Fibroblast growth factor 13 regulates glioma cell invasion and is important for bevacizumab-induced glioma invasion.

Glioblastoma has the poorest prognosis, and is characterized by excessive invasion and angiogenesis. To determine the invasive mechanisms, we previously used two glioma cell lines (J3T-1 and J3T-2) with different invasive phenotypes. The J3T-1 showed abundant angiogenesis and tumor cell invasion around neovasculature, while J3T-2 showed diffuse cell infiltration into surrounding healthy parenchyma. Microarray analyses were used to identify invasion-related genes in J3T-2 cells, and the expressed genes and their intracellular and intratumoral distribution patterns were evaluated in J3T-2 cell lines, human glioma cell lines, human glioblastoma stem cells and human glioblastoma specimens. To determine the role of the invasion-related genes, invasive activities were evaluated in vitro and in vivo. Fibroblast growth factor 13 (FGF13) was overexpressed in J3T-2 cells compared to J3T-1 cells, and in human glioma cell lines, human glioblastoma stem cells and human glioblastoma specimens, when compared to that of normal human astrocytes. Immunohistochemical staining and the RNA-seq (sequencing) data from the IVY Glioblastoma Atlas Project showed FGF13 expression in glioma cells in the invasive edges of tumor specimens. Also, the intracellular distribution was mainly in the cytoplasm of tumor cells and colocalized with tubulin. Overexpression of FGF13 stabilized tubulin dynamics in vitro and knockdown of FGF13 decreased glioma invasion both in vitro and in vivo and prolonged overall survival of several xenograft models. FGF13 was negatively regulated by hypoxic condition. Silencing of FGF13 also decreased in vivo bevacizumab-induced glioma invasion. In conclusion, FGF13 regulated glioma cell invasion and bevacizumab-induced glioma invasion, and could be a novel target for glioma treatment.

Port-site transversus abdominis fascia closure reduced the incidence of incisional hernia following retroperitoneal laparoscopic nephrectomy.

PURPOSE: The incidence of incisional hernia after laparoscopic surgery is reportedly 0-5.2 %; there are only a few reports of that following retroperitoneal laparoscopic nephrectomy. We evaluated the incidence of and risk factors for incisional hernia after retroperitoneal laparoscopic nephrectomy, and the efficacy of our novel prophylaxis technique. METHODS: A total of 207 renal cell carcinoma patients who underwent laparoscopic nephrectomy at Chiba University Hospital were retrospectively enrolled in this study. We compared the incidences of incisional hernia following the transperitoneal vs. retroperitoneal approaches, and, among the latter group, the incidences with vs. without use of our prophylaxis method. Also among the retroperitoneal-approach group, we evaluated selected patient characteristics as potential hernia risk factors. RESULTS: The rate of incisional hernias was 14 (8.7 %) after 161 retroperitoneal laparoscopic nephrectomies and one (2.2 %) after 46 transperitoneal laparoscopic nephrectomies (P = 0.132). For those undergoing the retroperitoneal approach, 14 (11.3 %) hernias were identified in 124 non-prophylaxed patients and none in 37 prophylaxed patients. Transversus abdominis fascia closure was a statistically significant factor for reducing the incidence of incisional hernia after retroperitoneal laparoscopic nephrectomy (P = 0.0324): rectus abdominis muscle thickness ≤7 mm and perioperative blood loss >100 ml were statistically significant independent risk factors, by multivariate analysis. CONCLUSIONS: To prevent incisional hernia after retroperitoneal laparoscopic nephrectomy in the patients with risk factors, it is useful to close the transversus abdominis fascia at the port sites from inside the surgical cavity, through the open specimen-removal trocar port site, under direct observation.

Integrin antagonist augments the therapeutic effect of adenovirus-mediated REIC/Dkk-3 gene therapy for malignant glioma.

Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) was identified as a gene whose expression is reduced in many human cancers. REIC/Dkk-3 expression is also downregulated in malignant glioma and regulates cell growth through caspase-dependent apoptosis. cRGD (EMD121974), an antagonist of integrins, has demonstrated preclinical efficacy against malignant glioma. In this study, we investigated the antiglioma effect of combination therapy using an adenovirus vector carrying REIC/Dkk-3 (Ad-REIC) and cRGD. Quantitative real-time reverse-transcription PCR revealed the reduction of REIC/Dkk-3 mRNA levels in malignant glioma cell lines. The reduction of REIC/Dkk-3 protein expression in malignant glioma cell lines was also confirmed with western blot analysis. After treatment with Ad-REIC and cRGD, the proliferative rate of malignant glioma cells was significantly reduced in a time-dependent manner. In vivo, there was a statistically significant increase in the survival of mice treated with Ad-REIC and cRGD combination therapy compared with Ad-REIC monotherapy. We identified an apoptotic effect following monotherapy with Ad-REIC. Moreover, cRGD augmented the antiglioma efficacy of Ad-REIC. These results may lead to a promising new approach for the treatment of malignant glioma.

Orbital masses: the usefulness of diffusion-weighted imaging in lesion categorization.

INTRODUCTION: Diffusion-weighted imaging (DWI) produces contrast among different kinds of tissues according to their diffusibility characteristics. The purpose of our study was to evaluate the role of DWI including measurement of apparent diffusion coefficient (ADC) values in recognizing benignancy or malignancy of orbital masses. METHODS: A total of 39 orbital masses were evaluated visually for signal characteristics on DWI and ADC maps. ADC values were calculated for each lesion. Visual signal characteristics were compared using the Fisher exact test. Receiver operating characteristic (ROC) analysis was carried out to determine sensitivity and specificity for distinguishing malignant from benign lesions using ADC values. The Mann-Whitney U test was applied to compare the ADC values between orbital lymphomas and idiopathic orbital inflammatory (IOI) lesions, and between optic nerve sheath meningiomas and gliomas. RESULTS: Visual assessment revealed no significant difference between benign and malignant lesions on DWI (p-value = 0.66). However, visual assessment of ADC maps revealed a statistically significant (p-value ≤ 0.0001) between benign and malignant lesions. ROC analysis showed a sensitivity of 83.33 % and a specificity of 85.71 % when using an optimal cut off ADC value of 0.84 × 10(-3) mm(2)/s for differentiating malignant from benign lesions. Significant differences in mean ADC values were observed between lymphomas and IOI lesions (p-value = 0.05), and between optic nerve sheath meningiomas and gliomas (p-value = 0.03). CONCLUSION: DWI is useful for differentiating malignant and benign orbital tumors if accompanied by visual assessment of ADC maps and ADC value calculations.

The integrin inhibitor cilengitide enhances the anti-glioma efficacy of vasculostatin-expressing oncolytic virus.

Oncolytic viral (OV) therapy has been considered as a promising treatment modality for brain tumors. Vasculostatin, the fragment of brain-specific angiogenesis inhibitor-1, shows anti-angiogenic activity against malignant gliomas. Previously, a vasculostatin-expressing oncolytic herpes simplex virus-1, Rapid Antiangiogenesis Mediated By Oncolytic virus (RAMBO), was reported to have a potent antitumor effect. Here, we investigated the therapeutic efficacy of RAMBO and cilengitide, an integrin inhibitor, combination therapy for malignant glioma. In vitro, tube formation was significantly decreased in RAMBO and cilengitide combination treatment compared with RAMBO or cilengitide monotherapy. Moreover, combination treatment induced a synergistic suppressive effect on endothelial cell migration compared with the control virus. RAMBO, combined with cilengitide, induced synergistic cytotoxicity on glioma cells. In the caspase-8 and -9 assays, the relative absorption of U87ΔEGFR cell clusters treated with cilengitide and with RAMBO was significantly higher than that of those treated with control. In addition, the activity of caspase 3/7 was significantly increased with combination therapy. In vivo, there was a significant increase in the survival of mice treated with combination therapy compared with RAMBO or cilengitide monotherapy. These results indicate that cilengitide enhanced vasculostatin-expressing OV therapy for malignant glioma and provide a rationale for designing future clinical trials combining these two agents.

Absorption, distribution and excretion of radioactivity by male rats after a single intravenous or subcutaneous dose of 14C-azacitidine.

