Switching mechanism from AR to EGFR signaling via 3-O-sulfated heparan sulfate in castration-resistant prostate cancer.

Androgen deprivation therapy is given to suppress prostate cancer growth; however, some cells continue to grow hormone-independently as castration-resistant prostate cancer (CRPC). Sulfated glycosaminoglycans promote ligand binding to receptors as co-receptors, but their role in CRPC remains unknown. Using the human prostate cancer cell line C4-2, which can proliferate in hormone-dependent and hormone-independent conditions, we found that epidermal growth factor (EGF)-activated EGFR-ERK1/2 signaling via 3-O-sulfated heparan sulfate (HS) produced by HS 3-O-sulfotransferase 1 (HS3ST1) is activated in C4-2 cells under hormone depletion. Knockdown of HS3ST1 in C4-2 cells suppressed hormone-independent growth, and inhibited both EGF binding to the cell surface and activation of EGFR-ERK1/2 signaling. Gefitinib, an EGFR inhibitor, significantly suppressed C4-2 cell proliferation and growth of a xenografted C4-2 tumor in castrated mouse. Collectively, our study has revealed a mechanism by which cancer cells switch to hormone-independent growth and identified the key regulator as 3-O-sulfated HS.

Effect of annealing on the magnetic microstructure of high-pressure torsion iron: the relevance of higher-order contributions to the magnetic small-angle neutron scattering cross section.

The development of higher-order micromagnetic small-angle neutron scattering theory in nanocrystalline materials is still in its infancy. One key challenge remaining in this field is understanding the role played by the microstructure on the magnitude and sign of the higher-order scattering contribution recently observed in nanocrystalline materials prepared by high-pressure torsion. By combining structural and magnetic characterization techniques, namely X-ray diffraction, electron backscattered diffraction and magnetometry with magnetic small-angle neutron scattering, this work discusses the relevance of higher-order terms in the magnetic small-angle neutron scattering cross section of pure iron prepared by high-pressure torsion associated with a post-annealing process. The structural analysis confirms: (i) the preparation of ultra-fine-grained pure iron with a crystallite size below 100 nm and (ii) rapid grain growth with increasing annealing temperature. The analysis of neutron data based on the micromagnetic small-angle neutron scattering theory extended to textured ferromagnets yields uniaxial magnetic anisotropy values that are larger than the magnetocrystalline value reported for bulk iron, supporting the existence of induced magnetoelastic anisotropy in the mechanically deformed samples. Furthermore, the neutron data analysis revealed unambiguously the presence of non-negligible higher-order scattering contributions in high-pressure torsion iron. Though the sign of the higher-order contribution might be related to the amplitude of the anisotropy inhomogeneities, its magnitude appears to be clearly correlated to the changes in the microstructure (density and/or shape of the defects) induced by combining high-pressure torsion and a post-annealing treatment.

Ovarian Follicular Lymphoma Diagnosed Due to Hydronephrosis.

A 74-year-old woman presented with left lateral abdominal pain. Abdominal echography revealed left hydronephrosis and a pelvic mass. The patient underwent left adnexal resection of a suspected left ovarian tumor and was diagnosed with follicular lymphoma (FL) of clinical stage IIIA, grade 2. The patient was treated with rituximab-combined chemotherapy and achieved complete remission. The most common histological types of ovarian lymphoma are diffuse large B-cell lymphoma and Burkitt lymphoma, with FL being an extremely rare variant. We herein report a case of ovarian FL diagnosed as hydronephrosis.

Severe Abdominal Recurrence of Low-grade Endometrial Stromal Sarcoma After Hysteroscopic Surgery.

BACKGROUND: Low-grade endometrial stromal sarcoma (LG-ESS) is an indolent tumor harboring gene fusion involving polycomb family genes. While early LG-ESS has a good clinical course, some tumors have pelvic recurrence. The etiology and genetic alterations involved in the process remain unknown. CASE REPORT: A 44-year-old nulliparous woman underwent hysteroscopic surgery for a 2.5 cm submucosal uterine tumor with negative endometrial cytology. Pathological evaluation revealed LG-ESS. On the 31st day, total laparoscopic hysterectomy was indicated. She was diagnosed with stage IA (pT1aNXM0) LG-ESS without lymphovascular invasion. At 4 years, positron-emission tomography showed multiple pelvic masses. Secondary debulking surgery was performed, which revealed severe intra-abdominal recurrence of LG-ESS with JAZF1-SUZ12 fusion. CONCLUSION: Hysteroscopic surgery is a convenient tool for benign uterine submucosal diseases. However, intrauterine morcellation with fluid can lead to unexpected recurrence of occult LG-ESS. It is important when seeking consent for surgery to inform patients about the possible risk of dissemination of uterine mesenchymal tumors.

