Molecular Microscopy of Brain Gangliosides: Illustrating their Distribution in Hippocampal Cell Layers

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Combinations of macrolide resistance determinants in field isolates of Mannheimia haemolytica and Pasteurella multocida

Respiratory tract infections in cattle are commonly associated with the bacterial pathogens Mannheimia haemolytica and Pasteurella multocida. These infections can generally be successfully treated in the field with one of several groups of antibiotics, including macrolides. A few recent isolates of these species exhibit resistance to veterinary macrolides with phenotypes that fall into three distinct classes. The first class has type I macrolide, lincosamide, and streptogramin B antibiotic resistance and, consistent with this, the 23S rRNA nucleotide A2058 is monomethylated by the enzyme product of the erm(42) gene. The second class shows no lincosamide resistance and lacks erm(42) and concomitant 23S rRNA methylation. Sequencing of the genome of a representative strain from this class, P. multocida 3361, revealed macrolide efflux and phosphotransferase genes [respectively termed msr(E) and mph(E)] that are arranged in tandem and presumably expressed from the same promoter. The third class exhibits the most marked drug phenotype, with high resistance to all of the macrolides tested, and possesses all three resistance determinants. The combinations of erm(42), msr(E), and mph(E) are chromosomally encoded and intermingled with other exogenous genes, many of which appear to have been transferred from other members of the Pasteurellaceae. The presence of some of the exogenous genes explains recent reports of resistance to additional drug classes. We have expressed recombinant versions of the erm(42), msr(E), and mph(E) genes within an isogenic Escherichia coli background to assess their individually contributions to resistance. Our findings indicate what types of compounds might have driven the selection for these resistance determinants.     

Formulated siRNAs targeting Rankl prevent osteolysis and enhance chemotherapeutic response in osteosarcoma models

The development of osteosarcoma, the most common malignant primary bone tumor is characterized by a vicious cycle established between tumor proliferation and paratumor osteolysis. This osteolysis is mainly regulated by the receptor activator of nuclear factor κB ligand (RANKL). Preclinical studies have demonstrated that Rankl blockade by soluble receptors is an effective strategy to prevent osteolytic lesions leading to osteosarcoma inhibition. A new therapeutic option could be to directly inhibit Rankl expression by small interfering RNAs (Rkl‐siRNAs) and combine these molecules with chemotherapy to counteract the osteosarcoma development more efficiently. An efficient siRNA sequence directed against both mouse and rat mRNAs coding Rankl was first validated in vitro and tested in two models of osteosarcoma: a syngenic osteolytic POS‐1 model induced in immunocompetent mice and a xenograft osteocondensant model of rat OSRGA in athymic mice. Intratumor injections of Rankl‐directed siRNAs in combination with the cationic liposome RPR209120/DOPE reduced the local and systemic Rankl production and protected bone from paratumor osteolysis. Although Rkl‐siRNAs alone had no effect on tumor development in both osteosarcoma models, it significantly blocked tumor progression when combined with ifosfamide compared with chemotherapy alone. Our results indicate that siRNAs could be delivered using cationic liposomes and thereby could inhibit Rankl production in a specific manner in osteosarcoma models. Moreover, the Rankl inhibition mediated by RNA interference strategy improves the therapeutic response of primary osteosarcoma to chemotherapy. © 2011 American Society for Bone and Mineral Research     

Geographical variations of inflammatory bowel disease in France: a study based on national health insurance data

BACKGROUND AND AIM: A north-south gradient in inflammatory bowel disease (IBD) incidence has been found in Europe and the United States. Its existence is inferred from comparisons of registries that cover only small portions of territories. Several studies suggest that IBD incidence in the north has reached a plateau, whereas in the south it has risen sharply. This evolution tends to reduce the north-south gradient, and it is uncertain whether it still exists. In France, patients with IBD are fully reimbursed for their health expenses by the national health insurance system, which is a potential source of data concerning the incidence of IBD at the national level. The aim of this study was to assess the geographical distribution of Crohn's disease (CD) and ulcerative colitis (UC) in France and to test the north-south gradient hypothesis. METHODS: This study was conducted in metropolitan France and included patients to whom IBD reimbursement was newly attributed between January 1, 2000 and December 31, 2002. Data provided relate to age, sex, postcode area of residence, and IBD type. The mapping of geographical distribution of smoothed relative risks (RR) of CD and UC was carried out using a Bayesian approach, taking into account autocorrelation and population size in each département. RESULTS: In the overall population, incidence rates were 8.2 for CD and 7.2 for UC per 100,000 inhabitants. A clear north-south gradient was shown for CD. Départements with the highest smoothed RR were located in the northern third of France. By contrast, the geographical distribution of smoothed RR of UC was homogeneous. CONCLUSIONS: This study shows a north-south gradient in France for CD but not for UC.     

Mechanisms involved in the swelling of erythrocytes caused by Pacific and Caribbean ciguatoxins

The mechanisms underlying the swelling of frog red blood cells (RBC), induced by Pacific (P-CTX-1) and Caribbean (C-CTX-1) ciguatoxins (CTXs), were investigated by measuring the length, width and surface of their elliptic shape. P-CTX-1 (0.5 to 5 nM) and C-CTX-1 (1 nM) induced RBC swelling within 60 min. The CTXs-induced RBC swelling was blocked by apamin (1 microM) and by Sr(2+) (1 mM). P-CTX-1-induced RBC swelling was prevented and inhibited by H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (27 microM), an inhibitor of soluble guanylate cyclase (sGC), and NOS blockade by NG methyl-l-arginine (l-NMA; 10 microM). Cytochalasin D (cytD, 10 microM) increased RBC surface and mimicked CTX effect but did not prevent the P-CTX-1-induced l-NMA-sensitive extra increase. Calculations revealed that P-CTX-1 and cytD increase RBC total surface envelop and volume. These data strongly suggest that the molecular mechanisms underlying CTXs-induced RBC swelling involve the NO pathway by an activation of the inducible NOS, leading to sGC activation which modulates intracellular cGMP and regulates L-type Ca(2+) channels. The resulting increase in intracellular Ca(2+) content, in turn, disrupts the actin cytoskeleton, which causes a water influx and triggers a Ca(2+)-activated K(+) current through SK2 isoform channels.