Predominance of T-bet-positive Th1 cells in infiltrating T-lymphocytes in most of active arteritis lesions of giant cell arteritis.

Immunological mechanisms through the activation of CD4-positive T-cells have been assumed to be involved in the pathogenesis of giant cell arteritis (GCA). Many studies employing frozen tissues of temporal artery biopsy, peripheral blood lymphocytes, and plasma of GCA patients have revealed the contribution of interferon-γ and interleukin-17 in both protein and mRNA levels. However, the analyses using formalin-fixed and paraffin-embedded (FFPE) tissue specimens, in which the correlation between histopathologic pictures and immunological circumstances would be elucidated, have been limited. Here, we performed the immunohistochemical analyses of infiltrating small lymphocytes in GCA lesions using FFPE specimens, especially of the subsets of CD4-positive T-cells by immunohistochemistry with antibodies against T-bet, GATA-3, RORγT, and Foxp3, which is the differentiation-specific transcription factor for Th1, Th2, Th17, and Treg cells, respectively. In these slides, the nuclear-positive staining is much more clearly and easily identifiable than the cytoplasmic staining for cytokines. The results indicate the predominance of T-bet-positive Th1 cells in infiltrating T-cells in most of active arteritis lesions of GCA. Furthermore, our data suggest the possible immunosuppressive microenvironment induced by T-reg cells and M2-type macrophages in the arteritis lesions throughout the course of GCA inflammation.

A case of urinary bladder metastasis of hepatocellular carcinoma following use of immunotherapy/tyrosine kinase inhibitor.

Introduction: Here we present a rare case of hepatocellular carcinoma metastasis to the urinary bladder in a patient with metastatic HCC. Case presentation: An 83-year-old man developed gross hematuria during combined treatment with an anti-programmed death-ligand 1 inhibitor and an anti-vascular endothelial growth factor for metastatic HCC. A contrast-enhanced CT revealed a 15 × 15 mm soft tissue mass protruding from the posterior bladder wall. Cystoscopy further revealed a solitary submucosal mass located on the posterior wall. The patient underwent transurethral resection of bladder tumor. The pathological findings were consistent with a diagnosis of bladder metastasis from HCC. Following a 3-week interval after the surgical intervention, salvage therapy was resumed. Conclusion: During follow-up after TUR-BT in HCC patients who present with a bladder tumor, the possibility of HCC metastases to the urinary bladder should be excluded.

Flumioxazin, a PPO inhibitor: A weight-of-evidence consideration of its mode of action as a developmental toxicant in the rat and its relevance to humans.

Flumioxazin, is a herbicide that has inhibitory activity on protoporphyrinogen oxidase (PPO), a key enzyme in the biosynthetic pathway for heme. Flumioxazin induces anemia and developmental toxicity in rats, including ventricular septal defect and embryofetal death. Studies to elucidate the mode of action (MOA) of flumioxazin as a developmental toxicant and to evaluate its relevance to humans have been undertaken. The MOA in the rat has now been elucidated. The first key event is PPO inhibition, which results in reduced heme synthesis in embryonic erythroblasts. The critical window for this effect is gestational day 12 when almost all erythroblasts are at the polychromatophilic stage, synthesizing heme very actively. Embryonic anemia/hypoxemia is induced and the heart pumps more strongly as a compensatory action during organogenesis, leading to thinning of the ventricular walls and failure of the interventricular septum to build completely and close. Investigations showed that this MOA is specific to rats and has no relevancy to humans. Flumioxazin inhibited PPO in rat hepatocyte mitochondria more strongly than in human. A 3-dimensional molecular simulation revealed that species differences in binding affinity of flumioxazin to PPO, observed previously in vitro, were due to differences in binding free energy. In vitro studies using several types of rat and human cells (erythroblasts derived from erythroleukemia cell lines, cord blood, or pluripotent stem cells), showed that flumioxazin decreased heme synthesis in rat cells but not in human cells, demonstrating a clear, qualitative species difference. Considering all available information, including data from PBPK modelling in rat and human, as well as the fact that anemia is not a symptom in patients with variegate porphyria, a congenital hereditary PPO defect, shows that the sequence of events leading to adverse effects in the rat embryo and fetus are very unlikely to occur in humans.

