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CheckMate 214 study revealed that nivolumab plus ipilimumab combination therapy showed a strong and durable effect compared to sunitinib for patients with advanced renal cell carcinoma (aRCC). Most of the patients underwent previous nephrectomy before systemic treatment. We retrospectively investigated the clinical outcomes of Japanese patients treated with cytoreductive nephrectomy following nivolumab plus ipilimumab for aRCC.Seventy-nine patients were treated with systemic therapy for aRCC between October 2018 and August 2021 at the Saitama Medical University International Medical Center. Ten of 61 patients treated with nivolumab plus ipilimumab underwent cytoreductive nephrectomy after the combined immunotherapy.The median overall survival and progression-free survival were 24.3 and 15.9 months, respectively. The objective response rate was 50.8%; 9.8% of patients had a complete response, and the median time to objective response was 3.2 (range=1.3-19.7) months. The estimated percentage of patients who sustained an objective response at 30 months was 73.0%. Twenty-three patients (74%) in the complete or partial response (CR/PR) group, 11 patients (52%) in the stable disease (SD) group, and two patients (22%) in the progressive disease (PD) group had immune-related adverse events of grade 3 or higher, respectively. For all 10 patients, cytoreductive nephrectomy following nivolumab plus ipilimumab treatment were completed safely. Three patients achieved a pathological complete response without viable cancer cells. Only two patients had residual lesions on images after deferred cytoreductive nephrectomy; the remaining patients achieved radiological CR.Cytoreductive nephrectomy after nivolumab plus ipilimumab treatment could be useful in a limited number of cases, possibly resulting in curative nephrectomy due to the durable therapeutic effect of immunotherapy.

Covered stent placement (CSP) is gaining popularity for the management of delayed massive hemorrhage (DMH) after pancreatic or biliary surgery. However, early studies have produced conflicting results regarding the potential advantages of the procedure. We aimed to compare the short- and medium-term outcomes of arterial embolization (AE) and CSP for DMH.We analyzed data for patients who underwent AE or CSP as an endovascular treatment (EVT) for DMH from the common hepatic artery (CHA) and its distal arteries between January 2009 and December 2019. We evaluated the major hepatic complications, in-hospital mortality, and 1-year mortality associated with the procedures, according to age, sex, reintervention, arterial variant, interval between surgery and EVT, and portal vein stenosis.All hemorrhages were treated using AE (n = 50) or CSP (n = 20). CSP was associated with no in-hospital mortality (32% vs. 0%, p = 0.003), and lower incidences of major hepatic complications (44% vs. 10%, p = 0.011) and 1-year mortality (54% vs. 25%, p = 0.035) compared with AE, respectively. There was no significant difference in technical success and reintervention rates. Compared with AE, the risk-adjusted odds ratios for CSP (95% confidence intervals) for major hepatic complications and 1-year mortality were 0.06 (0.01-0.39) and 0.19 (0.05-0.71), respectively.CSP is superior to AE regarding major hepatic complications and in-hospital- and 1-year mortality in patients with DMH from hepatic arteries.

Treatment for venous thromboembolic conditions differs significantly depending on whether the condition is acute or chronic. Endovenous treatment is now available for treating the most severe cases of acute massive pulmonary thromboembolism, and the goal is rapid central clot removal to relieve life-threatening pulmonary circulation. Endovenous catheter interventions include catheter-directed thrombolysis and catheter-assisted thrombus removal. The latter is divided into aspiration thrombectomy, fragmentation, and rheolytic thrombectomy. Data from cohort studies indicate that the clinical outcome and safety after open surgical treatment and endovenous treatment may be comparable. This paper reviews the current approaches to endovenous treatment for acute massive pulmonary thromboembolism, and presents our study of hybrid treatment using a combination of local fibrinolysis, mechanical fragmentation, and clot aspiration.

A formative evaluation of teaching, considering both students' perceptions and teachers' experiences, is essential for class plan improvement. This study investigated the class improvement process, involving the study of these two populations' input. Specifically, we examined a physical education (PE) teacher's class process by analysing all freshmen students' perceptions of that class via a quantitative content analysis. The course units were arranged in a particular order and those of 2015 were redesigned. We extracted eight codes after text mining students' responses: educational materials, group cohesion, play skills, game, interaction, others, self, and positive emotion. After the 2015 course ended, we re-analysed the students' class perceptions. The occurrence rates of 'interaction', 'group cohesion', and 'educational materials' were higher during the early stages in both units; game-based instruction had a positive effect on students' emotions. Thus, we identified the problem with the placement of course units and implemented improvement measures.

When the intercostal and lumbar arteries are occluded by plaque or thrombus, spinal cord perfusion depends on collateral circulation. Some reports have demonstrated collateral circulation to the artery of Adamkiewicz via computed tomography and magnetic resonance angiographies. However, intraspinal collateral circulation to the artery of Adamkiewicz along the spinal cord has not been reported previously. Here, we report two patients with intraspinal collateral circulation to the artery of Adamkiewicz along the spinal cord that was detected with intra-arterial injected computed tomography angiography.

Transcranial direct current stimulation (tDCS) has been reported to modify cortical function by inducing alterations in the underlying brain function. P50auditory evoked potentials, as assessed using a paired auditory stimulus (S1 and S2) paradigm, are thought to reflect a sensory gating process in which the functional involvement of the dorsolateral prefrontal cortex (DLPFC) is suggested. P50 sensory gating has also been reported to be associated with the pathogenesis of psychiatric diseases such as schizophrenia and anxiety-related disorders. Here we investigated whether the tDCS over the DLPFC could modulate the cortical function leading to alteration of the P50 sensory gating. P50 gating indices (the S2/S1 ratio and S1-S2 difference) were measured during the tDCS (current 1.0 mA, duration 15 min) over the DLPFC with different conditions (anodal, cathodal and sham). Ten male healthy volunteers were studied on separate days in a single blinded paradigm. We observed that the cathodaltDCS significantly altered the mean P50 gating indices compared to the other two conditions. Our results suggest that sensory gating could be modulated by cathodaltDCS on the left DLPFC but not by anodal/sham tDCS.

