After the publication of this article [1] it came to our attention that one author, Boon Yin Khoo, was erroneously omitted from the authorship list.
https://ift.tt/2NP9RdV
Πέμπτη 27 Σεπτεμβρίου 2018
Correction to: Standardized extract of Ficus deltoidea stimulates insulin secretion and blocks hepatic glucose production by regulating the expression of glucose-metabolic genes in streptozitocin-induced diabetic rats
Inhibitory effects of Euphorbia supina on Propionibacterium acnes-induced skin inflammation in vitro and in vivo
Euphorbia supina (ES) plant has been used as treatment for inflammatory conditions. The antibacterial effect and the anti-inflammatory mechanism of ES for Propionibacterium (P.) acnes-induced inflammation in THP-...
https://ift.tt/2OWxnSP
Leveraging Hypomethylating Agents for Better MDS Therapy
Abstract
Purpose of Review
Myelodysplastic syndrome (MDS) is a clinically and molecularly heterogeneous disease, which primarily occurs in older adults. Although hypomethylating agents have survival benefit and are the current standard of care, many MDS patients will not garner a response from therapy. For those who do respond, most responses are not durable, and the only hope for a cure is allogeneic stem cell transplant. New therapies to improve outcomes are urgently needed.
Recent Findings
Clinical trials combining standard hypomethylating agents with novel experimental agents are underway in an effort to improve clinical outcomes in MDS patients. Several of these small molecules have demonstrated the ability to augment the response rates of hypomethylating agents alone, including complete remission rates, in both the front line and refractory settings.
Summary
Combination approaches utilizing hypomethylating agents and novel-targeted therapies have demonstrated the ability to improve response rates in MDS patients in both the front line and salvage settings, and thus may change the standard of care.
https://ift.tt/2QhW2Bx
Microtubules provide a viscoelastic resistance to myocyte motion.
Microtubules (MT) buckle and bear load during myocyte contraction, a behavior enhanced by post-translational detyrosination. This buckling suggests a spring-like resistance against myocyte shortening, which could store energy and aid myocyte relaxation. Despite this visual suggestion of elastic behavior, the precise mechanical contribution of the cardiac MT network remains to be defined.
https://ift.tt/2xLLaoq
CRISPR-Cas genome engineering of esterase activity in Saccharomyces cerevisiae steers aroma formation
Saccharomyces cerevisiae is used worldwide for the production of ale-type beers. This yeast is responsible for the production of the characteristic fruity aroma compounds. Esters constitute an important group of ...
https://ift.tt/2NPc09h
Modulation of CaV1.3b L-type calcium channels by M1 muscarinic receptors varies with CaVβ subunit expression
We examined whether two G protein-coupled receptors (GPCRs), muscarinic M1 receptors (M1Rs) and dopaminergic D2 receptors (D2Rs), utilize endogenously released fatty acid to inhibit L-type Ca2+ channels, CaV1.3. ...
https://ift.tt/2Il1QXY
A Man With Tonsillitis and Hepatitis
A previously well Australian-born 28-year-old gentleman was diagnosed with a stage 1 non-seminomatous testicular cancer, for which he underwent a left radical orchidectomy, followed by a single cycle of adjuvant chemotherapy with bleomycin, etoposide and cisplatin. One week later, he presented to hospital with a one-day history of fevers, rigors and severe sore throat. There was no recent travel or animal contact, nor was there any risk factor for blood-borne viruses. He had recently entered into a new relationship with a female partner. On physical examination he was noted to have bilateral swollen, erythematous tonsils with exudates, associated with bilateral tender cervical lymphadenopathy. No visible mucocutaneous vesicles or ulcers were found. Initial investigation results showed neutrophilia of 13.4 × 10^9/L (2.0–8.0) but lymphopenia of 0.4 × 10^9/L (1.0–4.0), and a normal liver function test. Blood film demonstrated toxic changes of leukocytes with occasional reactive lymphocytes. Heterophile antibody test for infectious mononucleosis was negative. He was given penicillin following which he developed a widespread blanching macular rash two days later. He was then discharged home.
https://ift.tt/2N3YCZD
https://ift.tt/2N3YCZD
Cancers, Vol. 10, Pages 362: Rare Stochastic Expression of O6-Methylguanine- DNA Methyltransferase (MGMT) in MGMT-Negative Melanoma Cells Determines Immediate Emergence of Drug-Resistant Populations upon Treatment with Temozolomide In Vitro and In Vivo
Cancers, Vol. 10, Pages 362: Rare Stochastic Expression of O6-Methylguanine- DNA Methyltransferase (MGMT) in MGMT-Negative Melanoma Cells Determines Immediate Emergence of Drug-Resistant Populations upon Treatment with Temozolomide In Vitro and In Vivo
Cancers doi: 10.3390/cancers10100362
Authors: Thomas C. Chen Nymph Chan Radu O. Minea Hannah Hartman Florence M. Hofman Axel H. Schönthal
The chemotherapeutic agent temozolomide (TMZ) kills tumor cells preferentially via alkylation of the O6-position of guanine. However, cells that express the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), or harbor deficient DNA mismatch repair (MMR) function, are profoundly resistant to this drug. TMZ is in clinical use for melanoma, but objective response rates are low, even when TMZ is combined with O6-benzylguanine (O6BG), a potent MGMT inhibitor. We used in vitro and in vivo models of melanoma to characterize the early events leading to cellular TMZ resistance. Melanoma cell lines were exposed to a single treatment with TMZ, at physiologically relevant concentrations, in the absence or presence of O6BG. Surviving clones and mass cultures were analyzed by Western blot, colony formation assays, and DNA methylation studies. Mice with melanoma xenografts received TMZ treatment, and tumor tissue was analyzed by immunohistochemistry. We found that MGMT-negative melanoma cell cultures, before any drug treatment, already harbored a small fraction of MGMT-positive cells, which survived TMZ treatment and promptly became the dominant cell type within the surviving population. The MGMT-negative status in individual cells was not stable, as clonal selection of MGMT-negative cells again resulted in a mixed population harboring MGMT-positive, TMZ-resistant cells. Blocking the survival advantage of MGMT via the addition of O6BG still resulted in surviving clones, although at much lower frequency and independent of MGMT, and the resistance mechanism of these clones was based on a common lack of expression of MSH6, a key MMR enzyme. TMZ treatment of mice implanted with MGMT-negative melanoma cells resulted in effective tumor growth delay, but eventually tumor growth resumed, with tumor tissue having become MGMT positive. Altogether, these data reveal stochastic expression of MGMT as a pre-existing, key determinant of TMZ resistance in melanoma cell lines. Although MGMT activity can effectively be eliminated by pharmacologic intervention with O6BG, additional layers of TMZ resistance, although considerably rarer, are present as well and minimize the cytotoxic impact of TMZ/O6BG combination treatment. Our results provide rational explanations regarding clinical observations, where the TMZ/O6BG regimen has yielded mostly disappointing outcomes in melanoma patients.
https://ift.tt/2DzVPYD
Under What Conditions Can Recursion Be Learned? Effects of Starting Small in Artificial Grammar Learning of Center‐Embedded Structure
Cognitive Science, EarlyView.
https://ift.tt/2Ile42U
Pooling data from different populations: should there be regional differences in cerebral haemodynamics?
Though genetic and environmental determinants of systemic haemodynamic have been reported, surprisingly little is known about their influences on cerebral haemodynamics. We assessed the potential geographical ...
https://ift.tt/2NJhyCe
What goes in to organizing an EMS conference?
Our co-hosts are joined by EMS educator Joshua Ishmael, who coordinated this year's St. Elizabeth EMS Conference in Cincinnati, Ohio
https://ift.tt/2N7LTVX
To Pull or Not to Pull: Salvaging Central Line Catheters in Home Parenteral Nutrition
Abstract
Purpose of Review
Catheter-related blood stream infections (CRBSI) pose a significant risk to patients on home parenteral nutrition (HPN). Recurrent loss of catheters can lead to scarring and eventual loss of central access, a potentially fatal situation for patients dependent on HPN.
Recent Findings
In the past, the standard of care to treat these infections required catheter removal. More recently, several studies have indicated that many CRBSI can be treated without removal of the catheter. Successful treatment without removal can be achieved by intentionally following a catheter salvage protocol. We define this as a previously defined protocol to accurately diagnose CRBSI, identify the organism(s) involved, and effectively treat not only the blood stream infection, but also sterilize the catheter.
Summary
For patients on HPN with CRBSI, consider attempting line salvage if the patient is not suffering from severe sepsis, other infection related complications, or certain specific infections. Success rates vary depending on the organism causing the infection and the risks; benefits and chance of success should be considered when deciding to attempt line salvage.
https://ift.tt/2OgfReX
Role of Gut Microbiota-Generated Short-Chain Fatty Acids in Metabolic and Cardiovascular Health
Abstract
Purpose of this Review
This review assesses the latest evidence linking short-chain fatty acids (SCFA) with host metabolic health and cardiovascular disease (CVD) risk and presents the latest evidence on possible biological mechanisms.
Recent Findings
SCFA have a range of effects locally in the gut and at both splanchnic and peripheral tissues which together appear to induce improved metabolic regulation and have direct and indirect effects on markers of CVD risk.
Summary
SCFA produced primarily from the microbial fermentation of dietary fibre appear to be key mediators of the beneficial effects elicited by the gut microbiome. Not only does dietary fibre fermentation regulate microbial activity in the gut, SCFA also directly modulate host health through a range of tissue-specific mechanisms related to gut barrier function, glucose homeostasis, immunomodulation, appetite regulation and obesity. With the increasing burden of obesity worldwide, the role for gut microbiota-generated SCFA in protecting against the effects of energy dense diets offers an intriguing new avenue for regulating metabolic health and CVD risk.
https://ift.tt/2Qf9XrL
What goes in to organizing an EMS conference?
Our co-hosts are joined by EMS educator Joshua Ishmael, who coordinated this year's St. Elizabeth EMS Conference in Cincinnati, Ohio
https://ift.tt/2DCwbmg
The association between perinatal hypoxia exposure and externalizing symptoms and children’s decision making in conditions of uncertainty is moderated by DRD2 genotype
Developmental Psychobiology, EarlyView.
https://ift.tt/2xVZQAP
Dental research shows that smoking weakens immune systems
Researchers found that smoking weakens the ability for pulp in teeth to fight illness and disease.
https://ift.tt/2R51kRS
Caution When Using Pen Needles to Inject Medicines: FDA Safety Communication
Audience: Consumer, Health Professional, Pharmacy Audience: Patients and caregivers who use or are considering using pen injectors with pen needles to inject prescription medicines. Health care providers who treat patients, or who train...
https://ift.tt/2Q91oPa
Caution When Using Pen Needles to Inject Medicines: FDA Safety Communication
Audience: Consumer, Health Professional, Pharmacy Audience: Patients and caregivers who use or are considering using pen injectors with pen needles to inject prescription medicines. Health care providers who treat patients, or who train...