A case report of advanced ovarian cancer detected due to an inguinal metastasis in the canal of Nuck.

INTRODUCTION: Ovarian cancer has few subjective symptoms, so approximately 40%-50% of cases have already reached stage III or IV by the time of diagnosis. These are advanced stages of the disease and have poor prognosis. Among these cases, less than 3 % are reported to exhibit inguinal lymph node metastasis. This report documents a rare case of advanced ovarian cancer that we detected due to an inguinal metastasis in the canal of Nuck. The work has been reported in line with the SCARE criteria. PRESENTATION OF CASE: The patient was a 43-year-old, married, premenopausal woman (G2P1). She was examined by her local practitioner for a chief complaint of a mass in the right inguinal region and was found to have a right inguinal mass. Magnetic resonance imaging (MRI) scans revealed a left ovarian tumor, and she was referred to our department. Rapid intraoperative diagnosis showed a highly atypical serous carcinoma present in both the left ovary and the right inguinal region mass, where the tumor had extended into the canal of Nuck. DISCUSSION: In this case, the right inguinal mass was ovarian cancer that had metastasized to a cyst in the canal of Nuck via the round ligament of the uterus. Though, many adult women with these types of inguinal hydrocoeles sometimes undergo fine-needle aspiration. CONCLUSION: This finding may highlight the need for a careful search for metastasis to the inguinal region in cases of ovarian cancer.

Methicillin-Resistant Staphylococcus aureus Nasal Swab and Suction Drain Tip Cultures in 4573 Spinal Surgeries: Efficacy in Management of Surgical Site Infections.

STUDY DESIGN: A retrospective single-center study. OBJECTIVE: To assess the diagnostic value of methicillin-resistant Staphylococcus aureus (MRSA) nasal swab and suction drain tip cultures. SUMMARY OF BACKGROUND DATA: The prognostic value of MRSA nasal swab and suction drain tip cultures has not been firmly established in spinal surgery. METHODS: This study retrospectively included 4573 consecutive patients who underwent spinal surgery between January 2008 and December 2014. Patients diagnosed with infectious disease were excluded. Prophylactic antibiotics were administered intraoperatively and postoperatively for 48 hours. MRSA nasal swab cultures were taken from all patients before surgery. Drains were removed when the volume of postoperative fluid drainage was less than 50 mL in the preceding 24 hours and cultures were made. Surgical site infection (SSI) was defined according to Centers for Disease Control and Prevention criteria. RESULTS: SSI was identified in 94 cases (2.1%) and bacteria were isolated in 87 cases (92.6%). Positive MRSA nasal swab cultures were identified in 49 cases (1.1%). There was no significant difference in the SSI positivity rate between the MRSA nasal swab culture (+) and (-) groups. Positive drain tip cultures were found in 382 cases (8.4%), 28 of which developed SSI. There was a significant difference in the SSI positivity rate between the drain tip culture (+) and (-) groups. The sensitivity of drain tip culture was 29.8% and the specificity was 92.1%. In 16 of the 28 patients in the SSI (+) group with positive drain cultures, the same bacteria were isolated from the surgical site, giving a bacteria matching rate of 57.1%. CONCLUSION: MRSA nasal swab and drain tip cultures were not useful for predicting SSI. However, drain tip culture had a high positivity rate in the SSI group and the coincidence rate for the causative pathogen was relatively high. LEVEL OF EVIDENCE: 4.

Current Status of Uterine Leiomyosarcoma in the Tohoku Region: Results of the Tohoku Translational Center Development Network Survey.