This study investigated the anatomical relationship between the common carotid artery and internal jugular vein during head rotation for the effective performance of percutaneous transjugular procedures. The subjects included 30 volunteers who had never undergone internal jugular vein cannulation. In the supine position, two-dimensional ultrasonographic images of the right internal jugular vein and common carotid artery were obtained, 2 and 4 cm above the clavicle, along the lateral border of the sternal head of the sternocleidomastoid muscle. Ultrasonographic images were examined for head rotation at 0°, 15°, 30°, 45°, 60°, and 75° from the midline to the left. The percentage of overlap of the common carotid artery by the internal jugular vein and the flattening of the internal jugular vein at each head rotation position were measured and evaluated. The overlap of the common carotid artery by the internal jugular vein significantly increased at ≥45° of head rotation 2 cm above the clavicle (P

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related deaths in the world. The Barcelona Clinic Liver Cancer (BCLC) classification has recently emerged as the standard classification system for clinical management of patients with HCC. According to the BCLC staging system, curative therapies (resection, transplantation, and percutaneous ablation) can improve survival in HCC patients diagnosed at an early stage and offer potential long-term curative effects. Patients with intermediate-stage HCC benefit from transcatheter arterial chemoembolization (TACE), and those diagnosed at an advanced stage receive sorafenib, a multikinase inhibitor, or conservative therapy. Most patients receive palliative or conservative therapy only, and approximately 50% of patients with HCC are candidates for systemic therapy. TACE is often recommended for advanced-stage HCC patients all over the world because these patients desire therapy that is more effective than systemic chemotherapy or conservative treatment. This paper aims to summarize both the published data and important ongoing studies for TACE and to discuss technical improvements in TACE for advanced-stage HCC.

A 61-year-old man was referred with acute type A aortic dissection and underwent emergent hemiarch graft replacement with open stent graft implantation into the distal aortic arch. Atrial and ventricular bipolar temporary epicardial pacing wires (TEPWs) were placed after surgery. On the seventh post-operative day, the TEPWs were cut at the level of the skin, but left in …

Auditory P50 suppression, which is assessed using a paired auditory stimuli (S1 and S2) paradigm to record the P50 mid-latency evoked potential, is assumed to reflect sensory gating. Recently, P50 suppression deficits were observed in patients with anxiety disorders, including panic disorder, post-traumatic stress disorder and obsessive-compulsive disorder, as we previously reported. The processes of fear conditioning are thought to play a role in the pathophysiology of anxiety disorders. In addition, we found that the P50 sensory gating mechanism might be physiologically associated with fear conditioning and extinction in a simple human fear-conditioning paradigm that involved a light signal as a conditioned stimulus (CS+). Our objective was to investigate the different patterns of P50 suppression in a discrimination fear-conditioning paradigm with both a CS+ (danger signal) and a CS- (safety signal). Twenty healthy volunteers were recruited. We measured the auditory P50 suppression in the control (baseline) phase, in the fear-acquisition phase, and in the fear-extinction phase using a discrimination fear-conditioning paradigm. Two-way (CSs vs. phase) Analysis of variance with repeated measures demonstrated a significant interaction between the two factors. Post-hoc LSD analysis indicated that the P50 S2/S1 ratio in the CS+ acquisition phase was significantly higher than that in the CS- acquisition phase. These results suggest that the auditory P50 sensory gating might differ according to the cognition of the properties (potentially dangerous or safe) of the perceived signal.

Depression has been known to reduce the prefrontal activity associated with the execution of certain cognitive tasks, although whether a temporarily depressed or anxious mood in healthy individuals affects the prefrontal blood oxygen level during cognitive tasks is unknown. Combining the measurement of prefrontal activity with near-infrared spectroscopy (NIRS) and the two cognitive tasks, namely the letter version of the verbal fluency test (VFT-l) and the Stroop test, we measured the effect of a depressed or anxious mood and gender on the changes in the prefrontal oxygenated hemoglobin (Oxy-Hb) levels during those cognitive tests in healthy individuals. Depressed mood or anxious mood was assessed by the Hospital Anxiety and Depression Scale (HADS). Thereby we aimed to explore the possibility of NIRS measurement for detecting the early subclinical manifestation of major depression. Moreover, we examined the possible relationships between prefrontal activation and the functional Val66Met polymorphisms of the brain derived neurotropic factor (BDNF) gene and serum BDNF level. As a result, the increased prefrontal Oxy-Hb levels during cognitive tasks were significantly correlated with the severity of depressed mood in males. The course of the prefrontal Oxy-Hb increase was different depending on the cognitive tasks, i.e., the VFT-l or the Stroop test, in both genders. Correlations of BDNF genotype and serum BDNF level with the prefrontal Oxy-Hb levels during those cognitive tasks were negative. Our results suggest that the early subclinical manifestation of depressed mood in males might be detected by the NIRS measurement, which is not correlated with the individual properties of BDNF.

