Paxillin participates in the sphingosylphosphorylcholine-induced abnormal contraction of vascular smooth muscle by regulating Rho-kinase activation.

BACKGROUND: The Ca2+-independent contraction of vascular smooth muscle is a leading cause of cardiovascular and cerebrovascular spasms. In the previous study, we demonstrated the involvement of Src family protein tyrosine kinase Fyn and Rho-kinase in the sphingosylphosphorylcholine (SPC)-induced abnormal and Ca2+-independent contraction of vascular smooth muscle, but the specific mechanism has not been completely clarified. METHODS: Paxillin knockdown human coronary artery smooth muscle cells (CASMCs) and smooth muscle-specific paxillin knockout mice were generated by using paxillin shRNA and the tamoxifen-inducible Cre-LoxP system, respectively. CASMCs contraction was observed by time-lapse recording. The vessel contractility was measured by using a myography assay. Fyn, Rho-kinase, and myosin light chain activation were assessed by immunoprecipitation and western blotting. The paxillin expression and actin stress fibers were visualized by histological analysis and immunofluorescent staining. RESULTS: The SPC-induced abnormal contraction was inhibited in paxillin knockdown CASMCs and arteries of paxillin knockout mice, indicating that paxillin is involved in this abnormal contraction. Further study showed that paxillin knockdown inhibited the SPC-induced Rho-kinase activation without affecting Fyn activation. In addition, paxillin knockdown significantly inhibited the SPC-induced actin stress fiber formation and myosin light chain phosphorylation. These results suggest that paxillin, as an upstream molecule of Rho-kinase, is involved in the SPC-induced abnormal contraction of vascular smooth muscle. CONCLUSIONS: The present study demonstrated that paxillin participates in the SPC-induced abnormal vascular smooth muscle contraction by regulating Rho-kinase activation. Video Abstract.

Fyn-Mediated Paxillin Tyrosine 31 Phosphorylation Regulates Migration and Invasion of Breast Cancer Cells.

Metastasis is the leading cause of death in breast cancer patients due to the lack of effective therapies. Elevated levels of paxillin expression have been observed in various cancer types, with tyrosine phosphorylation shown to play a critical role in driving cancer cell migration. However, the specific impact of the distinct tyrosine phosphorylation events of paxillin in the progression of breast cancer remains to be fully elucidated. Here, we found that paxillin overexpression in breast cancer tissue is associated with a patient's poor prognosis. Paxillin knockdown inhibited the migration and invasion of breast cancer cells. Furthermore, the phosphorylation of paxillin tyrosine residue 31 (Tyr31) was significantly increased upon the TGF-ß1-induced migration and invasion of breast cancer cells. Inhibiting Fyn activity or silencing Fyn decreases paxillin Tyr31 phosphorylation. The wild-type and constitutively active Fyn directly phosphorylate paxillin Tyr31 in an in vitro system, indicating that Fyn directly phosphorylates paxillin Tyr31. Additionally, the non-phosphorylatable mutant of paxillin at Tyr31 reduces actin stress fiber formation, migration, and invasion of breast cancer cells. Taken together, our results provide direct evidence that Fyn-mediated paxillin Tyr31 phosphorylation is required for breast cancer migration and invasion, suggesting that targeting paxillin Tyr31 phosphorylation could be a potential therapeutic strategy for mitigating breast cancer metastasis.

The Utility of Pneumatic Cavity Volume in the Treatment of Exudative Otitis Media in Children with Cleft Palate.

