Anti-edematous effects of epinastine, cetirizine and its enantiomers in λ-carrageenan-induced edema in rat hind paw.

Urticaria is induced by the histamine released from mast cells which develops wheals (edema) as a visual feature. In clinical practice, second-generation histamine H1 -receptor blockers are routinely used as the first-line symptomatic treatment for urticaria. Nevertheless, not much research has directly examined the second-generation histamine H1-receptor blockers' ability to reduce edema. In this study, we directly evaluated the anti-edematous activities of three second-generation histamine H1-receptor blockers available in the market (epinastine hydrochloride, cetirizine hydrochloride, and levocetirizine hydrochloride) using a λ-carrageenan-induced footpad edema model. One hour before the induction of edema with 1% λ -carrageenan injection, all second-generation histamine H1 -receptor blockers (5, 10, 50 and 100 mg/kg) were subcutaneously administered to rats. At 0.5 and 3 hours after λ -carrageenan administration, the edema volume was evaluated using a Plethysmometer. Epinastine hydrochloride significantly suppressed the edema growth in a dose-dependent manner. Cetirizine hydrochloride showed a slight anti-edematous effect, while levocetirizine significantly inhibited the development of edema in a dose-dependent manner. On the other hand, dextrocetirizine did not prevent edema from growing. In summary, second-generation histamine H1 -receptor blockers, at least those examined in this study, may be able to reduce the clinical symptoms of urticaria associated with edema. Levocetirizine hydrochloride is also anticipated to have stronger anti-edematous effects than cetirizine hydrochloride because levocetirizine is responsible for cetirizine's anti-edematous activity.

Direct comparison of anti-inflammatory effects of 14-, 15-, and 16-membered macrolide antibiotics in experimental inflammation model induced by carrageenan in rats.

Some macrolide antibiotics, which share a basic lactone ring structure, also exhibit anti-inflammatory actions in addition to their antibacterial activities. However, no study has directly compared anti-inflammatory effects on acute inflammation among macrolide antibiotics with the distinct size of the lactone ring. In this study, we evaluated and compared the anti-inflammatory activities of four 14-membered macrolides (erythromycin, clarithromycin, roxithromycin, oleandomycin), one 15-membered macrolide (azithromycin), and three 16-membered macrolides (midecamycin, josamycin, leucomycin) using a rat carrageenan-induced footpad edema model. All macrolide antibiotics were intraperitoneally administered to rats one hour before the induction of inflammatory edema with 1% λ -carrageenan. The anti-inflammatory effects on acute inflammation were evaluated by changing the edema volume. All 14-membered and 15-membered macrolide antibiotics significantly suppressed the development of edema. Conversely, none of the 16-membered macrolide antibiotics inhibited the growth of edema. In conclusion, compared to 16-membered macrolide antibiotics, 14-membered and 15-membered macrolide antibiotics have stronger anti-inflammatory effects. Further research should be done to determine why different lactone ring sizes should have distinct anti-inflammatory effects.

Anti-Inflammatory Actions of Expectorants in a Rat Carrageenan-Induced Footpad Edema Model.

S-Carboxymethyl-L-cysteine (SCMS) exhibits sputum-regulating and anti-inflammatory actions. Previous studies reported the anti-inflammatory effects of SCMS on chronic inflammatory diseases, but no study has examined these effects on acute inflammatory diseases. In this study, we investigated the anti-inflammatory effects of SCMS in a rat carrageenan-induced footpad edema model, which is routinely used as an acute inflammation model. Expectorants were administered to rats with footpad edema induced by subcutaneously administering 1%λ-carrageenan to the footpad of the left posterior limb, and the dose dependency of the anti-inflammatory effects was evaluated. As a result, even when the dose of SCMS was increased to 400 mg/kg, there were no inhibitory effects on edema. Furthermore, we examined the inhibitory effects of other expectorants (ambroxol hydrochloride, N-acetyl-L-cysteine, L-cysteine ethylester hydrochloride, and L-cysteine methylester hydrochloride), which were reported to exhibit anti-inflammatory effects on chronic inflammation, on edema. However, none of these expectorants inhibited edema.

