Über die Wirkung des Pilocarpins auf die Nervenendigungen des Sympathicus

Pilocarpin wirkt auf das Trigonum vesicae und den Detrusor der Kaninchenharnblase immer erregend. Am Kaninchendarm und Uterus bewirkt es in kleinen bis mittelgrossen Dosen auch Erregung, während es nach grossen Gaben oft eine Hemmung hervorruft, welche nicht auf einer Muskellähmung beruht. Die erregende Wirkung von kleineren Dosen Pilocarpin wird, wie bekaunt, durch kleine Dosen Atropin völlig aufgehoben. Diejenige von grösseren Dosen Pilocarpin ist je nach dem Organe nicht eindeutig. Am Detrusor und Darm, bei denen keine Verteilung der fördernden Sympathicusfasern vorhanden ist, wird die Wirkung des Pilocarpins durch eine kleine Menge von Atropin ebenfalls gehemmt, während sie am Trigonum und Uterus, welch von den hemmenden und fördernden Sympathicusfasern innerviert werden, durch kleine Dosen Atropin nicht gehemmt, sondern erst durch grössere Dosen Atropin antagonistisch beeinflusst wird, wobei die Erregung in eine Hemmung umgekehrt wird. Infolge der versehiedenen Innervation dieser Organe mit Sympathicusfasern und auf Grund der Tatsache, dass Atropin in kleinen Dosen nur die parasympathischen Nervenfasern lähmt, dass es in grösseren Dosen aber auch die sympathischen fördernden Fasern lähmen kann, scheint es sehr wahrscheinlich zu sein, dass Pilocarpin in grösseren Dosen auch die fördernden Fasern des Sympathicus angreift. Da ferner Pilocarpin in grossen Dosen oft eine nicht von der Muskellähmung herrührende Hemmung bewirkt, und die erregende Wirkung des Pilocarpins durch eine genügende Menge von Atropin umgekehrt wird, so ist ersichtlich, dass dieses Gift auch die hemmenden Fasern des Sympathicus mitangreift. Diese Annahme wird durch folgende Tatsache bestätigt. Die Erregung des Uterus durch grössere Dosen Pilocarpin kann nicht durch kleine Dosen Atropin gehemmt, aber durch Mitwirkung von Yohimbin, das die fördernden Sympathicusfasern zu lähmen vermag, leicht beseitigt und umgekehrt werden. Wird der Uterus und das Trigonum mit kleineren Dosen Adrenalin vorbehandelt, so wirken grössere Dosen Pilocarpin auf die bestehende Erregung hemmend und kehren sie um. Auch wird die durch grössere Dosen Pilocarpin hervorgerufene Erregung durch Adrenalin aufgehoben und umgekehrt. Ebenfalls nach der Erregung durch Pilocarpin kann Pilocarpin eine Umkehrung der Wirkung erzeugen. Dabei verhält sich also Pilocarpin ähnlich wie Adrenalin. Diese Tatsache kann auch durch die erwähnte Annahme des Verfassers erklärt werden

Über den Einfluss der Ermüdung auf die toxische Wirkung der Gifte

Die Versuche wurden an der Maus angestellt. Wenn zentralwirkende Krampfgifte, wie Pikrotoxin, Strychnin, Apomorphin und Morphin bei der mit telst der Migos-Laufbahn für kleinere Tiere mit Elektromotor in starke Ermüdung versetzten Maus subkutan verabreicht werden, so zeigt sich die Giftigkeit dieser Gifte viel schwächer als bei der in Ruhe gehaltenen Maus. Bei zentral lähmenden Giften, wie Chloralhydrat, Urethan, Paraldehyd und Magnesiumsulfat wird dagegen die Giftigkeit bei der ermüdeten Maus etwas stärker gefunden als bei der normalen. Daraus ist zu entnehmen, dass, soweit es sich übersehen lässt, Steigerung oder Herabsetzung der Giftigkeit dieser Gifte durch die sauren sogenannten Ermüdungssubstanzen bedingt ist, welche auf die Nervenelemente lähmend wirken müssen

Changes in stenosis resistance and myocardial blood flow after a brief coronary occlusion in the dog.

