Unexpected Obstruction of a Parker Flex-Tip Endotracheal Tube Caused by Outward Bending of Its Tip: A Case Report.

We report a case of Parker Flex-Tip endotracheal tube obstruction caused by its tip bending outward against the tube lumen. The Parker Flex-Tip tube tip is designed to bend inward to prevent damage to airway structures during intubation. However, when its tip is bent outward, the tube aperture is distorted, shifts against the tracheal wall, and is occluded. Moreover, the cross-sectional area of the openings on the side of the endotracheal tube, the "Murphy's eyes" which are ellipses, decrease because the openings are pulled parallel to their long axis. Outward bending of the tip can obstruct the tube.

Comparison of effectiveness of the piston-pump method versus the pressure-infusor method for rapid infusion of crystalloids: A bench study.

BACKGROUND AND AIMS: The piston-pump method is a simple method for rapid administration of fluids but some problems are unsolved. We compared the effectiveness of using the piston-pump method with that of the pressure-infusor method. METHODS: Twelve anaesthetists were classified randomly into the piston-pump and pressure-infusor groups. They were asked to infuse 500 ml of saline three times successively through a 16-G intravenous cannula as rapidly as possible using a pump with a 50-ml syringe or a pressure-infusor at 300 mmHg. The time taken for infusion and the maximum or minimum pressure in the infusion circuit and substitute vessel were measured. Bacterial culture of the saline infused sterilely was performed to estimate bacterial contamination. RESULTS: The pressure-infusor group led to faster infusion of 500 ml of saline (233 ± 19 s) than the piston-pump group (301 ± 48 s) (P < 0.01). The infusion time at the third attempt (316 ± 43 s) was significantly longer than that at the first attempt (285 ± 53 s) only in the piston-pump group (P < 0.05). The maximum pressure (mmHg) in the circuit was 131 ± 9 and > 200 (P < 0.01) and in the substitute vessel was 5 ± 1 and 17 ± 7 (P < 0.01) in the pressure-infusor and piston-pump groups, respectively. A pressure of <-200 mmHg occurred at all infusion attempts in the piston-pump group. Bacterial contamination was not observed in either group. CONCLUSION: If fluids must be administered rapidly, the pressure-infusor method is more efficient than the piston-pump method because the latter is less effective in infusing fluids rapidly and associated with excessive positive and negative pressure in the infusion circuit.

The neurosteroid allopregnanolone sulfate inhibits Nav1.3 α subunit-containing voltage-gated sodium channels, expressed in Xenopus oocytes.

The neurosteroid allopregnanolone has potent analgesic effects, and its potential use for neuropathic pain is supported by recent reports. However, the analgesic mechanisms are obscure. The voltage-gated sodium channels (Nav) α subunit Nav1.3 is thought to play an essential role in neuropathic pain. Here, we report the effects of allopregnanolone sulfate (APAS) on sodium currents (INa) in Xenopus oocytes expressing Nav1.3 with ß1 or ß3 subunits. APAS suppressed INa of Nav1.3 with ß1 and ß3 in a concentration-dependent manner (IC50 values; 75 and 26 µmol/L). These results suggest the possible importance of Nav1.3 inhibition for the analgesic mechanisms of allopregnanolone.

Antidepressants inhibit Nav1.3, Nav1.7, and Nav1.8 neuronal voltage-gated sodium channels more potently than Nav1.2 and Nav1.6 channels expressed in Xenopus oocytes.

