One-step syntheses of nitrofuranyl benzimidazoles that are active against multidrug-resistant bacteria.

Nitrofuranyl benzimidazoles can be made in one synthetic step from commercially available starting materials. The compounds displayed unexpected antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci with MICs as low as 1 μg ml(-1).

New antimicrobial agents on the horizon.

Antibiotic resistance issues necessitate the continued discovery and development of new antibacterial agents. Efforts are ongoing in two approaches to find new compounds that are effective against antibiotic-resistant pathogens. These efforts involve modification of existing classes including fluoroquinolones, tetracyclines, aminoglycosides, and β-lactams and identification of inhibitors against previously unexploited antibacterial targets.

Chromosomal painting and ZW sex chromosomes differentiation in Characidium (Characiformes, Crenuchidae).

Background: The Characidium (a Neotropical fish group) have a conserved diploid number (2n = 50), but show remarkable differences among species and populations in relation to sex chromosome systems and location of nucleolus organizer regions (NOR). In this study, we isolated a W-specific probe for the Characidium and characterized six Characidium species/populations using cytogenetic procedures. We analyzed the origin and differentiation of sex and NOR-bearing chromosomes by chromosome painting in populations of Characidium to reveal their evolution, phylogeny, and biogeography.

Effect of capacitation on the endocannabinoid system of mouse sperm.

The presence of the elements of the endocannabinoid system (ECS) in sperm isolated from several species (from invertebrates to mammals, humans included) has supported the "evolutionary theory" that proposes endocannabinoids as check points in reproductive events like capacitation. In this study, we characterized the ECS elements at the mRNA, protein and functional levels in mouse sperm before and after capacitation. We found that the latter process increases the endogenous levels of the two major endocannabinoids (anandamide and 2-arachidonoylglycerol), through a decreased degradation and increased biosynthesis, respectively.

Endocannabinoid signaling and epidermal differentiation.

Endocannabinoids represent a class of endogenous lipid mediators, that are involved in various biological processes, both centrally and peripherally. The prototype member of this group of compounds, anandamide, regulates cell growth, differentiation and death; this holds true also in the skin, that is the largest organ of the body constantly exposed to physical, chemical, bacterial and fungal challenges. The epidermis is a keratinized multistratified epithelium that functions as a barrier to protect the organism from dehydration, mechanical trauma, and microbial insults, and epidermal differentiation represents one of the best characterized mechanisms of cell specialization.

Selenophene-containing inhibitors of type IIA bacterial topoisomerases.

We investigated compounds related to the previously reported antistaphyloccocal agent AVE6971 in an effort to attenuate inhibition of hERG potassium channel current that has been noted for this and related antibacterial drug classes. While most modifications of the original thiophene group compromised antibacterial activity, one selenophene analogue displayed (i) improved activity against the primary target enzyme DNA gyrase, (ii) similar activities against a panel of MRSA clinical isolates, and (iii) reduced hERG channel inhibition.

Exploration of the activity of 7-pyrrolidino-8-methoxyisothiazoloquinolones against methicillin-resistant Staphylococcus aureus (MRSA).

A series of 7-(3'-substituted)pyrrolidino-8-methoxyisothiazoloquinolone (ITQ) analogues were prepared, and their antibacterial potency against methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), and Escherichia coli were compared. Many of these analogues had MIC ≤ 0.25 μg/mL against quinolone-resistant MRSA strains.

Pharmacokinetic variability of long-acting stimulants in the treatment of children and adults with attention-deficit hyperactivity disorder.

Methylphenidate- and amfetamine-based stimulants are first-line pharmacotherapies for attention-deficit hyperactivity disorder, a common neurobehavioural disorder in children and adults. A number of long-acting stimulant formulations have been developed with the aim of providing once-daily dosing, employing various means to extend duration of action, including a transdermal delivery system, an osmotic-release oral system, capsules with a mixture of immediate- and delayed-release beads, and prodrug technology. Coefficients of variance of pharmacokinetic measures can estimate the levels of pharmacokinetic variability based on the measurable variance between different individuals receiving the same dose of stimulant (interindividual variability) and within the same individual over multiple administrations (intraindividual variability).

New quinolone antibiotics: a survey of the literature from 2005 to 2010.

Importance Of The Field: The quinolone class of antibacterial agents has a proven track record over the past several decades for the treatment of bacterial infections. Their unique mechanism of action and bactericidal properties make them attractive therapeutic agents.

Areas Covered In This Review: Significant research efforts continue to the present day in both academia and industry, which have provided a number of promising drug candidates for further development.

In vitro antituberculosis activities of ACH-702, a novel isothiazoloquinolone, against quinolone-susceptible and quinolone-resistant isolates.

ACH-702 is a new isothiazoloquinolone with potent in vitro and in vivo activities against important bacterial pathogens, including Staphylococcus aureus. In this study, ACH-702 was found to have promising in vitro antibacterial activity against Mycobacterium tuberculosis, with MICs of View Article and Find Full Text PDF

Duration of effect of oral long-acting stimulant medications for ADHD throughout the day.

Objective: To examine duration of efficacy in long-acting stimulant treatment of attention-deficit/hyperactivity disorder (ADHD) in clinical trials using analog classroom protocols.

Research Design And Methods: Published reports of clinical trials examining duration of medication efficacy using analog classroom protocols were identified in a systematic literature search of PubMed, BIOSYS, and EMBASE, through June 2009 using combinations of terms: attention-deficit/hyperactivity disorder, ADHD, attention-deficit disorder with hyperactivity, stimulant, methylphenidate (MPH), amphetamine, laboratory school or classroom, analog classroom, math test, and Permanent Product Measure of Performance (PERMP). Reports of short-acting, nonoral or nonstimulant formulations, or inadequate data on duration of efficacy were excluded.

Pitfalls and solutions in assaying anandamide transport in cells.

Nonspecific binding of anandamide to plastic exhibits many features that could be mistaken as biological processes, thereby representing an important source of conflicting data on the uptake and release of this lipophilic substance. Herein, we propose an improved method to assay anandamide transport, by using glass slides (i.e.

Characterization of the endocannabinoid system in mouse embryonic stem cells.

In this study, we have ascertained the presence and functionality in mouse embryonic stem cells (ESCs) of members of the endocannabinoid system that have been proposed as possible modulators of the survival and differentiation of various type of stem cells. We show that mouse ESCs, in addition to classical CB(1) and CB(2) cannabinoid receptors, express the transient receptor potential vanilloid receptor, at mRNA, protein, and binding levels. Remarkably, we demonstrate that ESCs have the mRNA, protein, and enzyme activity to synthesize and degrade the prominent endocannabinoids anandamide (through N-acyl-phosphatidylethanolamine-specific phospholipase D and fatty acid amide hydrolase) and 2-arachidonoylglycerol (through diacylglycerol lipase and monoacylglycerol lipase).

In vitro activity of ACH-702, a new isothiazoloquinolone, against Nocardia brasiliensis compared with econazole and the carbapenems imipenem and meropenem alone or in combination with clavulanic acid.

The in vitro activities of ACH-702 and other antimicrobials against 30 Nocardia brasiliensis isolates were tested. The MIC(50) (MIC for 50% of the strains tested) and MIC(90) values of ACH-702 were 0.125 and 0.

In vitro activity of a new isothiazoloquinolone, ACH-702, against Mycobacterium tuberculosis and other mycobacteria.

In this work, we describe the activity of ACH-702 against clinical isolates of Mycobacterium tuberculosis and six different nontuberculous mycobacteria. The MIC(50) and MIC(90) of both susceptible and drug-resistant M. tuberculosis strains tested were 0.

Systemic sclerosis-endothelial cell antiangiogenic pentraxin 3 and matrix metalloprotease 12 control human breast cancer tumor vascularization and development in mice.