Radial Spin Texture in Elemental Tellurium with Chiral Crystal Structure.

The chiral crystal is characterized by a lack of mirror symmetry and inversion center, resulting in the inequivalent right- and left-handed structures. In the noncentrosymmetric crystal structure, the spin and momentum of electrons are expected to be locked in the reciprocal space with the help of the spin-orbit interaction. To reveal the spin textures of chiral crystals, we investigate the spin and electronic structure in a p-type semiconductor, elemental tellurium, with the simplest chiral structure by using spin- and angle-resolved photoemission spectroscopy. Our data demonstrate that the highest valence band crossing the Fermi level has a spin component parallel to the electron momentum around the Brillouin zone corners. Significantly, we have also confirmed that the spin polarization is reversed in the crystal with the opposite chirality. The results indicate that the spin textures of the right- and left-handed chiral crystals are hedgehoglike, leading to unconventional magnetoelectric effects and nonreciprocal phenomena.

A multicenter phase II study of carboplatin and paclitaxel for advanced thymic carcinoma: WJOG4207L.

BACKGROUND: Thymic carcinoma (TC) is an exceptionally rare tumor, which has a very poor prognosis differing from thymoma. Till date, there has been no report of any results of clinical trials focusing on TC. The role of non-anthracycline-based chemotherapy has not been elucidated since the previous studies included a relatively small number of TC patients. This single-arm study evaluated carboplatin and paclitaxel (CbP) in chemotherapy-naive patients with advanced TC. PATIENTS AND METHODS: The study treatment consisted of carboplatin (area under the curve 6) and paclitaxel (200 mg/m(2)) every 3 weeks for a maximum of six cycles. The primary end point was objective response rate (ORR) by independent review. The secondary end points included overall survival (OS), progression-free survival (PFS), and safety. Based on the SWOG 2-stage design, the planned sample size of 40 patients was determined to reject the ORR of 20% under the expectation of 40% with a power of 0.85 and a type I error of 0.05. RESULTS: Forty patients from 21 centers were enrolled for this study from May 2008 to November 2010. Of the 39 patients evaluable for analysis, 36 were pathologically diagnosed by independent review, and 97% patients were eventually TC. There was 1/13 complete/partial responses with an ORR of 36% (95% confidence interval 21%-53%; P = 0.031). The median PFS was 7.5 (6.2-12.3) months, while OS did not reach the median value. Major adverse event was grade 3-4 neutropenia in 34 patients (87%). There was no treatment-related death. CONCLUSIONS: In this largest trial with TC, CbP showed promising efficacy in advanced TC when compared with anthracycline-based chemotherapy, which is the current standard treatment of thymic neoplasm. Our results established that CbP, one of the standard treatments for non-small-cell lung cancer, might be an option as a chemotherapy regimen for TC.

A phase II study of eribulin in Japanese patients with heavily pretreated metastatic breast cancer.

BACKGROUND: Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that recently gained Food and Drug Administration approval for late-line metastatic breast cancer (MBC). PATIENTS AND METHODS: In this single-arm, multicentre open-label phase II trial Japanese patients pretreated with an anthracycline and a taxane received 1.4 mg/m(2) eribulin mesylate (2- to 5-min i.v. infusion on days 1 and 8 of a 21-day cycle). The primary efficacy end point was overall response rate (ORR) by independent review. RESULTS: Patients (N = 80) had received a median of three prior chemotherapy regimens (range 1-5). ORR was 21.3% [95% confidence interval (CI) 12.9-31.8; all partial responses (PRs)], stable disease (SD) occurred in 30 patients (37.5%) and the clinical benefit rate (complete response + PR + SD ≥6 months) was 27.5% (95% CI 18.1-38.6). Median duration of response was 3.9 months (95% CI 2.8-4.9), progression-free survival was 3.7 months (95% CI 2.0-4.4) and overall survival was 11.1 months (95% CI 7.9-15.8). The most frequent treatment-related grade 3/4 adverse events were neutropenia (95.1%), leukopenia (74.1%) and febrile neutropenia (13.6%). Grade 3 peripheral neuropathy occurred in 3.7% of patients (no grade 4). CONCLUSIONS: Eribulin exhibited efficacy and tolerability in Japanese patients with heavily pretreated MBC.