Lack of human relevance for rat developmental toxicity of flumioxazin is revealed by comparative heme synthesis assay using embryonic erythroid cells derived from human and rat pluripotent stem cells.

Fetal rat anemia from flumioxazin, an N-phenylimide herbicide, is caused by suppression of heme synthesis resulting from inhibition of protoporphyrinogen oxidase (PPO). A series of studies to investigate the effects of flumioxazin have revealed that developmental toxicity is caused in rats but not in rabbits, and the adverse effects are not likely to occur in humans. In this study, as a final weight-of-evidence approach for assessing the human safety of flumioxazin, we compared the toxic potential of inhibition of heme synthesis leading to anemia between human and rat embryonic erythroid cells, which were degenerated as the target of flumioxazin in the rat developmental toxicity. To obtain embryonic erythroid cells, we established respective differentiation methods for embryonic erythroid cells from both human and rat pluripotent stem cells. Derived human and rat embryonic erythroid cells were treated with flumioxazin or dihydroartemisinin (DHA), an anti-malarial drug that causes reduction of embryonic erythroid cells and leads to anemia without species differences. In the human embryonic erythroid cells, DHA inhibited cell proliferation and heme synthesis, whereas there were no effects on heme content or cell proliferation with flumioxazin. In the rat embryonic erythroid cells, however, a dose-related reduction in heme synthesis occurred with treatment of flumioxazin and of DHA. These results confirmed that flumioxazin has no effect on heme synthesis in human embryonic erythroid cells. The present data were in accordance with the results of previous studies and demonstrated that there are no concerns in humans regarding the developmental toxicity of flumioxazin observed in rats.

Alpha-Fetoprotein-Producing Early Gastric Cancer with Intramucosal Hepatoid and Fetal Enteric Differentiation.

Alpha-fetoprotein (AFP)-producing gastric carcinomas (AFPGCs) are relatively rare tumors known to have a poor prognosis and commonly found as advanced lesions. Histologically, AFPGCs have been described as having hepatoid and fetal enteric (enteroblastic) morphology and are associated with conventional adenocarcinomas. Prior studies reported a hepatoid component present only in invasive areas and hypothesized that AFPGCs may develop hepatoid features during the process of tumor invasion. We report three cases of AFP-producing early gastric cancer which had an intramucosal hepatoid component. Immunohistochemistry showed that the hepatoid component was diffusely immunoreactive for SALL4, AFP, arginase-1, and HepPar1, and focally for CDX2 and PDX1. An intramucosal transition between the hepatoid component and conventional intramucosal adenocarcinoma was identified. Two patients also had a coexistent fetal enteric component, which was admixed with a hepatoid component. Although at an early stage one patient subsequently developed liver metastasis and a second patient was suspected of having liver metastasis, these were not biopsy-proven. The latter patient had a previous history of hepatocellular carcinoma (HCC) and SALL4 was used on the HCC to distinguish metastatic/further HCC from a gastric metastatic primary with hepatoid differentiation.

[Identification of the Risk Factors for Cabazitaxel-Induced Neutropenia with Preventive Administration of Pegfilgrastim].

Prophylaxis using pegfilgrastim is recommended to prevent cabazitaxel-induced neutropenia. We observed GradeB3 neutropenia in a patient after administration of cabazitaxel, despite prophylaxis using pegfilgrastim. To identify the risk factors associated with GradeB3 neutropenia, we retrospectively investigated the records of 10 patients who received prophylaxis with pegfilgrastim after administration of cabazitaxel. They were divided into GradeB3 neutropenia and non-GradeB3 neutropenia groups, and we compared the background data and laboratory values between the 2 groups. A univariate analysis revealed that hypoalbuminemia was significantly observed in patients with cabazitaxel-induced GradeB3 neutropenia. The incidence of GradeB3 neutropenia was significantly high in patients with serum albumin levels<3.6 g/dL. Cabazitaxel has a high rate of protein binding; moreover, serum albumin levels<3.6 g/dL might be associated with high concentrations of unbound cabazitaxel, and thus an increase in the incidence of GradeB3 neutropenia. Therefore, hypoalbuminemia at the time of administration of cabazitaxel may be a risk factor related to the development of GradeB3 neutropenia.

