•Rehydration properties of milk protein concentrates (MPCs) deteriorated as protein content increased.•‘Skins’ of inter-linked casein micelles at particle surfaces in high-protein MPCs were slow to ...disperse.•Partial dispersion of poorly-dispersible particles eventually resulted in a stable suspension.•Rehydration performance was improved when ionic strength of the dispersant and temperature of reconstitution were increased.
Low-(MPC35, MPC50), medium-(MPC60, MPC70) and high-(MPC80, MPC85, MPC90) protein content milk protein concentrate (MPC) powders, manufactured at pilot-scale, were evaluated for their rehydration characteristics. Optical tensiometry confirmed that water droplets were imbibed more slowly as protein content of the MPCs increased, indicating impaired wetting. Casein micelles comprised only<2% of the particle population by volume in MPC70, MPC80, MPC85 or MPC90 after 90min of rehydration at 25°C, as primary particles which had not dispersed fully remained in suspension. The quantity of sediment, measured using analytical centrifugation, increased in the order MPC70<MPC80<MPC85<MPC90 after 90min of rehydration at 25°C, with lower protein MPCs forming no sediment. No sediment formation was observed in any of the MPCs after 24h of rehydration at 25°C, despite the predominance of primary particles in suspensions of high-protein MPCs. Increasing the temperature of reconstitution from 25 to 50°C during 90min of rehydration caused a 41.4% decrease in sediment height for MPC90 in water; however, reductions in sediment height of 89.9% and 99.5% were achieved when MPC90 was rehydrated in milk permeate or 80mM KCl, respectively. It is evident that low ionic strength (confirmed using conductimetry) has a strong negative effect on the rehydration properties of high-protein MPCs, and that the synergistic effect of increasing ionic strength and temperature can substantially accelerate rehydration.
Abstract
A panel of national experts was convened by the Infectious Diseases Society of America (IDSA) to update the 2005 guidelines for the treatment of skin and soft tissue infections (SSTIs). The ...panel's recommendations were developed to be concordant with the recently published IDSA guidelines for the treatment of methicillin-resistant Staphylococcus aureus infections. The focus of this guideline is the diagnosis and appropriate treatment of diverse SSTIs ranging from minor superficial infections to life-threatening infections such as necrotizing fasciitis. In addition, because of an increasing number of immunocompromised hosts worldwide, the guideline addresses the wide array of SSTIs that occur in this population. These guidelines emphasize the importance of clinical skills in promptly diagnosing SSTIs, identifying the pathogen, and administering effective treatments in a timely fashion.
A panel of national experts was convened by the Infectious Diseases Society of America (IDSA) to update the 2005 guidelines for the treatment of skin and soft tissue infections (SSTIs). The panel's ...recommendations were developed to be concordant with the recently published IDSA guidelines for the treatment of methicillin-resistant Staphylococcus aureus infections. The focus of this guideline is the diagnosis and appropriate treatment of diverse SSTIs ranging from minor superficial infections to life-threatening infections such as necrotizing fasciitis. In addition, because of an increasing number of immunocompromised hosts worldwide, the guideline addresses the wide array of SSTIs that occur in this population. These guidelines emphasize the importance of clinical skills in promptly diagnosing SSTIs, identifying the pathogen, and administering effective treatments in a timely fashion.
Human milk is the ideal nutrition source for healthy infants during the first six months of life and a detailed characterisation of the composition of milk from mothers that deliver prematurely (<37 ...weeks gestation), and of how human milk changes during lactation, would benefit our understanding of the nutritional requirements of premature infants. Individual milk samples from mothers delivering prematurely and at term were collected. The human milk metabolome, established by nuclear magnetic resonance (NMR) spectroscopy, was influenced by gestational and lactation age. Metabolite profiling identified that levels of valine, leucine, betaine, and creatinine were increased in colostrum from term mothers compared with mature milk, while those of glutamate, caprylate, and caprate were increased in mature term milk compared with colostrum. Levels of oligosaccharides, citrate, and creatinine were increased in pre-term colostrum, while those of caprylate, caprate, valine, leucine, glutamate, and pantothenate increased with time postpartum. There were differences between pre-term and full-term milk in the levels of carnitine, caprylate, caprate, pantothenate, urea, lactose, oligosaccharides, citrate, phosphocholine, choline, and formate. These findings suggest that the metabolome of pre-term milk changes within 5-7 weeks postpartum to resemble that of term milk, independent of time of gestation at pre-mature delivery.
Metastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis. In mouse models of thyroid cancer, selective mitogen-activated protein kinase (MAPK) ...pathway antagonists increase the expression of the sodium-iodide symporter and uptake of iodine. Their effects in humans are not known.
We conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. After stimulation with thyrotropin alfa, dosimetry with iodine-124 positron-emission tomography (PET) was performed before and 4 weeks after treatment with selumetinib (75 mg twice daily). If the second iodine-124 PET study indicated that a dose of iodine-131 of 2000 cGy or more could be delivered to the metastatic lesion or lesions, therapeutic radioiodine was administered while the patient was receiving selumetinib.
Of 24 patients screened for the study, 20 could be evaluated. The median age was 61 years (range, 44 to 77), and 11 patients were men. Nine patients had tumors with BRAF mutations, and 5 patients had tumors with mutations of NRAS. Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS mutations). Eight of these 12 patients reached the dosimetry threshold for radioiodine therapy, including all 5 patients with NRAS mutations. Of the 8 patients treated with radioiodine, 5 had confirmed partial responses and 3 had stable disease; all patients had decreases in serum thyroglobulin levels (mean reduction, 89%). No toxic effects of grade 3 or higher attributable by the investigators to selumetinib were observed. One patient received a diagnosis of myelodysplastic syndrome more than 51 weeks after radioiodine treatment, with progression to acute leukemia.
Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. (Funded by the American Thyroid Association and others; ClinicalTrials.gov number, NCT00970359.).
Dissection of complex biological systems requires target-specific control of the function or abundance of proteins. Genetic perturbations are limited by off-target effects, multicomponent complexity, ...and irreversibility. Most limiting is the requisite delay between modulation to experimental measurement. To enable the immediate and selective control of single protein abundance, we created a chemical biology system that leverages the potency of cell-permeable heterobifunctional degraders. The dTAG system pairs a novel degrader of FKBP12
with expression of FKBP12
in-frame with a protein of interest. By transgene expression or CRISPR-mediated locus-specific knock-in, we exemplify a generalizable strategy to study the immediate consequence of protein loss. Using dTAG, we observe an unexpected superior antiproliferative effect of pan-BET bromodomain degradation over selective BRD4 degradation, characterize immediate effects of KRAS
loss on proteomic signaling, and demonstrate rapid degradation in vivo. This technology platform will confer kinetic resolution to biological investigation and provide target validation in the context of drug discovery.
Exacerbations of asthma cause a substantial global illness burden. Adults with uncontrolled persistent asthma despite maintenance treatment require additional therapy. Since macrolide antibiotics can ...be used to treat persistent asthma, we aimed to assess the efficacy and safety of oral azithromycin as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high dose inhaled corticosteroids plus a long-acting bronchodilator.
We did a randomised, double-blind, placebo controlled parallel group trial to determine whether oral azithromycin decreases the frequency of asthma exacerbations in adults (≥18 years) with symptomatic asthma despite current use of inhaled corticosteroid and long-acting bronchodilator, and who had no hearing impairment or abnormal prolongation of the corrected QT interval. Patients were randomly assigned (1:1) to receive azithromycin 500 mg or placebo three times per week for 48 weeks. Patients were centrally allocated using concealed random allocation from a computer-generated random numbers table with permuted blocks of 4 or 6 and stratification for centre and past smoking. Primary efficacy endpoints were the rate of total (severe and moderate) asthma exacerbations over 48 weeks and asthma quality of life. Data were analysed on an intention-to-treat basis. The trial is registered at the Australian and New Zealand Clinical Trials Registry (ANZCTR), number 12609000197235.
Between June 12, 2009, and Jan 31, 2015, 420 patients were randomly assigned (213 in the azithromycin group and 207 in the placebo group). Azithromycin reduced asthma exacerbations (1·07 per patient-year 95% CI 0·85–1·29) compared with placebo (1·86 per patient-year 1·54–2·18; incidence rate ratio IRR 0·59 95% CI 0·47–0·74; p<0·0001). The proportion of patients experiencing at least one asthma exacerbation was reduced by azithromycin treatment (127 61% patients in the placebo group vs 94 44% patients in the azithromycin group, p<0·0001). Azithromycin significantly improved asthma-related quality of life (adjusted mean difference, 0·36 95% CI 0·21–0·52; p=0·001). Diarrhoea was more common in azithromycin-treated patients (72 34% vs 39 19%; p=0·001).
Adults with persistent symptomatic asthma experience fewer asthma exacerbations and improved quality of life when treated with oral azithromycin for 48 weeks. Azithromycin might be a useful add-on therapy in persistent asthma.
National Health and Medical Research Council of Australia, John Hunter Hospital Charitable Trust.
Increased thickness of the airway smooth muscle (ASM) layer in asthma may result from hyperplasia or hypertrophy of muscle cells or increased extracellular matrix (ECM).
To relate ASM hypertrophy, ...ASM hyperplasia, and deposition of ECM to the severity and duration of asthma.
Airways from control subjects (n = 51) and from cases of nonfatal (n = 49) and fatal (n = 55) asthma were examined postmortem. Mean ASM cell volume (V(C)), the number of ASM cells per length of airway (N(L)), and the volume fraction of extracellular matrix (f(ECM)) within the ASM layer were estimated. Comparisons between subject groups were made on the basis of general linear regression models.
Mean V(C) was increased in the large airways of cases of nonfatal asthma (P = 0.015) and fatal asthma (P < 0.001) compared with control subjects. N(L) was similar in nonfatal cases and control subjects but increased in large (P < 0.001), medium (P < 0.001), and small (P = 0.034) airways of cases of fatal asthma compared with control subjects and with nonfatal cases (large and medium airways, P ≤ 0.003). The f(ECM) was similar in cases of asthma and control subjects. Duration of asthma was associated with a small increase in N(L).
Hypertrophy of ASM cells occurs in the large airways in both nonfatal and fatal cases of asthma, but hyperplasia of ASM cells is present in the large and small airways in fatal asthma cases only. Both are associated with an absolute increase in ECM. Duration of asthma has little or no effect on ASM hypertrophy or hyperplasia or f(ECM).
Abstract
More people globally depend on the water buffalo than any other domesticated species, and as the most closely related domesticated species to cattle they can provide important insights into ...the shared evolutionary basis of domestication. Here, we sequence the genomes of 79 water buffalo across seven breeds and compare patterns of between breed selective sweeps with those seen for 294 cattle genomes representing 13 global breeds. The genomic regions under selection between cattle breeds significantly overlap regions linked to stature in human genetic studies, with a disproportionate number of these loci also shown to be under selection between water buffalo breeds. Investigation of potential functional variants in the water buffalo genome identifies a rare example of convergent domestication down to the same mutation having independently occurred and been selected for across domesticated species. Cross-species comparisons of recent selective sweeps can consequently help identify and refine important loci linked to domestication.
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