Search

Background: Hybrid emergency rooms (ERs) allow computed tomography (CT) scanning, interventional radiology, and surgery all in the same suite. Severe trauma patients with blunt thoracic aortic injury (BTAI) require rapid diagnosis and treatment. Hybrid ERs allow the potential for clinicians to implement multiple therapeutic procedures, including thoracic endovascular aortic repair (TEVAR), for these types of conditions without the need to transport the patients., Case Presentation: A 35-year-old man sustained multiple injuries after a motor vehicle accident and was transferred to our hospital in shock status. CT revealed a grade IV BTAI rupturing into the thoracic cavity and pelvic fracture. Soon after preperitoneal pelvic packing and transcatheter arterial embolization for pelvic fracture, TEVAR was performed in the hybrid ER without transporting the patient. The patient was transferred to a rehabilitation hospital on postoperative day 41., Conclusion: Hybrid ERs enable clinicians to perform all life-saving procedures, including stent grafting for traumatic patients with aortic injuries, in the same place., Competing Interests: None., (© 2025 The Authors. Published by Elsevier Ltd.)

Pulmonary hypertension (PH) is a life-threatening disease characterized by a progressive narrowing of pulmonary arterioles. Although VEGF is highly expressed in lung of patients with PH and in animal PH models, the involvement of angiogenesis remains elusive. To clarify the pathophysiological function of angiogenesis in PH, we compared the angiogenic response in hypoxia (Hx) and SU5416 (a VEGFR2 inhibitor) plus Hx (SuHx) mouse PH models using 3D imaging. The 3D imaging analysis revealed an angiogenic response in the lung of the Hx-PH, but not of the severer SuHx-PH model. Selective VEGFR2 inhibition with cabozantinib plus Hx in mice also suppressed angiogenic response and exacerbated Hx-PH to the same extent as SuHx. Expression of endothelial proliferator-activated receptor γ coactivator 1α (PGC-1α) increased along with angiogenesis in lung of Hx-PH but not SuHx mice. In pulmonary endothelial cell-specific Ppargc1a-KO mice, the Hx-induced angiogenesis was suppressed, and PH was exacerbated along with increased oxidative stress, cellular senescence, and DNA damage. By contrast, treatment with baicalin, a flavonoid enhancing PGC-1α activity in endothelial cells, ameliorated Hx-PH with increased Vegfa expression and angiogenesis. Pulmonary endothelial PGC-1α-mediated angiogenesis is essential for adaptive responses to Hx and might represent a potential therapeutic target for PH.

