Nadir lymphocytopenia as a risk factor of bloodstream infection during molecular targeting pharmacotherapy in multiple myeloma.

OBJECTIVE: Molecular targeting pharmacotherapy (MTP) with proteasome inhibitors and immunomodulatory drugs has led to a remarkable improvement in the effectiveness of multiple myeloma (MM) therapy. However, the effect of MTP on the occurrence of infections in patients with MM remains unclear. We aimed to identify the incidence of and risk factors for bloodstream infection (BSI) in patients with MM undergoing MTP. MATERIALS AND METHODS: We conducted a retrospective cohort study. We reviewed the medical records of 108 inpatients with MM at the National Defense Medical College Hospital between January 2010 and January 2017. Univariate and multivariate analyses were conducted to identify risk factors for BSI. RESULTS: The incidence of BSI in patients with MM receiving MTP (n = 188) was 6.9%, which was significantly lower than the 52.6% in patients receiving cytotoxic chemotherapy (n = 57). We found that the most important risk factor for BSI in patients receiving MTP was lymphocytopenia at nadir (< 200/µL). In contrast, the risk factor for BSI in patients receiving cytotoxic chemotherapy was the number of regimens performed. CONCLUSION: Our study suggests that the incidence of BSI is lower in patients with MM receiving MTP than in those receiving cytotoxic chemotherapy and that lymphocytopenia at nadir may be a risk factor for BSI in patients with MM receiving MTP. Since previous clinical trials with MTP showed that the frequency of myelosuppression and infections was high in the Japanese population, these findings might provide novel insights into MTP for Japanese patients with MM.
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Ca2+ -dependent down-regulation of human histamine H1 receptors in Chinese hamster ovary cells.

Gq/11 protein-coupled human histamine H1 receptors in Chinese hamster ovary cells stimulated with histamine undergo clathrin-dependent endocytosis followed by proteasome/lysosome-mediated down-regulation. In this study, we evaluated the effects of a sustained increase in intracellular Ca2+ concentrations induced by a receptor-bypassed stimulation with ionomycin, a Ca2+ ionophore, on the endocytosis and down-regulation of H1 receptors in Chinese hamster ovary cells. All cellular and cell-surface H1 receptors were detected by the binding of [3 H]mepyramine to intact cells sensitive to the hydrophobic and hydrophilic H1 receptor ligands, mepyramine and pirdonium, respectively. The pretreatment of cells with ionomycin markedly reduced the mepyramine- and pirdonium-sensitive binding sites of [3 H]mepyramine, which were completely abrogated by the deprivation of extracellular Ca2+ and partially by a ubiquitin-activating enzyme inhibitor (UBEI-41), but were not affected by inhibitors of calmodulin (W-7 or calmidazolium) and protein kinase C (chelerythrine or GF109203X). These ionomycin-induced changes were also not affected by inhibitors of receptor endocytosis via clathrin (hypertonic sucrose) and caveolae/lipid rafts (filipin or nystatin) or by inhibitors of lysosomes (E-64, leupeptin, chloroquine, or NH4 Cl), proteasomes (lactacystin or MG-132), and a Ca2+ -dependent non-lysosomal cysteine protease (calpain) (MDL28170). Since H1 receptors were normally detected by confocal immunofluorescence microscopy with an antibody against H1 receptors, even after the ionomycin treatment, H1 receptors appeared to exist in a form to which [3 H]mepyramine was unable to bind. These results suggest that H1 receptors are apparently down-regulated by a sustained increase in intracellular Ca2+ concentrations with no process of endocytosis and lysosomal/proteasomal degradation of receptors.

Differential Regulation of Thermodynamic Binding Forces of Levocetirizine and (S)-Cetirizine by Lys191 in Human Histamine H1 Receptors.

