Efficacy of renin-angiotensin-aldosterone system blockades for acute phase hypertensive emergencies in patient complicating severe acute kidney injury.

Renin-angiotensin-aldosterone system (RAAS) is primarily involved with pathological mechanism of developing hypertensive emergencies. However, none of clinical practice guidelines mention RAAS blockers for the treatment of hypertensive emergencies. A 44 year-old woman presented with severe hypertension, brain stem posterior reversible encephalopathy syndrome and severe acute kidney injury (AKI). We started anti-hypertensive therapy with continuous intravenous nitroglycerin and oral calcium channel blocker (CCB) and spironolactone. Since severe AKI persisted despite this therapy, we administered losartan potassium, which resulted in improvement in her blood pressure and creatinine. Clinical course of our patient suggests that timely initiation of ARB and spironolactone for hypertensive emergencies could be beneficial in terms of blood pressure control and for protection of target organs from this condition.

Development of acute kidney injury with massive granular casts and microscopic hematuria in patients with COVID-19: two case presentations with literature review.

BACKGROUND: Complications of acute kidney injury (AKI) are common in patients with coronavirus disease in 2019 (COVID-19). However, clinical characteristics of COVID-19-associated AKI are poorly described. We present two cases of severe COVID-19 patients with AKI. CASE PRESENTATION: A 77-year-old woman was suspected of having vancomycin-associated AKI, and a 45-year-old man was suspected of having heme pigment-induced AKI caused by rhabdomyolysis. The granular cast, which is known to be a valuable diagnostic tool for confirming the diagnosis of acute tubular necrosis, was detected in both patients at the onset of AKI. Interestingly, both patients also developed microscopic hematuria at the occurrence of AKI, and one patient had elevated d-dimer and low platelet levels simultaneously. CONCLUSIONS: Some reports suggested that COVID-19-associated microangiopathy contributed to the kidney damage. Therefore, it is possible that our patients might have accompanied renal microangiopathy, and that this pathological background may have caused exaggerated tubular damage by vancomycin or heme pigment. The etiology of AKI in patients with COVID-19 is multifactorial. Superimposition of nephrotoxin(s) and virus-associate intra-renal microangiopathy may be a crucial trigger of kidney injury leading to severe AKI in COVID-19 patients. Therefore, in COVID-19 patients, risk factors for AKI should be taken into consideration to prevent its progression into severe AKI.

PI3K p85α Subunit-deficient Macrophages Protect Mice from Acute Colitis due to the Enhancement of IL-10 Production.

We investigated the role of the PI3K p85α subunit in the development of acute colitis with a focus on intestinal macrophages. Experimental acute colitis was induced using 3% dextran sulfate sodium (DSS) in drinking water for 7 days. The severity of DSS-induced acute colitis was significantly attenuated in p85α hetero-deficient (p85α+/-) mice compared with WT mice. The expression of proinflammatory mediators in intestinal macrophages isolated from the inflamed colonic mucosa was significantly suppressed in p85α+/- colitis mice compared with WT colitis mice. Interestingly, we found that bone marrow-derived macrophages (BMDMs) from p85α+/- mice produced a significantly higher amount of IL-10 than BMDMs from WT mice. The adoptive transfer of p85α+/- BMDMs, but not WT BMDMs, significantly improved the severity in WT colitis mice, and this effect was reversed by anti-IL-10 antibody. Furthermore, the expression of IL-10 in the intestinal macrophages of p85α+/- normal colonic mucosa was significantly higher than that in the intestinal macrophages of WT normal colonic mucosa. The present results demonstrate that p85α+/- mice exhibit a reduced susceptibility to DSS-induced acute colitis. Our study suggests that a deficiency of PI3K p85α enhances the production of IL-10 in intestinal macrophages, thereby suppressing the development of DSS-induced acute colitis.

Nicotine suppresses acute colitis and colonic tumorigenesis associated with chronic colitis in mice.