Aims Parkinson's disease (PD) affects the nigrostriatal projections leading to micturition disturbance in most cases. Overactive bladder (OAB) symptoms such as urinary urgency or urgent urinary incontinence are common amongst PD patients. Several urodynamic studies have revealed that detrusor overactivity causes OAB symptoms in PD patients. We assert that striatal dysfunction might contribute to the pathogenesis of detrusor overactivity in PD patients. However, the role of the striatum in bladder contraction remains unclear. Methods We generated spontaneous isovolumetric bladder contractions in 12 ketamine-anesthetized adult male cats and subsequently performed electrical stimulation and extracellular single-unit recording in the striatum. Results Electrical stimulation applied to the posterior ventral caudate nucleus and the adjacent putamen educed inhibition of the spontaneous bladder contraction. None of the responses were facilitatory. Electrical stimulation was most effective at an amplitude of 70–400 µA. Forty-six neurons that exhibited correlation to spontaneous bladder contraction were recorded in the striatum. Thirty-five neurons were found to be tonically active throughout the bladder relaxation phase, and the remaining 11 neurons were active during the bladder contraction phase. These particular neurons were located within the area in which spontaneous bladder contraction was inhibited by electrical stimulation. Conclusions Electrical stimulation was found to inhibit bladder contraction, and a correlation was observed between spontaneous bladder relaxation/contraction and neuronal firing in the posterior ventral striatum. Neurourol. Urodyn. 28:549–554, 2009. © 2009 Wiley-Liss, Inc.

Proteomic analysis of developmental toxicity by two-dimensional electrophoresis (2-DE) may detect gender-related toxic effects in embryos without visible gender characteristics. In the present study, we explored sexing of rat embryo stored in frozen 2-DE samples by polymerase chain reaction (PCR) of a male-specific gene sequence, sex determining region Y (Sry). The embryo proper and yolk sac membrane at gestation day 11 from Wistar rats were used for stored embryonic 2-DE samples. The embryonic 2-DE samples were desalted and their total DNA was extracted. The Sry sequence in the extracted DNA was amplified by PCR and the product was analyzed by agarose gel electrophoresis. The embryos with the PCR product of Sry were determined as male, and those without the product were determined as female. It was concluded that stored embryonic 2-DE samples could be used for retrospective examination of gender-related effects in proteomic analysis of developmental toxicity.

Indium, a precious metal classified in group 13 (IIIB) in the periodic table, has been used increasingly in the semiconductor industry. Because indium is a rare metal, technology for indium recycling from transparent conducting films for liquid crystal displays is desired, and its safety evaluation is becoming increasingly necessary. The developmental toxicity of indium in experimental animals was summarized. The intravenous or oral administration of indium to pregnant animals causes growth inhibition and the death of embryos in hamsters, rats, and mice. The intravenous administration of indium to pregnant animals causes embryonic or fetal malformation, mainly involving digit and tail deformities, in hamsters and rats. The oral administration of indium also induces fetal malformation in rats and rabbits, but requires higher doses. No teratogenicity has been observed in mice. Caudal hypoplasia, probably due to excessive cell loss by increased apoptosis in the tailbud, in the early postimplantation stage was considered to account for indium-induced tail malformation as a possible pathogenetic mechanism. Findings from in vitro experiments indicated that the embryotoxicity of indium could have direct effects on the conceptuses. Toxicokinetic studies showed that the embryonic exposure concentration was more critical than the exposure time regarding the embryotoxicity of indium. It is considered from these findings that the risk of the developmental toxicity of indium in humans is low, unless an accidentally high level of exposure or unknown toxic interaction occurs because of possible human exposure routes and levels (i.e. oral, very low-level exposure).

Tamoxifen (Tam) decreased the clearance of L-glutamate (L-Glu) by cultured astrocytes at 1 pM, 1 nM, and 1 μM, but became toxic at 10 μM. When L-Glu transporters were mostly inhibited by threo-β-benzyloxyaspartate (TBOA) (1 mM) or D,L-threo-β-hydroxyaspartate (THA) (1 mM), Tam (1 nM) did not change extracellular L-Glu concentration, confirming that Tam attenuates L-Glu transport through L-Glu transporters. ICI182,780, LY294002, and U0126 inhibited the effect of Tam dose-dependently, suggesting the involvement of estrogen receptors (ERs), the phosphatidylinositol 3-kinase (PI3K) cascade, and the mitogen-activated protein kinase (MAPK) cascade in the effect of Tam. Keywords:: tamoxifen, L-glutamate transporter, astrocyte

Objective Paradoxical vocal cord motion (PVCM) is a well recognized respiratory condition in which active adduction of the vocal cords during inspiration causes functional airway obstruction. It is considered that laryngeal reflex acceleration underlies the generation of nonorganic PVCM. In various situations producing PVCM, multiple system atrophy (MSA) is a representative neurological disease causing nocturnal laryngeal stridor attributed to PVCM. The purpose of this review is to identify the underlying mechanisms associated with nonorganic and MSA-related PVCM. The following issues are addressed in this review: (1) the pathophysiology of nonorganic and MSA-related PVCM, (2) the relationships between PVCM and airway reflexes, and (3) the treatment for MSA-related PVCM. Methods Review. Results and conclusions An abnormality of the laryngeal output-feedback control underlies nonorganic PVCM, which is usually triggered by an excessive response to external and internal airway stimuli. Similarly, several clinical and experimental evidence suggest that MSA-related PVCM is attributed to the airway reflex as well as to paradoxical central outputs resulting from the MSA-induced damage to the pontomedullary respiratory center. Application of continuous positive airway pressure (CPAP), which suppresses the reflexive inspiratory activation of adductors, is recommended as the treatment for MSA-related PVCM.

To examine whether motor commands of two or more distinct laryngeal motor patterns converge onto a common premotor network, we conducted dual recordings from the laryngeal adductor motoneuron and its premotor neuron within the brainstem respiratory circuitry during fictive breathing, coughing, sneezing, and swallowing in decerebrate paralyzed cats. Expiratory neurons with an augmenting firing pattern (EAUG), whose action potentials evoked monosynaptic IPSPs in the adductor motoneurons, sharply fired during the expulsive phases of fictive coughing and sneezing, during which the adductor motoneurons transiently repolarized. In contrast, these premotor neurons were silent during the swallow-related hyperpolarization in adductor motoneurons. These results show that one class of medullary respiratory neuron, EAUG, is multifunctional and shared among the central pattern generators (CPGs) for breathing, coughing, and sneezing. In addition, although the CPGs underlying these three behaviors and the swallowing CPG do overlap, EAUG neurons are not part of the swallowing CPG and, in contrast to the other three behaviors, are not a source of inhibitory input to adductor motoneurons during swallowing.