Osteoporotic changes of subchondral trabecular bone in osteoarthritis of the knee: a 3-T MRI study.

SUMMARY: Subchondral trabecular bone structure was analyzed in knee osteoarthritis (OA) patients using 3-T MRI to investigate structural features of subchondral trabecular bone of knee OA. With OA progression, osteoporotic changes were observed in the lateral joint, showing a higher correlation than sclerotic changes in the medial joint. INTRODUCTION: To investigate structural features of subchondral trabecular bone of knee osteoarthritis (OA). METHODS: Sixty knees with KL grade 0-4 (all female) were examined. Fast imaging employing steady-state acquisition-cycled phases (FIESTA-c) and FatSat Spoiled gradient recalled acquisition in the steady state (SPGR) images were acquired by 3-T MRI. At four sites (the medial femur, medial tibia, lateral femur, and lateral tibia), subchondral trabecular bone structure was analyzed by FIESTA-c imaging, cartilage area was measured by SPGR imaging, and their correlation was analyzed. In addition, the subjects were classified into four groups from the cartilage area measured by SPGR imaging, and subchondral trabecular bone structure in each group was compared. RESULTS: As cartilage area decreased in the medial joint, bone volume fraction and trabecular thickness in the medial tibia increased, and bone volume fraction, trabecular thickness, number, and connectivity in the lateral femur and lateral tibia decreased (r ≥ 0.4 or ≤-0.4, p ≤ 0.001). Compared to medially, the changes laterally showed a higher correlation. When the medial-lateral ratio of trabecular thickness in the tibia was determined, it had the highest correlation coefficient (r=-0.7, p < 0.001). These changes were not significantly detected in the early stage. CONCLUSIONS: To more sensitively detect OA changes in subchondral trabecular bone structure, a focus on osteoporotic changes in the lateral joint and the medial-lateral ratio would be useful. Detectability of early OA remains unknown, but based on a strong correlation with the degree of OA progression, trabecular structural analysis of subchondral bone may be a useful parameter to evaluate OA severity and evaluate treatment.

Successful and long-lasting treatment of solar urticaria with ultraviolet A rush hardening therapy.

BACKGROUND: Solar urticaria (SU) is a photodermatosis that is thought to be caused through the effects of mast cell mediators released because of an altered chromophore, possibly a photoallergen recognized by IgE. Phototherapy for SU to induce a tolerant state appears to be most effective, but is often time consuming and provides only short-lived remission. Ultraviolet (UV) A rush hardening has been successful and less time consuming in serum factor-negative patients with SU. However, the mechanism of action and long-lasting effects of UVA rush hardening therapy remain unclear. OBJECTIVES: We aimed to evaluate whether UVA rush hardening exhibits long-lasting therapeutic effects in serum factor-positive patients with SU and to examine the action mechanism of tolerance. METHODS: Two serum factor-positive patients with SU were exposed to multiple UVA irradiations at 1-h intervals per day for 2 or 3 days. Intradermal injection of their in vitro-irradiated autologous serum or compound 48/80 and a prick test for histamine were performed before and after UVA rush hardening. RESULTS: The two serum factor-positive patients with SU benefited greatly from UVA rush hardening, as documented by a marked increase in minimal wealing dose, and remained symptom free without using sunscreen in their daily life. Intradermal injection of in vitro-irradiated autologous serum induced wealing before hardening, but not in tolerized skin after hardening. The responses to compound 48/80 and histamine were unaltered. CONCLUSIONS: UVA rush hardening is an effective and long-lasting treatment even in serum factor-positive patients with SU. The mechanism of tolerance may involve continued blockade of photoallergen binding to IgE on mast cells, rather than depletion of mast cell mediators or histamine tachyphylaxis.

