Effect of reduced bronchial circulation on lung fluid flux after smoke inhalation in sheep

We determined the effect of reduced bronchialblood flow on lung fluid flux through changes in lung lymph flow, lungwet weight-to-dry weight (wet/dry) ratios, and pulmonary microvascularreflection coefficient (). In the first of two surgical procedures,Merino ewes (n = 21) were surgicallyprepared for chronic study. Five to seven days later, in a secondoperation, the bronchial artery of the injection group(n = 7) was ligated, and 4 ml of 70%ethanol were injected into the bronchial artery to cause sclerosis of the airway circulation. In the ligation group(n = 7), only the bronchial artery wasligated. In the sham group (n = 7),the bronchial artery was surgically exposed but left intact withoutligation or ethanol injection. One day after these operations theanimals received a tracheotomy and 48 breaths of cotton smoke. Thevalue of  was determined at two points: 24 h before the secondsurgical procedure and 24 h after smoke inhalation. Lung lymph flow,blood-gas parameters, and hemodynamic data were measured every 4 hafter injury. At the end of investigation, samples of lung were taken for determination of blood-free wet/dry ratio. In the sham group, inhalation injury induced a gradual increase in pulmonary vascular resistance and lung lymph flow, which was associated with deterioration of oxygenation. Reduction of the bronchial blood flow attenuated thesepathophysiological changes, and the degree of this attenuation wasgreater in the injection group than in the ligation group. The value of was significantly higher after smoke inhalation in the injectiongroup compared with the sham group (0.77 ± 0.04 vs. 0.61 ± 0.03, means ± SE) at 24 h. The mean wet/dry ratio value of theinjection group animals was 30% less than that of the sham group. Ourdata show that the bronchial circulation contributes to edema formationin the lung occurring after acute lung injury with smoke inhalation.

     

A Multicenter,Randomized, Double-Blind,Placebo-Controlled Trial of High-Dose Rebamipide Treatment for Low-Dose Aspirin-Induced Moderate-to-Severe Small Intestinal Damage

Background

Low-dose aspirin (LDA) frequently causes small bowel injury. While some drugs have been reported to be effective in treating LDA-induced small intestinal damage, most studies did not exclude patients with mild damage thought to be clinically insignificant.

Aim

We conducted a multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy of a high dose of rebamipide, a gastroprotective drug, for LDA-induced moderate-to-severe enteropathy.

Methods

We enrolled patients who received 100 mg of enteric-coated aspirin daily for more than 3 months and were found to have more than 3 mucosal breaks (i.e., erosions or ulcers) in the small intestine by capsule endoscopy. Eligible patients were assigned to receive either rebamipide 300 mg (triple dose) 3 times daily or placebo for 8 weeks in a 2:1 ratio. Capsule endoscopy was then repeated. The primary endpoint was the change in the number of mucosal breaks from baseline to 8 weeks. Secondary endpoints included the complete healing of mucosal breaks at 8 weeks and the change in Lewis score (an endoscopic score assessing damage severity) from baseline to 8 weeks.

Results

The study was completed by 38 patients (rebamipide group: n = 25, placebo group: n = 13). After 8 weeks of treatment, rebamipide, but not placebo, significantly decreased the number of mucosal breaks (p = 0.046). While the difference was not significant (p = 0.13), the rate of complete mucosal break healing in the rebamipide group (32%, 8 of 25) tended to be higher than that in the placebo group (7.7%, 1 of 13). Rebamipide treatment significantly improved intestinal damage severity as assessed by the Lewis score (p = 0.02), whereas placebo did not. The triple dose of rebamipide was well tolerated.

Conclusions

High-dose rebamipide is effective for the treatment of LDA-induced moderate-to-severe enteropathy.

Trial Registration

UMIN Clinical Trials Registry UMIN000003463     

Efficient generation of genome-modified mice via offset-nicking by CRISPR/Cas system

The mammalian zygote-mediated CRISPR/Cas system can efficiently generate targeted genome-modified animals. However, this system is limited by the risk of off-target mutations. Here we show that offset-nicking by Cas9 nickase and paired gRNAs allows us to generate region deleted mice and targeted knock-in mice without off-target mutations.     

Discoidin domain receptor 2 (DDR2) is required for maintenance of spermatogenesis in male mice

Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase (RTK). We recently identified homozygous smallie mutant mice (BKS.HRS. Ddr2^slie/slie/J, Ddr2^slie/slie mutants), which lack a functional DDR2. Ddr2^slie/slie mutant mice are dwarfed and infertile due to peripheral dysregulation of the endocrine system. To understand the role of DDR2 signaling in spermatogenesis, we studied the expression of several receptors, enzymes, and proteins related to spermatogenesis in wild‐type and Ddr2^slie/slie mutant mice at 10 weeks and 5 months of age. DDR2 were expressed in adult wild‐type male mice in Leydig cells. The number of differentiated spermatozoa in the seminal fluid was significantly lower in the Ddr2^slie/slie mutant mice than in the wild‐type mice. The number of TUNEL‐positive cells was significantly greater in 5‐month‐old Ddr2^slie/slie mutants. Testosterone was significantly reduced at 5 months of age, but LH was similar in both types of mice at both 10 weeks and 5 months of age. The expression levels of LH receptors (Lhcgr), StAR, P450scc, and Hsd3β6 were not significantly different between the two types of mice at 10 weeks of age, but they were significantly reduced in 5‐month‐old Ddr2^slie/slie mutants compared to wild‐type mice of the same age. DDR2 was expressed in the Leydig cells of adult wild‐type male mice. In conclusion, our results indicated that DDR2 signaling plays a critical role in the maintenance of male spermatogenesis. Mol. Reprod. Dev. 77: 29–37, 2010. © 2009 Wiley‐Liss, Inc.     