https://ift.tt/2Q91oPa
A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome
A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome
A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome, Published online: 27 September 2018; doi:10.1038/s41419-018-1042-7
A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcomehttps://ift.tt/2xUZ6fa
Keratin 80 promotes migration and invasion of colorectal carcinoma by interacting with PRKDC via activating the AKT pathway
Keratin 80 promotes migration and invasion of colorectal carcinoma by interacting with PRKDC via activating the AKT pathway
Keratin 80 promotes migration and invasion of colorectal carcinoma by interacting with PRKDC via activating the AKT pathway, Published online: 27 September 2018; doi:10.1038/s41419-018-1030-y
Keratin 80 promotes migration and invasion of colorectal carcinoma by interacting with PRKDC via activating the AKT pathwayhttps://ift.tt/2Ohppq9
Blockade of Na/H exchanger stimulates glioma tumor immunogenicity and enhances combinatorial TMZ and anti-PD-1 therapy
Blockade of Na/H exchanger stimulates glioma tumor immunogenicity and enhances combinatorial TMZ and anti-PD-1 therapy
Blockade of Na/H exchanger stimulates glioma tumor immunogenicity and enhances combinatorial TMZ and anti-PD-1 therapy, Published online: 27 September 2018; doi:10.1038/s41419-018-1062-3
Blockade of Na/H exchanger stimulates glioma tumor immunogenicity and enhances combinatorial TMZ and anti-PD-1 therapyhttps://ift.tt/2xVfn3H
Modulation of intracellular calcium signaling by microRNA-34a-5p
Modulation of intracellular calcium signaling by microRNA-34a-5p
Modulation of intracellular calcium signaling by microRNA-34a-5p, Published online: 27 September 2018; doi:10.1038/s41419-018-1050-7
Modulation of intracellular calcium signaling by microRNA-34a-5phttps://ift.tt/2OhppGF
Comparing Genome-Wide Association Study Results from Different Measurements of an Underlying Phenotype
Increasing popularity of high-throughput phenotyping technologies, such as image-based phenotyping, offer novel ways for quantifying plant growth and morphology. These new methods can be more or less accurate and precise than traditional, manual measurements. Many large-scale phenotyping efforts are conducted to enable genome-wide association studies (GWAS), but it is unclear exactly how alternative methods of phenotyping will affect GWAS results. In this study we simulate phenotypes that are controlled by the same set of causal loci but have differing heritability, similar to two different measurements of the same morphological character. We then perform GWAS with the simulated traits and create receiver operating characteristic (ROC) curves from the results. The areas under the ROC curves (AUCs) provide a metric that allows direct comparisons of GWAS results from different simulated traits. We use this framework to evaluate the effects of heritability and the number of causative loci on the AUCs of simulated traits; we also test the differences between AUCs of traits with differing heritability. We find that both increasing the number of causative loci and decreasing the heritability reduce a trait's AUC. We also find that when two traits are controlled by a greater number of causative loci, they are more likely to have significantly different AUCs as the difference between their heritabilities increases. When simulation results are applied to measures of tassel morphology, we find no significant difference between AUCs from GWAS using manual and image-based measurements of typical maize tassel characters. This finding indicates that both measurement methods have similar ability to identify genetic associations. These results provide a framework for deciding between competing phenotyping strategies when the ultimate goal is to generate and use phenotype-genotype associations from GWAS.
https://ift.tt/2NMapRP
A GAL80 Collection To Inhibit GAL4 Transgenes in Drosophila Olfactory Sensory Neurons
Fruit flies recognize hundreds of ecologically relevant odors and respond appropriately to them. The complexity, redundancy and interconnectedness of the olfactory machinery complicate efforts to pinpoint the functional contributions of any component neuron or receptor to behavior. Some contributions can only be elucidated in flies that carry multiple mutations and transgenes, but the production of such flies is currently labor-intensive and time-consuming. Here, we describe a set of transgenic flies that express the Saccharomyces cerevisiae GAL80 in specific olfactory sensory neurons (OrX-GAL80s). The GAL80s effectively and specifically subtract the activities of GAL4-driven transgenes that impart anatomical and physiological phenotypes. OrX-GAL80s can allow researchers to efficiently activate only one or a few types of functional neurons in an otherwise nonfunctional olfactory background. Such experiments will improve our understanding of the mechanistic connections between odorant inputs and behavioral outputs at the resolution of only a few functional neurons.
https://ift.tt/2DChUWF
Correction to: Cost-effectiveness analysis of rotavirus vaccination in China: Projected possibility of scale-up from the current domestic option
After the publication of our article [1] we have been made aware of a number of mislabelling and reporting errors, which were introduced in the preparation of the manuscript. The conclusions are not affected b...
https://ift.tt/2R5kYgK
Incubation period of typhoidal salmonellosis: a systematic review and meta-analysis of outbreaks and experimental studies occurring over the last century
Salmonella Typhi is a human pathogen that causes typhoid fever. It is a major cause of morbidity and mortality in developing countries and is responsible for several outbreaks in developed countries. Studying cer...
https://ift.tt/2OSAVW1
Adverse effects of antiretroviral therapy in pregnant women infected with HIV in Brazil from 2000 to 2015: a cohort study
Antiretroviral therapy (ART) use in pregnancy presents unquestionable benefits in preventing mother-to-child transmission (MTCT) of HIV although it is associated with maternal adverse effects. The aim of this ...
https://ift.tt/2R5TuHF
Current treatment of multidrug resistant tuberculosis in Ethiopia: an aggregated and individual patients’ data analysis for outcome and effectiveness of the current regimens
The programmatic management of Multidrug-resistant tuberculosis (MDR-TB) is entirely based on a WHO recommended long-term, 18–24 month lasting treatment regimen. However, growing evidence shows that low treatm...
https://ift.tt/2OSO41d
Healthcare-associated transmission of Panton-Valentine leucocidin positive methicillin-resistant Staphylococcus aureus: the value of screening asymptomatic healthcare workers
Three patients hospitalised in the coronary care unit of a general district hospital (England, UK) were tested positive for Panton-Valentine leucocidin methicillin-resistant Staphylococcus aureus colonisation dur...
https://ift.tt/2R5Tl75
CBP modulates sensitivity to dasatinib in pre-BCR+ acute lymphoblastic leukemia
Dasatinib is a multi-tyrosine kinase inhibitor approved for treatment of Ph+ acute lymphoblastic leukemia (ALL), but its efficacy is limited by resistance. Recent preclinical studies suggest that dasatinib may be a candidate therapy in additional ALL subtypes including pre-BCR+ ALL. Here we utilized shRNA library screening and global transcriptomic analysis to identify several novel genes and pathways that may enhance dasatinib efficacy or mitigate potential resistance in human pre-BCR+ ALL. Depletion of the transcriptional co-activator CBP increased dasatinib sensitivity by activating transcription of the pre-BCR signaling pathway previously associated with dasatinib sensitivity. Acquired resistance was due in part to upregulation of alternative pathways including WNT through a mechanism suggesting transcriptional plasticity. Small molecules that disrupt CBP interactions with the CREB KID domain or β-catenin showed promising preclinical efficacy in combination with dasatinib. These findings highlight novel modulators of sensitivity to targeted therapies in human pre-BCR+ ALL, which can be reversed by small molecules inhibitors. They also identify promising therapeutic approaches to ameliorate dasatinib sensitivity and prevent resistance in ALL.
https://ift.tt/2OWr15R
New Partners to Develop Immune Engagers [News in Brief]
Genentech/Affimed deal promotes research on antibody drugs that direct T cells and natural killer cells to tumors.
https://ift.tt/2N7ItT4
Hairy Cell Leukemia Treatment Approved [News in Brief]
Moxetumomab pasudotox-tdfk generates high objective response rate, lasting responses.
https://ift.tt/2zAkOXP
Roundtable: Experts reflect on findings, trends from the 2018 EMS Trend Report
Our EMS expert panel identifies actions EMS leaders can take to improve clinical and operational performance, and to advance the profession
https://ift.tt/2N7IUNc
For Whom the Cell Tolls? Intratumoral Treatment Links Innate and Adaptive Immunity
Intratumoral immunotherapy can potentially modulate the tumor microenvironment and potentiate the effects of concomitant or sequential systemic immunotherapies. Intratumoral administration of different Toll-like receptor agonists, including TLR4, can potentiate these effects through innate and adaptive immunity connection.
https://ift.tt/2zC3CBp
A designer cross-reactive DNA immunotherapeutic vaccine that targets multiple MAGE-A family members simultaneously for cancer therapy
Purpose:Cancer/testis antigens have emerged as attractive targets for cancer immunotherapy. Clinical studies have targeted MAGE-A3, a prototype antigen that is a member of the MAGE-A family of antigens, in melanoma and lung carcinoma. However, these studies have not yet had a significant impact due to poor CD8+ T cell immunogenicity, platform toxicity, or perhaps limited target antigen availability. In this study we develop an improved MAGE-A immunogen with cross-reactivity to multiple family members. Experimental Design:In this study we analyzed MAGE-A expression in The Cancer Genome Atlas and observed that many patients express multiple MAGE-A isoforms, not limited to MAGE-A3, simultaneously in diverse tumors. Based on this, we designed an optimized consensus MAGE-A DNA vaccine capable of cross-reacting with many MAGE-A isoforms, and tested immunogenicity and anti-tumor activity of this vaccine in a relevant autochthonous melanoma model. Results:Immunization of this MAGE-A vaccine by electroporation in C57Bl/6 mice generated robust IFN- and TNF-α CD8+ T cell responses as well as cytotoxic CD107a/IFN-/T-bet triple-positive responses against multiple isoforms. Furthermore, this MAGE-A DNA immunogen generated a cross-reactive immune response in 14 out of 15 genetically diverse, outbred mice. We tested the anti-tumor activity of this MAGE-A DNA vaccine in Tyr::CreER;BRAFCa/+;Ptenlox/lox transgenic mice that develop melanoma upon tamoxifen induction. The MAGE-A DNA therapeutic vaccine significantly slowed tumor growth and doubled median mouse survival. Conclusions:These results support the clinical use of consensus MAGE-A immunogens with the capacity to target multiple MAGE-A family members to prevent tumor immune escape.
https://ift.tt/2xWn6yE
Roundtable: Experts reflect on findings, trends from the 2018 EMS Trend Report
Our EMS expert panel identifies actions EMS leaders can take to improve clinical and operational performance, and to advance the profession
https://ift.tt/2QbuddZ
Providers vs. Leaders: Trend report reveals divide on issues of safety, fatigue, mental health
An organization's leadership culture may explain the stark difference in opinion between providers and leaders on issues of patient and provider safety
https://ift.tt/2xYxFRA
Solutions for EMS recruitment and retention are hiding in plain sight
Even though the race to recruit, hire, engage and retain EMS employees is as intense as ever, there are working solutions within reach for every agency
https://ift.tt/2zB9bjp
How do providers and leaders perceive EMS?
