ame Allergies: As American as Apple Pie? By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Allergies: As American as Apple Pie?Category: Health NewsCreated: 4/29/2013 4:35:00 PMLast Editorial Review: 4/30/2013 12:00:00 AM Full Article
ame Steep Rise in Suicides Among Middle-Aged Americans, CDC Says By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Steep Rise in Suicides Among Middle-Aged Americans, CDC SaysCategory: Health NewsCreated: 5/2/2013 12:35:00 PMLast Editorial Review: 5/3/2013 12:00:00 AM Full Article
ame 4 in 10 Americans Breathe Unhealthy Air: Report By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: 4 in 10 Americans Breathe Unhealthy Air: ReportCategory: Health NewsCreated: 4/29/2015 12:00:00 AMLast Editorial Review: 4/30/2015 12:00:00 AM Full Article
ame Most Americans Turn to Prayer for Healing, Survey Finds By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Most Americans Turn to Prayer for Healing, Survey FindsCategory: Health NewsCreated: 4/22/2016 12:00:00 AMLast Editorial Review: 4/25/2016 12:00:00 AM Full Article
ame Americans Getting Adequate Water Daily, CDC Finds By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Americans Getting Adequate Water Daily, CDC FindsCategory: Health NewsCreated: 4/26/2016 12:00:00 AMLast Editorial Review: 4/27/2016 12:00:00 AM Full Article
ame 1 in 3 Americans May Have Had Warning Stroke Without Knowing It By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: 1 in 3 Americans May Have Had Warning Stroke Without Knowing ItCategory: Health NewsCreated: 5/1/2017 12:00:00 AMLast Editorial Review: 5/2/2017 12:00:00 AM Full Article
ame Life Expectancy Goes Up for Black Americans By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Life Expectancy Goes Up for Black AmericansCategory: Health NewsCreated: 5/2/2017 12:00:00 AMLast Editorial Review: 5/3/2017 12:00:00 AM Full Article
ame Americans Uneasy With Push to Repeal Obamacare: <i>HealthDay/Harris Poll</i> By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Americans Uneasy With Push to Repeal Obamacare: HealthDay/Harris PollCategory: Health NewsCreated: 5/4/2017 12:00:00 AMLast Editorial Review: 5/4/2017 12:00:00 AM Full Article
ame House to Vote Thursday on Amended Bill to Repeal and Replace Obamacare By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: House to Vote Thursday on Amended Bill to Repeal and Replace ObamacareCategory: Health NewsCreated: 5/4/2017 12:00:00 AMLast Editorial Review: 5/4/2017 12:00:00 AM Full Article
ame How to Tame Morning Chaos By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: How to Tame Morning ChaosCategory: Health NewsCreated: 4/30/2019 12:00:00 AMLast Editorial Review: 4/30/2019 12:00:00 AM Full Article
ame AHA News: Director John Singleton's Fatal Stroke Spotlights Black Americans' Hypertension Risk By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: AHA News: Director John Singleton's Fatal Stroke Spotlights Black Americans' Hypertension RiskCategory: Health NewsCreated: 5/2/2019 12:00:00 AMLast Editorial Review: 5/2/2019 12:00:00 AM Full Article
ame Most Americans Hit Hard by Medical Bills By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Most Americans Hit Hard by Medical BillsCategory: Health NewsCreated: 5/2/2019 12:00:00 AMLast Editorial Review: 5/2/2019 12:00:00 AM Full Article
ame A Heart-Healthy Prescription for America's Food System By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: A Heart-Healthy Prescription for America's Food SystemCategory: Health NewsCreated: 5/2/2019 12:00:00 AMLast Editorial Review: 5/3/2019 12:00:00 AM Full Article
ame There Aren't Enough Coronavirus Test Kits to Safely Reopen America, Experts Warn By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: There Aren't Enough Coronavirus Test Kits to Safely Reopen America, Experts WarnCategory: Health NewsCreated: 4/27/2020 12:00:00 AMLast Editorial Review: 4/27/2020 12:00:00 AM Full Article
ame Costs Would Keep 1 in 7 Americans From Seeking COVID-19 Treatment By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Costs Would Keep 1 in 7 Americans From Seeking COVID-19 TreatmentCategory: Health NewsCreated: 4/28/2020 12:00:00 AMLast Editorial Review: 4/29/2020 12:00:00 AM Full Article
ame Pandemic Delaying Medical Care of Older Americans By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Pandemic Delaying Medical Care of Older AmericansCategory: Health NewsCreated: 4/30/2020 12:00:00 AMLast Editorial Review: 4/30/2020 12:00:00 AM Full Article
ame Many Americans in the Dark About Eye Health By www.medicinenet.com Published On :: Mon, 27 Jan 2020 00:00:00 PDT Title: Many Americans in the Dark About Eye HealthCategory: Health NewsCreated: 1/26/2020 12:00:00 AMLast Editorial Review: 1/27/2020 12:00:00 AM Full Article
ame Rising Number of Older Americans at Risk of Vision Loss By www.medicinenet.com Published On :: Fri, 13 Mar 2020 00:00:00 PDT Title: Rising Number of Older Americans at Risk of Vision LossCategory: Health NewsCreated: 3/12/2020 12:00:00 AMLast Editorial Review: 3/13/2020 12:00:00 AM Full Article
ame During Droughts, Many Poor Americans Will Lack Clean Tap Water: Study By www.medicinenet.com Published On :: Fri, 1 May 2020 00:00:00 PDT Title: During Droughts, Many Poor Americans Will Lack Clean Tap Water: StudyCategory: Health NewsCreated: 4/30/2020 12:00:00 AMLast Editorial Review: 5/1/2020 12:00:00 AM Full Article