We investigated the effect of beta-estradiol (E2) on synaptogenesis in the hippocampus using organotypic hippocampal slice cultures and subregional hippocampal neuron cultures. E2 increased the expression of PSD95, a postsynaptic marker, specifically in stratum lucidum of Cornu Ammonis 3 (CA3SL) in cultured hippocampal slices. E2 also increased the spine density at the proximal site of CA3 apical dendrites in CA3SL and PSD95 was clustered on these spine heads. The effects of E2 on the expression of PSD95 and the spine density disappeared when the dentate gyrus (DG) had been excised at 1 day in vitro (DIV). FM1-43 analysis of subregional hippocampal neuron cultures which were comprised of Ammon's horn neurons, DG neurons, or a mixture of these neurons, revealed that E2 increased the number of presynaptic sites in the cultures that contained DG neurons. K252a, a potent inhibitor of the high affinity receptor of brain-derived neurotrophic factor (BDNF), and function-blocking antibody to BDNF (BDNFAB) completely inhibited the effects of E2 in hippocampal slice cultures and subregional neuron cultures, whereas ICI182,780 (ICI), a strong antagonist of nuclear estrogen receptors (nERs), did not. Expression of BDNF in DG neurons was markedly higher than that in Ammon's horn neurons and E2 did not affect these expression levels. E2 significantly increased the BDNF release from DG neurons. KT5720, a specific inhibitor of 3'-5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA), and Rp-adenosine 3', 5'-cyclic monophosphorothioate triethylammonium salt (Rp-cAMP), a non-hydrolyzable diastereoisomer and a potent inhibitor of PKA, completely suppressed the E2-induced increase in BDNF release, whereas ICI and U0126, a potent inhibitor of MAP kinase kinase (MEK), did not. These results suggest that E2 induces synaptogenesis between mossy fibers and CA3 neurons by enhancing BDNF release from DG granule cells in a nER-independent and PKA-dependent manner.

In the human palm/sole, mental or physical stimuli induce an increase in sweat secretion and a decrease in skin blood flow (SkBF). However, the central pathways of these responses remain unclear. We measured sweat secretion and SkBF in the cat footpad by electrically stimulating the raphe. Stimulation of the rostral raphe magnus/pallidus elicited a reduction in SkBF without affecting sweat secretion. Stimulation of the mid to caudal raphe magnus/pallidus elicited an increase in both sweat secretion and SkBF. The raphe magnus/pallidus may play a crucial role in skin vasomotor and sudomotor responses in the cat footpad.

The raphe nucleus has a variety of physiological functions, including emotion, regulation of skeletal muscle motoneurons, spinal transmission of nociceptive signals, sleep, respiration, gastric motility, and cardiovascular function. Recent evidence has shown that centrally administered serotonin has modulatory effects on micturition function, and that decreased brain serotonin might underlie depression and an overactive bladder. We applied high-frequency stimulation (HFS; 0.2-ms duration, 100 Hz) in the raphe nucleus and the adjacent midline area in 20 supracollicular decerebrate cats, which mostly elicited inhibition of the micturition reflex. The effective amplitude of the electrical stimulation for evoking inhibitory responses was less than 50 muA. We also examined single neuronal activities in the raphe nucleus in response to isovolumetric spontaneous micturition reflexes. In total, 79 neurons were recorded in the raphe nucleus that were related to urinary storage/micturition cycles. Of the neurons recorded, the most common were tonic storage neurons (48%), followed by tonic micturition neurons (28%), phasic storage neurons (18%), and phasic micturition neurons (6%). In addition to the tonic/phasic as well as storage/micturition classification, the neurons showed diverse discharge patterns: augmenting, constant and decrementing, with the constant discharge pattern being most common. Among neurons in the raphe nucleus, the neurons with a decrementing discharge pattern were concentrated in the rostral portion, whereas the augmenting and constant neurons existed diffusely. The storage and micturition neurons were intermingled in the rostral portion, whereas they were separate in the caudal portion. In conclusion, the results of the present study indicate that HFS of the raphe area inhibits the micturition reflex and that there are micturition-related neuronal firings in the raphe area in cats, suggesting that the raphe nucleus is involved in neural control of micturition.

To determine the synaptic source of the respiratory-related activity of laryngeal motoneurons, spike-triggered averaging of the membrane potentials of laryngeal motoneurons was conducted using spikes of respiratory neurons located between the Bötzinger complex and the rostral ventral respiratory group as triggers in decerebrate, paralyzed cats. We identified one excitatory and two inhibitory sources for inspiratory laryngeal motoneurons, and two inhibitory sources for expiratory laryngeal motoneurons. In inspiratory laryngeal motoneurons, monosynaptic excitatory postsynaptic potentials were evoked by spikes of inspiratory neurons with augmenting firing patterns, and monosynaptic inhibitory postsynaptic potentials (IPSPs) were evoked by spikes of expiratory neurons with decrementing firing patterns and by spikes of inspiratory neurons with decrementing firing patterns. In expiratory laryngeal motoneurons, monosynaptic IPSPs were evoked by spikes of inspiratory neurons with decrementing firing patterns and by spikes of expiratory neurons with augmenting firing patterns. We conclude that various synaptic inputs from respiratory neurons contribute to shaping the respiratory-related trajectory of membrane potential of laryngeal motoneurons.

