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Background: We previously reported that endogenous prostaglandin [I.sub.2], generated by a mild irritant, sensitised calcitonin gene related peptide (CGRP) containing sensory nerves and facilitated the release of CGRP and gastric [...]

Coronary risk factors such as diabetes mellitus, hypertension and hyperlipidemia are thought to be linked to insulin resistance (IR). It has been shown that IR may aggravate ischemic heart disease (IHD). We consider that to evaluate IR of patients with IHD is significant when attempting to suppress the aggravation of IHD. This study aimed to evaluate IR of patients after coronary artery bypass grafting (CABG) and to examine for availability of homeostasis model assessment (HOMA-R), which is usually employed in daily practice as a simple index of IR. The IR of twelve patients after CABG and ten healthy subjects was evaluated with the use of the glucose clamp technique, which is the most reliable method for evaluating IR. In this method, IR was quantitated by the rate of whole-body glucose disposal. Furthermore, we looked at the association between HOMA-R and the glucose clamp technique in the patients after CABG. The results were as follows : M-value was lower in the patients after CABG than in the healthy subjects (5.20 ± 2.37mg/kg/min vs. 8.89 ± 3.26mg/kg/min, p = 0.007). A significant correlation between the index of HOMA-R and the rate of whole-body glucose disposal measured by the glucose clamp technique was found in the patients after CABG (r= -0.85, p = 0.004). In conclusion, the patients after CABG possessed IR, and HOMA-R was a useful index of IR in the patients after CABG. [ABSTRACT FROM AUTHOR]

The article investigates the relation of inhaled monoethanolamine (MEA) to the occurrence of bronchoconstriction. Changes in airway opening pressure were measured in guinea pigs as an index of bronchoconstriction. It was found that stronger bronchoconstriction is caused by an aerosol of 3.3% MEA solution inhaled through a tracheal cannula, compared to an aerosol of potassium hydroxide solution. Also, premedication with intravenously injected atropine sulfate, a muscarinic receptor agonist or diphenhydramine hydrochloride was observed to suppress MEA-induced bronchoconstriction.

Background: Upregulation of oligopeptide transport activity by dietary protein, certain dipeptides and amino acids has been reported in the rat intestine and a human intestinal cell line. Objective: In this study, the pharmacokinetics of cefdinir were investigated afterl-phenylalanine supplementation and a high-protein diet (HPD) in humans to explore changes in the activities of intestinal and renal oligopeptide transporters. Methods: A normal-protein diet (NPD, 73·2 ± 2·6 g/day), NPD + l-phenylalanine (7·5 g/day), or HPD (141·3 ± 3·7 g/day) was given to six male healthy volunteers for 12 days followed by a single dose of cefdinir after an overnight fast in a randomized three-way crossover study with a 22-day washout. Blood and urine were collected over a 12-h period after administration of cefdinir. Concentrations of cefdinir in plasma and/or urine were measured by high-performance liquid chromatography. Results: Plasma concentrations and urinary excretion of the drug did not change throughout the study. Physiological variables and laboratory values did not reveal any differences between the three periods except for serum and urinary nitrogen levels and serum triglyceride. Discussion: A reason for the unchanged pharmacokinetics of cefdinir may be due to lower doses ofl-phenylalanine and protein in humans than in animals when converting animal effective doses to humans. Conclusion: In humans,l-phenylalanine supplementation and HPD do not seem to upregulate intestinal and renal oligopeptide transport in the ranges of duration and dose examined. [ABSTRACT FROM AUTHOR]

The study compared maximum drug concentration (C(max)) and area under the time-concentration curve (AUC) after normalization of doses to body weight and to body surface area and developed relationships for C(max) and AUC between humans and animals for 75 oral and 10 intravenous investigational drugs. For the oral drugs, animal-human ratios of C(max) were different among animals in both normalizations. Surface area-normalized AUC ratios were not different, whereas weight-normalized ones were different. For both normalizations for intravenous drugs, AUC ratios were not different. Drugs exhibiting 1/10 or smaller ratios tended to have low bioavailability. Regression of the relationships for dose-normalized C(max) and AUC transformed logarithmically between humans and animals were significant for the drugs with relatively high bioavailability. As approaches for predicting human C(max) and AUC from animals, surface area normalization seems to surpass weight normalization, and the equation obtained can be applied to drugs with high bioavailability. [ABSTRACT FROM AUTHOR]