ame Americans' Cholesterol Levels Decline: Study By www.medicinenet.com Published On :: Wed, 13 Nov 2019 00:00:00 PDT Title: Americans' Cholesterol Levels Decline: StudyCategory: Health NewsCreated: 11/12/2019 12:00:00 AMLast Editorial Review: 11/13/2019 12:00:00 AM Full Article
ame Fewer Americans Have High Cholesterol By www.medicinenet.com Published On :: Thu, 23 Apr 2020 00:00:00 PDT Title: Fewer Americans Have High CholesterolCategory: Health NewsCreated: 4/22/2020 12:00:00 AMLast Editorial Review: 4/23/2020 12:00:00 AM Full Article
ame KoreaMed Synapse Adds PubReader as a Display Option By www.ncbi.nlm.nih.gov Published On :: Fri, 1 Feb 2013 08:00:00 EST KoreaMed Synapse, a digital archive and reference linking platform of Korean medical journals, is now using NCBI’s new PubReader presentation style to display their full-text journal articles. KoreaMed’s database of 122 journals now includes a blue ‘PubReader’ icon for each full-text article. NCBI launched PubReader in December 2012 as a convenient new way to view full-text articles in PubMed Central on desktops as well as tablets and mobile devices. In tandem with the launch, NCBI made the code used to create PubReader freely available on GitHub. Full Article
ame AHA News: Being an African American 'Superwoman' Might Come With a Price By www.medicinenet.com Published On :: Wed, 12 Feb 2020 00:00:00 PDT Title: AHA News: Being an African American 'Superwoman' Might Come With a PriceCategory: Health NewsCreated: 2/11/2020 12:00:00 AMLast Editorial Review: 2/12/2020 12:00:00 AM Full Article
ame Anti-KIT DNA Aptamer for Targeted Labeling of Gastrointestinal Stromal Tumor By mct.aacrjournals.org Published On :: 2020-05-04T05:39:42-07:00 Gastrointestinal stromal tumor (GIST), the most common sarcoma, is characterized by KIT protein overexpression, and tumors are frequently driven by oncogenic KIT mutations. Targeted inhibition of KIT revolutionized GIST therapy and ushered in the era of precision medicine for the treatment of solid malignancies. Here, we present the first use of a KIT-specific DNA aptamer for targeted labeling of GIST. We found that an anti-KIT DNA aptamer bound cells in a KIT-dependent manner and was highly specific for GIST cell labeling in vitro. Functionally, the KIT aptamer bound extracellular KIT in a manner similar to KIT mAb staining, and was trafficked intracellularly in vitro. The KIT aptamer bound dissociated primary human GIST cells in a mutation agnostic manner such that tumors with KIT and PDGFRA mutations were labeled. In addition, the KIT aptamer specifically labeled intact human GIST tissue ex vivo, as well as peritoneal xenografts in mice with high sensitivity. These results represent the first use of an aptamer-based method for targeted detection of GIST in vitro and in vivo. Full Article
ame 3D Printed Teeth with Enamel and Dentin Layer for Educating Dental Students in Crown Preparation By www.jdentaled.org Published On :: 2019-12-01T06:00:19-08:00 Commonly used model teeth are so far uniform in color and hardness. There is no discrimination between enamel and dentin part of a tooth. This condition makes it difficult to train a preparation technique, which is adapted to real tooth substance. The aim of this study was to design and establish a 3D printed tooth with different layers for enamel and dentin for education in crown preparation. A printable tooth with different layers for enamel and dentin was designed, and all 38 fourth-year dental students in the first clinical course in prosthodontics and 30 experienced dentists were trained during a voluntary hands-on course in 2019. Prior to the study, the students had used standard model teeth and real-teeth models in their preclinical education. They had experience in caries removal and preparation on real patients. The perceived benefits of the 3D printed tooth were evaluated by a questionnaire. All individuals in both groups completed the questionnaire, for a 100% response rate. The results showed that the printed tooth was given an overall mean grade of 2.3 (students) and 2.0 (experts) on a scale from 1=excellent to 5=poor. The difference in hardness between the dentin and enamel layer was given a mean of 2.4 (students and experts) and the difference in color a 1.7 (students) and 1.8 (experts). The tooth model with the prepared tooth illustrating an ideal preparation was graded 1.6 (students and experts). In this study, the students had the opportunity to learn a correct crown preparation on a printed tooth with different material properties for enamel and dentin. The learning effect with this tooth model was rated as good on the questionnaire by both students and expert dentists. Full Article
ame Report from the American Society for Microbiology COVID-19 International Summit, 23 March 2020: Value of Diagnostic Testing for SARS-CoV-2/COVID-19 By mbio.asm.org Published On :: 2020-03-26T14:58:07-07:00 Full Article
