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The abundant in neuroepithelium area (ana) gene was originally identified as a member of the tob/btg family of antiproliferative genes. Like the other family members, Ana inhibits growth of NIH3T3 cells when overexpressed. However, whether or not Ana is involved in tumor progression has been elusive. Here, we show that expression of ana is relatively high in the lung, the expression being restricted in type II alveolar epithelial cells. We further show that ana expression is reduced in 97% of the human lung cancer cell lines examined (61/63) and 86% of clinical samples from lung adenocarcinoma patients (36/42). Long-term observation of ana-deficient (ana−/–) mice reveals that 8% of them develop lung tumors (5/66) by 21 months after birth, while 0% of wild-type mice (0/35) develop the same type of tumors. We also show that exogenously expressed ana gene product suppresses the levels of matrix metalloproteinase-2 (MMP-2) and plasminogen activator inhibitor-1 (PAI-1) expression in lung cancer cells. Taken together, we propose that ana functions as a tumor suppressor and that its product inhibits tumor progression as well by suppressing angiogenesis, invasion, and metastasis.

We report successful real-time three-channel self-mixing laser-Doppler measurements with extreme optical sensitivity using a laser-diode-pumped thin-slice Nd:GdVO(4) laser in the carrier-frequency-division-multiplexing scheme with three pairs of acoustic optical modulators (i.e., frequency shifters) and a three-channel FM-wave demodulation circuit. We demonstrate (1) simultaneous independent measurement of three different nanometer-vibrating targets, (2) simultaneous measurements of small particles in Brownian motion from three directions, and (3) identification of the velocity vector of small particles moving in water flowing in a small-diameter glass pipe.

Recent research discovered that economic processes influence national averages of customer satisfaction. Using time-series data from Japanese and South Korean hospitals, we conducted principal component regression analyses to examine whether these findings are transferable to patient satisfaction. Our results reveal that aggregate income has a positive impact and economic expectations have a negative impact on patient satisfaction. Further analyses demonstrate that these strong economic influences make it difficult for hospital managers to use patient satisfaction scores to assess the performance impact of their customer-oriented actions. In order to improve performance evaluations based on patient surveys, we thus recommend managers to remove economic influences from time-series of patient satisfaction.

Neutral particle fluxes measured by neutral particle analyzers can provide information about the ion temperature as well as the non-Maxwellian anisotropic ion distribution tails from neutral beam injection and ion cyclotron radio frequency heating. In the case of multidirectional diagnostics employing high resolution atomic energy spectrometers, the neutral atomic flux source is not localized in contrast to pellet charge exchange or diagnostic neutral beam methods. The correct interpretation of such measurements from plasma in a complex toroidally asymmetric geometry, like that of LHD, requires careful numerical modeling of the neutral flux formation. Previously a measured neutral flux calculation scheme was developed and was used for the LHD geometry and a suitable analytic expression for ionization cross sections sigma(s)(z)(E,n(e),T(e),Z(eff)) of impurities was formulated by Janev et al. [Nucl. Fusion 29, 2125 (1989)]. In this paper, the attenuation of fast particles by impurities is incorporated into the neutral flux calculation scheme and the influence of impurities on the calculated neutral flux spectra is shown. Finally, the behavior of the calculated and experimental suprathermal particle distributions is compared for pure hydrogen and for argon impurity seeded plasmas.

A case of familial frontotemporal dementia with parkinsonism (FTDP) similar to progressive supranuclear palsy (PSP) was reported. A 58-year-old man developed personality change followed by parkinsonism and dementia. Three family members showed similar symptoms. Cerebral atrophy was marked on the anterior frontotemporal lobes. The substantia nigra, hippocampus, peri-aqueductal gray matter and pontine nucleus were affected with globose neurofibrillary tangles (NFT) and glial tangles. Argyrophilic grains were distributed in the CA1-CA2. NFT, glial tangles and argyrophilic grains expressed four-repeat microtubule-associated protein tau (MAPT). MAPT gene had no mutation. Familial occurrence of FTDP with PSP-like tauopathy is rare.

Broadband dielectric measurements for triethyleneglycol (3EG)-water mixtures with various concentrations were performed in the frequency range of 10 muHz-10 GHz and in the temperature range of 130-298 K . For each mixture, the separation of the primary (alpha) and secondary processes is observed below the crossover temperature, TC. In the case of 80-100 wt% 3EG-water mixtures, the Kohlrausch-Williams-Watts-type primary process above TC continues to the alpha process below TC, and an additional secondary process is observed in the frequency range higher than that of the alpha process below TC. On the other hand, the primary process for 65 and 70 wt% 3EG-water mixtures above TC continues to the higher-frequency secondary process below TC, and an additional alpha process appears at a frequency lower than that of the secondary process. The contribution of water to relaxation processes is discussed, to clarify the molecular mechanism of the separation behavior. The characteristic separation behavior of the relaxation processes for high-water-content 3EG-water mixtures is due to the existence of excess water, which cannot move cooperatively with solute 3EG molecules below TC.

Study Objectives: To examine the comparative effects of propofol, landiolol, and nicardipine on hemodynamic responses and bispectral index (BIS) changes to endotracheal intubation., Setting: Operating room of a university-affiliated general hospital., Patients: 27 ASA physical status I and II patients who were scheduled to undergo elective general surgical, urological, or gynecological procedures with general anesthesia., Study Design: Prospective, randomized, double-blinded study., Interventions: Patients were divided into three groups as follows: Group 1 received propofol, 1 mg/kg; Group 2 received landiolol, 0.1 mg/kg; and Group 3 received nicardipine, 1 mg. After baseline measurements were recorded, anesthesia was induced with propofol, fentanyl, and vecuronium. Patients' lungs were ventilated with 100% oxygen for 120 seconds, at which time one of one of the study drugs was administered. Laryngoscopy and tracheal intubation were performed 4 minutes after anesthetic induction., Measurements: Cardiac index (CI) and stroke volume index (SVI) were monitored continuously. Bispectral index was also monitored continuously from 5 minutes after tracheal intubation., Main Results: Heart rate values in Group 3 increased 30 seconds after intubation; this increase lasted for 1 minute after intubation. Systolic blood pressure in all three groups decreased after induction of anesthesia and before tracheal intubation, and values returned closer to baseline values 30 seconds after intubation. In the propofol group, CI and SVI decreased after administration of additional propofol, lasting for 30 seconds after intubation. The BIS values rapidly decreased after induction of anesthesia, with no intergroup differences noted in BIS values (propofol group, 39+/-7; landiolol group, 44+/-14; nicardipine group, 41+/-9). However, BIS was significantly lower in the propofol group than in the other two groups from 30 seconds to 5 minutes after intubation., Conclusions: Landiolol, 0.1 mg/kg, before intubation provides effective hemodynamic stability in the postintubation period.

