Historical Study on the Irrigation Reservoirs in Sasayama District

(1)江戸時代において極めて米作率の高かつた篠山藩の灌漑水源は, その7割余が溜池に依存し, その造営は江戸初頭から中期にかけて過半が完成された。斯る短期間に幕藩制のもとで造営が急がれたのは, 庄園制以来隷属下におかれていた耕作農民に独立の機会を与え, 本百姓化して直接的に彼らから領主が生産物地代を確保するに外ならなかつた。そしてその当初の目的は達せられ, 近世村落の成立によつて農業生産上の諸計劃が, その成員の自律性によつて或る程度維持されていた。(2)池の位置は造営の容易性から山腹の谷に多く散在し, 且池元たる山村の耕地に導水の優先権があつたゝめに, 水田の多くを有し水を特に要する盆地内が常に旱損に見舞れ, 江戸時代を通じておくれた技術によつて農業が支えられていた。(3)盆地内は水に窮乏し乍らも, 溜池が農業の発展に果した役割は大であつた。(溜池のない湧水灌漑による地域に比し)そして江戸中期以後藩経済の窮乏に乗じ, 小作料取得の土地所有者の中から藩に代り池を造営する者があらわれ, 或は村方所有の池を集中して, この地方での大地主に成長した

Peripheral glucocorticoid receptor antagonism by relacorilant with modest HPA axis disinhibition

Glucocorticoid stress hormones are produced in response to hypothalamic-pituitary-adrenal (HPA) axis activation. Glucocorticoids are essential for physiology and exert numerous actions via binding to the glucocorticoid receptor (GR). Relacorilant is a highly selective GR antagonist currently undergoing a phase 3 clinical evaluation for the treatment of endogenous Cushing's syndrome. It was found that increases in serum adrenocorticotropic hormone (ACTH) and cortisol concentrations after relacorilant treatment were substantially less than the increases typically observed with mifepristone, but it is unclear what underlies these differences. In this study, we set out to further preclinically characterize relacorilant in comparison to the classical but non-selective GR antagonist mifepristone. In human HEK-293 cells, relacorilant potently antagonized dexamethasone- and cortisol-induced GR signaling, and in human peripheral blood mononuclear cells, relacorilant largely prevented the anti-inflammatory effects of dexamethasone. In mice, relacorilant treatment prevented hyperinsulinemia and immunosuppression caused by increased corticosterone exposure. Relacorilant treatment reduced the expression of classical GR target genes in peripheral tissues but not in the brain. In mice, relacorilant induced a modest disinhibition of the HPA axis as compared to mifepristone. In line with this, in mouse pituitary cells, relacorilant was generally less potent than mifepristone in regulating Pomc mRNA and ACTH release. This contrast between relacorilant and mifepristone is possibly due to the distinct transcriptional coregulator recruitment by the GR. In conclusion, relacorilant is thus an efficacious peripheral GR antagonist in mice with only modest disinhibition of the HPA axis, and the distinct properties of relacorilant endorse the potential of selective GR antagonist treatment for endogenous Cushing's syndrome

Digital quantification of somatostatin receptor subtype 2a immunostaining: a validation study

Objective: The aim of this study was to develop an open-source and reproducible digital quantitative analysis (DIA) of somatostatin receptor subtype 2a (SST2) staining in formalin-fixed paraffin-embedded tissues of pancreatic neuroendocrine tumors (panNETs) and growth hormone (GH)-secreting pituitary adenomas (GHomas). Design: SST2 immunostaining of 18 panNETs and 39 GHomas was assessed using a novel DIA protocol and compared with a widely used semi-quantitative immunoreactivity score (IRS). Methods: The DIA software calculates the staining intensity/area and the percentage of positive cells (%PC). Four representative images were selected for each sample by two independent selectors (S1 and S2), with the analysis performed by two independent analyzers (A1 and A2). Agreement between observers was calculated using the concordance correlation coefficient (CCC). Results: In panNETs, the CCC ranged 0.935-0.977 for intensity/area and 0.942-0.983 for %PC. In GHomas, the CCC ranged 0.963-0.997 for intensity/area and 0.979-0.990 for %PC. In both panNETs and GHomas, the DIA staining intensity was strongly correlated with the IRS (Spearman rho: 0.916-0.969, P < 0.001), as well as the DIA %PC with the IRS %PC (Spearman rh: 0.826-0.881, P < 0.001). In GHomas, the biochemical response to somatostatin receptor ligands correlated with SST2 expression, evaluated both as DIA intensity/area (Spearman rho: -0.448 to -0.527, P = 0.007-0.004) and DIA %PC (Spearman rho: -0.558 to -0.644, P ≤ 0.001). Conclusions: The DIA has an excellent inter-observer agreement and showed a strong correlation with the widely used semi-quantitative IRS. The DIA protocol is an open-source, highly reproducible tool and provides a reliable quantitative evaluation of SST2 immunohistochemistry