Total dosage of gardenia fruit used by patients with mesenteric phlebosclerosis.

BACKGROUND: Mesenteric phlebosclerosis (MP) is a disease characterized by fibrotic change or calcification of the mesenteric vein. Recently, there has been an increase in case reports of MP related to herbal medicine usage. Long-term intake of gardenia fruit (GF) is suspected as a possible cause. However, many GF users do not develop this disease and the association between GF and MP remains unclear. In this study, we investigated for the first time the dosage of GF used by patients with and without MP. METHODS: We used a medical chart review study design to assess the association between GF and MP. We reviewed patients with a history of intake of herbal medicines containing GF. Among these patients, we selected patients who were examined by colonoscopy and abdominal plain computed tomography (CT). We investigated the findings of colonoscopy, CT scan and histological examination. We assessed the total dosages of GF alongside the duration of ambulatory visit, the administration period of herbal medicine containing GF and pre-existing disease in order to compare MP cases and non-MP patients. RESULTS: Ten MP cases and 42 non-MP patients were analyzed. We summarized clinical findings of MP cases. All MP cases used more GF than non-MP patients and were administered more than approximately 5,000 grams of GF in cumulative dosage. CONCLUSIONS: This study indicated that excessive intake of GF contributes to and/or accelerates the development of MP suggesting that long-term usage of GF in excessive amounts increases the risk of MP.

Clinical Search for Undiagnosed Mesenteric Phlebosclerosis at Outpatient Departments Specializing in Herbal (Kampo) Medicine.

OBJECTIVE: Mesenteric phlebosclerosis (MP) is a disease characterized by calcification of the mesenteric vein, which causes chronic mesenteric ischemia. Recently, the long-term intake of gardenia fruit ('Sanshishi' in Japanese) has been attracting attention as a possible cause. Usually, only advanced, severe MP cases get reported. However, we suspected that some latent cases of this disease may exist. We performed this study in order to determine the prediagnostic cases at our outpatient departments of herbal (Kampo) medicine, with particular attention paid to the initial changes, such as any slight color change of the colon, as shown in colonoscopy. METHODS: We recommend colonoscopy and computed tomography (CT) scans for patients with a long-term history of taking herbal medicines containing gardenia fruit. Clinical examinations were performed upon receiving patients' consent from December 2013 to November 2014. RESULTS: Of the 103 patients who took gardenia fruit long-term, 29 agreed to be checked for MP. 14 patients underwent colonoscopy. Four patients were confirmed to have MP due to the presence of fibrotic deposition of the colonic membrane on histological inspection. Twenty-one patients underwent abdominal CT screening. Characteristic calcification of the mesenteric vein was observed on CT scans in 2 patients. All 4 MP patients took Kampo formulas containing gardenia fruit for more than 6.8 years. The other patients did not develop MP, despite long-term gardenia fruit intake. CONCLUSION: We detected the latent and undiagnosed MP cases. All diagnoses were made while paying careful attention to any slight changes in colonoscopy and CT scans.

Optical parametric gain and bandwidth in highly nonlinear tellurite hybrid microstructured optical fiber with four zero-dispersion wavelengths.

The parametric amplification gain and bandwidth in highly nonlinear tellurite hybrid microstructured optical fiber (HMOF) are simulated based on four wave mixing process. The fiber core and cladding materials are made of TeO(2)­Li(2)O­WO(3)­MoO(3)­Nb(2)O(5) and TeO(2)­ZnO­Na(2)O­P(2)O(5) glass, respectively. The fiber has four zero-dispersion wavelengths and the chromatic dispersion is flattened near the zerodispersion wavelengths. A broad gain bandwidth as wide as 1200 nm from 1290 to 2490 nm can be realized in the near infrared window by using a tellurite HMOF as short as 25 cm.