Tissue rinse liquid-based cytology: a feasible tool for the intraoperative pathological evaluation of sentinel lymph nodes in breast cancer patients.

OBJECTIVES: A unique diagnostic method was designed for the intraoperative pathological evaluation of sentinel lymph nodes (SLNs) in breast cancer patients, and the results were verified with 2 years of experience. METHODS: Excised lymph nodes were cut into 2-mm-thick slices and rinsed thoroughly in CytoRich Red(®). The sliced tissues were embedded in a paraffin block. Three cytological glass slides of the cells exfoliated in CytoRich Red(®) were prepared by the SurePath(®) liquid-based cytology (LBC) technique. Two slides were stained by the Papanicolaou method, and the remaining slide was immunostained with an anti-keratin antibody. This process is called tissue rinse liquid-based cytology (TRLBC). The results of TRLBC were compared with those of the final pathological diagnoses, including immunostaining with an anti-keratin antibody on paraffin blocks (PB). RESULTS: This study analysed 444 SLNs from 247 consecutive breast cancer patients. It required 35 minutes to complete the intraoperative diagnosis on a single node, and it took an additional 5 minutes per node if more than one node was submitted. When the results of PB were assumed to be the gold standard, the sensitivity and specificity of TRLBC were 81.9% and 96.1%, respectively. TRLBC detected all nodes with macrometastasis and 23 of 24 nodes with micrometastasis. Fifteen false-negative TRLBC results were 'isolated tumour cell clusters' on PB, but there was one with micrometastasis histologically. Four of 14 false-positive TRLBC results were proven to be true positive by supplementary examination using step sectioning of the paraffin blocks of the nodes. CONCLUSION: TRLBC is a feasible and promising intraoperative cytopathological tool showing a comparable efficacy to PB while still allowing the conventional postoperative histological examination.

Association between Malnutrition Severity and Swallowing Function in Convalescent Rehabilitation Wards: A Multi-Center Cohort Study in Malnourished Patients with Sarcopenic Dysphagia.

OBJECTIVES: To evaluate the characteristics of sarcopenic dysphagia (SD) and the prognosis of swallowing function in convalescent rehabilitation hospital patients; and to investigate the association between malnutrition severity and SD. DESIGN: A prospective, multi-center, cohort study. SETTING: We extracted registry data from the Japanese Sarcopenic Dysphagia Database, focusing on patients admitted to convalescent rehabilitation hospitals. PARTICIPANTS: A total of 207 participants were recruited and stratified according to the presence or absence of SD. Next, the participants were divided into groups based on nutrition status using the Global Leadership Initiative on Malnutrition criteria: normal nutrition, moderate malnutrition, and severe malnutrition. We also compared the outcomes between patients with SD (SD group) and those without SD (no-SD group) according to malnutrition status. MEASUREMENTS: The Food Intake LEVEL Scale (FILS) score was the outcome measure. Higher scores on the FILS indicate better swallowing function. We compared the patient characteristics between the SD and non-SD groups among all patients and then according to the severity of malnutrition. RESULTS: A total of 207 patients were recruited. 11 were diagnosed with normal nutrition, 72 with moderate malnutrition, and 124 with severe malnutrition. There were 128 participants with SD and 79 participants without SD; the prevalence of SD was 61.8%. Hip fracture was the most common disease among the SD patients (34.4%). The median time to the end of follow-up was 73.5 days for the SD group and 84.0 days for the no-SD group. There was no significant difference in the FILS score between the SD and no-SD groups, but the increase in the FILS score was significantly lower in the SD group than the no-SD group among patients with severe malnutrition after adjusting for confounding factors (age, sex, FILS at admission, BMI, cognitive functional independence measure, and care level before onset) (ß = -0.206, p = 0.011, 95% confidence interval = -0.723, -0.098). CONCLUSION: Orthopedic diseases are the most common type of disease among SD patients in convalescent rehabilitation hospitals. Swallowing dysfunction was particularly severe in malnourished patients with SD. This result suggests the importance of the definition of SD for malnourished patients. We should practice nutritional management as soon as possible in severely malnourished patients diagnosed with SD.