Background: MKC-733, a 5-HT3 receptor partial agonist, is a novel enteroprokinetic compound. Objective: The aim of this study was to explore the effects of MKC-733 on bowel motility and symptoms in a small group of subjects with constipation. Tolerability was also examined. Methods: The study was conducted in a single-blind and dose-escalation manner on 14 male and female subjects with constipation aged 22–67 years. After a 1 week run-in period, subjects were treated with placebo (b.i.d.) for 1 week, and 0·2 and 0·5 mg of MKC-733 (b.i.d.) for 2 weeks sequentially. Geometric mean and per cent elimination of surrogate markers of bowel motility were measured by a radio-opaque marker technique at the end of each treatment period. They were analysed on the whole group and subgroups with low ( n = 6) and high ( n = 8) bowel motility based upon the geometric mean value after placebo treatment. Subjects kept diaries of their bowel habits and gastrointestinal symptoms. Results: Percent elimination increased after treatment with 0·5 mg MKC-733 compared with placebo treatment in the whole group (70·4 ± 33·5% vs. 47·1 ± 36·6%, mean ± SD, P < 0·05). In the low bowel motility group, both geometric mean and percent elimination increased after treatment with 0·5 mg MKC-733 compared with placebo (7·1 ± 0·9 vs. 5·9 ± 0·5, P < 0·05; 60·0 ± 35·8% vs. 13·3 ± 19·4%, P < 0·05). Stool frequency increased after the first-week treatment with MKC-733 compared with placebo ( P < 0·05). Numbers of sensation of incomplete evacuation and gastrointestinal symptoms decreased to half and less after the treatment with MKC-733. No serious adverse effect was noted. Conclusion: Multiple doses of 0·5 mg MKC-733 improve bowel motility, which was clearly demonstrated in the subjects with decreased bowel motility. MKC-733 at the doses studied might be effective in increasing stool frequency and reduce gastrointestinal symptoms related to constipation. MKC-733 was well tolerated. Further studies will be needed to clarify efficacy and safety of MKC-733 on a larger population. [ABSTRACT FROM AUTHOR]

PURPOSE: To determine the effects of exercise on waist circumference and plasma lipids in obese men with heart disease. METHODS: Ten obese men with heart disease were randomly assigned to participate either in a control group (n=5)or in a three month exercise group(n=5). Measurements were taken of the waist circumference, total cholesterol (TC), high-density lipoprotein(HDL-C), and triglyceride(TG). Participants in the exercise group were asked to perform exercise that expended 200 kcal day beyond their usual level of physical activity. All patients were asked to maintain all isocaloric diet for the duration of the treatment period. RESULTS: The patients in the exercise group increased their physical activity by a mean of 237.4 kcal/day (p < 0.01)from pre- to post-intervention. Waist circumference decreased in the exercise group significantly (94.4 ± 3.7 ± 92.9 ± 4.6cm ; p <0.05)and did not change in the control group. The level of TC, HDL-C and TG did not change in either of the groups. CONCLUSIONS: The results indicated that a 3 month exercise training program induces favorable alterations of waist circumference in obese men with heart disease. However, there were no effects on the plasma lipid levels. [ABSTRACT FROM AUTHOR]

