Neoadjuvant therapy has been gradually applied to the treatment of colorectal liver metastasis in recent years. Many clinic researches indicate neoadjuvent chemotherapy, neoadjuvent radiotherapy and neoadjuvent chemoradiotherapy can improve surgical reaction rate and radical rate of colorectal liver metastasis,and can shrink the primary tumor and metastasis, improve the resection rate and sphincter preservation rate, and reduce the recurrence rate of locally advanced lower rectal cancer. Neoadjuvent therapy has great clinical practical value in the multi-modality treatment for colorectal metastasis.

The paper is to report the pharmacokinetics of sulfamethoxazole in healthy Han volunteers living at plain (PH) and native Han and Tibetan healthy volunteers living at high altitude (HNH and HNT). After healthy volunteers were administrated orally cotrimoxazole tablets, plasma concentration of sulfamethoxazole and metabolite N4-acetylsulfamethoxazole was determined by RP-HPLC, and plasma concentration-time data were analyzed by DAS 2.0 software to get the related pharmacokinetic parameters. The main pharmacokinetic parameters t(1/2) of sulfamethoxazole in PH, HNH and HNT were, respectively, 9.30 +/- 1.11, 10.99 +/- 1.23 and 10.44 +/- 1.05 h; tmax were 1.4 +/- 0.3, 2.0 +/- 1.1 and 1.8 +/- 0.4 h; Cmax were 94.42 +/- 15.26, 89.33 +/- 7.67 and 87.43 +/- 11.61 micro x mL(-1); AUC(0-t) were 1202.5 +/- 238.3, 1 434.7 +/- 193.9 and 1302.8 +/- 103.0 microg x h x mL(-1); AUC(0-infinity) were 1240.7 +/- 255.3, 1511.5 +/- 211.9 and 1363.9 +/- 116.5 microg x h x mL(-1); CL were 1.01 +/- 0.22, 0.81 +/- 0.12 and 0.89 +/- 0.08 L x h(-1) x kg(-1); V were 13.27 +/- 1.73, 12.81 +/- 2.15 and 13.28 +/- 1.20 L x kg(-1). Sulfamethoxazole pharmacokinetic parameters of HNH and HNT were significantly different from that of PH. The t(1/2) was significantly higher and the CL was significantly lower in HNH and HNT than that in PH, and the AUC(0-infinity) was significantly lower in HNT compared with HNH. This study found significant changes in the disposition of sulfamethoxazole under the special environment of high altitude hypoxia. This finding may provide some references for clinical rational application of sulfamethoxazole in HNH and HNT.

OBJECTIVE:To study the effects of Tibetan medicine Zuotai on the activities of cytochrome oxidase (CYP1A2) and drug metabolism enzyme N-acetyltransferase 2(NAT2)in rats. METHODS:70 SD rats were equally randomized into a normal control (normal saline) group,the groups of single administration of low,middle and high-dose (1.2,3.8 and 12 mg/kg) Zuotai and the groups of multiple administrations thereof(once daily for 12 consecutive days). The rats were given drugs ig. caffeine(25 mg/kg)was given ig to the rats in the normal control group and the groups of single administration on the 2nd day,and to those in the groups of multiple administrations on the 13th day. 5 h later,their urine was collected and added with vitamin C based on 10 mg/ml. High performance liquid chromatography (HPLC) was adopted to determine the cafeine metabolites contents of 5-acetami-do-6-formamido-3-methyl-uric acid(AFMU),1-methylxanthine(1X),1-methyl-uric acid(1U)and 1,7-dimethyl uric acid(17U) in rats’urine,and the activities of CYP1A2 and NAT2 were reflected through (AFMU+1X+1U)/17U and AFMU/(AFMU+1X+1U). RESULTS:Compared with normal control group,the(AFMU+1X+1U)/17U and AFMU/(AFMU+1X+1U)in rats were de-creased,namely the activities of CYP1A2 and NAT2 were lower in the groups of single administration of middle-dose Zuotai and multiple administrations of middle and high-dose Zuotai than in the normal control group. There was statistical difference (P<0.05). CONCLUSIONS:Zuotai can obviously inhibit the activities of CYP1A2 and NAT2 in rats.