BACKGROUND: To prepare for a future clinical trial for improving the long-term prognosis of patients with uterine leiomyosarcoma (ULMS), we conducted a multi-institutional survey in the Tohoku region of Japan. METHODS: We conducted a retrospective cohort study between 2011 and 2014 in member institutions of the Tohoku Translational Research Center Development Network. RESULTS: A total of 53 patients with ULMS were registered in 31 institutions for the present survey. The median patient age was 56 years, 67.9% of the patients were postmenopausal, 88.7% had a performance status of 0 or 1, and only 6 patients (11.3%) showed preoperative evidence of malignancy. Although retroperitoneal lymphadenectomy was performed in only 26.4% of patients, 64.2% patients were identified as having FIGO stage 1 disease; 73.6% were eligible to undergo complete surgery. Among 36 patients who were treated with postoperative chemotherapy, 28 (77.8%) received docetaxel and gemcitabine combination therapy. The most frequent recurrence site was the lungs, and the median progression-free survival of all enrolled patients was 11.7 months. However, the median progression-free survival and the median overall survival in patients with stages III and IV disease were 3.4 and 11.4 months, respectively. CONCLUSION: Although ULMS was associated with a high rate of complete or optimal surgery, the long-term prognosis was poor. Effective postoperative therapy should be developed to improve the long-term prognosis of patients with ULMS.

A Comparative Study of Anterior Decompression With Fusion and Posterior Decompression With Laminoplasty for the Treatment of Cervical Spondylotic Myelopathy Patients With Large Anterior Compression of the Spinal Cord.

STUDY DESIGN: This is a retrospective observational single-center study. OBJECTIVES: To compare anterior decompression and fusion (ADF) and laminoplasty (LAMP) for the treatment of cervical spondylotic myelopathy (CSM) patients with large anterior compression in terms of clinical and radiologic outcomes. SUMMARY OF BACKGROUND DATA: We have reported that insufficient posterior decompression could be often seen after laminoplasty for CSM patients with preoperative anterior clearance of the spinal cord, defined as an interval <4 mm between the preoperative the modified K-line and anterior structure of the spinal canal at most compressive segment on sagittal T1-weighted magnetic resonance imaging. Here we conduct a study comparing ADF and LAMP for the treatment of CSM patients with such a risk factor. MATERIALS AND METHODS: Of the 221 consecutive CSM patients treated with either ADF or LAMP between 2008 and 2012 at our hospital, 79 patients in whom the interval was <4 mm with age ranged from 50 to 79 years were enrolled. Patients with myelopathy caused by single-level disk herniation, tumor or ossification of posterior longitudinal ligament, or patients with a history of cervical spine injury were excluded. The Japanese Orthopedic Association (JOA) scoring system for cervical myelopathy, recovery rate of the JOA score at the time of 2 years after surgery were investigated as clinical outcomes to compare these 2 groups. RESULTS: Demographics were almost similar between ADF and LAMP groups. The mean preoperative and postoperative JOA scores were 10.9 and 13.8 points for ADF group and 10.1 and 12.4 points for LAMP group, indicating that the recovery rate of JOA score was significantly greater in ADF group (49.6%) than that in LAMP group (38.2%; P=0.047). In LAMP group, spinal cord deformity was a significant predictive factor for unsatisfactory clinical outcome. CONCLUSION: ADF provided better surgical treatment for the patients with absence of preoperative anterior clearance of the spinal cord.

Psychological stress exacerbates NSAID-induced small bowel injury by inducing changes in intestinal microbiota and permeability via glucocorticoid receptor signaling.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are popular painkillers, but they have serious side effects, not only in the upper gastrointestinal tract but also in the small intestine. It is well known that psychological stress may exacerbate various gastrointestinal diseases. The aim of this study was to determine whether psychological stress exacerbates NSAID enteropathy and to determine the possible underlying mechanisms for this. METHODS: Experiment 1: mice were exposed to water avoidance stress (WAS) or sham stress for 1 h per day for 8 consecutive days, and then enteropathy was induced by indomethacin. Experiment 2: cecal contents from stress (-) or (+) mice were transplanted into mice that had received antibiotics and in which NSAID enteropathy had been induced without WAS. Experiment 3: mifepristone, a glucocorticoid receptor antagonist, was injected before WAS for 8 days. Small intestinal injury, mRNA expression of TNFα, intestinal permeability, and the microbial community were assessed. RESULTS: Psychological stress exacerbated NSAID enteropathy and increased intestinal permeability. Psychological stress induced changes in the ileal microbiota that were characterized by increases in the total number of bacteria and the proportion of Gram-negative bacteria. The increased susceptibility to NSAIDs and intestinal permeability due to WAS was transferable via cecal microbiota transplantation. The increased permeability and aggravation of NSAID enteropathy caused by WAS were blocked by the administration of mifepristone. CONCLUSIONS: This study demonstrated a relationship between NSAID enteropathy and psychological stress, and showed the utility of studying the intestinal microbiota in order to elucidate the pathophysiology of NSAID enteropathy. It also showed the impact of stress on the intestinal microbiota and the mucosal barrier in gastrointestinal diseases.