The 2018 EMS Trend Report asks EMS field providers, as well as leaders and chiefs, about their perceptions of the state of EMS in the U.S.
https://ift.tt/2NIi6bD
Business Degree Increasingly Useful for Doctors
THURSDAY, Sept. 27, 2018 -- Having a Master of Business Administration degree (M.B.A.) can help doctors with important, practice-related decisions, according to a report published recently in Physician Practice. With the move to value-based care and...
https://ift.tt/2xITeGF
80,000 Americans Died From Influenza Over Last Year
THURSDAY, Sept. 27, 2018 -- Influenza was deadlier last season than it has been for at least four decades, killing 80,000 Americans. So said the head of the U.S. Centers for Disease Control and Prevention late Tuesday in an interview with the...
https://ift.tt/2xGYGKi
Final Update on Salmonella-Tainted Honey Smacks Cereal
THURSDAY, Sept. 27, 2018 -- A total of 135 people across 36 states fell ill with Salmonella after eating Kellogg's Honey Smacks cereal, according to a final update from the U.S. Centers for Disease Control and Prevention. Many of the illnesses...
https://ift.tt/2IkyvNi
Opioid Bill Gets Bipartisan Support
THURSDAY, Sept. 27, 2018 -- In a rare bipartisan move, both the House and Senate have reached a compromise on legislation to address the opioid epidemic. Containing a mix of law enforcement and public health measures, including one that aims to...
https://ift.tt/2Io2bcv
AAP Provides Recommendations for Teen Drivers, Parents
THURSDAY, Sept. 27, 2018 -- In a policy statement published online Sept. 24 in Pediatrics, recommendations are presented to help pediatricians provide guidance for teenage drivers and their families. In an update to a 2006 American Academy of...
https://ift.tt/2Io2aFt
SGLT-2 Inhibitors and DPP-4 Inhibitors as Second-Line Drugs in Patients with Type 2 Diabetes: A Meta-Analysis of Randomized Clinical Trials
Horm Metab Res
DOI: 10.1055/a-0733-7919
Sodium-glucose co-transporter 2 (SGLT-2) inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors are both novel and second-line therapies in type 2 diabetes mellitus, yet no well-rounded comparison of these two drugs has been published. Upon searching randomized controlled trials in databases from inception to July 2018, we collected studies on the efficacy or safety of SGLT-2 inhibitors compared with those of DPP-4 inhibitors for the treatment of type 2 diabetes mellitus. A total of 12 randomized controlled studies including 4342 patients were included in this meta-analysis. Compared with DPP-4 inhibitors, SGLT-2 inhibitors achieved greater reductions in HbA1c (SMD –0.22; 95% CI: –0.30, –0.14; p=0.000) and fasting plasma glucose (SMD –0.48; 95% CI: –0.56, –0.41; p=0.000). In addition, these reductions increased with a prolonged treatment duration from 12 to 78 weeks. Geographically, significant reductions of SGLT-2 inhibitors in HbA1c and FPG were found in North America and Europe, but not in Asia. Furthermore, SGLT-2 inhibitors showed greater reductions in body weight (SMD −0.72; 95% CI: –0.81, –0.63; p=0.000) from baseline, with an increased incidence of genital infections (OR 4.49; 95% CI: 2.96, 6.83; p=0.000) and pollakiuria (OR 2.24; 95% CI: 1.05, 4.79; p=0.037) and a decreased incidence of hypertension and hyperglycemia. Overall, the current meta-analysis demonstrated that compared to DPP-4 inhibitors, SGLT-2 inhibitors have beneficial effects on HbA1c, FPG, body weight, SBP, DBP, and HDL-cholesterol in patients with type 2 diabetes. However, SGLT-2 inhibitors are associated with increased total cholesterol and LDL-cholesterol and a higher incidence of genital infections and pollakiuria.
[...]
© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
https://ift.tt/2N7jyPJ
Perioperative statin therapy in cardiac and non-cardiac surgery: a systematic review and meta-analysis of randomized controlled trials
The effects of perioperative statin therapy on clinical outcome after cardiac or non-cardiac surgery are controversial. We aimed to assess the association between perioperative statin therapy and postoperative...
https://ift.tt/2R3gHKJ
Development, Validation, and Comparative Assessment of an International Scoring System to Determine Risk of Upper Gastrointestinal Bleeding
The Glasgow-Blatchford score (GBS) and pre-endoscopy Rockall score (pRS) are used in determining prognoses of patients with acute upper gastrointestinal bleeding, but neither predicts outcomes of patients with a high level of accuracy. A scoring system is needed to identify patients at risk of adverse outcomes and patients at low risk of harm.
https://ift.tt/2IlevdE
Retrospective Analysis of Safety of Vedolizumab in Patients With Inflammatory Bowel Diseases
There are few real-world data on the safety of vedolizumab for treatment of Crohn's disease (CD) or ulcerative colitis (UC). We quantified rates and identified factors significantly associated with infectious and non-infectious adverse events in clinical practice.
https://ift.tt/2NNBWlA
Risk Factors for Ovarian Carcinoma
Ovarian cancer is the leading gynecologic killer of women in the United States. At diagnosis, most women present with advanced-stage disease. There are currently no effective screening strategies for average-risk women, thus understanding disease development and progression is important for developing risk-reduction strategies and identifying high-risk populations who can benefit from preventive surgery. Cancer epidemiology has greatly contributed to the understanding of this complex, heterogeneous disease by identifying various factors that may modify disease development. This article comprehensively reviews the current evidence regarding risk factors using the newest epidemiologic research for further insight into this lethal disease.
https://ift.tt/2xHiDQO
Fully automated diagnostic system with artificial intelligence using endocytoscopy to identify the presence of histologic inflammation associated with ulcerative colitis (with video)
In the treatment of ulcerative colitis (UC), an incremental benefit of achieving histologic healing beyond that of endoscopic mucosal healing has been suggested; persistent histological inflammation increases the risk of exacerbation and dysplasia. However, identification of persistent histologic inflammation is extremely difficult using conventional endoscopy. Furthermore, the reproducibility of endoscopic disease activity is poor. We developed and evaluated a computer-aided diagnosis (CAD) system to predict persistent histological inflammation using endocytoscopy (520-fold ultra-magnifying endoscope).
https://ift.tt/2N7bhLF
Criteria wanted. Is the brain dead or alive?
Just as the physiologic activities that comprise life form a continuum, the changes during the process of dying also form a continuum. However, medicine, government, and popular culture force the binary determination as to whether a human is alive or dead. This necessitates applying a set of threshold criteria to the available clinical information. One criterion is the Uniform Determination of Brain Death Act (Anonymous 1981) used in the United States which states: "An individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions, or (2) irreversible cessation of all functions of the entire brain, including the brain stem, is dead.
https://ift.tt/2OPVLFj
Factors Influencing Information and Communication Technology Knowledge and Use Among Nurse Managers in Selected Hospitals in the Volta Region of Ghana
This study adopted a cross-sectional design to examine the factors that influence the use of information and communication technology among 108 nurse managers in selected hospitals in the Volta Region of Ghana. A self-administered questionnaire was used to gather data. A χ2 test of association identified sex (P
https://ift.tt/2N6JmLB
https://ift.tt/2N6JmLB
Health-Related Quality of Life in Children and Young Adults with Marfan Syndrome
To assess health-related quality of life (HRQOL) in a large multicenter cohort of children and young adults with Marfan syndrome participating in the Pediatric Heart Network Marfan Trial.
https://ift.tt/2DD2ph9
Neonatal Outcomes in Extremely Preterm Newborns Admitted to Intensive Care after No Active Antenatal Management: A Population-Based Cohort Study
To evaluate the association between active antenatal management and neonatal outcomes in extremely preterm newborns admitted to a neonatal intensive care unit (NICU).
https://ift.tt/2DCm4hr
A Structured Gradual Exposure Protocol to Baked and Heated Milk in the Treatment of Milk Allergy
To evaluate the efficacy and safety of a structured gradual exposure protocol (SGEP) with extensively heated and baked milk in promoting allergy resolution in children with cow milk allergy (CMA).
https://ift.tt/2OhJTin
Early Mobility in the Pediatric Intensive Care Unit: Can We Move On?
"It means a great deal…to be put on their own feet in a short time, rather than be confined to bed, having their weak backs and general debility increase rather than disappear after the operation which was to cure them."—Dr Emil Ries, JAMA 18991
https://ift.tt/2OgjaCY
Ocular Complications in PHACE Syndrome: A True Association or a Coincidence?
To characterize the risk for ocular complications in patients with PHACE syndrome.
https://ift.tt/2Dy0vOV
Surfactant Components and Tracheal Aspirate Inflammatory Markers in Preterm Infants with Respiratory Distress Syndrome
In 93 preterm infants ≤32 weeks of gestational age and 12 control infants, epithelial lining fluid disaturated-phosphatidylcholine, surfactant protein A and B, albumin, and myeloperoxidase activity were assessed after intubation and before exogenous surfactant administration. We found that disaturated-phosphatidylcholine, surfactant protein B, and myeloperoxidase were significantly higher in preterms with chorioamnionitis.
https://ift.tt/2DyMeS0
Antenatal and Intrapartum Risk Factors for Hypoxic-Ischemic Encephalopathy in a US Birth Cohort
To identify risk factors for hypoxic-ischemic encephalopathy (HIE) within a recent US birth cohort.
https://ift.tt/2OhJWe3
Sedative and Anesthetic Neurotoxicity in Infants and Young Children: Not Just an Operating Room Concern
In December 2016, the US Food and Drug Administration (FDA) issued a drug safety announcement warning that repeated or lengthy (>3 hours) use of general anesthetic and sedating drugs during surgeries or procedures in children <3 years of age or in pregnant women during their third trimester may affect the development of children's brains.1 As of April 27, 2017, the FDA now requires drug manufacturers to add warning labels regarding children <3 years of age to the following general anesthetics and sedative medications: desflurane, etomidate, halothane, isoflurane, ketamine, lorazepam injection, methohexital, midazolam injection and syrup, pentobarbital, propofol, and sevoflurane.
https://ift.tt/2OhK11l
Bronchopulmonary Dysplasia in Very Preterm Infants with Symptomatic Congenital Cytomegalovirus Infection: A Propensity Score- Matched Analysis
To assess whether symptomatic congenital cytomegalovirus infection (cCMV) is associated with bronchopulmonary dysplasia (BPD) and mortality in very preterm infants (gestational age ≤32 weeks).
https://ift.tt/2DB95wo
Cutaneous Leishmaniasis in a Boy from Belize
A 9-year-old boy from Belize presented with a 3-month history of enlarging plaques on his arm. Originating as papules, the lesions had progressed despite treatment with topical mupirocin, oral amoxicillin, and cephalexin. At presentation, physical examination revealed 2 well-circumscribed, round plaques with rolled borders and central erosion on the right forearm (Figure 1). A previous biopsy demonstrated amastigotes within histiocytes, consistent with a diagnosis of cutaneous leishmaniasis. Repeat biopsy sent for polymerase chain reaction, conducted by the Centers for Disease Control and Prevention (CDC), confirmed infection by Leishmania mexicana.
https://ift.tt/2DxkAVs
Prevalence of Congenital Heart Disease at Live Birth in China
To investigate the prevalence of congenital heart disease (CHD) in China based on a large prospective multicenter screening study.
https://ift.tt/2DyMf8w
Fluid-Fluid Levels in Aneurysmal Bone Cysts
An 11-year-old girl complained about persistent thoracolumbar junction pain. Magnetic resonance imaging revealed a lesion in the body of L1. Biopsy confirmed the lesion as an aneurysmal bone cyst. Several endovascular embolization procedures were attempted, with poor results. The lesion grew progressively over the next 5 months, extending into the posterior elements and surrounding soft tissues and encasing the spinal cord. Pain increased, making it impossible for the patient to sit for prolonged periods or ambulate long distances.
https://ift.tt/2Ogjf9K
A Simplified Risk Stratification Method for Women With Stage I Endometrial Carcinoma
Objectives: Available risk stratification methods for women with endometrial carcinoma are controversially defined. We sought to develop a simplified and an individualized prognostic index for cancer recurrence in women with International Federation of Gynecology and Obstetrics (FIGO) stage I endometrial carcinoma, solely of endometrioid histology. Materials and Methods: We identified 976 women who underwent a hysterectomy and did not receive any adjuvant therapy. Cox proportional hazards model was used to identify independent predictors of recurrence. Prognostic groups were created based on the number of independent predictors of recurrence (0, 1, or 2 or 3 risk factors). These groups were then validated using a separate cohort of 611 women treated at another academic institution. The model's performance for predicting cancer recurrence was measured by the concordance probability estimate along with a 95% confidence interval. Results: Median follow-up was 65 months. The final recurrence model included 3 risk groups based on 3 independent predictors of recurrence (tumor grade 2 or 3, the presence of lymphovascular space invasion and stage IB). Five-year recurrence rates were 4%, 16%, and 44% for groups 0, 1, and 2 or 3, respectively. The performance of the model was very good with a concordance probability estimate of 0.72 and 0.80 for the development and validation cohorts, respectively. Conclusions: On the basis of 3 well-known prognostic factors, we have developed and externally validated a simplified prognostic model that accurately predicts cancer recurrence in women with stage I endometrial carcinoma. This simplified predictive tool may be helpful in estimating individualized risk of recurrence and guide counseling with regard to adjuvant treatment. The authors declare no conflicts of interest. Reprints: Mohamed A. Elshaikh, MD, Department of Radiation Oncology, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202. E-mail: melshai1@hfhs.org. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
https://ift.tt/2xHbvE3
https://ift.tt/2xHbvE3
How do providers and leaders perceive EMS?