A novel factor FLOURY ENDOSPERM2 is involved in regulation of rice grain size and starch quality

Rice (Oryza sativa) endosperm accumulates a massive amount of storage starch and storage proteins during seed development. However, little is known about the regulatory system involved in the production of storage substances. The rice flo2 mutation resulted in reduced grain size and starch quality. Map-based cloning identified FLOURY ENDOSPERM2 (FLO2), a member of a novel gene family conserved in plants, as the gene responsible for the rice flo2 mutation. FLO2 harbors a tetratricopeptide repeat motif, considered to mediate a protein-protein interactions. FLO2 was abundantly expressed in developing seeds coincident with production of storage starch and protein, as well as in leaves, while abundant expression of its homologs was observed only in leaves. The flo2 mutation decreased expression of genes involved in production of storage starch and storage proteins in the endosperm. Differences between cultivars in their responsiveness of FLO2 expression during high-temperature stress indicated that FLO2 may be involved in heat tolerance during seed development. Overexpression of FLO2 enlarged the size of grains significantly. These results suggest that FLO2 plays a pivotal regulatory role in rice grain size and starch quality by affecting storage substance accumulation in the endosperm.     

Serum interleukin-6 and C-reactive protein are markedly elevated in acute decompensated heart failure patients with left ventricular systolic dysfunction

Cytokines play important roles in heart failure (HF). We examined whether cytokine levels are different in acute decompensated heart failure (ADHF) patients between with left ventricular systolic dysfunction (LVSDF) and with preserved LV ejection function (PLVEF). We studied 81 HF patients who were admitted to our hospital with acute decompensation. They were divided into two groups: LVSDF (LVEF) < 45% and PLVEF (LVEF ? 45%). Serum interleukin-6 (IL-6), highly sensitive C-reactive protein (hsCRP), tumor necrosis factor alpha (TNF-α), and IL-18 and plasma brain natriuretic peptide (BNP) were measured on admission and at discharge. On admission, IL-6 and hsCRP were higher in LVSDF than in PLVEF. IL-6 and hsCRP decreased after treatment in LVSDF, but not in PLVEF, while plasma BNP levels decreased in both HF with treatment. There was no difference in TNF-α or in IL-18 level between LVSDF and PLVEF, and they did not change after treatment in either group. In conclusion, cytokine profiles were different in ADHF between those with LVSDF and PLVEF. Activation of IL-6–hsCRP pathway may play a specific role in ADHF with LVSDF.     

First Report of AG-A of Binucleate Rhizoctonia in China, Pathogenic to Soya Bean, Pea, Snap Bean and Pak Choy

Twenty binucleate Rhizoctonia (BNR) isolates were collected from roots of soya bean, pea, snap bean and pak choy with root rot symptoms in Yunnan Province, China. Chinese isolates anastomosed with the tester isolate of anastomosis group‐A (AG‐A; C‐517) with a high C2 fusion rate (>70%). Chinese isolates were pathogenic to soya bean, pea, snap bean and pak choy and had 97% similarity sequence of 5.8S rDNA‐internal transcribed spacer with AG‐A tester isolates SN‐2 and C‐662. When compared with other groups, AG‐Ba and AG‐Bb, Chinese isolates showed 77% sequence similarity. These results show that Chinese isolates belong to AG‐A of BNR. Growth rate, hyphal diameter, cultural characteristics and pathogenicity of the Chinese isolates differed significantly from the tester isolate of AG‐A. This is the first report on AG‐A in China.     

Chelating Compound,Chrysoidine, Is More Effective in Both Antiprion Activity and Brain Endothelial Permeability Than Quinacrine

1. As an extension of our previous study of quinacrine and its derivatives, chelating chemicals were screened to obtain more effective, better brain-permeable antiprion compounds using either prion-infected neuroblastoma cells or brain capillary endothelial cells. 2. Eleven chemicals were found to have antiprion activity. Most of them shared a common structure consisting of benzene or naphthalene at either end of an azo bond. Structure–activity data suggest that chelating activity is not necessary but might contribute to the antiprion action. 3. Chrysoidine, a representative compound found here, was about 27 times more effective in the antiprion activity and five times more efficiently permeable through the brain capillary endothelial cells than quinacrine was. 4. These chemicals might be useful as compounds for development of therapeutics for prion diseases.     

An Inhibitory Role of Nitric Oxide in the Dynamic Regulation of the Blood-Brain Barrier Function

1. The present study aimed at elucidating the effect of nitric oxide (NO) on blood-brain barrier (BBB) function with mouse brain capillary endothelial (MBEC4) cells. 2. Histamine (20–100 μM) evoked NO production (1.6–7 μM) in MBEC4 cells in a dose-dependent manner. 3. The permeability coefficient of sodium fluorescein for MBEC4 cells and the cellular accumulation of rhodamine 123 in MBEC4 cells were increased dose-dependently by the addition of NO solutions (14 and 28 μM) every 10 min during a 30-min period. 4. The present study demonstrated that NO increased the permeability and inhibited the P-glycoprotein efflux pump of brain capillary endothelial cells, suggesting that NO plays an inhibitory role in the dynamic regulation of the BBB function.