Background: Treating patients with out-of-hospital cardiac arrest (OHCA) requires early prediction of outcome, ideally on hospital arrival, as it can inform the clinical decisions involved. This study evaluated whether partial pressure of carbon dioxide (PCO 2 ) on arrival is associated with outcome at one month OHCA patients., Methods: This was a single-center retrospective study of adult OHCA patients treated between January 2016 and December 2020. Outcomes were defined along the Cerebral Performance Category (CPC) scale. Primary outcome was mortality (CPC 5) at one month. Secondary outcomes were death or unfavorable neurological outcome (CPC 3-5) and unfavorable neurological outcome (CPC 3-4) at one month. Multivariable analysis was adjusted for age, sex, witnessed cardiac arrest, bystander cardiopulmonary resuscitation, initial shockable rhythm, and time from call to emergency medical services to hospital arrival., Results: Out of 977 OHCA patients in the study period, 19 were excluded because they were aged under 18 years, 79 because they underwent extracorporeal cardiopulmonary resuscitation, and 101 due to lack of PCO 2 data. This study included 778 patients total; mortality (CPC 5) at one month was observed in 706 (90.7%), death or unfavorable neurological outcome (CPC 3-5) in 743 (95.5%), and unfavorable neurological outcome (CPC 3-4) in 37 (4.8%). In multivariable analysis, high PCO 2 levels showed significant association with mortality (CPC 5) at one month (odds ratio [OR] [per 5 mmHg], 1.14; 95% confidence interval [CI], 1.08-1.21), death or unfavorable neurological outcome (CPC 3-5) (OR [per 5 mmHg], 1.29; 95% CI, 1.17-1.42), and unfavorable neurological outcome (CPC 3-4) (OR [per 5 mmHg], 1.21; 95% CI, 1.04-1.41)., Conclusions: High PCO 2 on arrival was significantly associated with mortality and unfavorable neurological outcome in OHCA patients., Competing Interests: Declaration of Competing Interest All authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Stress hyperglycemia is a normal response to stress and has been associated with outcomes in out-of-hospital cardiac arrest (OHCA) patients. However, this association remained unknown in OHCA patients receiving extracorporeal cardiopulmonary resuscitation (ECPR). This study aimed to examine the association between degree of stress hyperglycemia on admission and neurological outcomes at discharge in OHCA patients receiving ECPR., Patients and Methods: This was a retrospective cohort study of adult OHCA patients receiving ECPR between 2011 and 2021. Patients were classified into three groups: absence of stress hyperglycemia (blood glucose level on admission < 200 mg/dL), moderate stress hyperglycemia (200-299 mg/dL), and severe stress hyperglycemia (≥ 300 mg/dL). The primary outcome was unfavorable neurological outcome (Cerebral Performance Category: 3-5) at discharge., Results: This study included 160 patients; unfavorable neurological outcomes totaled 79.4% (n = 127). There were 23, 52, and 85 patients in the absence, moderate, and severe stress hyperglycemia groups, respectively. Of each group, unfavorable neurological outcomes constituted 91.3%, 71.2%, and 81.2%, respectively. Multivariable analysis showed that, compared with moderate stress hyperglycemia, absence of stress hyperglycemia on admission was significantly associated with unfavorable neurological outcome at discharge (odds ratio [OR], 4.70; 95% confidence interval [CI], 1.07-33.35; p = 0.039)., Conclusion: Compared with moderate stress hyperglycemia on admission, absence of stress hyperglycemia showed significant association with unfavorable neurological outcome at discharge in OHCA patients receiving ECPR., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Studies describing the effectiveness of extracorporeal cardiopulmonary resuscitation (ECPR) for peripartum cardiopulmonary arrest are lacking., Case Presentation: A 39-year-old woman underwent elective cesarean section. Right after surgery, she fell into a cardiac arrest and was promptly transferred to our institute by ambulance. On arrival, we immediately initiated ECPR, within 63 min of the cardiac arrest. Return of spontaneous circulation was achieved 80 min after induction of extracorporeal membrane oxygenation. As the hemodynamics of the patient stabilized, extracorporeal membrane oxygenation was discontinued on day 3 of hospitalization. The patient's cerebral performance category score was 3 at discharge, which improved to 2 after 3 months., Conclusion: This case suggests that prompt interhospital transfer and ECPR might be effective for peripartum cardiac arrest due to nonhemorrhagic events., (© 2021 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

Aim: As an emergency measure during the coronavirus disease pandemic, the monitoring interval for clozapine use was temporarily extended beyond the regulatory requirement in Japan, which is the safest monitoring interval worldwide. In this study, we aimed to explore the effect of this measure on patients undergoing clozapine treatment., Methods: This retrospective chart review study included patients with treatment-resistant schizophrenia (TRS) who were undergoing clozapine treatment at four psychiatric institutions in Japan. Demographic characteristics and clinical information of these patients were collected on April 27, 2020, when Japanese psychiatrists were virtually allowed to prescribe clozapine beyond the regulatory requirement. Furthermore, information of adverse events related to the emergency measure was collected and analyzed., Results: Of the 41 patients with TRS included in this study, 19 patients underwent extended hematological monitoring during clozapine treatment. No psychiatric or hematological adverse events were observed in the patients during the extended monitoring interval., Conclusion: This study suggested that there were few adverse events of clozapine-treated patients related to emergency measures in Japan. However, hematological monitoring intervals during clozapine treatment have been emergently extended worldwide; hence, it is necessary to verify the results of these measures., (© 2021 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of Neuropsychopharmacology.)

Increased transforming growth factor-β (TGF-β) signaling contributes to the pathophysiology of aortic aneurysm in Marfan syndrome (MFS). Recent reports indicate that a small but significant number of inflammatory cells are infiltrated into the aortic media and adventitia in MFS. However, little is known about the contribution of myeloid cells to aortic aneurysmal formation. In this study, we ablated the TGF-β type II receptor gene Tgfbr2 in myeloid cells of Fbn1C1039G/+ MFS mice (Fbn1C1039G/+;LysM-Cre/+;Tgfbr2fl/fl mice, hereinafter called Fbn1C1039G/+;Tgfbr2MyeKO) and evaluated macrophage infiltration and TGF-β signaling in the aorta. Aneurysmal formation with fragmentation and disarray of medial elastic fibers observed in MFS mice was significantly ameliorated in Fbn1C1039G/+;Tgfbr2MyeKO mice. In the aorta of Fbn1C1039G/+;Tgfbr2MyeKO mice, both canonical and noncanonical TGF-β signals were attenuated and the number of infiltrated F4/80-positive macrophages was significantly reduced. In vitro, TGF-β enhanced the migration capacity of RAW264.7 macrophages. These findings suggest that TGF-β signaling in myeloid cells promotes aortic aneurysmal formation and its inhibition might be a novel therapeutic target in MFS., Competing Interests: The authors have declared that no competing interests exist.