Stress-induced changes in the resistance due to coronary arterial stenosis of a fixed diameter and in the myocardial blood flow distal to the stenosis were investigated in the open-chest dog. Myocardial blood flow in the inner and outer third of the left ventricular wall was continuously measured with heated cross-thermocouples. The circumflex coronary artery was constricted with a thick string so that myocardial reactive hyperemia was nearly eliminated. Without constriction, a 15-second occlusion of the artery produced no significant changes in the resistance of large coronary arteries. On the contrary, in the presence of coronary constriction, a brief coronary occlusion caused a sustained decrease in distal coronary pressure and subendocardial myocardial flow during reactive hyperemia, while coronary flow returned quickly to the pre-occlusion level with significant reactive hyperemia of subepicardial flow. This change resulted in a long-lasting increase in the stenosis resistance. These results suggest that stenosis resistance changes dynamically, resulting in additional myocardial ischemia especially in the subendocardial myocardial layers.</p

Angiotensin II induces tumor progression and fibrosis in intrahepatic cholangiocarcinoma through an interaction with hepatic stellate cells

富山県立中央病院金沢大学医薬保健研究域医学系金沢大学附属病院胃腸外科Intrahepatic cholangiocarcinoma (ICC) is characterized as a highly fatal tumor with poor prognosis because of its strong progression, early invasion, widespread metastasis and rich cancerous stroma. Although it is widely accepted that fibroblasts facilitate stromal fibrosis and tumor progression, the mechanisms of the interaction between cancer cells and activated fibroblasts have not been fully elucidated thus far. In this study, we demonstrate the presence of angiotensin II (AngII) in ICC tissues and explore the interaction between hepatic stellate cells (HSCs) and ICC cells as one of the sources of stromal fibrosis and tumor progression through the interaction of the AngII/AngII type 1 receptor (AT-1) axis. The concentrations of AngII in ICC tissues were significantly higher than those of HCC and normal liver. Two human ICC cell lines (HuCCT-1, CCKS-1) and a human HSC cell line (LI-90) expressed AT-1 mRNA and protein. The proliferative activity of ICC cells and HSCs to which AngII was added dose-dependently increased and AT-1 antagonist inhibited the proliferative effects. HSCs to which AngII was added showed a higher expression of α-smooth muscle actin (α-SMA, a marker of activated HSCs and myofibroblasts), glial fibrillary acidic protein (GFAP, a specific marker of HSCs) and collagen type I than control cells. AT-1 antagonist also inhibited the activation and transformation of HSCs stimulated by AngII. These findings suggested that locally formed AngII in ICC tissues plays a role in the proliferation and activation of ICC cells and HSCs expressing AT-1 as a growth factor in autocrine and paracrine fashions. Our mechanistic findings provide the first insight into an autocrine and paracrine AngII-initiated signaling pathway that regulates ICC proliferation and fibrosis

The Japanese Clinical Practice Guideline for acute kidney injury 2016

Acute kidney injury (AKI) is a syndrome which has a broad range of etiologic factors depending on different clinical settings. Because AKI has significant impacts on prognosis in any clinical settings, early detection and intervention are necessary to improve the outcomes of AKI patients. This clinical guideline for AKI was developed by a multidisciplinary approach with nephrology, intensive care medicine, blood purification, and pediatrics. Of note, clinical practice for AKI management which was widely performed in Japan was also evaluated with comprehensive literature search

Sodium valproate blocks the transforming growth factor (TGF)-β1 autocrine loop and attenuates the TGF-β1-induced collagen synthesis in a human hepatic stellate cell line

