Chronopharmacological Study of Cephalexin in Dogs

Recent studies have identified a 24 h rhythm in the expression and function of PEPT1 in rats, with significantly higher levels during the nighttime than daytime. Similarly, temporal variations have been described in glomerular filtration rate and renal blood flow, both being maximal during the activity phase and minimal during the rest phase in laboratory rodents. The aim of this study was to assess the hypothesis that the absorption of the first‐generation cephalosporin antibiotic cephalexin by dogs would be less and the elimination would be slower after evening (rest span) compared to morning (activity span) administration, and whether such administration‐time changes could impair the medication's predicted clinical efficacy. Six (3 male, 3 female; age 4.83±3.12 years) healthy beagle dogs were studied. Each dog received a single dose of 25 mg/kg of cephalexin monohydrate per os at 10∶00 and 22∶00 h, with a two‐week interval of time between the two clock‐time experiments. Plasma cephalexin concentrations were determined by microbiological assay. Cephalexin peak plasma concentration was significantly reduced to almost 77% of its value after the evening compared to morning (14.52±2.7 vs. 18.77±2.8 µg/mL) administration. The elimination half‐life was prolonged 1.5‐fold after the 22∶00 h compared to the 10∶00 h administration (2.69±0.9 vs. 1.79±0.2 h). The area under the curve and time to reach peak plasma concentration did not show significant administration‐time differences. The duration of time that cephalexin concentrations remained above the minimal inhibitory concentrations (MIC) for staphylococci susceptiblity (MIC=0.5 µg/mL) was>70% of each of the 12 h dosing intervals (i.e., 10∶00 and 22∶00 h). It can be concluded that cephalexin pharmacokinetics vary with time of day administration. The findings of this acute single‐dose study require confirmation by future steady‐state, multiple‐dose studies. If such studies are confirmatory, no administration‐time dose adjustment is required to ensure drug efficacy in dogs receiving an oral suspension of cephalexin in a dosage of 25 mg/kg at 12 h intervals.     

Biologically relevant effects of mRNA amplification on gene expression profiles

Background  

Gene expression microarray technology permits the analysis of global gene expression profiles. The amount of sample needed limits the use of small excision biopsies and/or needle biopsies from human or animal tissues. Linear amplification techniques have been developed to increase the amount of sample derived cDNA. These amplified samples can be hybridised on microarrays. However, little information is available whether microarrays based on amplified and unamplified material yield comparable results.     

MicroRNAs与疾病和发育

作为模式生物实验系统,线虫可用于研究控制动物发育和人类疾病遗传机制。研究发育缺陷的线虫突变体有助于在动物中发现对发育和生理过程有重要调控作用的基因。其中一些基因编码一类小RNA,如microRNA(miRNA),通过作用于特定基因信使RNA来调控其蛋白质表达。一些在线虫发育过程中有功能的miRNA在人体中也存在。它们参与调控与疾病相关的生物学过程,如癌症、糖尿病和神经退行性疾病。通过分析miRNA在临床样品、哺乳动物细胞和模式生物线虫中的表达,从而揭示miRNA调控途径在相关人类疾病中的功能。     

Nuclear morphometry as a prognostic indicator in colorectal carcinoma resected for cure

The prognostic value of nuclear morphometry in addition to clinical and pathologic features was retrospectively studied in 64 cases of colorectal carcinoma resected for cure with a minimum of five years of follow-up. By univariate analysis, patient outcome was found to correlate with the presence of serosal involvement (P = .003), the presence of lymph node involvement (P = .01), the number of involved lymph nodes (P = .0001) and the mean nuclear area (P = .02). With multivariate analysis, only the number of involved lymph nodes significantly correlated with the survival (P = .0001). In a subsequent multivariate model expressing lymph node status as the presence or absence of metastasis, the presence or absence of serosal involvement and the mean nuclear area were both found to independently correlate with the outcome (P = .003 and P = .02, respectively). Linear regression analysis revealed significant colinearity between the mean nuclear area and the number of involved lymph nodes (P = .03). Accelerated failure time models based on determination of serosal involvement and then either specification of the number of involved lymph nodes or calculation of the mean nuclear area were of comparable predictive value to the determination of the number of involved lymph nodes alone. The former appeared to be better at identifying a subgroup of patients with good prognosis. This study demonstrates that two or more models based on pathologic features may be of comparable predictive value in colorectal carcinoma resected for cure, including models that incorporate mean nuclear area.     