Carcinogenesis in humans is thought to result from exposure to numerous environmental factors. Little is known, however, about how these different factors work in combination to cause cancer. Because thymic lymphoma is a good model of research for combined exposure, we examined the occurrence of mutations in thymic DNA following exposure of B6C3F1 gpt-delta mice to both ionizing radiation and N-ethyl-N-nitrosourea (ENU). Mice were exposed weekly to whole body X-irradiation (0.2 or 1.0 Gy), ENU (200 ppm) in the drinking water, or X-irradiation followed by ENU treatment. Thereafter, genomic DNA was prepared from the thymus and the number and types of mutations in the reporter transgene gpt was determined. ENU exposure alone increased mutant frequency by 10-fold compared to untreated controls and over 80% of mutants had expanded clonally. X-irradiation alone, at either low or high dose, unexpectedly, reduced mutant frequency. Combined exposure to 0.2 Gy X-rays with ENU dramatically decreased mutant frequency, specifically G:C to A:T and A:T to T:A mutations, compared to ENU treatment alone. In contrast, 1.0 Gy X-rays enhanced mutant frequency by about 30-fold and appeared to accelerate clonal expansion of mutated cells. In conclusion, repeated irradiation with 0.2 Gy X-rays not only reduced background mutation levels, but also suppressed ENU-induced mutations and clonal expansion. In contrast, 1.0 Gy irradiation in combination with ENU accelerated clonal expansion of mutated cells. These results indicate that the mode of the combined mutagenic effect is dose dependent.

Anxiety has been shown to be associated with cardiovascular disease. Atherosclerosis is responsible for the vast majority of cardiovascular events. Recent evidence is accumulating to show that insulin resistance (IR) plays a central role in determining the clinical manifestations of established atherosclerotic lesions. The current preliminary study aimed to investigate the associations between trait anxiety, IR, and atherosclerotic progression in healthy elderly subjects with normal fasting glucose and without metabolic syndrome. Thirty-five healthy elderly subjects (19 males and 16 females, mean age 64.5+/-4.7 years) were enrolled in this study. Trait anxiety was measured using a questionnaire corresponding to the trait anxiety scale taken from the State and Trait Anxiety Inventory. The homeostasis model assessment (HOMA-R) and plasma leptin-to-adiponectin ratio (L/A ratio), which are convenient IR indexes calculated from fasting blood sampling, were examined. As measurements of atherosclerotic progression, we performed two ultrasound methods, namely brachial artery flow-mediated dilation (FMD), an endothelial function assessment quantitatively reflecting the endothelium-dependent vasodilation responses following hyperemia, and measurement of carotid intima-media thickness (IMT). The severity of trait anxiety was positively associated with HOMA-R and L/A ratio, and negatively associated with the percent change of brachial artery FMD (%FMD). HOMA-R and L/A ratio were positively associated with carotid IMT, and L/A ratio was negatively associated with %FMD. These data showed the associations between trait anxiety, IR indexes and endothelial dysfunction or atherosclerotic progression. This pilot study, with a cross-sectional design, supports the promising role of IR for clarifying the pathophysiological mechanism by which anxiety contributes to an increasing risk of atherosclerosis.

Adiponectin is an adipocyte-specific secretory protein that circulates in serum as three oligomeric complexes known as the high, medium and low molecular weight form (HMW, MMW and LMW). HMW adiponectin has been suggested to be a better predictor of metabolic variables, and it was recently reported that the ratio of HMW to total adiponectin or to LMW, not the absolute amount of plasma adiponectin, might be crucial in determining insulin sensitivity. Insulin resistance (IR) is considered to be a primary component of vascular risk factors. Although the association of depression with atherosclerotic vascular diseases has been well documented, the contribution of IR to the evolution and progression of depression-associated vascular morbidity and mortality remains unknown. The current preliminary study showed that the ratio of HMW to total adiponectin or to LMW, not the absolute amount of plasma adiponectin, was negatively associated with depression severity in healthy elderly subjects without metabolic syndrome. This pilot study supports a promising role of adiponectin multimer distribution for clarifying the pathophysiological mechanism by which depression is associated with increased risk for IR, leading to cardiovascular disease, metabolic syndrome or type 2 diabetes.

To understand which soil chemical properties are the best predictors of CH4 production in rice paddy soils, a model was developed with empirical data from nine types of rice soils collected around Japan and anaerobically incubated at 30 degrees C for 16 wk in laboratory conditions. After 1, 2, 4, 8, and 16 wk of incubation, CO2, CH4, and Fe(II) were measured to understand soil organic matter decomposition and iron (Fe) reduction. Available N (N ava) was also measured at the end of incubation. The results showed that decomposable C and reducible Fe are two key parameters that regulate soil CH(4) production (P CH4). There was a significant relationship between decomposable C and available N (N ava) (r2 = 0.975**). Except for a sandy soil sample, a significant relationship between total Fe (Fe total) and reducible Fe was found. From this experiment, a simple model of soil CH4 production was developed: P CH4 = 1.593N(ava) - 2.460Fe total/1000 (each unit was mg kg(-1) soil). After simulated CH4 production by two soil chemical properties as above, there was a significant consistency between model simulation and actual measurement (r2 = 0.831**).

We describe a highly sensitive, real-time method of detecting small particles in a fluid flow by self-mixing laser Doppler measurement with a laser-diode-pumped, thin-slice solid-state laser with extremely high optical sensitivity. Asymmetric power spectra of the laser output modulated by the re-injected scattered light from the small particles moving in a dilute sample-flow, through a small-diameter glass pipe, were observed. The observed power spectra are shown to reflect the velocity distribution of the fluid flow, which obeys Poiseuille's law. Quick measurements of flow rate and kinetic viscosities of water-glycerol mixtures were also performed successfully. Measurable low-concentration limits for 262-nm polystyrene latex spheres and 3-mum red blood cells in a fluid flow were below 1 and 10 ppm, respectively, in the present self-mixing laser Doppler velocimeter system.

Complex permittivity has been determined for mixtures of ethyleneglycol-1,4-dioxane (EG-DX) with various concentrations in the frequency range from 100 MHz to 30 GHz at 25 degrees C by time domain reflectometry (TDR). A primary process with an asymmetric shape and a Debye-type small-amplitude high-frequency process are observed for each mixture. The deviation of the relaxation time for the primary process from that of the ideal mixture shows a maximum value at a mole fraction of 1,4-dioxane, xDX approximately =0.8. The static permittivity for the mixtures can be explained using the Luzar model by assuming the formation of two types of hydrogen-bonded dimers, one between EG-EG (pair 1) and the other between EG-DX (pair 2). The number of these pairs is also estimated as a function of concentration. These results of the relaxation time and static permittivity are interpreted on the basis of a model of two kinds of cooperative domains coexisting in the mixtures.

