Medicine by Alexandros G.Sfakianakis: 10/27/18

Σάββατο 27 Οκτωβρίου 2018

Hypermethylated Promoters of Secreted Frizzled-Related Protein Genes are Associated with Colorectal Cancer

Abstract

Colorectal cancer (CRC) is one of the leading causes of death worldwide. Aberrant DNA methylation has been recognized as one of the most common molecular alterations in CRC. The goal of this study was to investigate the diagnostic value of SFRP1 and SFRP2 methylation for CRC. A total of 80 pairs of CRC patients were recruited to test the association of SFRP1 and SFRP2 promotor methylation with CRC. Methylation assay was performed using quantitative methylation-specific polymerase chain reaction (qMSP) method. In this study, we found the methylation levels of SFRP1 and SFRP2 in CRC tumor tissues were significantly higher than those in the adjacent non-tumor tissues (SFRP1: P = 2E-5; SFRP2: P = 0.014). Further bioinformatics analysis of TCGA data confirmed the association of the two genes with CRC (SFRP1: P = 7E-21; SFRP2: P = 5E-24). Luciferase reporter gene assay showed that the recombinant plasmids with SFRP1 and SFRP2 fragments could significantly enhance promoter activity (SFRP1: P = 0.002; SFRP2: P = 0.004). In addition, SFRP1 and SFRP2 methylation were inversely correlated with the mRNA expression displayed by TCGA data mining (SFRP1: r = −0.432, P = 4E-11; SFRP2: r = −0.478, P = 1E-13). GEO data analysis indicated that SFRP1 and SFRP2 expression were increased in three CRC cell lines (COLO320, HCT116 and HT29) after 5′-AZA-deoxycytidine treatment, suggesting that DNA methylation played an important role in regulating gene expression of the two genes. Our results confirmed that promoter methylation of SFRP1 and SFRP2 contributed to the risk of CRC.

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Importance of Cadherins Methylation in Ovarian Cancer: a Next Generation Sequencing Approach

Abstract

Epigenetic aberrations are well known to play an important role in carcinogenesis, and also have a great potential to serve as biomarkers in many types of cancers, including ovarian cancer in which sensitive and specific biomarkers and detection methods are critically needed. The aim of this study was to investigate methylation of cadherin genes CDH10, CDH13 and CDH18 in ovarian cancer tissue by comparison with control tissue. The study group consisted of 38 patients with ovarian cancer and 25 control patients. For detection of epigenetic events we used next generation sequencing, the most important data were confirmed using high-resolution melting analysis and real-time PCR. We observed significantly higher methylation in CDH13, sporadic methylation in CDH10 and loss of methylation in CDH18 in the ovarian cancer group compared with the control group. These observations suggest that changes in methylation of cadherin genes may be one of the major mechanisms associated with ovarian cancer progression. In addition, because of the high frequency of methylation of the CDH13 gene in the early stages of ovarian cancer, the analyzed CpG sites might be good targets for next study of potential ovarian cancer screening biomarkers.

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Prognostic Importance of Tumor Deposits in the Ipsilateral Axillary Region of Breast Cancer Patients

Abstract

Tumor deposits (TD) are irregular discrete tumor masses in adipose tissue, discontinuous from the primary tumor, that are described in various cancers. The incidence and/or prognostic value of TD in breast carcinomas have not been studied so far. We reevaluated 145 breast cancer patients, diagnosed and treated between 2001 and 2006 at our institution for the presence and incidence of TD. Histologic type, grade, size of the primary tumor, estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2 status of the tumor, and presence of peritumoral lymphovascular invasion were included in the data. TD were detected in 42 cases (29.0%). The mean age of the patients was 52.2 years (27–82). Most patients (79.3%) had either invasive carcinoma of no special type (NST) or invasive lobular carcinoma, and most tumors (86.9%) were either grade 2 or 3. After excluding TD from the number of metastatic lymph nodes, the pN status of 9 patients changed. Univariate analysis of 110 patients with follow-up information revealed that the new pN status (p = 0.036), presence of local recurrence (p = 0.016) and TD (p = 0.003) were significantly correlated with distant metastases. The median follow-up of the patients was 84 months (5–161), 10-year disease-free survival and overall survival were 67.2% and 73.7%, respectively. In multivariate analysis, presence of TD remained independently associated with distant metastasis (p = 0.002). The probability of distant metastasis was 3.3 times higher in patients with TD. These results emphasize that TD are present in breast cancer patients, and that their presence should warn the clinician in terms of possible distant metastasis. Therefore, presence of TD, the evaluation of which is neither time consuming nor require sophisticated methods, should be included in pathology reports.