Pseudomonas aeruginosa cleaves the decoding center of Caenorhabditis elegans ribosomes

Pathogens such as Pseudomonas aeruginosa advantageously modify animal host physiology, for example, by inhibiting host protein synthesis. Translational inhibition of insects and mammalian hosts by P. aeruginosa utilizes the well-known exotoxin A effector. However, for the infection of Caenorhabditis elegans by P. aeruginosa, the precise pathways and mechanism(s) of translational inhibition are not well understood. We found that upon exposure to P. aeruginosa PA14, C. elegans undergoes a rapid loss of intact ribosomes accompanied by the accumulation of ribosomes cleaved at helix 69 (H69) of the 26S ribosomal RNA (rRNA), a key part of ribosome decoding center. H69 cleavage is elicited by certain virulent P. aeruginosa isolates in a quorum sensing (QS)–dependent manner and independently of exotoxin A–mediated translational repression. H69 cleavage is antagonized by the 3 major host defense pathways defined by the pmk-1, fshr-1, and zip-2 genes. The level of H69 cleavage increases with the bacterial exposure time, and it is predominantly localized in the worm’s intestinal tissue. Genetic and genomic analysis suggests that H69 cleavage leads to the activation of the worm’s zip-2-mediated defense response pathway, consistent with translational inhibition. Taken together, our observations suggest that P. aeruginosa deploys a virulence mechanism to induce ribosome degradation and H69 cleavage of host ribosomes. In this manner, P. aeruginosa would impair host translation and block antibacterial responses.

During infection of the nematode Caenorhabditis elegans by the bacterium Pseudomonas aeruginosa, a bacterial virulence mechanism leads to the cleavage of host ribosomal RNAs at the decoding center, thereby shutting down translation.     

B and C Types Natriuretic Peptides Modify Norepinephrine Uptake and Release in the Rat Adrenal Medulla

Vatta, M. S., M. F. Presas, L. G. Bianciotti, M. Rodriguez–fermepin, R. Ambros and B. E. Fernandez. B and C types natriuretic peptides modify norepinephrine uptake and release in the rat adrenal medulla. Peptides 18(10) 1483–1489, 1997.—We have previously reported that atrial natriuretic factor (ANF) modulates adrenomedullar norepinephrine (NE) metabolism. On this basis, the aim of the present work was to study the effects of B and C types natriuretic peptides (BNP and CNP) on the uptake, intracellular distribution and release of ³H-NE. Experiments were carried out in rat adrenal medulla slices incubated “in vitro.” Results showed that 100 nM of both, CNP and BNP, enhanced total and neuronal NE uptake. Both peptides (100 nM) caused a rapid increase in NE uptake during the first minute, which was sustained for 60 min. NE intracellular distribution was only modified by CNP (100 nM), which increased the granular fraction and decreased the cytosolic pool. On the other hand, spontaneous as well as evoked (KCl) NE release, was decreased by BNP and CNP (50 and 100 nM for spontaneous release and 1, 10, 50 and 100 nM for evoked output). The present results suggest that BNP and CNP may regulate catecholamine secretion and modulate adrenomedullary biological actions mediated by catecholamines, such as blood arterial pressure, smooth muscle tone, and metabolic activities.     

Increase of the production of tumor necrosis factor in endotoxin shock in mice presensitized with sera of tumor-bearing mice or tumor cell factor]

We investigated the phenomenon of increased sensitivity of tumor-bearing mice to endotoxin shock. I/V administration of sera from tumor (EL-4, B16, R815, MOPC-315) bearers or tumoral culture media into intact mice caused the increased sensitivity to lethal action of LPS plus GMDP. Production of TNF in above mice was also significantly increased under the influence of LPS plus GMDP. Sensitivity induced factors in tumor bearing mice sera have mol. weight more than 50 kDa. This action was partially abolished by indomethacin.