Increased oxyradical production and membrane lipid peroxidation (MLP) occur under physiological and degenerative conditions in neurons. We investigated whether 4-hydroxynonenal (4HN), one of the membrane lipid peroxidation products, affects long-term potentiation (LTP) in the rat dentate gyrus in vitro. Treatment of hippocampal slices with 4HN (10 microM) enhanced LTP without affecting basal evoked potentials. The enhancement was completely inhibited by 2 microM nifedipine, a blocker of L-type Ca2+ channels. In cultured dentate gyrus neurons, treatment of the cells with 4HN for 24 h resulted in a significant amount of cell death that was detoxified by glutathione, whereas short-term treatment with 4HN (< or = 6 h) had no effect. Nifedipine partially but significantly suppressed the 4HN-induced cell death. These results suggest that 4HN modulates LTP and induces delayed cell death through L-type Ca2+ channel activation in the dentate gyrus. 4HN thereby plays an important role in both physiological and pathophysiological events in the hippocampus.

To study cerebral cortical function in equilibrium, cortical oxyhemoglobin saturation rate was measured during Caloric test for five volunteers. Near-infrared spectroscopy (NIRS) measuring backscattered reflection is a non-invasive, good method to study human cortical activation. Over both temporal areas, the oxyhemoglobin saturation rate changed during the irrigation to the auricle, the irrigation to the ear meatus, and during nystagmus. Caloric test induced various cortical activation; e.g., the sensation in irrigating iced water, vestibulo-autonomic response, vestibulo-ocular response, anticipation to the stimuli and so on.

We studied the patterns of membrane potential changes in vocal cord tensor motoneurons, i.e. cricothyroid muscle motoneurons (CTMs), during fictive breathing, vocalization, coughing, and swallowing in decerebrate paralyzed cats to determine the nature of central drives to CTMs during these behaviors. CTMs were identified by antidromic activation from the superior laryngeal nerve. During breathing, CTMs always depolarized during the inspiratory phase, and sometimes depolarized during the expiratory phase as well. During vocalization, CTMs strongly depolarized. During coughing, CTMs exhibited depolarizations during both inspiratory and expiratory phases, but it was interrupted by a transient repolarization between the last part of the inspiratory phase and the first part of the abdominal burst during which chloride-dependent inhibitory postsynaptic potentials were revealed. During swallowing, most CTMs hyperpolarized, and this hyperpolarization was sometimes followed by a weak depolarization. We conclude that the main role of the cricothyroid muscle is vocalization but the functional roles in coughing and swallowing are minor, and that the CTM activity during resting breathing and vocalization are primarily controlled by excitatory inputs, while during coughing and swallowing, inhibitory inputs play roles in shaping membrane potential trajectories.

Objectives/Hypothesis: The authors have shown previously that the vocal cord adductor is activated during inspiration in patients with vocal cord abduction impairment and that this adductor inspiratory activity is abolished by relief from inspiratory tracheal negative pressure by opening the tracheostoma. (Shiba K. Isono S, Sekita Y, Tanaka A. Inspiratory activation of the vocal cord adductor, Part I: human study in patients with restricted abduction of the vocal cords. Laryngoscope 2004;114:372–375). The authors hypothesized that insufficient opening of the glottis during inspiration generates strong negative pressure in the trachea and that this negative pressure triggers an airway reflex that activates the adductor. Study Design: Experimental study of the mechanism of laryngeal obstruction using an animal model of restricted abduction of the vocal cords. Methods: To identify such an airway reflex, the authors recorded the adductor electromyogram in anesthetized cats whose vocal cords were mechanically adducted by stitching both cords together. To determine whether this reflex modulation of adductor activity is induced through afferents from the larynx or from the lower airway, the authors applied negative pressure to the subglottic space and lower airway separately. Results: The adductor was activated during inspiration with powerful negative pressure in the trachea. Negative pressure in the subglottic space had a more marked effect on the adductor activity than did pressure in the lower airway. The adductor inspiratory activity was virtually abolished by laryngeal deafferentation. Conclusion: Glottal narrowing during inspiration reflexly activates the vocal cord adductor. This paradoxical inspiratory-related adductor activation is induced by an airway reflex triggered mainly through afferents from the larynx and probably contributes to stridor and dyspnea in patients with laryngeal obstruction.

Modification of voltage-gated Ca(2+) channels by hydrogen peroxide, a membrane-permeable form of reactive oxygen species, in cultured dentate granule cells was examined using the whole cell patch clamp technique. Pretreatment with hydrogen peroxide (1 and 10 microM) for 2 h enhanced the Ca(2+) current without affecting its voltage dependence. The enhancement was completely cancelled by 1 mM glutathione, an antioxidant, and 2 microM nifedipine, an L-type Ca(2+) channel blocker. In contrast, the enhancement of the Ca(2+) current was not mimicked by pretreatment with 10 microg/ml tunicamycin, an endoplasmic reticulum stressor. These results suggest that oxidative stress induced by hydrogen peroxide selectively regulates the activity of L-type Ca(2+) channels.

Although recent studies have suggested that dentate granule cells play a key role in hippocampal functions, electrophysiological properties in these cells have not been sufficiently explored. In the present study, modification of voltage-gated Ca2+ channels by 4-hydroxynonenal (4HN), a major aldehydic product of membrane lipid peroxidation, in cultured dentate granule cells was examined using the whole-cell patch clamp technique. When whole-cell voltage clamp was applied, the cells exhibited a high-voltage-activated Ca2+ current, which was totally sensitive to 30 microM Cd2+ and partially sensitive to 2 microM nifedipine. 4HN enhanced the Ca2+ current in these cells. When L-type Ca2+ channels were blocked by application of nifedipine, the enhancement was completely canceled, whereas application of omega-conotoxin-GVIA or omega-agatoxin-IVA, blockers of N- and P/Q-type Ca2+ channels, respectively, had no effect. These results suggest that 4HN modulates L-type Ca2+ channels in the dentate granule cells, and thereby plays a role in the physiological and pathophysiological responses of these cells to oxidative stress.

