fully understood. We examined mice overexpressing IKKß, an essential component of the NF-κB pathway, under keratin 5 promoter (K5-Ikkß). K5-Ikkß mice showed supernumerary incisors whose formation was accompanied by up-regulation of canonical Wnt signaling. Apoptosis that is normally observed in wild-type incisor epithelium was reduced in K5-Ikkß mice. The supernumerary incisors in K5-Ikkß mice were found to phenocopy extra incisors in mice with mutations of Wnt inhibitor, Wise. Excess NF-κB activity thus induces an ectopic odontogenesis program that is usually suppressed under physiological conditions.

Transition from neurogenic to myogenic receptivity for thyrotropin-releasing hormone (TRH) in the duodenum of the neonatal rat.

A tetrodotoxin- and hexamethonium-sensitive response to thyrotropin-releasing hormone (TRH), an in vitro contraction, first appeared in the duodenum of the 3 day old rat, was increased by day 16, decreased there-after and was extinguished after weaning. A tetrodotoxin-resistant response to TRH, a relaxation, appeared at day 13 and became distinct after weaning. The development of neurogenic receptivity for TRH precedes the appearance of myogenic receptivity in the rat duodenum.

Phorbol ester and okadaic acid-resistant cells: the crossroads of signal transduction and drug resistance.

Many factors are involved in the development of drug resistance for anticancer drugs. The drugs should pharmacokinetically attain the appropriate concentration. They should be metabolized to the active forms. Tumor cells should have sensitivity to them. Several molecular and biochemical mechanisms that may explain cellular drug resistance have been identified. The contribution of protein phosphorylation and dephosphorylation for drug resistance is demonstrated in phorbol ester and okadaic-acid-resistant cells. The modulation of drug resistance by substances that affect the signal transduction pathway is an important issue in the development of an effective method for overcoming drug resistance.

Influence of age on NMDA receptor complex in rat brain studied by in vitro autoradiography.

N-methyl-D-aspartate (NMDA) receptors are known to play an important role in learning and memory and to be involved in neuron cell death accompanying cerebral ischemia, seizures, and Alzheimer's disease. The NMDA receptor complex has been considered to consist of an L-glutamate recognition site, a strychnine-insensitive glycine modulatory site, and a voltage-dependent cation channel. In the present study, effects of age on an L-glutamate recognition site and a glycine site were examined in rat brain by quantitative in vitro autoradiography with [3H]-CPP and [3H]-glycine. Both [3H]-glycine and [3H]-CPP binding sites were most abundant in the hippocampus and cerebral cortex, and they showed a similar distribution pattern throughout the brain. [3H]-glycine binding sites were severely decreased in the telencephalic regions, including the hippocampus and cerebral cortex, in aged brain. Conversely, [3H]-CPP binding sites were well preserved in these brain areas. In the mid-brain regions and cerebellum, neither [3H]-glycine nor [3H]-CPP binding sites changed in the aged brain. Our results indicate that within the NMDA receptor complex, glycine receptors are primarily affected in the aging process.

Postnatal changes in response to adenosine and adenine nucleotides in rat duodenum.

1. The effects of adenosine and adenine nucleotides were studied in rat duodenum from postnatal day 1 to day 70. The mechanical activity of duodenal segments was recorded through an isotonic transducer connected to a polygraphic recorder. 2. In rat duodenal segments, adenosine-5'-triphosphate (ATP, 10(-4) M) and adenosine-5'-diphosphate (ADP, 10(-4) M) produced a contractile response on postnatal day 1. This response increased with age, peaking on day 7, followed by a gradual decrease and was non-existent by day 21. In contrast, a relaxant response to ATP and ADP was apparent on day 21, and continued to increase up to day 70. 3. The contraction caused by ATP was inhibited by indomethacin or the P2y-purinoceptor antagonist, reactive blue-2 but not by tetrodotoxin or hyoscine. Thus, it may be mediated by production of prostaglandin through the P2y-purinoceptor. The relaxation produced by ATP was inhibited by reactive blue-2 but not by tetrodotoxin, guanethidine or the P1-purinoceptor antagonist, 8-phenyltheophylline indicating that ATP acts on smooth muscle directly through the P2y-purinoceptor. The pD2 for the contractile response to ATP was 5.15 on day 7 and that for the relaxant response, 6.64 on day 70. 4. Adenosine (10(-4) M) and adenosine-5'-monophosphate (AMP, 10(-4) M) elicited no response before day 14. On day 14, both adenosine and AMP produced a small relaxant response which increased with age. The relaxation produced by adenosine was inhibited by 8-phenyltheophylline but not by tetrodotoxin or guanethidine, indicating that it is mediated by an action on the P1-purinoceptor of smooth muscle. 5. It is evident from these results that in neonatal rat, a contractile response to ATP and ADP occurs initially in the duodenum, followed by a relaxant response to adenosine and AMP on day 14 and to ADP and ATP on day 21. 6. The smooth muscle of rat duodenum may tentatively be concluded to contain separate purinoceptors for adenosine and AMP (Pj) and ADP and ATP (P2) and the responses to P1- and P2-agonists change during the course of development.