金沢大学医薬保健研究域医学系Histone acetylation and deacetylation have been thought to be related to gene expression, and there are many reports indicating that histone deacetylase inhibitors (HDACis) exert antifibrogenic effects in several organs. In injured livers, hepatic stellate cells (HSCs) are activated in response to profibrogenic mediators and produce large amounts of extracellular matrix. In particular, transforming growth factor-β1 (TGF-β1) is considered as a key factor in accelerating hepatic fibrosis because it is released from activated HSCs and further stimulates them. The present study aimed to clarify whether sodium valproate (VPA) has suppressive effects on cultured human HSCs (LI90). We showed that treatment with VPA had no significantly suppressive effect on cell proliferation at a concentration of 1 mM, which corresponded approximately to the serum concentration obtained by the administration of a clinical dose. However, VPA prevented the morphological changes characteristic for activation and inhibited the expression of collagen type 1 α1 (COL1A1) and TGF-β1 in activated LI90 cells at the mRNA and protein levels. Our results support the hypothesis that VPA exerts antifibrogenic activity with little cytotoxicity at 1 mM, and HDACis are expected to be used in clinical practice for the treatment of fibrotic diseases.Embargo Period 6 month

A Prospective Multicenter Observational Study of Venous Thromboembolism after Gastric Cancer Surgery (SHISA-1601).

Introduction:This study aimed to clarify the frequency and risk factors of intercurrent venous thromboembolism (VTE) in patients undergoing major curative gastric cancer surgery.Methods:This prospective, multicenter, observational study included patients with gastric cancer who underwent radical gastrectomy at 5 hospitals between June 2016 and May 2018. Patients who were preoperatively administered anticoagulants were excluded.Results:A total of 126 patients were eligible to participate. VTE occurred within 9 days postoperatively in 5 cases (4.0%; 2 symptomatic and 3 asymptomatic). Postoperative day (POD) 1 plasma D-dimer and soluble fibrin (SF) levels were significantly higher in the VTE group than in the non-VTE group. Receiver-operating characteristic curve (ROC) analysis indicated a statistically significant ability of POD 1 D-dimer and SF levels to predict postoperative VTE development after gastrectomy; this finding was reflected by an area under the curve (AUC) of 0.97 (95% CI 0.92-1.0) and 0.87 (95% CI 0.74-1.0), respectively. Cutoff values of D-dimer (24.6 µg/mL) and SF (64.1 µg/mL) were determined. Intraoperative blood transfusion (odds ratio [OR] 7.86), POD 1 D-dimer ≥24.6 µg/mL (OR 17.35), and POD 1 SF ≥64.1 µg/mL (OR 19.5) were independent predictive factors for postoperative VTE (p < 0.05).Conclusion:VTE occurred in 4.0% patients (1.6% symptomatic and 2.4% asymptomatic) after gastric cancer surgery; however, with an early diagnosis and anticoagulant therapy, no patients experienced progression. Careful observation of patients with a high risk for VTE, including intraoperative blood transfusion and high POD 1 D-dimer or SF levels, would contribute to the early detection of VTE

Tumor-derived trypsin enhances proliferation of intrahepatic cholangiocarcinoma cells by activating protease-activated receptor-2

金沢大学医薬保健研究域医学系In primary malignant liver tumors, trypsinogen-immunoreactivity was present in 70% of intrahepatic cholangiocarcinoma (ICC) specimens, but absent in hepato-cellular carcinoma (HCC) specimens. We suggest the secretion of trypsinogen to be a key difference in biological behavior between ICC and HCC cells. The purpose of this study was to investigate the secretion of tumor-derived trypsin and the expression of its specific receptor, protease-activated receptor-2 (PAR-2), in ICC using cell lines and surgical specimens. The expression of trypsinogen-1 mRNA was observed in three of four ICC cell lines, but none of three HCC cell lines. Western blot analysis detected trypsinogen-1 in serum-free conditioned medium from one of the ICC cell lines positive for the mRNA. Gelatin zymography revealed a gelatinolytic activity for trypsin, the activated form of trypsinogen, in the same conditioned medium. PAR-2 mRNA and protein were observed in ICC cell lines. The proliferative activity of ICC cells was increased by concentrations of trypsin as low as 10 nM, and peaked at 100 nM. The effect of trypsin was suppressed by a serine protease inhibitor, gabexate mesilate. PAR-2 expression was detected in 64% of ICC surgical specimens immunohistochemically. In addition, stroma fibroblasts expressed PAR-2 in 52% of ICC specimens. These results suggest that trypsinogen-1 contributes to the growth of ICC cells and also tumor-associated fibroblasts.Embargo Period 6 month

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection