Effect of posterior hypothalamic knife cuts on the baroreflex and hemorrhage-induced hormonal responses.

We made posterior hypothalamic knife cuts in rats to transect the fibers of the medial forebrain bundle (MFB) at the level of the mammillary body. The role of the MFB in the baroreflex and hemorrhage-induced hormonal responses was then examined in the unanesthetized, freely moving condition. The slopes for the relationship between changes in pulse interval and mean arterial pressure (MAP) in the posterior-cut group were significantly steeper than those in the sham-cut group both when there were phenylephrine-induced increases in MAP (1.13 +/- 0.07 vs 0.86 +/- 0.10 msec/mmHg) and nitroprusside-induced decreases in MAP (1.16 +/- 0.10 vs 0.77 +/- 0.05 msec/mmHg). This result indicates that posterior cuts elevated baroreflex sensitivity when MAP was increased or decreased. The resting MAP was not changed, but the resting heart rate (HR) was lowered by the posterior cuts. Furthermore, the posterior cuts augmented hypotensive hemorrhage-induced bradycardia. Hypotensive hemorrhage (16-17 ml/kg) caused elevation of the plasma catecholamine, ACTH and vasopressin (AVP) levels, but the posterior cuts attenuated these hormonal responses. These results indicate that the fibers in the MFB have a tonic inhibitory effect on the baroreflex in the resting condition, and play a stimulatory role in hemorrhage-induced catecholamine, ACTH and AVP responses.</p

The Skn7 Response Regulator of \u3ci\u3eSaccharomyces cerevisiae\u3c/i\u3e Interacts with Hsf1 In Vivo and Is Required for the Induction of Heat Shock Genes by Oxidative Stress

The Skn7 response regulator has previously been shown to play a role in the induction of stress-responsive genes in yeast, e.g., in the induction of the thioredoxin gene in response to hydrogen peroxide. The yeast Heat Shock Factor, Hsf1, is central to the induction of another set of stress-inducible genes, namely the heat shock genes. These two regulatory trans-activators, Hsf1 and Skn7, share certain structural homologies, particularly in their DNA-binding domains and the presence of adjacent regions of coiled-coil structure, which are known to mediate protein–protein interactions. Here, we provide evidence that Hsf1 and Skn7 interact in vitro and in vivo and we show that Skn7 can bind to the same regulatory sequences as Hsf1, namely heat shock elements. Furthermore, we demonstrate that a strain deleted for the SKN7 gene and containing a temperature-sensitive mutation in Hsf1 is hypersensitive to oxidative stress. Our data suggest that Skn7 and Hsf1 cooperate to achieve maximal induction of heat shock genes in response specifically to oxidative stress. We further show that, like Hsf1, Skn7 can interact with itself and is localized to the nucleus under normal growth conditions as well as during oxidative stress

Comparison of the Effects of Intra-Third Ventricular Administration of Interleukin-1 or Platelet Activating Factor on ACTH Secretion and the Sympathetic-AdrenomeduIIary System in Conscious Rats

The effects of centrally administered interleukin-1 beta (IL-1) or platelet activating factor (PAF) on adrenocorticotropin (ACTH) and catecholamine secretion, blood pressure and heart rate were examined to determine if these agents stimulate similarly the hypothalamic-pituitary-adrenal (HPA) axis or the sympathetic-adrenomedullary system. Intra-third ventricular administration of IL-1 (50, 200 ng) evoked significant ACTH secretion. Centrally administered IL-1 (50 ng) elevated plasma noradrenaline and adrenaline levels, systolic blood pressure and heart rate. Plasma ACTH, noradrenaline and adrenaline levels were also increased by the higher dose (200 ng) of IL-1 while systolic blood pressure and heart rate were not affected. Intra-third ventricular administration of 9 micrograms of PAF elevated the plasma ACTH level while 3 micrograms of PAF did not stimulate ACTH secretion. Neither dose of centrally administered PAF affected any plasma catecholamine level or systolic blood pressure. These results suggest that central IL-1 stimulates both the HPA axis and the sympathetic-adrenomedullary system, that a higher dose of IL-1 stimulates a mechanism to antagonize the elevation of blood pressure and heart rate and that central PAF is not involved in the control of the sympathetic-adrenomedullary system. Thus, IL-1 and PAF do not interact in the brain, although they interact peripherally.</p

Effect of acute ether or restraint stress on plasma corticotropin-releasing hormone, vasopressin and oxytocin levels in the rat.