We examined the effects of selective cyclooxygenase COX) inhibition on hepatic warm ischemia/reperfusion I/R) injury in mice. A selective COX-1 inhibitor, SC-560, selective COX-2 inhibitors, NS-398 and celecoxib, and indomethacin were administered 30 min before ischemia. Four hours after reperfusion, an in vivo microscopic study showed that I/R caused significant accumulation of leukocytes adhering to the hepatic microvessels and nonperfused sinusoids. Levels of plasma alanine transaminase (ALT) and tumor necrosis factor (TNF)-α also showed increases. SC-560, NS-398, celecoxib and indomethacin significantly reduced hepatic responses to I/R including microcirculatory dysfunction and release of ALT and TNF-α. Moreover, the effects of the thromboxane (TX) A[sub2] (TXA[sub2]) synthase inhibitor OKY-046 and the TXA[sub2] receptor antagonist S-1452 on hepatic responses to I/R exhibited results similar to those obtained with COX inhibitors. These results suggest that COX-1 and COX-2 contribute to I/R-induced hepatic microvascular and hepatocellular injury partly through TNF-α production, and that TXs derived from COX are partly responsible for I/R-induced liver injury. [ABSTRACT FROM AUTHOR]

After coronary artery bypass grafting (CABG), 6l consecutive patients (60.9 ± 10.5 years old, male: female 54:7) participated in supervised cardiac rehabilitation (average 15.2 days). The rehabilitation program included 30 minutes endurance training by upright cycle ergometer at anaerobic threshold (AT) level twice a day, 6 times a week. Training intensity was 68.6% of peak V̇O2 and 51.8% of work rate at AT. An educational program of diet and daily exercise counseling was also included. We evaluated exercise tolerance before and after rehabilitation by cardiopulmonary exercise testing. Peak V̇O2 was improved from 14.3 ± 3.0 to 16.6 ± 3.2 ml/min/kg (p<0.0001) and AT also increased from 10.2 ± 1.7 to 10.7 ± 1.6 ml/min/kg (p=0.008) before and after rehabilitation. These changes were more evident in patients who had less exercise capacity but were not significant between groups for age, rehabilitation period and preoperative clinical diagnosis. We performed effectively comprehensive cardiac rehabilitation including AT level endurance training for patients after CABG. [ABSTRACT FROM AUTHOR]

Over the last 7 years, snowboarding has become established as a popular sport in Japan. The present-day skier uses a high, rigid boot and multiple angle release bindings, but most snowboarders use a low, soft boot and rigid bindings. This study evaluates ankle ligament injuries in snowboarding and skiing. We report on 37 snowboarders and 48 skiers who sustained ankle ligament injury during 3 ski seasons. With the aid of stress roentgenograms, the extent of injury was established and conservative treatment was performed on all patients. Comparing skiers' versus snowboarder' injuries, 24(65%) versus 25(52%) were male, the mean age was 24.8 versus 22.1 years, constituting 6.8% versus 4.3% of all injuries, 35(94%) versus 46(96%) were involved the lateral ligamentous structures, and sprains of the ankle were classified as grade I:10(27%), grade II: 21(57%), and grade III: 6(16%) versos 12(25%), 33(69%), and 3(6%), respectively. A high percentage of injury in their first to third year of snowboarding and skiing was demonstrated in this study. It is important to understand the ankle ligament injuries that can occur during snowboarding and skiing. With proper diagnosis, appropriate treatment for these injuries can he provided. Additional research is needed to better understand the characteristics of these injuries. [ABSTRACT FROM AUTHOR]

Capsaicin acts specifically on primary afferent neurons to release neuropeptides, including calcitonin gene-related peptide (CGRP), and prevents ethanol-induced mucosal injury. To investigate the microvascular changes in the gastric mucosa in response to ethanol using intravital microscopy to elucidate the mechanism of capsaicin-induced gastroprotection. Ethanol (50%) applied to the mucosa constricted the collecting venules and venuls but dilated arterioles. The constriction of the collecting venules resulted in mucosal congestion, which caused mucosal injury. Application of capsaicin to the mucosa dilated the arterioles but not the collecting venules or venules. Arteriolar dilation was inhibited by a CGRP antagonist, CGRP-(8–37). Prior application of capsaicin prevented ethanol-induced constriction of the collecting venules, and the action of capsaicin was inhibited by prior application of CGRP-(8–37). The results suggest that the inhibition of ethanol-induced gastric injury by capsaicin is attributable to the suppression of collecting venule constriction, via CGRP release. [ABSTRACT FROM AUTHOR]

