Urinary tract infections (UTIs) are common, recurrent infections that can be mild to life-threatening. The continued emergence of antibiotic resistance, together with our increasing understanding of ...the detrimental effects conferred by broad-spectrum antibiotic use on the health of the beneficial microbiota of the host, has underscored the weaknesses in our current treatment paradigm for UTIs. In this Review, we discuss how recent microbiological, structural, genetic and immunological studies have expanded our understanding of host-pathogen interactions during UTI pathogenesis. These basic scientific findings have the potential to shift the strategy for UTI treatment away from broad-spectrum antibiotics targeting conserved aspects of bacterial replication towards pathogen-specific antibiotic-sparing therapeutics that target core determinants of bacterial virulence at the host-pathogen interface.
The tooth provides an excellent system for deciphering the molecular mechanisms of organogenesis, and has thus been of longstanding interest to developmental and stem cell biologists studying ...embryonic morphogenesis and adult tissue renewal. In recent years, analyses of molecular signaling networks, together with new insights into cellular heterogeneity, have greatly improved our knowledge of the dynamic epithelial-mesenchymal interactions that take place during tooth development and homeostasis. Here, we review recent progress in the field of mammalian tooth morphogenesis and also discuss the mechanisms regulating stem cell-based dental tissue homeostasis, regeneration and repair. These exciting findings help to lay a foundation that will ultimately enable the application of fundamental research discoveries toward therapies to improve oral health.
Parkinson's disease has long been considered idiopathic, with most cases having no apparent genetic cause. However, Klein and Mazzulli argue that recent data instead indicate that Parkinson's disease ...is a complex genetic disorder, involving a combinatorial code made up of partially penetrant mutations that converge on lysosomal cellular clearance pathways.
Abstract
Common forms of Parkinson's disease have long been described as idiopathic, with no single penetrant genetic factor capable of influencing disease aetiology. Recent genetic studies indicate a clear association of variants within several lysosomal genes as risk factors for idiopathic Parkinson's disease. The emergence of novel variants suggest that the aetiology of idiopathic Parkinson's disease may be explained by the interaction of several partially penetrant mutations that, while seemingly complex, all appear to converge on cellular clearance pathways. These newly evolving data are consistent with mechanistic studies linking α-synuclein toxicity to lysosomal abnormalities, and indicate that idiopathic Parkinson's disease resembles features of Mendelian lysosomal storage disorders at a genetic and biochemical level. These findings offer novel pathways to exploit for the development of disease-altering therapies for idiopathic Parkinson's disease that target specific components of the lysosomal system.
Purpose
The EUPHRATES trial examined the impact of polymyxin B hemoperfusion (PMX) on mortality in patients with septic shock and endotoxemia, defined as EAA ≥ 0.60. No difference was found in 28-day ...all-cause mortality. However, the trial showed that in some patients with septic shock the burden of endotoxin activity was extreme (EAA ≥ 0.9). In a post hoc analysis, we evaluated the impact of PMX use in patients with septic shock and endotoxin activity measured between 0.6–0.89.
Methods
Post-hoc analysis of the EUPHRATES trial for the 194 patients with EAA ≥ 0.6–0.89 who completed two treatments (PMX or sham). The primary end point was mortality at 28 days adjusted for APACHE II score and baseline mean arterial pressure (MAP). Additional end points included changes in MAP, cumulative vasopressor index (CVI), median EAA reduction, ventilator-free days (VFD), dialysis-free days (DFD) and hospital length of stay. Subpopulations analyzed were site and type of infection and those with norepinephrine dose > 0.1 mcg/kg/min at baseline.
Results
At 28 days, 23 patients of 88 (26.1%) in the PMX group died versus 39 of 106 (36.8%) in the sham group risk difference 10.7%, OR 0.52, 95% CI (0.27, 0.99),
P
= 0.047. When unadjusted for baseline variables,
P
= 0.11. The 28-day survival time in the PMX group was longer than for the sham group HR 0.56 (95% CI 0.33, 0.95)
P
= 0.03. PMX treatment compared with sham showed greater change in MAP median (IQR) 8 mmHg (− 0.5, 19.5) vs. 4 mmHg (− 4.0, 11)
P
= 0.04 and VFD median (IQR) 20 days (0.5, 23.5) vs. 6 days (0, 20),
P
= 0.004. There were no significant differences in other end points. There was a significant difference in mortality in PMX-treated patients with no bacterial growth on culture PMX, 6/30 (20%) vs. sham, 13/31 (41.9%),
P
= 0.005. The median EAA change in the population was − 12.9% (range: increase 49.2%–reduction 86.3%). The mortality in the above median EAA change group was PMX: 6/38 (15.7%) vs. sham 15/49 (30.6%),
P
= 0.08.
Conclusions
These hypothesis-generating results, based on an exploratory post hoc analysis of the EUPHRATES trial, suggest measurable responses in patients with septic shock and an EAA ≥ 0.6 to 0.89 on changes in mean arterial pressure, ventilator-free days and mortality.
Trial registration
Clinicaltrials.gov Identifier: NCT01046669. Funding Spectral Medical Incorporated.
Magnetic insulators are a key resource for next-generation spintronic and topological devices. The family of layered metal halides promises varied magnetic states, including ultrathin insulating ...multiferroics, spin liquids, and ferromagnets, but device-oriented characterization methods are needed to unlock their potential. Here, we report tunneling through the layered magnetic insulator CrI
as a function of temperature and applied magnetic field. We electrically detect the magnetic ground state and interlayer coupling and observe a field-induced metamagnetic transition. The metamagnetic transition results in magnetoresistances of 95, 300, and 550% for bilayer, trilayer, and tetralayer CrI
barriers, respectively. We further measure inelastic tunneling spectra for our junctions, unveiling a rich spectrum consistent with collective magnetic excitations (magnons) in CrI
.