[The prevalence of hypertension after adrenalectomy in patients with primary aldosteronism].

The cure rate of hypertension after surgery for primary aldosteronism (PA) was assessed in a single institution. In the present study, we studied the risk factors on the cure rate of hypertension after surgery in patients with PA. Thirty-five patients who underwent surgery for PA between January 2004 and December 2009, with a follow-up time of 1 year or longer were studied. The mean age at surgery was 50.7 years old. The male to female ratio was 24 : 11. Factors confounding the cure rate of hypertension after surgery were analyzed using the univariate and the multivariate analysis. Nineteen (54%) of the 35 patients were completely cured after surgery. In most cases, a complete cure was seen within 1 month after surgery. At 1 year after surgery, the dose of medication for hypertension could be decreased in 11 (13%) of the 16 non cured patients. Although hypertension in patients with PA may be curable by surgery, the cure rate of hypertension after surgery has been reported to be from 16 to 67%. In the present study, age, gender, preoperative serum creatinine, the period of hypertension, the number of medications for hypertension, and family history for hypertension were significant in the univariate analysis for the cure rate of hypertension (persistent hypertension) after surgery. Multivariate analysis showed that the age of 55 years old or older was a significant predictor for non-curable hypertension after surgery. Our result suggests that earlier surgery may contribute to a better outcome on the cure rate of postoperative hypertension in patients with PA.

Pathophysiology of urinary incontinence in murine models.

Urethral closure mechanisms under stress conditions consist of passive urethral closure involving connective tissues, fascia and/or ligaments in the pelvis and active urethral closure mediated by hypogastric, pelvic and pudendal nerves. Furthermore, we have previously reported that the active urethral closure mechanism might be divided into two categories: (i) the central nervous control passing onto Onuf's nucleus under sneezing or coughing; and (ii) the bladder-to-urethral spinal reflex under Valsalva-like stress conditions, such as laughing, exercise or lifting heavy objects. There are over 200 million people worldwide with urinary incontinence, a condition that is associated with a significant social impact and reduced quality of life. Therefore, basic research for urinary continence mechanisms in response to different stress conditions can play an essential role in developing treatments for stress urinary incontinence. It has been clinically shown that the etiology of stress urinary incontinence is divided into urethral hypermobility and intrinsic sphincter deficiency, which could respectively correspond to passive and active urethral closure dysfunction. In this review, we summarize the representative stress urinary incontinence animal models and the methods to measure leak point pressures under stress conditions, and then highlight stress-induced urinary continence mechanisms mediated by active urethral closure mechanisms, as well as future pharmacological treatments of stress urinary incontinence. In addition, we introduce our previous reports including sex differences in urethral closure mechanisms under stress conditions and urethral compensatory mechanisms to maintain urinary continence after pudendal nerve injury in female rats.

Hematogenous extraneural metastasis of the germinomatous component of a pineal mixed germ cell tumor.

A 23-year-old man presented with a mass in the pineal region and obstructive hydrocephalus. A neuroendoscopicbiopsy for the lesion, ventriculoperitoneal (VP)shunting, and focal irradiation were conducted as initial treatment. Histological diagnosis of the biopsy specimen was germinoma. He underwent further irradiation and two tumor resections. Histological diagnosis was mature teratoma without a germinomatous component. After serial treatments, the intracranial lesion was controlled. However,14 months after presentation, extraneural lesions were confirmed in the posterior mediastinum and retroperitoneal space. The biopsy specimen of the retroperitoneal space lesion was histologically diagnosed as germinoma. Although chemotherapy with cisplatin and etoposide was undertaken,extraneural lesions ware uncontrollable and he died. At autopsy, extraneural lesions were confirmed in the posterior mediastinum, retroperitoneal space, and right lung. Histological diagnosis of extraneural lesions was germinoma.This case was considered to be a pineal mixed germ cell tumor mainly consisting of germinoma and mature teratoma,which caused hematogenous metastasis of the germinoma component. Systemic chemotherapy and irradiation for primary lesions as an initial treatment is important to cure the primary lesion and prevent extraneural metastasis.

