Gaucher disease (GD, ORPHA355) is a rare, autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its ...substrate, glucosylceramide, in macrophages. In the general population, its incidence is approximately 1/40,000 to 1/60,000 births, rising to 1/800 in Ashkenazi Jews. The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells. Type-1 Gaucher disease, which affects the majority of patients (90% in Europe and USA, but less in other regions), is characterized by effects on the viscera, whereas types 2 and 3 are also associated with neurological impairment, either severe in type 2 or variable in type 3. A diagnosis of GD can be confirmed by demonstrating the deficiency of acid glucocerebrosidase activity in leukocytes. Mutations in the
gene should be identified as they may be of prognostic value in some cases. Patients with type-1 GD-but also carriers of
mutation-have been found to be predisposed to developing Parkinson's disease, and the risk of neoplasia associated with the disease is still subject to discussion. Disease-specific treatment consists of intravenous enzyme replacement therapy (ERT) using one of the currently available molecules (imiglucerase, velaglucerase, or taliglucerase). Orally administered inhibitors of glucosylceramide biosynthesis can also be used (miglustat or eliglustat).
A number of life-saving drugs require therapeutic drug monitoring (TDM) for safe and effective use. Currently, however, TDM is performed using sophisticated analytical techniques relegated to central ...labs, increasing the cost per test and time to answer. Here, using a novel vertical flow membrane system with inkjet-printed surface enhanced Raman sensors, along with a portable spectrometer, we demonstrate a low cost and easy to use device to quantify levels of flucytosine, an antifungal that requires TDM for effective patient care, from undiluted human serum. To our knowledge, this work represents the first report of a passive vertical flow sample cleanup method with surface enhanced Raman detection. We first investigated and optimized the parameters of the vertical flow system for the detection of flucytosine in spiked serum samples. Then, using an optimized vertical-flow system utilizing nitrocellulose membranes and a paper SERS sensor, we achieved detection of down to 10 μg mL−1 flucytosine in undiluted serum, with quantitative detection across the entire therapeutic range. This system reduces the assay time to about 15 min, far quicker than the current gold standards. We anticipate that this novel system will enable near-patient therapeutic drug monitoring, leading to the safe and effective administration of a number of life-saving drugs. Furthermore, it will spawn the development of SERS detection systems capable of separating target analytes from real-world biological matrices.
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•We demonstrate the use of paper SERS sensors for therapeutic drug monitoring.•Paper SERS sensors are integrated into a passive vertical flow system for serum separation.•We demonstrate detection of down to 10 μg/mL flucytosine in undiluted serum.•We show quantitative detection across the entire therapeutic range.
Pruritus in the Older Patient: A Clinical Review Berger, Timothy G; Shive, Melissa; Harper, G. Michael
JAMA : the journal of the American Medical Association,
12/2013, Letnik:
310, Številka:
22
Journal Article
Recenzirano
IMPORTANCE Pruritus is a common problem among elderly people and, when severe, causes as much discomfort as chronic pain. Little evidence supports pruritus treatment, limiting therapeutic ...possibilities and resulting in challenging management problems. OBJECTIVES To present the evidence on the etiology, diagnosis, and treatment of pruritus in the elderly and, using the best available evidence, provide an approach for generalist physicians caring for older patients with pruritus. EVIDENCE REVIEW PubMed and EMBASE databases were searched (1946–August 2013).The Cochrane Database of Systematic Reviews and the Agency for Healthcare Research and Quality Systematic Review Data Repository were also searched from their inception to August 2013. References from retrieved articles were evaluated. FINDINGS More than 50% of elderly patients have xerosis (dry skin). Xerosis treatment should be included in the initial therapy for pruritus in all elderly patients. Calcium channel blockers and hydrochlorothiazide are important causes of pruritic skin eruptions in older patients. Neuropathic pruritus is infrequently considered but may cause localized itching (especially in the genital area) and generalized truncal pruritus (especially in patients with diabetes mellitus). Certain skin conditions are more common in elderly patients, including scabies, bullous pemphigoid, transient acantholytic dermatosis, and mycosis fungoides, and should be considered in elderly patients with pruritus. CONCLUSIONS AND RELEVANCE It is important to evaluate elderly patients for dermatological, systemic, and neurological etiologies of itch. A simple-to-apply diagnostic and therapeutic algorithm can be used. Xerosis, drug reactions, and neuropathy should be considered when evaluating pruritus.
This book is an introduction to the fascinating world of aroma chemicals, essential oils, fragrances and flavour compositions for the food, cosmetics and pharmaceutical industry. The present ...state-of-the-art technology, the future use of resources and biotechnological approaches for the production of the respective chemical compounds are described. A large section is devoted to the description of the renewable resources of flavours: spice plants, fruits from moderate to tropical climates, vegetables, fermented and heated plants. Analytical methods, such as gas chromatography coupled to human or electronic noses or to a mass spectrometer, are outlined and consumer trends, legal and safety aspects are described. Novel renewable resources come from biotechnology. Enzymes, for example, bio-transform cheap substrates to produce flavours de novo, plant cells in culture may serve as a rich resource of genes coding for metabolic activities in transgenic producers. The book will be of great interest to scientists and engineers in the food, flavour, fragrance and pharmaceutical industries and all respective researchers in academia.