Human serum albumin hydropersulfide is a potent reactive oxygen species scavenger in oxidative stress conditions such as chronic kidney disease.

Recently, hydropersulfide (RSSH) was found to exist in mammalian tissues and fluids. Cysteine hydropersulfide can be found in free cysteine residues as well as in proteins, and it has potent antioxidative activity. Human serum albumin (HSA) is the most abundant protein in mammalian serum. HSA possesses a free thiol group in Cys-34 that could be a site for hydropersulfide formation. HSA hydropersulfide of high purity as a positive control was prepared by treatment of HSA with Na2S. The presence of HSA hydropersulfide was confirmed by spectroscopy and ESI-TOFMS analysis where molecular weights of HSA hydropersulfide by increments of approximately 32 Da (Sulfur atom) were detected. The fluorescent probe results showed that Alexa Fluor 680 conjugated maleimide (Red-Mal) was a suitable assay and bromotrimethylammoniumbimane bromide appeared to be a selective reagent for hydropersulfide. The effect of oxidative stress related disease on the existence of albumin hydropersulfides was examined in rat 5/6 nephrectomy model of chronic kidney disease (CKD). Interestingly, the level of hydropersulfides in rat 5/6 nephrectomy model serum was decreased by a uremic toxin that increases oxidative stress in rat 5/6 nephrectomy model. Furthermore, we demonstrated that the levels of HSA hydropersulfide in human subjects were reduced in CKD but restored by hemodialysis using Red-Mal assay. We conclude that HSA hydropersulfide could potentially play an important role in biological anti-oxidative defense, and it is a promising diagnostic and therapeutic marker of oxidative diseases.

Antibiotics Suppress Activation of Intestinal Mucosal Mast Cells and Reduce Dietary Lipid Absorption in Sprague-Dawley Rats.

BACKGROUND & AIMS: The gut microbiota affects intestinal permeability and mucosal mast cells (MMCs) responses. Activation of MMCs has been associated with absorption of dietary fat. We investigated whether the gut microbiota contributes to the fat-induced activation of MMCs in rats, and how antibiotics might affect this process. METHODS: Adult male Sprague-Dawley rats were given streptomycin and penicillin for 4 days (n = 6-8) to reduce the abundance of their gut flora, or normal drinking water (controls, n = 6-8). They underwent lymph fistula surgery and after an overnight recovery were given an intraduodenal bolus of intralipid. We collected intestinal tissues and lymph fluid and assessed activation of MMCs, intestinal permeability, and fat transport parameters. RESULTS: Compared with controls, intestinal lymph from rats given antibiotics had reduced levels of mucosal mast cell protease II (produced by MMCs) and decreased activity of diamine oxidase (produced by enterocytes) (P < .05). Rats given antibiotics had reduced intestinal permeability in response to dietary lipid compared with controls (P < .01). Unexpectedly, antibiotics also reduced lymphatic transport of triacylglycerol and phospholipid (P < .01), concomitant with decreased levels of mucosal apolipoproteins B, A-I, and A-IV (P < .01). No differences were found in intestinal motility or luminal pancreatic lipase activity between rats given antibiotics and controls. These effects were not seen with an acute dose of antibiotics or 4 weeks after the antibiotic regimen ended. CONCLUSIONS: The intestinal microbiota appears to activate MMCs after the ingestion of fat in rats; this contributes to fat-induced intestinal permeability. We found that the gut microbiome promotes absorption of lipid, probably by intestinal production of apolipoproteins and secretion of chylomicrons.

Platelet interaction with lymphatics aggravates intestinal inflammation by suppressing lymphangiogenesis.