Effect of HER2 status on risk of recurrence in women with small, node-negative breast tumours.

BACKGROUND: Adjuvant trastuzumab for small, node-negative, human epidermal growth factor receptor 2 (HER2)-positive breast cancer remains controversial. The purpose of this study was to investigate the risk of recurrence in women with pathological tumour node (pTN) T1 N0 tumours. METHODS: Patients with pT1 N0 breast cancer diagnosed at the National Kyushu Cancer Centre between 2001 and 2007 were reviewed. Patients were categorized according to HER2 status. RESULTS: Four hundred and fifty-four patients who had pT1 N0 tumours, and had not received adjuvant trastuzumab, were identified. The HER2-negative and -positive groups comprised 376 and 78 patients (17·2 per cent) respectively. At a median follow-up of 46·3 months, there were 18 recurrences.The 5-year relapse-free survival (RFS) rates were 97·2 and 88 per cent in the HER2-negative and -positive groups respectively (P < 0·001). Multivariable analysis identified HER2-positive tumour as an independent predictor of RFS in patients with pT1 N0 tumours (hazard ratio 6·65, 95 per cent confidence interval 2·53 to 17·49; P < 0·001). CONCLUSION: Women with pT1 N0 HER2-positive breast cancer have a high risk of recurrence.

Kinetics of phase separation and coarsening in dilute surfactant pentaethylene glycol monododecyl ether solutions.

We investigated the phase separation phenomena in dilute surfactant pentaethylene glycol monodedecyl ether (C(12)E(5)) solutions focusing on the growth law of separated domains. The solutions confined between two glass plates were found to exhibit the phase inversion, characteristic of the viscoelastic phase separation; the majority phase (water-rich phase) nucleated as droplets and the minority phase (micelle-rich phase) formed a network temporarily, then they collapsed into an usual sea-island pattern where minority phase formed islands. We found from the real-space microscopic imaging that the dynamic scaling hypothesis did not hold throughout the coarsening process. The power law growth of the domains with the exponent close to 1/3 was observed even though the coarsening was induced mainly by hydrodynamic flow, which was explained by Darcy's law of laminar flow.

Novel anti-idiotype antibody therapy for lipooligosaccharide-induced experimental autoimmune neuritis: use relevant to Guillain-Barré syndrome.

Campylobacteriosis is a frequent antecedent event in Guillain-Barré syndrome (GBS), inducing high-titer serum antibodies for ganglioside antigens in the peripheral nervous system (PNS). Molecular mimicry between the lipooligosaccharide (LOS) component of Campylobacter jejuni and human peripheral nerve gangliosides is believed to play an important role in the pathogenesis of GBS. Conventional treatment strategies for patients with GBS include plasmapheresis, intravenous immunoglobulin (IVIG), and immunosuppression, which are invasive or relatively ineffective. In this study, we used our animal model of GBS, in which Lewis rats were immunized with GD3-like LOS isolated from C.jejuni. The animals developed anti-GD3 ganglioside antibodies and manifested neuromuscular dysfunction. To develop novel therapeutic strategies, we treated the animals by intraperitoneal administration of an anti-GD3 antiidiotype monoclonal antibody (BEC2) that specifically interacts with the pathogenic antibody. The treated animals had a remarkable reduction of anti-GD3 antibody titers and improvement of motor nerve functions. The results suggest that ganglioside mimics, such as antiidiotype antibodies, may be powerful reagents for therapeutic intervention in GBS by neutralizing specific pathogenic antiganglioside antibodies.

Isolation of novel mycobacteria contaminating an aquarium fish tank in a Japanese university hospital.

AIMS: To better understand nontuberculous mycobacteria (NTM) contamination in a hospital setting, six freshwater fish gut homogenates and water in an aquarium fish tank placed on the reception counter of a nursing station were cultured for mycobacteria. METHODS AND RESULTS: By direct sequencing of 16s rRNA, rpoB and hsp65, scotochromogenic and nonchromogenic Mycobacterium szulgai isolates containing hsp65 type II (GenBank accession nos. FJ384762 and FJ384764, respectively), Mycobacterium gordonae isolates containing rpoB clusters B and E (GenBank accession no. FJ384766), and Mycobacterium kansasii isolates containing hsp65 type VI were collected from the gut homogenates and water from the fish tank. However, no isolates were obtained from the tap water used to refill the fish tank. A randomly amplified polymorphic DNA (RAPD) analysis using a 10-mer primer (5'-TGGTCGCGGC) showed that some NTM from the fish tank water were identical to those obtained from the gut homogenates. CONCLUSIONS: Fish and water in the tank were contaminated by the novel NTM. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings could help to elucidate infection routes and contamination sources of novel NTM from water sources.

Switching of band inversion and topological surface states by charge density wave.

Topologically nontrivial materials host protected edge states associated with the bulk band inversion through the bulk-edge correspondence. Manipulating such edge states is highly desired for developing new functions and devices practically using their dissipation-less nature and spin-momentum locking. Here we introduce a transition-metal dichalcogenide VTe2, that hosts a charge density wave (CDW) coupled with the band inversion involving V3d and Te5p orbitals. Spin- and angle-resolved photoemission spectroscopy with first-principles calculations reveal the huge anisotropic modification of the bulk electronic structure by the CDW formation, accompanying the selective disappearance of Dirac-type spin-polarized topological surface states that exist in the normal state. Thorough three dimensional investigation of bulk states indicates that the corresponding band inversion at the Brillouin zone boundary dissolves upon the CDW formation, by transforming into anomalous flat bands. Our finding provides a new insight to the topological manipulation of matters by utilizing CDWs' flexible characters to external stimuli.

Identification of Piccolo as a regulator of behavioral plasticity and dopamine transporter internalization.

Dopamine transporter (DAT) internalization is a mechanism underlying the decreased dopamine reuptake caused by addictive drugs like methamphetamine (METH). We found that Piccolo, a presynaptic scaffolding protein, was overexpressed in the nucleus accumbens (NAc) of the mice repeatedly administrated with METH. Piccolo downexpression by antisense technique augmented METH-induced behavioral sensitization, conditioned reward and synaptic dopamine accumulation in NAc. Expression of Piccolo C2A domain attenuated METH-induced inhibition of dopamine uptake in PC12 cells expressing human DAT. Consistent with this, it slowed down the accelerated DAT internalization induced by METH, thus maintaining the presentation of plasmalemmal DAT. In immunostaining and structural modeling Piccolo C2A domain displays an unusual feature of sequestering membrane phosphatidylinositol 4,5-bisphosphate, which may underlie its role in modulating DAT internalization. Together, our results indicate that Piccolo upregulation induced by METH represents a homeostatic response in the NAc to excessive dopaminergic transmission. Piccolo C2A domain may act as a cytoskeletal regulator for plasmalemmal DAT internalization, which may underlie its contributions in behavioral plasticity.

[Metastatic lung cancer origin from osteosarcoma of mandible invading tracheal lumen].

A 52-year-old woman underwent the surgical treatment for osteosarcoma of the left mandible in 2003 and was followed up afterward. She suffered from dry cough and bloody sputum, and was admitted to our hospital in April 2007. Computed tomography (CT) revealed several nodules in bilateral lung, and bronchofiberscopy showed the endobronchial tumor obstructing in the right main bronchus. The metastatic tumor progressed in the right main bronchus from the right S6 lung segment. The tumor rapidly progressed in the right bronchus in comparison with the CT findings in about 2 weeks, and the possibility of the tracheal obstruction was considered. She underwent the right middle and lower lobectomy, and the endobronchial tumor was pulled through the right main bronchus. The postoperative course was uneventful, the patient was discharged on 14th postoperative day, and the chemotherapy using cisplatin (CDDP) and adriamycin (ADR) is on-going.

