Involvement of central metastin in the regulation of preovulatory luteinizing hormone surge and estrous cyclicity in female rats

Ovulation is caused by a sequence of neuroendocrine events: GnRH and LH surges that are induced by positive feedback action of estrogen secreted by the mature ovarian follicles. The central mechanism of positive feedback action of estrogen on GnRH/LH secretion, however, is not fully understood yet. The present study examined whether metastin, the product of metastasis suppressor gene KiSS-1, is a central neuropeptide regulating GnRH/LH surge and then estrous cyclicity in the female rat. Metastin had a profound stimulation on LH secretion by acting on the preoptic area (POA), where most GnRH neurons projecting to the median eminence are located, because injection of metastin into the third ventricle or POA increased plasma LH concentrations in estrogen-primed ovariectomized rats. Metastin neurons were immunohistochemically found in the arcuate nucleus (ARC) to be colocalized with estrogen receptors with some fibers in the preoptic area (POA) in close apposition with GnRH neuronal cell bodies or fibers. Quantitative RT-PCR has revealed that KiSS-1 and GPR54 mRNAs were expressed in the ARC and POA, respectively. The blockade of local metastin action in the POA with a specific monoclonal antibody to rat metastin completely abolished proestrous LH surge and inhibited estrous cyclicity. Metastin-immunoreactive cell bodies in the ARC showed a marked increase and c-Fos expression in the early proestrus afternoon compared with the day of diestrus. Thus, metastin released in the POA is involved in inducing the preovulatory LH surge and regulating estrous cyclicity.     

Steroid pulse therapy in patients with encephalopathy associated with severe fever with thrombocytopenia syndrome

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne infectious disease caused by the SFTS virus (SFTSV). Clinical symptoms of SFTS often involve encephalopathy and other central neurological symptoms, particularly in seriously ill patients; however, pathogenesis of encephalopathy by SFTSV is largely unknown. Herein, we present case reports of three patients with SFTS, complicated by encephalopathy, admitted to Tokushima University hospital: one patient was a 63-year-old man, while the other two were 83- and 86-year-old women. All of them developed disturbance of consciousness around the 7th day post onset of fever. After methylprednisolone pulse therapy of 500 mg/day, all of them recovered without any neurological sequelae. SFTSV genome was not detected in the cerebrospinal fluid of 2 out of the 3 patients that were available for examination. In these patients, disturbance of consciousness seemed to be an indirect effect of the cytokine storm triggered by SFTSV infection. We propose that short-term glucocorticoid therapy might be beneficial in the treatment of encephalopathy during early phase of SFTSV infection.     

Therapeutic action of 5-HT3 receptor antagonists targeting peritoneal macrophages in post-operative ileus

Background and Purpose

Post-operative ileus (POI) is induced by intestinal inflammation. Here, we aimed to clarify the effects of 5-HT₃ receptor antagonists against POI.

Experimental Approach

We administered three 5-HT₃ receptor antagonists, ondansetron, tropisetron and palonosetron, to a mouse model of POI induced by surgical intestinal manipulation (IM). Immunohistochemistry, intestinal transit, inflammatory mediator mRNA expression and 5-HT content were measured. In some experiments, 5-HT₃A receptor null mice were used.

Key Results

Three 5-HT₃ receptor antagonists reduced IM-induced infiltration of inflammatory CD68-positive macrophages and myeloperoxidase-stained neutrophils. Ondansetron exhibited no anti-inflammatory actions in 5-HT₃A receptor null mice. Ondansetron inhibited expression of the chemokine CCL2, IL-1β, IL-6, TNF-α and iNOS mRNAs up-regulated by IM, and also ameliorated the delayed gastrointestinal transit. Peritoneal macrophages, but not most infiltrating monocyte-derived macrophages, expressed 5-HT₃ receptors. IM stimulation increased the 5-HT content of peritoneal lavage fluid, which up-regulated mRNA expression of proinflammatory cytokines in peritoneal macrophages. Immunohistochemical localization of 5-HT₃ receptors suggests that ondansetron suppressed expression of these mRNAs in activated peritoneal macrophages, adhering to the serosal region of the inflamed intestinal wall.

Conclusion and Implications

5-HT₃ receptor antagonists were anti-inflammatory, mainly targeting peritoneal macrophages expressing these receptors. They also restored the delayed gastrointestinal transit by IM. 5-HT₃ receptor antagonists should be therapeutically useful agents against POI.     

