Over the last decade, methicillin-resistant Staphylococcus aureus (MRSA) strains have emerged as serious pathogens. These strains are often multiresistant to several antibiotic classes and are a ...major cause of serious hospital- and now community-acquired infections and associated morbidity and mortality. As a result of increasing antimicrobial resistance, glycopeptides, such as vancomycin, are widely used as first-line therapy for serious MRSA infections. However, the emergence of glycopeptide tolerance and resistance has complicated treatment and there remains a clinical need for new antibiotics with suitable pharmacokinetic properties with activity against MRSA and other Gram-positive pathogens. Infections caused by MRSA and other bacteria usually respond as well to bacteriostatic agents as to bactericidal ones. Nevertheless, there is evidence that rapid bacterial killing has potential clinical advantages over bacteriostatic therapy in certain infections. Daptomycin, the first of the cyclic lipopeptides, shows rapid bactericidal activity against S. aureus, including strains tolerant or resistant to other agents. This review outlines the methods by which bactericidal and bacteriostatic properties are defined and tested, discusses the potential importance of bactericidal therapy in MRSA and other infections and examines the potential role of daptomycin in treatment.
Summary Over the past decade, community-associated meticillin-resistant Staphylococcus aureus (MRSA) has emerged in patients without health-care contact, especially in the USA. Although data are ...limited, the prevalence of community-associated MRSA in Europe seems to be low but is increasing. The organism has been reported in most European countries, including the Netherlands and Nordic countries, which have low rates of health-care-associated MRSA. In Greece, rates of community-associated MRSA in some centres approach those of the USA. By contrast with North America, where the USA300 clone (ST8-IV) predominates, community-associated MRSA in Europe is characterised by clonal heterogeneity. The most common European strain is the European clone (ST80-IV), although reports of USA300 are increasing. Several community-associated MRSA clones have arisen in Europe, most notably the ST398-V pig-associated MRSA clone in the Netherlands and Denmark. An understanding of the epidemiology of community-associated MRSA is essential to guide new control initiatives to prevent these organisms from becoming endemic in Europe.
Pre-rRNA transcription by RNA Polymerase I (Pol I) is very robust on active rDNA repeats. Loss of yeast Topoisomerase I (Top1) generated truncated pre-rRNA fragments, which were stabilized in strains ...lacking TRAMP (Trf4/Trf5-Air1/Air2-Mtr4 polyadenylation complexes) or exosome degradation activities. Loss of both Top1 and Top2 blocked pre-rRNA synthesis, with pre-rRNAs truncated predominately in the 18S 5' region. Positive supercoils in front of Pol I are predicted to slow elongation, while rDNA opening in its wake might cause R-loop formation. Chromatin immunoprecipitation analysis showed substantial levels of RNA/DNA hybrids in the wild type, particularly over the 18S 5' region. The absence of RNase H1 and H2 in cells depleted of Top1 increased the accumulation of RNA/DNA hybrids and reduced pre-rRNA truncation and pre-rRNA synthesis. Hybrid accumulation over the rDNA was greatly exacerbated when Top1, Top2, and RNase H were all absent. Electron microscopy (EM) analysis revealed Pol I pileups in the wild type, particularly over the 18S. Pileups were longer and more frequent in the absence of Top1, and their frequency was exacerbated when RNase H activity was also lacking. We conclude that the loss of Top1 enhances inherent R-loop formation, particularly over the 5' region of the rDNA, imposing persistent transcription blocks when RNase H is limiting.
In this multicenter, randomized, placebo-controlled trial involving women with bacterial vaginosis who had completed a course of vaginal metronidazole gel, treatment with vaginally administered
...Lactobacillus crispatus
CTV-05 (Lactin-V) resulted in a lower incidence of recurrence of bacterial vaginosis at 12 weeks than placebo.
Summary
Background
It has been shown that the interleukin (IL)‐23/IL‐17 axis is critical in the pathogenesis of psoriasis.
Objectives
To present the primary end point (week 12) and safety and ...efficacy data up to week 24 from a head‐to‐head trial (IXORA‐S) of the IL‐17A inhibitor ixekizumab (IXE) vs. the IL‐12/23 inhibitor ustekinumab (UST).
Methods
Randomized patients received IXE (160‐mg starting dose, then 80 mg every 2 weeks for 12 weeks, then 80 mg every 4 weeks, n = 136) or UST (45 mg or 90 mg weight‐based dosing per label, n = 166). The primary end point was the proportion of patients reaching ≥ 90% Psoriasis Area and Severity Index improvement (PASI 90). Hommel‐adjusted key secondary end points at week 12 included PASI 75, PASI 100, static Physician's Global Assessment (sPGA) score of 0 or 1, sPGA score of 0, Dermatology Life Quality Index (DLQI) score of 0 or 1, ≥ 4‐point reduction on the itch numerical rating scale (NRS) and changes in itch NRS and skin pain visual analogue scale.
Results
At week 12, IXE (n = 99, 72·8%) was superior to UST (n = 70, 42·2%) in PASI 90 response (response difference 32·1%, 97·5% confidence interval 19·8−44·5%, P < 0·001). Response rates for PASI 75, PASI 100 and sPGA (0,1) were significantly higher for IXE than for UST (adjusted P < 0·05). At week 24, IXE‐treated patients had significantly higher response rates than UST‐treated patients for PASI, sPGA and DLQI (unadjusted P < 0·05). No deaths were reported, and the treatments did not differ with regard to overall incidences of adverse events (P = 0·299).