We investigated the effects of estrogen-related compounds including xenoestrogens [17beta-estradiol (E2), 17alpha-ethynylestradiol (EE), diethylstilbestrol (DES), p-nonylphenol (PNP), bisphenol A (BPA) and 17alpha-estradiol (17alpha)] on l-glu uptake by cultured astrocytes via glutamate-aspartate transporter (GLAST). After 24 h treatment, E2 inhibited the l-glu uptake at 1 micro m and higher concentrations. EE and DES also inhibited the l-glu uptake at 1 nm and higher concentrations. The other four compounds had no effect. The effects of E2, EE and DES were completely blocked by 10 nm of ICI182 780 (ICI). beta-Estradiol 17-hemisuccinate : bovine serum albumin (E2-BSA), a membrane-impermeable conjugate of E2, also elicited the inhibition of l-glu uptake at 1 nm and higher concentrations, and the effect was blocked by ICI. 16alpha-Iodo-17beta-estradiol (16alphaIE2), an estrogen receptor alpha (ERalpha) selective ligand, revealed an inhibitory effect at 10 nm, while genistein, an ERbeta selective ligand, failed to reveal such an effect at this concentration. Western blot analysis showed that the predominant ER of cultured astrocytes was ERalpha. The colocalization of ERalpha with GLAST on plasma membranes was immunohistochemically detected in these cells. From these results, we concluded that estrogens down-regulate l-glu uptake activity of astrocytes via membrane ERalpha.

The role of intracellular cysteine residues in P2X 2 receptor/channel was investigated. When dithiothreitol was intracellularly applied, both the maximal response and the sensitivity of the wild-type channel to ATP were decreased. On the other hand, Cu 2+ phenanthroline did not affect the responsiveness. When two intracellular cysteine residues (Cys 9 and Cys 430 ) were replaced with alanine, both the maximal response and the sensitivity was decreased with the replacement at Cys 9 , whereas no such decrease was observed with the replacement at Cys 430 . These results suggest that an intracellular disulfide bond involving Cys 9 regulates the responsiveness of P2X 2 receptor/channel to ATP.

ATP produces a variety of Ca2+ responses in astrocytes. To address the complex spatio-temporal Ca2+ signals, we analyzed the ATP-evoked increase in intracellular Ca2+ concentration ([Ca2+]i) in cultured rat hippocampal astrocytes using fura-2 or fluo-3 based Ca2+ imaging techniques. ATP at less than 10 nM produced elementary Ca2+ release event "puffs" in a manner independent of extracellular Ca2+. Stimulation with higher ATP concentrations (3 or 10 micro M) resulted in global Ca2+ responses such as intercellular Ca2+ wave. These Ca2+ responses were mainly mediated by metabotropic P2Y receptors. ATP acting on both P2Y1 and P2Y2 receptors produced a transient Ca2+ release by inositol 1,4,5-trisphosphate (InsP3). When cells were stimulated with ATP much longer, the transient [Ca2+]i elevation was followed by sustained Ca2+ entry from the extracellular space. This sustained rise in [Ca2+]i was inhibited by Zn2+ (

Effects of amino acid replacement at the channel pore mouth of P2X 2 receptor/channel on multivalent cation channel block were investigated. When Asn 333 was replaced with various amino acid residues with neutral side chains (Gly, Ala, Val, Leu and Ile), the block by Ca 2+ was attenuated according to the sizes of the side chains. The block by La 3+ was also greatest with the Gly-substituted mutant, but this preference was not found for the block by other multivalent cations tested. The side chain at the channel pore mouth may interfere with the access of Ca 2+ block by steric hindrance.

The pontine storage centre (PSC) and the pontine micturition centre (PMC) are known to be critical for urinary filling and emptying, respectively. In the present study, firing patterns of 45 neurons in the PSC area where electrical stimulation induced inhibition of the micturition reflex were analyzed in 20 male decerebrated and paralyzed cats. The electrically determined PSC area was widespread in the dorsolateral pontine reticular formation (P0-P4), ventrolateral to the PMC. Four major types of neurons were detected according to urinary storage/micturition cycles: tonic storage neurons (38%), phasic storage neurons (40%), tonic micturition neurons (9%) and phasic micturition neurons (13%). These four types of neurons were intermingled in the PSC. However, the tonic and phasic micturition neurons tended to be located within a limited area (P2-P3). These neurons were further classified into augmenting, constant and decrementing firing patterns. Some increased their firing prior to the storage/micturition phase initiation. Such preceding pattern was more frequently found in the tonic neurons than in the phasic neurons. In conclusion, the PSC neurons with diverse heterogeneous discharge patterns suggest that these neurons may organize a complex neuronal circuitry, which is critical in the neural control of the urinary continence.

The role of a tryptophane residue (Trp(256)) in the extracellular loop of a neuronal P2X receptor clone (P2X(2) receptor/channel) was investigated using site-directed mutagenesis and Xenopus oocyte expression. When Trp(256) was replaced with leucine, serine or phenylalanine (W256L, W256S or W256F), a current response to adenosine triphosphate (ATP) mediated through the P2X2 receptor/channel was abolished. When replaced with tyrosine (W256Y), the response was not abolished, but a reduced current response to ATP was observed. The insertion of a tryptophane residue in W256L at positions close to position 256 failed to recover the responsiveness to ATP. These results suggest that an amino acid residue with a side chain of an aromatic ring with a hydroxy group (tryptophane or tyrosine) is necessary exactly at position 256 for P2X(2) receptor/channel activation.