Loeys-Dietz syndrome (LDS) is caused by variants of transforming growth factor-β (TGF-β)-related genes and is characterized by aortic aneurysm and dissection. We report an LDS patient with a de novo missense variant of TGFBR1 [c.1126A>G, p.(Lys376Glu)] in which active TGF-β signaling was observed in the aorta, despite the in vitro demonstration that the loss-of-function mutation lies within the serine/threonine kinase domain. The mechanism underlying this TGF-β paradox in LDS aortopathy should be further investigated., Competing Interests: The authors declare that they have no conflict of interest.

Accumulating data suggest that new cardiomyocytes in adults are generated from existing cardiomyocytes throughout life. To enhance the endogenous cardiac regeneration, we performed chemical screenings to identify compounds that activate pro-proliferative YES-associated protein and transcriptional enhancer factor domain activities in cardiomyocytes. We synthesized a novel fluorine-containing TT-10 (C 11 H 10 FN 3 OS 2 ) from the biologically hit compound. TT-10 promoted cardiomyocyte proliferation and simultaneously exerted antioxidant and antiapoptotic effects in vitro. TT-10 treatment in mice ameliorated myocardial infarction-induced cardiac dysfunction at least in part via enhancing clonal expansion of existing cardiomyocytes with nuclear YES-associated protein expression. Stimulating cardiomyocyte proliferation and/or protection with TT-10 might complement current therapies for myocardial infarction.

Variants in TGFBR1 have been reported to induce two completely distinct diseases, namely Loeys-Dietz syndrome (LDS) and multiple self-healing squamous epithelioma (MSSE). However, detailed mechanisms underlying this effect remain unknown. We report a Japanese familial case of LDS with a novel splice donor site variant in TGFBR1 gene (c.973 + 1 G > A; NG&#95;007461.1). The intronic variant was predicted to mediate in-frame exon 5 skipping within the serine/threonine kinase (STK) domain, which may also be mediated by a similar TGFBR1 variant of a splice acceptor site in intron 4 (c.806-2 A > C), identified in a British familial case of MSSE. Therefore, ex vivo splicing and functional assays were performed in mammalian cells to evaluate the effect of these sequence variants. The MSSE variant activated a cryptic acceptor site at 76 bp downstream of the 3' natural splice acceptor site, which produced an out-of-frame transcript (r.807&#95;882del, p.Asn270Thrfs*8). In contrast, the LDS variant generated two types of in-frame transcription products, r.[806&#95;973del, 965&#95;973 del], and produced two functionally inactivated proteins, p.[Asp269&#95;Gln324del, Thr323&#95;Gly325del], as a result of exon 5 skipping and the activation of a cryptic donor splice site at 9 bp upstream of the 5' natural splice donor site, respectively. Our results support the previously proposed but not yet approved mechanism that dominant-negative and truncating variants in STK domain induce LDS and MSSE, respectively.

Transforming growth factor-β (TGF)-β signaling plays a crucial role in the development and maintenance of various organs, including the vasculature. Accordingly, the mutations in TGF-β signaling pathway-related genes cause heritable disorders of the connective tissue, such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and Shprintzen-Goldberg syndrome (SGS), and these syndromes may affect skeletal, ocular, pulmonary, and cardiovascular systems. Aortic root aneurysms are common problems that can result in aortic dissection or rupture, which is the leading cause of sudden death in the natural history of MFS and LDS, and recent improvements in surgical treatment have improved life expectancy. However, there is currently no genotype-specific medical treatment. Accumulating evidence suggest that not only structural weakness of connective tissue but also increased TGF-β signaling contributes to the complicated pathogenesis of aortic aneurysm formation, but a comprehensive understanding of governing molecular mechanisms remains lacking. Inhibition of angiotensin II receptor signaling and endothelial dysfunction have gained attention as a possible MFS treatment strategy, but interactions with TGF-β signaling remain elusive. Heterozygous loss-of-function mutations in TGF-β receptors 1 and 2 ( TGFBR1 and TGFBR2 ) cause LDS, but TGF-β signaling is activated in the aorta (referred to as the TGF-β paradox) by mechanisms yet to be elucidated. In this review, we present and discuss the current understanding of molecular mechanisms responsible for aortopathies of MFS and related disorders.

Background: Marfan syndrome can cause life-threatening aortic complications. We investigated the relationship between FBN1 genotype and severe aortopathy (aortic root replacement, type A dissections, and related death)., Methods: We evaluated 248 patients with pathogenic or likely pathogenic FBN1 variants. The variants were classified as haploinsufficient type (HI, n=93) or dominant-negative type (DN, n=155) based on their location and predicted amino acid alterations, and we examined the effects of the FBN1 genotype on severe aortic events (aortic root replacement, type A dissections, and related death)., Results: The cumulative event-free probability was significantly lower in the HI group than in the DN group (adjusted hazard ratio, 2.1; 95% confidence interval, 1.4 -3.2; P <0.001)., Conclusions: DN-CD+HI patients should be monitored more carefully than DN-nonCD patients for rapid development of aortic root aneurysms., (© 2018 American Heart Association, Inc.)

Atypical aortic coarctation (AAC) has been reported to occur anywhere along the aorta, except for the ascending aorta. The associated symptoms include hypotension in the lower half of the body, secondary hypertension in the upper half of the body, and heart failure. Here we present an 80-year-old Asian woman complaining of progressive exertional dyspnea. She was diagnosed with acute decompensated heart failure and kidney injury due to severely calcified stenosis of the thoracoabdominal aorta, the so called AAC. She received hemodiafiltration, and pulmonary congestion improved in part. Generally, surgical treatments are quite invasive in elderly patients. Endovascular stent graft placement is less invasive, however, fracture and rupture should be considered at severely calcified lesions like this case. Therefore, we selected extra-anatomical axillofemoral bypass. Her recovery after the surgery was remarkable. In a few days, she became free from hemodiafiltration, intravenous diuretics, and oxygen administration. We thought the contributive factors are the increase in kidney blood flow and the correction of afterload mismatch. The decrease in pulse pressure may reflect the reduction in systemic arterial compliance by axillofemoral bypass. The operative mortality of axillofemoral bypass was reported to be acceptable, although the patency of the axillofemoral bypass graft was not high enough. In conclusion, axillofemoral bypass is effective and feasible for elderly patients with acute decompensated heart failure and kidney injury due to AAC.

Mutations in the bone morphogenetic protein receptor type II ( BMPR2 ) gene may result in the development of pulmonary arterial hypertension (PAH). However, the contribution of disease-causing mutations to the disease characteristics and responsiveness to recent treatment remains to be elucidated. We report three Japanese cases of advanced PAH with novel BMPR2 mutations, including two splicing mutations (IVS8-6&#95;7delTTinsA and IVS9-2A>G) and one deletion (c.1279delG) mutation., Competing Interests: The authors declare no conflict of interest.

A 79-year-old Asian man was hospitalized because of progressive exertional dyspnea with decreasing left ventricular ejection fraction and frequent non-sustained ventricular tachycardia. Pre-procedure venography for implantable cardioverter defibrillator (ICD) implantation showed occlusion of the bilateral subclavian veins. In consideration of subcutaneous humps in the sterno-clavicular area and palmoplantar pustulosis, we diagnosed him as having synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome and speculated that it induced peri-osteal chronic inflammation in the sterno-clavicular area, resulting in occlusion of the adjacent bilateral subclavian veins. An automatic external defibrillator (AED) was installed in the patient's house and total subcutaneous ICD was considered. Venous thrombosis in SAPHO syndrome is not frequent but has been reported. To the best of our knowledge, this is the first case of bilateral subclavian vein occlusion in a SAPHO syndrome patient who needs ICD implantation.

Coronary arterial complications associated with Kawasaki disease (KD), such as a giant coronary aneurysm, determine the relative risk of future cardiac events and require lifelong medical treatment. Here, we describe a 24-year-old man who developed myocardial infarction due to poor adherence to medical treatment for a giant coronary aneurysm in the chronic phase of KD. He was hospitalized two hours after the onset of chest pain. The presence of the giant coronary aneurysm made primary percutaneous coronary intervention (PCI) difficult. However, we were able to perform primary PCI successfully utilizing previous coronary computed tomography (CT) angiographic pictures as a reference. This case provides valuable insight for the management of coronary arterial complications associated with KD. Patients in the chronic phase of KD are usually asymptomatic, even in the presence of giant coronary aneurysms which have been reported to have a high risk of morbidity and mortality. Therefore, patient education is critical for preventing poor adherence to medical treatment for coronary arterial complications. In preparation for potential coronary intervention in the future, it is also useful to perform coronary CT angiography, coronary magnetic resonance (MR) angiography, and/or coronary angiography on a regular basis while patients remain free from serious cardiac events.