Ether and restraint stress-induced peripheral plasma corticotropin releasing hormone (CRH), arginine vasopressin (AVP), oxytocin (OXY) and adrenocorticotropin (ACTH) levels were measured by radioimmunoassays. Plasma CRH, AVP, OXY and ACTH rose to approximately twice the level of control rats 2 min after the onset of a 1-min exposure to ether. Plasma CRH rose further 5 min after the onset of ether stress, while plasma AVP and OXY returned to the baseline levels at 5 min. Plasma CRH, OXY and ACTH showed significant elevation 2 min after the onset of restraint stress, while plasma AVP did not show a significant change. Plasma OXY and ACTH rose further 5 min after the onset of restraint stress, whereas plasma CRH returned to baseline levels. CRH and OXY concentrations in the hypothalamic median eminence decreased 5 min after the onset of ether exposure and restraint, while the AVP concentration did not differ from control levels. The results, including the discrepancy between plasma CRH and ACTH 5 min after stress, suggest that CRH in the peripheral plasma is derived from both hypothalamic and extrahypothalamic tissues. The levels of stress-induced CRH in the peripheral plasma were sufficient to stimulate ACTH release. These results suggest that ether and restraint stress elevate plasma CRH shortly after the onset of the stress, and that this elevation in the plasma CRH level is at least partly responsible for stress-induced ACTH secretion.</p

Direct interaction of insulin-like growth factor-1 receptor with leukemia-associated RhoGEF

Insulin-like growth factor (IGF)-1 plays crucial roles in growth control and rearrangements of the cytoskeleton. IGF-1 binds to the IGF-1 receptor and thereby induces the autophosphorylation of this receptor at its tyrosine residues. The phosphorylation of the IGF-1 receptor is thought to initiate a cascade of events. Although various signaling molecules have been identified, they appear to interact with the tyrosine-phosphorylated IGF-1 receptor. Here, we identified leukemia-associated Rho guanine nucleotide exchange factor (GEF) (LARG), which contains the PSD-95/Dlg/ZO-1 (PDZ), regulator of G protein signaling (RGS), Dbl homology, and pleckstrin homology domains, as a nonphosphorylated IGF-1 receptor-interacting molecule. LARG formed a complex with the IGF-1 receptor in vivo, and the PDZ domain of LARG interacted directly with the COOH-terminal domain of IGF-1 receptor in vitro. LARG had an exchange activity for Rho in vitro and induced the formation of stress fibers in NIH 3T3 fibroblasts. When MDCKII epithelial cells were treated with IGF-1, Rho and its effector Rho-associated kinase (Rho-kinase) were activated and actin stress fibers were enhanced. Furthermore, the IGF-1–induced Rho-kinase activation and the enhancement of stress fibers were inhibited by ectopic expression of the PDZ and RGS domains of LARG. Taken together, these results indicate that IGF-1 activates the Rho/Rho-kinase pathway via a LARG/IGF-1 receptor complex and thereby regulates cytoskeletal rearrangements

Combined anterior pituitary function test using CRH, GRH, LH-RH, TRH and vasopressin in patients with non-functioning pituitary tumors.

We examined 8 normal subjects and 16 patients with non-functioning pituitary tumors with a combined anterior pituitary test to evaluate the clinical usefulness of the test. Diagnoses included 9 of chromophobe adenoma, 3 of craniopharyngioma, 2 of Rathke's cleft cyst, and 1 each of intrasellar cyst and tuberculum sella meningioma. All subjects received hypothalamic releasing hormones: 1 micrograms/kg corticotropin releasing hormone (CRH), 1 micrograms/kg growth hormone releasing hormone (GRH), 500 micrograms thyrotropin-releasing hormone (TRH), 100 micrograms luteinizing hormone releasing hormone (LH-RH), and a relatively small dose (5 mU/kg) of lysine vasopressin (LVP). In the normal subjects, the addition of LVP potentiated the secretion of adenocorticotropic hormone (ACTH) induced by CRH, but had no significant effect on the secretion of other anterior pituitary hormones. In the combined test with 5 releasing hormones, the plasma ACTH and cortisol responses were not impaired in the majority of the patients before pituitary surgery. Serum thyroid-stimulating hormone (TSH), prolactin (PRL) and follicle-stimulating hormone (FSH) responses were not impaired in 82%, 70% and 67% of the patients, respectively, while the serum LH and GH responses were impaired in 67% and 73% of the patients, respectively. Following pituitary surgery, responses of these hormones to combined testing were similarly impaired in more than 75% of the patients. These results indicate that plasma ACTH, cortisol and serum TSH responses are fairly good before pituitary surgery but are impaired significantly after surgery. No subjects experienced any serious adverse effects related to the testing. These results suggest that combined testing with hypothalamic hormones is a convenient and useful method for evaluating pituitary function.</p

Multidetector-CT findings of dissecting aortic aneurysum and coronary artery disease. Based on the case of dissecting aortic aneurysum and coronary artery disease.