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CRP and LOX-1: a Mechanism for Increasing the Tumorigenic Potential of Colorectal Cancer Carcinoma Cell Line

Abstract

Chronic inflammation and dyslipidemia are associated with an increase in the incidence of colorectal cancer (CRC). Serum C- reactive protein (CRP) and oxidized low-density lipoprotein (oxLDL), as Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) ligands, increase during inflammation and dyslipidemia, respectively. To evaluate the effects of CRP on the expression of important genes involved in the development of CRC, the CRC cell line, LS174T, was treated with the commercial CRP. Based on the Real-time PCR data, in the presence of CRP, LOX-1, CEA, MMP1, and MMP2 mRNA expression significantly increased, compared to the control group. Moreover, in the presence of CRP, secretion, and expression of CEA in the cell lysate and conditioned media increased in a concentration-dependent manner. The results of flow cytometry showed that expression of LOX-1 receptors at the cell surface increased significantly in the presence of 10 mg/L of CRP. However, inhibition of LOX-1 receptors with a specific monoclonal antibody reduced the effects of CRP on protein/mRNA expression. In conclusion, Increased CRP level, can potentially elevate the expression of important genes in CRC by stimulating LOX-1 receptors.

https://ift.tt/2CNInyi

Computer-aided detection of fasciculations and other movements in muscle with ultrasound: development and clinical application

Muscle ultrasound imaging is an increasingly important addition to the diagnostic arsenal for diagnosing neuromuscular disease, providing an anatomical assessment of muscle structure to complement standard neurological examination and electrophysiologic function testing (Simon, 2015). In addition to its well-known advantages of being patient-friendly, non-invasive and a point of care imaging technique, the dynamic nature of ultrasound images as a result of the high temporal resolution enables visualization of spontaneous or voluntary muscle movements, including fasciculations.

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The Revised Cerebral Recovery Index Improves Predictions of Neurological Outcome after Cardiac Arrest

About half of all comatose patients after cardiac arrest (CA) never regain consciousness because of severe postanoxic encephalopathy (PAE) (Sivaraju et al., 2015). Early prognosis may guide treatment decisions. Monitoring of cerebral functioning in the first 24 hours after CA with electroencephalography (EEG) has been demonstrated to enable reliable prediction of either good or poor neurological outcome in about 50% of the patients (Hofmeijer et al., 2015, 2014; Maher et al., 2015; Oddo and Rossetti, 2011; Rossetti et al., 2012, 2010; Tjepkema-Cloostermans et al., 2015).

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Outcome in ulcerative colitis after switch from Adalimumab/Golimumab to infliximab: A multicenter retrospective study

anti-TNF therapies Infliximab (IFX), Adalimumab (ADA), and Golimumab (GOL) are approved for treating moderate to severe ulcerative colitis (UC). In UC, only the switch from IFX to ADA has been investigated, reaching no more than 10–43% remission rates at 12 months.

https://ift.tt/2Pt0xfM

Long-term treatment with linaclotide of intestinal pseudo-obstruction secondary to Ehlers-Danlos syndrome

https://ift.tt/2JkQdAJ

A Japanese survey of malignant disease in pregnancy

Abstract

Background

In recent years, the incidence of malignant disease in pregnancy has been increasing, but there are few large-scale surveys of malignant disease in pregnancy in Japan. The aim of this study was to survey malignant disease occurring during pregnancy in Japan.

Methods

Malignant disease in pregnancy was defined as diagnosis or treatment for malignant disease, except in situ carcinoma during pregnancy, or within 1-year postpartum. First, a primary survey questionnaire of the incidence of malignant disease in pregnancy and the number of deliveries over the course of 2014 was sent to 510 medical centers in Japan. Second, the survey questionnaires on the incidence of malignant diseases in pregnancy were collected and analyzed in detail.

Results

Of the 510 medical centers, 411 (81%) responded to the survey. There were 215,372 deliveries and 189 incidents (0.09%) of malignant disease in pregnancy. Of the 189 patients with malignancy, 157 detailed responses about the patients were received. The most frequently encountered cancer types were cervical cancer (36%), breast cancer (24%), and ovarian cancer (15%). During the 2 years after delivery, 15 patients (1 with breast cancer, 2 with ovarian cancer, 3 with hematologic malignancy, 4 with intestinal cancer, and 5 with others) died of the disease; most of them had advanced disease. In particular, 88% of the patients with intestinal cancers at diagnosis had advanced disease, and half of them died of disease.

Conclusions

In Japan, the most common malignancies in pregnancy in order of frequency are cervical cancer, breast cancer, and ovarian cancer. Early diagnosis and appropriate management of cancer during pregnancy are important for improving maternal and neonatal outcomes, because advanced diseases have a poor prognosis.

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Molten-Salt Synthesis of Complex Metal Oxide Nanoparticles

Here, we demonstrate a unique, relatively low-temperature, molten-salt synthesis method for preparing uniform complex metal oxide lanthanum hafnate nanoparticles.

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Associations among regorafenib concentrations, severe adverse reactions, and ABCG2 and OATP1B1 polymorphisms

Abstract

Purpose

The ability of predicting severe adverse reactions caused by regorafenib is important. We evaluated regorafenib concentrations for adverse reaction risks and assessed the relevance of laboratory values and gene polymorphisms.