The total synthesis of an antitumor antibiotic, fostriecin (CI-920), via a highly convergent route is described. A characteristic feature of the present total synthesis is that the synthesis was achieved via a coupling procedure of three segments A, B, and C. The unsaturated lactone moiety of fostriecin, corresponding to segment A, was constructed from a known Horner-Emmons reagent, and the stereochemistry of the C-5 position was introduced by asymmetric reduction with (R)-BINAl-H. Segment B having a series of stereogenic centers was synthesized from (R)-malic acid and the stereogenic centers at the C-8 and C-9 positions were prepared by a combination of Wittig reaction and Sharpless asymmetric dihydroxylation reaction. The conjugated Z,Z,E-triene moiety of fostriecin, corresponding to segment C, was eventually constructed by Wittig reaction and Stille coupling reaction. The phosphate moiety, which is known to be essentially important for the antitumor activity, was introduced via two routes: (i) direct phosphorylation of the monohydroxyl derivative in which other hydroxyl groups are protected with silyl groups; (ii) cyclic phosphorylation and selective cleavage of the cyclic phosphate derivative. Although the former route is basically the same as those reported by other groups, the latter route is novel and more effective than the former one. The present total synthesis would serve as a versatile synthetic route to not only fostriecin, but also its various analogues including stereoisomers.

Fostriecin, a potent and promising antitumor antibiotic, was stereoselectively synthesized via a convergent route involving a three-segement coupling procedure.

Objectives: Experimental models of lymph node metastasis were developed for Doppler sonography., Methods: Cervical lymph node (LN) metastasis was induced by the implantation of a VX-2 tumor on the oral floor of 10 rabbits. Twenty metastatic LNs were observed weekly by power Doppler sonography, and the presence of an avascular area and the peripheral vessels were evaluated. The time-averaged maximum velocity (TAMx) at the hilum was also measured., Results: The percentage of the metastatic LNs presenting with an avascular area increased over time. The peripheral vessels were detected in 14 of 20 LNs. The peak time of the TAMx significantly correlated to that of the initial detection of the avascular area., Conclusions: In the beginning, metastatic LNs were depicted as hypervascular structures while the TAMx at the hilum increased. Later, an avascular area was detected and the TAMx at the hilum decreased, which resulted in a blood supply to the node from the peripheral vessels.

The modifying potential of two Kampo medicines (Japanese traditional herbal medicines), Sho-saiko-to (TJ-9) and Sairei-to (TJ-114), on urinary bladder carcinogenesis in male F344 rats initiated with N-butyl-N-(4-hydroxybutyl)- nitrosamine (BBN) was evaluated. Groups of 20 animals were given 0.05% BBN in their drinking water for 4 weeks and then 0.7 or 2.8% TJ-9, 0.9 or 3.6% TJ-114, or 3.0% sodium bicarbonate (NaHCO(3)) as a positive control substance in their diet for 32 weeks. All rats were killed after 36 weeks and examined histopathologically. No adverse effects of the test compounds were found in terms of survival, clinical sign, and body weight. Administration of 0.7 and 2.8% TJ-9 and 0.9 and 3.6% TJ-114 in the diet did not affect the incidences or extent of PN hyperplasia in the BBN-treated rats. Incidences and multiplicities of papillomas were also not affected in rats fed 0.7 or 2.8% TJ-9 and 0.9% TJ-114, while they were significantly decreased in animals given 3.6% TJ-114 in the diet. The results thus demonstrated that neither of the test chemicals exerted any promotional activity on urinary bladder carcinogenesis, in clear contrast to NaHCO(3). In addition, bladder carcinogenesis was reduced by 3.6% TJ-114 in the diet, under the present experimental conditions., (Copyright 2002 Wiley-Liss, Inc.)