OBJECTIVE: Measure the volume of air-containing space in children with cleft palate and assess age-related changes, recurrence rate of otitis media with effusion (OME) after tube removal, and temporal bone development trend based on time of tube placement. DESIGN: Interventional prospective study. SETTING: Cleft Lip and Palate Center at a Tertiary-level institution. PATIENTS/PARTICIPANTS: One hundred sixty-eight ears of 86 patients who visited our center from January 2018 to December 2019. INTERVENTIONS: We performed tympanometry (impedance audiometry) after tube placement. MAIN OUTCOME MEASURES: Recurrence (at least one episode of OME after tympanic membrane closure), tympanic cavity volumes, and timing of tube placement. RESULTS: The mean air-containing cavity volume was 1.62 mL, 2.99 mL, and 3.29 mL in patients aged 1, 2, and 3 years, respectively. A rapid increase in volume was observed around 2 years of age. Twenty-two (42.3%) of the 52 ears with pneumatic cavity volumes <3 mL, and four (14.3%) of the 28 ears with pneumatic cavity volumes ≥3 mL had recurrence. Tubes were placed at ages <1 year and ≥1 year in 28 and 62 ears, respectively. The pneumatic cavity volume tended to be greater in the ears with tube placement at age <1 year. CONCLUSION: This study provided insights into using pneumatic cavity volume measurements to determine the appropriate timing for tube removal. Tubes should be placed as early as possible (before the age of 2 years) for prolonged OME associated with children with cleft palate.

Paxillin controls actin stress fiber formation and migration of vascular smooth muscle cells by directly binding to the active Fyn.

Rho-kinase (ROK)-mediated migration of vascular smooth muscle cells plays a crucial role in cardiovascular diseases. Previously we demonstrated Fyn tyrosine kinase as an upstream molecule of ROK to mediate actin stress fiber formation that plays an important role in cell migration, but the molecular mechanism between the two kinases was unclear. To discover a novel signaling molecule that exists between Fyn and ROK, we identified paxillin acting downstream of the active Fyn by combined use of pulldown assay and mass spectrometry. Immunofluorescence staining confirmed co-localization of Fyn and paxillin at the ends of actin stress fibers in human coronary artery smooth muscle cells (CASMCs). Surface plasmon resonance assay demonstrated direct binding between constitutively active Fyn (CA-Fyn) and N-terminus of paxillin (N-pax). The sphingosylphosphorylcholine (SPC)-induced ROK activation, actin stress fiber formation and cell migration were inhibited by paxillin knockdown, which were rescued by full-length paxillin (FL-pax) but not N-pax. N-pax co-localized with CA-Fyn at the cytosol and overexpression of N-pax inhibited the SPC-induced actin stress fiber formation and cell migration, indicating that the direct binding of FL-pax and CA-Fyn at the ends of actin stress fibers is essential for the ROK-mediated actin stress fiber formation and cell migration. Paxillin, as a novel signalling molecule, mediates the SPC-induced actin stress fiber formation and migration in human CASMCs via the Fyn/paxillin/ROK signalling pathway by direct binding of active Fyn.

Hesperetin Inhibits Sphingosylphosphorylcholine-Induced Vascular Smooth Muscle Contraction by Regulating the Fyn/Rho-Kinase Pathway.

ABSTRACT: Cardiovascular diseases are the leading cause of mortality and disability worldwide. We have previously found that sphingosylphosphorylcholine (SPC) is the key molecule leading to vasospasm. We have also identified the SPC/Src family protein tyrosine kinase Fyn/Rho-kinase (ROK) pathway as a novel signaling pathway for Ca2+ sensitization of vascular smooth muscle (VSM) contraction. This study aimed to investigate whether hesperetin can inhibit the SPC-induced contraction with little effect on 40 mM K+-induced Ca2+-dependent contraction and to elucidate the underlying mechanisms. Hesperetin significantly inhibited the SPC-induced contraction of porcine coronary artery smooth muscle strips with little effect on 40 mM K+-induced contraction. Hesperetin blocked the SPC-induced translocation of Fyn and ROK from the cytosol to the membrane in human coronary artery smooth muscle cells (HCASMCs). SPC decreased the phosphorylation level of Fyn at Y531 in both VSMs and HCASMCs and increased the phosphorylation levels of Fyn at Y420, myosin phosphatase target subunit 1 at T853, and myosin light chain (MLC) at S19 in both VSMs and HCASMCs, which were significantly suppressed by hesperetin. Our results indicate that hesperetin inhibits the SPC-induced contraction at least in part by suppressing the Fyn/ROK pathway, suggesting that hesperetin can be a novel drug to prevent and treat vasospasm.

Inhibitory mechanism of tangeretin, a citrus flavone on the sphingosylphosphorylcholine (SPC)-induced vascular smooth muscle contraction.