Cetirizine is a zwitterionic second-generation antihistamine containing R- and S-enantiomers, levocetirizine, and (S)-cetirizine. Levocetirizine is known to have a higher affinity for the histamine H1 receptors than (S)-cetirizine; ligand-receptor docking simulations have suggested the importance of the formation of a salt bridge (electrostatic interaction) between the carboxylic group of levocetirizine and the Lys191 residue at the fifth transmembrane domain of human histamine H1 receptors. In this study, we evaluated the roles of Lys191 in the regulation of the thermodynamic binding forces of levocetirizine in comparison with (S)-cetirizine. The binding enthalpy and entropy of these compounds were estimated from the van 't Hoff equation, by using the dissociation constants obtained from their displacement curves against the binding of [³H]mepyramine to the membrane preparations of Chinese hamster ovary cells expressing wild-type human H1 receptors and their Lys191 mutants to alanine at various temperatures. We found that the higher binding affinity of wild-type H1 receptors for levocetirizine than (S)-cetirizine was achieved by stronger forces of entropy-dependent hydrophobic binding of levocetirizine. The mutation of Lys191 to alanine reduced the affinities for levocetirizine and (S)-cetirizine, through a reduction in the entropy-dependent hydrophobic binding forces of levocetirizine and the enthalpy-dependent electrostatic binding forces of (S)-cetirizine. These results suggested that Lys191 differentially regulates the binding enthalpy and entropy of these enantiomers, and that Lys191 negatively regulates the enthalpy-dependent electrostatic binding forces of levocetirizine, contrary to the predictions derived from the ligand-receptor docking simulations.

A role for the tyrosine kinase Pyk2 in depolarization-induced contraction of vascular smooth muscle.

Depolarization of the vascular smooth muscle cell membrane evokes a rapid (phasic) contractile response followed by a sustained (tonic) contraction. We showed previously that the sustained contraction involves genistein-sensitive tyrosine phosphorylation upstream of the RhoA/Rho-associated kinase (ROK) pathway leading to phosphorylation of MYPT1 (the myosin-targeting subunit of myosin light chain phosphatase (MLCP)) and myosin regulatory light chains (LC20). In this study, we addressed the hypothesis that membrane depolarization elicits activation of the Ca(2+)-dependent tyrosine kinase Pyk2 (proline-rich tyrosine kinase 2). Pyk2 was identified as the major tyrosine-phosphorylated protein in response to membrane depolarization. The tonic phase of K(+)-induced contraction was inhibited by the Pyk2 inhibitor sodium salicylate, which abolished the sustained elevation of LC20 phosphorylation. Membrane depolarization induced autophosphorylation (activation) of Pyk2 with a time course that correlated with the sustained contractile response. The Pyk2/focal adhesion kinase (FAK) inhibitor PF-431396 inhibited both phasic and tonic components of the contractile response to K(+), Pyk2 autophosphorylation, and LC20 phosphorylation but had no effect on the calyculin A (MLCP inhibitor)-induced contraction. Ionomycin, in the presence of extracellular Ca(2+), elicited a slow, sustained contraction and Pyk2 autophosphorylation, which were blocked by pre-treatment with PF-431396. Furthermore, the Ca(2+) channel blocker nifedipine inhibited peak and sustained K(+)-induced force and Pyk2 autophosphorylation. Inhibition of Pyk2 abolished the K(+)-induced translocation of RhoA to the particulate fraction and the phosphorylation of MYPT1 at Thr-697 and Thr-855. We conclude that depolarization-induced entry of Ca(2+) activates Pyk2 upstream of the RhoA/ROK pathway, leading to MYPT1 phosphorylation and MLCP inhibition. The resulting sustained elevation of LC20 phosphorylation then accounts for the tonic contractile response to membrane depolarization.

C-terminal of human histamine H1 receptors regulates their agonist-induced clathrin-mediated internalization and G-protein signaling.