ame Modulation of the Gut Microbiota during High-Dose Glycerol Monolaurate-Mediated Amelioration of Obesity in Mice Fed a High-Fat Diet By mbio.asm.org Published On :: 2020-04-07T01:31:16-07:00 ABSTRACT Obesity and associated metabolic disorders are worldwide public health issues. The gut microbiota plays a key role in the pathophysiology of diet-induced obesity. Glycerol monolaurate (GML) is a widely consumed food emulsifier with antibacterial properties. Here, we explore the anti-obesity effect of GML (1,600 mg/kg of body weight) in high-fat diet (HFD)-fed mice. HFD-fed mice were treated with 1,600 mg/kg GML. Integrated microbiome, metabolome, and transcriptome analyses were used to systematically investigate the metabolic effects of GML, and antibiotic treatment was used to assess the effects of GML on the gut microbiota. Our data indicated that GML significantly reduced body weight and visceral fat deposition, improved hyperlipidemia and hepatic lipid metabolism, and ameliorated glucose homeostasis and inflammation in HFD-fed mice. Importantly, GML modulated HFD-induced gut microbiota dysbiosis and selectively increased the abundance of Bifidobacterium pseudolongum. Antibiotic treatment abolished all the GML-mediated metabolic improvements. A multiomics (microbiome, metabolome, and transcriptome) association study showed that GML significantly modulated glycerophospholipid metabolism, and the abundance of Bifidobacterium pseudolongum strongly correlated with the metabolites and genes that participated in glycerophospholipid metabolism. Our results indicated that GML may be provided for obesity prevention by targeting the gut microbiota and regulating glycerophospholipid metabolism. Full Article
ame Immediate reactions with glatiramer acetate: Diagnosis of allergy and desensitization protocols By cp.neurology.org Published On :: 2020-04-06T12:45:20-07:00 Purpose of review Diverse adverse events have been associated with administration of glatiramer acetate (GA), mainly local reactions at the injection site. Other, less frequent generalized reactions include isolated postinjection reactions and anaphylaxis, which may lead to discontinuation of GA. Recent findings Close collaboration between the allergy and neurology departments is needed to study adverse reactions to GA. The allergy study should include a detailed history and skin prick and intradermal tests with GA and, if possible, determination of specific IgE levels. Furthermore, the implication of other drugs should be ruled out. Summary An accurate diagnosis of reactions to GA is essential if we are to confirm or rule out allergy to GA. When an allergy diagnosis is confirmed or firmly suspected based on clinical evidence, desensitization protocols are increasingly seen as safe methods for reintroduction of GA. Full Article
ame Optimizing Resources in Childrens Surgical Care: An Update on the American College of Surgeons' Verification Program By pediatrics.aappublications.org Published On :: 2020-05-01T01:00:46-07:00 Surgical procedures are performed in the United States in a wide variety of clinical settings and with variation in clinical outcomes. In May 2012, the Task Force for Children’s Surgical Care, an ad hoc multidisciplinary group comprising physicians representing specialties relevant to pediatric perioperative care, was convened to generate recommendations to optimize the delivery of children’s surgical care. This group generated a white paper detailing the consensus opinions of the involved experts. Following these initial recommendations, the American College of Surgeons (ACS), Children’s Hospital Association, and Task Force for Children’s Surgical Care, with input from all related perioperative specialties, developed and published specific and detailed resource and quality standards designed to improve children’s surgical care (https://www.facs.org/quality-programs/childrens-surgery/childrens-surgery-verification). In 2015, with the endorsement of the American Academy of Pediatrics (https://pediatrics.aappublications.org/content/135/6/e1538), the ACS established a pilot verification program. In January 2017, after completion of the pilot program, the ACS Children’s Surgery Verification Quality Improvement Program was officially launched. Verified sites are listed on the program Web site at https://www.facs.org/quality-programs/childrens-surgery/childrens-surgery-verification/centers, and more than 150 are interested in verification. This report provides an update on the ACS Children’s Surgery Verification Quality Improvement Program as it continues to evolve. Full Article
ame Ames SG, Davis BS, Marin JR, L. Fink EL, Olson LM, Gausche-Hill M, Kahn JM. Emergency Department Pediatric Readiness and Mortality in Critically Ill Children. Pediatrics. 2019;144(3):e20190568 By pediatrics.aappublications.org Published On :: 2020-05-01T01:00:46-07:00 Full Article
ame Fear and Foxes: An Educational Primer for Use with "Anterior Pituitary Transcriptome Suggests Differences in ACTH Release in Tame and Aggressive Foxes" [Primer] By www.genetics.org Published On :: 2020-05-05T06:43:41-07:00 The way genes contribute to behavior is complicated. Although there are some single genes with large contributions, most behavioral differences are due to small effects from many interacting genes. This makes it hard to identify the genes that cause behavioral differences. Mutagenesis screens in model organisms, selective breeding experiments in animals, comparisons between related populations with different behaviors, and genome-wide association studies in humans are promising and complementary approaches to understanding the heritable aspects of complex behaviors. To connect genes to behaviors requires measuring behavioral differences, locating correlated genetic changes, determining when, where, and how these candidate genes act, and designing causative confirmatory experiments. This area of research has implications from basic discovery science to human mental health. Full Article