We previously discovered that the SPC/Fyn/Rho-kinase (ROK) pathway mediates the Ca2+-sensitization of coronary arterial smooth muscle (CASM) contraction leading to vasospasm, a major cause of sudden death. Lately, we have been trying to find and develop more natural edible compounds which can treat and/or prevent the SPC-induced abnormal CASM contraction, and finally the first to discover that tangeretin (5,6,7,8,4'-pentamethoxyflavone), a natural compound extracted from citrus plants, can inhibit the SPC-induced CASM contraction both in the pretreatment and posttreatment. In porcine CASM tissues, tangeretin showed remarkable inhibitory effects on the SPC-induced contraction with modest inhibitory effects on the high K+-depolarization-induced Ca2+-dependent contraction, both in pretreatment and posttreatment at the optimal concentrations; Regarding the mechanisms, tangeretin markedly abolished the SPC-induced cell contraction through inhibiting the SPC-induced activation and translocation of Fyn and ROK from the cytoplasm to the cell membrane in cultured CASM cells, resulting in the reduction of phosphorylation of myosin light chain. Taken together, these findings indicate that tangeretin, upon pre- or post-treatment, inhibits the SPC-induced CASM contraction through suppressing the Fyn/ROK signaling pathway, thereby suggesting that tangeretin can be a potential candidate for the treatment and/or prevention of vasospasm.

Eicosapentaenoic acid ameliorates pulmonary hypertension via inhibition of tyrosine kinase Fyn.

Pulmonary arterial hypertension (PAH) is a multifactorial disease characterized by pulmonary arterial vasoconstriction and remodeling. Src family tyrosine kinases, including Fyn, play critical roles in vascular remodeling via the inhibition of STAT3 signaling. EPA is known to inhibit Fyn kinase activity. This study investigated the therapeutic potential and underlying mechanisms of EPA and its metabolite, resolvin E1 (RvE1), to treat PAH using monocrotaline-induced PAH model rats (MCT-PAH), human pulmonary artery endothelial cells (HPAECs), and human pulmonary artery smooth muscle cells (HPASMCs). Administration of EPA 1 and 2 weeks after MCT injection both ameliorated right ventricular hypertrophy, remodeling and dysfunction, and medial wall thickening of the pulmonary arteries and prolonged survival in MCT-PAH rats. EPA attenuated the enhanced contractile response to 5-hydroxytryptamine in isolated pulmonary arteries of MCT-PAH rats. Mechanistically, the treatment with EPA and RvE1 or the introduction of dominant-negative Fyn prevented TGF-ß2-induced endothelial-to-mesenchymal transition and IL-6-induced phosphorylation of STAT3 in cultured HPAECs. EPA and RvE1 suppressed Src family kinases' activity as evaluated by their phosphorylation status in cultured HPAECs and HPASMCs. EPA and RvE1 suppressed vasocontraction of rat and human PA. Furthermore, EPA and RvE1 inhibited the enhanced proliferation and activity of Src family kinases in HPASMCs derived from patients with idiopathic PAH. EPA ameliorated PAH's pathophysiology by mitigating vascular remodeling and vasoconstriction, probably inhibiting Src family kinases, especially Fyn. Thus, EPA is considered a potent therapeutic agent for the treatment of PAH.

Add-on therapy with traditional Chinese medicine: An efficacious approach for lipid metabolism disorders.

Add-on therapy with traditional Chinese medicine (TCM) has been extensively researched in the intractable diseases, such as asthma, cancer, and Alzheimer's disease. As an entirely new concept, add-on therapy of TCM has been also used to prevent and treat hyperlipidemia via lowering cholesterol level. However, the efficacy of add-on therapy with TCM for mediating lipid metabolism disorders remains controversial. In this review, we summarize and provide strong evidence that add-on therapy of TCM as a novel approach is efficacious and safe for hyperlipidemia associated diseases based on the mediation of lipid metabolism disorders.

Fatty acid-binding protein 7 regulates function of caveolae in astrocytes through expression of caveolin-1.