Ulcerative colitis is a chronic inflammatory disease that frequently progresses to colon cancer. The tumor-promoting effect of inflammation is now widely recognized and understood. Recent studies have revealed that treatment with nicotine ameliorates colitis in humans and experimental murine models, whereas the effect of nicotine on colitis-associated colonic tumorigenesis remains unclear. In the present study, we examined the effect of nicotine on the development of acute colitis and colitis-associated cancer (CAC). The acute colitis model was induced by treatment with 3% dextran sulfate sodium (DSS) for 7 days, whereas the CAC model was induced by a combination of azoxymethane and repeated DSS treatment. Nicotine and a selective agonist of the α7-nicotinic acetylcholine receptor (α7-nAChR) reduced the severity of DSS-induced acute colonic inflammation. In addition, the suppressive effect of nicotine on acute colitis was attenuated by an antagonist of α7-nAChR. Furthermore, nicotine inhibited the IL-6 production of CD4 T cells in the DSS-induced inflamed colonic mucosa. We found that nicotine significantly reduced the number and size of colonic tumors in mice with CAC. Nicotine markedly inhibited the elevation of TNF-α and IL-6 mRNA as well as phosphorylated signal transducer and activator of transcription (Stat) 3 expression in the colons of the tumor model mice. These results demonstrate that nicotine suppresses acute colitis and colitis-associated tumorigenesis, and this effect may be associated with the activation of α7-nAChR. Furthermore, it is presumed that nicotine downregulates the expression of inflammatory mediators such as IL-6/Stat3 and TNF-α, thereby reducing the colonic tumorigenesis associated with chronic colitis.

CGRP, a neurotransmitter of enteric sensory neurons, contributes to the development of food allergy due to the augmentation of microtubule reorganization in mucosal mast cells.

Neuro-immune interaction in the gut is substantially involved in the maintenance of intestinal immune homeostasis and the pathology of intestinal immune diseases. We have previously demonstrated that mucosal mast cells and nerve fibers containing CGRP, a neurotransmitter of intrinsic enteric sensory neurons, are markedly increased and exist in close proximity to each other in the colon of food allergy (FA) mice. In the present study, a CGRP-receptor antagonist BIBN4096BS significantly alleviated allergic symptoms in the murine FA model. In addition, the elevated numbers of mucosal mast cells in the proximal colon of FA mice were significantly decreased in that of BIBN4096BS-treated FA mice. Thus, we investigated the effects of CGRP on calcium-independent process in degranulation of mucosal mast cells since CGRP increases intracellular cAMP levels, but not Ca(2+) concentration. CGRP did not alter a calcium ionophore A23187-increased cytosolic Ca(2+) concentration in mucosal-type bone marrow-derived mast cells (mBMMCs), but did augment microtubule reorganization in resting and A23187-activated mBMMCs. Furthermore, CGRP alone failed to cause the degranulation of mBMMCs, but CGRP significantly enhanced the degranulation of mBMMCs induced by A23187. Together, these data indicate that CGRP- enhanced microtubule reorganization augments IgE-independent/non-antigenic stimuli-induced mucosal mast cell degranulation, thereby contributing to the development of FA.

The impact of hepatic denervation on the accumulation of hepatic progenitor cells during liver regeneration in rats.

BACKGROUND/AIMS: All autonomic hepatic nerves are transected following liver transplantation. Recent studies have shown the relationship between an inhibition of autonomic nerves and the accumulation of hepatic progenitor cells (HPC). This study aims to elucidate the influence of hepatic denervation on the accumulation of HPC in the process of liver regeneration. METHODOLOGY: Male Sprague-Dawley rats underwent hepatic denervation. Immediately after either denervation (DN group, n=30) or a sham operation (control group, n=30), a two-thirds hepatectomy was performed, and these were sacrificed chronologically. An immunohistochemical analysis of HPC was performed with a mouse monoclonal OV6 type antibody. RESULTS: The liver per body weight ratio gradually increased in both groups. On postoperative day (POD) 7, the DN group showed a significantly higher ratio. The HPC expression gradually increased in both groups. The maximal HPC number was observed on POD 7 in the DN group and on POD 3 in the control group. Although there was no significant difference in the HPC numbers between the DN and control group until POD 3, the number of HPC were significantly higher in livers of the denervated rats than in those of the sham operated rats between POD 5 and 14. CONCLUSIONS: The hepatic autonomic nerves were thus suggested to play an important role in the accumulation of HPC during liver regeneration in rats.