Time-dependent changes in bladder function and plantar sensitivity in a rat model of fibromyalgia syndrome induced by hydrochloric acid injection into the gluteus.

OBJECTIVE: To examine the correlation between muscular pain and bladder hypersensitivity in order to clarify the pathogenesis of comorbidity of bladder pain syndrome/interstitial cystitis with other chronic pain conditions such as fibromyalgia syndrome (FMS). MATERIALS AND METHODS: Under isoflurane anaesthesia, 0.2 mL of hydrochloric acid (HCl) solution (pH 4.0) was injected into the bilateral gluteus muscles of female Sprague-Dawley rats to produce an FMS model, as the gluteus is one of the specific tender points in patients with FMS. Control rats received saline injection (0.2 mL). The mechanical sensitivity of the plantar was evaluated using the mean number of bilateral hindlimb withdrawals in response to tactile stimulation with a 2.0-g von Frey filament at 1, 2 and 3 weeks after the HCl injection. In a separate rat group, cystometry was performed with the rats awake during saline infusion (0.06 mL/min) into the bladder before and after 1% lidocaine injection (0.2 mL) into the bilateral gluteus 1, 2 and 3 weeks after the HCl injection. RESULTS: The mean number of hindlimb withdrawals was significantly higher in FMS rats than in controls at 1 and 2 weeks. Using cystometry, we found that the intercontraction interval (ICI) and voided volume (VV) were significantly lower in FMS rats than in controls at 1 and 2 weeks. In addition, the voiding threshold pressure, ICI and VV were significantly higher after lidocaine injection in FMS rats, but not in controls, at 1 and 2 weeks. CONCLUSIONS: HCl injection (pH 4.0) into the gluteus can induce plantar hypersensitivity and urinary frequency for up to 2 weeks after the injection, suggesting that somatic (gluteus)-to-visceral (bladder) cross-sensitization might underlie bladder hypersensitivity in patients with FMS. Moreover, intervention at specific tender points outside the bladder could be effective in treating urinary frequency because lidocaine injection into the gluteus normalized bladder function in FMS rats for up to 2 weeks.

Urethral compensatory mechanisms to maintain urinary continence after pudendal nerve injury in female rats.

INTRODUCTION AND HYPOTHESIS: This study was conducted to investigate the urethral compensatory mechanisms to maintain urinary continence after pudendal nerve injury. METHODS: In naive, acute pudendal nerve transection (PNT) and 4 weeks after PNT (PNT-4w) female rats, leak point pressures (LPPs) during bladder compression were measured before and after the application of hexamethonium (C6), propranolol, and N (ω)-nitro-L: -arginine-methyl ester (L: -NAME), or terazosin and atropine. Responses to carbachol and phenylephrine of proximal and middle urethral muscle strips from naive and PNT-4w rats were also examined. RESULTS: LPPs were significantly decreased in PNT rats but not in PNT-4w rats. LPPs in PNT rats were significantly increased by C6 or L-NAME while LPPs in PNT-4w rats were significantly decreased by C6, or terazosin and atropine. Excitatory responses to carbachol and phenylephrine in the proximal urethral muscle were significantly larger in PNT-4w rats. CONCLUSIONS: These results suggest that α(1)-adrenoceptor and muscarinic receptor-mediated contractility is upregulated in the proximal urethra 4 weeks after PNT.

Full-thickness chest-wall resection followed by thorax reconstruction for recurrent malignant phyllodes tumor.

We present a case of a 39-year-old woman with a giant recurrent malignant phyllodes tumor accompanied with bleeding and infection. She underwent full-thickness chest-wall resection. Bony thorax reconstruction and stabilization was accomplished using a Composix mesh™, and soft tissue reconstruction was performed with a musculocutaneous flap of latissimus dorsi muscle. The patient had a good postoperative outcome, and the surgical treatment remarkably improved her quality of life. Because chemotherapy and radiation are not established for treating malignant phyllodes tumors, an aggressive surgical approach should be considered for patients with a locally advanced malignant phyllodes tumor.