The 2018 EMS Trend Report asks EMS field providers, as well as leaders and chiefs, about their perceptions of the state of EMS in the U.S.
https://ift.tt/2QdUKHI
Oral Intubation of Adult Zebrafish: A Model for Evaluating Intestinal Uptake of Bioactive Compounds
https://ift.tt/2xIsmq4
Solution-Processed "Silver-Bismuth-Iodine" Ternary Thin Films for Lead-Free Photovoltaic Absorbers
https://ift.tt/2OS0FSp
How do providers and leaders perceive EMS?
The 2018 EMS Trend Report asks EMS field providers, as well as leaders and chiefs, about their perceptions of the state of EMS in the U.S.
https://ift.tt/2QdUKHI
Lyoprotection and stabilization of laccase extract from Coriolus hirsutus, using selected additives
The development of stable lyophilized laccase, obtained from Coriolus hirsutus, using a wide range of temperature treatments and storage conditions, was investigated. Using selected lyoprotectants, including, dex...
https://ift.tt/2xGUOsm
Bacteriocin production of the probiotic Lactobacillus acidophilus KS400
In the last years, the use of probiotics, including Lactobacillus species, has received much attention to prevent and treat vaginal disorders. These species have been described as having the ability to colonize t...
https://ift.tt/2Dy2dj6
The R50 Research Specialist Award: Ensuring a Stable Cancer Research Workforce
With the increasing reliance on advanced technologies and the rise of big data in cancer research, NCI launched the R50 Research Specialist Award to help sustain a stable workforce of experienced scientists who can take fullest advantage of these tools and resources.
https://ift.tt/2xPArtt
Cape and Skyfire Consulting team up to support end-to-end drone integration for public safety
REDWOOD CITY, Calif. — Cape, the leading cloud platform for drone telepresence and data management, today announced a partnership with Skyfire Consulting to provide comprehensive technology solutions and support for the safe integration of commercial drones across public safety agencies, including law enforcement, fire rescue, and emergency management services. As part of the partnership,...
https://ift.tt/2xV6BTs
Reconstitution of Cell-cycle Oscillations in Microemulsions of Cell-free Xenopus Egg Extracts
We present a method for the generation of in vitro self-sustained mitotic oscillations at the single-cell level by encapsulating egg extracts of Xenopus laevis in water-in-oil microemulsions.
https://ift.tt/2QcwzJy
Guidelines Updated for Adult Congenital Heart Disease
THURSDAY, Sept. 27, 2018 -- Updated guidelines have been developed for management of adult congenital heart disease (ACHD), according to a report published online Aug. 16 in Circulation. Karen K. Stout, M.D., from the University of Washington in...
https://ift.tt/2Ok9tDx
Heading a Soccer Ball Found to Be Riskier for Female Players
THURSDAY, Sept. 27, 2018 -- Female soccer players exhibit more widespread evidence of microstructural white matter alteration than males, despite having similar exposure to heading, according to a study recently published in Radiology. Todd G....
https://ift.tt/2Og0OSy
Grip Strength Tied to Pulmonary Function in Older Women
THURSDAY, Sept. 27, 2018 -- For older Korean women, handgrip strength is positively associated with pulmonary function, according to a study published in the July issue of the Journal of the American Geriatrics Society. Da-Hye Son, M.D., from Yonsei...
https://ift.tt/2DxBBPr
Kidney Function Recovery Seen in Some Children on Dialysis
THURSDAY, Sept. 27, 2018 -- Roughly 2 percent of pediatric patients on maintenance dialysis recover within two years after dialysis initiation, according to a study published online Sept. 20 in the Clinical Journal of the American Society of...
https://ift.tt/2Of1R59
Machine Learning Can Improve Chemical Toxicity Prediction
THURSDAY, Sept. 27, 2018 -- Machine learning of toxological big data can predict the toxicity of chemicals, and may be more reliable than animal testing, according to a study published in the September issue of Toxicological Sciences. Noting that...
https://ift.tt/2DJoYRA
Time to Defib Not Linked to Survival in Pediatric IHCA
THURSDAY, Sept. 27, 2018 -- For pediatric patients with in-hospital cardiac arrest (IHCA), time to first defibrillation attempt is not associated with survival, according to a study published online Sept. 21 in JAMA Network Open. Elizabeth A. Hunt,...
https://ift.tt/2OiYJW6
Single Agent Treats Two Cancers With Same Genetic Cause
THURSDAY, Sept. 27, 2018 -- A single checkpoint inhibitor can be used to successfully treat two simultaneous types of primary cancer in a patient with Lynch syndrome, according to a research letter published online Sept. 25 in the Annals of Internal...
https://ift.tt/2DJoVFo
Newer Hormonal Contraception May Cut Ovarian Cancer Risk
THURSDAY, Sept. 27, 2018 -- There is a reduction in ovarian cancer risk associated with use of contemporary combined hormonal contraceptives, according to a study published online Sept. 26 in The BMJ. Lisa Iversen, Ph.D., from the University of...
https://ift.tt/2OiiBsn
Practices Should Set Rules for Staff Social Media Use
THURSDAY, Sept. 27, 2018 -- Medical practices can take steps to avoid problems related to use of social media by staff members, according to an article published in Medical Economics. Some practices encourage staff members to keep their phones...
https://ift.tt/2Dz4Nph
Gallic acid inhibits fibroblast growth and migration in keloids through the AKT/ERK signaling pathway
Abstract
Keloids are a fibroproliferative disorder of the skin resulted from abnormal healing of injured or irritated skin and are characterized by the ability to spread beyond the original boundary of the wound. Here, we tested the effect of gallic acid (GA), a plant polyphenol with selective growth inhibitory effects in cancer, on the proliferation and invasion of keloid fibroblasts (KFs) isolated from patients undergoing surgery. GA inhibited KF proliferation, migration, and invasion in parallel with the downregulation of matrix metalloproteinase-1 and -3 and upregulation of tissue inhibitors of metalloproteinase-1. Flow cytometric analysis showed that GA inhibited cell cycle progression and induced apoptosis. The effects of GA on KFs occurred in parallel with the inhibition of AKT and ERK1/2, suggesting that GA acts by suppressing the AKT/ERK signaling pathway. In ex vivo explant cultures of keloid tissues, GA inhibited the migration of KFs to the wound area and suppressed the expression of angiogenic markers concomitant with the inhibition of collagen deposition. These results identify GA as a potential therapeutic agent for the treatment of keloids and suggest a potential mechanism underlying its protective effect.https://ift.tt/2Ilu70A
A novel CD81 homolog identified in lamprey, Lampetra japonica, with roles in the immune response of lamprey VLRB+ lymphocytes
Abstract
The cluster of differentiation 81 (CD81), a member of the transmembrane 4 superfamily, is primarily found to be expressed in a wide variety of cells including T and B cells of vertebrates as a critical modulator. In the present study, the open reading frame of a CD81 gene homolog (Lja-CD81) was cloned in lamprey, Lampetra japonica, which is 702 bp long and encodes a protein of 233-amino acids. Although Lja-CD81 seems to be close to CD9 molecules in their full-length sequences, Lja-CD81 possesses higher identity to vertebrates' CD81 than to CD9 (including a lamprey CD9) molecules in their large extracellular loops. In addition, it also possesses a myristoylation site (Met-Gly-Val-Glu-Gly-Cys-Leu-Lys) in its N-terminal region which is identical to the N-terminal regions of CD81 molecules. These data suggest that CD9 and CD81 molecules diverged no later than the emergence of jawless vertebrates. The mRNA levels of Lja-CD81 in lymphocytes and supraneural myeloid bodies were up-regulated significantly after stimulation with mixed antigens, and a similar expressional pattern of Lja-CD81 at protein level was also confirmed. Furthermore, Lja-CD81 was found to be co-localized with variable lymphocyte receptor B (VLRB) evenly on the cell membrane of peripheral blood lymphocytes isolated from control group, but they were found to aggregate on one side of the membrane of peripheral blood VLRB+ lymphocytes after stimulation with mixed antigens. All these results indicate that the Lja-CD81 identified in lamprey may play an important role in the immune response of lamprey VLRB+ lymphocytes.https://ift.tt/2xGZa2Y
Subtype-specific Optical Action Potential Recordings in Human Induced Pluripotent Stem Cell-derived Ventricular Cardiomyocytes
Here we present a method to optically image action potentials, specifically in ventricular-like induced pluripotent stem cell-derived cardiomyocytes. The method is based on the promoter-driven expression of a voltage-sensitive fluorescent protein.
https://ift.tt/2NI71XY
Identification of Virulence Markers of Mycobacterium abscessus for Intracellular Replication in Phagocytes
https://ift.tt/2QdkAvd
Recent advances in searching c-Myc transcriptional cofactors during tumorigenesis
Abstract
Background
The mechanism by which c-Myc exerts its oncogenic functions is not completely clear and different hypotheses are still under investigation. The knowledge of the capacity of c-Myc to bind exclusively E-box sequences determined the discrepancy between, on the one hand, genomic studies showing the binding of c-Myc to all active promoters and, on the other hand, the evidence that only 60% or less of the binding sites have E-box sequences.
Main body
In this review, we provide support to the hypothesis that the cooperation of c-Myc with transcriptional cofactors mediates c-Myc-induced cellular functions. We produce evidence that recently identified cofactors are involved in c-Myc control of survival mechanisms of cancer cells.
Conclusion
The identification of new c-Myc cofactors could favor the development of therapeutic strategies able to compensate the difficulty of targeting c-Myc.
https://ift.tt/2N8l1VQ
Autonomous and Rechargeable Microneurostimulator Endoscopically Implantable into the Submucosa
https://ift.tt/2xUMJjl
Low-Dose Oral Food Challenge with Hazelnut: Efficacy and Tolerability in Children
Background: Hazelnut allergy (HA) is one of the more common food allergies (FAs) in Europe with a prevalence of 0.2%. The gold standard for diagnosing FA is oral food challenge (OFC) with the culprit food. Another purpose of OFC is to identify the "threshold level" of food as the dose that elicits symptoms. In this way it is possible to avoid a strict elimination diet and to determine the minimal quantity of the culprit food tolerated by the patient. Objective: The aim of our study was to assess the efficacy and tolerability of hazelnut low-dose OFC (H-LDOFC) in children with HA. Methods: From January 2015 to December 2016, we retrospectively analyzed the charts of patients referred to Allergy Unit of Meyer Children's Hospital, Florence, Italy for a history of HA. Prick by prick (PbP) and specific serum IgE (s-IgE) to hazelnut were performed. We proposed conducting an H-LDOFC to parents of children with HA. The H-LDOFC was considered completed when a cumulative dose of 2.5 g of hazelnut was reached. We divided the patients who underwent the H-LDOFC into an asymptomatic and a symptomatic group. For statistics we used SPSS for Windows version 16.0 and conducted a t test for comparing the averages, considering a p value of #x3c; 0.05 significant. Results: Forty-three out of 70 patients (61.4%) with HA underwent an H-LDOFC. The PbP to hazelnut (mean ± SD) was 7.2 ± 2.9 mm and the s-IgE to hazelnut 25.3 ± 32.5 kU/L. Twenty-eight out of the 43 patients (65.1%) who underwent H-LDOFC reached the cumulative dose of 2.5 g of hazelnut. During the H-LDOFC, 20/43 patients (46.5%) had no reactions and 23/43 patients had a total of 55 reactions: 34 (61.8%) oral allergy syndrome, 8 (14.5%) rash, 6 (10.9%) abdominal pain, 2 (3.6%) urticaria, 2 (3.6%) angioedema, and 3 (5.4%) dyspnea. Atopic dermatitis was found to present the only statistically significant difference (p = 0.002) in patients with symptoms compared to asymptomatic patients during H-LDOFC. Conclusions: To our knowledge, this was the first study to assess the efficacy and tolerability of H-LDOFC in a pediatric population. Our study suggests that in children with HA, H-LDOFC is well accepted and safe because adverse reactions are mild and the majority are represented by localized symptoms (oral allergy syndrome) and efficient, especially in terms of improvement of quality of life. For these reasons it could be more extensively used in the treatment of HA.