Tricyclic antidepressants (TCAs) and duloxetine are used to treat neuropathic pain. However, the mechanisms underlying their analgesic effects remain unclear. Although many investigators have shown inhibitory effects of antidepressants on voltage-gated sodium channels (Nav) as a possible mechanism of analgesia, to our knowledge, no one has compared effects on the diverse variety of sodium channel α subunits. We investigated the effects of antidepressants on sodium currents in Xenopus oocytes expressing Nav1.2, Nav1.3, Nav1.6, Nav1.7, and Nav1.8 with a ß1 subunit by using whole-cell, two-electrode, voltage clamp techniques. We also studied the role of the ß3 subunit on the effect of antidepressants on Nav1.3. All antidepressants inhibited sodium currents in an inactivated state induced by all five α subunits with ß1. The inhibitory effects were more potent for Nav1.3, Nav1.7, and Nav1.8, which are distributed in dorsal root ganglia, than Nav1.2 and Nav1.6, which are distributed primarily in the central nervous system. The effect of amitriptyline on Nav1.7 with ß1 was most potent with a half-maximal inhibitory concentration (IC50) 4.6 µmol/L. IC50 for amitriptyline on Nav1.3 coexpressed with ß1 was lowered from 8.4 to 4.5 µmol/L by coexpression with ß3. Antidepressants predominantly inhibited the sodium channels expressed in dorsal root ganglia, and amitriptyline has the most potent inhibitory effect. This is the first evidence, to our knowledge, showing the diverse effects of antidepressants on various α subunits. Moreover, the ß3 subunit appears important for inhibition of Nav1.3. These findings may aid better understanding of the mechanisms underlying the pain relieving effects of antidepressants.

Identification of Programmed Death Ligand 1-derived Peptides Capable of Inducing Cancer-reactive Cytotoxic T Lymphocytes From HLA-A24+ Patients With Renal Cell Carcinoma.

Molecular therapy targeting tumor angiogenesis has been the standard treatment for metastatic renal cell carcinoma (mRCC). However, despite their significant antitumor effects, most of patients with mRCC have not been cured. Under such circumstances, anticancer immunotherapy has been considered a promising treatment modality for mRCC, and cancer-reactive cytotoxic T lymphocytes (CTLs) are the most powerful effectors among several immune cells. However, anticancer CTLs can be inhibited by several immune inhibitory mechanisms, including the interaction between programmed death 1 (PD-1) and its ligand PD-L1, on T cells and cancer cells, respectively. Alternatively, this also means that PD-L1 could be a promising target for anticancer immunotherapy. Therefore, we searched for PD-L1-derived peptides that are applicable for anticancer vaccine for HLA-A24(+) RCC patients. Among 5 peptides derived from PD-L1, which were prepared based on the binding motif to the HLA-A24(+) allele, both PD-L1(11-19) and PD-L1(41-50) peptides induced peptide-specific CTLs from peripheral blood mononuclear cells of HLA-A24(+) RCC patients. Such PD-L1 peptide-stimulated CD8 T cells showed cytotoxicity against HLA-A24(+) and PD-L1-expressing RCC cells. Although IFN-γ treatment increased PD-L1 expression on PD-L1(low) RCC cells, their sensitivity to cytotoxicity of PD-L1 peptide-stimulated CD8(+) T cells varied between patients. Altogether, these results indicate that both PD-L1(11-19) and PD-L1(41-50) peptides could be candidates for peptide-based anticancer vaccines for HLA-A24(+) mRCC patients.

Disturbance of cardiac gene expression and cardiomyocyte structure predisposes Mecp2-null mice to arrhythmias.

Methyl-CpG-binding protein 2 (MeCP2) is an epigenetic regulator of gene expression that is essential for normal brain development. Mutations in MeCP2 lead to disrupted neuronal function and can cause Rett syndrome (RTT), a neurodevelopmental disorder. Previous studies reported cardiac dysfunction, including arrhythmias in both RTT patients and animal models of RTT. In addition, recent studies indicate that MeCP2 may be involved in cardiac development and dysfunction, but its role in the developing and adult heart remains unknown. In this study, we found that Mecp2-null ESCs could differentiate into cardiomyocytes, but the development and further differentiation of cardiovascular progenitors were significantly affected in MeCP2 deficiency. In addition, we revealed that loss of MeCP2 led to dysregulation of endogenous cardiac genes and myocardial structural alterations, although Mecp2-null mice did not exhibit obvious cardiac functional abnormalities. Furthermore, we detected methylation of the CpG islands in the Tbx5 locus, and showed that MeCP2 could target these sequences. Taken together, these results suggest that MeCP2 is an important regulator of the gene-expression program responsible for maintaining normal cardiac development and cardiomyocyte structure.

Cardiac-Specific SOCS3 Deletion Prevents In Vivo Myocardial Ischemia Reperfusion Injury through Sustained Activation of Cardioprotective Signaling Molecules.