It has been suggested that the agonist-induced internalization of G-protein-coupled receptors from the cell surface into intracellular compartments regulates cellular responsiveness. We previously reported that Gq/11 -protein-coupled human histamine H1 receptors internalized via clathrin-dependent mechanisms upon stimulation with histamine. However, the molecular determinants of H1 receptors responsible for agonist-induced internalization remain unclear. In this study, we evaluated the roles of the intracellular C-terminal of human histamine H1 receptors tagged with hemagglutinin (HA) at the N-terminal in histamine-induced internalization in Chinese hamster ovary cells. The histamine-induced internalization was evaluated by the receptor binding assay with [3 H]mepyramine and confocal immunofluorescence microscopy with an anti-HA antibody. We found that histamine-induced internalization was inhibited under hypertonic conditions or by pitstop, a clathrin terminal domain inhibitor, but not by filipin or nystatin, disruptors of the caveolar structure and function. The histamine-induced internalization was also inhibited by truncation of a single amino acid, Ser487, located at the end of the intracellular C-terminal of H1 receptors, but not by its mutation to alanine. In contrast, the receptor-G-protein coupling, which was evaluated by histamine-induced accumulation of [3 H]inositol phosphates, was potentiated by truncation of Ser487, but was lost by its mutation to alanine. These results suggest that the intracellular C-terminal of human H1 receptors, which only comprises 17 amino acids (Cys471-Ser487), plays crucial roles in both clathrin-dependent internalization of H1 receptors and G-protein signaling, in which truncation of Ser487 and its mutation to alanine are revealed to result in biased signaling toward activation of G-proteins and clathrin-mediated internalization, respectively.

Differential Regulation of Plasma Copeptin Levels in Patients with Heart Failure: A Single-Center Prospective Study.

Elevated levels of arginine vasopressin (AVP) have been reported to be involved in the pathogenesis of heart failure (HF). Recent evidence has shown the role of copeptin, the C-terminal fragment of pro-AVP, as a biomarker in patients with HF. However, the relevant information is still limited. Therefore, we evaluated 39 Japanese patients admitted for HF between 2013 and 2015 (23 males and 16 females with an average age of 79.2 years). They were treated according to the Japanese acute HF guideline. Plasma copeptin levels were measured on admission and about 1 week later. The median plasma copeptin levels on admission were 0.5 (0.1-50.6) pmol/L, higher than the normal values (0.24 ± 0.06 pmol/L). Despite the similar clinical severity on admission, the patients showed great variability in plasma copeptin levels. They were divided into three groups (13 patients/group) according to plasma copeptin levels on admission: highest (> 30.8 pmol/L), midrange, and lowest (< 0.2 pmol/L) groups. Initial treatment improved HF symptoms in 37 of 39 patients, with the two unresponsive patients in the lowest group. Notably, plasma copeptin responses to initial treatment were different, depending on admission copeptin levels. The initial treatment significantly decreased copeptin levels in the highest group, but increased copeptin levels in the lowest group. By contrast, patients in the midrange group showed no significant changes. Thus, the treatment appears to restore the plasma copeptin levels. In conclusion, HF is a complex syndrome with the differential integration of stimulatory and inhibitory inputs to the AVP/copeptin secretory system.

Molecular determinants responsible for sedative and non-sedative properties of histamine H1-receptor antagonists.

There is argument whether non-sedative properties of histamine H1-receptor antagonists (antihistamines) are determined by their active extrusions from the brain via P-glycoprotein or their restricted penetration through the blood-brain barrier. We have reported that sedative and non-sedative antihistamines can be well discriminated by measuring changes in their binding to H1 receptors upon receptor internalization in intact cells, which depends on their membrane-penetrating ability. In this study, molecular determinants responsible for sedative and non-sedative properties of antihistamines were evaluated by quantitative structure-activity relationship (QSAR) analyses. Multiple regression analyses were applied to construct a QSAR model, taking internalization-mediated changes in the binding of antihistamines as objective variables and their structural descriptors as explanatory variables. The multiple regression model was successfully constructed with two explanatory variables, i.e., lipophilicity of the compounds at physiological pH (logD) and mean information content on the distance degree equality (IDDE) (r(2) = 0.753). The constructed model discriminated between sedative and non-sedative antihistamines with 94% accuracy for external validation. These results suggest that logD and IDDE concerning lipophilicity and molecular shapes of compounds, respectively, predominantly determine the membrane-penetrating ability of antihistamines for their side effects on the central nervous system.