ame A New Gorilla Adenoviral Vector with Natural Lung Tropism Avoids Liver Toxicity and Is Amenable to Capsid Engineering and Vector Retargeting [Gene Delivery] By jvi.asm.org Published On :: 2020-05-04T08:00:46-07:00 Human adenoviruses have many attractive features for gene therapy applications. However, the high prevalence of preexisting immunity against these viruses in general populations worldwide has greatly limited their clinical utility. In addition, the most commonly used human adenovirus, human adenovirus subgroup C serotype 5 (HAd5), when systemically administered, triggers systemic inflammation and toxicity, with the liver being the most severely affected organ. Here, we evaluated the utility and safety of a new low-seroprevalence gorilla adenovirus (GAd; GC46) as a gene transfer vector in mice. Biodistribution studies revealed that systemically administered GAd had a selective and robust lung endothelial cell (EC) tropism with minimal vector expression throughout many other organs and tissues. Administration of a high dose of GAd accomplished extensive transgene expression in the lung yet elicited no detectable inflammatory histopathology in this organ. Furthermore, GAd, unlike HAd5, did not exhibit hepatotropism or induce liver inflammatory toxicity in mice, demonstrating the exceptional safety profile of the vector vis-à-vis systemic utility. We further demonstrated that the GAd capsid fiber shared the flexibility of the HAd5 equivalent for permitting genetic modification; GAd with the pan-EC-targeting ligand myeloid cell-binding peptide (MBP) incorporated in the capsid displayed a reduced lung tropism and efficiently retargeted gene expression to vascular beds in other organs. IMPORTANCE In the aggregate, our mouse studies suggest that GAd is a promising gene therapy vector that utilizes lung ECs as a source of therapeutic payload production and a highly desirable toxicity profile. Further genetic engineering of the GAd capsid holds the promise of in vivo vector tropism modification and targeting. Full Article
ame Peer Reviewers for the Journal of the American Board of Family Medicine in 2019 By www.jabfm.org Published On :: 2020-03-16T09:31:37-07:00 Full Article
ame The Journal of the American Board of Family Medicine By www.jabfm.org Published On :: Full Article
ame Journal of the American Society of Nephrology By jasn.asnjournals.org Published On :: Full Article
ame A single unidirectional piRNA cluster similar to the flamenco locus is the major source of EVE-derived transcription and small RNAs in Aedes aegypti mosquitoes [ARTICLE] By rnajournal.cshlp.org Published On :: 2020-04-16T06:30:22-07:00 Endogenous viral elements (EVEs) are found in many eukaryotic genomes. Despite considerable knowledge about genomic elements such as transposons (TEs) and retroviruses, we still lack information about nonretroviral EVEs. Aedes aegypti mosquitoes have a highly repetitive genome that is covered with EVEs. Here, we identified 129 nonretroviral EVEs in the AaegL5 version of the A. aegypti genome. These EVEs were significantly associated with TEs and preferentially located in repeat-rich clusters within intergenic regions. Genome-wide transcriptome analysis showed that most EVEs generated transcripts although only around 1.4% were sense RNAs. The majority of EVE transcription was antisense and correlated with the generation of EVE-derived small RNAs. A single genomic cluster of EVEs located in a 143 kb repetitive region in chromosome 2 contributed with 42% of antisense transcription and 45% of small RNAs derived from viral elements. This region was enriched for TE-EVE hybrids organized in the same coding strand. These generated a single long antisense transcript that correlated with the generation of phased primary PIWI-interacting RNAs (piRNAs). The putative promoter of this region had a conserved binding site for the transcription factor Cubitus interruptus, a key regulator of the flamenco locus in Drosophila melanogaster. Here, we have identified a single unidirectional piRNA cluster in the A. aegypti genome that is the major source of EVE transcription fueling the generation of antisense small RNAs in mosquitoes. We propose that this region is a flamenco-like locus in A. aegypti due to its relatedness to the major unidirectional piRNA cluster in Drosophila melanogaster. Full Article