14-3-3 proteins play roles in phosphorylation of tau proteins in neurofibrillary tangles (NFT) in Alzheimer's disease (AD). Tau is phosphorylated at serine (pSer) and threonine (pThr) in NFT, and NFT morphology varies according to phosphorylated sites and tau isoform. The roles of 14-3-3 proteins in NFT morphology remain unknown. This study was performed to examine the relationships between 14 and 3-3 proteins and tau phosphorylation of NFT. NFT were labeled with Gallyas impregnation, tau and 14-3-3 immunohistochemistry in paraffin-embedded hippocampal sections from seven AD and three control brains. Anti-tau antisera included monoclonal antisera that recognize pSer262 (pSer262), pSer422 (pSer422), pSer202/pThr205 (AT8), Thr231 (AT180), three-repeat (RD3) and four-repeat (RD4) tau isoform. Anti-14-3-3 protein isoform antisera included polyclonal antisera to beta, gamma, zeta, epsilon, tau, mu and sigma isoforms and monoclonal antiserum to beta antiserum (H8-beta). NFT density was obtained by counting labeled NFT in cornu ammonis (CA) 1-CA4, subiculum and entorhinal cortex. H8-beta and zeta isoforms were strongly expressed in NFT. Regional densities of NFT positive for pSer262, AT8, AT180, and Gallyas impregnation were similar to RD3-positive NFT density with high densities in CA1 and entorhinal cortex. NFT positive for pSer422 showed a similar regional distribution to RD4-positive NFT with high NFT density in CA2-CA4. H8-beta-positive NFT showed a similar regional distribution to RD3-positive NFT. In contrast, zeta isoform-positive NFT showed no specific distribution. In conclusion, H8-beta isoform is associated with development of 3-repeats NFT but a role of 14-3-3 zeta isoform in NFT could not be specified.

The relaxin and insulin-like peptide 3 receptors, LGR7 and LGR8, respectively, are unique members of the leucine-rich repeat-containing G-protein-coupled receptor (LGR) family, because they possess an N-terminal motif with homology to the low density lipoprotein class A (LDLa) modules. By characterizing several LGR7 and LGR8 splice variants, we have revealed that the LDLa module directs ligand-activated cAMP signaling. The LGR8-short variant encodes an LGR8 receptor lacking the LDLa module, whereas LGR7-truncate, LGR7-truncate-2, and LGR7-truncate-3 all encode truncated secreted proteins retaining the LGR7 LDLa module. LGR8-short and an engineered LGR7 variant missing its LDLa module, LGR7-short, bound to their respective ligands with high affinity but lost their ability to signal via stimulation of intracellular cAMP accumulation. Conversely, secreted LGR7-truncate protein with the LDLa module was able to block relaxin-induced LGR7 cAMP signaling and did so without compromising the ability of LGR7 to bind to relaxin or be expressed on the cell membrane. Although the LDLa module of LGR7 was N-glycosylated at position Asn-14, an LGR7 N14Q mutant retained relaxin binding affinity and cAMP signaling, implying that glycosylation is not essential for optimal LDLa function. Using real-time PCR, the expression of mouse LGR7-truncate was detected to be high in, and specific to, the uterus of pregnant mice. The differential expression and evolutionary conservation of LGR7-truncate further suggests that it may also play an important role in vivo. This study highlights the essential role of the LDLa module in LGR7 and LGR8 function and introduces a novel model of GPCR regulation.

Human chorionic gonadotropin (HCG) is the glycoprotein hormone in pregnancy. It is known that hCG molecule has a variety of isoforms showing different potency in bioactivity. Taking advantage of rat Leydig cell assay to evaluate hCG bioactivity, we first tried to predict the prognosis of pregnancy in hormone replacement (HR)-cryopreserved embryo transfer cycles. There was no significant difference in serum estradiol (E2) level, immuno-hCG, or bioactive to immunoreactive hCG ratio (b/i) between normal pregnancies and miscarriages at 4 weeks of gestation. Linear regression did not show a significant correlation in E2 or b/i between normal pregnancies and miscarriages. The same analysis was performed on serum samples collected from spontaneously pregnant patients. In normal pregnancies b/i was significantly lower than that in miscarriages while serum E2 was significantly higher. The linear regression analysis was also performed to clarify the correlation between E2 and b/i, and no significant correlation was observed. To confirm the effect of E2 on hCG production, we treated trophoblastic cells with E2. E2 increased the immunoreactivity of hCG to a non-physiologically high concentration; however, it did not change its bioactivity, suggesting that E2 did not change hCG bioactivity by affecting trophoblasts directly. In this study, we presumed it possible to speculate the prognosis of the pregnancy in spontaneous cycles from b/i of hCG, but not in HR cycles. It is suggested that process of hCG secretion could undergo different endocrine regulations between the artificial sex steroid replacement cycles and spontaneous cycles with corpus luteum function.

Broadband dielectric measurements for blends of poly(vinyl pyrrolidone) (PVP) and ethylene glycol oligomer (EGO) from 0 to 40 wt % PVP were carried out at 25 degrees C in the frequency range from 20 Hz to 20 GHz. The EGOs used in this study were ethylene glycol (EG), diethylene glycol (2EG), and PEG400 (MW = 400). For the PVP-EG, -2EG, and -PEG400 blends, relaxation processes caused by the motion of EGO in the GHz range and the micro-Brownian motion of the PVP chain at 10 kHz-1 MHz were observed. Although the PVP-EGO blend is miscible, relaxation processes caused by the molecular motion of EGO and the local chain motion of PVP were observed individually. The relaxation time of the local chain motion of PVP showed a strong PVP concentration dependence and a solvent viscosity dependence, which are similar to those reported so far for the solutions in nonpolar solvents.

We performed broadband dielectric measurements of a polyethyleneglycol-water mixture in the frequency range between 10 GHz and 1 microHz and the temperature range between 300 and 133 K. One relaxation process is observed throughout the whole temperature range. The temperature dependence of the relaxation time clearly obeys the Vogel-Fulcher law above 183 K, and the Arrhenius law below 183 K. This observed relaxation process is the secondary process, and the primary process related to the glass transition is masked by the low-frequency ionic contribution below 183 K. The glass transition concerned with the masked primary process leads to the Vogel-Fulcher to Arrhenius transition of the secondary process.

Background/aims: Mannose-binding lectin (MBL) is characteristic of an acute-phase-reacting protein like C-reactive protein (CRP). However, the prognostic value of the serum MBL level has not been examined. The aim of this study was to evaluate whether the serum MBL level can predict all-cause mortality in hemodialysis (HD) patients., Methods: A total of 131 patients without active infection, who had been on maintenance HD for at least 2 years, were included in this study. The serum MBL, high-sensitivity CRP (hs-CRP) level, nutrition markers, and biochemical parameters were measured in June 1999. The cohort was then followed prospectively for 36 months, and clinical data were recorded., Results: The MBL level of the 131 HD patients was 9.054 +/- 5.115 microg/ml (mean +/- SD). During the follow-up period, 18 patients (9 males and 9 females) died and 113 (64 males and 49 females) survived. The two leading causes of death were cardiovascular events (n = 6, 33.3%) and infection (n = 4, 22.2%). The serum MBL level was significantly lower among the nonsurvivors (6.596 +/- 4.990 microg/ml) than among the survivors (9.445 +/- 5.046 microg/ml; p < 0.05). There was a significant, although very weak, correlation between the MBL level and albumin level (p < 0.05), but there was no correlationbetween the MBL level and the hs-CRP level. The patients were divided into two groups according to the serum MBL level (< 5 and > 5 microg/ml). Multivariate analysis of factors predicting all-cause mortality in multivariate logistic regression analysis identified a serum MBL level < 5 microg/ml as a variable that independently predicted all-cause mortality (adjusted odds ratio: 7.632; 95% CI: 2.244-25.961; p = 0.0011). Other significant and independent predictors for mortality included the hs-CRP level (every 100 microg/dl increase), hypertension and diabetes mellitus., Conclusions: Our findings suggest that the serum MBL level is a significant predictor of outcome in HD patients. HD patients with a low level of serum MBL should be carefully monitored.