Fatty acid-binding proteins (FABPs) bind and solubilize long-chain fatty acids, controlling intracellular lipid dynamics. FABP7 is expressed by astrocytes in the developing brain, and suggested to be involved in the control of astrocyte lipid homeostasis. In this study, we sought to examine the role of FABP7 in astrocytes, focusing on plasma membrane lipid raft function, which is important for receptor-mediated signal transduction in response to extracellular stimuli. In FABP7-knockout (KO) astrocytes, the ligand-dependent accumulation of Toll-like receptor 4 (TLR4) and glial cell-line-derived neurotrophic factor receptor alpha 1 into lipid raft was decreased, and the activation of mitogen-activated protein kinases and nuclear factor-κB was impaired after lipopolysaccharide (LPS) stimulation when compared with wild-type astrocytes. In addition, the expression of caveolin-1, not cavin-1, 2, 3, caveolin-2, and flotillin-1, was found to be decreased at the protein and transcriptional levels. FABP7 re-expression in FABP7-KO astrocytes rescued the decreased level of caveolin-1. Furthermore, caveolin-1-transfection into FABP7-KO astrocytes significantly increased TLR4 recruitment into lipid raft and tumor necrosis factor-α production after LPS stimulation. Taken together, these data suggest that FABP7 controls lipid raft function through the regulation of caveolin-1 expression and is involved in the response of astrocytes to the external stimuli. GLIA 2015;63:780-794.

[Complete response in a case of advanced oropharyngeal cancer (T4aN2bM0) treated with concomitant cetuximab and radiotherapy].

We report favorable results achieved using a combination of cetuximab and radiotherapy to treat an elderly patient with advanced oropharyngeal cancer complicated by cardiovascular disease and renal dysfunction.The case was a 78-year-old man who was referred to our hospital with the chief complaint of pharyngeal pain and swelling of the right side of the neck. The patient was diagnosed with oropharyngeal cancer (T4aN2bM0) based on a cytological diagnosis of Class V squamous cell carcinoma and CT findings.Because the patient had a history of hypertension, chronic renal failure, diabetes mellitus, cerebral infarction, angina pectoris, and prostate cancer, we determined that surgical excision and chemoradiotherapy using platinum-based drugs would be difficult.We therefore treated the patient with a combination of cetuximab and radiotherapy. Grade 3 mucous membrane disorder and Grade 2 dermatitis were observed during the course of treatment, but the treatment was completed without any other adverse events.A contrasted CT image taken after the completion of treatment showed that the primary tumor and cervical lymph node metastases had disappeared and the patient thus achieved a complete response.As of 6 months after treatment, there has been no recurrence or metastasis.As shown in this case, combination therapy with cetuximab and radiotherapy can be curative even in elderly patients with advanced oropharyngeal cancer and numerous complicating conditions.

Phosphorylation of the kinase domain regulates autophosphorylation of myosin IIIA and its translocation in microvilli.

Motor activity of myosin III is regulated by autophosphorylation. To investigate the role of the kinase activity on the transporter function of myosin IIIA (Myo3A), we identified the phosphorylation sites of kinase domain (KD), which is responsible for the regulation of kinase activity and thus motor function. Using mass spectrometry, we identified six phosphorylation sites in the KD, which are highly conserved among class III myosins and Ste20-related misshapen (Msn) kinases. Two predominant sites, Thr¹84 and Thr¹88, in KD are important for phosphorylation of the KD as well as the motor domain, which regulates the affinity for actin. In the Caco2 cells, the full-length human Myo3A (hMyo3AFull) markedly enlarged the microvilli, although it did not show discrete localization within the microvilli. On the other hand, hMyo3AFull(T184A) and hMyo3AFull(T188A) both showed clear localization at the microvilli tips. Our results suggest that Myo3A induces large actin bundle formation to form microvilli, and phosphorylation of KD at Thr¹84 and Thr¹88 is critical for the kinase activity of Myo3A, and regulation of Myo3A translocation to the tip of microvilli. Retinal extracts potently dephosphorylate both KD and motor domain without IQ motifs (MDIQo), which was inhibited by okadaic acid (OA) with nanomolar range and by tautomycetin (TMC) with micromolar range. The results suggest that Myo3A phosphatase is protein phosphatase type 2A (PP2A). Supporting this result, recombinant PP2Ac potently dephosphorylates both KD and MDIQo. We propose that the phosphorylation-dephosphorylation mechanism plays an essential role in mediating the transport and actin bundle formation and stability functions of hMyo3A.

