Fosfomycin Trometamol in Patients with Renal Insufficiency and in the Elderly

Single oral dose therapy with fosfomycin trometamol (FT) 3 g is recommended inthe treatment of uncomplicated urinary tract infection (UTI) not only in premenopausal,but also in postmenopausal elderly, otherwise healthy women. It can alsobe used as reapplication every 10 days for prophylaxis of recurrent uncomplicatedcystitis. FT 3 g has also been used with two oral doses of 3 g (on two consecutivedays) for perioperative prophylaxis in transurethral interventions or with three doses(every other day, three times) for treatment of complicated lower UTI includingmany elderly patients. The tolerance and safety in the patients above 65 yearsof age did not differ from younger ones. Therefore, there is also an indication toadminister oral FT 3g in adults above 65 years of age for treatment or prophylaxisof uncomplicated UTI.Patients with renal insufficiency up to a creatinine clearance of 20 ml/min can beexpected to have still sufficiently high urinary concentrations of fosfomycin, thattreatment of cystitis should be justified from pharmacokinetic/pharmacodynamicpoint of view. From preliminary clinical results there is also an indication to useoral FT 3 g in adults with renal insufficiency up to a creatinine clearance of 20 ml/min, with single dose for treatment of lower uncomplicated UTI with otherwisenormal urinary tract or with repeated doses (every second or third day accordingto the degree of renal insufficiency) for treatment of lower complicated UTI causedby fosfomycin susceptible pathogens resistant to other oral antimicrobial drugs

Resequencing PNMT in European hypertensive and normotensive individuals: no common susceptibilily variants for hypertension and purifying selection on intron 1

<p>Abstract</p> <p>Background</p> <p>Human linkage and animal QTL studies have indicated the contribution of genes on Chr17 into blood pressure regulation. One candidate gene is <it>PNMT</it>, coding for phenylethanolamine-N-methyltransferase, catalyzing the synthesis of epinephrine from norepinephrine.</p> <p>Methods</p> <p>Fine-scale variation of <it>PNMT </it>was screened by resequencing hypertensive (n = 50) and normotensive (n = 50) individuals from two European populations (Estonians and Czechs). The resulting polymorphism data were analyzed by statistical genetics methods using Genepop 3.4, PHASE 2.1 and DnaSP 4.0 software programs. <it>In silico </it>prediction of transcription factor binding sites for intron 1 was performed with MatInspector 2.2 software.</p> <p>Results</p> <p><it>PNMT </it>was characterized by minimum variation and excess of rare SNPs in both normo- and hypertensive individuals. None of the SNPs showed significant differences in allelic frequencies among population samples, as well as between screened hypertensives and normotensives. In the joint case-control analysis of the Estonian and the Czech samples, hypertension patients had a significant excess of heterozygotes for two promoter region polymorphisms (SNP-184; SNP-390). The identified variation pattern of <it>PNMT </it>reflects the effect of purifying selection consistent with an important role of PNMT-synthesized epinephrine in the regulation of cardiovascular and metabolic functions, and as a CNS neurotransmitter. A striking feature is the lack of intronic variation. <it>In silico </it>analysis of <it>PNMT </it>intron 1 confirmed the presence of a human-specific putative Glucocorticoid Responsive Element (GRE), inserted by <it>Alu</it>-mediated transfer. Further analysis of intron 1 supported the possible existence of a full Glucocorticoid Responsive Unit (GRU) predicted to consist of multiple gene regulatory elements known to cooperate with GRE in driving transcription. The role of these elements in regulating <it>PNMT </it>expression patterns and thus determining the dynamics of the synthesis of epinephrine is still to be studied.</p> <p>Conclusion</p> <p>We suggest that the differences in PNMT expression between normotensives and hypertensives are not determined by the polymorphisms in this gene, but rather by the interplay of gene expression regulators, which may vary among individuals. Understanding the determinants of PNMT expression may assist in developing PNMT inhibitors as potential novel therapeutics.</p

Human skin commensals augment Staphylococcus aureus pathogenesis

All bacterial infections occur within a polymicrobial environment, from which a pathogen population emerges to establish disease within a host. Emphasis has been placed on prevention of pathogen dominance by competing microflora acting as probiotics1. Here we show that the virulence of the human pathogen Staphylococcus aureus is augmented by native, polymicrobial, commensal skin flora and individual species acting as ‘proinfectious agents’. The outcome is pathogen proliferation, but not commensal. Pathogenesis augmentation can be mediated by particulate cell wall peptidoglycan, reducing the S. aureus infectious dose by over 1,000-fold. This phenomenon occurs using a range of S. aureus strains and infection models and is not mediated by established receptor-mediated pathways including Nod1, Nod2, Myd88 and the NLPR3 inflammasome. During mouse sepsis, augmentation depends on liver-resident macrophages (Kupffer cells) that capture and internalize both the pathogen and the proinfectious agent, leading to reduced production of reactive oxygen species, pathogen survival and subsequent multiple liver abscess formation. The augmented infection model more closely resembles the natural situation and establishes the role of resident environmental microflora in the initiation of disease by an invading pathogen. As the human microflora is ubiquitous2, its role in increasing susceptibility to infection by S. aureus highlights potential strategies for disease prevention

Active layers of high-performance lead zirconate titanate at temperatures compatible with silicon nano- and microelecronic devices

Applications of ferroelectric materials in modern microelectronics will be greatly encouraged if the thermal incompatibility between inorganic ferroelectrics and semiconductor devices is overcome. Here, solution-processable layers of the most commercial ferroelectric compound ─ morphotrophic phase boundary lead zirconate titanate, namely Pb(Zr0.52Ti0.48)O3 (PZT) ─ are grown on silicon substrates at temperatures well below the standard CMOS process of semiconductor technology. The method, potentially transferable to a broader range of Zr:Ti ratios, is based on the addition of crystalline nanoseeds to photosensitive solutions of PZT resulting in perovskite crystallization from only 350 °C after the enhanced decomposition of metal precursors in the films by UV irradiation. A remanent polarization of 10.0 μC cm−2 is obtained for these films that is in the order of the switching charge densities demanded for FeRAM devices. Also, a dielectric constant of ~90 is measured at zero voltage which exceeds that of current single-oxide candidates for capacitance applications. The multifunctionality of the films is additionally demonstrated by their pyroelectric and piezoelectric performance. The potential integration of PZT layers at such low fabrication temperatures may redefine the concept design of classical microelectronic devices, besides allowing inorganic ferroelectrics to enter the scene of the emerging large-area, flexible electronics