Chronic salt loading upregulates expression of adrenomedullin and its receptors in adrenal glands and kidneys of the rat

The vasodilator peptide adrenomedullin (AM) elicits diuresis and natriuresis and inhibits aldosterone secretion. The aim of this study was to better understand the role of AM in maintaining water and electrolyte balance during chronic salt loading. Male Wistar rats were divided into a high salt (HS) group that received a diet containing 8% sodium chloride (NaCl) and a normal salt group that received a diet containing 0.4% NaCl. Plasma AM concentrations as well as expression of AM mRNA in the adrenal gland and kidney were then measured after 3, 7, 14, and 28 days. After 28 days, sodium and water excretion were significantly higher in HS rats than in control, although blood pressure and fluid volume were not significantly affected. Moreover, although plasma AM remained unchanged for up to 14 days, it was increased 2.5-fold in HS rats after 28 days on a high salt diet, and there were corresponding 3-fold and 1.5-fold increases in the levels of AM mRNA in the adrenal gland and kidney, respectively. At the same time, expression of calcitonin receptor-like receptor mRNA was significantly upregulated in both kidney and adrenal gland, as was expression of receptor activity-modify protein 1 (RAMP1) and RAMP2 mRNA in the adrenals and expression of RAMP3 in kidneys. Taken together, these results suggest that AM plays a role in the regulation of water and electrolyte balance in animals chronically ingesting high levels of salt.     

Human pancreatic growth hormone-releasing factor stimulates release of growth hormone in conscious unrestrained male rabbits

The effect on GH secretion of GH-releasing factor (GRF), a 44-amino acid peptide recently isolated from a human pancreatic tumor (hpGRF), was examined in conscious male rabbits. During a 6-h period (1030-1630 h) of the control study individual rabbits exhibited pulsatile GH release with a surge at 1030-1200 h, a trough at 1200-1400 h, and a second peak at 1400-1630 h. Intravenous bolus injections of 1 and 10 micrograms hpGRF caused significant and dose-related increases in plasma GH during both the period of the trough (1300 h) and the surge (1530 h), although the GH responses were obviously higher during the latter than the former period. Passive immunization with anti-somatostatin (SRIF) sheep serum resulted in a prompt increase in plasma GH immediately after an injection of the antiserum. When 0.1, 1, and 10 micrograms hpGRF were successively injected iv at 1215, 1345, and 1515 h, respectively, maximum levels of plasma GH after hpGRF in anti-SRIF sheep serum-treated rabbits were significantly higher than in animals given normal sheep serum. The plasma GH responses to 10 micrograms hpGRF, given iv only once at 1515 h in normal sheep serum-treated animals, were not different from those to 10 micrograms hpGRF injected at 1515 h after the prior administration either of the smaller hpGRF dose (0.1 micrograms, 1215 h; 1 microgram, 1345 h), nor of the large dose (10 micrograms, 1100 h). These findings suggest the following: 1) that the secretion of GH is pulsatile in conscious, unrestrained male rabbits; 2) that hpGRF is a potent secretagogue for GH release in rabbits as well as other species; 3) that the magnitude of plasma GH response to hpGRF is different according to timing of the injection during the course of pulsatile GH secretion but is not influenced by the prior administration of hpGRF (no priming effect); and 4) that the responsiveness of plasma GH to hpGRF is affected by circulating endogenous SRIF.     

A case of hypersensitivity pneumonitis caused by Humicola fuscoatra

A 51-year-old housewife with hypersensitivity pneumonitis caused by Humicola fuscoatra is reported. The diagnosis was made by an inhalation challenge with H. fuscoatra antigen. She was admitted for diagnosis and treatment of a fever and productive cough. Auscultation of her lungs revealed inspiratory fine crackles. Her chest CT showed diffuse miliary nodules in a centri-lobular distribution with patchy ground glass opacities. Findings of transbronchial lung biopsy and BAL fluid were compatible with a hypersensitivity pneumonitis. Her symptoms worsened on returning home, which suggested the existence of some aetiological agent in the subject's house. H. fuscoatra, Penicillium decumbens and Aspergillus versicolor were isolated from a number of rooms. High titres of serum anti H. fuscoatra, P. decumbens and A. versicolor were detected. Inhalation challenge tests with both P. decumbens and A. versicolor antigen were negative, in contrast to that with H. fuscoatra which was positive. Based on these results, we advised the patient to cleanse her entire house. Since cleaning, her symptoms have not worsened upon returning home. This is the first report of hypersensitivity pneumonitis caused by H. fuscoatra antigen.     