Fibre based cellular transfection.

Optically assisted transfection is emerging as a powerful and versatile method for the delivery of foreign therapeutic agents to cells at will. In particular the use of ultrashort pulse lasers has proved an important route to transiently permeating the cell membrane through a multiphoton process. Though optical transfection has been gaining wider usage to date, all incarnations of this technique have employed free space light beams. In this paper we demonstrate the first system to use fibre delivery for the optical transfection of cells. We engineer a standard optical fibre to generate an axicon tip with an enhanced intensity of the remote output field that delivers ultrashort (~ 800 fs) pulses without requiring the fibre to be placed in very close proximity to the cell sample. A theoretical model is also developed in order to predict the light propagation from axicon tipped and bare fibres, in both air and water environments. The model proves to be in good agreement with the experimental findings and can be used to establish the optimum fibre parameters for successful cellular transfection. We readily obtain efficiencies of up to 57 % which are comparable with free space transfection. This advance paves the way for optical transfection of tissue samples and endoscopic embodiments of this technique.

Involvement of the protein kinase Cgamma isoform in development of tolerance to nitrous oxide-induced antinociception in mice.

Prolonged exposure to nitrous oxide (N2O) results in development of acute tolerance to its antinociceptive effect. Cross-tolerance to N2O-induced antinociception is also observed in morphine-tolerant animals. Despite increasing evidence of tolerance development to N2O-induced antinociception, the details of the mechanisms that underlie this tolerance remain unknown. The present study was conducted to investigate the involvement of brain protein kinase C (PKC) isoform in these two types of tolerance to N2O-induced antinociception in mice. Prolonged exposure (41 min in total, including 30 min pre-exposure and 11 min of antinociceptive testing) to 70% N2O produced a reduction in N2O-induced antinociception, indicating development of acute tolerance. The prolonged exposure to 70% N2O caused an activation of PKCgamma isoform in the brain, but not the PKCepsilon isoform. Pretreatment with a PKCgamma-antisense oligonucleotide but not the corresponding mismatch oligonucleotide (i.c.v.) prevented the development of acute tolerance to N2O-induced antinociception. Chronic morphine treatment (10 mg/kg, s.c., b.i.d. for 5 days) resulted in development of tolerance to morphine-induced antinociception and cross-tolerance to N2O-induced antinociception. The development of tolerance to morphine and cross-tolerance to N2O were both inhibited by pretreatment with PKC inhibitor, chelerythrine (1 nmol, i.c.v.). Morphine-tolerant mice showed an activation of PKC within the brain, which was suppressed by pretreatment with chelerythrine (1 nmol, i.c.v.). Thus, activation of brain PKC, in particular, the PKCgamma isoform, appears to play an important role in the development of both acute tolerance and cross-tolerance to N2O-induced antinociception in mice.

Contaminated oral intubation equipment associated with an outbreak of carbapenem-resistant Pseudomonas in an intensive care unit.

Twenty intensive care patients were diagnosed as infected or colonized by Pseudomonas aeruginosa within a one-month period; a rate three to four times higher than the typical background frequency of this infection in the intensive care unit (ICU). Patients with positive respiratory specimens were mechanically ventilated, which included re-used disinfected bite blocks during intubation. Fourteen specimens from 20 positive patients originated in the respiratory tract. Seven clonal variants were isolated and identified as originating from the same strain by pulsed-field analysis. These isolates were also matched to the strain detected on the re-used bite blocks, which had been disinfected with 140ppm sodium hydrochloride. Notably, Staphylococcus aureus was also detected on bite blocks sterilized with ethylene dioxide, indicating incomplete disinfection. In immunocompromised patients, re-use of bite blocks during intubation must be prohibited. Single-use kits or intubation without the use of bite blocks is recommended.