Efficacy of H2 receptor antagonists for prevention of upper gastrointestinal bleeding during dual-antiplatelet therapy.

Proton pump inhibitors (PPI) are frequently used to prevent upper gastrointestinal bleeding (UGIB) in patients receiving dual-antiplatelet therapy (DAPT) with aspirin and clopidogrel. However, the concomitant therapy of PPI and DAPT has been associated with a decreased effect of the antiplatelet drugs and an increased risk of major adverse cardiovascular events (MACE). It has been suggested that histamine H2 receptor antagonists (H2RA) can be used as alternatives to PPI to prevent UGIB during DAPT without an increase in the risk of MACE. We tested this hypothesis in a retrospective cohort study including patients without a prior history of upper gastrointestinal events. We examined the incidence of UGIB and MACE in 296 patients treated with H2RA (H2RA group) and 447 patients not treated with H2RA (control group) during DAPT with aspirin and clopidogrel after drug-eluting stent implantation. The patients treated with PPI were excluded. In the 1-year follow-up, UGIB occurred in 2 patients (0.7%) in the H2RA group and 12 (2.7%) in the control group. The incidence of UGIB was significantly different between the two groups (p = 0.049 in log-rank test). MACE occurred in 31 patients (10.5%) in the H2RA group and in 54 patients (12.1%) in the control group, and the incidence was not significantly different (p = 0.447 in logrank test). Thus, H2RA may be effective safe alternatives to PPI during DAPT in patients without a prior history of upper gastrointestinal events.

The affinity of histamine for Gq protein-coupled histamine H(1)-receptors is predominantly regulated by their internalization in human astrocytoma cells.

We examined the regulatory mechanisms of the affinity of Gq protein-coupled histamine H(1)-receptors for histamine after histamine pretreatment in intact human U373 MG astrocytoma cells. In control cells, the displacement curves for histamine against the binding of 5 nM [(3)H]mepyramine, a radioligand for H(1)-receptors, showed the presence of two binding sites for histamine, that is, high and low affinity sites. Pretreatment with 0.1 mM histamine for 30 min at 37°C induced a significant reduction in the percentage of high affinity sites for histamine and a concomitant increase in the percentage of low affinity sites with no change in their pIC(50) values. These histamine-induced changes were insensitive to 30 µM KN-62, an inhibitor of Ca(2+)/calmodulin-dependent protein kinase II, but they were completely inhibited either by 0.4 mM ZnCl(2), an inhibitor of G protein-coupled receptor kinases (GRKs), or under hypertonic conditions, where clathrin-mediated endocytosis is known to be inhibited. These results suggest that histamine-induced conversion of high to low affinity sites for histamine is predominantly regulated by GRK/clathrin-mediated internalization of H(1)-receptors in human astrocytoma cells.

Dysfunction of neurotransmitter modulation system on adrenergic nerves of caudal artery in type 2 diabetic Goto-Kakizaki rats.