PURPOSE We evaluated usefulness of transcatheter arterial embolization (TAE) for deep renal injury, and investigated whether there is any difference in outcomes for transcatheter arterial embolization (TAE) performed for deep renal injury in a large-sized hospital (university hospital) in comparison with a middle-sized hospital (local hospital). METHODS We retrospectively reviewed the outcomes of 42 patients with renal injury who were transported to the critical care center of Nippon Medical School (NMS) Hospital in Tokyo from April 2001 to April 2011 and 33 patients of renal injury transported to the critical care center of Ohtawara Red Cross (ORC) Hospital in Tochigi prefecture from April 2001 to April 2009. Therefore, a total of 75 patients, which is the sum of the patients presenting to both the hospitals for renal injury were reevaluated according to the guidelines developed by the Japanese Association for the Surgery of Trauma (JAST) and published in 2008. RESULTS Forty-two patients in NMS hospital included 6 women and 36 men who were 16 to 88 years old (mean 41.6), and they were divided into Type I (16), Type II (11), and Type III (15) and were treated with bedrest (30), TAE (7), or laparotomy (5). Five patients died, but no one succumbed solely due to the renal injury. On the other hand, 33 Patients in ORC Hospital included 8 women and 25 men who were 16 to 87 years old (mean 46.6). They were divided into Type I (9). Type II (12), and Type III (12) and were treated with bedrest (24) or TAE (9). Eight patients died, but no one succumbed solely due to the renal injury. Sixteen patients were treated successfully with TAE in the 2 hospitals, and 15 of these 16 patients were divided into type III renal injury. Therefore, we believe that nephrectomy should be avoided in such patients because of the benefits offered by TAE. CONCLUSION TAE was found to be useful for the treatment of type III renal injury in both institutions, irrespective of the size of a hospital.

Behaviors of the same individual medullary respiratory interneurons were examined during both swallowing and vomiting. In 8 decerebrated and paralyzed cats, 18 neurons having either augmenting expiratory (E-AUG), decrementing expiratory (E-DEC), decrementing inspiratory (I-DEC), or constant inspiratory (I-CON) firing patterns were recorded near the most rostral part of the nucleus ambiguus. All neurons exhibited elementary reflexes to single-shock stimulation of the superior laryngeal nerve. During fictive swallowing elicited by superior laryngeal nerve stimulation, all neurons were basically inactive. During fictive vomiting induced by vagal stimulation and/or emetic drugs, all E-AUG and E-DEC neurons tested either were silent or fired weakly between successive retches, whereas I-DEC and I-CON neurons tested exhibited burst activity during the retching and early-expulsion phases. These results indicate that these bulbar respiratory neurons, which may be involved in respiratory rhythmogenesis, are multifunctional neurons that could also be involved in vomiting but not likely in swallowing. (Otolaryngol Head Neck Surg 1999;120:412-8.)

1.5-Hydroxytryptamine (10 μM) enhanced ionic current mediated through the wild-type P2X2 receptor/channel expressed in Xenopus oocytes.

Single channel currents were recorded from Xenopus oocytes expressing wild-type and mutated P2X2 receptors. When 100 mM Na+ was used as the permeant cation, unitary currents of about 80 pS were recorded from the oocyte expressing the wild-type channels. The single channel conductance was roughly halved when Asn333 was replaced by Ile (N333I). A similar decrease in single channel currents was also observed when 100 mM Li+ or Cs+ was used as the permeant cation. With two other mutants, in which Asp315 was replaced by Val (D315V) or Tyr330 was replaced by lie (T333I), single channel conductance was almost the same as that of the wild-type channels. The results suggest that Asn333, which is believed to be involved in the channel pore, plays an essential role in ion transport through P2X2 receptor/channels.

Charged or polarized amino acid residues near or within the second transmembrane (M2) segment of neuronal ATP receptor/channels (P2X2 receptors) were neutralized by site-directed mutagenesis, and the properties of the mutants were electrophysiologically characterized using Xenopus oocytes. When Asp315 was substituted with Val (D315V), the sensitivity to ATP was reduced by about 60-fold. The sensitivity to ATP was not affected by the neutralization of Lys324, which is involved in a Walker type A ATP-binding sequence, Lys366, Tyr330, or Asn333. With D315V channels, the sensitivities to other agonists (ADP, ATP gamma S, and 2-methylthio ATP) were also reduced. The sensitivities to antagonists (suramin and Cibacron Blue F3GA) were, however, not affected by this neutralization. The results suggest that Asp315, which is assumed to be present in the extracellular region near the M2 segment of P2X2 receptor/channels, serves to maintain agonist sensitivity.

This paper describes our experience with a case of inflammatory breast carcinoma with psoas muscle metastasis. The patient was a 56-year-old woman. She underwent standard radical mastectomy for a right inflammatory breast carcinoma on Feburary 27, 1995. After chemotherapy, she was followed on an ambulant basis. In August, 1995, she complained of lumbago and was found to have a tumor by ultrasound. She was admitted to the hospital for examination and treatment. The tumor was diagnosed as neurinoma or sarcoma by ultrasound, computed tomography, magnetic resonance image and angiography. She was operated on October 9, 1995. There was hematoma rather than a tumor of the left psoas muscle and we resected it with psoas muscle. Pathologically, cancer cells infiltrated the psoas muscle and resembled the breast carcinoma cells. The pathological diagnosis was inflammatory breast carcinoma with psoas muscle metastasis. Inflammatory breast carcinoma with psoas muscle metastasis is rare. Only two cases have been reported, to date. Though the diagnosis of retroperitoneal tumor should be made comprehensively with a variety of imagingmodalities, definitive diagnosis relies upon pathological examination. The tumor occasionally has a malignant potential, such that surgical resection is recommended.

Vestibular inputs to medullary respiratory interneurons were studied in decerebrated and artificially ventilated cats. Extracellular recordings were made from 40 neurons located in the area of pre-Bötzinger complex and activated antidromically from the contralateral ventral respiratory group. Neuronal populations analyzed included inspiratory and expiratory neurons with augmenting, constant and decrementing firing patterns, and a late inspiratory neuron. Seventeen neurons responded to ipsilateral and/or contralateral vestibular nerve electrical stimulation. These responses were observed in all seven cell types. Most neuronal reflex responses consisted of inhibition, while a few consisted of either excitation or a combination of both inhibition and excitation. These results indicate that pre-Bötzinger respiratory interneurons, which may be involved in respiratory rhythmogenesis, also participate in vestibulorespiratory responses.