There are more than 30 human transforming growth factor beta/bone morphogenetic protein/growth differentiation factor (TGFbeta/BMP/GDF)-related ligands known to be important during embryonic development, organogenesis, bone formation, reproduction, and other physiological processes. Although select TGFbeta/BMP/GDF proteins were found to interact with type II and type I serine/threonine receptors to activate downstream Smad and other proteins, the receptors and signaling pathways for one-third of these TGFbeta/BMP/GDF paralogs are still unclear. Based on a genomic analysis of the entire repertoire of TGFbeta/BMP/GDF ligands and serine/threonine kinase receptors, we tested the ability of three orphan BMP/GDF ligands to activate a limited number of phylogenetically related receptors. We characterized the dimeric nature of recombinant GDF6 (also known as BMP13), GDF7 (also known as BMP12), and BMP10. We demonstrated their bioactivities based on the activation of Smad1/5/8-, but not Smad2/3-, responsive promoter constructs in the MC3T3 cell line. Furthermore, we showed their ability to induce the phosphorylation of Smad1, but not Smad2, in these cells. In COS7 cells transfected with the seven known type I receptors, overexpression of ALK3 or ALK6 conferred ligand signaling by GDF6, GDF7, and BMP10. In contrast, transfection of MC3T3 cells with ALK3 small hairpin RNA suppressed Smad signaling induced by all three ligands. Based on the coevolution of ligands and receptors, we also tested the role of BMPRII and ActRIIA as the type II receptor candidates for the three orphan ligands. We found that transfection of small hairpin RNA for BMPRII and ActRIIA in MC3T3 cells suppressed the signaling of GDF6, GDF7, and BMP10. Thus, the present approach provides a genomic paradigm for matching paralogous polypeptide ligands with a limited number of evolutionarily related receptors capable of activating specific downstream Smad proteins.

Glycoprotein hormones play important roles in thyroid and gonadal function in vertebrates. The glycoprotein hormone alpha-subunit forms heterodimers with different beta-subunits to activate TSH or gonadotropin (LH and FSH) receptors. Recent genomic analyses allowed the identification of another alpha-subunit, GPA2, and another beta-subunit, GPB5, in human, capable of forming heterodimers to activate TSH receptors. Based on comparative genomic searches, we isolated the fly orthologs for human GPA2 and GPB5, each consisting of 10 cysteine residues likely involved in cystine-knot formation. RT-PCR analyses in Drosophila melanogaster demonstrated the expression of GPA2 and GPB5 at different developmental stages. Immunoblot analyses further showed that fly GPA2 and GPB5 subunit proteins are of approximately 16 kDa, and coexpression of these subunits yielded heterodimers. Purified recombinant fly GPA2/GPB5 heterodimers were found to be glycoproteins with N-linked glycosylated alpha-subunits and nonglycosylated beta-subunits, capable of stimulating cAMP production mediated by fly orphan receptor DLGR1 but not DLGR2. Although the fly GPA2/GPB5 heterodimers did not activate human TSH or gonadotropin receptors, chimeric fly GPA2/human GPB5 heterodimers stimulated human TSH receptors. These findings indicated that fly GPA2/GPB5 is a ligand for DLGR1, thus showing the ancient origin of this glycoprotein hormone-seven transmembrane receptor-G protein signaling system. The fly GPA2 also could form heterodimers with human GPB5 to activate human TSH receptors, indicating the evolutionary conservation of these genes and suggesting that the GPA2 subunit may serve as a scaffold for the beta-subunit to activate downstream G protein-mediated signaling.

This study reports correlation of the hippocampal neurofibrillary tangles (NFT) density with beta-amyloid (Abeta) precursor protein (APP) 717 mutation, presenilin (PS)-1 mutation and apolipoprotein E (Apo-E) e4 alleles (E4), being graded as 3 forms (no-E4, one-E4 and two-E4) in autopsied brains from patients with familial and non-familial Alzheimer's disease (AD). We studied the density of NFT-free neurons, intracellular NFT (I-NFT), extracellular NFT (E-NFT) and total NFT (I-NFT plus E-NFT) in the six hippocampal subdivisions: cornu ammonis (CA) 1-CA4, subiculum and entorhinal cortex. The APP mutation cases showed significantly higher total NFT density in the CA1-CA2 region, and the PS-1 mutation cases also showed higher density of total NFT in the CA1-CA3 than non-familial cases. Moreover, high densities of the E-NFT contributed to these high total NFT densities. Non-familial AD cases showed a stereotypical NFT distribution with entorhinal accentuation in the hippocampus irrespective of E4 frequency. Thus, APP and PS-1 mutations predominantly affect the CA regions with profound neurodegeneration, which contributes early and severe clinical features of familial AD.

Because of the coevolution of ligands and their cognate receptors, analysis of human genomic sequences allows prediction of the pairing of these elements. Initially, we identified a group of five human leucine-rich repeat-containing G-protein-coupled receptor (LGR) genes homologous to LH, FSH, and TSH receptors. Based on common phenotypes of INSL3 null mice and transgenic mice with LGR8 gene deletion, we hypothesized that INSL3, relaxin, and related genes are likely ligands for the paralogous LGR7 and LGR8 genes. Matching the relaxin family peptides with these two orphan LGRs led to the finding that relaxin is capable of activating LGR7 and LGR8 through the Gs pathway. In addition, INSL3 and relaxin 3 were found to be specific ligands for LGR8 and LGR7, respectively. Based on the known production of INLS3 by testicular Leydig cells and ovarian theca cells, we demonstrated the expression of the INSL3 receptor LGR8 in oocytes in ovary and in male germ cells in the testis. Furthermore, we found that LH stimulates INSL3 transcripts in ovarian theca and testicular Leydig cells. INSL3, in turn, binds LGR8 expressed in germ cells to initiate the meiotic progression of arrested oocytes in preovulatory follicles in vitro and in vivo and to suppress male germ cell apoptosis in vivo. INSL3 interacts with germ cells to activate the inhibitory G protein, thus leading to decreases in cAMP production. Our data demonstrate the importance of the INSL3-LGR8 paracrine system in mediating gonadotropic actions in both ovary and testis.