Role of alpha2-adrenoceptors and glutamate mechanisms in the external urethral sphincter continence reflex in rats.

PURPOSE: We investigated the role of alpha(2)-adrenoceptors and glutamate mechanisms in the urethral continence reflex in response to abdominal pressure increases. MATERIALS AND METHODS: Under urethane anesthesia external urethral sphincter electromyogram activity was evaluated in spinal cord transected (T8-T9) female rats during lower abdominal wall compression before and after intravenous application of test drugs. The effects of the N-methyl-D-aspartate glutamate receptor antagonist MK-801 (Sigma) or the alpha(2)-adrenoceptor agonist medetomidine (Tocris Cookson, Ellisville, Missouri) (each 0.03, 0.3 and 3 mg/kg intravenously) on external urethral sphincter activity were examined. A 0.3 mg/kg intravenous dose of the alpha(2)-adrenoceptor antagonist idazoxan (Sigma) was then administered before or after the application of 1 mg/kg MK-801 intravenously. In addition, 0.3 mg/kg idazoxan were administered intravenously following the application of 1 mg/kg of the serotonin/norepinephrine reuptake inhibitor duloxetine (Kemprotec, Middlesbrough, United Kingdom) intravenously. RESULTS: MK-801 and medetomidine dose dependently decreased external urethral sphincter activity. Idazoxan significantly increased external urethral sphincter activity by 64% but the increase in activity after idazoxan was abolished by MK-801. On the other hand, idazoxan did not reverse the inhibitory effects of MK-801. In addition, idazoxan significantly potentiated the duloxetine effects on external urethral sphincter activity by 120%. CONCLUSIONS: These results indicate that 1) glutamate is a major excitatory neurotransmitter in the urethral continence reflex response to abdominal pressure increases, 2) alpha(2)-adrenoceptor activation suppresses external urethral sphincter activity, probably via presynaptic inhibition of glutamate release and 3) the effects of serotonin/norepinephrine reuptake inhibitors are enhanced by alpha(2)-adrenoceptor inhibition. Therefore, alpha(2)-adrenoceptor antagonists could be beneficial for treating stress urinary incontinence.

A rare case of a tracheal fibroepithelial polyp treated by an endobronchial resection.

This report describes a very rare case of a tracheal fibroepithelial polyp. A 69-year-old male had been treated in this department because of chronic obstructive pulmonary disease since 2006. In July 2007, chest computed tomography revealed a bronchial tumor located at the distal end of the trachea. A bronchoscopic examination revealed a multilocular polyp. An endobronchial resection was performed to remove the lesion. A tracheobronchial fibroepithelial polyp is very rare. We herein describe and discuss the appropriate therapeutic policy and also review the pertinent literature.

Psychological support for junior high school students: sibling order and sex.

This study is a re-analysis of published data on psychological support for 609 junior high school students (317 boys, 292 girls, mean age = 14.1, SD = 0.8) based on the self-report, Psychological Support Scale, to evaluate sibling order as eldest or youngest and sex. In an earlier study, the questionnaire had been modified to be applicable to junior high school students. The study re-examined the data by extracting samples for categories of eldest and youngest siblings, for re-analysis of self-reported psychological support by sibling order and sex. Eldest children reported receiving more psychological support from both mother and father than youngest. Also, eldest boys received significantly greater psychological support from both the parents than the youngest boys or girls.

[Primary, nonviral, hepatocellular carcinoma in patients with prostate cancer treated by hormone therapy: 2 case reports].

We studied two cases of primary, hepatocellular carcinoma (HCC) that occurred following hormone therapy (estrogen therapy in one case and total androgen blockade therapy in another) for stage D2 prostate cancer. Prostate cancer is considered to be hormone-dependent, and androgens appear to be important hormonal factors. However, hepatocellular carcinoma has been shown to have both estrogen and androgen receptors, suggesting that this may be dependent on estrogen or androgen. Reported here are two unique cases of hepatocellular carcinoma in patients with prostate cancer; the pathogenesis of HCC in these patients was suspected to be related to diethylstilbestrol (DES) therapy and antiandrogen therapy for their prostate cancer.