To determine the role of endogenous substance P in ethanol-induced mucosal damage, two experiments were performed. In the first experiment, the stomachs of anesthetized rats were doubly cannulated and gastric damage was induced with 5ml of 30% ethanol in the gastric lumen. The damage was ameliorated by pretreatment with capsaicin (0.16 and 1.6 mM) and spantide (100 mg/kg, i.v.). In the second experiment, the gastric mucosa of these rats was perfused with physiological saline containing pepstatin (10 microliters/ml). Endogenous substance P (SP) in the perfusate was measured by enzyme immunoassay (EIA). The peak SP levels were increased by capsaicin (0.16-1.6 mM) in a concentration-dependent manner. Perfusion with 50% ethanol for 5 min increased the SP levels approximately threefold. Perfusion with 1.6 mM capsaicin, followed by 50% ethanol, reduced the injured area to about one-quarter of the original injured area. The peak SP levels during perfusion with 50% ethanol after pretreatment with 1.6 mM capsaicin did not differ from those observed after vehicle pretreatment (control). The area under the curve for SP release during 50% ethanol perfusion after vehicle perfusion was not reduced by previous perfusion with 1.6 mM capsaicin followed by 50% ethanol, indicating that the prevention of ethanol-induced injury by capsaicin may be due to excess amounts of different neuropeptides released simultaneously. [ABSTRACT FROM AUTHOR]

Abstract: Cyclooxygenase-2 (COX-2) is known to correlate with a poor prognosis of prostate cancer and contribute to tumor metastasis. However, the precise mechanism of this phenomenon remains unknown. We have previously reported that host stromal microsomal prostaglandin E synthase-1 (mPGES-1) appeared critical for tumor-associated angiogenesis and tumor growth. Here, we tested whether or not mPGES-1 has a critical role in lung metastasis formation of prostate cancer. Murine prostate cancer cells (RM9) were intravenously injected and lung metastasis was estimated by counting colonies in the lungs. Mice treated with a selective COX-2 inhibitor, celocoxib, were suppressed lung metastasis compared to vehicle mice. This lung metastasis formation was also reduced in mPGES-1 knockout (mPGES-1 KO) mice, compared with wild type (WT) mice. This was accompanied with reduced angiogenesis around the metastasized colonies of RM9. Plasma protein levels and metastasized lung tissue mRNA levels of vascular endothelial growth factor (VEGF) and stromal cell derived factor-1 (SDF-1) were significantly suppressed in mPGES-1 KO mice in comparison with WT mice. In addition, the expressions of matrix metalloproteinases (MMP)-9, and metalloproteinases (MMP)-2 were down-regulated in metastatic lungs in mPGES-1 KO mice. These results suggested that host mPGES-1 was essential for MMP-2 and MMP-9 up-regulation that enhances tumor metastasis. mPGES-1 appears to be critical for tumor metastasis in prostate cancers. mPGES-1 inhibitors may be useful to protect against prostate cancer metastasis. [Copyright &y& Elsevier]