The Goto-Kakizaki (GK) rat is a non-obese and spontaneous model of mild Type 2 diabetes mellitus. In the present study, we compared the regulatory mechanisms of endogenous norepinephrine (NE) release from sympathetic nerves of caudal arteries of 12-week-old GK rats and age-matched normal Wistar rats. Electrical stimulation (ES) evoked significant NE release from caudal arteries of Wistar and GK rats. The amounts of NE released by ES were almost equal in Wistar and GK rats, although the NE content in caudal artery of GK rats was significantly lower than that of Wistar rats. We examined the effects of an α2-adrenoceptor agonist, clonidine (CLO), and an α2-adrenoceptor antagonist, yohimbine (YOH), on the release of endogenous NE evoked by ES. CLO significantly reduced NE release from caudal arteries of Wistar but not GK rats. On the other hand, YOH significantly increased NE release from both rats. Furthermore, we examined the effects of an A1-adenosine receptor agonist, 2-chloroadenosine (2CA), and an A1-adenosine receptor antagonist, 8-sulfophenyltheophylline (8SPT), on the release of endogenous NE evoked by ES. 2CA significantly reduced NE release from caudal arteries of Wistar but not GK rats. On the other hand, 8SPT did not affect NE release from both rats. These results suggest that the dysfunction of negative feedback regulation of NE release via presynaptic receptors on sympathetic nerves in GK rats may be involved in the autonomic nervous system dysfunction associated with diabetic autonomic neuropathy.

Desensitization of depolarization-mediated contractile pathways does not necessarily regulate receptor-mediated excitation-contraction coupling in longitudinal smooth muscle of guinea pig ileum.

1. Activation of G(q) protein-coupled receptors, such as muscarinic M(3) and histamine H(1) receptors, induces smooth muscle contraction through activation of voltage-dependent Ca channels. 2. To evaluate roles of depolarization-mediated contractile pathways in the desensitization of receptor-mediated contraction, we compared the development of carbachol-induced desensitization to receptor agonists, carbachol and histamine, and to receptor-bypassed stimulation of voltage-dependent Ca channels with depolarizing high K in longitudinal smooth muscle of guinea pig ileum. 3. Under Ca-containing physiological conditions, pretreatment with 10(-4) mol/L carbachol for 15 s-30 min induced desensitization to carbachol as well as to high K, whereas contractile responses to histamine remained normal. 4. In contrast, under Ca-free conditions containing 0.2 mmol/L EGTA, carbachol pretreatment induced desensitization to high K in a manner similar to that induced under Ca-containing physiological conditions, whereas contractile responses to carbachol and histamine remained normal. 5. Thus, it was shown that contractile responses to carbachol and histamine were not necessarily desensitized, even under conditions where contractile responses to high K were desensitized. These results suggest that desensitization of depolarization-mediated contractile pathways might not necessarily regulate excitation-contraction coupling through muscarinic M(3) and histamine H(1) receptors in longitudinal smooth muscle of guinea pig ileum.

Ubiquitin/proteasome-dependent down-regulation following clathrin-mediated internalization of histamine H1-receptors in Chinese hamster ovary cells.

We investigated the regulatory pathways responsible for agonist-induced internalization and down-regulation of G(q) protein-coupled histamine H(1)-receptors in Chinese hamster ovary cells. Histamine-induced internalization and down-regulation of H(1)-receptors were detected as the loss of [(3)H]mepyramine binding sites on intact cells accessible to hydrophilic and hydrophobic H(1)-receptor antagonists, pirdonium and mepyramine, respectively. Pretreatment of cells with 0.1 mM histamine for 30 min at 37 degrees C induced internalization as well as down-regulation of H(1)-receptors, both of which were inhibited either in the presence of an inhibitor against G protein-coupled receptor kinases (ZnCl(2)) or under hypertonic conditions where clathrin-dependent endocytosis is known to be inhibited, but were not affected by inhibitors against caveolae/raft-dependent endocytosis (filipin and nystatin). Down-regulation of H(1)-receptors, but not their internalization, was inhibited by protein kinase C inhibitors (chelerythrin or GF109203X), a ubiquitin E1 inhibitor (UBEI-41) and proteasome inhibitors (lactacystin and MG-132). Neither a Ca(2+)/calmodulin-dependent protein kinase II inhibitor (KN-62) nor lysosomal protease inhibitors (E-64, leupeptin, chloroquine and NH(4)Cl) affected the internalization and down-regulation of H(1)-receptors. These results suggest that H(1)-receptors internalize upon agonist stimulation via G protein-coupled receptor kinase/clathrin-dependent but caveolae/raft-independent mechanisms and are delivered to proteasomes, preferentially to lysosomes, for their prompt down-regulation.