Brain Disorders Due to Lysosomal Dysfunction Fraldi, Alessandro; Klein, Andrés D; Medina, Diego L ...
Annual review of neuroscience,
07/2016, Letnik:
39, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Recent studies of autophagic and lysosomal pathways have significantly changed our understanding of lysosomes; once thought to be simple degradative and recycling centers, lysosomes are now known to ...be organelles capable of influencing signal transduction, via the mammalian target of rapamycin complex 1 (mTORC1), and regulating gene expression, via transcription factor EB (TFEB) and other transcription factors. These pathways are particularly relevant to maintaining brain homeostasis, as dysfunction of the endolysosomal and autophagic pathways has been associated with common neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's, and lysosomal storage disorders, a group of inherited disorders characterized by the intralysosomal buildup of partially degraded metabolites. This review focuses on the cellular biology of lysosomes and discusses the possible mechanisms by which disruption of their function contributes to neurodegeneration. We also review and discuss how targeting TFEB and lysosomes may offer innovative therapeutic approaches for treating a wide range of neurological conditions.
Complementary medicine (CM) is popular in Switzerland. Several CM methods (traditional Chinese medicine/acupuncture, homeopathy, anthroposophic medicine, neural therapy, and herbal medicine) are ...currently covered by the mandatory basic health insurance when performed by a certified physician. Treatments by non-medical therapists are partially covered by a supplemental and optional health insurance. In this study, we investigated the frequency of CM use including the evolvement over time, the most popular methods, and the user profile.
Data of the Swiss Health Surveys 2007 and 2012 were used. In 2007 and 2012, a population of 14,432 and 18,357, respectively, aged 15 years or older answered the written questionnaire. A set of questions queried about the frequency of use of various CM methods within the last 12 months before the survey. Proportions of usage and 95% confidence intervals were calculated for these methods and CM in general. Users and non-users of CM were compared using logistic regression models.
The most popular methods in 2012 were homeopathy, naturopathy, osteopathy, herbal medicine, and acupuncture. The average number of treatments within the 12 months preceding the survey ranged from 3 for homeopathy to 6 for acupuncture. 25.0% of the population at the age of 15 and older had used at least one CM method in the previous 12 months. People with a chronic illness or a poor self-perceived health status were more likely to use CM. Similar to other countries, women, people of middle age, and those with higher education were more likely to use CM. 59.9% of the adult population had a supplemental health insurance that partly covered CM treatments.
Usage of CM in Switzerland remained unchanged between 2007 and 2012. The user profile in Switzerland was similar to other countries, such as Germany, United Kingdom, United States or Australia.
β-Glucocerebrosidase (GCase) mutations lead to glucosylceramide build-up in the lysosome, impacting α-synuclein aggregation and autophagy. Recently, Baden and colleagues found GCase in mitochondria, ...supporting mitochondrial complex I function and energy metabolism. We believe the newly described role of GCase in the mitochondria will inform new Parkinson’s and Gaucher’s disease therapeutics.
The objective of this review is to provide the reader with an overview of thermoregulatory mechanisms and the influence of climatic conditions in different housing systems on the development, ...performance, and health of calves. Thermic stress is observed in association with extreme temperatures and large temperature variations, but other variables such as relative humidity and wind speed can also contribute to thermic stress. Thermoregulation in calves is similar to that in adult cattle, but especially dystocial calves are more prone to heat loss. Heat or cold stress results in direct economic losses because of increased calf mortality and morbidity, as well as indirect costs caused by reduced weight gain, performance, and long-term survival. The climatic conditions in a variety of housing systems, associated health problems, and strategies to mitigate thermic stress are discussed in this review. The goal of housing is to alleviate the effect of climate on calves and provide a microclimate. Adequate ventilation with fresh air is essential to reduce respiratory disease. Common practices such as raising calves in individual outdoor enclosures have been challenged lately. Recent research seeks to evaluate the suitability of group housing under practical, economic, and animal welfare considerations. Limited results for reducing thermic stress can be achieved by simple measures such as shades or shelter, but additional heat or cold stress relieving strategies can be required depending on the housing system.
Rhodanines and related five-membered heterocycles with multiple heteroatoms have recently gained a reputation of being unselective compounds that appear as "frequent hitters" in screening campaigns ...and therefore have little value in drug discovery. However, this judgment appears to be based mostly on anecdotal evidence. Having identified various rhodanines and related compounds in screening campaigns, we decided to perform a systematic study on their promiscuity. An amount of 163 rhodanines, hydantoins, thiohydantoins, and thiazolidinediones were synthesized and tested against several targets. The compounds were also characterized with respect to aggregation and electrophilic reactivity, and the binding modes of rhodanines and related compounds in published X-ray cocrystal structures were analyzed. The results indicate that the exocyclic, double bonded sulfur atom in rhodanines and thiohydantoins, in addition to other structural features, offers a particularly high density of interaction sites for polar interactions and hydrogen bonds. This causes a promiscuous behavior at concentrations in the "screening range" but should not be regarded as a general knockout criterion that excludes such screening hits from further development. It is suggested that special criteria for target affinity and selectivity are applied to these classes of compounds and that their exceptional and potentially valuable biomolecular binding properties are consequently exploited in a useful way.
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