Altered controls of proliferation in proximal small intestine of the senescent rat.

The proximal small intestine responds to starvation by rapidly reducing crypt cell proliferation rate and villus cellularity and to resumption of food intake (refeeding) by abruptly increasing proliferation and the number of villus epithelial cells. We show that villus cellularity responds to starvation and refeeding similarly in young and aging animals. However, as compared to young animals, senescent rats showed increased basal DNA synthetic activity, starvation resulted in a smaller decrease in DNA labeling of crypt cells, and refeeding produced an abrupt broadening of the proliferative zone in older animals without concomitant increased numbers of villus cells. Such altered crypt proliferative responses resemble precancerous changes seen in the colon and the aberrant proliferation found in both small and large intestine after administration of the carcinogen dimethylhydrazine.     

Preoperative staging of gastric cancer by endoscopic ultrasound: the prognostic usefulness of ascites detected by endoscopic ultrasound

BACKGROUND: Endoscopic ultrasound (EUS) is the standard modality in local preoperative staging of gastric cancers and is reputedly able to detect ascites. However, the association between ascites detected by EUS and local tumor staging, peritoneal carcinomatosis, or survival after surgery is not well documented. GOALS: To assess the accuracy, sensitivity, and specificity of EUS in the preoperative staging and detection of ascites in gastric cancers. We also try to correlate ascites with histologic staging, tumor differentiation, and survival rate of gastric carcinoma after surgery. STUDY: The retrospective analysis was made in 57 consecutive patients with histologically confirmed gastric adenocarcinomas that underwent EUS before surgery. The accuracy of EUS was compared with the final surgical-pathologic findings. We estimated the prognostic usefulness by analyzing the clinicopathologic features of gastric adenocarcinomas and following up their survival rates. RESULTS: The overall T staging was 88% accurate by EUS. The accuracy for T staging was as follows: T1, 100%; T2, 33%; T3, 93%; and T4, 100%. About 50% of T2 cases were overstaged. The overall accuracy, sensitivity, and specificity of detecting lymph node metastasis by EUS were 79%, 79%, and 80%, respectively. One of the seven T1 cancers had regional lymph node metastasis, and it was missed by EUS, although the T classification was precisely staged based on finding submucosal invasion. A total of 22 patients (39%) had ascites detected by EUS; both the sensitivity and specificity of EUS in demonstrating ascites were 100% in our study. Ascites was significantly correlated with the depth of tumor invasion ( = 0.036), lymph node metastasis ( = 0.008), and poor cellular differentiation ( = 0.007), but it was not significantly correlated with macroscopic peritoneal carcinomatosis. The survival rate after surgical treatment was poor in those with gastric cancers with lymph node metastasis, ascites, or poorly differentiated tumors ( < 0.05). However, multivariate analysis showed that lymph node metastasis was the only significant prognostic predictor ( = 0.004). CONCLUSIONS: Endoscopic ultrasound is a valuable diagnostic tool in the local staging of gastric cancers and demonstration of ascites. Although the surgical treatment of gastric cancers with lymph node metastasis, ascites, or poor differentiation had poorer survival rate, only lymph node metastasis was proved to be a significant prognostic predictor in multivariate analysis.     

Integrated phytoremediation focused on microbial investigation

Phytoremediation is an environmentally friendly green rehabilitation technology that is often incorporated with an application to improve phytohormones required for the growth of agricultural plants with the expectation to improve the effectiveness of plant rehabilitation. This study adopts phytoremediation, a green remediation technology, for the sake of restoring soil fertility and ensuring environmental sustainability, and adds ethylenediaminedisuccinic acid (EDDS) and the plant growth regulator (GA₃) to examine the overall efficiency of phytoremediation. The experiments using pots in this study finds that environmentally sustainable phytoremediation achieves the greatest efficacy regarding the remediation of soil polluted by copper, zinc and nickel. The best combination of operational factors is the addition of the EDDS and GA₃. The environment where the EDDS is added shows a poorer performance in the remediation of the heavy metal lead. In addition, the PCR(Polymerase chain reaction)-DGGE analysis results of bacterial flora change show that the combination “heavy metal + EDDS + GA₃” brings about the richest bacterial flora, indicating that the addition of EDDS and GA₃ can stimulate microbial growth, thereby achieving richer bacterial flora.

Phytoremediation is a green rehabilitation technology that is often incorporated with an application to improve phytohormones required for the growth of agricultural plants with the expectation to improve the effectiveness of plant rehabilitation.     

GPCR dimerization in brainstem nuclei contributes to the development of hypertension

Background and Purpose

μ-Opioid receptors, pro-opiomelanocortin and pro-enkephalin are highly expressed in the nucleus tractus solitarii (NTS) and μ receptor agonists given to the NTS dose-dependently increased BP. However, the molecular mechanisms of this process remain unclear. In vitro, μ receptors heterodimerize with α_2A-adrenoceptors. We hypothesized that α_2A-adrenoceptor agonists would lose their depressor effects when their receptors heterodimerize in the NTS with μ receptors.