Attenuation of store-operated Ca2+ entry and enhanced expression of TRPC channels in caudal artery smooth muscle from Type 2 diabetic Goto-Kakizaki rats.

1. Previously, we found that Ca(2+) entry from the extracellular space via alpha(1)-adrenoceptor-activated, Ca(2+)-permeable channels, but not voltage-gated Ca(2+) channels, is impaired in endothelium-denuded caudal artery smooth muscle from Type 2 diabetic Goto-Kakizaki (GK) rats. In the present study, we investigated the impairment of Ca(2+) entry mechanisms via Ca(2+)-permeable channels from the extracellular space in response to alpha(1)-adrenoceptor stimulation (cirazoline) in endothelium-denuded caudal artery strips isolated from GK rats. 2. The contraction of caudal artery strips from GK rats in response to the sarcoplasmic reticulum Ca(2+)-ATPase inhibitor cyclopiazonic acid (10 micromol/L), which causes depletion of Ca(2+) stores and subsequent store-operated Ca(2+) (SOC) entry, was significantly depressed compared with that of Wistar rats (maximal force 0.023 +/- 0.004 vs 0.058 +/- 0.005 mN/mg tissue wet weight, respectively). These results suggest that receptor-activated Ca(2+) entry through SOC channels is impaired in caudal artery smooth muscle in GK rats. 3. The classic transient receptor potential (TRPC) channels, which constitute SOC and receptor-operated cation channels, play an important role in Ca(2+) regulation. Therefore, we investigated the mRNA and protein expression of TRPC channels in caudal artery smooth muscle from Wistar and GK rats using reverse transcription-polymerase chain reaction and immunoblotting. 4. Expression of TRPC1, TRPC3 and TRPC6 mRNA and protein was found in Wistar rats. However, in GK rats, in addition to the expression of these TRPC channels, mRNA and protein expression of TRPC4 was found. The expression of TRPC1 and TRPC6, but not TRPC3, was increased approximately twofold in GK rats compared with Wistar rats. 5. These results suggest that changes in TRPC channel expression may be responsible, in part, for the dysfunction of receptor-mediated Ca(2+) entry in caudal artery smooth muscle of GK rats.

Impairment of α1-adrenoceptor-mediated contractile activity in caudal arterial smooth muscle from type 2 diabetic Goto-Kakizaki rats.

1. In the present study, we compared the responsiveness of de-endothelialized caudal artery smooth muscle strips, isolated from Type 2 diabetic Goto-Kakizaki (GK) and normal Wistar rats, to alpha(1)-adrenoceptor stimulation (cirazoline) and membrane depolarization (K(+)). 2. The contractile and myosin 20 kDa light chain (LC(20)) phosphorylation responses to 0.3 micromol/L cirazoline of caudal artery strips isolated from 12-week-old GK rats were significantly reduced compared with those of age-matched Wistar rats, whereas the contractile and LC(20) phosphorylation responses to 60 mmol/L K(+) were unaltered. 3. Stimulation of fura 2-AM-loaded strips from GK rats with 0.3 micromol/L cirazoline induced a significantly smaller rise in [Ca(2+)](i) (by approximately 20%) compared with that in strips from Wistar rats, whereas comparable Ca(2+) transients were evoked by K(+) in both. 4. Using quantitative polymerase chain reaction, no significant differences were detected in the mRNA expression of alpha(1A)-, alpha(1B)- and alpha(1D)-adrenoceptor subtypes between GK and Wistar rats. 5. Cirazoline (1 micromol/L)- and caffeine (20 mmol/L)-induced contractions in the absence of extracellular Ca(2+) were unaltered in GK rats, suggesting that the release of Ca(2+) from the sarcoplasmic reticulum in response to cirazoline does not differ between GK and Wistar rats. 6. The results of the present study suggest that Ca(2+) entry from the extracellular space via alpha(1)-adrenoceptor-activated, Ca(2+)-permeable channels, but not via membrane depolarization and voltage-gated L-type Ca(2+) channels, is impaired in caudal artery smooth muscle of GK rats.