Relaxin family peptide 1 (RXFP1) receptor (LGR7) and RXFP2 receptor (LGR8) were recently identified as the receptor targets for H2 relaxin and insulin-like peptide 3 (INSL3), respectively. In this study, we define the pharmacology of these two receptors by using a number of receptor chimeras and relaxin family peptides. We have identified two binding sites on these receptors: one primary, high-affinity site within the ectodomain and a secondary, lower affinity site within the transmembrane region. The primary site was found to dictate receptor binding characteristics, although the lower affinity site also exerts some influence and modulates ligand affinity for the primary site in a manner dependent upon the peptide in question. Not all relaxin peptides were able to bind to the RXFP2 receptor, indicating that the relaxin-RXFP2 receptor interaction is species-specific. INSL3 was found to exhibit characteristics of a partial agonist at the RXFP2 and chimeric RXFP1/2 receptors, with low maximal cAMP responses but high potency in coupling to this pathway. cAMP accumulation studies also revealed that the binding sites couple to cAMP signaling pathways with differing efficiency: the high-affinity site signals with high efficiency, whereas the lower affinity site signals with little to no efficiency. Comparisons between RXFP1, RXFP2, the chimeric receptors, and the truncated receptors revealed that the interaction between receptor sites is critical for optimal ligand binding and signal transduction and that the ectodomain is essential for signaling. Evidence obtained in this study supports a two-stage binding model of receptor activation: binding to the primary site allows a conformational change and interaction with the low-affinity transmembrane site.

The ectodomains of both the relaxin (LGR7) and the INSL3 (LGR8) receptors can be expressed on the cell surface using only a single transmembrane domain. These membrane-anchored proteins retain the ability to bind relaxin and can be cleaved from the cell surface. The subsequent LGR7 protein, 7BP, binds relaxin and can act as a functional relaxin antagonist. By contrast, the equivalent LGR8 protein 8BP does not bind relaxin or antagonize LGR8 activity. The 7BP protein has been successfully immobilized onto chemically derivatized surfaces for the capture of relaxin peptides and subsequent identification via SELDI-MS analysis.

This study defines the pharmacologic characteristics of LGR7 and LGR8, the receptors for H2 relaxin and INSL3 respectively, and determines the relative activity of relaxin-related peptides. We show, for the first time, the availability of two binding sites at LGR8 and confirm the presence of two sites at LGR7. Relaxin-related peptides had differing rank orders of affinity and potency at LGR7 and LGR8, but chimeric receptors were highly similar to their ectodomain-origin native receptors. The high-affinity site on the ectodomain coupled efficiently to cAMP production, whereas the low-affinity site in the transmembrane region coupled with decreased efficiency.

We demonstrate real-time two-channel self-mixing laser-Doppler measurement with extreme optical sensitivity using a laser-diode-pumped thin-slice LiNdP4O12 laser. Successful carrier-frequency-division-multiplexed two-channel operations are realized by using one laser, two sets of optical frequency shifters, and a two-channel frequency-modulated-wave demodulation circuit. Simultaneous independent measurements of vibrations of speakers and averaged motions of small Brownian particles in different scattering cells are demonstrated. Self-mixing photon correlation spectroscopy of particle size distributions is also discussed.

All arthropods periodically molt to replace their exoskeleton (cuticle). Immediately after shedding the old cuticle, the neurohormone bursicon causes the hardening and darkening of the new cuticle. Here we show that bursicon, to our knowledge the first heterodimeric cystine knot hormone found in insects, consists of two proteins encoded by the genes burs and pburs (partner of burs). The pburs/burs heterodimer from Drosophila melanogaster binds with high affinity and specificity to activate the G protein-coupled receptor DLGR2, leading to the stimulation of cAMP signaling in vitro and tanning in neck-ligated blowflies. Native bursicon from Periplaneta americana is also a heterodimer. In D. melanogaster the levels of pburs, burs, and DLGR2 transcripts are increased before ecdysis, consistent with their role in postecdysial cuticle changes. Immunohistochemical analyses in diverse insect species revealed the colocalization of pburs- and burs-immunoreactivity in some of the neurosecretory neurons that also express crustacean cardioactive peptide. Forty-three years after its initial description, the elucidation of the molecular identity of bursicon and the verification of its receptor allow for studies of bursicon actions in regulating cuticle tanning, wing expansion, and as yet unknown functions. Because bursicon subunit genes are homologous to the vertebrate bone morphogenetic protein antagonists, our findings also facilitate investigation on the function of these proteins during vertebrate development.

A 47-year old man presented with atrial fibrillation, weight loss, hand tremor, and hyperperspiration concurrent with the reactivation of the disease activity of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated glomerulonephritis. Laboratory findings indicated that the hyperthyroidism had already existed when glomerulonephritis was detected, and Graves' disease became evident while decreasing the dose of prednisolone. Although the levels of thyroid-stimulating hormone receptor antibody, antithyroid peroxidase antibody, and myeloperoxidase antibody increased, both disease activities were suppressed by increasing the dose of prednisolone. This case indicates that MPO-ANCA-associated glomerulonephritis and Graves' disease may share a common pathogenesis.

Broadband dielectric measurements for 65 wt % ethylene glycol oligomer (EGO)-water mixtures with one to six repeat units of EGO molecules were performed in the frequency range of 10 microHz-10 GHz and the temperature range of 128-298 K. In the case of the water-EGO mixtures with one and two repeat units of the EGO molecule (small EGO), the shape of the dielectric loss peak of the primary process is asymmetrical about the logarithm of the frequency of maximum loss above the crossover temperature, T(C). The asymmetric process continues to the alpha process at a low frequency, and an additional beta process appears in the frequency range higher than that of the alpha process below T(C). In contrast, the water-EGO mixtures with three or more repeat units of the EGO molecule (large EGO) show a broad and symmetrical loss peak of the primary process above T(C). The symmetric process continues to the beta process, and an additional alpha process appears in the frequency range lower than that of the beta process below T(C). These different scenarios of the alpha-beta separation related to the shape of the loss peak above T(C) are a result of the difference in the cooperative motion of water and solute molecules. The solute and water molecules move cooperatively in the small EGO-water mixtures above T(C), and this cooperative motion leads to the asymmetric loss peak above T(C) and the alpha process below T(C). For the large EGO-water mixtures, the spatially restricted motion of water confined by solute molecules leads to the symmetric loss peak above T(C) and the beta process below T(C).

Leucine-rich repeat-containing, G protein-coupled receptors (LGRs) belong to the largest mammalian superfamily of proteins with seven-transmembrane domains. LGRs can be divided into three subgroups based on their unique domain arrangement. Although two subgroups have been found to be receptors for glycoprotein hormones and relaxin-related ligands, respectively, the third LGR subgroup, consisting of LGR4-6, are orphan receptors with unknown physiological roles. To elucidate the functions of this subgroup of LGRs, LGR4 null mice were generated using a secretory trap approach to delete the majority of the LGR4 gene after the insertion of a beta-galactosidase reporter gene immediately after exon 1. Tissues expressing LGR4 were analyzed based on histochemical staining of the transgene driven by the endogenous LGR4 promoter. LGR4 was widely expressed in kidney, adrenal gland, stomach, intestine, heart, bone/cartilage, and other tissues. The expression of LGR4 in these tissues was further confirmed by immunohistochemical studies in wild-type animals. Analysis of the viability of 250 newborn animals suggested a skewed inheritance pattern, indicating that only 40% of the expected LGR4 null mice were born. For the LGR4 null mice viable at birth, most of them died within 2 d. Furthermore, the LGR4 null mice showed intrauterine growth retardation as reflected by a 14% decrease in body weight at birth, together with 30% and 40% decreases in kidney and liver weights, respectively. The present findings demonstrate the widespread expression of LGR4, and an essential role of LGR4 for embryonic growth, as well as kidney and liver development. The observed pre- and postnatal lethality of LGR4 null mice illustrates the importance of the LGR4 signaling system for the survival and growth of animals during the perinatal stage.