Over the past several decades, the incidence of early-onset colorectal cancer (EOCRC; in patients <50 years old) has increased at an alarming rate. Although robust and scientifically rigorous ...epidemiological studies have sifted out environmental elements linked to EOCRC, our knowledge of the causes and mechanisms of this disease is far from complete. Here, we highlight potential risk factors and putative mechanisms that drive EOCRC and suggest likely areas for fruitful research. In addition, we identify inconsistencies in the evidence implicating a strong effect of increased adiposity and suggest that certain behaviours (such as diet and stress) might place nonobese and otherwise healthy people at risk of this disease. Key risk factors are reviewed, including the global westernization of diets (usually involving a high intake of red and processed meats, high-fructose corn syrup and unhealthy cooking methods), stress, antibiotics, synthetic food dyes, monosodium glutamate, titanium dioxide, and physical inactivity and/or sedentary behaviour. The gut microbiota is probably at the crossroads of these risk factors and EOCRC. The time course of the disease and the fact that relevant exposures probably occur in childhood raise important methodological issues that are also discussed.
To accelerate the translation of cancer nanomedicine, we used an integrated genomic approach to improve our understanding of the cellular processes that govern nanoparticle trafficking. We developed ...a massively parallel screen that leverages barcoded, pooled cancer cell lines annotated with multiomic data to investigate cell association patterns across a nanoparticle library spanning a range of formulations with clinical potential. We identified both materials properties and cell-intrinsic features that mediate nanoparticle-cell association. Using machine learning algorithms, we constructed genomic nanoparticle trafficking networks and identified nanoparticle-specific biomarkers. We validated one such biomarker: gene expression of
, which inversely predicts lipid-based nanoparticle uptake in vitro and in vivo. Our work establishes the power of integrated screens for nanoparticle delivery and enables the identification and utilization of biomarkers to rationally design nanoformulations.
Traditional smoke flavours bear the risk of containing a multitude of contaminating carcinogenic side-products. Enzymatic decarboxylation of ferulic acid released from agro-industrial side-streams by ...ferulic acid esterases (FAE) enables the sustainable generation of pure, food grade 4-vinylguaiacol (4-VG), the impact compound of smoke flavour. The first basidiomycetous ferulic acid decarboxylase (FAD) was isolated from Schizophyllum commune (ScoFAD) and heterologously produced by Komagataella phaffii. It showed a molecular mass of 21 kDa, catalytic optima at pH 5.5 and 35°C, and a sequence identity of 63.6% to its next relative, a FAD from the ascomycete Cordyceps farinosa. The ScoFAD exhibited a high affinity to its only known substrate ferulic acid (FA) of 0.16 mmol L-1 and a turnover number of 750 s-1. The resulting catalytic efficiency kcat KM-1 of 4,779 L s-1 mmol-1 exceeded the next best known enzyme by more than a factor of 50. Immobilised on AminoLink Plus Agarose, ScoFAD maintained its activity for several days. The combination with FAEs and agro-industrial side-streams paves the way for a new generation of sustainable, clean, and safe smoke flavours.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The DNA damage response involves a complex network of processes that detect and repair DNA damage. Here we show that miRNA biogenesis is globally induced upon DNA damage in an ATM-dependent manner. ...About one-fourth of miRNAs are significantly upregulated after DNA damage, while loss of ATM abolishes their induction. KH-type splicing regulatory protein (KSRP) is a key player that translates DNA damage signaling to miRNA biogenesis. The ATM kinase directly binds to and phosphorylates KSRP, leading to enhanced interaction between KSRP and pri-miRNAs and increased KSRP activity in miRNA processing. Mutations of the ATM phosphorylation sites of KSRP impaired its activity in regulating miRNAs. These findings reveal a mechanism by which DNA damage signaling is linked to miRNA biogenesis.
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► One-fourth of miRNAs are induced upon DNA damage in an ATM-dependent manner ► KSRP-induced miRNAs are upregulated in the DNA damage response ► The ATM kinase directly binds to and phosphorylates KSRP ► ATM phosphorylation increases KSRP activity in miRNA processing
•Model estimated yield was not more accurate than a simple regression estimation.•Assimilating remote sensing data into a crop model correctly estimated yield spatial variability.•Remote ...sensing-model data assimilation could be useful to recreate yield maps from archive data.•Adjusted model parameters during assimilation could provide useful derived metrics of the site.
Early prediction of crop yields has been a challenge frequently resolved through the combination of remote sensing data and crop models. The aim of this study was to evaluate two different methods based on remote sensing data for predicting winter wheat (Triticum aestivum L.) yield at field scale. We compared the accuracy of: (i) a simple regression method between different vegetation indices at anthesis and grain yield, and (ii) a crop model method based on optimization of two parameters (specific leaf nitrogen and initial aboveground-biomass) using time series of vegetation indices. Vegetation indices were derived from Landsat-7 Enhanced Thematic Mapper Plus (ETM+) and Landsat-8 Operational Land Imager (OLI) images acquired for two growing seasons (2013, 2014) across 22 fields in south western Uruguay with an average size of 128 ha. At all sites, leaf area index (LAI) was measured during a field campaign, and grain yield was measured with yield monitors on harvesters. The simple regression method (SRM) achieved higher accuracy than the model-based method (CMM) for the estimation of yield at field scale (RMSE = 966 kg ha−1 and RMSE = 1532 kg ha−1, respectively). When deviations between observed and estimated yields were evaluated at pixel (30 × 30 m) level, the model-based method was better at detecting existing spatial variability in grain yield and at identifying areas of different yield potential. Even though both methods have limited utility to estimate yield at field scale with very high accuracy due to large RMSE, the methodologies are suitable to predict harvest volumes at large agricultural areas or at country level, and to construct synthetic yield maps reflecting within field variability. Higher temporal resolution of images would improve accuracy in estimating yield and spatial variability at field scale.
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