Low-dose recombinant human hepatocyte growth factor enhances effect of hepatocyte transplantation in rats treated with retrorsine.

BACKGROUND/AIMS: The aim of this study was to regenerate transplanted hepatocytes selectively in a recipient using retrorsine and recombinant human hepatocyte growth factor (rhHGF). METHODOLOGY: Nagase analbuminemic rats (NARs) received pretreatment with retrosine and were divided into three experimental groups. Group1: Hepatocyte transplantation (HcTx) + 50 microg/kg/day rhHGF. Group2: HcTx + 250 microg/kg/day rhHGF. Group3: HcTx + normal saline. The serum levels of albumin and the albumin-positive hepatocytes in the liver were investigated. The rat endogenous HGF of the rats given only retrorsine was measured. RESULTS: The serum albumin levels of Group11 were higher than those of Group2, while there was no significant difference between Group2 and GroupS. Histological examination of Group1 and 3 showed the presence of a large number of albumin-positive hepatocytes, which frequently consisted of large clusters and occupied 53.90 +/- 2.31% and 31.25 +/- 5.36% of host liver, respectively. The liver sections of Group2 showed numerous albumin-positive hepatocyte, which were not seen as clusters. The rat endogenous HGF concentration was extremely high. CONCLUSION: Low-dose rhHGF enhances the effect of HcTx under the suppressive state of proliferation of host hepatocytes. Because of the high endogenous HGF, the administration of a high concentration of rhHGF suppressed the regenerative activity of the transplanted hepatocytes.

Torsion of the gallbladder in a 3-year-old infant.

A 3-year-old girl was admitted to hospital with complaints of severe upper abdominal pain and vomiting. On admission, a board-like rigidity in the right hypochondrium was noted, along with a high white blood cell count and a high C-reactive protein value. Abdominal ultrasonography (US) revealed a left-sided enlarged gallbladder with a thickened wall, without gallstones. Contrast-enhanced computed tomography (CT) demonstrated an enlarged gallbladder without enhancement effects and a cystic duct located on the right side of the gallbladder. The patient underwent an emergency operation following a diagnosis of torsion of the gallbladder. The gallbladder appeared gangrenous, and 180 degrees clockwise torsion was found at the neck of the gallbladder. The gallbladder was straightened and then removed without difficulty because there was only slight inflammation around Calot's triangle and the gallbladder was not fixed to the liver. Histopathological examination revealed an acute bleeding infarction of the gallbladder. The patient was discharged on the ninth day after surgery, without any complications. The present case suggested that abdominal US and contrast-enhanced CT examinations are helpful in making a correct diagnosis of torsion of the gallbladder even in an infant; in the event of this diagnosis, prompt cholecystectomy is necessary.

Effects of hypertonic stimuli and arginine vasotocin (AVT) on water absorption response in Japanese treefrog, Hyla japonica.

Anuran amphibians do not drink orally but absorb water osmotically through the highly permeable ventral skin. In this cutaneous water absorption, roles of the putative cerebral osmoreceptors and functions of arginine vasotocin (AVT) were examined in the central nervous system of the Japanese treefrog, Hyla japonica. Intracerebroventricular (ICV) or intralymphatic sac (ILS) administration of various hypertonic solutions (NaCl, mannitol and urea) significantly extended the residence time in water in a dose-dependent manner, suggesting facilitation of water absorption in frogs. ICV injection of AVT also increased significantly the residence time in a dose-dependent manner. The water absorption effect of AVT was significantly inhibited by pretreatment of ICV OPC-21268, a vasopressin V(1) receptor antagonist. But pre-ICV injection of OPC-31260, a vasopressin V(2) receptor antagonist, did not block the water absorption effect of AVT. Extension of the residence time induced by hyperosmotic NaCl (1000 mOsm) ICV injection was significantly inhibited by pretreatment of ICV OPC-21268. The present results showed that increases of osmotic pressure in plasma and/or cerebrospinal fluid stimulate water absorption response, suggesting that osmoreceptors are certainly present in the central nervous system and AVT may directly stimulate water absorption in the treefrog. It is also suggested that AVT activates cellular mechanisms via V(1)-like but not V(2)-like receptors in the central nervous system and facilitates water absorption response in the treefrog.