Topical application of mustard oil (allyl isothiocyanate) to the skin or injection into joints induces hyperalgesia, allodynia, and neuroinflammation. However, when applied to the oral or nasal mucosa, mustard oil evokes a desensitizing pattern of irritation. Presently we investigated the responses of neurons in superficial laminae of trigeminal subnucleus caudalis (Vc) to noxious thermal (53 degrees C) and chemical (pentanoic acid; 200 mM) stimuli prior to and following lingual mustard oil application. A low concentration of mustard oil (0.125%) applied by constant flow (0.5 ml/min; 15 min), initially excited Vc neurons followed by partial desensitization. Responses to noxious heat were unchanged following mustard oil. A high concentration of mustard oil (1.25%) initially excited Vc neurons followed quickly (within 20 s) by nearly complete desensitization. The desensitization was transient since reapplication of mustard oil approximately 20 min later elicited a comparable response that also rapidly desensitized. Mustard oil also transiently cross-desensitized Vc responses to pentanoic acid (to 52%), in striking contrast to noxious heat-evoked responses which were significantly sensitized to approximately 160% of pre-mustard oil levels. The data suggest that the effect of mustard oil on subsequent lingual nociceptive responses is concentration dependent, transient, and modality specific.

Background: The level of complement receptor type 1 (CR1) on erythrocytes (E-CR1) is determined by the presence of high (H) or low (L) expression alleles. We investigated whether acquired loss of E-CR1 occurs in haemodialysis patients and, if so, which factors may contribute to acquired loss of E-CR1 in these patients., Methods: The E-CR1 level was determined in 195 Japanese haemodialysis patients, and we selected patients with a high or low E-CR1 level. In patients with low E-CR1 expression, sequence analysis of polymorphic sites (A3650G and C5507G) in the CR1 gene was performed. To assess the effect of the type of dialysis membrane used in the patients with low E-CR1 expression, the dialysis membrane was changed from a cellulose membrane to a biocompatible membrane (to a polyacrylonitrile membrane and then to a polysulfone membrane). To evaluate the susceptibility of E-CR1 to proteolysis, erythrocytes were incubated with various concentrations of trypsin, and the level of remaining CR1 on the erythrocytes was determined., Results: Among patients with high E-CR1 expression (n = 30), 87% had HH alleles and 13% had HL alleles. Among patients with low E-CR1 expression (n = 29), 24% had LL alleles, 45% had HL alleles and 31% had HH alleles. Nucleotides 3650G and 5507G in the CR1 gene were associated with the L allele. Nucleotides 3650A and 5507C were associated with the H allele. Only one patient with HH alleles had nucleotides 3650G and 5507C. Three months after changing the haemodialysis membrane, the E-CR1 level significantly increased (P<0.02). The proteolysis curves of E-CR1 of patients with low or high E-CR1 expression and normal controls were similar., Conclusion: Use of a non-biocompatible dialysis membrane may contribute to acquired loss of E-CR1 in haemodialysis patients.

Bone morphogenetic proteins (BMPs) are important for body patterning and morphogenesis, whereas several BMP antagonists regulate the functions of BMPs during embryonic development and tissue differentiation. Protein related to DAN and cerberus (PRDC) is a secreted protein with a cystine knot structure identified by gene trapping in embryonic stem cells. Although PRDC shows sequence homology with proteins of the BMP antagonist family, its biological activity and physiological functions are unclear. We generated recombinant PRDC and its paralog, gremlin, and tested their ability to suppress actions initiated by diverse BMP proteins. Similar to the known BMP antagonist, gremlin, PRDC blocked ligand signaling induced by BMP2 and BMP4 but had minimal effects on reporter gene activation induced by GDF-9, activin, or transforming growth factor-beta. Co-precipitation assays further demonstrated the direct protein-protein interactions between PRDC and BMP2 or BMP4. Reverse transcriptase-PCR analyses indicated that PRDC transcripts are widely expressed showing higher levels in ovary, brain, and spleen. In mouse ovary, PRDC transcripts were increased following gonadotropin treatment. In situ hybridization analyses further indicated that ovarian PRDC transcripts are localized in granulosa cells of selective follicles. In addition, co-treatment with PRDC antagonized the inhibitory effects of BMP4 on the follicle-stimulating hormone stimulation of progesterone production by cultured rat granulosa cells. Thus, PRDC is a potent BMP antagonist with a wide tissue expression pattern, and ovarian PRDC expressed in granulosa cells could be involved in follicular development by antagonizing the actions of theca cell-derived BMPs.

Mammalian oocytes are arrested at the prophase of meiosis before induction of maturation by the preovulatory luteinizing hormone (LH) surge. LH also promotes the survival of meiotic male germ cells in the testis. Because LH binds somatic cells, the mechanism underlying its regulation of germ cell function is unclear. We found that LH stimulates Leydig insulin-like 3 (INSL3) transcripts in ovarian theca and testicular Leydig cells. INSL3, in turn, binds a G protein-coupled receptor, LGR8 (leucine-rich repeat-containing G protein-coupled receptor 8), expressed in germ cells to activate the inhibitory G protein, thus leading to decreases in cAMP production. Treatment with INSL3 initiates meiotic progression of arrested oocytes in preovulatory follicles in vitro and in vivo and suppresses male germ cell apoptosis in vivo, thus demonstrating the importance of the INSL3-LGR8 paracrine system in mediating gonadotropin actions.

Evidence for a reduction of heat transport inside the magnetic island O point is observed from the propagation of a cold pulse produced by a tracer encapsulated solid pellet in the Large Helical Device. A small peak and slow propagation of the cold pulse are observed inside the island. A significant result is that electron heat diffusivity inside the island is estimated to be 0.2 m(2)/s which is smaller than that outside the island by an order of magnitude.

We investigated the role of neuronal nicotinic acetylcholine receptors (nAChRs) in nicotine cross-desensitization of chemonociceptive responses of trigeminal subnucleus caudalis (Vc) neurons in rats. Vc responses to lingually applied pentanoic acid were significantly reduced following nicotine, and this was prevented when the nAChR antagonist mecamylamine was applied before or after nicotine. A peripheral site of nicotine cross-desensitization is suggested via a nAChR-mediated reduction in acidic excitation of lingual nociceptors that project to Vc.