Myocardial ischemia reperfusion injury (IRI) adversely affects cardiac performance and the prognosis of patients with acute myocardial infarction. Although myocardial signal transducer and activator of transcription (STAT) 3 is potently cardioprotective during IRI, the inhibitory mechanism responsible for its activation is largely unknown. The present study aimed to investigate the role of the myocardial suppressor of cytokine signaling (SOCS)-3, an intrinsic negative feedback regulator of the Janus kinase (JAK)-STAT signaling pathway, in the development of myocardial IRI. Myocardial IRI was induced in mice by ligating the left anterior descending coronary artery for 1 h, followed by different reperfusion times. One hour after reperfusion, the rapid expression of JAK-STAT-activating cytokines was observed. We precisely evaluated the phosphorylation of cardioprotective signaling molecules and the expression of SOCS3 during IRI and then induced myocardial IRI in wild-type and cardiac-specific SOCS3 knockout mice (SOCS3-CKO). The activation of STAT3, AKT, and ERK1/2 rapidly peaked and promptly decreased during IRI. This decrease correlated with the induction of SOCS3 expression up to 24 h after IRI in wild-type mice. The infarct size 24 h after reperfusion was significantly reduced in SOCS3-CKO compared with wild-type mice. In SOCS3-CKO mice, STAT3, AKT, and ERK1/2 phosphorylation was sustained, myocardial apoptosis was prevented, and the expression of anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) was augmented. Cardiac-specific SOCS3 deletion led to the sustained activation of cardioprotective signaling molecules including and prevented myocardial apoptosis and injury during IRI. Our findings suggest that SOCS3 may represent a key factor that exacerbates the development of myocardial IRI.

[13-year history of scleroderma complicated by renal crisis and thrombotic microangiopathy treated with plasma exchange: A case report].

A 77-year-old man with a 13-year history of systemic sclerosis (SSc) was admitted to our hospital with fever, appetite loss, and disorientation. The patient was well 2 days prior to the admission and had been taking a low dose of a steroid and vasodilators over the previous 10 years. In regular clinic visits, his blood pressure was normotensive and serum creatinine (Cr) was within the normal range. On admission, hypertension (blood pressure 214/105 mmHg), proteinuria, and hypercreatinemia (3.6 mg/dL) led to the diagnosis of sclerotic renal crisis (SRC). Thrombocytopenia (5.4 × 10(4)/µL), erythrocyte fragmentation, and elevated lactate dehydrogenase were suggestive of thrombotic microangiopathy (TMA). The immediate initiation of angiotensin-converting enzyme inhibitor therapy and plasma exchange (PE) rapidly improved the disorientation and thrombocytopenia. It is notable that SRC might occur in patients with a 13-year history of SSc. PE should be considered as a treatment option for SRC complicated by TMA.

Renal Nerve-Mediated Erythropoietin Release Confers Cardioprotection During Remote Ischemic Preconditioning.

BACKGROUND: Remote ischemic preconditioning (RIPC) induced by transient limb ischemia is a powerful innate mechanism of cardioprotection against ischemia. Several described mechanisms explain how RIPC may act through neural pathways or humoral factors; however, the mechanistic pathway linking the remote organ to the heart has not yet been fully elucidated. This study aimed to investigate the mechanisms underlying the RIPC-induced production of Janus kinase (JAK)-signal transducer and activator of the transcription (STAT)-activating cytokines and cardioprotection by using mouse and human models of RIPC. METHODS AND RESULTS: Screened circulating cardioprotective JAK-STAT-activating cytokines in mice unexpectedly revealed increased serum erythropoietin (EPO) levels after RIP induced by transient ischemia. In mice, RIPC rapidly upregulated EPO mRNA and its main transcriptional factor, hypoxia-inducible factor-1α (HIF1α), in the kidney. Laser Doppler blood flowmetry revealed a prompt reduction of renal blood flow (RBF) after RIPC. RIPC activated cardioprotective signaling pathways and the anti-apoptotic Bcl-xL pathway in the heart, and reduced infarct size. In mice, these effects were abolished by administration of an EPO-neutralizing antibody. Renal nerve denervation also abolished RIPC-induced RBF reduction, EPO production, and cardioprotection. In humans, transient limb ischemia of the upper arm reduced RBF and increased serum EPO levels. CONCLUSIONS: Based on the present data, we propose a novel RIPC mechanism in which inhibition of infarct size by RIPC is produced through the renal nerve-mediated reduction of RBF associated with activation of the HIF1α-EPO pathway.