Triethylenetetramine dihydrochloride (trientine-2HCl, TJA-250), a copper chelating agent used to treat Wilson's disease, was administered orally to male and female F-344 rats for 4 or 8 weeks at dosages of 0, 100, 350 or 1200 mg/kg/day or for 26 weeks at dosages of 50, 175 or 600 mg/kg/day. 4 or 8-week study. Two males receiving 1200 mg/kg/day died during week 8 of treatment. In males receiving 1200 mg/kg/day during weeks 5 to 8 of treatment, body weight gain and food consumption were decreased and hunched posture and thin build were observed. During week 4 or 8 of treatment urinalysis revealed, for males receiving 100 mg/kg/day or animals receiving 350 mg/kg/day or more, increased electrolyte outputs possibly due to the hydrochloride nature of trientine-2HCl, with low plasma alkaline phosphatase activities evident in animals receiving 350 or 1200 mg/kg/day. After 4 and 8 weeks, and during 8 weeks of treatment, high lung weights and bronchiolar epithelium hypertrophy and broncho-alveolar pneumonia were recorded for animals receiving 1200 mg/kg/day, and submucosal acute inflammation within the glandular region of the stomach was recorded for males receiving 350 or 1200 mg/kg/day and in all treated female groups. 26-week study. One male receiving 175 mg/kg/day and three males receiving 600 mg/kg/day died, showing lung changes. The body weight gain of animals receiving 600 mg/kg/day was slightly decreased. Blood chemistry and urinalysis examinations showed changes similar to those indicated in the 4- or 8-week study. The low plasma copper concentrations seen in males receiving 600 mg/kg/day, the slightly low liver copper concentrations found in animals receiving 600 or 175 mg/kg/day and the high urinary copper concentrations found in all treated groups, are attributed to the pharmacological action of trientine-2HCl. Histopathology revealed a dosage-related incidence and severity of focal chronic interstitial pneumonitis accompanied by fibrosis of the alveolar walls in females receiving 175 mg/kg/day or more and all treated male groups, but no significant pathological changes in the stomach. Apart from the histological changes found in the lung, all the above changes were reversible. In conclusion, the NOAEL of trientine-2HCl in this 26-week study was considered to be 50 mg/kg/day for females and less than 50 mg/kg/day for males.

Age-related changes of 27 items in serum chemistry were investigated in Sprague-Dawley rats of both sexes from 6 to 30 weeks of age. The following 12 items were shown as an increase in those values during growth and maturity, i.e., total protein, albumin (female only), glucose, total cholesterol, triglyceride, phospholipid (female only), beta-lipoprotein, cholinesterase (female only), asparate aminotransferase (female only), creatinine, direct-bilirubin and total-bilirubin. However, the following 4 items decreased with aging, i.e., asparate aminotransferase, alkaline phosphatase, creatine phosphokinase and inorganic phosphorus. No age-related changes were found in the values for calcium, sodium and chloride in both sexes and for alanine aminotransferase, cholinesterase and albumin in males. The sex differences were shown in the following 12 items: higher values in males were alkaline phosphatase, creatinephosphokinase, glucose and inorganic phosphorus, and higher values in females were cholinesterase, albumin, phospholipid, non-esterified fatty acid, urea nitrogen, direct-bilirubin, total-bilirubin and serum iron. No sex-related differences were found in the values for calcium, sodium, chloride and total cholesterol.

TJ-114 (Tsumura Sairei-to) is a powdered extract made from 12 Chinese herbal drugs. TJ-114 is used against various nephrotic diseases and used as an inhibitory treatment for the side effects of glucocorticoids. We expected that TJ-114 would increase the survival ratio of rats given a high dose of glucocorticoid. Therefore, in this study, we investigated the combined effects of glucocorticoid and TJ-114 in rats. An ointment containing fluocinolone acetonide (FA) was applied on the back of 7-week-old Wistar male rats for various periods. TJ-114 was administered orally at the doses of 0.5, 1.0 or 2.0 g/kg simultaneously. The combination with TJ-114 suppressed the loss of body weight by FA. The survival ratio of the FA group was 50%, but it was 83% for the group treated with FA in combination with 0.5 g/kg TJ-114 and no deaths were observed in the other drug combined group. With a lower dose of FA, we investigated its hematological effects and determined the white blood cell (WBC) count. Although the lymphocytes were decreased by FA, the combination with TJ-114 depressed this decrease of lymphocytes significantly. Furthermore, TJ-114 significantly suppressed the insulin increase elicited by FA. Macroscopic observations showed atrophy and decreases in the weights of the thymus, spleen and adrenal, all being target organs of glucocorticoid. The combination with TJ-114 decreased these effects of FA. Moreover, microscopic examinations revealed that FA induced the degeneration of lymphocytes and lymphocyte depletion in the cortex of the thymus, caused atrophy of the white pulp, decreased the extramedullary hematopoiesis of the spleen, and caused the atrophy of zona fasciculata in the adrenal cortex. The combination with TJ-114 depressed these effects significantly. These results suggest that TJ-114 suppresses the adverse side effects of gucocorticoids.