1. Block by philanthotoxin-343 (PhTX-343), a neurotoxin from wasps, of ionic currents mediated through neuronal nicotinic acetylcholine (ACh) receptor/channels was characterized in rat phaeochromocytoma PC12 cells, by use of whole cell voltage-clamp techniques. 2. In the cells held at -60 mV, PhTX-343 at 0.1 and 1 microM inhibited an inward current activated by 100 microM ACh. The current inhibition was relieved by depolarizing steps, and augmented at negative potentials, suggesting that PhTX-343 blocks the channel in a voltage-dependent manner. Joro spider toxin-3 (JSTX-3) also exerted voltage-dependent inhibition of ACh-activated currents in a similar concentration range, but argiotoxin636 did not affect the currents. 3. Analysis of the current decay during hyperpolarizing steps indicated that the current inhibition by 100 nM PhTX-343 develops in an order of several hundres of milliseconds. On the other hand, the recovery from the current inhibition during depolarizing steps developed in an order of about 100 ms. 4. The results suggest that PhTX-343 blocks neuronal nicotinic receptor channels in PC12 cells at concentrations lower than those required for channel block in non-mammalian cells, and the block exhibits clear voltage-dependence. Estimated from the voltage-dependence, the binding site of PhTX-343 may be located near the outer mouth of the channel.

The purpose of this paper is to elucidate the possible role of pulmonary afferent inputs in triggering inspiratory-vocal (I-V) and Vocal-inspiratory (V-I) transitions during periaqueductal gray (PAG)-induced vocalization. Under ketamine anesthesia, we investigated the effects of changes in pulmonary afferent inputs on the PAG-induced vocal motor pattern by transection and electrical stimulation of the cervical vagus nerve in non-paralyzed cats and by lung inflation and deflation in paralyzed cats. After bilateral vagotomy, PAG stimulation induced apneusis; strong suppression of the I-V transition disrupted the vocal rhythmicity. Electrical stimulation of the central end of the cut vagus nerve during PAG stimulation immediately caused an I-V transition. In paralyzed cats during the withholding of lung inflation, the I-V transition was also suppressed during PAG stimulation. Lung inflation during PAG stimulation caused a phase switch from inspiration to fictive vocalization, i.e. I-V transition. In contrast, this fictive vocal phase maintained by lung inflation was terminated by lung deflation, i.e. V-I transition. These findings suggest that pulmonary vagal afferent feedback plays an important role in triggering and terminating vocalization.

Fifteen pre-inspiratory (pre-I) neurons were extracellularly recorded in the pre-Botzinger complex and their involvements in vestibular (VN) and superior laryngeal (SLN) nerve reflexes and in fictive swallowing and vomiting were tested in decerebrated and artificially ventilated cats. Both type I (1 of 9) and type II (1 of 6) pre-I neurons could project to the contralateral ventral respiratory group region. Pre-I neurons changed their firing during VN and SLN respiratory reflexes and fictive swallowing and vomiting; different response properties were observed among individual pre-I neurons. These results suggest that pre-I neurons are a population of heterogeneous and multifunctional propriobulbar neurons.

Sensitivities to dopamine, 5-hydroxytryptamine, Zn2+ and Cd2+ were studied in P2X1, P2X2, P2X3 and P2X4 purinoceptors and mutants of P2X2 purinoceptors expressed in Xenopus oocytes. Dopamine (10 and 100 microM) and 5-hydroxytryptamine (1 to 100 microM) enhanced the inward current activated by extracellular ATP through P2X2 and P2X4 purinoceptors. Zn2+ (1 to 100 microM) and Cd2+ (10 microM to 1 microM) enhanced the current through P2X2 purinoceptors. As for P2X4 purinoceptors, the ATP-activated current was, however, enhanced after the washout of Zn2+ (100 microM) or Cd2+ (1 mM). Three mutants of P2X2 purinoceptors were constructed by substituting negatively charged amino-acid residues. The magnitude of the enhancement by Zn2+, Cd2+ and dopamine was attenuated when Asp221 was replaced by histidine. The results suggest that dopamine, Zn2+ and Cd2+ require some common motif for the current enhancement.

The effects of electrical stimulation, applied to the superior salivatory nucleus (SSN) or the cervical sympathetic nerve, on vascular permeability in nasal mucosa were studied in 16 cats. Plasma extravasation was quantified by using Evans blue. Vascular permeability in the cat nasal mucosa was increased by the electrical stimulation of SSN. Plasma extravasation induced by SSN stimulation was reduced by administration of nitric oxide synthase (NOS) antagonist, N(omega)-nitro-L-arginine methyl ester (L-NAME). Administration of atropine did not affect increased vascular permeability by SSN stimulation. We conclude that neurogenic plasma extravasation in cat nasal mucosa evoked by the parasympathetic nerve is not mediated by cholinergic fibers but rather by nitric oxide.

The astrocytic L-glutamate (L-Glu) transporter EAAT1 participates in the removal of L-Glu from the synaptic cleft and maintenance of non-toxic concentrations in the extracellular fluid. We have shown that niflumic acid (NFA), a non-steroidal anti-inflammatory drug (NSAIDs), alters L-Glu-induced EAAT1 currents in a voltage-dependent manner using the two-electrode voltage clamp technique in Xenopus oocytes expressing EAAT1. In this study, we characterised the effects of NFA on each type of ion-flux through EAAT1. NFA modulated currents induced by both L-Glu and L-aspartate (L-Asp) in a voltage-dependent manner. Ion-substitution experiments revealed that the activation of additional H(+) conductance was involved in the modulation of currents induced by L-Asp and L-Glu, but Cl(-) was involved only with the L-Asp currents. NFA activated additional currents of EAAT1 in a substrate-dependent manner.