ame The asymmetry and cooperativity of tandem glycine riboswitch aptamers [ARTICLE] By rnajournal.cshlp.org Published On :: 2020-04-16T06:30:22-07:00 Glycine riboswitches utilize both single- and tandem-aptamer architectures. In the tandem system, the relative contribution of each aptamer toward gene regulation is not well understood. To dissect these contributions, the effects of 684 single mutants of a tandem ON switch from Bacillus subtilis were characterized for the wild-type construct and binding site mutations that selectively restrict ligand binding to either the first or second aptamer. Despite the structural symmetry of tandem aptamers, the response to these mutations was frequently asymmetrical. Mutations in the first aptamer often significantly weakened the K1/2, while several mutations in the second aptamer improved the amplitude. These results demonstrate that this ON switch favors ligand binding to the first aptamer. This is in contrast to the tandem OFF switch variant from Vibrio cholerae, which was previously shown to have preferential binding to its second aptamer. A bioinformatic analysis of tandem glycine riboswitches revealed that the two binding pockets are differentially conserved between ON and OFF switches. Altogether, this indicates that tandem ON switch variants preferentially utilize binding to the first aptamer to promote helical switching, while OFF switch variants favor binding to the second aptamer. The data set also revealed a cooperative glycine response when both binding pockets were maximally stabilized with three GC base pairs. This indicates a cooperative response may sometimes be obfuscated by a difference in the affinities of the two aptamers. This conditional cooperativity provides an additional layer of tunability to tandem glycine riboswitches that adds to their versatility as genetic switches. Full Article
ame A flexible network of vimentin intermediate filaments promotes migration of amoeboid cancer cells through confined environments [Cell Biology] By www.jbc.org Published On :: 2020-05-08T03:41:14-07:00 Tumor cells can spread to distant sites through their ability to switch between mesenchymal and amoeboid (bleb-based) migration. Because of this difference, inhibitors of metastasis must account for each migration mode. However, the role of vimentin in amoeboid migration has not been determined. Because amoeboid leader bleb–based migration (LBBM) occurs in confined spaces and vimentin is known to strongly influence cell-mechanical properties, we hypothesized that a flexible vimentin network is required for fast amoeboid migration. To this end, here we determined the precise role of the vimentin intermediate filament system in regulating the migration of amoeboid human cancer cells. Vimentin is a classic marker of epithelial-to-mesenchymal transition and is therefore an ideal target for a metastasis inhibitor. Using a previously developed polydimethylsiloxane slab–based approach to confine cells, RNAi-based vimentin silencing, vimentin overexpression, pharmacological treatments, and measurements of cell stiffness, we found that RNAi-mediated depletion of vimentin increases LBBM by ∼50% compared with control cells and that vimentin overexpression and simvastatin-induced vimentin bundling inhibit fast amoeboid migration and proliferation. Importantly, these effects were independent of changes in actomyosin contractility. Our results indicate that a flexible vimentin intermediate filament network promotes LBBM of amoeboid cancer cells in confined environments and that vimentin bundling perturbs cell-mechanical properties and inhibits the invasive properties of cancer cells. Full Article
ame {alpha}-Synuclein filaments from transgenic mouse and human synucleinopathy-containing brains are maȷor seed-competent species [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-05-08T03:41:14-07:00 Assembled α-synuclein in nerve cells and glial cells is the defining pathological feature of neurodegenerative diseases called synucleinopathies. Seeds of α-synuclein can induce the assembly of monomeric protein. Here, we used sucrose gradient centrifugation and transiently transfected HEK 293T cells to identify the species of α-synuclein from the brains of homozygous, symptomatic mice transgenic for human mutant A53T α-synuclein (line M83) that seed aggregation. The most potent fractions contained Sarkosyl-insoluble assemblies enriched in filaments. We also analyzed six cases of idiopathic Parkinson's disease (PD), one case of familial PD, and six cases of multiple system atrophy (MSA) for their ability to induce α-synuclein aggregation. The MSA samples were more potent than those of idiopathic PD in seeding aggregation. We found that following sucrose gradient centrifugation, the most seed-competent fractions from PD and MSA brains are those that contain Sarkosyl-insoluble α-synuclein. The fractions differed between PD and MSA, consistent with the presence of distinct conformers of assembled α-synuclein in these different samples. We conclude that α-synuclein filaments are the main driving force for amplification and propagation of pathology in synucleinopathies. Full Article