Thyrotropin releasing hormone-induced hyperthermia in mice: possible involvement of adrenal and pituitary glands.

To investigate the hyperthermic effect of thyrotropin releasing hormone (TRH) and its potentiation by exogenous catecholamines (CA), the role of the adrenal medulla and of the pituitary gland was studied in unoperated, adrenal-demedullated or hypophysectomized mice. In unoperated mice, TRH 40 mg kg-1 i.p. produced a hyperthermia which was accompanied by an increase in plasma noradrenaline (NA) and adrenaline (Ad). NA or Ad, both at a dose of 1 mg kg-1 i.p., enhanced the TRH-induced hyperthermia. Adrenal demedullation suppressed the hyperthermia and the increase of plasma CA produced by TRH but not the potentiation of this hyperthermia by exogenous CA. Hypophysectomy abolished the TRH-induced hyperthermia but not the increase of plasma CA or the potentiation of this hyperthermia by exogenous CA. These results suggest that, in mice, both the adrenal medulla and the pituitary gland play an essential role in TRH-induced hyperthermia but not in its potentiation.

Serum concentrations of thyroid hormones and activity of iodothyronine deiodinase in peripheral tissues of the house musk shrew, Suncus murinus.

Serum concentrations of thyroid hormones and the properties of iodothyronine deiodinase in tissues of the house musk shrew, Suncus murinus, were examined and compared with those of the rat. Serum concentrations of thyroxine (T4) and 3,3',5'-tri-iodothyronine (rT3) were higher, while the serum concentration of 3,5,3'-tri-iodothyronine (T3) was lower in the shrew than in the rat. Among liver, kidney, skeletal muscle, heart, brown adipose tissue (BAT), spleen, lung, testes and thymus homogenates of the shrew, T(4)5'-deiodinase (5'D) activity was highest in BAT, and rT3 5'D activity was highest in both the liver and BAT. Intermediate or low T3 5-deiodinase activity was noted in all tissues examined. Activity of 5'D for T4 and rT3 in liver and kidney was much lower, while that of BAT was much higher in the shrew than in the rat. Liver and kidney 5'D may be type-I and that of BAT may be type-II in the shrew, judging from its response to 6-n-propyl-2-thiouracil and iopanoic acid and substrate preference. Thus 5'D of the shrew was similar to that of the rat in type, but was different with respect to its activity in some peripheral tissues. This difference may have relevance to the low T3 state of the shrew.

Central action of cesium chloride in streptozotocin-diabetic mice.

The changes in the pharmacological responses to cesium were examined in streptozotocin(STZ)-induced diabetic mice. An acute administration of cesium chloride (10 mEqCs+/kg IP) to non-diabetic control mice elicited increased salivation and inhibition of respiration followed by death in about half of the animals examined. These effects of cesium were diminished in STZ-diabetic mice. LD50 for acute cesium was higher in STZ-diabetic mice (14.3 mEq/kg) than non-diabetic buffer controls (11.7 mEq/kg): however, subchronic administration of cesium did not decrease the LD50 in STZ-diabetic mice. The sleeping time induced by pentobarbital was reduced in STZ-diabetic mice and the reduction of the pentobarbital-induced hypnosis was reversed by subchronic cesium pretreatment but not by acute cesium administration. Methamphetamine-induced mortality was increased in STZ-diabetic mice and acute administration of cesium decreased the toxicity in both control and diabetic mice. Inhibition of locomotor activity elicited by acute single injection of cesium chloride was observed in both STZ-diabetic and non-diabetic mice. These results indicate that responses to cesium as well as centrally-acting drugs are affected differentially in STZ-diabetic mice.

Effects of the enkephalin analogue FK33-824 on rectal temperature and respiratory rate in male mice.

