Dysfunction or deficiency of the Na(+)/K(+)-ATPase appears to be a common event in a variety of pathological conditions in the central nervous system. Studies on neurotoxicity associated to impaired Na(+)/K(+)-ATPase activity have focused on NMDA receptors, while the involvement of non-NMDA receptors has been much less explored. We show that mild, non-toxic, exposures to the Na(+)/K(+)-ATPase inhibitor palytoxin synergistically sensitized the vulnerability of neurons to normally non-toxic concentrations of domoic acid, leaving NMDA receptor-mediated excitotoxic response unaltered. Enhancement of excitotoxicity required at least 1 h pre-exposure to palytoxin, was not observed after longer exposures to palytoxin, and did not require RNA synthesis. Palytoxin caused a voltage-sensitive Na(+) channel-independent increase in intracellular Na(+). Both intracellular Na(+) increase and potentiation of excitotoxicity depended upon the external concentrations of Na(+) and Cl(-), and were suppressed by the anion exchanger blocker 4,4'-diisothiocyanatostilbene-2, 2'-disulfonic acid (DIDS) in a dose-dependent manner. Other stilbene derivatives, chloride channel antagonists or Na(+) cotransporter inhibitors proved ineffective. Our results demonstrate a crucial role for Na(+)/K(+)-ATPase activity in determining neuronal vulnerability to domoic acid-mediated excitotoxicity. They also raise reasonable concern about possible risks for human health associated to the ingestion of low amounts of phycotoxins palytoxin and domoic acid in food.

This article summarizes the recommendations drawn up by the Italian Society of Chemotherapy regarding the proper use of antimicrobial agents for infectious diseases.

ABSTRACT: BACKGROUND: Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH) consists of congenital aplasia of the uterus and the upper part of vagina due to anomalous development of Mullerian ducts, either isolated or associated with other congenital malformations, including renal, skeletal, hearing and heart defects. This disorder has an incidence of approximately 1 in 4500 newborn girls and the aetiology is poorly understood. Methods and Results: we report on two patients affected by MRKH syndrome in which array-CGH analysis disclosed an identical deletion spanning 1.5 Mb of genomic DNA at chromosome 17q12. One patient was affected by complete absence of uterus and vagina, with bilaterally normal ovaries, while the other displayed agenesis of the upper part of vagina, right unicornuate uterus, non cavitating rudimentary left horn and bilaterally multicystic kidneys. The deletion encompassed two candidate genes, TCF2 and LHX1. Mutational screening of these genes in a selected group of 20 MRKH females without 17q12 deletion was negative. CONCLUSION: Deletion 17q12 is a rare albeit recurrent anomaly mediated by segmental duplications, previously reported in subjects with developmental kidney abnormalities and diabetes. The present two patients expand the clinical spectrum associated with this imbalance and suggest that this region is a candidate locus for a subset of MRKH syndrome individuals, with or without renal defects.

Drug classes for the treatment of invasive fungal infections include the polyenes, the triazoles and the echinocandins. Older agents such as the commonly used amphotericin B have a number of limitations, including toxicity and requirements for monitoring during treatment. These limitations led to the development of a number of new formulations of the agent, with the aim of reducing toxicity while maintaining or improving efficacy. Regarding other drug classes, some of the newer agents, such as the echinocandins, have more favourable pharmacokinetic/pharmacodynamic (PK/PD) profiles, with less toxicity and no need for monitoring. The newest echinocandin, anidulafungin, offers significant promise for antifungal infections, and has a number of favourable features, including a lack of known drug interactions and no need for dosage adjustment for any degree of renal or hepatic failure. From a pharmacological point of view, knowledge of both PK and PD characteristics of antifungal drugs is mandatory for evaluating the role of the different agents in the clinical setting. Overall, in the search for safer and more efficacious antifungal agents, PK/PD investigations have been valuable for defining optimal antifungal dosing regimens and developing in vitro susceptibility breakpoints. This article reviews the PK/PD properties of the polyenes, the triazoles and the echinocandins, with a focus on anidulafungin.

We used Affymetrix 6.0 GeneChip SNP arrays to characterize copy number variations (CNVs) in a cohort of 70 patients previously characterized on lower-density oligonucleotide arrays affected by idiopathic mental retardation and dysmorphic features. The SNP array platform includes approximately 900 000 SNP probes and 900 000 non-SNP oligonucleotide probes at an average distance of 0.7 Kb, which facilitates coverage of the whole genome, including coding and noncoding regions. The high density of probes is critical for detecting small CNVs, but it can lead to data interpretation problems. To reduce the number of false positives, parameters were set to consider only imbalances >75 Kb encompassing at least 80 probe sets. The higher resolution of the SNP array platform confirmed the increased ability to detect small CNVs, although more than 80% of these CNVs overlapped to copy number 'neutral' polymorphism regions and 4.4% of them did not contain known genes. In our cohort of 70 patients, of the 51 previously evaluated as 'normal' on the Agilent 44K array, the SNP array platform disclosed six additional CNV changes, including three in three patients, which may be pathogenic. This suggests that about 6% of individuals classified as 'normal' using the lower-density oligonucleotide array could be found to be affected by a genomic disorder when evaluated with the higher-density microarray platforms.European Journal of Human Genetics advance online publication, 7 October 2009; doi:10.1038/ejhg.2009.154.

Whereas infections caused by multidrug-resistant micro-organisms are increasing worldwide, there are few new molecules, especially ones that are active against Gram-negative strains. There are extensive data showing that the administration of antimicrobials according to pharmacokinetic/pharmacodynamic parameters improves the possibility of a positive clinical outcome, particularly in severely ill patients. Evidence is growing that when pharmacokinetic/pharmacodynamic parameters are used to target not only clinical cure but also eradication, the spread of resistance will also be contained. The present paper summarizes the most relevant papers published in this field and provides some suggestions for dosing regimens that can be adopted in the clinical setting to limit the spread of resistance.