Histamine develops homologous desensitization under Ca(2+)-free conditions with increase in basal tone in smooth muscle of guinea pig taenia caeci.

Histamine regulates a variety of physiological or pathophysiological processes via the activation of G(q/11) protein-coupled and Ca(2+)-mobilizing histamine H(1) receptors, including smooth muscle contraction. We have found that histamine induces progression from heterologous to homologous desensitization of contraction under normal physiological conditions in smooth muscle of guinea pig taenia caeci. In this study, we characterized the development of histamine-induced desensitization under Ca(2+)-free conditions and we found that histamine developed only a homologous phase of desensitization to histamine with an increase in EC(50) values for histamine and basal tone. In contrast, histamine treatment reduced EC(50) values for a muscarinic agonist, carbachol, and depolarizing high K(+). These results suggest that the failure of excess histamine to induce a normal Ca(2+) response under Ca(2+)-free conditions may lead to homologous desensitization to histamine with apparent hyper-reactivity of smooth muscles to cholinergic and depolarizing stimuli. We estimate that this characteristic of histamine to change smooth muscle contractility may be potentially involved in its physiological and pathophysiological aspects, including histamine-induced allergic conditions, depending on cellular circumstances.

[Systematic review on the short-term efficacy and safety of nicorandil for stable angina pectoris in comparison with those of ß-blockers, nitrates and calcium antagonists].

Nicorandil significantly reducted the incidence of major coronary events in patients with stable angina in a long-term trial, although there are few reports on its short-term efficacy in the treatment and prevention of angina symptoms. We performed a meta-analysis of the short-term efficacy of nicorandil compared with antianginal drugs for stable angina. We selected 20 reports (vs. ß-blockers, n=6; vs. nitrates, n=6; vs. calcium antagonists, n=8) of prospective controlled trials from MEDLINE, the Cochrane Library, and Japana Centra Revuo Medicina. The trials were short in duration (median 5 weeks). We combined the results using odds ratios (OR) for discrete data and weighted mean differences (WMD) for continuous data. Compared with antianginal drugs, nicorandil did not show significant reduction of angina episodes per week (vs. ß-blockers, -1.50 [95% confidence interval (CI): -4.09, 1.09]; vs. nitrates, 0.22 [95% CI: -1.22, 1.65]; vs. calcium antagonists, -0.23 [95% CI: -1.37, 0.90]). Furthermore, there were no significant differences in time to ischemia (total exercise duration, time to 1-mm ST depression, time to onset of pain). Although the total numbers of adverse events with each antianginal drug were similar, heart rate and blood pressure were significantly decreased by calcium antagonists but not changed by nicorandil (8.09 [95% CI: 3.20, 12.98] and 8.64 [95% CI: 3.28, 13.99], respectively). Thus this study suggests that short-term therapy with nicorandil is as effective as standard therapy and that nicorandil can also be used as a first-line agent in patients with stable angina.

[A case of advanced gastric and rectal cancer (double cancer) successfully treated with mFOLFOX6 therapy].