Alpha-methyldopa (alpha-MDP) is a widely used hypotensive agent, and it is considered to act on the central nervous system. In the present study, 6-hydroxydopa (6-OHDP) was injected into spontaneously hypertensive rats in a dose of 50 mg/kg on the 19th and 21st days of gestation. Dopamine contents were not changed, but norepinephrine (NE) decreased at 12 weeks of age. When the effect of alpha-MDP was examined at the age of 30 to 40 weeks, the decrease in blood pressure induced by 300 mg/kg alpha-MDP i.p. was significantly attenuated in the 6-OHDP treated rats. Whenever the hypotensive effects of alpha-MDP were inhibited, production of alpha-methylnorepinephrine (alpha-MNE) was markedly reduced only in the spinal cord. 6-Hydroxydopamine (6-OHDA) was also injected into the spinal cord at the C4 level. Although alpha-MDP lowered blood pressure in both 6-OHDA treated and non-treated control rats, the decreased in 6-OHDA treated rats tended to be less pronounced. The accumulation of alpha-MNE in the caudal area of the spinal cord was markedly reduced. Furthermore, in order to destroy the spinal serotonergic neurons selectively, we used intraspinal 5,7-dihydroxytryptamine (5,7-DHT) in the same manner as 6-OHDA injection. In 5,7-DHT treated rats, the blood pressure was decreased fully. These observations seem sufficient to hypothesize, although not to conclude, that the effect of alpha-MDP on the blood pressure is dependent at least partly on the biotransformation to alpha-MNE in the spinal noradrenergic neurons.

Effects of oral administration of gomisin A, one of the components isolated from Schizandra fruits, on liver injuries induced by CCl4, d-galactosamine and dl-ethionine and on liver microsomal drug-metabolizing enzyme activities were investigated. Gomisin A suppressed the increase of serum transaminase activities and the appearances of histological changes such as degeneration and necrosis of hepatocyte, inflammatory cell infiltration and fatty deposition in each type of liver injury. The repeated administration of gomisin A (30 or 100 mg/kg, p.o., daily for 4 days) induced an apparent increase of liver weight in liver-injured and normal rats. Gomisin A decreased serum triglyceride and lipid contents of the liver in biochemical studies. Increases of microsomal cytochrome b5 and P-450, elevations of NADPH cytochrome C reductase, aminopyrine N-demethylase and 7-ethoxycoumarin O-deethylase activities and decrease of 3,4-benzo(a)pyrene hydroxylase activity per cytochrome P-450 were observed after the administration of gomisin A. In addition, gomisin A was found to enhance the incorporation of 14C-phenylalanine into liver protein and to shorten the hexobarbital-induced sleeping time. These changes caused by gomisin A were similar to those by phenobarbital. However, gomisin A is distinctly different from phenobarbital in the finding that phenobarbital lessened the survival ratio of CCl4-intoxicated mice, but gomisin A did not. Our observation suggest that gomisin A shows an antihepatotoxic action by oral application and also has hypolipidemic (mainly triglyceridemic) and liver protein synthesis-facilitating actions and that the enlargement of the liver seen with gomisin A is the adaptive hypertrophy which is due to the induction of drug-metabolizing enzymes.

The rate of secretion of dopamine (DA) was investigated along with those of norepinephrine (NE) and epinephrine (E) in the case of hemorrhagic hypotension. Blood samples were collected directly from the adrenal vein and DA, NE and E contents were measured using a gas-liquid chromatograph equipped with an electron-capture detector (GLC-ECD). Under the condition of hemorrhagic hypotension, the rates of secretion of DA, NE and E increased from 0.22, 3.4 and 13.7 ng/kg/min to 10.7, 89.7 and 361.4 ng/kg/min in 90 min, respectively. After reinfusion, the levels of DA, NE and E decreased. The concentration of DA in the femoral artery was 1.0 and 1.5 ng/ml at 70 and 90 min after hemorrhage. In spinal transected preparations, increases in the rates of DA, NE and E secretion did not occur during hemorrhagic hypotension. Thus, the rates of secretion of DA, NE and E varies with the hemodynamic changes, the secretion of DA from the adrenal gland is primarily controlled by the central nervous system, and the pattern of increase in level of DA differs from the patterns in the case of NE and E in hemorrhagic hypotension.