Giant cystic meconium peritonitis associated with a cloacal anomaly: case report.

This report describes a case of giant cystic meconium peritonitis (GCMP) associated with a cloacal anomaly. Antenatal ultrasonography and magnetic resonance imaging demonstrated persistent fetal ascites, bilateral hydronephrosis, and 3 pelvic cystic structures. The baby girl showed duplicated hydrocolpos and a single orifice of the cloaca with a long common channel inducing a urinary outflow obstruction. After constructing a diversion colostomy, a cutaneous vesicostomy was necessary to prevent recurrent urinary tract infections. These findings are consistent with a prenatal diagnosis of cloacal anomalies, thus suggesting an association with severe obstruction of lower urinary tract and meconium peritonitis. Most of reported cases of meconium peritonitis associated with the cloaca show fibroadhesive types with scattered intraperitoneal calcifications and adhesions. However, the present case showed a rare GCMP suggesting continuous urinary influx via the fallopian tubes until the later stage of intrauterine life.

Protective effects of a hibernation-inducer on hepatocyte injury induced by hypothermic preservation.

BACKGROUND/PURPOSE: For hepatocyte-based cell therapy to be realistic, the method chosen for cryopreservation or hypothermic preservation is critical. The aim of the present study was to clarify whether D-Ala2-Leu5-enkephalin (DADLE), a hibernation inducer, has protective effects on hepatocytes with regard to hypothermic preservation injury. METHODS: A suspension of rat hepatocytes was stored at 4 degrees C for 24 h with or without DADLE. Their viability was measured by the trypan blue dye exclusion method, and alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels in the preservation solution were measured. After 24 h of cold storage, viable hepatocytes were cultured at 37 degrees C for another 24 h. Then albumin production and lidocaine clearance were measured. RESULTS: DADLE significantly improved the survival rate of hepatocytes. The levels of ALT and LDH in the preservation solution with DADLE were significantly lower than those in the preservation solution without DADLE. The treated viable hepatocytes maintained both albumin synthesis and lidocaine clearance. CONCLUSIONS: DADLE appears to have protective effects on hepatocytes with regard to hypothermic preservation injury in vitro. This hibernation-inducer is useful in prolonged hypothermic preservation for hepatocyte-based therapy.

The effect of denervation on liver regeneration in partially hepatectomized rats.

BACKGROUND/AIM: In a partial liver transplantation, the dissected hepatic nerves are left unrepaired during active liver regeneration. In fact, the pathophysiological influence of such hepatic denervation on liver regeneration has not yet been fully clarified. The aim of the present study is to elucidate the effect of total hepatic denervation on liver regeneration. METHODS: Experiment 1: To confirm the effect of hepatic denervation, the hepatic contents of norepinephrine were measured in both denervated (n = 5) and sham (n = 5) rats. The changes in the hepatic microcirculation were also measured in both denervated (n = 5) and sham (n = 5) rats. Experiment 2: The rats (n = 80) were randomly assigned to two groups: DN group (n = 40); hepatic denervation followed by a partial hepatectomy (PH). Control group (n = 40); sham hepatic denervation followed by PH. In both groups, the animals were killed at 12, 24, 36, 48, 72, 120, and 168 h after PH, respectively. The liver to body weight ratio and the proliferating cell nuclear antigen (PCNA) labeling index were measured at each time point. RESULTS: Experiment 1: Nearly a total depletion of norepinephrine (<99%) was observed in the DN rats. In addition, the hepatic tissue blood flow significantly increased in the DN rats. Experiment 2: The liver to body weight ratio of the DN group was also significantly higher than that of the control group at 168 h (P < 0.05). The PCNA labeling index peaked between 24 and 36 h in the control group, while that in the DN group showed a delayed peak. At 72 and 120 h, the PCNA labeling index was significantly higher in the DN group than in the control group (P < 0.05). CONCLUSION: Total hepatic denervation was thus found to enhance liver regeneration after a partial hepatectomy. This phenomenon is partially triggered by the increased hepatic blood flow to the remnant liver.