Quantitative evaluation of the pulmonary microdistribution of TiO2 nanoparticles using X‐ray fluorescence microscopy after intratracheal administration with a microsprayer in rats

The unevenness of pulmonary nanoparticle (NP) distribution, which hinders the establishment of an absolute dose–response relationship, has been described as one of the limitations of intratracheal administration techniques for toxicological assessment of inhaled NPs. Quantification of the NP microdistribution would facilitate the establishment of a concentration–response relationship in localized regions of the lung; however, such quantitative methods have not been reported. Here, we established a quantitative method for evaluating pulmonary TiO₂ NP microdistribution in rats using X‐ray fluorescence microscopy. Ti intensity in lung sections from rats intratracheally administered 10 mg kg^–1 TiO₂ NPs with a microsprayer was measured using X‐ray fluorescence with a 100 µm beam size. Ti reference samples were prepared by dropping different concentrations of Ti solutions on glass slide or lung sections of untreated rat. Ti intensity increased linearly with Ti content in the reference samples on both substrates. The detection limit of TiO₂ was estimated to be 6.3 ng mm^–2. The reproducibility was confirmed for measurements done in the short‐ (2 weeks) and long‐term (6 months). The quantitative results of TiO₂ NP microdistribution suggested that more TiO₂ NPs were distributed in the right caudal and accessory lobes, which are located downstream of the administration direction of the NP suspension, and the lower portion of each lobe. The detection rates of TiO₂ NPs were 16.6–25.0%, 5.19–15.6%, 28.6–39.2%, 21.4–38.7% and 10.6–23.2% for lung sections from the right cranial, middle, caudal, accessory and left lobes, respectively. Copyright © 2015 John Wiley & Sons, Ltd.     

Predictive factors for subsequent intrahepatic cholangiocarcinoma associated with hepatolithiasis: Japanese National Cohort Study for 18 years

Journal of Gastroenterology - Predictive factors for intrahepatic cholangiocarcinoma in long-term follow-up of hepatolithiasis are unknown. We thus conducted a cohort study to investigate the...     

Acute Myeloid Leukemia Developing with Acute Pancreatitis Mimicking Autoimmune Pancreatitis

A 33-year-old man was admitted to our hospital for fever and abdominal pain. A blood analysis revealed pancytopenia and increased serum pancreatic enzymes with disseminated intravascular coagulation. A detailed examination revealed acute pancreatitis, with diffuse swelling of the pancreas and diffuse beaded dilatation of the main pancreatic duct, which mimicked autoimmune pancreatitis complicated by acute myeloid leukemia. Systemic cytotoxic chemotherapy led to the remission of leukemia and pancreatitis. We hypothesized that the etiology of acute pancreatitis was invasion of leukemia cells. Acute pancreatitis is rare as a symptom of leukemia; however, we should consider the possibility of leukemia during the differential diagnosis of acute pancreatitis.     

Efficacy and safety of endoscopic submucosal dissection for gastric tube cancer: A multicenter retrospective study

BACKGROUNDRecent improvements in the prognosis of patients with esophageal cancer have led to the increased occurrence of gastric tube cancer (GTC) in the reconstructed gastric tube. However, there are few reports on the treatment results of endoscopic submucosal dissection (ESD) for GTC.AIMTo evaluate the efficacy and safety of ESD for GTC after esophagectomy in a multicenter trial.METHODSWe retrospectively investigated 48 GTC lesions in 38 consecutive patients with GTC in the reconstructed gastric tube after esophagectomy who had undergone ESD between January 2005 and December 2019 at 8 institutions participating in the Okayama Gut Study group. The clinical indications of ESD for early gastric cancer were similarly applied for GTC after esophagectomy. ESD specimens were evaluated in 2-mm slices according to the Japanese Classification of Gastric Carcinoma with curability assessments divided into curative and non-curative resection based on the Gastric Cancer Treatment Guidelines. Patient characteristics, treatment results, clinical course, and treatment outcomes were analyzed.RESULTSThe median age of patients was 71.5 years (range, 57-84years), and there were 34 men and 4 women. The median observation period after ESD was 884 d (range, 8-4040 d). The median procedure time was 81 min (range, 29-334 min), the en bloc resection rate was 91.7% (44/48), and the curative resection rate was 79% (38/48). Complications during ESD were seen in 4% (2/48) of case, and those after ESD were seen in 10% (5/48) of case. The survival rate at 5 years was 59.5%. During the observation period after ESD, 10 patients died of other diseases. Although there were differences in the procedure time between institutions, a multivariate analysis showed that tumor size was the only factor associated with prolonged procedure time.CONCLUSIONESD for GTC after esophagectomy was shown to be safe and effective.