Int Arch Allergy Immunol
https://ift.tt/2OmlZlQ
Int Arch Allergy Immunol
https://ift.tt/2OmlZlQ
Therapeutic Effectiveness of Galphimia glauca in Young People with Social Anxiety Disorder: A Pilot Study
Social anxiety is one of the most common disorders found in the population attending the first level of health care. Galphimia glauca has been used for many years in Mexican traditional medicine to treat "nervous disorders". A standardized extract of this species has been evaluated in clinical studies that have proven its efficacy and safety in patients with generalized anxiety disorder. In this work, a double-blind clinical trial was carried out, using sertraline as a control. Patients from both sexes (18 to 35 years old) with moderate or severe social anxiety were included. Experimental group was treated daily (orally), for 10 weeks, with an extract from G. glauca containing 0.374 mg/dose of Galphimine-B (G-B, active compound). Patients in the control group were given sertraline (50 mg) in the same conditions. All patients were evaluated every two weeks. Another assessment was done one month after the end of the administration period. A total of 34 patients was included, 17 in each group. Women were predominant, and the mean age was 25 ± 4.7 years. In patients who received the G. glauca standardized extract, a significant reduction in anxiety was observed, with a value (in the Brief Social Phobia Scale) of 41.1±10.3 points at the start and 11.2±5.6 points at the end of treatment, while patients treated with sertraline had a value of 37.7±7.3 points at the beginning and 11.1±5.2 points at the end. No significant difference was observed between the treated groups. In a similar way, the health scale showed a gradual and continuous improvement in each of the five evaluations. In conclusion, the 10-week oral administration of G. glauca standardized extract showed efficacy and safety in patients with social anxiety disorder, without showing a significant difference from patients treated with sertraline.
https://ift.tt/2ORTJEL
Cancers, Vol. 10, Pages 361: Comprehensive Analysis of Germline Variants in Mexican Patients with Hereditary Breast and Ovarian Cancer Susceptibility
Cancers, Vol. 10, Pages 361: Comprehensive Analysis of Germline Variants in Mexican Patients with Hereditary Breast and Ovarian Cancer Susceptibility
Cancers doi: 10.3390/cancers10100361
Authors: Rosalía Quezada Urban Clara Díaz Velásquez Rina Gitler María Rojo Castillo Max Sirota Toporek Andrea Figueroa Morales Oscar Moreno García Lizbeth García Esquivel Gabriela Torres Mejía Michael Dean Iván Delgado Enciso Héctor Ochoa Díaz López Fernando Rodríguez León Virginia Jan Víctor Garzón Barrientos Pablo Ruiz Flores Perla Espino Silva Jorge Haro Santa Cruz Héctor Martínez Gregorio Ernesto Rojas Jiménez Luis Romero Cruz Claudia Méndez Catalá Rosa Álvarez Gómez Verónica Fragoso Ontiveros Luis Herrera Isabelle Romieu Luis Terrazas Yolanda Chirino Cecilia Frecha Javier Oliver Sandra Perdomo Felipe Vaca Paniagua
Hereditary breast and ovarian cancer syndrome (HBOC) represents 5–10% of all patients with breast cancer and is associated with high-risk pathogenic alleles in BRCA1/2 genes, but only for 25% of cases. We aimed to find new pathogenic alleles in a panel of 143 cancer-predisposing genes in 300 Mexican cancer patients with suspicion of HBOC and 27 high-risk patients with a severe family history of cancer, using massive parallel sequencing. We found pathogenic variants in 23 genes, including BRCA1/2. In the group of cancer patients 15% (46/300) had a pathogenic variant; 11% (33/300) harbored variants with unknown clinical significance (VUS) and 74% (221/300) were negative. The high-risk group had 22% (6/27) of patients with pathogenic variants, 4% (1/27) had VUS and 74% (20/27) were negative. The most recurrent mutations were the Mexican founder deletion of exons 9-12 and the variant p.G228fs in BRCA1, each found in 5 of 17 patients with alterations in this gene. Rare VUS with potential impact at the protein level were found in 21 genes. Our results show for the first time in the Mexican population a higher contribution of pathogenic alleles in other susceptibility cancer genes (54%) than in BRCA1/2 (46%), highlighting the high locus heterogeneity of HBOC and the necessity of expanding genetic tests for this disease to include broader gene panels.
https://ift.tt/2xUAinL
Paediatric ocular super glue injuries: assessment of two cases
In this report, we elaborate the clinical findings and the optimal management of two cases with ocular glue injuries in two paediatric patients. Both the patients were presented to the ocular emergency with completely closed eyelid and periocular erythema. The eyelids were completely closed due to matting of the eyelashes with glue retention up to lash roots. Thus, in both cases, after the application of local anaesthetic agent, immediate lash trimming was performed along with the removal of crystallised glue particles. However, the ocular surface showed only congestion in absence of any added corneal complications. Patients were followed up with standard treatment protocol as per chemical injuries. Until the end of 5 months, the clinical course was uneventful.
https://ift.tt/2QbJE64
Comorbid presentation of syringomyelia and Guillain-Barre syndrome, attributed to mycoplasma, in a 6-year-old female patient
Syringomyelia is the development of a fluid-filled cavity or syrinx within the spinal cord that can cause loss of sensation and muscle spasticity. Guillain-Barre syndrome (GBS) is a postinfection autoimmune disease, classified as an acute polyneuropathy. This report describes the emergency admission of a 6-year-old girl presenting with sudden pallor and pain in both lower limbs. The patient's reflexes were normal, as were the results of her sonography, radiography and biochemical tests; however, spinal MRI revealed extensive compartmentalised syringomyelia extending from C2 to T3. A sensory and motor nerve conduction study revealed a demyelinating type motor polyneuropathy which, along with positive Mycoplasma pneumoniae test, was suggestive of GBS. Intravenous immunoglobulin infusion showed excellent results. In conclusion, we report a rare paediatric case of syringomyelia coexisting with GBS. It is important to bear in mind the possibility of other coexisting diseases even if MRI reveals definitive characteristics of another condition.
https://ift.tt/2zA9FGq
Diagnosis of a tick-borne coinfection in a patient with persistent symptoms following treatment for Lyme disease
A 67-year-old woman presented with 5 days of myalgias and fevers on completion of a 21-day course of amoxicillin for Lyme disease (Borrelia burgdorferi infection). She was found to have profound thrombocytopenia, as well as new anaemia and leucopenia. Workup revealed Babesia microti as the causative agent of her symptoms. The patient quickly improved after appropriate antimicrobial therapy directed against babesiosis was started. This case illustrates the importance of basic microbiology, including epidemiology and common vectors, when creating a differential diagnosis. Because the Ixodes scapularis tick can harbour and transmit multiple parasites simultaneously, the possibility of coinfection should be considered in any patient not responding to appropriate initial medical therapy.
https://ift.tt/2Q8BUS6
Desire for lasting long in bed led to contact allergic dermatitis and subsequent superficial penile gangrene: a dreadful complication of benzocaine-containing extended-pleasure condom
Description
A 30-year-old non-atopic, non-diabetic man presented with complaints of swelling, pain and patchy blackening of penile skin for the last 3 days. He stated that for improving the duration of sexual intercourse and for better sexual performance, he recently used a new brand of condom, which contained 5% benzocaine. He, however, denied about the use of any lubricants or topical substance at the time of sexual act. There was no history of fever, inguinal or scrotal swelling, genital trauma, insect bite, known drug allergy, substance abuse or similar complaints in the past. In the past, he was using non-medicated natural rubber latex condom for contraception without any adverse effects. Local examination revealed vesicle eruption, sloughing and patchy blackening of penile skin extending from prepuce to base of penis with a clear demarcation line with non-palpable inguinal lymph nodes suggestive of allergic contact dermatitis as shown in figure 1. The underlying...
https://ift.tt/2zzKPqe
Knotted electric wire in urinary bladder: Can such complex foreign body be retrieved endoscopically!
Various types of foreign bodies have been recovered from the urinary bladder and urethra including telephone cables, pocket battery, little fish, pen tips and so on. Management of such cases include either endoscopic removal or open surgery. We report the case of an 18-year-old boy who inserted an electric wire in the urethra for eroticism and was managed by endoscopic removal following fragmentation of wire under local anaesthesia using holmium laser.
https://ift.tt/2QdFESt
Recurrent aseptic meningitis with PIGT mutations: a novel pathogenesis of recurrent meningitis successfully treated by eculizumab
We report the case of a patient with PIGT mutations who experienced recurrent aseptic meningitis 121 times over 16 years before developing paroxysmal nocturnal haemoglobinuria (PNH). Each episode was preceded by urticaria and arthralgia. After developing PNH, haemolysis occurred prior to meningitis. Flow cytometry revealed deficiency of the glycophosphatidylinositol (GPI)-anchored complement regulatory proteins, CD59 and CD55, and he was diagnosed with PNH. All the symptoms disappeared on administering eculizumab, an anti-C5 antibody. We did not detect mutation in PIGA, which is regarded as the cause of PNH. However, we detected a germ-line mutation and a somatic microdeletion in chromosome 20q including PIGT; PIGT is essential for transferring GPI anchor to the precursors of CD59 and CD55, which play important roles in complement regulation. Loss of these proteins leads to complement overactivation, causing inflammatory symptoms, including recurrent meningitis. PIGT mutations should be considered a novel pathogenesis of recurrent meningitis of unknown aetiology.
https://ift.tt/2zAyO45
Obstructive urosepsis secondary to ureteric herniation into the sciatic foramen
A 65-year-old female patient presented with a 2-day history of worsening right-sided abdominal pain and clinical signs of sepsis, on the background of a recent admission for pancolitis. Imaging revealed right ureteric herniation through the sciatic foramen with subsequent hydroureteronephrosis and radiological signs of severe pyelonephritis. The patient underwent emergency decompression with a percutaneous nephrostomy, followed by insertion of an antegrade stent to correct the ureteric hernia once the sepsis was appropriately treated. We describe the presentation and management of this unusual case of herniation of the right ureter into the sciatic foramen.
https://ift.tt/2QfcMtc
Acromioclavicular joint cyst formation in a patient with rotator cuff-tear arthropathy: a rare cause of shoulder discomfort
We report a case of a 77-year-old man who presented to our shoulder department with a soft tissue mass on his right acromioclavicular (AC) joint. Previously attempted puncture aspiration had revealed serous fluid retention which recurred after each of several drainage attempts. Conventional radiography and MRI of the affected shoulder joint demonstrated a progressed cuff-tear arthropathy with an irreparable tear of the supraspinatus tendon, static superior migration of the humeral head, opening of the AC joint capsule and a superior joint-fluid 'eruption' and accumulation called 'Geyser sign'. Given that the patient's cuff-tear arthropathy was very well compensated, arthroscopic rotator cuff debridement and open cyst excision were performed. Closure of the superior aspect of the AC joint capsule was performed by the aid of a collagen matrix with additional closure of the deltotrapezial fascia. One year postoperatively, no cyst recurrence was noted.