Asymmetric transfer hydrogenation of alpha-aminoalkyl alpha'-chloromethyl ketones with chiral Rh complexes.

Asymmetric transfer hydrogenation of N-substituted (3S)-3-amino-1-chloro-4-phenyl-2-butanones in the presence of CpRhCl[(R,R)-Tsdpen] (S/C = 1000) with a mixture of formic acid/triethylamine gave N-substituted (2R,3S)-3-amino-1-chloro-2-hydroxy-4-phenylbutanes with up to 93% de in a quantitative yield, and reduction with the enantiomeric catalyst CpRhCl[(S,S)-Tsdpen] gave (2S,3S)-diastereomeric alcohol with up to 96% de.

Z-shaped anastomosis for the treatment of a benign rectosigmoid stricture.

A girl with malrotation underwent a Ladd's operation at 35 days of age and later had an adhesiotomy at 115 days of age. After the adhesiotomy, she suffered from sepsis and subsequent disseminated intravascular coagulation (DIC). At 178 days of age, she developed an intestinal obstruction because of a rectosigmoid stricture probably caused by DIC-associated ischemia. As a result, an ileostomy was performed. At one year, 4 months of age, she underwent a resection of the proximal part of the rectosigmoid stricture and a reconstruction by means of a Z-shaped anastomosis. Based on our experience, Z-shaped anastomosis appears to be an excellent treatment not only for Hirschsprung's disease but also for benign rectosigmoid stricture.

Practical synthesis of optically active styrene oxides via reductive transformation of 2-chloroacetophenones with chiral rhodium catalysts.

[reaction: see text] A practical method for the synthesis of optically active styrene oxides has been developed via formation of optically active 2-chloro-1-phenylethanols generated by reductive transformation of ring-substituted 2-chloroacetophenones. The optically active alcohols with up to 98% ee are obtainable from the asymmetric reduction of acetophenones with an S/C = 1000-5000 with a formic acid triethylamine mixture containing a well-defined chiral Rh complex, CpRhCl[(R,R)-Tsdpen].

P-chirogenic binaphthyl-substituted monophosphines: synthesis and use in enolate vinylation/arylation reactions.

[reaction: see text] New phosphine ligands possessing both axial chirality and a chirogenic phosphorus center were prepared from (R)-2-bromo-2'-N,N-(dimethylamino)-1,1'-binaphthyl (1) via a simple Li-halogen exchange protocol. The asymmetric vinylation of a ketone enolate with (R,R(P))-2-(tert-butylphenylphosphino)-2'-N,N-(dimethylamino)-1,1'-binaphthyl (2a) afforded the coupling product with good enantiomeric excess.

An improved catalyst for the asymmetric arylation of ketone enolates.

A new catalyst system for the enantioselective alpha-arylation of ketones is reported. This catalyst, prepared from Pd(2)(dba)(3) and a bulky dialkylphosphino-binaphthyl ligand, is able to effect the asymmetric arylation of ketone enolates with aryl bromides utilizing NaO(t)()Bu as base. These new catalysts enjoy much higher reactivity than previous systems; arylation reactions could be effected at room temperature with only 2 mol % of the Pd catalyst. The coupling of alpha-alkyl-alpha'-protected cyclopentanones proceeded in high yield, and the resulting quaternary stereogenic center was installed in up to 94% ee.