Cryptorchidism is the most frequent congenital anomaly of the urogenital tract in the male. Although in Western countries 1-2% of males at the age of 3 months are diagnosed with this condition, its aetiology is still unknown. Animal models suggest a possible genetic basis for this disorder. Recently, the INSL3 (Leydig insulin-like peptide) gene and its cognate receptor, LGR8, were found to be important in testicular descent by regulating gubernacular development. Male mice null for either INSL3 or LGR8 genes exhibited bilateral cryptorchidism. Because earlier studies indicated that mutation of the INSL3 gene is not associated with the development of human cryptorchidism, this study analysed whether mutations in the LGR8 gene could be associated with this disorder. Sequencing of 18 exons of the LGR8 gene in 23 cryptorchid Finnish patients and a group of 33 control subjects allowed the identification of three nucleotide changes in exons 12 and 17, showing single base substitutions from A to G at positions 957, 993, and 1810 of LGR8. Among the three changes, only the 1810 A to G substitution is associated with an amino acid change from isoleucine to valine (Ile604Val) located in the fifth transmembrane domain of this seven-transmembrane receptor. This change was more frequent in a control group of normal fertile adult males and infant boys than in the group of cryptorchid males. The change is not associated with altered receptor signalling, thus suggesting the presence of a polymorphism unrelated to the cryptorchid phenotype. These data indicate that mutations involving the human LGR8 gene do not represent a frequent cause of cryptorchidism in the Finnish population.

Sawtooth oscillations have been observed in current-carrying helical plasmas by using electron-cyclotron-emission diagnostics in the Large Helical Device. The plasma current, which is driven by neutral beam injection, reduces the beta threshold of the sawtooth oscillation. When the central q value is increased due to the plasma current, the core region crashes, and, when it is decreased, the edge region crashes annularly. Observed rapid mixture of the plasma in the limited region suggests that these sawtooth crashes are reconnection phenomena. Unlike previous experiments, no precursor oscillation has been observed.

We investigated the possible role of amiloride-sensitive ion channels of the ENaC/DEGenerin superfamily in the activation of trigeminal nociceptive neurons elicited by noxious chemical stimulation of the oral mucosa using two methodologies, single-unit recording and c-fos immunohistochemistry. In pentobarbital-anesthetized rats, single-unit recordings were made from neurons in superficial laminae of dorsomedial trigeminal subnucleus caudalis (Vc) that responded to noxious thermal and chemical stimuli applied to the dorsal tongue. Successive application of each of three chemicals (250 mM pentanoic acid, n=6 units; 250 mM citric acid, n=8; 5 M NaCl, n=6) evoked responses that were not affected following topical application of amiloride (1 mM). In separate experiments, pentobarbital-anesthetized rats received one of the following stimuli delivered to the dorsal tongue: 250 mM pentanoic acid (n=6); 1 mM amiloride followed by 250 mM pentanoic (N=6); 5 M NaCl (n=5); or 1 mM amiloride followed by 5 M NaCl (n=5). Two hours later they were perfused with 4% paraformaldehyde and the brain stems processed for c-fos immunoreactivity. Both pentanoic acid and 5 M NaCl evoked similar numbers and patterns of fos-like immunoreactivity (FLI) in dorsomedial Vc and other brain stem regions, with no significant difference in counts of FLI in animals pretreated with amiloride. These results suggest that amiloride-sensitive Na(+) channels are not essential in mediating the activation of intraoral trigeminal nociceptors.

Leucine-rich repeat-containing, G protein-coupled receptors (LGRs) represent a unique subgroup of G protein-coupled receptors with a large ectodomain. Recent studies demonstrated that relaxin activates two orphan LGRs, LGR7 and LGR8, whereas INSL3/Leydig insulin-like peptide specifically activates LGR8. Human relaxin 3 (H3 relaxin) was recently discovered as a novel ligand for relaxin receptors. Here, we demonstrate that H3 relaxin activates LGR7 but not LGR8. Taking advantage of the overlapping specificity of these three ligands for the two related LGRs, chimeric receptors were generated to elucidate the mechanism of ligand activation of LGR7. Chimeric receptor LGR7/8 with the ectodomain from LGR7 but the transmembrane region from LGR8 maintains responsiveness to relaxin but was less responsive to H3 relaxin based on ligand stimulation of cAMP production. The decreased ligand signaling was accompanied by decreases in the ability of H3 relaxin to compete for (33)P-relaxin binding to the chimeric receptor. However, replacement of the exoloop 2, but not exoloop 1 or 3, of LGR7 to the chimeric LGR7/8 restored ligand binding and receptor-mediated cAMP production. These results suggested that activation of LGR7 by H3 relaxin involves specific binding of the ligand to both the ectodomain and the exoloop 2, thus providing a model with which to understand the molecular basis of ligand signaling for this unique subgroup of G protein-coupled receptors.

Background: One of the complications of hemodialysis (HD) therapy is anemia caused by erythropoietin (EPO) deficiency. Recombinant EPO (rEPO) has been used routinely as a supplemental treatment. Erythrocyte expression of the complement regulatory proteins decay accelerating factor (DAF) and CD59 restricts complement activation and inhibits hemolysis. We hypothesized that the efficacy of rEPO treatment may be caused in part by the ability of rEPO to increase erythrocyte expression of DAF and CD59., Methods: DAF, CD59, and complement receptor 1 (CR1) levels were analyzed for a group of 95 HD patients and compared with those of a control group. To evaluate effects of discontinuation of rEPO therapy, rEPO therapy was stopped for 12 HD patients until hematocrits decreased to less than 25%. DAF and CD59 levels then were reanalyzed., Results: In the 95 HD patients, three factors correlated significantly: DAF and CD59 (r = 0.642), DAF and CR1 (r = 0.503), and CD59 and CR1 (r = 0.324), whereas no correlations were found in the group of 42 healthy controls. In the experiment in which rEPO therapy was discontinued, 8 of 12 patients reached the defined level of anemia 4 to 7 weeks after rEPO treatment had been withheld. Both DAF and CD59 levels decreased significantly after discontinuation of rEPO therapy (P < 0.01). DAF and CD59 levels increased in all 8 patients after rEPO treatment was reinitiated (P < 0.01), and CR1 levels increased in 5 of 8 patients. Four of 12 patients showed no evidence of anemia after discontinuation of rEPO treatment. In these patients, DAF, CD59, and CR1 levels did not change before or after withholding rEPO therapy., Conclusion: One of the mechanisms mediating the efficacy of EPO therapy is increased DAF and CD59 expression., (Copyright 2003 by the National Kidney Foundation Inc.)

Background: Toxic hypermagnesemia is a wellknown adverse effect of intravenous magnesium., Case: A woman with postpartum eclampsia was treated with intravenous magnesium at another hospital and then transferred to our hospital due to cardiopulmonary failure. Blood magnesium and creatinine levels were markedly elevated. Hemodialysis rapidly improved her condition., Conclusion: Hemodialysis is effective for toxic hypermagnesemia caused by intravenous magnesium in a case of severe renal insufficiency.