Lymphatic failure is a histopathological feature of inflammatory bowel disease (IBD). Recent studies show that interaction between platelets and podoplanin on lymphatic endothelial cells (LECs) suppresses lymphangiogenesis. We aimed to investigate the role of platelets in the inflammatory process of colitis, which is likely to be through modulation of lymphangiogenesis. Lymphangiogenesis in colonic mucosal specimens from patients with IBD was investigated by studying mRNA expression of lymphangiogenic factors and histologically by examining lymphatic vessel (LV) densities. Involvement of lymphangiogenesis in intestinal inflammation was studied by administering VEGF-receptor 3 (VEGF-R3) inhibitors to the mouse model of colitis using dextran sulfate sodium and evaluating platelet migration to LVs. The inhibitory effect of platelets on lymphangiogenesis was investigated in vivo by administering antiplatelet antibody to the colitis mouse model and in vitro by coculturing platelets with lymphatic endothelial cells. Although mRNA expressions of lymphangiogenic factors such as VEGF-R3 and podoplanin were significantly increased in the inflamed mucosa of patients with IBD compared with those with quiescent mucosa, there was no difference in LV density between them. In the colitis model, VEGF-R3 inhibition resulted in aggravated colitis, decreased lymphatic density, and increased platelet migration to LVs. Administration of an antiplatelet antibody increased LV densities and significantly ameliorated colitis. Coculture with platelets inhibited proliferation of LECs in vitro. Our data suggest that despite elevated lymphangiogenic factors during colonic inflammation, platelet migration to LVs resulted in suppressed lymphangiogenesis, leading to aggravation of colitis by blocking the clearance of inflammatory cells. Modulating the interaction between platelets and LVs could be a new therapeutic means for treating IBD.

Profuse bleeding from a pseudoaneurysm of the right superior thyroid artery after tracheostomy.

Case: A 70-year-old man was brought to our hospital emergency department with accidental thermal burns. Surgical tracheostomy was carried out on day 8 after admission, followed by several profuse bleeding episodes from the orifice. Contrast-enhanced computed tomography of the neck revealed a small nodule with arterial phase enhancement that was suspected to be a pseudoaneurysm. During emergency angiography, the nodule was revealed to be a pseudoaneurysm arising from the right superior thyroid artery with contrast medium extravasation. Outcome: The patient underwent transcatheter arterial embolization, which resolved bleeding from the tracheostomy orifice. Conclusion: Pseudoaneurysm of the superior thyroid artery is an extremely rare and life-threatening tracheostomy complication. All clinicians certified to perform tracheostomy should be acquainted with the various complications and methods for managing life-threatening post-tracheostomy complications.

Toll-like receptor (TLR) 2 agonists ameliorate indomethacin-induced murine ileitis by suppressing the TLR4 signaling.

BACKGROUND AND AIM: Few drugs have been found satisfactory in the treatment of nonsteroidal anti-inflammatory drugs (NSAIDs)-induced enteropathy. Toll-like receptor (TLR) 4 and aberrant leukocyte migration to the intestinal mucosa are reported to be involved in the pathology of intestinal enteropathy and TLR2 agonists have been found to evoke hyposensitivity to TLR4 stimulation in vitro. In this study, we investigated whether and how lipoarabinomannan (LAM) or lipoteichoic acid (LTA), TLR2 agonists, attenuated indomethacin (IND)-induced intestinal damage. METHODS: LAM (0.5 mg/kg) or LTA (15 mg/kg) was administered intraperitoneally to mice before IND (10 mg/kg) administration. Disease activity was evaluated macroscopically and histologically. In the migration analysis, fluorescence-labeled leukocyte movement in the intestinal microvessels was observed by intravital microscopy. Expression of P-selectin, MAdCAM-1, TLR2, TLR4, and F4/80 was observed immunohistochemically. In the in vitro analysis, RAW264.7 macrophage cells were preincubated with LAM and stimulated with lipopolysaccharide (LPS), and the mRNA expression levels of TLR4, tumor necrosis factor-α, and interleukin-12p40 were measured. RESULTS: Pretreatment with LAM or LTA significantly decreased IND-induced injury as well as decreased leukocyte infiltration. Pretreatment with LAM decreased IND-induced TLR4 expression on F4/80(+) macrophages, the level of P-selectin expression, and leukocyte migration in the small intestinal vessels. In the in vitro study, a single administration of LAM decreased TLR4 mRNA expression and inhibited the increase in mRNA expression of inflammatory cytokines by LPS in a dose-dependent manner. CONCLUSION: TLR2 agonists attenuated IND-induced small intestinal lesions and leukocyte infiltration probably by suppressing the TLR4 signaling pathway in tissue macrophages.