Objective To investigate the expression of phosphatase and tensin homolog gene (PTEN) and 1-phosphatidylinositol 3-kinase (PI3K) in rectal cancer and its correlation with clinical pathology.Methods MaxVisionTM immunohistochemical method was used to detect the expressions of PTEN and PI3K in 60 rectal cancer tissues,30 adenoma tissues and 10 normal rectal tissues,and the correlation between the expression levels and its clinicopathologic characteristics was discussed.Results The positive expression rate of PTEN in rectal cancer tissue was significantly lower than that in normal rectal tissue and adenoma tissue [43.3％ (26/60) vs.100.0％ (10/10),93.3％ (28/30),P ＜ 0.05].The positive expression rate of PI3K in rectal cancer tissue was significantly higher than that in normal rectal tissue and adenoma tissue [75.0％ (45/60) vs.30.0％ (3/10),33.3％ (10/30),P ＜ 0.05].The positive expression of PTEN and PI3K were correlated with carcinoembryonic antigen,degree of cell differentiation,TNM stage,lymph node metastasis and distant metastasis(P＜ 0.01 or ＜ 0.05 ),but had no correlation with age,gender,neoplasm location,neoplasm appearance (P ＞ 0.05).The correlated analysis showed that the positive expression of PTEN had negative correlation with PI3K (r =-0.269,P =0.023 ).Conclusions The high expression of PI3K and down regulation of PTEN in rectal cancer are closely related to its invasion and metastasis.There are some values to monitor PTEN and PI3K expression for determining biological behavior of rectal cancer.

This study is to investigate the effect of high altitude hypoxia on the activity and protein expression of CYP2C9 and CYP2C19. Rats from plain (P) and rats with acute middle altitude hypoxia (AMH), chronic middle altitude hypoxia (CMH), acute high altitude hypoxia (AHH) and chronic high altitude hypoxia (CHH) were administered orally phenytoin sodium (PHT) and omeprazole (OMZ) to evaluate the activity of CYP2C9 and CYP2C19, separately. The serum concentrations of PHT and metabolite 4'-hydroxyphenytoin (HPPH) at 12 h after treatment and the serum concentrations of OMZ and metabolite 5-hydroxy omeprazole (5-OHOMZ) at 3 h after treatment were determined by RP-HPLC. The activity of CYP2C9 and CYP2C19 was evaluated by the ratio of HPPH to PHT and the ratio of 5-OHOMZ to OMZ, respectively. The protein expressions of CYP2C9 and CYP2C19 were determined by ELISA method. The activities of CYP2C9 (HPPH/PHT) in P, AMH, CMH, AHH and CHH were 0.67 +/- 0.31, 0.75 +/- 0.29, 0.76 +/- 0.23, 0.79 +/- 0.31 and 0.75 +/- 0.18, respectively, and the activities of CYP2C19 (5-OHOMZ/OMZ) in P, AMH, CMH, AHH and CHH were 0.17 +/- 0.06, 0.20 +/- 0.10, 0.11 +/- 0.05, 0.37 +/- 0.13 and 0.19 +/- 0.05, respectively. The protein expressions of CYP2C9 in P, AMH, CMH, AHH and CHH were 4.20 +/- 1.27, 3.95 +/- 0.81, 3.93 +/- 1.11, 4.32 +/- 1.03 and 4.12 +/- 0.86 ng x g(-1), respectively, and the protein expressions of CYP2C19 in P, AMH, CMH, AHH and CHH were 3.91 +/- 1.82, 3.63 +/- 2.07, 2.55 +/- 0.85, 4.78 +/- 2.37 and 3.51 +/- 1.03 ng x g(-1), respectively. The activities and protein expressions of CYP2C9 in AMH, CMH, AHH and CHH were not significantly different with those of P. The protein expressions of CYP2C19 in AMH, CMH, AHH and CHH were not significantly different with those of P, but the activity of CYP2C19 in AHH was significantly higher than that of P. This study found significant changes in the activity of CYP2C19 under the special environment of acute high altitude hypoxia.

Objective To explore the feasibility and effectiveness of interventional transcatheter destruction of the aortic valve to establish an animal model with acute aortic valve regurgitation. Methods Eight healthy goats were used for this study. A limited sternotomy approach was used to access the apex of the heart. Puncturing of the apex of the heart was performed to establish a wire track, then, under fluoroscopic guidance a 10 F sheath was inserted along this track of hard wire until to the ascending aorta above the aortic valve. The internal sheath was removed. Via the 10 F sheath a 10 mm occluder of ventricular septal defect (VSD) was introduced into the ascending aorta above the aortic valve. The sheath was pulled back to the left ventricle, while the occluder remained in the ascending aorta above the aortic valve. Then the occluder was quickly pulled back into the left ventricle in order to make some certain damage to the aortic valve. And an acute aortic valve regurgitation model was thus established. Angiography of ascending aorta above the aortic Among the 8 animals, two died of acute left ventricular failure on the spot due to excessive regurgitation blood flow after the operation. Macroscopically, damage of the aortic valve was seen. In the six survivors, angiography of ascending aorta above the aortic valve and Doppler echocardiography showed that moderate degree of regurgitation was detected in 5 and small amount of regurgitation in one. Two experimental goats with moderate degree of regurgitation died of heart failure separately at seven days and fifteen days after the operation. The remaining four experimental goats survived for more than three months. Follow- up checkups with echocardiography suggested the presence of mild- moderate degree of regurgitation. Conclusion Acute aortic valve regurgitation model in experimental goats can be established through transapical transcatheter damage of aortic valve by quickly pulling back a VSD occluder which has been placed in the ascending aorta above the aortic valve. This method is clinically feasible, technically simple and repeatable, the result is reliable, and the degree of regurgitation is controllable.