https://ift.tt/2zAvNAC
Atypical presentation of molar pregnancy
The classic features of molar pregnancy are irregular vaginal bleeding, hyperemesis, enlarged uterus for gestational age and early failed pregnancy. Less common presentations include hyperthyroidism, early onset pre-eclampsia or abdominal distension due to theca lutein cysts. Here, we present a case of molar pregnancy where a woman presented to the emergency department with symptoms of acute abdomen and was treated as ruptured ectopic pregnancy. The woman underwent laparoscopy and evacuation of retained products of conception. Histological examination of uterine curettage confirmed the diagnosis of a complete hydatidiform mole. The woman was discharged home in good general condition with a plan for serial beta-human chorionic gonadotropin (beta-hCG) follow-up. Complete follow-up includes use of contraception and follow-up after beta-hCG is negative for a year.
https://ift.tt/2QbFTx8
Lupus causing small bowel obstruction
A 20-year-old female patient was admitted to hospital in 2015 with 1 year history of recurrent abdominal pain, distension, borborygmi and nausea. The patient had a background of systemic lupus erythematous (SLE) diagnosed 4 years before, with skin, joint and renal involvement. The initial investigations have shown a long segment of ileal inflammation with upstream obstruction. Differential diagnoses were mainly SLE enteritis or concomitant Crohn's. Patient failed the initial conservative management and had a laparotomy with small bowel (SB) resection and ileostomy. The histology was suggestive of autoimmune enteritis. Although bowel involvement is a frequent feature of SLE, surgery for obstruction is extremely rare. Postoperatively, she had an emergency admission and was diagnosed with SB volvulus with perforation. She underwent further resection and stoma refashioning in 2016. As a consequence, she developed short gut syndrome. Eventually, the stoma was reversed and parenteral nutrition was stopped and weight became stable.
https://ift.tt/2zzfbcw
Idiopathic macrocheilia
A 13-year-boy presented with painless swelling of upper and lower lips accompanied with gingival enlargement. The aetiology for these symptoms included vast pathological varieties but none of them could fit in. Clinical features were similar to orofacial graulomatosis but histopathological examination revealed chronic non-specific infection. Therefore, the final diagnosis was made as idiopathic macrocheilia through exclusion criteria. Management with intralesional triamcinolone acetonide 40 mg, twice a week for 3 weeks, resulted in significant remission in lip swelling without recurrence after a 6-month follow-up.
https://ift.tt/2QbT3ug
Massive gastric dilatation leading to acute respiratory distress 1 year after a Nissen fundoplication
Acute massive gastric dilatation (AMGD) is a recognised complication after Nissen fundoplication.1 A 63-year-old man recently presented to our emergency department in acute respiratory distress, acute abdominal pain and distension, having had an elective umbilical port incisional hernia repair a day prior. In the year preceding his presentation, the patient had undergone a laparoscopic paraoesophageal hiatus hernia repair and excision of sac, posterior cruropexy, dual mesh reinforcement of repair and 360° fundoplication, as a day case. In between these two events, the patient was asymptomatic, and had a free diet with no further medical or surgical intervention. We hereby present successful management and discuss implications of this exceptional yet potentially life-threatening complication.
https://ift.tt/2zA92gp
Diabetic ketoacidosis and thyroid storm: coexistence of a double trouble
Diabetic ketoacidosis (DKA) and thyrotoxic crisis are both endocrine emergencies. Here, we present a case of a patient who presented with DKA and on further evaluation was found to also have a thyrotoxic crisis. The coexistence of both of these endocrine emergencies simultaneously is extremely rare and heralds grave prognosis unless identified and treated promptly.
https://ift.tt/2QaNWdG
Bilateral submandibular gland nodular oncocytic hyperplasia with papillary cystadenoma-like areas
A 57-year-old man presented in 2016 with a 4-month history of a right submandibular mass, having undergone left submandibular gland (SMG) excision in 2003. Imaging suggested a benign tumour and subsequent core biopsy findings suggested a nodular oncocytic hyperplasia, similar to the tumour removed from the contralateral side. This was confirmed on histological analysis following right submandibular gland excision which showed characteristic features of nodular oncocytic hyperplasia along with an unusual diffuse papillary cystadenoma-like ductal proliferation, similar to that seen in the 2003 specimen. A diagnosis of multinodular adenomatous oncocytic hyperplasia (MAOH) was rendered in order to communicate the unique histological features that have otherwise not been described in the literature. We believe that this is the first reported case of non-synchronous multinodular oncocytic hyperplasia and the first case affecting the submandibular glands.
https://ift.tt/2zzPVTw
Gossypiboma masquerading as nephrocutaneous fistula
Nephrocutaneous fistula is a rare complication of surgical procedures involving the kidney. Fistula formation is also a complication seen in gossypiboma. We present the case of a patient who was initially suspected to have nephrocutaneous fistula after open pyelolithotomy. Later while undergoing open resection of fistula, he was found to have a retained surgical sponge (gossypiboma) near the lower pole of kidney. Gossypiboma is a term used for mass formed around a surgical sponge accidentally left in the body. It is most of the times not diagnosed by radiological imaging and thus results in unnecessary investigations to rule out other causes for the patient's symptoms. Having a high index of suspicion may lead to an earlier diagnosis. But the prevention of gossypiboma is of the utmost importance. A meticulous approach while operating by the surgeon and operating rooms staff is very important in doing so.
https://ift.tt/2Qde4Vl
Chronic urinary retention due to diabetic cystopathy masquedering as mesenteric cyst
Description
A 55-year-old previously diabetic man presented with progressive abdominal distension for the last three months. He denied any bowel/bladder complaints. His medical/surgical history was unremarkable. On examination his vitals were stable and a huge abdominal mass (10x11 cm) was palpable. The mass was having side-to-side mobility. There was no hepatosplenomegaly or clinically significant lymphadenoapathy. On evaluation with ultrasonography of abdomen and CT scan, there was evidence of huge, cystic and homogenous mass (13x11 cm) with clear margins occupying almost entire abdominal cavity (figure 1). There was no evidence of calcification, septations or nodules in the mass, and it appeared to be separate from both the kidneys and bowel. A provisional diagnosis of mesenteric cyst was made, and the patient was taken for laparotomy. A per-urethral catheter was placed intraoperatively and surgery was started. During laparotomy it came as an element of surprise that the swelling was actually chronically distended bladder...
https://ift.tt/2zA9taa
Fetishism in ADHD: an impulsive behaviour or a paraphilic disorder?
A boy with attention deficit and hyperactivity disorder (ADHD) presented with a fetish for and the subsequent stealing of female undergarments. He was predominantly inattentive and had been a slow learner. Psychological tests showed that he had significant cognitive and inattention problems without significant hyperactivity, and was at risk of dyslexia as well as conduct disorder.
https://ift.tt/2QddTJF
Pneumonia and bacteraemia caused by Gemella morbillorum in a previously healthy infant: first reported case in literature
A 5-month-old baby presented with a low-grade fever and tachypnoea and was found to have right upper lobe consolidation on chest radiograph. He was admitted with the diagnosis of bronchopneumonia and the treatment protocol for pneumonia was initiated. Blood culture samples were collected, and he was started on a course of intravenous amoxicillin–clavulanate. Blood culture results displayed pansensitive Gemella morbillorum bacteraemia and he was continued on intravenous antibiotic to which he responded in a short period and was discharged in good condition on the fourth day.
https://ift.tt/2zzCnXW
Gastric emphysema secondary to severe vomiting: a comparative review of 14 cases
Gastric emphysema is characterised by the presence of air within the wall of the stomach. The radiographic finding of gastric emphysema with hepatic portal venous gas is classically an ominous sign, associated with a high mortality rate. We report one case from our clinical experience and undertake a review of the previously reported cases of vomiting-induced gastric emphysema retrieved from the PubMed. A total of 14 cases were found to date. The mean age at the time of diagnosis was 45.6 years (range, 9 months to 81 years). Computed tomography abdomen was the frequently used diagnostic modality. Interestingly, conservative treatment led to a clinical cure and resolution of gastric emphysema as well as the associated hepatic portal venous gas in most of the patients. This review illustrates that vomiting-related gastric emphysema entails a more benign course and surgical intervention can be avoided with a prompt aetiology establishment in these patients.
https://ift.tt/2Q9X2Yj
Aneurysmal dilation of the vein of Galen and straight sinus with resultant obstructive hydrocephalus
Description
A 20-year-old woman was admitted to the emergency department on a previous occasion with tonic-clonic seizures. Her medical history was significant for headaches and hypertension. The headaches were associated with nausea and vomiting. She had no history of developmental delay or epilepsy. CT scan of the brain showed signs of obstructive hydrocephalus due to venous hypertension as a result of vein of Galen malformation, and hence a ventriculoperitoneal shunt was placed. Now on follow-up, her MRI brain demonstrates a round flow void in the suprapineal cisterns with engorged straight sinus, compatible with vein of Galen arteriovenous fistulous communication and shunting (figure 1). The resultant venous hypertension leads to mild to moderate compensated hydrocephalus.
Figure 1
(A) Axial T2, (B) axial T1 and (C) sagittal T2 MRI brain. MRI brain demonstrates a round flow void in the suprapineal cisterns with engorged straight sinus (green arrow),...
https://ift.tt/2zyNwsj
Second-Generation Bioethanol from Coconut Husk
Coconut palm (Cocos nucifera) is an important commercial crop in many tropical countries, but its industry generates large amounts of residue. One way to address this problem is to use this residue, coconut husk, to produce second-generation (2G) ethanol. The aim of this review is to describe the methods that have been used to produce bioethanol from coconut husk and to suggest ways to improve different steps of the process. The analysis performed in this review determined that alkaline pretreatment is the best choice for its delignification potential. It was also observed that although most reported studies use enzymes to perform hydrolysis, acid hydrolysis is a good alternative. Finally, ethanol production using different microorganisms and fermentation strategies is discussed and the possibility of obtaining other added-value products from coconut husk components by using a biorefinery scheme is addressed.
https://ift.tt/2ImendS
Epigenetic Restoration of Fetal-like IGF1 Signaling Inhibits Leukemia Stem Cell Activity
Giambra et al. show that NOTCH1 leukemias generated from fetal liver are less transplantable than those from adult bone marrow. NOTCH1 activates auto/paracrine IGF1 signaling in FL, but not BM cells, due to EZH2-dependent H3K27 trimethylation at the IGF1 promoter. This mechanism can be exploited to exhaust/deplete leukemia stem cells.
https://ift.tt/2OkpUzC
Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations
Normal human epidermis harbors p53 mutant clones, very few of which form tumors. Murai et al. track p53 mutant clones as they colonize the epidermis in a transgenic mouse model showing how the tissue adapts to the mutant cells and uncovering distinct roles for physiological UV light exposure.
https://ift.tt/2ImXtf8
Homeostatic Epidermal Stem Cell Self-Renewal Is Driven by Local Differentiation
By capturing all stem cell activity in large regions of the mouse epidermis, Mesa et al. report that stem cell self-renewal is induced by the differentiation of neighbors. This study identifies the physiological factors that drive stem cell self-renewal, expanding the current understanding of epidermal homeostasis and regeneration.