Experimental Approach

We microinjected μ-opioid agonists and antagonists into the NTS of rats and measured changes in BP. Formation of μ receptor/α_2A-adrenoceptor heterodimers was assessed with immunofluorescence and co-immunoprecipitation methods, along with proximity ligation assays.

Key Results

Immunofluorescence staining revealed colocalization of α_2A-adrenoceptors and μ receptors in NTS neurons. Co-immunoprecipitation revealed interactions between α_2A-adrenoceptors and μ receptors. In situ proximity ligation assays confirmed the presence of μ receptor/α_2A-adrenoceptor heterodimers in the NTS. Higher levels of endogenous endomorphin-1 and μ receptor/α_2A-adrenoceptor heterodimers were found in the NTS of hypertensive rats, than in normotensive rats. Microinjection of the μ receptor agonist [D-Ala², MePhe⁴, Gly⁵-ol]-enkephalin (DAMGO), but not that of the α_2A-adrenoceptor agonist guanfacine, into the NTS of normotensive rats increased μ receptor/α_2A-adrenoceptor heterodimer formation and BP elevation. The NO-dependent BP-lowering effect of α_2A-adrenoceptor agonists was blunted following increased formation of μ receptor/α_2A-adrenoceptor heterodimers in the NTS of hypertensive rats and DAMGO-treated normotensive rats.

Conclusions and Implications

Increases in endogenous μ receptor agonists in the NTS induced μ receptor/α_2A-adrenoceptor heterodimer formation and reduced the NO-dependent depressor effect of α_2A-adrenoceptor agonists. This process could contribute to the pathogenesis of hypertension.     

Pharmacokinetic Interaction of the Direct Renin Inhibitor Aliskiren with Furosemide and Extended‐Release Isosorbide‐5‐Mononitrate in Healthy Subjects

This study investigated the pharmacokinetics, safety, and tolerability of aliskiren administered alone or in combination with either the loop diuretic furosemide or an oral extended‐release formulation of isosorbide‐5‐mononitrate (ISMN). In separate studies, 22 healthy subjects (ages 18–45 years) received either ISMN 40 mg or furosemide 20 mg once‐daily for 3 days followed by a 3‐day washout. Subjects then received aliskiren 300 mg once‐daily for 7 days followed by combination therapy for 3 days. Pharmacokinetic assessments were taken at regular intervals over 24 h after dosing on the last day of each treatment period. At steady state, aliskiren AUC_τ was decreased by 7% (geometric mean ratio [90% CI], 0.93 [0.84, 1.04]), and C_max by 20% (0.80 [0.65, 0.97]) with furosemide coadministration compared with aliskiren administration alone. Aliskiren coadministration reduced furosemide AUC_τ by 28% (0.72 [0.64, 0.81]) and C_max by 49% (0.51 [0.39, 0.66]) compared with furosemide alone. Coadministration of aliskiren and ISMN was associated with only minor changes in the pharmacokinetic parameters of aliskiren (AUC_τ 1.03 [0.90, 1.18]; C_max 0.94 [0.69, 1.29]) and ISMN (AUC_τ 0.88 [0.71, 1.10]; C_max 0.94 [0.79, 1.13]). Headache and dizziness were the most common adverse events in both studies; dizziness and BP values below normal (SBP <90 and/or DBP <50 mmHg) were more frequent with aliskiren and ISMN coadministration than with either agent alone. Coadministration of aliskiren and ISMN had no clinically relevant effect on either aliskiren or ISMN pharmacokinetics. In conclusion, coadministration of aliskiren and furosemide reduced furosemide exposure and had a minor effect on aliskiren pharmacokinetics. The clinical significance of reduced systemic exposure to furosemide during coadministration of aliskiren is uncertain.     

Presence of interferon in acute- and convalescent-phase sera of humans with influenza or influenza-like illness of undetermined etiology

Interferon (IFN;titer, greater than 10 units) was present in the acute-phase sera of 30 of 40 subjects with culture and/or serologically documented, naturally acquired influenza A/Brazil/78 (H1N1) and in the acute-phase sera of five of 27 subjects with an influenza-like illness of undetermined etiology. No statistical correlation existed between the quantity of IFN in acute-phase serum and the course of the clinical illness. Antiviral activity in all of nine acute-phase sera and three of four sera obtained on the fifth to seventh days of illness was neutralized to greater than 50% by antibody to virus-induced human leukocyte IFN (HuIFN-alpha). In contrast, none of five sera collected between 21 and 23 days after the onset of illness contained IFN sensitive to neutralization by antibody to HuIFN-alpha. Resistance of IFN in convalescent-phase sera to neutralization by antibody to HuIFN-alpha suggests that multiple IFN species may evolve during viral infections.