Conclusions
The superior efficacy of IXE demonstrated at week 12 persisted up to week 24. The safety profiles were consistent with those previously reported for both treatments.
What's already known about this topic?
With the advancements in new biologics targeting the interleukin (IL)‐17A pathway, the majority of patients with moderate‐to‐severe psoriasis are now able to achieve complete or near complete clearance of psoriasis.
What does this study add?
The IL‐17A inhibitor ixekizumab provides superior efficacy over the IL‐12/23 inhibitor ustekinumab, with a similar safety profile after 24 weeks of treatment.
Linked Comment: Chu et al. Br J Dermatol 2017; 177:896–897.
Studies in the 1970s and 1980s suggested that environmental surface contamination played a negligible role in the endemic transmission of healthcare-associated infections. However, recent studies ...have demonstrated that several major nosocomial pathogens are shed by patients and contaminate hospital surfaces at concentrations sufficient for transmission, survive for extended periods, persist despite attempts to disinfect or remove them, and can be transferred to the hands of healthcare workers. Evidence is accumulating that contaminated surfaces make an important contribution to the epidemic and endemic transmission of Clostridium difficile, vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, Acinetobacter baumannii, Pseudomonas aeruginosa, and norovirus and that improved environmental decontamination contributes to the control of outbreaks. Efforts to improve environmental hygiene should include enhancing the efficacy of cleaning and disinfection and reducing the shedding of pathogens. Further high-quality studies are needed to clarify the role played by surfaces in nosocomial transmission and to determine the effectiveness of different interventions in reducing associated infection rates.
The Deepwater Horizon disaster released more than 636 million L of crude oil into the northern Gulf of Mexico. The spill oiled upper surface water spawning habitats for many commercially and ...ecologically important pelagic fish species. Consequently, the developing spawn (embryos and larvae) of tunas, swordfish, and other large predators were potentially exposed to crude oil-derived polycyclic aromatic hydrocarbons (PAHs). Fish embryos are generally very sensitive to PAH-induced cardiotoxicity, and adverse changes in heart physiology and morphology can cause both acute and delayed mortality. Cardiac function is particularly important for fast-swimming pelagic predators with high aerobic demand. Offspring for these species develop rapidly at relatively high temperatures, and their vulnerability to crude oil toxicity is unknown. We assessed the impacts of field-collected Deepwater Horizon (MC252) oil samples on embryos of three pelagic fish: bluefin tuna, yellowfin tuna, and an amberjack. We show that environmentally realistic exposures (1–15 µg/L total PAH) cause specific dose-dependent defects in cardiac function in all three species, with circulatory disruption culminating in pericardial edema and other secondary malformations. Each species displayed an irregular atrial arrhythmia following oil exposure, indicating a highly conserved response to oil toxicity. A considerable portion of Gulf water samples collected during the spill had PAH concentrations exceeding toxicity thresholds observed here, indicating the potential for losses of pelagic fish larvae. Vulnerability assessments in other ocean habitats, including the Arctic, should focus on the developing heart of resident fish species as an exceptionally sensitive and consistent indicator of crude oil impacts.
This study examined plasma levels of soluble urokinase-type plasminogen activator receptor (suPAR) and the estimated glomerular filtration rate at baseline and incident CKD. Higher suPAR levels ...predicted incident CKD and an accelerated decline in the eGFR.
Chronic kidney disease and progressive loss of kidney function constitute a major public health problem affecting 11% of the U.S. population.
1
Patients with chronic kidney disease are at high risk for cardiovascular disease and death.
2
It is thus important to identify patients at high risk for chronic kidney disease and to treat underlying disease processes that drive kidney injury.
3
In clinical practice, methods of screening for kidney disease are limited to measurement of urinary protein excretion and calculation of the estimated glomerular filtration rate (eGFR). Proteinuria and a decline in the eGFR are relatively insensitive indexes of early injury and . . .
Summary
Neutrophils constitute essential players in inflammatory responses and are the first line of defence against harmful stimuli. However, dysregulation of neutrophil homeostasis can result in ...excessive inflammation and subsequent tissue damage. Neutrophilic dermatoses are a spectrum of inflammatory disorders characterized by skin lesions resulting from a neutrophil‐rich inflammatory infiltrate in the absence of infection. The exact molecular pathophysiology of neutrophilic dermatoses has long been poorly understood. Interestingly, neutrophil‐rich cutaneous inflammation is also a cardinal feature of several autoinflammatory diseases with skin involvement, the latter being caused by aberrant innate immune responses. Overactivation of the innate immune system leading to increased production of interleukin‐1 family members and ‘sterile’ neutrophil‐rich cutaneous inflammation are features of both inherited autoinflammatory syndromes with skin involvement and an increasing number of neutrophilic dermatoses. Therefore, we propose that autoinflammation may be a cause of neutrophilic dermatoses.
What's already known about this topic?
Many inherited autoinflammatory diseases have characteristic skin manifestations composed of a neutrophil‐rich cutaneous inflammatory infiltrate.
Neutrophilic dermatoses have similar clinical skin manifestations to inherited autoinflammatory diseases caused by overproduction of certain cytokines of the interleukin‐1 family.
What does this study add?
Certain unifying features of these disorders suggest that they are a cutaneous consequence of autoinflammation and may be considered as autoinflammatory diseases.
Some of these neutrophilic dermatoses may lack IL‐1 as a triggering cytokine, but can still benefit from IL‐1‐targeted therapy.
PDF