The fractionation of the liver of goldfish (Carassius auratus) was studied, and the properties of the microsomal fraction were examined. The microsomal fraction contained cytochrome P-450 and catalyzed the oxidation of aminopyrine, aniline, 7-ethoxycoumarin and benzo(a)pyrene. The oxidation activities were significantly lower than those of rat liver microsomes. The titration of cytochrome P-450 by potassium cyanide indicated the presence of multiple forms of cytochrome P-450 in goldfish liver microsomes. Feeding of goldfish with 3-methylcholanthrene-containing food greatly induced benzo(a)pyrene hydroxylation activity of the liver microsomes. The Soret peak of the carbon monoxide compound of cytochrome P-450 was shifted from 450 to 448 nm.

When small doses of pindolol and propranolol (0.1 mg/kg and 5 mg/kg, respectively) were administered intraperitoneally to conscious normotensive Kyoto Wistar rats, acute hypotension occurred. However, these hypotensive effects diminished when the doses were increased to 5 mg/kg and 20 mg/kg, respectively. Unilateral adrenalectomy had no effect on these hypotensive effects but they were suppressed by bilateral adrenalectomy. Subsequently, marked and lasting hypotensive effects (20-35 mm Hg) were observed. In urethane-anaesthetized rats, intravenous infusions of the blocking agents produced a rise in blood pressure and an increase in the content of epinephrine, norepinephrine and dopamine in adrenal venous blood. These hypertensive actions were not seen in adrenalectomized rats. When rats were given 6-hydroxydopamine (2 micrograms/microliters) bilaterally at the C4 level of the spinal cord 7 days before or 5,7-dihydroxytryptamine (2 micrograms/microliters, after desmethylimipramine, 25 mg/kg i.p.), the catecholamine content of adrenal venous blood and the catecholamine releasing actions of these blocking agents decreased, but were not completely abolished. These results suggest that the lack of hypotensive effects with higher doses of beta-adrenoceptor blocking agents may have been due partly to the direct release of catecholamines from the adrenal medulla and partly to central noradrenergic or serotonergic nerve action.

The role of adrenal catecholamines (CAs) was investigated with regard to the etiology of hypertension and cerebral stroke in the spontaneously hypertensive rats-stroke prone (SHRSP). The adrenal CAs in SHRSP were measured by high performance liquid chromatography with an electrochemical detector or by gas-liquid chromatography with an electron capture detector and the findings were compared with those in the spontaneously hypertensive rats (SHR) and Wistar-Kyoto strain (WKY). It has been proposed that the facilitation of peripheral sympathetic norepinephrine (NE) neurons in the young animals may act as a trigger in the development of hypertension in the SHR. This was verified by estimating the adrenal NE contents in both SHRSP and SHR at 4 weeks of age. A deficiency in adrenal dopamine (DA) in 4-week-old SHRSP was also observed. This deficiency may contribute to the facilitation of the adrenal NE cell. SHRSP was clearly distinguished from SHR by comparing the adrenal catecholamine contents of each strain. The contents of all three CAS in SHRSP were similar to those in WKY during the development of hypertension, while the contents of epinephrine and DA in the SHR were much higher than those in the WKY. Only in SHRSP did the contents of all three CAs increase rapidly after the development of hypertension. These rapid increases may be related to stroke.

Differences by routes of administration of the effects of prostaglandins and vasoactive substances on blood pressure, peripheral blood flow and respiration were investigated. Intravenous prostaglandins evoked respiratory excitation in rabbits, and lowered blood pressure more prominently and longer after intracarotid injection than after the intrajugular administration. The effects of prostaglandins were apparently more conspicuous after vertebral artery than via carotid artery. In rats, 1 microgram/kg i.v. of PGE1 and PGE2 caused a fall of blood pressure but 1 microgram/kg i.v. of PGF2 alpha caused a rise. PGF2 alpha produce a decrease of blood pressure when injected 10 micrograms/kg i.v.. A remarkable elevation of blood pressure occurred in rats following injection into the lateral cerebral ventricle of 0.1 microgram/kg of PGE1 or PGF2 alpha or of the same dose of 5-hydroxytryptamine (5-HT). Intra-arterial injection of PGE1 gave rise to an increase in blood flow of rabbit dorsal skeletal muscle whereas that of PGF2 alpha resulted in blood flows. The above results indicate that the effects of prostaglandins on these parameters essentially vary to slight extents with the species of animals and differ in intensity with routes of administration.