A 75-year-old man was diagnosed with gastric cancer (UL post c0- II c (c T1N0) and M-less ctype II (cT2N0)) and rectal cancer (Rb ctype II (cT2N1) with multiple lung metastases (M1). The patient was treated with modified (m) FOLFOX6 regimen (oxaliplatin in combination with infusional 5-fluorouracil/Leucovorin). Chest and abdominal CT scan revealed that multiple lung metastases and abdominal lymph node metastases were obviously reduced in size. The primary lesion of the rectum almost disappeared on endoscopic examination. As for the lesions of the stomach, the UL post c0- II c lesion completely disappeared, and the M-less ctype II lesion was reduced remarkably. Thus, a significant reduction of the tumors was observed. This case suggests that mFOLFOX6 regimen can be an option for gastric cancer.

Early changes in insulin receptor signaling and pain sensation in streptozotocin-induced diabetic neuropathy in rats.

UNLABELLED: The objective of the present study was to evaluate the time course of changes in peripheral nerve insulin receptor (IR) signaling and compare observed findings with behavioral responses to noxious mechanical and thermal stimuli in streptozotocin (STZ)-diabetic rats over 12 weeks of diabetes. Diabetic rats developed mechanical hyperalgesia, as indicated by decreased paw withdrawal thresholds to mechanical stimuli that were detectable after 2 weeks of diabetes; they also developed thermal hypoalgesia, as indicated by increased tail flick latencies to thermal stimuli that were detectable at 1 week of diabetes. Western blot analysis revealed decreased phosphorylated: total IR protein ratio that was detectable as early as 2 weeks of diabetes, whereas phosphorylated:total Akt protein ratio was decreased at 2 weeks and increased at 12 weeks of diabetes with unchanged PI-3K protein levels. To our knowledge, the present study is the first to demonstrate that impaired peripheral nerve IR signaling, as indicated by decreased phosphorylated:total IR protein ratio, coincides with early mechanical hyperalgesia and thermal hypoalgesia in STZ-diabetic rats. This finding may improve understanding of how altered pain sensation develops rapidly in this model. PERSPECTIVE: This study examined peripheral nerve IR signaling during the early course of altered nociception in STZ-diabetic rats. In diabetic rats, impaired peripheral nerve IR signaling is observed shortly after STZ injection, as is altered nociception. This finding suggests a possible role of impaired IR signaling in diabetic sensory neuropathy.

[Recent progress in vasopressin research on cardiovascular diseases].

Arginine vasopressin (AVP) plays an important role in volume homeostasis and cardiovascular regulation. This review briefly describes recent clinical studies which evaluated the significance of AVP in cardiovascular diseases. Several AVP receptor antagonists, including tolvaptan and conivaptan, have shown promise in human trials for the treatment of heart failure. As plasma AVP concentrations are elevated in patients with heart failure in accordance with their severity, elevated AVP may contribute to their clinical syndrome of fluid retention and vasoconstriction. In some forms of hypertension, circulating AVP are also elevated; however, the precise role of AVP in the pathophysiology of hypertension is controversial. We performed a case-control study in a random sample of 620 rural residents and found an association between nonobese hypertension and -6951G/A single nucleotide polymorphism in the promoter region of the AVP V1a receptor gene. Our results suggest that AVP might contribute to the subdivision of human hypertension. Antiplatelet agents have been shown effective to prevent cardiovascular events. AVP has been known to stimulate platelet aggregation through V1a receptor. Genetic factors are thought to be involved in the heterogeneity of platelet activation. Some studies have been undertaken to identify genetic markers of platelet sensitivity to AVP.

[Consultation service of clinical laboratory in Hirosaki University Hospital].

For clinical laboratories, it has become important to place an emphasis on consultation service as well as quality management. Because everyday there arise various questions and complains among customers toward clinical laboratories in any kind of hospitals. The present clinical examinations are enormous and updated rapidly. Busy clinicians and nurses hardly cover them. In order to support attentive medical practice as clinical laboratory professionals, we have set the working committee of the clinical laboratory operation for more than 10 years. The committee, comprising laboratory experts and practitioners from our hospital, has worked very well to make a mutual interrelationship among the hospital staffs. In this paper, we introduce our consultation service through the committee of the clinical laboratory operation including a rare but meaningful request.