To study the effect of Tibetan medicine Zuotai on the activity, protein and mRNA expression of CYP1A2 and NAT2, three different doses (1.2, 3.8 and 12 mg x kg(-1)) of Zuotai were administrated orally to rats once a day or once daily for twelve days, separately. Rats were administrated orally caffeine (CF) on the second day after Zuotai administration, and the urine concentration of CF metabolite 5-acetylamino-6-formylamino-3-methyl-uracil (AFMU), 1-methyluric acid (1U), 1-methylxanthine (1X), 1, 7-dimethylxanthine (17U) at 5 h after study drug administration was determined by RP-HPLC. The activity of CYP1A2 and NAT2 was evaluated by the ratio of metabolites (AFMU+1X+1U)/17U and the ratio of AFMU/(AFMU+1X+1U), respectively. The protein and mRNA expression of CYP1A2 and NAT2 were determined by ELISA and RT-PCR method, respectively. After single administration of Zuotai 3.8 mg x kg(-1) and repeated administration of Zuotai 3.8 and 12 mg x kg(-1), the activity of CYP1A2 and NAT2 decreased significantly compared with control group and there was no significant difference between other dose group and control group. The protein expression of CYP1A2 was significant lower than that in control group after repeated administration of Zuotai 12 mg x kg(-1), and the mRNA expression of CYP1A2 decreased significantly compared with that of control group after single administration of Zuotai 3.8 mg x kg(-1) and repeated admistration of Zuotai 12 mg x kg(-1), separately. The protein expression of NAT2 decreased significantly compared with that of control group after single and repeated administration of Zuotai 3.8 mg x kg(-1), respectively, and the mRNA expression of CYP1A2 decreased significantly compared with control group after single administration of Zuotai 3.8 mg x kg(-1). This study found that Tibetan medicine Zuotai had significant effect on the activity, protein and mRNA expression of CYP1A2 and NAT2.

OBJECTIVETo determine the effects of ginsenosides Rb1(GSRb1) on learning and memory and expression of somatostatin (SS) in the hippocampus and the frontal cortex in rat model of sleep deprivation (SD).

METHODSRats were randomized into groups of SD 2 d, SD 4 d, SD 6 d, and SD 0 d, while each group was sub-divided into GSRb1 group and normal saline (NS) sub-groups. Rats were intraperitoneal administered with 30 mg/(kg*d) of GSRb1 or NS for 7 d, then the learning and memory abilities were examined by measuring average swimming speed and mean escape latency using Morris maze.Expression of somatostatin was detected with immunohistochemical method and image analysis in the hippocampus and the frontal cortex.

RESULTSCompared with SD 0 d rats, SD rats exhibited significant decrease in the average swimming speed and increase in the escape latency (P <0.01). The expression of somatostatin in the hippocampus was decreased significantly in SD 2 d, SD 4 d and SD 6 d rats (P<0.05). However, decrease was only observed in SD 4 d and SD 6 d rats in the frontal cortex (P <0.05). Parallel comparison between NS control and GSRb1 treated rats demonstrated that rats treated with GSRb1 in each subgroup exhibited faster swimming speed and shorter escape latency (P <0.05). Meanwhile, the expression of somatostatin was increased in SD 2 d, SD 4 d and SD 6 d rats in the hippocampus and in SD 4 d and SD 6 d rats in the frontal cortex (P <0.05), respectively.

CONCLUSIONGSRb1 enhances the expression of somatostatin in sleep deprivation rats and subsequently may improve learning and memory abilities of rats.

Animals ; Brain ; metabolism ; Disease Models, Animal ; Ginsenosides ; pharmacology ; Learning ; drug effects ; Male ; Memory ; drug effects ; Rats ; Rats, Sprague-Dawley ; Sleep Deprivation ; metabolism ; Somatostatin ; metabolism

AIM:We investigated how AT 1-R stimulated by mechanical stresses induces cardiac fibrosis .METHODS:We produced in vivo cardiac pressure overload model in angiotensinogen knockout ( ATG-/-) mice and in vitro mechanically-stretched cell model in cultured neonatal cardiac cells of ATG-/-mice both lack the participation of Ang II .RESULTS: Pressure overload for 4 weeks in ATG-/-mice induced myocardial hypertrophy accompanied by the significant interstitial fibrosis , however , the TGF-β, a key regulatory factor of fibrosis, was not significantly increased in these ATG-/-mice.Meanwhile, the inhibitor for AT1-R significantly inhibited mechani-cal stress-induced cardiac fibrosis in these ATG-/-models whereas inhibition of TGF-βdid not.CONCLUSION:The results showed that mechanical stress-induced fibrotic responses through AT 1-R required the phosphorylation of Smad 2 but not the involvement of TGF-β.