New polycomb group protein enhancer of zeste homolog (EZH) 2-derived peptide with the potential to induce cancer-reactive cytotoxic T lymphocytes in prostate cancer patients with HLA-A3 supertype alleles.

Analyses on reactivity of anti-cancer cytotoxic T lymphocytes (CTLs) and clinical application of peptide-based anti-cancer vaccine have been mainly focused on patients with HLA-A2 or -A24 alleles. In this study, we identified an enhancer of zeste homolog (EZH) 2-derived peptide applicable for anti-cancer vaccine for prostate cancer patients with HLA-A3 supertype alleles. Five EZH2-derived peptides that were prepared based on the binding motif to the HLA-A3 supertype alleles (HLA-A11, -A31, and -A33) were functionally screened for their potential to induce peptide-specific CTLs from peripheral blood mononuclear cells (PBMCs) of HLA-A3 supertype allele(+) prostate cancer patients. As a result, EZH2733-741 peptide was found to efficiently induce peptide-specific CTLs. The EZH2733-741 peptide-stimulated and purified CD8(+) T cells from PBMCs of HLA-A3 supertype allele(+) prostate cancer patients showed higher cytotoxicity against HLA-A3 supertype allele-expressing LNCaP prostate cancer cells than against parental LNCaP cells. This cytotoxicity against HLA-A3 supertype allele-expressing LNCaP cells was partially but significantly inhibited by the addition of EZH2733-741 peptide-pulsed competitive cells. These results indicate that the EZH2733-741 peptide could be a promising candidate for peptide-based immunotherapy for HLA-A3 supertype allele(+) prostate cancer patients.

Lidocaine preferentially inhibits the function of purinergic P2X7 receptors expressed in Xenopus oocytes.

BACKGROUND: Lidocaine has been widely used to relieve acute pain and chronic refractory pain effectively by both systemic and local administration. Numerous studies reported that lidocaine affects several pain signaling pathways as well as voltage-gated sodium channels, suggesting the existence of multiple mechanisms underlying pain relief by lidocaine. Some extracellular adenosine triphosphate (ATP) receptor subunits are thought to play a role in chronic pain mechanisms, but there have been few studies on the effects of lidocaine on ATP receptors. We studied the effects of lidocaine on purinergic P2X3, P2X4, and P2X7 receptors to explore the mechanisms underlying pain-relieving effects of lidocaine. METHODS: We investigated the effects of lidocaine on ATP-induced currents in ATP receptor subunits, P2X3, P2X4, and P2X7 expressed in Xenopus oocytes, by using whole-cell, two-electrode, voltage-clamp techniques. RESULTS: Lidocaine inhibited ATP-induced currents in P2X7, but not in P2X3 or P2X4 subunits, in a concentration-dependent manner. The half maximal inhibitory concentration for lidocaine inhibition was 282 ± 45 µmol/L. By contrast, mepivacaine, ropivacaine, and bupivacaine exerted only limited effects on the P2X7 receptor. Lidocaine inhibited the ATP concentration-response curve for the P2X7 receptor via noncompetitive inhibition. Intracellular and extracellular N-(2,6-dimethylphenylcarbamoylmethyl) triethylammonium bromide (QX-314) and benzocaine suppressed ATP-induced currents in the P2X7 receptor in a concentration-dependent manner. In addition, repetitive ATP treatments at 5-minute intervals in the continuous presence of lidocaine revealed that lidocaine inhibition was use-dependent. Finally, the selective P2X7 receptor antagonists Brilliant Blue G and AZ11645373 did not affect the inhibitory actions of lidocaine on the P2X7 receptor. CONCLUSIONS: Lidocaine selectively inhibited the function of the P2X7 receptor expressed in Xenopus oocytes. This effect may be caused by acting on sites in the ion channel pore both extracellularly and intracellularly. These results help to understand the mechanisms underlying the analgesic effects of lidocaine when it is administered locally at least.

A pilot three-month sitagliptin treatment increases serum adiponectin level in Japanese patients with type 2 diabetes mellitus--a randomized controlled trial START-J study.