ame A kainate receptor-selective RNA aptamer [Neurobiology] By www.jbc.org Published On :: 2020-05-08T03:41:14-07:00 Kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are two major, closely related receptor subtypes in the glutamate ion channel family. Excessive activities of these receptors have been implicated in a number of central nervous system diseases. Designing potent and selective antagonists of these receptors, especially of kainate receptors, is useful for developing potential treatment strategies for these neurological diseases. Here, we report on two RNA aptamers designed to individually inhibit kainate and AMPA receptors. To improve the biostability of these aptamers, we also chemically modified these aptamers by substituting their 2'-OH group with 2'-fluorine. These 2'-fluoro aptamers, FB9s-b and FB9s-r, were markedly resistant to RNase-catalyzed degradation, with a half-life of ∼5 days in rat cerebrospinal fluid or serum-containing medium. Furthermore, FB9s-r blocked AMPA receptor activity. Aptamer FB9s-b selectively inhibited GluK1 and GluK2 kainate receptor subunits, and also GluK1/GluK5 and GluK2/GluK5 heteromeric kainate receptors with equal potency. This inhibitory profile makes FB9s-b a powerful template for developing tool molecules and drug candidates for treatment of neurological diseases involving excessive activities of the GluK1 and GluK2 subunits. Full Article
ame Monitoring of radiologic disease activity by serum neurofilaments in MS By nn.neurology.org Published On :: 2020-04-09T14:01:03-07:00 Objective To determine whether serum neurofilament light chain (sNfL) levels are associated with recent MRI activity in patients with relapsing-remitting MS (RRMS). Methods This observational study included 163 patients (405 samples) with early RRMS from the Study of Early interferon-beta1a (IFN-β1a) Treatment (SET) cohort and 179 patients (664 samples) with more advanced RRMS from the Genome-Wide Association Study of Multiple Sclerosis (GeneMSA) cohort. Based on annual brain MRI, we assessed the ability of sNfL cutoffs to reflect the presence of combined unique active lesions, defined as new/enlarging lesion compared with MRI in the preceding year or contrast-enhancing lesion. The probability of active MRI lesions among patients with different sNfL levels was estimated with generalized estimating equations models. Results From the sNfL samples ≥90th percentile, 81.6% of the SET (OR = 3.4, 95% CI = 1.8-6.4) and 48.9% of the GeneMSA cohort samples (OR = 2.6, 95% CI = 1.7-3.9) was associated with radiological disease activity on MRI. The sNfL level between the 10th and 30th percentile was reflective of negligible MRI activity: 1.4% (SET) and 6.5% (GeneMSA) of patients developed ≥3 active lesions, 5.8% (SET) and 6.5% (GeneMSA) developed ≥2 active lesions, and 34.8% (SET) and 11.8% (GeneMSA) showed ≥1 active lesion on brain MRI. The sNfL level <10th percentile was associated with even lower MRI activity. Similar results were found in a subgroup of clinically stable patients. Conclusions Low sNfL levels (≤30th percentile) help identify patients with MS with very low probability of recent radiologic disease activity during the preceding year. This result suggests that in future, sNfL assessment may substitute the need for annual brain MRI monitoring in considerable number (23.1%–36.4%) of visits in clinically stable patients. Full Article
ame 2020 American Society for Microbiology Awards Program Honorees in Clinical Microbiology [Editorial] By jcm.asm.org Published On :: 2020-04-23T08:00:28-07:00 Full Article
ame Cinnamaldehyde Inhibits Inflammation of Human Synoviocyte Cells Through Regulation of Jak/Stat Pathway and Ameliorates Collagen-Induced Arthritis in Rats [Inflammation, Immunopharmacology, and Asthma] By jpet.aspetjournals.org Published On :: 2020-04-21T11:17:48-07:00 Cinnamaldehyde (Cin), a bioactive cinnamon essential oil from traditional Chinese medicine herb Cinnamomum cassia, has been reported to have multipharmacological activities including anti-inflammation. However, its role and molecular mechanism of anti-inflammatory activity in musculoskeletal tissues remains unclear. Here, we first investigated the effects and molecular mechanisms of Cin in human synoviocyte cells. Then in vivo therapeutic effect of Cin on collagen-induced arthritis (CIA) also studied. Cell Counting Kit CCK-8 assay was performed to evaluate the cell cytotoxicity. Proinflammatory cytokine expression was evaluated using quantitative polymerase chain reaction and ELISA. Protein expression was measured by western blotting. The in vivo effect of Cin (75 mg/kg per day) was evaluated in rats with CIA by gavage administration. Disease progression was assessed by clinical scoring, radiographic, and histologic examinations. Cin significantly inhibited interleukin (IL)-1β–induced IL-6, IL-8, and tumor necrosis factor-α release from human synoviocyte cells. The molecular analysis revealed that Cin impaired IL-6–induced activation of Janus kinase 2 (JAK2), signal transducer and activator of transcription 1 (STAT1), and STAT3 signaling pathway by inhibiting the phosphorylation of JAK2, STAT1, and STAT3, without affecting NF-B pathway. Cin reduced collagen-induced swollen paw volume of arthritic rats. The anti-inflammation effects of Cin were associated with decreased severity of arthritis, joint swelling, and reduced bone erosion and destruction. Furthermore, serum IL-6 level was decreased when Cin administered therapeutically to CIA rats. Cin suppresses IL-1β–induced inflammation in synoviocytes through the JAK/STAT pathway and alleviated collagen-induced arthritis in rats. These data indicated that Cin might be a potential traditional Chinese medicine–derived, disease-modifying, antirheumatic herbal drug. SIGNIFICANCE STATEMENT In this study, we found that cinnamaldehyde (Cin) suppressed proinflammatory cytokines secretion in rheumatology arthritis synoviocyte cells by Janus kinase/signal transducer and activator of transcription pathway. The in vivo results showed that Cin ameliorated collagen-induced arthritis in rats. These findings indicate that Cin is a potential traditional Chinese medicine–derived, disease-modifying, antirheumatic herbal drug. Full Article