The absorption, distribution and excretion of radioactivity were investigated in male Sprague-Dawley rats after a single intravenous or subcutaneous dose of 14C-azacitidine. After subcutaneous administration, 14C-azacitidine was rapidly absorbed and the radioactivity was distributed to the tissues. The absorption of radioactivity after subcutaneous administration was 76.6% of that observed after intravenous administration. There were no marked differences in the tissue distribution of the radioactivity between administration routes. The concentrations of radioactivity in most tissues, including the spleen and bone marrow, which are sites of action of azacitidine, were higher than those in the plasma. Particularly high concentrations of radioactivity were detected in the spleen, kidney and liver. The accumulation of radioactivity in blood cells increased from 0.5 to 48 h. The binding of azacitidine to serum protein was low at <9%, and the cumulative urinary and fecal excretion of radioactivity for 168 h after intravenous or subcutaneous administration was >95% of the administered dose, indicating that radioactivity did not accumulate in the tissues. The radioactivity was mainly excreted in the urine.

Impact of pre-treatment prostate tissue androgen content on the prediction of castration-resistant prostate cancer development in patients treated with primary androgen deprivation therapy.

Great advances in tissue androgen analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) have made it possible to evaluate the tissue androgen content from a single needle prostate biopsy specimen. In this study, we investigated if pre-treatment androgen content in prostate biopsy specimens could predict their response to primary androgen deprivation therapy (ADT) and future castration-resistant prostate cancer (CRPC). One-hundred and sixty-five prostate cancer patients who received primary ADT were enrolled. They had received multiple core prostate needle biopsy at diagnosis, and an additional one needle biopsy specimen was obtained for tissue androgen determination using LC-MS/MS. The patients' prostate specific antigen (PSA) values were periodically followed during the treatment and patients were determined to have CRPC when their PSA value increased continuously to 25% above the nadir and a 2.0 ng/mL increase. A significant correlation was found between PSA value decline velocity (PSA half-time) after ADT and pre-ADT tissue androgen content. Twenty-three patients were determined to have CRPC. These CRPC patients had a significantly high concentration of tissue T (p < 0.01) and low concentration of tissue 5α-dihydrotestosterone (DHT) (p < 0.01), resulting in a higher tissue T/DHT ratio (p < 0.001). A multivariate Cox proportional hazard model revealed the pre-ADT tissue T/DHT ratio and Gleason score as independent predictors for CRPC development. By using the two statistically significant variables, the relative risk of CRPC development could be calculated. The results of this study suggest that the evaluation of prostate androgen content in a single needle biopsy specimen may be useful to predict future CRPC development after primary ADT. Further studies are required for the clinical application of T/DHT ratio evaluation.

Therapeutic effect of suicide gene-transferred mesenchymal stem cells in a rat model of glioma.

We evaluated a new therapeutic strategy for malignant glioma, which combines intratumoral inoculation of mesenchymal stem cells (MSCs) expressing cytosine deaminase gene with 5-fluorocytosine (5-FC) administration. For in vitro and in vivo experiments, MSCs were transfected with adenovirus carrying either enhanced green fluorescent protein gene (AdexCAEGFP) or cytosine deaminase gene (AdexCACD), to establish MSC-expressing EGFP (MSC-EGFP) or CD (MSC-CD). Co-culture of 9L glioma cells with MSC-CD in a medium containing 5-FC resulted in a remarkable reduction in 9L cell viability. The migratory ability of MSC-EGFP toward 9L cells was demonstrated by double-chamber assay. For the in vivo study, rats harboring 9L brain tumors were inoculated with MSC-EGFP or MSC-CD. Immunohistochemistry of rat brain tumors inoculated with MSC-EGFP showed intratumoral distribution of MSC-EGFP. Survival analysis of rats bearing 9L gliomas treated with intratumoral MSC-CD and intraperitoneal 5-FC resulted in significant prolongation of survival compared with control animals. In conclusion, molecular therapy combining suicide gene therapy and MSCs as a targeting vehicle represents a potential new therapeutic approach for malignant glioma, both with respect to the antitumor potential of this system and its neuroprotective effect on normal brain tissue.

Associated demographics of persistent exhaled nitric oxide elevation in treated asthmatics.