Abstract: Chronic inflammation, which is characterized by the proliferation of granulation tissues, is known to be regulated by angiogenesis. Recent results suggest that bone marrow-derived (BM-derived) hematopoietic cells regulate angiogenesis in vivo. We previously reported that the angiogenesis occurring during chronic inflammation is enhanced in response to the endogenous prostaglandins (PGs) derived from an inducible cyclooxygenase-2 (COX-2). In the present study, we examined the role of BM-derived cells expressing an E-type PG receptor subtype, EP3, in sponge-induced angiogenesis. The replacement of wild-type (WT) BM with BM cells (BMCs) from green fluorescent protein (GFP) transgenic mice revealed that the formation of granulation tissue around the sponge implants developed via the recruitment of BMCs. This recruitment was enhanced by topical injections of vascular endothelial growth factor (VEGF)-A, and a VEGF-dependent increase in the recruitment of BMCs was inhibited by a COX-2 inhibitor, celecoxib. FACS analysis of the granulation tissues after treatment with collagenase revealed that the Mac-1-positive macrophage fraction was enhanced by topical injections of VEGF-A, and that this increased recruitment of Mac-1-positive BMCs was inhibited by celecoxib. Selective knockdown of EP3 performed by BM transplantation with BMCs isolated from EP3 knockout (EP3) mice reduced sponge-induced angiogenesis, as estimated by mean vascular number and CD31 expression in the granulation tissues. This reduction in angiogenesis in EP3−/− BM chimeric mice was accompanied by reductions in the recruitment of BMCs, especially of Mac-1-positive cells and Gr-1-positive cells. These results indicate that the recruited bone marrow cells that express the EP3 receptor have a significant role in enhancing angiogenesis during chronic proliferative inflammation. [Copyright &y& Elsevier]

A 58-year-old man who had inhaled acetylene while welding 2 and 4 days previously and subsequently developed cough, dyspnea, and fever was referred by his general practitioner. A computed tomography scan showed diffuse ground-glass opacities in both lungs, and bronchoalveolar lavage fluid showed an increased proportion of eosinophils (25 %). Acute eosinophilic pneumonia (AEP) was diagnosed. Inhalation of acetylene was considered to be the most likely cause of AEP. Respiratory symptoms improved rapidly with intravenous corticosteroids. This is a rare case of AEP caused by inhalation of acetylene., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Acetaminophen (APAP)-induced liver injury is the most common cause of acute liver failure. Macrophages are key players in liver restoration following APAP-induced liver injury. Thromboxane A 2 (TXA 2 ) and its receptor, thromboxane prostanoid (TP) receptor, have been shown to be involved in tissue repair. However, whether TP signaling plays a role in liver repair after APAP hepatotoxicity by affecting macrophage function remains unclear., Methods: Male TP knockout (TP -/- ) and C57BL/6 wild-type (WT) mice were treated with APAP (300 mg/kg). In addition, macrophage-specific TP-knockout (TP △mac ) and control WT mice were treated with APAP. We explored changes in liver inflammation, liver repair, and macrophage accumulation in mice treated with APAP., Results: Compared with WT mice, TP -/- mice showed aggravated liver injury as indicated by increased levels of alanine transaminase (ALT) and necrotic area as well as delayed liver repair as indicated by decreased expression of proliferating cell nuclear antigen (PCNA). Macrophage deletion exacerbated APAP-induced liver injury and impaired liver repair. Transplantation of TP-deficient bone marrow (BM) cells to WT or TP -/- mice aggravated APAP hepatotoxicity with suppressed accumulation of macrophages, while transplantation of WT-BM cells to WT or TP -/- mice attenuated APAP-induced liver injury with accumulation of macrophages in the injured regions. Macrophage-specific TP -/- mice exacerbated liver injury and delayed liver repair, which was associated with increased pro-inflammatory macrophages and decreased reparative macrophages and hepatocyte growth factor (HGF) expression. In vitro, TP signaling facilitated macrophage polarization to a reparative phenotype. Transfer of cultured BM-derived macrophages from control mice to macrophage-specific TP -/- mice attenuated APAP-induced liver injury and promoted liver repair. HGF treatment mitigated APAP-induced inflammation and promoted liver repair after APAP-induced liver injury., Conclusions: Deletion of TP signaling in macrophages delays liver repair following APAP-induced liver injury, which is associated with reduced accumulation of reparative macrophages and the hepatotrophic factor HGF. Specific activation of TP signaling in macrophages may be a potential therapeutic target for liver repair and regeneration after APAP hepatotoxicity., (© 2024. The Author(s).)