To determine the influence of FSH receptor variants Thr307-Asn680 (TN) and Ala307-Ser680 (AS) on ovarian function, we investigated the frequency of these gene polymorphisms by using restriction fragment length polymorphism analysis and observed their effects on clinical manifestations. In a population of 522 Japanese women, the overall frequency of TN/TN (NN), TN/AS (NS), and AS/AS (SS) was 41.0, 46.9 and 12.1% respectively. In polycystic ovary patients, the NS population was significantly larger when compared with the spontaneously ovulating group (66.7 versus 43.5%, P < 0.05). In the SS group, a significantly higher (46%) basal level of serum FSH was observed as compared with that in the NS group (P < 0.05). A higher dose of the exogenous gonadotrophin was required to achieve ovulation induction in the SS group as compared with the NS group (P < 0.05). At the time of hCG administration, estradiol levels per oocyte retrieved for IVF in the SS group were significantly lower as compared with the levels in the NS and NN groups (P < 0.05). There were no significant differences in FSH-stimulated cAMP production and PI turnover as well as ligand-binding affinity between the two receptor isoforms when overexpressed in transfected 293T cells. These results suggest that although FSH receptor polymorphisms have no discernible effect on FSH receptor function in vitro, there are associations between the genotype and some aspects of patient status.

In human studies, repeated intraoral application of strong acidic or salt stimuli induces irritation that progressively increases across trials (sensitization), whereas irritation elicited by nicotine progressively decreases (desensitization). We investigated whether nociceptive neurons in trigeminal subnucleus caudalis (Vc) exhibit increasing or decreasing patterns of firing to the intraoral application of these irritants. In rats anesthetized with halothane and thiopental, single-unit recordings were made from nociceptive neurons in superficial layers of dorsomedial Vc that responded to mechanical and noxious thermal and chemical stimulation of the tongue. NaCl (5M), citric acid (300 mM), pentanoic acid (300 mM) or nicotine (600 mM) were separately delivered to the tongue by constant flow (0.32 ml/min) for 15 or 25 min. NaCl, citric acid and pentanoic acid each elicited a progressive, significant increase in Vc neuronal firing over the initial 10 min to a plateau level that was maintained for the stimulus duration. Nicotine induced a significant increase in firing rate of Vc neurons within 6 min, followed by a decline back to the baseline level over the ensuing 10 min. Following a rest period, reapplication of nicotine no longer activated Vc neurons, indicative of self-desensitization. We additionally tested for nicotine cross-desensitization to acid. After recording the responses of Vc neurons to pentanoic acid and noxious heat, nicotine was then applied for 15 min. Post-nicotine responses to pentanoic acid were markedly reduced (to 13% of control), indicative of cross-desensitization; responses to noxious heat were also reduced to a lesser degree (to 71% of control). The progressive increase in Vc neuronal firing elicited by NaCl and acid, and the decline in firing after initial nicotinic excitation, resemble psychophysical patterns of sensitization and desensitization, respectively, and support the involvement of Vc neurons in the signaling of oral irritant sensations.

In the Large Helical Device plasma discharges, the size of an externally imposed island with mode number ( n/m = 1/1) decreases substantially when the plasma is collisionless ( nu(*)< approximately 1) and the beta is finite ( > approximately 0.1%) at the island location. For the collisional plasmas with finite beta, on the other hand, the size of the island increases. However, there is a threshold in terms of the vacuum island size below which the island enlargement is not seen.

It was observed that the vacuum magnetic island produced by an external error magnetic field in the large helical device shrank in the presence of plasma. This was evidenced by the disappearance of flat regions in the electron temperature profile obtained by Thomson scattering. This island behavior depended on the magnetic configuration in which the plasmas were produced.

Membranes used for dialysis therapy activate complement. Complement activation is maximal after initiating dialysis and returns to predialysis values by the end of dialysis. No changes in C3 levels have been detected after dialysis. We hypothesized that although C3 levels were unchanged, C3 activity could be altered by dialysis. We measured complement activation in vitro in serum from patients randomized to dialysis treatments using different types of membranes. The classical pathway was activated with aggregated immunoglobulin G (IgG), and the alternative pathway was activated with inulin. Both the classical and alternative pathways were suppressed after dialysis using cellulose membranes (aggregate IgG, P < 0.01; inulin, P < 0.001). When polyacrylonitrile (PAN) or polyethylene glycol grafted cellulose membranes were used for dialysis, only minor suppression of complement pathways was measured. Levels of the control factor SP-40,40 increased at later times for dialysis using cellulose membranes (P < 0.05). Factor H levels were also greater after dialysis using cellulose membranes compared with PAN membranes (P < 0.05). In summary, cellulose membranes suppress complement activation in serum. One suppressing factor may be the complement control factor SP-40,40.

Recent large helical device experiments revealed that the transition from ion root to electron root occurred for the first time in neutral-beam-heated discharges, where no nonthermal electrons exist. The measured values of the radial electric field were found to be in qualitative agreement with those estimated by neoclassical theory. A clear reduction of ion thermal diffusivity was observed after the mode transition from ion root to electron root as predicted by neoclassical theory when the neoclassical ion loss is more dominant than the anomalous ion loss.

Unlabelled: Anesthetics such as isoflurane act in the spinal cord to suppress movement in response to noxious stimulation. Spinal anesthesia decreases hypnotic/sedative requirements, possibly by decreasing afferent transmission of stimuli. We hypothesized that isoflurane action in the spinal cord would similarly depress the ascending transmission of noxious input to the thalamus and cerebral cortex. In six isoflurane-anesthetized goats, we measured electroencephalographic (EEG) and thalamic single-unit responses to a clamp applied to the forelimb. Cranial bypass permitted differential isoflurane delivery to the torso and cranial circulations. When the cranial-torso isoflurane combination was 1.3% +/- 0.2%-1.0% +/- 0.4% the noxious stimulus did not evoke significant changes in the EEG or thalamic activity: 389 (153-544) to 581 (172-726) impulses/min, (median, 25th-75th percentile range, P: > 0.05). When the cranial-torso isoflurane combination was 1.3% +/- 0.2%-0.3% +/- 0.2%, noxious stimulation increased thalamic activity: 804 (366-1162) to 1124 (766-1865) impulses/min (P: < 0.05), and the EEG "desynchronized": total EEG power decreased from 25 +/- 20 microV(2) to 12 +/- 8 microV(2) (P: < 0.05). When the cranial-torso isoflurane was 1.7% +/- 0.1%-0.3% +/- 0.2%, the noxious stimulus did not significantly affect thalamic: 576 (187-738) to 1031 (340-1442) impulses/min (P: > 0.05), or EEG activity. The indirect torso effect of isoflurane on evoked EEG total power (12.6 +/- 2.7 microV(2)/vol%, mean +/- SE) was quantitatively similar to the direct cranial effect (17.7 +/- 3.0 microV(2)/vol%; P: > 0.05). These data suggest that isoflurane acts in the spinal cord to blunt the transmission of noxious inputs to the thalamus and cerebral cortex, and thus might indirectly contribute to anesthetic endpoints such as amnesia and unconsciousness., Implications: Isoflurane action in the spinal cord diminished the transmission of noxious input to the brain. Because memory and consciousness are likely dependent on the "arousal" state of the brain, this indirect action of isoflurane could contribute to anesthetic-induced amnesia and unconsciousness.