ame NO-Releasing Nanoparticles Ameliorate Detrusor Overactivity in Transgenic Sickle Cell Mice via Restored NO/ROCK Signaling [Cellular and Molecular] By jpet.aspetjournals.org Published On :: 2020-04-13T13:53:50-07:00 Sickle cell disease (SCD) is associated with overactive bladder (OAB). Detrusor overactivity, a component of OAB, is present in an SCD mouse, but the molecular mechanisms for this condition are not well-defined. We hypothesize that nitric oxide (NO)/ ras homolog gene family (Rho) A/Rho-associated kinase (ROCK) dysregulation is a mechanism for detrusor overactivity and that NO-releasing nanoparticles (NO-nps), a novel NO delivery system, may serve to treat this condition. Male adult SCD transgenic, combined endothelial NO synthases (eNOSs) and neuronal NOS (nNOS) gene-deficient (dNOS–/–), and wild-type (WT) mice were used. Empty nanoparticle or NO-np was injected into the bladder, followed by cystometric studies. The expression levels of phosphorylated eNOS (Ser-1177), protein kinase B (Akt) (Ser-473), nNOS (Ser-1412), and myosin phosphatase target subunit 1 (MYPT1) (Thr-696) were assessed in the bladder. SCD and dNOS–/– mice had a greater (P < 0.05) number of voiding and nonvoiding contractions compared with WT mice, and they were normalized by NO-np treatment. eNOS (Ser-1177) and AKT (Ser-473) phosphorylation were decreased (P < 0.05) in the bladder of SCD compared with WT mice and reversed by NO-np. Phosphorylated MYPT1, a marker of the RhoA/ROCK pathway, was increased (P < 0.05) in the bladder of SCD mice compared with WT and reversed by NO-np. nNOS phosphorylation on positive (Ser-1412) regulatory site was decreased (P < 0.05) in the bladder of SCD mice compared with WT and was not affected by NO-np. NO-nps did not affect any of the measured parameters in WT mice. In conclusion, dysregulation of NO and RhoA/ROCK pathways is associated with detrusor overactivity in SCD mice; NO-np reverses these molecular derangements in the bladder and decreases detrusor overactivity. SIGNIFICANCE STATEMENT Voiding abnormalities commonly affect patients with sickle cell disease (SCD) but are problematic to treat. Clarification of the science for this condition in an animal model of SCD may lead to improved interventions for it. Our findings suggest that novel topical delivery of a vasorelaxant agent nitric oxide into the bladder of these mice corrects overactive bladder by improving deranged bladder physiology regulatory signaling. Full Article
ame Managing Excipient Supplier Name and Address Changes in the Pharmaceutical Quality System By journal.pda.org Published On :: 2020-04-09T09:40:03-07:00 It is important to identify, assess, and address current barriers to implementation of post-approval changes that are intended to ensure continued (uninterrupted) operations and drive innovation and continual improvement in a maximally efficient, agile, and flexible pharmaceutical manufacturing sector. Leveraging the International Conference for Harmonisation Quality Guideline Q10 provides regulatory relief when it comes to addressing changes related to excipients, specifically excipient supplier's name and address changes, which will ensure a sustainable, reliable global supply and the availability of high quality product to patients through the entire commercial lifecycle of a product without extensive regulatory oversight. Full Article
ame How Should Home-Based Maternal and Child Health Records Be Implemented? A Global Framework Analysis By ghspjournal.org Published On :: 2020-03-31T15:28:55-07:00 ABSTRACTBackground:A home-based record (HBR) is a health document kept by the patient or their caregivers, rather than by the health care facility. HBRs are used in 163 countries, but they have not been implemented universally or consistently. Effective implementation maximizes both health impacts and cost-effectiveness. We sought to examine this research-to-practice gap and delineate the facilitators and barriers to the effective implementation and use of maternal and child health HBRs especially in low- and middle-income countries (LMICs).Methods:Using a framework analysis approach, we created a framework of implementation categories in advance using subject expert inputs. We collected information through 2 streams. First, we screened 69 gray literature documents, of which 18 were included for analysis. Second, we conducted semi-structured interviews with 12 key informants, each of whom had extensive experience with HBR implementation. We abstracted the relevant data from the documents and interviews into an analytic matrix. The matrix was based on the initial framework and adjusted according to emergent categories from the