Combination of rRT-PCR and Clinical Features to Predict Coronavirus Disease 2019 for Nosocomial Infection Control.

Background: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), immediately became a pandemic. Therefore, nosocomial infection control is necessary to screen for patients with possible COVID-19. Objective: This study aimed to investigate commonly measured clinical variables to predict COVID-19. Methods: This cross-sectional study enrolled 1087 patients in the isolation ward of a university hospital. Conferences were organized to differentiate COVID-19 from non-COVID-19 cases, and multiple nucleic acid tests were mandatory when COVID-19 could not be excluded. Multivariate logistic regression models were employed to determine the clinical factors associated with COVID-19 at the time of hospitalization. Results: Overall, 352 (32.4%) patients were diagnosed with COVID-19. The majority of the non-COVID-19 cases were predominantly caused by bacterial infections. Multivariate analysis indicated that COVID-19 was significantly associated with age, sex, body mass index, lactate dehydrogenase, C-reactive protein, and malignancy. Conclusion: Some clinical factors are useful to predict patients with COVID-19 among those with symptoms similar to COVID-19. This study suggests that at least two real-time reverse-transcription polymerase chain reactions of SARS-CoV-2 are recommended to exclude COVID-19.

Effect of Paxillin Expression and Phosphorylation on Colorectal Cancer Prognosis and Metastasis.

BACKGROUND/AIM: Colorectal cancer (CRC) is the third most common cancer worldwide, and metastasis is strongly associated with poor prognosis in patients with CRC. We have previously found that the expression and phosphorylation of paxillin (PXN) play an important role in the metastatic potential of breast cancer. This study examined the potential role of PXN in CRC metastasis. MATERIALS AND METHODS: Resected tumor specimens from 92 patients with CRC were subjected to immunohistochemical analysis of PXN levels. Three human CRC cell lines, HCT116, LoVo, and SW480 were used for scratch and transwell invasion assays to examine the effects of PXN over-expression. RNA sequencing was performed to obtain the expression profiles under PXN over-expression. RESULTS: High levels of PXN were significantly correlated with advanced stage, higher carcinoembryonic antigen and carbohydrate antigen 19-9 levels, and poorer overall survival. The migration ability of CRC cells was enhanced by exogenous PXN over-expression, but this enhancement was not observed in cells harboring exogenously mutated PXN at Tyr31 or Tyr88 phosphorylation sites. In PXN-over-expressing cells, TNF-α signaling via NF-[Formula: see text]B was positively enriched. CONCLUSION: PXN expression and phosphorylation at Tyr31 or Tyr88 may influence the migration and invasion of CRC cells. PXN expression and phosphorylation at Tyr31 or Tyr88 are promising targets for evaluating prognosis and treating CRC.

Isobutyric acid enhances the anti-tumour effect of anti-PD-1 antibody.

The low response rate of immune checkpoint inhibitors (ICIs) is a challenge. The efficacy of ICIs is influenced by the tumour microenvironment, which is controlled by the gut microbiota. In particular, intestinal bacteria and their metabolites, such as short chain fatty acids (SCFAs), are important regulators of cancer immunity; however, our knowledge on the effects of individual SCFAs remains limited. Here, we show that isobutyric acid has the strongest effect among SCFAs on both immune activity and tumour growth. In vitro, cancer cell numbers were suppressed by approximately 75% in humans and mice compared with those in controls. Oral administration of isobutyric acid to carcinoma-bearing mice enhanced the effect of anti-PD-1 immunotherapy, reducing tumour volume by approximately 80% and 60% compared with those in the control group and anti-PD-1 antibody alone group, respectively. Taken together, these findings may support the development of novel cancer therapies that can improve the response rate to ICIs.

Effects of CPAP treatment interruption due to disasters: patients with sleep-disordered breathing in the Great East Japan Earthquake and tsunami area.