https://ift.tt/2OdxiNr
Impact of hydrologic boundaries on microbial planktonic and biofilm communities in shallow terrestrial subsurface environments
Abstract
Subsurface environments contain a large proportion of planetary microbial biomass and harbor diverse communities responsible for mediating biogeochemical cycles important to groundwater used by human society for consumption, irrigation, agriculture, and industry. Within the saturated zone, capillary fringe, and vadose zones, microorganisms can reside in two distinct phases (planktonic or biofilm), and significant differences in community composition, structure, and activity between free-living and attached communities are commonly accepted. However, largely due to sampling constraints and the challenges of working with solid substrata, the contribution of each phase to subsurface processes is largely unresolved. Here, we synthesize current information on the diversity and activity of shallow freshwater subsurface habitats, discuss the challenges associated with sampling planktonic and biofilm communities across spatial, temporal, and geological gradients, and discuss how biofilms may be constrained within shallow terrestrial subsurface aquifers. We suggest that merging traditional activity measurements and sequencing/-omics technologies with hydrological parameters important to sediment biofilm assembly and stability will help delineate key system parameters. Ultimately, integration will enhance our understanding of shallow subsurface ecophysiology in terms of bulk-flow through porous media and distinguish the respective activities of sessile microbial communities from more transient planktonic communities to ecosystem service and maintenance.https://ift.tt/2IjKomG
USC-γ cluster dominates the methanotroph communities in the karst Heshang Cave
Abstract
Microorganisms are thought to play a critical role in methane consumption in karst caves, however, the presence and diversity of methane-oxidizing bacteria (MOB) are still mysterious. In Heshang Cave, CH4 concentration decreases from 1.9 ppm at the entrance to 0.65 ppm into the cave. To explore the presence and diversity of MOB in this cave, weathered rocks and sediment samples were collected across the cave and subject to molecular analysis. The abundances of MOB were 107–108 copies g−1 dry sample via quantification of the pmoA gene, which are comparable to or even higher than those reported in other terrestrial environments and account for up to 20% of the total microbial communities. Phylogenetically MOB communities were dominated by the 'high-affinity' upland soil γ cluster (USCγ), although the predominance of type Ia MOB was also detected in the permanent waterlogged stream sediment. The estimated CH4 oxidation potential varied dramatically among samples in the range of 0.6–80 CH4 m−3 d−1. Collectively, this study provided compelling evidence that the high-affinity MOB capable of oxidizing methane at the atmospheric level are present in Heshang Cave, which may play an important role in the methane consumption and supports karst caves as an important atmospheric CH4 sink.https://ift.tt/2xJUzwP
PMT1 deficiency extends the shortened replicative lifespan of TED1-deficient yeast in a Hac1p-dependent manner
Abstract
Protein O-mannosyltransferase-1 (Pmt1p) deficiency extends the replicative lifespan (RLS) of Saccharomyces cerevisiae, which is related to the activation of the unfolded protein response (UPR), an important pathway for alleviating endoplasmic reticulum (ER) stress. Trafficking of Emp24p/Erv25p-dependent cargo disrupted 1 (Ted1p) has been reported as a binding partner of yeast Pmt1p. We explored the potential relationship between Pmt1p and Ted1p in the cell lifespan and ER stress responses. The TED1-deleted strain (ted1Δ) had a shorter RLS with no increase in UPR activity. However, PMT1 deficiency prolonged the short lifespan of ted1Δ in a manner dependent on Hac1p, an upstream transcription factor of the UPR pathway. In addition, PMT1 deficiency enhanced the UPR activity and alleviated the ER stress resistance of the ted1Δ strain. Thus, the enhanced UPR activity was hypothesized to explain the longevity of the pmt1Δted1Δ strain, but this long-lived pmt1Δted1Δ strain showed decreased ER stress resistance compared with the short-lived ted1Δ strain. Taken together, our results suggest a possible relationship between PMT1 and TED1 regarding lifespan regulation and the ER stress response.https://ift.tt/2OVMUCc
Genome mining for the search and discovery of bioactive compounds: The Streptomyces paradigm
Abstract
The need for new antimicrobials is indisputable. The flight from natural products in drug discovery was unfortunate. However, the revolution that is genome mining, enabled by the explosion in sequencing technology, is a cause for hope. Nevertheless, renewed search and discovery is still a challenge. We explore novel metabolite diversity and the challenges in Streptomyces. Estimating novel bioactive metabolites remaining to be discovered is an important driver for future investment. Frequent re-discovery of known natural products was a major factor in big pharma exiting search and discovery and remains a reality. We explore whether this is exhaustive isolation and frequent lateral gene transfer. Analyzing all biosynthetic gene clusters across all genomes is challenging. Therefore, representative examples of the patterns of secondary metabolite diversity suggest re-discovery is linked to frequent expression in frequently isolated (and frequently mis-identified) strains. Lateral gene transfer of complete biosynthetic clusters is less frequent than might be perceived but frequent gene exchange implies a massive combinatorial biosynthesis experiment. Genome sequencing emphasizes rare expression of many secondary metabolite gene clusters and diversification at the finest levels of phylogenetic discrimination. And, we are only just beginning to unravel the impact of ecology. The hidden diversity suggests that cluster cloning and heterologous expression in microbial cell factories will explore this diversity more effectively.https://ift.tt/2R4SLXb
Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors
Abstract
Introduction
Venetoclax, a substrate of cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), is approved for the treatment of patients with chronic lymphocytic leukemia who have received at least one prior therapy. This study evaluated the effect of azithromycin, a commonly used antibiotic in cancer patients and a P-gp inhibitor, on the pharmacokinetics of venetoclax.
Methods
In this single-center, open-label, nonfasting, two-period study, 12 healthy female subjects received a single 100 mg dose of venetoclax on day 1 of period 1 and day 3 of period 2. Subjects received azithromycin 500 mg on day 1 and 250 mg once daily on days 2 through 5. Serial blood samples for the determination of venetoclax concentrations were collected after dosing in both periods. Safety was evaluated throughout the study.
Results
Following coadministration of venetoclax with multiple doses of azithromycin, venetoclax maximum concentration and area under the curve to infinite time were 25% and 35% lower, respectively, compared to venetoclax administered alone. Venetoclax half-life and time to maximum concentration remained relatively unchanged when administered with azithromycin. Venetoclax was well tolerated with no serious adverse events reported.
Conclusions
The modest changes in venetoclax exposures when given with azithromycin indicate that no dose adjustment would be needed when venetoclax is coadministered with azithromycin or other drugs with P-gp inhibitory potential. Azithromycin represents an alternative to other antimicrobial agents with higher potential to alter venetoclax pharmacokinetics such as clarithromycin, erythromycin, and ciprofloxacin.
Funding
AbbVie in collaboration with Genentech/Roche.
https://ift.tt/2N8IQg6
Circular RNA hsa_circ_0008305 (circPTK2) inhibits TGF-β-induced epithelial-mesenchymal transition and metastasis by controlling TIF1γ in non-small cell lung cancer
Abstract
Background
TGF-β promotes tumor invasion and metastasis through inducing epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC). Circular RNAs (circRNAs) are recognized as functional non-coding RNAs involved in human cancers. However, whether and how circRNAs contribute to TGF-β-induced EMT and metastasis in NSCLC remain vague. Here, we investigated the regulation and function of Circular RNA hsa_circ_0008305 (circPTK2) in TGF-β-induced EMT and tumor metastasis, as well as a link between circPTK2 and transcriptional intermediary factor 1 γ (TIF1γ) in NSCLC.
Methods
Circular RNAs were determined by human circRNA Array analysis, real-time quantitative reverse transcriptase PCR and northern blot. Luciferase reporter, RNA-binding protein immunoprecipitation (RIP), RNA pull-down and fluorescence in situ hybridization (FISH) assays were employed to test the interaction between circPTK2 and miR-429/miR-200b-3p. Ectopic overexpression and siRNA-mediated knockdown of circPTK2, TGF-β-induced EMT, Transwell migration and invasion in vitro, and in vivo experiment of metastasis were used to evaluate the function of circPTK2. Transcription and prognosis analyses were done in public databases.
Results
CircPTK2 and TIF1γ were significantly down-regulated in NSCLC cells undergoing EMT induced by TGF-β. CircPTK2 overexpression augmented TIF1γ expression, inhibited TGF-β-induced EMT and NSCLC cell invasion, whereas circPTK2 knockdown had the opposite effects. CircPTK2 functions as a sponge of miR-429/miR-200b-3p, and miR-429/miR-200b-3p promote TGF-β-induced EMT and NSCLC cell invasion by targeting TIF1γ. CircPTK2 overexpression inhibited the invasion-promoting phenotype of endogenous miR-429/miR-200b-3p in NSCLC cells in response to TGF-β. CircPTK2 overexpression significantly decreased the expression of Snail, an important downstream transcriptional activator of TGF-β/Smad signaling. In an in vivo experiment of metastasis, circPTK2 overexpression suppressed NSCLC cell metastasis. Moreover, circPTK2 expression was dramatically down-regulated and positively correlated with TIF1γ expression in human NSCLC tissues. Especially, circPTK2 was significantly lower in metastatic NSCLC tissues than non-metastatic counterparts.
Conclusion
Our findings show that circPTK2 (hsa_circ_0008305) inhibits TGF-β-induced EMT and metastasis by controlling TIF1γ in NSCLC, revealing a novel mechanism by which circRNA regulates TGF-β-induced EMT and tumor metastasis, and suggesting that circPTK2 overexpression could provide a therapeutic strategy for advanced NSCLC.
https://ift.tt/2N2sLIY
A Case of Malaria Predisposing to Salmonella Bacteremia in a Returning Traveler from Nigeria
We describe a febrile adult returning to the U.S. from Nigeria. Malaria was diagnosed by rapid antigen testing, but recognition of invasive nontyphoidal Salmonella disease was delayed. While the moniker, "typhomalaria," once used to describe an illness with features of malaria and typhoid fever, has fallen out of favor, it may nevertheless be a helpful reminder to clinicians that both infectious diseases can arise in the same patient. Blood cultures should be obtained routinely in febrile returning travelers from malaria-endemic regions, including those in whom the diagnosis of malaria has already been established.
https://ift.tt/2OgaI6x
Data mining of digitized health records in a resource-constrained setting reveals that timely immunophenotyping is associated with improved breast cancer outcomes
Abstract
Background
Organizations that issue guidance on breast cancer recommend the use of immunohistochemistry (IHC) for providing appropriate and precise care. However, little focus has been directed to the identification of maximum allowable turnaround times for IHC, which is necessary given the diversity of hospital settings in the world. Much less effort has been committed to the development of digital tools that allow hospital administrators to monitor service utilization histories of their patients.
Methods
In this retrospective cohort study, we reviewed electronic and paper medical records of all suspected breast cancer patients treated at one secondary-care hospital of the Mexican Institute of Social Security (IMSS), located in western Mexico. We then followed three years of medical history of those patients with IHC testing.
Results
In 2014, there were 402 breast cancer patients, of which 30 (7.4% of total) were tested for some IHC biomarker (ER, PR, HER2). The subtyping allowed doctors to adjust (56.7%) or confirm (43.3%) the initial therapeutic regimen. The average turnaround time was 56 days. Opportune IHC testing was found to be beneficial when it was available before or during the first rounds of chemotherapy.
Conclusions
The use of data mining tools applied to health record data revealed that there is an association between timely immunohistochemistry and improved outcomes in breast cancer patients. Based on this finding, inclusion of turnaround time in clinical guidelines is recommended. As much of the health data in the country becomes digitized, our visualization tools allow a digital dashboard of the hospital service utilization histories.
https://ift.tt/2IkXkJ2
Engaging the older cancer patient; Patient Activation through Counseling, Exercise and Mobilization – Pancreatic, Biliary tract and Lung cancer (PACE-Mobil-PBL) - study protocol of a randomized controlled trial
Abstract
Background
Several intervention studies have demonstrated that exercise training has beneficial effects among cancer patients. However, older cancer patients are underrepresented in clinical trials, and only few exercise-based studies have focused specifically on older patients with cancer. In particular, research investigating the effects of exercise training among older patients with advanced cancer is lacking. The purpose of the current study is to investigate the effect of a 12-week multimodal and exercise-based intervention among older patients (≥65 years) with advanced pancreatic, biliary tract or lung cancer, who are treated with first-line palliative chemotherapy, immunotherapy or targeted therapy.