data.Results:We identified 8 contributors to successful HBR implementation. These include establishing high-level support from the government and ensuring clear communication between all ministries and nongovernmental organizations involved. Choice of appropriate contents within the record was noted as important for alignment with the health system and for end user acceptance, as were the design, its physical durability, and timely redesigns. Logistical considerations, such as covering costs sustainably and arranging printing and distribution, could be potential bottlenecks. Finally, end users' engagement with HBRs depended on how the record was initially introduced to them and how its importance was reinforced over time by those in leadership positions.Conclusions:This framework analysis is the first study to take a more comprehensive and broad approach to the HBR implementation process in LMICs. The findings provide guidance for policy makers, donors, and health care practitioners regarding best implementation practice and effective HBR use, as well as where further research is required. Full Article
ame Unmet Need for Family Planning and Experience of Unintended Pregnancy Among Female Sex Workers in Urban Cameroon: Results From a National Cross-Sectional Study By ghspjournal.org Published On :: 2020-03-31T15:28:55-07:00 ABSTRACTBackground:Female sex workers (FSWs) in Cameroon commonly have unmet need for contraception posing a high risk of unintended pregnancy. Unintended pregnancy leads to a range of outcomes, and due to legal restrictions, FSWs often seek unsafe abortions. Aside from the high burden of HIV, little is known about the broader sexual and reproductive health of FSWs in Cameroon.Methods:From December 2015 to October 2016, we recruited FSWs aged ≥18 years through respondent-driven sampling across 5 Cameroonian cities. Cross-sectional data were collected through a behavioral questionnaire. Modified-robust Poisson regression was used to approximate adjusted prevalence ratios (aPR) for TOP and current use of effective nonbarrier contraception.Results:Among 2,255 FSWs (median age 28 years), 57.6% reported history of unintended pregnancy and 40.0% reported prior TOP. In multivariable analysis, TOP history was associated with current nonbarrier contraceptive use (aPR=1.23, 95% confidence interval [CI]=1.07, 1.42); ever using emergency contraception (aPR=1.34, 95% CI=1.17, 1.55); >60 clients in the past month (aPR=1.29, 95% CI= 1.07, 1.54) compared to ≤30; inconsistent condom use with clients (aPR=1.17, 95% CI=1.00, 1.37); ever experiencing physical violence (aPR=1.24, 95% CI=1.09, 1.42); and older age. Most (76.5%) women used male condoms for contraception, but only 33.2% reported consistent condom use with all partners. Overall, 26.4% of women reported currently using a nonbarrier contraceptive method, and 6.2% reported using a long-acting method. Previous TOP (aPR=1.41, 95%CI=1.16, 1.72) and ever using emergency contraception (aPR=2.70, 95% CI=2.23, 3.26) were associated with higher nonbarrier contraceptive use. Recent receipt of HIV information (aPR=0.72, 95% CI=0.59, 0.89) and membership in an FSW community-based organization (aPR=0.73, 95% CI=0.57, 0.92) were associated with lower use nonbarrier contraceptive use.Conclusions:Experience of unintended pregnancies and TOP is common among FSWs in Cameroon. Given the low use of nonbarrier contraceptive methods and inconsistent condom use, FSWs are at risk of repeat unintended pregnancies. Improved integration of client-centered, voluntary family planning within community-led HIV services may better support the sexual and reproductive health and human rights of FSWs consistent with the United Nations Declaration of Human Rights. Full Article
ame Phase I/Ib study of carfilzomib and panobinostat with or without dexamethasone in patients with relapsed/refractory multiple myeloma By www.haematologica.org Published On :: 2020-05-01T00:05:42-07:00 Full Article
ame Vitamin D Receptor Overexpression in {beta}-Cells Ameliorates Diabetes in Mice By diabetes.diabetesjournals.org Published On :: 2020-04-20T12:00:34-07:00 Vitamin D deficiency has been associated with increased incidence of diabetes, both in humans and in animal models. In addition, an association between vitamin D receptor (VDR) gene polymorphisms and diabetes has also been described. However, the involvement of VDR in the development of diabetes, specifically in pancreatic β-cells, has not been elucidated yet. Here, we aimed to study the role of VDR in β-cells in the pathophysiology of diabetes. Our results indicate that Vdr expression was modulated by glucose in healthy islets and decreased in islets from both type 1 diabetes and type 2 diabetes mouse models. In addition, transgenic mice overexpressing VDR in β-cells were protected against streptozotocin-induced diabetes and presented a preserved β-cell mass and a reduction in islet inflammation. Altogether, these results suggest that sustained VDR levels in β-cells may preserve β-cell mass and β-cell function and protect against diabetes. Full Article
ame STFM OFFERS MEDICAL SCHOOL FACULTY FUNDAMENTALS CERTIFICATE PROGRAM [Family Medicine Updates] By www.annfammed.org Published On :: 2020-03-09T14:00:11-07:00 Full Article