BACKGROUND: The dipeptidyl-peptidase-IV (DPP-4) inhibitors, including sitagliptin, are used for the treatment of type 2 diabetes mellitus (T2DM). Adiponectin, an adipocyte-derived circulating protein, has anti-atherosclerotic and anti-diabetic properties and is effectively elevated in bloodstream by thiazolidinediones, an insulin sensitizer. However, the effect of sitagliptin treatment on serum adiponectin level in T2DM has not fully elucidated in Japanese T2DM patients. The aim of the present study was to examine the effect of sitagliptin treatment on serum adiponectin levels in T2DM subjects. METHODS: Twenty-six consecutive Japanese T2DM outpatients were recruited between April 2011 and March 2013, and randomized into the control (conventional treatment, n = 10) group and sitagliptin treatment group (n = 16). Serum adiponectin was measured by enzyme-linked immunosorbent assay. RESULTS: Indices of glycemic control, such as hemoglobin A1c, glycated albumin, and 1.5-anhydro-D-glucitol, were significantly improved after the three-month treatment in both the control and sitagliptin groups. Serum adiponectin level was significantly increased in sitagliptin group from 6.7 ± 0.8 to 7.4 ± 1.0 µg/mL without change of body mass index (p = 0.034), while serum adiponectin level was not altered in the control group (p = 0.601). CONCLUSION: In Japanese T2DM patients, serum adiponectin level was elevated by three-month treatment with sitagliptin without change of body weight. TRIAL REGISTRATION: UMIN000004721.

Neurosteroids allopregnanolone sulfate and pregnanolone sulfate have diverse effect on the α subunit of the neuronal voltage-gated sodium channels Nav1.2, Nav1.6, Nav1.7, and Nav1.8 expressed in xenopus oocytes.

BACKGROUND: The neurosteroids allopregnanolone and pregnanolone are potent positive modulators of γ-aminobutyric acid type A receptors. Antinociceptive effects of allopregnanolone have attracted much attention because recent reports have indicated the potential of allopregnanolone as a therapeutic agent for refractory pain. However, the analgesic mechanisms of allopregnanolone are still unclear. Voltage-gated sodium channels (Nav) are thought to play important roles in inflammatory and neuropathic pain, but there have been few investigations on the effects of allopregnanolone on sodium channels. METHODS: Using voltage-clamp techniques, the effects of allopregnanolone sulfate (APAS) and pregnanolone sulfate (PAS) on sodium current were examined in Xenopus oocytes expressing Nav1.2, Nav1.6, Nav1.7, and Nav1.8 α subunits. RESULTS: APAS suppressed sodium currents of Nav1.2, Nav1.6, and Nav1.7 at a holding potential causing half-maximal current in a concentration-dependent manner, whereas it markedly enhanced sodium current of Nav1.8 at a holding potential causing maximal current. Half-maximal inhibitory concentration values for Nav1.2, Nav1.6, and Nav1.7 were 12 ± 4 (n = 6), 41 ± 2 (n = 7), and 131 ± 15 (n = 5) µmol/l (mean ± SEM), respectively. The effects of PAS were lower than those of APAS. From gating analysis, two compounds increased inactivation of all α subunits, while they showed different actions on activation of each α subunit. Moreover, two compounds showed a use-dependent block on Nav1.2, Nav1.6, and Nav1.7. CONCLUSION: APAS and PAS have diverse effects on sodium currents in oocytes expressing four α subunits. APAS inhibited the sodium currents of Nav1.2 most strongly.

Identification of erythropoietin receptor-derived peptides having the potential to induce cancer-reactive cytotoxic T lymphocytes from HLA-A24(+) patients with renal cell carcinoma.