INTRODUCTION: The 2011 Great East Japan Earthquake caused major disruptions in the provision of health care, including that for patients with sleep-disordered breathing (SDB) using a nasal continuous positive airway pressure (nCPAP) device. This study investigated the ability of SDB patients to continue using the nCPAP device in the weeks immediately following the earthquake, whether inability to use the nCPAP device led to symptom relapse, and measures that should be taken to prevent disruptions in nCPAP therapy during future disasters. Hypothesis If nCPAP devices cannot be used during disasters, SDB patients' health will be affected negatively. METHODS: Within 14 days of the disaster, 1,047 SDB patients completed a questionnaire that collected data regarding ability to use, duration of inability to use, and reasons for inability to use the nCPAP device; symptom relapse while unable to use the nCPAP device; ability to use the nCPAP device use at evacuation sites; and recommendations for improvement of the nCPAP device. RESULTS: Of the 1,047 patients, 966 (92.3%) had been unable to use the nCPAP device in the days immediately following the earthquake. The most common reason for inability to use the nCPAP device was power failure, followed by anxiety about sleeping at night due to fear of aftershocks, involvement in disaster-relief activities, loss of the nasal CPAP device, and fear of being unable to wake up in case of an emergency. Among the 966 patients, 242 (25.1%) had experienced relapse of symptoms, the most common of which was excessive daytime sleepiness (EDS), followed by insomnia, headache, irritability, and chest pain. CONCLUSION: Developing strategies for the continuation of nCPAP therapy during disasters is important for providing healthy sleeping environments for SDB patients in emergency situations.

Direct active Fyn-paxillin interaction regulates vascular smooth muscle cell migration.

Vascular smooth muscle cell (VSMC) migration plays an important role in cardiovascular diseases, including atherosclerotic plaque formation and restenosis after vascular intervention. The mechanisms involved in VSMC migration are complex and have not been fully elucidated. Recently, we discovered a novel interaction, direct binding of active Fyn-paxillin at focal adhesions, which plays an important role in actin stress fiber formation and migration in VSMCs. In this review, we highlight paxillin as an intermediate signaling molecule that mediates actin stress fiber formation and VSMC migration through the Fyn/paxillin/Rho-kinase signaling pathway by directly binding to active Fyn. We also discuss the inhibition of VSMC migration by blocking the active Fyn-paxillin interaction and the potential of this interaction as a therapeutic target for cardiovascular diseases.

Antimicrobial Stewardship Program for Patients in the Hematological Department Receiving Carbapenem Therapy: A Single-Center and Interrupted Time Series Analysis.

As antibiotic resistance has become a global problem, the intervention of an antimicrobial stewardship team (AST) is warranted. In hematological disorders, infectious complications are crucial owing to abnormal neutrophil function and decreased cell-mediated immunity. Despite the widespread implementation of AST intervention, the effectiveness of stewardship practices for immunocompromised patients remains uncertain. We determined the effect of AST interventions on carbapenem therapy in the department of hematology. Patients admitted to the department and undergoing carbapenem therapy were enrolled. We compared carbapenem use between the pre-AST (April 2016-March 2018) and post-AST (April 2018-March 2021) periods. Factors associated with long-term carbapenem therapy were investigated. Overall, 515 episodes of carbapenem therapy in 264 patients in the department were evaluated. According to the interrupted time series analysis, the number of days of therapy decreased with AST intervention (ß = -0.263, p = 0.011). In multivariate analysis, predictive factors associated with long-term carbapenem therapy (>8 days) were outpatient onset, chronic obstructive pulmonary disease, acute myeloid leukemia, multiple myeloma, and infection with resistant bacteria (such as extended spectrum ß-lactamases and AmpC) (95% confidence interval, 1.030-2.818, 1.067-66.667, 1.057-2.782, 0.168-0.742, and 1.382-5.750, respectively). The AST intervention reduced carbapenem use in patients with hematological disorders.

Differentiation between IgG4-related Mikulicz disease and Sjögren's syndrome: A review case report and literature review.

RATIONALE: IgG4-related diseases cause lesions in various organs throughout the body. In otorhinolaryngology, IgG4-related Mikulicz's disease is suspected and diagnosed based on the presence of lesions of the head and neck, salivary and lacrimal gland enlargement, and bilateral sinus opacity concentrated on the maxillary sinuses. However, in some cases, it is necessary to consider about differentiation between IgG4-related Mikulicz's disease and Sjögren syndrome. PATIENT CONCERNS AND DIAGNOSIS: A 75-years-old male patient visited our hospital with bilateral otitis media with effusion, which was resistant to conservative treatment. Other symptoms at presentation included enlarged bilateral submandibular and sublingual glands marked oral dryness, severe decrease in saliva secretion (1 mL/10 minutes), and dry eyes. We conducted a Schirmer's and fluorescent dye tests, both of which were positive. High serum IgG4 levels were observed, and although the Sjögren syndrome (SS)-A/SS-B antibodies were negative, marked hypolacrimation and tear secretion were observed. Therefore, a detailed examination considering both IgG4-related Mikulicz's disease and SS was conducted. Salivary gland scintigraphy performed prior to the salivary gland biopsy revealed a marked decrease in uptake, which satisfied the diagnostic criteria for SS; however, it was difficult to diagnose IgG4-related disease based on the diagnostic definition. INTERVENSIONS: Although a definitive diagnosis of SS was made, the persistent otitis media with effusion that was resistant to conservative treatment and bilateral mixed hearing loss were confirmed. As mixed hearing loss is considered an otological symptom of IgG4-related disease, oral steroid treatment was administered. OUTCOME: Thereafter, marked recovery of hearing and reduced swelling and induration of the bilateral parotid and submandibular glands were observed. Clinically, IgG4-related Mikulicz's disease was strongly suspected, but a definite diagnosis of SS was made. LESSONS: In the absence of an IgG4-related Mikulicz's disease diagnosis, careful differentiation between IgG4-related Mikulicz's disease and 2 diseases and their diagnostic criteria was essential.

Perivascular Adipose Tissue Is a Major Source of Nitric Oxide in Saphenous Vein Grafts Harvested via the No-Touch Technique.

Background Saphenous vein grafts (SVGs) are broadly used in coronary artery bypass grafting despite their inferior patency compared with arterial grafts. Recently, the no-touch technique (NT), in which an SVG is harvested with a pedicle of perivascular adipose tissue (PVAT) without conduit distension, was shown to improve long-term patency compared with conventional preparation (CV), wherein outer tissue is removed with distension. The NT was also reportedly associated with reduced atherosclerosis. Although endothelial damage provoked by conventional distension may underlie poor patency when CV is performed, the precise mechanisms underlying the salutary effects of the NT have been unclear. Methods and Results Residual SVGs prepared with CV (CV-SVGs) or NT (NT-SVGs) were obtained during coronary artery bypass grafting. Nitric oxide (NO2-/NO3- (NOx)) levels after 24 hours of tissue culture were quantified. The protein expression and localization were analyzed. The isometric force of SVG strips was measured. NT-SVGs showed superior NOx production to CV-SVGs. PVAT generated the majority of NOx in NT-SVGs. PVAT highly expressed arginosuccinate synthase 1, a rate-limiting enzyme in the molecular circuit for NO synthesis, thereby continuously providing the substrate for NO. A substantial level of endothelial NO synthase was also expressed in PVAT. Pharmacological inhibition of arginosuccinate synthase 1 or endothelial NO synthase significantly suppressed the NOx production in NT-SVGs. PVAT induced vasorelaxation through NO production, even in the endothelium-denuded SVG strips. Conclusions Preserving PVAT was predominantly involved in the superior NOx production in NT-SVGs. Since NO plays crucial roles in suppressing atherosclerosis, this mechanism may greatly contribute to the excellent patency in NT-SVGs.

[Efficacy of concurrent chemoradiotherapy with S-1 plus nedaplatin for hypopharyngeal cancer].

Many reports have been published on the treatment for hypopharyngeal cancer, and the treatment modalities and results have become uniform to some extent. More specifically, reconstruction by means of free jejunal grafts has become widespread, and the results of surgical treatments have stabilized. On the other hand concurrent chemoradiotherapy has been widely performed, and the results from the standpoint of organ and function preservation have revealed the various differences between institutions. In our department, we have been using concurrent chemoradiotherapy for advanced cancer with a view to organ and function preservation. In this article, we report 6 cases with hypopharyngeal cancer treated by concurrent chemoradiotherapy with S-1 plus nedaplatin(SN therapy)in our department between January 2005 and December 2008. The complete response rate after SN therapy was 83. 3%, and the laryngeal preservation rate was 100%.