Methods
PACE-Mobil-PBL is a two-armed randomized controlled trial. Participants will be randomized 1:1 to an intervention group (N = 50) or a control group (N = 50). Participants in the intervention group will receive standard oncological treatment and a 12-week multimodal intervention, comprised of: (I) supervised exercise training, twice weekly in the hospital setting, (II) home-based walking with step counts and goal-setting, (III) supportive and motivational nurse-led counseling, and (IV) protein supplement after each supervised training session. Participants in the control group will receive standard oncological treatment. The primary outcome is physical function measured by the 30-s chair stand test. Secondary outcomes include measures of feasibility, activity level, physical capacity and strength, symptom burden, quality of life, toxicity to treatment, dose reductions, inflammatory biomarkers, body weight and composition, hospitalizations and survival. Assessments will be conducted at baseline, and after 6, 12 and 16 weeks.
Discussion
The current study is one of the first to investigate the effect of an exercise-based intervention specifically targeting older patients with advanced cancer. PACE-Mobil-PBL supports the development of health promoting guidelines for older patients with cancer, and the study results will provide new and valuable knowledge in this understudied field.
Trial registration
The study was prospectively registered at ClinicalTrials.gov on January 26, 2018 (ID: NCT03411200).
https://ift.tt/2zzhaO1
An Italian Delphi study to evaluate consensus on adjuvant endocrine therapy in premenopausal patients with breast cancer: the ERA project
Abstract
Background
Several trials evaluated the role of ovarian function suppression for the adjuvant treatment of premenopausal patients with hormone receptor-positive early breast cancer. Based on the results of the SOFT and TEXT trials, international guidelines recommend the addition of ovarian function suppression to standard adjuvant endocrine therapy for patients at higher risk of relapse.
Methods
The ERA project (Evaluation of Risk factors in the Adjuvant treatment of breast cancer in premenopausal patients) was devised with the objective of obtaining a consensus on the identification of risk factors and the use of ovarian function suppression in the adjuvant treatment of these women. To this aim, a panel of 31 Italian oncologists with expertise in breast cancer participated in a Delphi consensus study in June 2017.
Results
A total of 29 statements related to prognostic factors, therapeutic strategies and ovarian function suppression were defined and voted to gain final consensus. For each topic we report data supporting the acquired consensus and the relevant issues discussed.
Conclusions
The SOFT and TEXT trials have changed the standard adjuvant treatment of premenopausal patients with hormone receptor-positive early breast cancer, but the available treatment options require a careful risk assessment and toxicities evaluation to ensure the greatest clinical benefit for each patient.
https://ift.tt/2ImHrls
Second primary colorectal cancer after the initial primary colorectal cancer
Abstract
Background
Initial primary colorectal cancer (IPCRC) has a high risk of developing into second primary colorectal cancer (SPCRC). Right-sided colon cancer (RCC) and left-sided colon cancer (LCC) have different characteristics and are considered to be two different entities. However, the different risks for SPCRC in categorized tumor sites and SPCRC subcategorized sites have not been fully elucidated to date. We aimed to compare incidence and survival of IPCRC and SPCRC and characterize the risk factors of SPCRC while also comparing the different SPCRC characteristics.
Methods
We used the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) data to compute standardized incidence ratios (SIR) in order to estimate risk of SPCRC after IPCRC diagnosis. The most prominent risk factors for SPCRC were measured by multivariate regression analysis and the temporal trend of SPCRC incidence was assessed with Joinpoint regression. Survival of patients with SPCRC and IPCRC was compared by Kaplan-Meier analysis.
Results
Patients with IPCRC were 1.73 times more likely to develop SPCRC (SIR = 1.73, 95% CI 1.69–1.78). SPCRC incidence declined since the first 8 years of IPCRC diagnosis to baseline. We demonstrated poorer survival with SPCRC compared with IPCRC while second RCC resulted in better survival compared with second LCC. Black ethnicity, age range 70–79, and LCC were associated with the highest risk of developing SPCRC.
Conclusion
The characteristic differences between second LCC and RCC were relatively narrow. Furthermore, in those with SPCRC, RCC had the best survival outcome.
https://ift.tt/2zyULAo
Image Quality and Patient-Specific Organ Doses in Stone Protocol CT: A Comparison of Traditional CT to Low Dose CT with Iterative Reconstruction
Objective. To compare organ specific radiation dose and image quality in kidney stone patients scanned with standard CT reconstructed with filtered back projection (FBP-CT) to those scanned with low dose CT reconstructed with iterative techniques (IR-CT). Materials and Methods. Over a one-year study period, adult kidney stone patients were retrospectively netted to capture the use of noncontrasted, stone protocol CT in one of six institutional scanners (four FBP and two IR). To limit potential CT-unit use bias, scans were included only from days when all six scanners were functioning. Organ dose was calculated using volumetric CT dose index and patient effective body diameter through validated conversion equations derived from previous cadaveric, dosimetry studies. Board-certified radiologists, blinded to CT algorithm type, assessed stone characteristics, study noise, and image quality of both techniques. Results. FBP-CT (n=250) and IR-CT (n=90) groups were similar in regard to gender, race, body mass index (mean BMI = 30.3), and stone burden detected (mean size 5.4 ± 1.2 mm). Mean organ-specific dose (OSD) was 54-62% lower across all organs for IR-CT compared to FBP-CT with particularly reduced doses (up to 4.6-fold) noted in patients with normal BMI range. No differences were noted in radiological assessment of image quality or noise between the cohorts, and intrarater agreement was highly correlated for noise (AC2=0.873) and quality (AC2=0.874) between blinded radiologists. Conclusions. Image quality and stone burden assessment were maintained between standard FBP and low dose IR groups, but IR-CT decreased mean OSD by 50%. Both urologists and radiologists should advocate for low dose CT, utilizing reconstructive protocols like IR, to reduce radiation exposure in their stone formers who undergo multiple CTs.
https://ift.tt/2xJITdt
Clinical Value of Combined Determination of Serum B7-H4 with Carcinoembryonic Antigen, Osteopontin, or Tissue Polypeptide-Specific Antigen for the Diagnosis of Colorectal Cancer
Aim. B7-H4 is member of the B7 family that negatively regulates the immune response, which are associated with tumor development and prognosis. The present study is aimed at examining serum B7-H4 expression and exploring its contribution to diagnosis in patients with colorectal cancer. Methods. We determined serum expressions of B7-H4, carcinoembryonic antigen (CEA), osteopontin (OPN), and tissue polypeptide-specific antigen (TPS) in 59 patients with colorectal cancer and 29 healthy volunteers and analyzed the diagnostic value of B7-H4 combined with CEA, OPN, or TPS detection for colorectal cancer. B7-H4, OPN, and TPS serum expressions were measured by enzyme-linked immunosorbent assay, and CEA was measured by electrochemical luminescence detection. Results. Serum B7-H4 levels were significantly higher in colorectal cancer patients compared with paired normal controls (). B7-H4 serum level was positively correlated with infiltration depth, tumor masses, and lymph node metastasis (, , and , respectively). We also detected serum expression of B7-H4 before and after radical resection and showed that B7-H4 levels decreased significantly during the first week postoperation (). We used receiver operating characteristic (ROC) curve analysis to indicate the potential diagnostic values of these markers. The areas under the ROC curves (AUC) for B7-H4, OPN, TPS, and CEA were 0.867, 0.805, 0.812, and 0.833, respectively. The optimal sensitivity and specificity of B7-H4 for discriminating between colon cancer patients and healthy controls were 88.2% and 86.7%, respectively, using a cut-off of value of 78.89 ng/mL. However, combined ROC analysis using B7-H4 and CEA revealed an AUC of 0.929, with a sensitivity of 98.9% and a specificity of 80.4% for discriminating colon cancer patients from healthy controls. Conclusions. B7-H4 was highly expressed in the serum in colorectal cancer patients. Detection of B7-H4 plus CEA showed significantly increased sensitivity and specificity for discriminating between colorectal cancer patients and healthy controls compared to individual detection of these markers. Combined detection of serum B7-H4 and CEA may thus have the potential to become a new laboratory method for the early clinical diagnosis and prognostic evaluation of colorectal cancer.
https://ift.tt/2DIR7bs
Anti-Double-Stranded DNA Isotypes and Anti-C1q Antibody Improve the Diagnostic Specificity of Systemic Lupus Erythematosus
Objectives. We aimed to evaluate the value of immunoglobulin (Ig) G, IgM, and IgA isotypes of anti-double-stranded DNA (anti-dsDNA) and anti-C1q antibody in diagnosing systemic lupus erythematosus (SLE) patients and elucidate their association with disease activity and lupus nephritis. Methods. Blood samples were obtained from 96 SLE patients, 62 other autoimmune disease patients, and 60 healthy blood donors. Anti-dsDNA IgG, IgM, and IgA isotypes and anti-C1q antibody were measured by enzyme-linked immunosorbent assay. Disease activity of SLE patients was assessed according to the SLE Disease Activity Index score. Results. When specificity was greater than 90%, the sensitivity of anti-dsDNA IgG, IgM, and IgA isotypes and anti-C1q antibody in diagnosing SLE was 75%, 45%, 33%, and 49%, respectively. The prevalence of anti-dsDNA IgG (), anti-dsDNA IgA (), and anti-C1q antibody () in active cases was significantly higher than those in inactive ones. In addition, the presence of anti-C1q antibody was associated with renal involvement (). Anti-dsDNA IgM showed no significant association with disease activity, but it was inversely linked with lupus nephritis (). When anti-dsDNA IgG and IgA and anti-C1q were combined to evaluate SLE disease activity, the specificity reached the highest level (90%). When anti-C1q positive was accompanied by anti-dsDNA IgM negative, the specificity of diagnosing lupus nephritis was up to 96%. Conclusions. This study demonstrated the role of anti-dsDNA IgG, IgM, and IgA isotypes and anti-C1q antibody alone or combination in diagnosing SLE. Anti-dsDNA IgG and IgA and anti-C1q were shown to be associated with disease activity, while anti-dsDNA IgM and anti-C1q were associated with lupus nephritis. When the related antibodies were combined, the diagnostic specificity was significantly higher.
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Metabolomics Analysis of the Lipid-Regulating Effect of Allium hookeri in a Hamster Model of High-Fat Diet-Induced Hyperlipidemia by UPLC/ESI-Q-TOF Mass Spectrometry
Hyperlipidemia is a risk factor for atherosclerotic cardiovascular disease and is a major public health concern. Allium hookeri (AH) is an Allium species containing high levels of bioactive organosulfur compounds such as methiin and cycloalliin. AH exerts hypolipidemic effects in animals fed a high-fat diet. However, there exists little information on the mechanisms underlying these effects. To address this issue, we used a metabolomic approach based on ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry to identify factors mediating the lipid-lowering effects of AH. Principal component and partial least-squares discriminant analyses of serum metabolome profiles revealed 25 metabolites as potential biomarkers for the effects of AH on lipid levels. These compounds were predominantly phospholipids, including phosphatidylcholines (PCs), lysoPCs, and lysophosphatidylethanolamines. Glycerophospholipid metabolism was identified as a significantly enriched pathway. These results provide mechanistic insight into the antihyperlipidemic effects of AH and evidence for its efficacy as a therapeutic agent.
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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