Subcutaneous administration of the enkephalin analogue FK33-824 (FK) elicited a dose-related decrease in rectal temperature and respiratory rate in male ddY strain mice. Naloxone and 3 days' implantation of morphine pellet decreased the effects of FK, suggesting the involvement of opioid receptors and cross-tolerance with morphine to both effects of FK. A positive correlation was found between the FK-induced decrease in rectal temperature and that in respiratory rate among the 6 strains of inbred mice including BALB/c, C3H, A/J, CBA, C57BL/6 and DBA/2. The degree of hypothermia elicited by FK was different among strains, whereas marginal strain difference was seen in the respiratory depression induced by FK. The strain difference in the FK responses may be due to the difference in the opioid receptor subtypes in the brain.

Impairment of cold-induced increase in thyroxine 5'-deiodinase activity in mouse brown adipose tissue by the intracerebroventricular administration of bombesin.

Effects of bombesin on brown adipose tissue (BAT) thyroxine (T4) 5'-deiodinase (5'D) activity and rectal temperature were examined in male mice. Immediately following an intracerebroventricular (ICV) or intravenous (IV) injection of bombesin (0.1-100 ng/animal) or vehicle (20 mM bacitracin dissolved in 0.9% saline), the mice were placed in a room at 4 degrees C or 22 degrees C for 30, 60, 120 or 240 min. The ICV injection of bombesin dose-dependently lessened cold-induced increase in BAT 5'D activity and increased hypothermia determined at 120 min of cold exposure, whereas the IV injection of bombesin was without effect. Bombesin (ICV)-induced hypothermia preceded the inhibition of BAT 5'D activity by at least 30 min at 4 degrees C. BAT 5'D activity was not affected by ICV injection of bombesin in mice kept at 22 degrees C, although the rectal temperature was significantly decreased. Bombesin thus appears to prevent cold-induced increase in T4 5'D activity in mouse BAT by its central effect. Bombesin-induced excessive hypothermia itself and/or the decrease in sympathetic tone of BAT by bombesin might decrease cold-induced increase in BAT 5'D activity.

Contractile response to neuropeptide Y of rat isolated duodenum.

The response of isolated duodenum to neuropeptide Y (NPY) was studied isotonically in neonatal and adult rats. Neuropeptide Y (10(-8) to 10(-6) M) elicited a biphasic contraction of isolated duodenum from neonatal rats, but monophasic and weak contraction of adult duodenum. The first phase of NPY-induced contraction of neonatal duodenum was concentration dependent and partially inhibited by preincubation with tetrodotoxin, a Na+ channel blocker, hyoscine, a muscarinic antagonist, suramin, a P2 purinoceptor antagonist, and indomethacin, an inhibitor for prostaglandin biosynthesis. Neuropeptide Y(13-36), a specific Y2 NPY receptor agonist, elicited a concentration-dependent contraction of neonatal rat duodenum. The duodenal response to NPY thus changes during development in rats. Both cholinergic and purinergic transmission and prostaglandin biosynthesis may be involved in the NPY-induced contraction of neonatal duodenum. Neuropeptide Y-induced contraction may be mediated through presynaptic Y2 receptors.

Cholecystokinin increases intracellular Ca2+ concentration in cultured striatal neurons.

Although it has been established that pancreatic cholecystokinin (CCK) receptors are coupled to phosphatidylinositol turnover, the events which follow activation of CCK receptors in the central nervous system have not received much attention. In this paper, changes in intracellular Ca2+ concentration ([Ca2+]1) in response to CCK peptides were measured in single cultured rat striatal neuron by fura-2 fluorometry. CCK peptides dose-dependently increased [Ca2+]i in a monophasic manner. The order of the potencies of CCK peptides to increase [Ca2+]i was as follows: caerulein greater than CCK-8 greater than desulfated CCK-8 greater than CCK-4. The effect of caerulein was completely blocked in a Ca2(+)-depleted medium. In addition, omega-conotoxin GVIA completely inhibited the effect of caerulein, while neither nifedipine nor verapamil affected it. Our results indicate that CCK receptors couple to N-type voltage-sensitive Ca2+ channels in cultured rats striatal neurons.

Mitral valve repair in a patient with severe porcelain aorta.

We repaired the mitral valve in a patient with severe porcelain aorta. Significant mitral regurgitation developed in a 66-year-old woman with heavy calcification throughout the whole aorta. At operation, cardiopulmonary bypass was properly established by combined axillary and femoral arterial cannulations for sufficient systemic flow. Likewise, the combination of a superior mitral approach and profound hypothermic fibrillatory arrest in conjunction with low-flow cardiopulmonary bypass allowed us to repair the mitral valve successfully.