Magnetic resonance enterocolonography in detecting erosion and redness in intestinal mucosa of patients with Crohn's disease.

BACKGROUND AND AIM: In Crohn's disease (CD), assessment of disease activity and extension is important for clinical management. Endoscopy is the most reliable tool for evaluating disease activity in these patients and it distinguishes between lesions based on ulcer, erosion, and redness. Magnetic resonance imaging (MRI) is less invasive than endoscopy; however, the sensitivity of MRI in detecting lesions is believed to be lower, and whether MRI can detect milder lesions has not been studied. The aim of this study was to compare the detection ability of magnetic resonance enterocolonography (MREC) with ileocolonic endoscopy in patients with CD. METHODS: A total of 27 patients with CD underwent both MREC and ileocolonoscopy. There were 55 lesions (18 ileum and 37 colon) endoscopically detected, and the findings of MREC were compared with each ileocolonoscopic finding to determine sensitivity and specificity. RESULTS: For a positive lesion defined as having at least one of the following: wall thickness, edema, diffusion-weighted imaging (DWI) high intensity and relative contrast enhancement (RCE) on MREC, the sensitivities were 100% for ulcer, 84.6% for erosion, and 52.9% for redness, suggesting an ability to detect milder lesions such as erosion or redness. Moreover, RCE values were well correlated with the severity of endoscopically identified active lesions. CONCLUSION: MREC findings may be useful not only for evaluation of ulcers, but also for detection of endoscopically identified milder lesions in CD, suggesting a clinical usefulness of MREC for disease detection and monitoring.

Pregnant woman with non-comatose autoimmune acute liver failure in the second trimester rescued using medical therapy: A case report.

We present the case of a 25-year-old woman at 16 weeks of gestation who presented with non-comatose autoimmune acute liver failure and was at high risk of developing fulminant hepatitis. Predictive formulas indicated a high probability of developing fulminant hepatitis. Unenhanced computed tomography showed marked hepatic atrophy and broadly heterogeneous hypoattenuating areas. The course of her illness was subacute, and the etiology of liver injury was unclear. Considering all of the above, we predicted a poor prognosis. Plasma exchange (PE) and continuous hemodiafiltration (CHDF) therapy were initiated just after admission. A few days after admission, a high titer (×80) of antinuclear antibody was noted. Because autoimmune hepatitis (AIH) was considered a cause of liver failure, treatment with moderate prednisolone (30 mg/day) doses was administrated, with careful consideration of her pregnancy. Thereafter, her laboratory findings and clinical course gradually improved without the need for liver transplantation. A liver biopsy at 18 days after admission indicated a diagnosis of AIH. She continued the pregnancy and delivered a healthy baby without any complications. Eventually, prednisolone doses were decreased to 10 mg, after which her liver function worsened. The second liver biopsy also indicated a diagnosis of AIH. Accordingly, low-dose prednisolone and azathioprine doses (50 mg/day) were administrated to recover her liver function, after which her liver function regained normalcy. This case illustrates that a pregnant woman with non-comatose autoimmune acute liver failure in the first or second trimester of pregnancy and her fetus can be rescued by PE/CHDF therapy and safe moderate doses of prednisolone.

Phlebosclerotic colitis that was difficult to distinguish from collagenous colitis.

Phlebosclerotic colitis is a rare and recently known disease entity and its etiology is still to be elucidated. Some phlebosclerotic colitis cases are difficult to distinguish from collagenous colitis because of the similarity of pathological findings. In all Japanese case reports of phlebosclerotic colitis in which an association with the use of Chinese herbal medicine is suspected, sansisi (gardenia fruit) was included, suggesting pathogenesis of this disease. We report a case of phlebosclerotic colitis that wasdifficult to be distinguished from collagenous colitis, and an association with the use of Chinese herbal medicine was suspected as the cause of the disease.

Favorable outcomes of patients with vasospastic angina associated with cardiac arrest.