Angiogenesis, the formation of new blood vessels from the preexistent microvasculature, is an essential component of wound repair and tumor growth. Nonsteroidal anti-inflammatory drugs that suppress prostanoid biosynthesis are known to suppress the incidence and progression of malignancies including colorectal cancers, and also to delay the wound healing. However, the precise mechanisms are not fully elucidated. Accumulated results obtained from prostanoid receptor knockout mice indicate that a prostaglandin E-type receptor signaling EP 3 in the host microenvironment is critical in tumor angiogenesis inducing vascular endothelial growth factor A (VEGF-A). Further, lymphangiogenesis was also enhanced by EP signaling via VEGF-C/D inductions in pathological settings. These indicate the importance of EP receptor to facilitate angiogenesis and lymphangiogenesis in vivo. Prostanoids act beyond their commonly understood activities in smooth muscle contraction and vasoactivity, both of which are quick responses elicited within several seconds on stimulations. Prostanoid receptor signaling will be a potential therapeutic target for disease conditions related to angiogenesis and lymphangiogenesis., (Copyright © 2024 Cold Spring Harbor Laboratory Press; all rights reserved.)

Background/aim: Intestinal lymphatic vessels (lacteals) play a critical role in the absorption and transport of dietary lipids into the circulation. Calcitonin gene-related peptide and receptor activity-modifying protein 1 (RAMP1) are involved in lymphatic vessel growth. This study aimed to examine the role of RAMP1 signaling in lacteal morphology and function in response to a high-fat diet (HFD)., Materials and Methods: RAMP1 deficient (RAMP1 -/- ) or wild-type (WT) mice were fed a normal diet (ND) or HFD for 8 weeks., Results: RAMP1 -/- mice fed a HFD had increased body weights compared to WT mice fed a HFD, which was associated with high levels of total cholesterol, triglycerides, and glucose. HFD-fed RAMP1 -/- mice had shorter and wider lacteals than HFD-fed WT mice. HFD-fed RAMP1 -/- mice had lower levels of lymphatic endothelial cell gene markers including vascular endothelial growth factor receptor 3 (VEGFR3) and lymphatic vascular growth factor VEGF-C than HFD-fed WT mice. The concentration of an absorbed lipid tracer in HFD-fed RAMP1 -/- mice was higher than that in HFD-fed WT mice. The zipper-like continuous junctions were predominant in HFD-fed WT mice, while the button-like discontinuous junctions were predominant in HFD-fed RAMP1 -/- mice., Conclusion: Deletion of RAMP1 signaling suppressed lacteal growth and VEGF-C/VEGFR3 expression but accelerated the uptake and transport of dietary fats through discontinuous junctions of lacteals, leading to excessive obesity. Specific activation of RAMP1 signaling may represent a target for the therapeutic management of diet-induced obesity., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objectives: The aim of this article is to evaluate the effectiveness and safety of rituximab (RTX) for microscopic polyangiitis and granulomatosis with polyangiitis in Japan., Methods: In this prospective observational study, all patients with microscopic polyangiitis and granulomatosis with polyangiitis administered RTX were enrolled at each institution. During the observation period of 2 years, data up to 6 months were analysed. Cox proportional hazards analysis was used to assess the factors associated with an outcome., Results: Of the 75 patients who received RTX for remission induction therapy, 53 achieved remission by the sixth month and 50 were in remission at the sixth month. During therapy, 38 serious adverse events were observed in 24 patients, 21 serious infections in 16 patients, and 9 patients died. No factors were associated with remission; however, there was a significant difference between patients with and without remission in serious adverse events (22.6% vs. 54.5%), serious infections (11.3% vs. 45.4%), and death (1.9% vs. 36.4%). The hazard ratio (95% confidence interval) for serious infection was 3.49 (1.29-9.74) for patients aged ≥ 75 years and 3.53 (1.31-9.53) for pulmonary complications. Four patients maintained remission for 6 months., Conclusions: The effectiveness and safety of RTX for microscopic polyangiitis and granulomatosis with polyangiitis for up to 6 months was demonstrated., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)