L-dopa stimulates release of hypothalamic growth hormone-releasing hormone in humans

A sensitive RIA for human GH-releasing hormone-(1-44)-NH2 [hGHRH-(1-44)-NH2] was developed which allows its measurement in human plasma extracts. The assay did not detect hGHRH-(1-37)-OH or hGHRH-(1-40)-OH. A method to extract hGHRH from plasma was developed using silicic acid and acid-acetone, by which recovery of synthetic hGHRH-(1-44)-NH2 from plasma averaged 74.3%. Serial dilutions of plasma extracts gave an inhibition curve parallel with that of synthetic hGHRH-(1-44)-NH2 in the RIA system. On Sephadex G-50 columns, hGHRH-like immunoreactivity (hGHRH-LI) in plasma extracts eluted as a single peak corresponding to hGHRH-(1-44)-NH2. This hGHRH-LI peak, when subjected to reverse phase HPLC, emerged at the position where hGHRH-(1-44)-NH2 was eluted. hGHRH-LI was detectable in the peripherally circulating plasma of all subjects tested. The mean basal level of plasma hGHRH-LI in normal subjects was 9.4 +/- 0.7 (+/- SE) pg/ml (n = 22; range, 2.8-18.1 pg/ml), comparable to the basal plasma hGHRH-LI concentration in patients with hypothalamic lesions (11.3 +/- 1.1 pg/ml; n = 7). Oral administration of L-dopa (0.5 g) caused a significant increase in both plasma hGHRH-LI and GH levels in normal subjects, and the plasma hGHRH-LI peak slightly preceded or coincided with that of plasma GH in individual subjects. There was also a significant correlation between plasma hGHRH-LI and the GH rises after L-dopa administration when their net increments were compared. All of the patients with hypothalamic lesions had significant increases in plasma GH after hGHRH-(1-44)-NH2 injection (1 microgram/kg BW, iv), indicating the presence of functioning somatotrophs in their pituitaries. When L-dopa was orally administered to these patients, neither plasma hGHRH-LI nor GH concentration changed throughout a 120-min observation period. These findings suggest that 1) hGHRH, immunologically and chromatographically indistinguishable from synthetic hGHRH-(1-44)-NH2, is detectable in peripheral plasma in humans; 2) L-dopa stimulates the release of hypothalamic hGHRH, alterations of which are reflected in changes in peripheral levels; and 3) the source of circulating hGHRH is not restricted to the hypothalamus, since hGHRH-LI is present in the peripheral plasma of patients with hypothalamic lesions in amounts similar to those found in normal subjects.     

Metachronous solitary mediastinal lymph node metastases of hepatocellular carcinoma treated by video‐assisted thoracic surgery twice: Report of a case

Solitary mediastinal lymph node metastasis of hepatocellular carcinoma (HCC) is rare. We report a case of metachronically solitary mediastinal metastases of HCC treated by video‐assisted thoracic surgery (VATS) twice. A 66‐year‐old man underwent repeated laparoscopic radiofrequency ablation or trans‐arterial catheter chemo‐embolization against HCC for more than 10 years. The level of alpha fetoprotein protein was elevated, and radiological modalities including FDG‐PET revealed solitary mediastinal tumor metachronically. VATS was performed bilaterally twice. The postoperative course was uneventful and there had no recurrence of extra‐hepatic metastases and tumor markers are within normal limits at 18 months after second VATS. VATS is a minimally invasive and useful procedure for solitary mediastinal lymph node metastasis of HCC. If primary HCC was controlled and lymph node metastasis was solitary, mediastinum lymphadenectomy using VATS might give good short and long term results.     

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.     

Comprehensive genetic characterization of rectal cancer in a large cohort of Japanese patients: differences according to tumor location

Journal of Gastroenterology - In clinical practice, rectal cancer (RC) is classified according to tumor location. However, RC’s genetic characteristics according to tumor location remain...     

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.