Molecular targeting therapy with anti-angiogenic agents, including sunitinib and sorafenib, has been proven to be the first- and second-line standard treatments for metastatic renal cell carcinoma (mRCC) worldwide. Despite their significant antitumor effects, most of the patients with mRCC have not been cured. Under such circumstances, anti-cancer immunotherapy has been considered as a promising treatment modality for mRCC, and cytotoxic T lymphocytes (CTLs) are the most powerful effectors among several immune cells and molecules. Therefore, we previously conducted anti-cancer vaccine therapy with peptides derived from carbonic anhydrase-9 and vascular endothelial growth factor receptor-1 as phase-I/II trials for mRCC patients and reported their clinical benefits. Alternatively, up-regulated expression of erythropoietin (Epo) and its receptor (EpoR) in RCC has been reported, and their co-expression is involved in tumorigenesis. In order to increase options for peptide-based vaccination therapy, we searched for novel EpoR-peptides for HLA-A24(+) RCC patients. Among 5 peptides derived from EpoR, which were prepared based on the binding motif to the HLA-A24 allele, EpoR52-60 peptide had the potential to induce peptide-specific CTLs from peripheral blood mononuclear cells of HLA-A24(+) RCC patients. Cytotoxicity toward HLA-A24(+) and EpoR-expressing RCC cells was ascribed to peptide-specific CD8(+) T cells. These results indicate that the EpoR52-60 peptide could be a promising candidate for a peptide-based anti-cancer vaccine for HLA-A24(+) mRCC patients.

Cardiomyocyte-specific transgenic expression of lysyl oxidase-like protein-1 induces cardiac hypertrophy in mice.

Lysyl oxidase (LOX) and LOX-like protein-1 (LOXL-1) are extracellular matrix-embedded amine oxidases that have critical roles in the cross-linking of collagen and elastin. LOX family proteins are abundantly expressed in the remodeled heart of animals and humans and are implicated in cardiac fibrosis; however, their role in cardiac hypertrophy is unknown. In this study, in vitro stimulation with hypertrophic agonists significantly increased LOXL-1 expression, LOX enzyme activity and [(3)H] leucine incorporation in neonatal rat cardiomyocytes. A LOX inhibitor, beta-aminopropionitrile (BAPN), inhibited agonist-induced leucine incorporation in cardiomyocytes in vitro, suggesting the involvement of LOXL-1 in cardiomyocyte hypertrophy. Abdominal aortic constriction in rats produced left ventricular hypertrophy in parallel with LOXL-1 mRNA upregulation. And BAPN administration significantly inhibited angiotensin II-induced cardiac hypertrophy in vivo. These results suggest a role of LOXL-1 in cardiac hypertrophy in vivo. We generated transgenic mice with cardiomyocyte-specific expression of LOXL-1. LOXL-1 transgenic mice pups were born normally and grew to adulthood without increased mortality; these mice exhibited a greater left ventricle to body weight ratio, larger myocyte diameter, and more brain natriuretic peptide expression than their wild-type littermates. Echocardiography revealed that the LOXL-1 transgenic mice also had greater wall thickness with preserved cardiac contraction. Our results indicate a possible fundamental role of LOXL-1 in cardiac hypertrophy.

Sleep-wake cycle irregularities in type 2 diabetics.

BACKGROUND: The incidence of type 2 diabetes mellitus (T2DM) has been increasing in recent years. Sleep loss and circadian rhythm abnormalities are thought to be one of the underlying causes of adverse metabolic health. However, little is known about sleep-wake cycle irregularities in T2DM. The present study compared the bedtime, waking time, and estimated sleep duration between T2DM and non-T2DM subjects. METHODS: The study subjects were 106 consecutive outpatients with lifestyle-related diseases (males/females = 56/50), who answered a questionnaire on sleep status. Subjects were divided into two groups; non-T2DM (n = 32) and T2DM (n = 74) subjects. RESULTS: T2DM subjects retired to bed on weekdays and holidays significantly later than non-T2DM subjects (23:43 versus 22:52, p = 0.0032; 23:45 versus 22:53, p = 0.0038, respectively), and woke up significantly later on weekdays and holidays, compared with non-T2DM subjects (06:39 versus 06:08, p = 0.0325; 06:58 versus 06:24, p = 0.0450, respectively). There was no significant difference in the estimated sleep duration between the two groups. Daytime sleepiness was reported significantly more commonly by T2DM subjects than non-T2DM subjects (p = 0.0195). CONCLUSIONS: Sleep-wake cycle irregularities are more common in T2DM subjects than non-T2DM. Confirmation that such irregularity plays a role in the metabolic abnormalities of T2DM requires further investigation in the future. TRIAL REGISTRATION: UMIN 000002998.