We have previously shown that endothelial cell matrix metalloprotease 12 (MMP12) and pentraxin 3 (PTX3) overproduction is the main alteration accounting for reduced proneness to angiogenesis in systemic sclerosis (SSc). On this basis, we stably transfected MMP12 and PTX3 in two breast cancer cell lines expressing very low amounts of the target molecules when compared with normal breast epithelial cells, relying on the hypothesis that antiangiogenic molecules released by cancer cells could confer an SSc-like antiangiogenic pattern on target endothelial cells. In Matrigel Boyden chamber invasion and capillary morphogenesis studies, transfected clones reduced endothelial cell invasion and capillary tube formation, which were abolished by tumor cell populations expressing both molecules.

Sorption/desorption of arsenate on/from Mg-Al layered double hydroxides: influence of phosphate.

We have studied: (i) the sorption of arsenate on Mg-Al layered double hydroxides (LDHs) containing chloride (LDH-Cl) or carbonate (LDH-CO(3)) in the absence or presence of phosphate; (ii) the competitive sorption of arsenate and phosphate as affected by reaction time and pH and; (iii) the desorption of arsenate previously sorbed on the LDH by phosphate. The LDH samples were uncalcined (LDH-Cl-20 and LDH-CO(3)-20) or calcined at 450 degrees C (LDH-Cl-450 and LDH-CO(3)-450). More phosphate than arsenate was sorbed onto all the minerals but LDH-Cl-450 sorbed much lower amounts of both the ligands than LDH-Cl-20; vice versa LDH-CO(3)-450 showed a capacity to sorb arsenate and phosphate much greater than LDH-CO(3)-20.

TGFbeta1 antagonistic peptides inhibit TGFbeta1-dependent angiogenesis.

The role of transforming growth factor beta (TGFbeta) in tumor promotion and in angiogenesis is context-dependent. While TGFbeta prevents tumor growth and angiogenesis in early phases of tumor development, evidence is accumulating about its pro-angiogenic and tumor promotion activities in late-stages of tumor progression. Here we have studied, in an experimental context previously reported to disclose the pro-angiogenic effects of TGFbeta, the blocking activity of TGFbeta antagonist peptides.

Dietary salt induces transcription of the prostaglandin transporter gene in renal collecting ducts.

Prostaglandin E(2) (PGE(2)) plays an important role in maintaining body fluid homeostasis by activating its receptors on the renal collecting duct (CD) to stimulate renal Na(+) and water excretion. The PG carrier prostaglandin transporter (PGT) is expressed on the CD apical membrane, where it mediates PG reuptake as part of the termination of autocrine PG signaling. Here we tested the hypothesis that dietary salt loading regulates PGT gene transcription in renal CDs.

Recent advances in bacterial topoisomerase inhibitors.

Bacterial topoisomerase inhibitors continue to be actively developed as clinical antibacterial agents, largely owing to the success of the currently marketed inhibitors, the quinolones, and the increasing resistance to these agents. New quinolone analogs such as isothiazoloquinolones and quinazolinediones show some potential in overcoming this problem. Quinolones linked to other antibacterial agents such as rifamycins and oxazolidinones are designed to overcome both quinolone-specific resistance and resistance to the coupled agents.

The plasminogen activation system in inflammation.

Inflammation is an adaptive response to damage of vascularized tissues, which develops according to a stereotyped sequence governed by the local production of the so-called "chemical mediators of inflammation". Here we review the evidences indicating a role of the plasminogen activation system in the regulation of all the phases of the inflammation process. Plasminogen activation controls the formation of complement anaphylotoxins (responsible for vasodilatation, increase of venular permeability and leukocyte chemotaxis) and of bradykinin (which accounts for vasodilatation, increase of venular permeability and pain) by regulating the plasma contact system.

A method to assay penicillin-binding proteins.

Key enzymes that assemble the bacterial cell wall are also the target of the Beta-lactam class of antibiotics. The covalent binding of labeled penicillin to these proteins has been used in numerous studies in drug discovery, antibiotic mechanisms of action and resistance, and cell wall physiology. Methods to label and measure penicillin binding proteins in two prototypical organisms, a Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus), are described.

A new method based on contact surface profilometry for quantitative measurement of resorbed bone volume.

Bone is a dynamic tissue. Its continuous remodeling depends on the balance between bone formation and bone resorption. These two processes are carried out by specialized cells called osteoblast and ostreoclast respectively.