BACKGROUND: The fraction of exhaled nitric oxide (FENO) is reduced by anti-inflammatory treatment in asthma. However, the FENO level is also regulated by individual demographics and there is considerable variation among clinically stable patients. OBJECTIVE: We hypothesized that some demographics may be responsible for persistent FENO elevation despite inhaled corticosteroids (ICS) therapy in asthma. METHODS: This was a prospective observational study. We initially screened 250 stable asthmatics and determined the FENO cut-off point for identifying poorly controlled asthma defined by one of the following criteria: Asthma control test <20, or forced expiratory volume in one-second % of predicted <80%, or peak expiratory flow variability <80% (Study 1). After 12-weeks, 229 patients who maintained high or low FENO were selected and the independent factors which might contribute to a high FENO were examined (Study 2). RESULTS: A FENO level >39.5 p.p.b. yielded 67% sensitivity and 76% specificity for identifying the patients with poorly controlled asthma. The persistent high FENO group (≥ 40 p.p.b.) was more likely to be ex-smokers, to show evidence of atopy (positive specific IgE, higher serum IgE and blood eosinophils), and to have allergic comorbidities. Especially, past smoking history, blood eosinophils, and chronic rhinosinusitis were identified to be independent predictors of high FENO. Neither the dose of ICS nor other medication use showed any difference between the groups. CONCLUSIONS AND CLINICAL RELEVANCE: These results suggested that past smoking history, blood eosinophilia, and chronic rhinosinusitis are involved in the persistent airway inflammation detected by FENO. Although their relative contributions on FENO values should be further quantified, clarification of the features of the subjects with high FENO might provide clues for adjustment of the treatment approach in asthma.

Tumour suppressors miR-1 and miR-133a target the oncogenic function of purine nucleoside phosphorylase (PNP) in prostate cancer.

BACKGROUND: Our recent analyses of miRNA expression signatures showed that miR-1 and miR-133a were significantly reduced in several types of cancer. Interestingly, miR-1 and miR-133a are located on the same chromosomal locus in the human genome. We examined the functional significance of miR-1 and miR-133a in prostate cancer (PCa) cells and identified the novel molecular targets regulated by both miR-1 and miR-133a. METHODS AND RESULTS: The expression levels of miR-1 and miR-133a were significantly downregulated in PCa compared with non-PCa tissues. Restoration of miR-1 or miR-133a in PC3 and DU145 cells revealed significant inhibition of proliferation, migration, and invasion. Molecular target identification by genome-wide gene expression analysis and luciferase reporter assay showed that purine nucleoside phosphorylase (PNP) was directly regulated by both miRNAs. Silencing of the PNP gene inhibited proliferation, migration, and invasion in both PC3 and DU145 cells. Immunohistochemistry detected positive staining of PNP in PCa specimens. CONCLUSIONS: Downregulation of miR-1 and miR-133a was a frequent event in PCa and both function as tumour suppressors. The PNP is a novel target gene of both miRNAs and potentially functions as an oncogene. Therefore, identification of novel molecular networks regulated by miRNAs may provide new insights into the underlying causes of PCa oncogenesis.

Is liver-targeted FOXp3 staining beneficial after living-donor liver transplantation?

As treatments for acute cellular rejection (ACR) and recurrent hepatitis caused by hepatitis C virus (HCV) are dramatically different, making a precise diagnosis is considered to be essential in patients after liver transplantation. Therefore, we investigated whether immunohistochemical detection of FOXp3, a marker for regulatory T cells (CD4+ CD25+), could be used to differentiate between recurrent hepatitis C and ACR. From a group of 103 cases of living-donor liver transplantation (LDLT), 48 samples were taken via liver biopsy from 20 patients with HCV infection. An initial diagnosis was made based on hematoxylin and eosin staining, which was scored with the hepatitis activity index (HAI) grading, whereas ARC was scored with the rejection activity index (RAI). The FOXp3 immunohistochemical staining on serial specimens was retrospectively analyzed, scoring from 0 to III. The time after LDLT was a median of 270 (range: 14-2000) days, whereas the median number of biopsies per patient was 3 (range: 1-8). The HAI was significantly different between 0 vs. I, and II vs. III, in terms of the FOXp3 score. On the other hand, a significant difference in the RAI was only found between 0 vs. I. In conclusion, FOXp3 may represent a surrogate marker for recurrent HCV infection after LDLT.

Magnetic resonance diffusion-weighted imaging in the characterization of pancreatic mucinous cystic lesions.