BACKGROUND: The long-term survival of vasospastic angina (VSA) patients is generally good, so long as they remain on calcium channel blockers (CCBs) and avoid smoking. However, the pathogenesis, appropriate treatments, and prognosis of VSA associated with cardiac arrest remain unclear. This study aimed to elucidate the clinical features and long-term outcomes of patients with VSA associated with cardiac arrest. METHODS AND RESULTS: Eighteen consecutive patients with VSA associated with cardiac arrest [13 patients resuscitated after out-of-hospital cardiac arrest (OHCA) and 5 resuscitated after in-hospital-cardiac arrest] were retrospectively analyzed. Sixteen of the eighteen patients were smokers. None had other cardiac diseases possibly causing cardiac arrest. Although 1 patient resuscitated after OHCA later died of cerebral hypoxia, the remaining 17 were discharged without complications. One patient died of cancer 50 months after resuscitation. The other 16 patients are still alive and none have shown ventricular arrhythmias, syncope, or cardiac arrest during a mean follow-up of 67 months. All are treated with long-acting CCBs/nitrates and successfully quit smoking. Six patients received implantable cardioverter defibrillators (ICD). However, none demonstrated any ventricular arrhythmias and appropriate ICD actuation was achieved. CONCLUSION: Appropriate medical treatment can achieve favorable long-term outcomes even for patients with VSA associated with cardiac arrest.

1,4-Dihydroxy-2-naphthoic acid from Propionibacterium freudenreichii reduces inflammation in interleukin-10-deficient mice with colitis by suppressing macrophage-derived proinflammatory cytokines.

The anti-inflammatory mechanism of prebiotics has recently been shown to have an impact on the host immune system. DHNA from Propionibacterium freudenreichii is known to promote the proliferation of Bifidobacterium and can ameliorate colitis, although its mode of action remains unknown. In this study, we investigated whether DHNA attenuates inflammation in piroxicam-treated IL-10(-/-) mice, particularly focusing on the changes of the host immune mechanism. DHNA was administered to IL-10(-/-) mice with colitis, and the expression of adhesion molecules and mRNA levels of proinflammatory cytokines were determined. DHNA pretreatment attenuated the piroxicam-induced histological changes. The increased F4/80-positive cell infiltration and VCAM-1 expression were decreased by DHNA administration. The increased mRNA levels of proinflammatory cytokines were also suppressed by DHNA. In in vitro experiments, increased mRNA levels of proinflammatory cytokines after endotoxin exposure were decreased significantly by DHNA pretreatment in RAW264.7, a macrophage cell line, and IL-10(-/-) mice BMMs, whereas the expression of VCAM-1 in bEnd.3 cells, a endothelial cell line, was not affected. Taken together, these findings suggest that administration of DHNA is useful for the treatment of colitis in piroxicam-treated IL-10(-/-) mice and that attenuation of colitis by DHNA may partly be a result of its direct action on intestinal macrophages to inhibit proinflammatory cytokine production.

Involvement of autotaxin/lysophospholipase D expression in intestinal vessels in aggravation of intestinal damage through lymphocyte migration.

Lysophosphatidic acid (LPA) has a critical role in lymphocyte migration to secondary lymphoid organs. Autotaxin (ATX)/lysophospholipase D, in the vascular endothelium, is the main enzyme involved in LPA production. Whether ATX is involved in pathological lymphocyte migration to the inflamed mucosa has not been studied. We investigated the involvement of ATX in inflammatory bowel disease patients and two murine models of colitis. Tissue samples were obtained by intestinal biopsies from patients with Crohn's disease and those with ulcerative colitis with informed consent. ATX immunoreactivity was colocalized with MAdCAM-1-positive high-endothelial-like vessels, close to sites of lymphocyte infiltration. Enhanced expression of ATX mRNA was observed in the inflamed mucosa from Crohn's disease and ulcerative colitis patients. ATX mRNA expression level was remarkably higher in the actively inflamed mucosa than in the quiescent mucosa in the same patient. In the T-cell-transferred mouse model, ATX mRNA expression level gradually increased as colitis developed. In the dextran sodium sulfate mouse model, the expression level was considerably higher in colonic mucosa of chronically developed colitis than in colonic mucosa of acute colitis. Administration of an ATX inhibitor, bithionol, remarkably decreased lymphocyte migration to the intestine and ameliorated both dextran sodium sulfate-induced colitis and CD4-induced ileocolitis. In transwell assays, administration of bithionol or 1-bromo-3(s)-hydroxy-4-(palmitoyloxy) butylphosphonate (BrP-LPA) significantly decreased transmigration of splenocytes through high-endothelial-like vessels induced by TNF-α. We conclude that enhanced expression of ATX in the active mucosa has been implicated in the pathophysiology of inflammatory bowel disease through enhancing aberrant lymphocyte migration to the inflamed mucosa.