2000年になり多列検出器高速CT (Multi-detector CT,以下MDCT)が出現し,大動脈疾患や心電図同期での冠動脈狭窄病変診断への臨床応用が開始された.当院でも2001年7月からMDCTが稼動し,日常臨床診療に貢献している. 今回,解離性上行大動脈瘤(DeBakeyII)(以下DAA)と冠動脈疾患(LAD# 7の閉塞)を合併した患者を診療した.MDCTによるCT - Angiography (以下CTA)が両者の診断に非常に有用であった.患者の負担は100mlの末梢静脈内への造影剤の投与と約数十秒間の呼吸停止だけで,解離性大動脈瘤並びに冠動脈狭窄病変の診断にそれぞれ非常に有用であった.三次元診断の鮮明な画像が得られ,かつ低侵襲度のMDCT並びにCTAは,今後益々臨床の場で血管造影検査の強力なファーストチョイスの診療手段になると考える.Multidetector-CT (MDCT) and CT-Angio hase proven to be extremely useful in diagnosis of dissecting aortic aneurysum (DM) and coronary artery disease (CAD) . We report a case of DM complicated with CAD which was diagnosed by new MDCT

The level of plasma BNP continued remarkably high in the elderly presented with old myocardial infarction.

心不全が比較的良好にコントロールされているのにもかかわらず,高齢の陳旧性心筋梗塞後患者等で脳性ナトリウム利尿ペプチド(BNP)の異常高値が持続する場合がある.今回,また超高齢の心不全患者で同所見を認めたので,考察を含めて報告する. 93歳高齢の陳急性心筋梗塞患者で,BNP1600-1200の著明な高値が持続した.主に心尖部と一部の前側壁の陳旧性心筋梗塞症であったが,利尿薬等による治療によって心不全はコントロールできており,救急入院時を除いては,鬱血性心不全の状態ではなかった.心願超音 波検査でも心内圧の上昇や下大静脈の拡張も認めなかった.利尿薬を増量するとむしろ脱水による腎機能障害の増悪を認めていた. 入院中に狭心痛を認めることがあり,心筋逸脱酔素の軽度の上昇を認めた.BNPの著明な高値持続は,陳旧性心筋梗塞後の心臓機能障害や左室肥大,僧帽弁閉頚不全等による慢性心不全･心負荷のための心筋でのBNP合成･分泌元進の他に,新たな小梗塞(非貫壁性心筋梗塞)や持続する無症候性の心筋虚血による心筋でのBNP合成･分泌亢進,高齢によるBNPクリアランスの低下と分泌の持続的亢進,慢性腎機能障害によるBNPクリアランスの低下,心筋障害後の心筋再構築(リモデリング)の訳節と心筋繊維化抑制の為に合成が元進していると考えられる.更に,いわゆる老人肺･慢性呼吸機能低下による右心系の負荷による心室からの分泌元進,ステロイドホルモン内服による鉱井コルチコイド作用,貧血,低栄養状態等の様々な要因が重なっているものと考えられた. 心臓でBNPの産生･分泌が亢進するのは,心不全に伴う全身の体液量バランスや血行動態等の悪化を改善,調節するためだけではなく,心臓自身のリモデリングの調節･抑制,再構築の調薪のため,さらには心臓･心筋の繊維化や拡張障害の増悪を抑制するための自己防衛 機構としても機能している.心臓は,単に循環系のポンプではなく,利尿ペプチドホルモンを分泌する内分泌器官でもある. 一般的に加齢に伴いBNPは上昇してくる.特に70歳以上の高齢者では顕著になる.考察ではその点についても新たな文献的考察も含めて報告し,高齢者のBNPの捉え方と治療についても述べる.The level of plasma BNP (Brain Natriuretic Peptide) increases with many factors, especially among the elderly. The heart increases the secretion of BNP to improves and maintains body fluid balance and hemodynamic state. Furthennore, BNP works as the mechanism for self-protection in order to control remodeling the heart itself as well as to protect the heart from fibrotic progression and dyastolic dysfunction. The heart acts not only as the cardiovascular pump but also as the endocrine organ which secretes diuretic peptide honnones

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target