AIM: The aim of the study was to evaluate the utility of diffusion-weighted imaging (DWI), including apparent diffusion coefficient (ADC) measurement, in order to differentiate mucinous cystic neoplasms (MCNs) from intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. MATERIALS AND METHODS: Fifty cases of IPMN with a total of 62 lesions, and eight cases of MCN, were retrospectively selected for the study. The cases of IPMN were selected using multimodality clinical or histopathological criteria, while all MCN lesions were histopathologically proven. DWI was carried out using b values of 500 and 1000s/mm(2). Visual assessment was performed by two radiologists who used two categories (low-iso or high signal intensity). ADC values of the lesions were also calculated. Fisher's exact test and the Mann-Whitney U test were used for statistical analysis. RESULTS: All IPMN lesions demonstrated low-iso signal intensities compared with the pancreatic parenchyma on DWI. Two of the MCN lesions demonstrated low-iso signal intensities, and six lesions demonstrated high signal intensities. The ADC values for IPMNs (mean 2.9 ± 0.024 × 10(-3)mm(2)/s) were significantly higher than those for MCNs (mean 2.1 ± 0.30 × 10(-3)mm(2)/s). ROC analysis showed an optimal cut-off value of 2.4 × 10(-3)mm(2)/s for differentiating between the two types of lesions, providing a sensitivity of 98% and a specificity of 88%. CONCLUSION: The results of the present study suggest that ADC values in mucinous cystic lesions of the pancreas can be advantageous for their characterization into IPMN and MCN.

B cell-targeted therapy with anti-CD20 monoclonal antibody in a mouse model of Graves' hyperthyroidism.

Graves' disease is a B cell-mediated and T cell-dependent autoimmune disease of the thyroid which is characterized by overproduction of thyroid hormones and thyroid enlargement by agonistic anti-thyrotrophin receptor (TSHR) autoantibody. In addition to antibody secretion, B cells have recently been recognized to function as antigen-presenting/immune-modulatory cells. The present study was designed to evaluate the efficacy of B cell depletion by anti-mouse (m) CD20 monoclonal antibody (mAb) on Graves' hyperthyroidism in a mouse model involving repeated injection of adenovirus expressing TSHR A-subunit (Ad-TSHR289). We observe that a single injection of 250 µg/mouse anti-mCD20 mAb eliminated B cells efficiently from the periphery and spleen and to a lesser extent from the peritoneum for more than 3 weeks. B cell depletion before immunization suppressed an increase in serum immunoglobulin (Ig)G levels, TSHR-specific splenocyte secretion of interferon (IFN)-γ, anti-TSHR antibody production and development of hyperthyroidism. B cell depletion 2 weeks after the first immunization, a time-point at which T cells were primed but antibody production was not observed, was still effective at inhibiting antibody production and disease development without inhibiting splenocyte secretion of IFN-γ. By contrast, B cell depletion in hyperthyroid mice was therapeutically ineffective. Together, these data demonstrate that B cells are critical not only as antibody-producing cells but also as antigen-presenting/immune-modulatory cells in the early phase of the induction of experimental Graves' hyperthyroidism and, although therapeutically less effective, B cell depletion is highly efficient for preventing disease development.

Macrophage-dominant sialadenitis in human T-cell leukemia virus type I-associated myelopathy after living-donor liver transplantation.

A 64-year-old man who suffered from human T-cell leukemia virus type I (HTLV-I)-associated myelopathy (HAM) after living-donor liver transplantation (LDLT) for liver cirrhosis due to hepatitis C virus infection complained of xerostomia. Although exocrine function test results were positive, autoantibodies including anti-SS-A/SS-B antibodies and sialography showed negative findings. Labial salivary gland biopsy revealing infiltration of 60 counts of mononuclear cells (MNCs) in minor salivary glands led to a diagnosis of Sjögren's syndrome-like sialadenitis. Immunohistochemistry demonstrated dominant CD68 staining and major histocompatibility complex class II on the surface of infiltrating MNCs. Herein we have reported a rare condition of macrophage-dominant sialadenitis in a patient with HAM after LDLT.

Effect of anaesthesia maintained with sevoflurane and propofol on surgical site infection after elective open gastrointestinal surgery.

Perioperative increase in oxidative activity in surgical patients reportedly prevents postoperative surgical site infection (SSI). Several clinical studies have shown that oxidative activity under sevoflurane anaesthesia was higher than that under propofol anaesthesia. Therefore, we hypothesised that sevoflurane anaesthesia would discourage SSI compared with propofol anaesthesia. To examine the effect of anaesthesia maintained with sevoflurane and propofol on SSI, a total of 265 consecutive adult patients, with American Society of Anesthesiologists physical status 1-3, who underwent elective open gastrointestinal surgery under general anaesthesia, were surveyed for SSI between January 2007 and December 2008. Sevoflurane or propofol was selected to maintain anaesthesia in 95 and 170 patients, respectively. A propensity score was used for pairwise matching of these patients to avoid selection biases between the two methods of anaesthesia. Propensity matching yielded 84 pairs of patients. We compared standardised infection ratios (SIRs), i.e. the quotient of the number of SSI cases observed and the number of SSI cases expected, calculated using data from the National Nosocomial Infection Surveillance, between sevoflurane and propofol anaesthesia. After propensity matching, SIR after sevoflurane anaesthesia was 1.89 [95% confidence interval (CI): 1.46-2.32], which was significantly lower than after propofol anaesthesia (4.78; 95% CI: 4.30-5.27) (P=0.02). This study suggests that sevoflurane tends to suppress SSI after elective open gastrointestinal surgery compared with propofol.

Plk1 regulates liver tumor cell death by phosphorylation of TAp63.

We previously found that Plk1 inhibited the p53/p73 activity through its direct phosphorylation. In this study, we investigated the functional role of Plk1 in modulating the p53 family member TAp63, resulting in the control of apoptotic cell death in liver tumor cells. Immunoprecipitation and in vitro pull-down assay showed that p63 binds to the kinase domain of Plk1 through its DNA-binding region. in vitro kinase assay indicated that p63 is phosphorylated by Plk1 at Ser-52 of the transactivating (TA) domain. Plk1 decreased the protein stability of TAp63 by its phosphorylation and suppressed TAp63-induced cell death. Furthermore, Plk1 knockdown in p53-mutated liver tumor cells transactivated p53 family downstream effectors, PUMA, p21(Cip1/WAF1) and 14-3-3sigma, and induced apoptotic cell death. Double knockdown of Plk1/p63 attenuated Plk1 knockdown-induced apoptotic cell death and transactivation. Intriguingly, both Plk1 and p63 are highly expressed in the side population (SP) fraction of liver tumor cells compared to non-SP fraction cells, suggesting the significance of Plk1/TAp63 in the control of cell death in tumor-initiating SP fraction cells. Thus, Plk1 controls TAp63 by its phosphorylation and regulates apoptotic cell death in liver tumor cells. Plk1/TAp63 may be a suitable candidate as a molecular target of liver tumor treatments.

3-Nitrotyrosine inhibits fibroblast-mediated collagen gel contraction and chemotaxis.

Reactive nitrogen species induce tissue inflammation and nitrate tyrosine residues of various kinds of proteins. Recent studies have established that the free amino acid form of 3-nitrotyrosine induces cytotoxity and growth inhibition and alters the cellular function in cultured cells. The aim of this study was to evaluate whether 3-nitrotyrosine could affect tissue remodelling in fibroblasts. To accomplish this, human fetal lung fibroblasts (HFL-1) were used to assess the fibroblast-mediated contraction of floating gels and chemotaxis towards fibronectin. In addition, the ability of fibroblasts to release fibronectin, transforming growth factor (TGF)-beta1, fibronectin and vascular endothelial growth factor (VEGF) was assessed. 3-Nitrotyrosine significantly inhibited gel contraction (p<0.01) compared with control and this inhibition was abolished by nitric oxide synthase (NOS) inhibitor. 3-Nitrotyrosine did not affect TGF-beta1 and VEGF but significantly decreased fibronectin release (p<0.01) into the media. 3-Nitrotyrosine significantly inhibited chemotaxis towards fibronectin through suppression of alpha(5)beta(1) integrin expression (p<0.01). NOS inhibitor also reversed 3-nitrotyrosine-inhibited chemotaxis (p<0.01). Finally, 3-nitrotyrosine enhanced the expression of the inducible type of NOS (p<0.01) and nitric oxide release (p<0.01) through nuclear factor-kappaB activation. These results suggest that the free amino acid form of 3-nitrotyrosine can affect the tissue repair process by modulating nitric oxide production.

Rebamipide, a cytoprotective drug, increases gastric mucus secretion in human: evaluations with endoscopic gastrin test.

We have previously developed a rapid, simple endoscopic method for evaluating gastrin-stimulated maximal acid output (the endoscopic gastrin test, EGT). In EGT, gastric fluid newly secreted over 10 min after gastrin stimulation is collected under direct endoscopic visualization. In this study, employing the EGT, we evaluated the effect of rebamipide, a cytoprotective anti-ulcer drug, on gastric mucus secretion. In ten Helicobacter pylori-negative healthy volunteers, gastric juice was collected by EGT prior to and after 4-week administration of rebamipide. The collected gastric juice was subjected to analysis for gastric mucus output. Total gastric mucin output was significantly increased by 53% by rebamipide administration from 3.2 +/- 1.2 mg hexose/10 min to 4.9 +/- 2.2 mg hexose/10 min (P < 0.01). Further analysis by ion-exchange chromatography revealed that rebamipide administration induced a specific increase in acidic mucin rich in sialic acid. Applying EGT, this study demonstrated that rebamipide administration increased gastric mucus secretion in human.

Does presence of prostate cancer affect serum testosterone levels in clinically localized prostate cancer patients?

The relationships between serum level of testosterone (T) and prostate cancer (PCa) are complex. The present study evaluated whether presence of PCa alters serum T levels. Subjects were 125 patients with clinically localized PCa treated using radical prostatectomy (RP), for whom pretreatment T levels were recorded. We investigated clinical and pathological factors such as pretreatment serum T level, age, pretreatment prostate-specific antigen, Gleason score and pathological stage. Serum T and human luteinizing hormone (LH) levels before and after RP were then compared in 118 of the 125 patients. Mean pretreatment T level was significantly higher in patients with organ-confined PCa (pT2; 4.03+/-1.50 ng ml(-1)) than in patients with nonorgan-confined cancer (pT3; 3.42+/-1.06 ng ml(-1); P=0.0438). No association existed between pretreatment serum T level and pathological Gleason score. After RP, serum T level (5.60+/-1.90 ng ml(-1)) was significantly elevated compared to preoperative level (3.89+/-1.43 ng ml(-1); P<0.0001). In parallel, significant increases were seen in postoperative serum LH level (6.86+/-3.64 ng ml(-1)) compared to preoperative level (5.11+/-2.47 ng ml(-1); P=0.0001). In contrast, differences in serum T levels according to pathological stage disappeared postoperatively (P=0.5513). Significant increases in serum T and LH levels were seen after RP, compared to preoperative levels in parallel. This study suggests that serum T levels are altered by the presence of PCa, supporting the possibility that PCa may inhibit serum T levels with negative feedback in the hypothalamic-pituitary axis.

Prevalence of interrelated autoantibodies in thyroid diseases and autoimmune disorders.

OBJECTIVE: We determined the autoantibody profile in autoimmune thyroid diseases (AITD) and examined the distribution of thyroid-related autoantibodies in other autoimmune disorders. METHODS: We tested sera from 234 patients with Graves' disease (GD), 130 with Hashimoto's thyroiditis (HT), 249 with other autoimmune diseases, and 50 healthy controls by enzyme-linked immunosorbent assay or radioimmunoassay. RESULTS: Autoantibodies except TSH receptor antibody (Ab), anti-thyroglobulin (Tg) Ab and anti-thyroid peroxidase (TPO) Ab were not significantly prevalent in patients with AITD despite a significantly high elevation of thyroid-related Ab. Significant prevalence of autoantibodies related to AITD was observed in type 1 diabetes patients. Elevation of anti-Tg Ab was seen in patients with primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH), and anti-TPO Ab was elevated in patients with PBC. Although the prevalence of anti-acetylcholine receptor Ab and systemic lupus erythematosus (SLE)- related Ab was significant in AIH, primary Sjögren's syndrome (pSS)-related Ab were also found in both liver diseases. In myasthenia gravis (MG) patients, thyroid-related Ab and pSS-related Ab were detected in both MG groups, although SLE-related Ab were limited to the anti-muscle specific kinase Ab-positive MG patients. In patients with connective tissue diseases, anti- Tg Ab and anti-TPO Ab were significantly prevalent. CONCLUSION: Thyroid-related Ab were significantly elevated in all autoimmune diseases. Conversely, the elevations of Ab were not significant in the patients with AITD, suggesting a close relationship between AITD and other immune-mediated diseases.