Methods

A total of 28 Japanese cancer patients who were treated with regorafenib were evaluated for the steady state of serum regorafenib concentrations and adverse reactions for 28 days. In addition, we determined the association of regorafenib concentrations with ABCG2 and OATP1B1 polymorphisms, which are regorafenib transporters.

Results

Regorafenib concentrations were significantly higher in the group with Grade 2 or higher total bilirubin elevation and thrombocytopenia compared with the group with grades 0 or 1 [3.45 (2.18–7.31) vs. 1.76 (0.26–2.77) µg/mL, P = 0.01 and 3.45 (2.12–7.31) vs. 1.76 (0.26–2.77) µg/mL, P = 0.02, respectively]. A strong association was noted between serum regorafenib concentrations and total bilirubin levels, but the physical and genetic factors predicting regorafenib pharmacokinetics could not be clarified.

Conclusions

Regorafenib concentrations were associated with total bilirubin elevation and thrombocytopenia. Total serum bilirubin could be a useful marker when estimating regorafenib pharmacokinetics.

https://ift.tt/2yAsl8o

Lumen-apposing metal stent acted as an interim role in walled-off necrosis drainage

Recently, Bang et al1 conducted the first randomised trial on lumen-apposing metal stents (LAMS) versus plastic stents for endoscopic ultrasonography (EUS)-guided drainage of walled-off necrosis (WON), which provided significant information for the clinical application of LAMS. We agree with Bang et al1 that the wider diameter of LAMS facilitates more rapid drainage of necrotic contents leading to faster WON resolution, and we agree that LAMS must be removed at 3 weeks postprocedure if the WON resolved. Our endoscopy centre observed LAMS-related adverse events, including stent buried in tissue2 and cardia occlusion,3 at more than 3 weeks postprocedure.

Bang et al1 stated that disconnected pancreatic duct syndrome (DPDS) is an important but often overlooked symptom of EUS. Recently, the consensus guideline on interventional EUS made by the Asian EUS group pointed out that the risk of pseudocyst recurrence increases in patients with...

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Devil hepatitis D: an orphan disease or largely underdiagnosed?

Hepatotropic viruses can infect hepatocytes causing a host defence reaction and subsequently scaring of the liver—if the infection is not cleared. The threats of chronic viral hepatitis partially vanished due to the revolution of antiviral treatment options first for hepatitis B and more recently for hepatitis C. Persistent HCV infection can nowadays be cleared with direct acting antiviral agents leading to impressive improvements in the clinical long-term outcome with reduced incidences of hepatic decompensation and hepatocellular carcinoma. Similarly, durable suppression of HBV replication has been shown to prevent disease progression and even to normalise life expectancy unless hepatocellular carcinoma appears.1 Unfortunately, the scenario is completely different for hepatitis D virus (HDV) infection. Coinfection of HBsAg-positive individuals with HDV causes the most severe form of chronic viral hepatitis with earlier development of liver cirrhosis, higher incidence of hepatocellular carcinoma and increased liver-related and overall mortality.2 3

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C9orf72 -FTD/ALS pathogenesis: evidence from human neuropathological studies

Abstract

What are the most important and treatable pathogenic mechanisms in C9orf72-FTD/ALS? Model-based efforts to address this question are forging ahead at a blistering pace, often with conflicting results. But what does the human neuropathological literature reveal? Here, we provide a critical review of the human studies to date, seeking to highlight key gaps or uncertainties in our knowledge. First, we engage the C9orf72-specific mechanisms, including C9orf72 haploinsufficiency, repeat RNA foci, and dipeptide repeat protein inclusions. We then turn to some of the most prominent C9orf72-associated features, such as TDP-43 loss-of-function, TDP-43 aggregation, and nuclear transport defects. Finally, we review potential disease-modifying epigenetic and genetic factors and the natural history of the disease across the lifespan. Throughout, we emphasize the importance of anatomical precision when studying how candidate mechanisms relate to neuronal, regional, and behavioral findings. We further highlight methodological approaches that may help address lingering knowledge gaps and uncertainties, as well as other logical next steps for the field. We conclude that anatomically oriented human neuropathological studies have a critical role to play in guiding this fast-moving field toward effective new therapies.

https://ift.tt/2JklnZ8

High expression of CCL2 in tumor cells and abundant infiltration with CD14 positive macrophages predict early relapse in breast cancer

Abstract

Macrophages are important for the function of the innate immune system, and in solid tumors, they represent a significant proportion of the tumor mass. Tumor-associated macrophages (TAM) have a M2 phenotype and show a multitude of pro-tumoral functions, promoting tumor cell survival, proliferation, and dissemination. CCL2, synthesized by tumor and stromal cells, initiates a chemokine cascade inducing these processes. We studied by immunohistochemistry (IHC) the frequency of TAMs and CCL2 expressing cells in three groups of primary tumor (PT)-recurrence (R) pairs, where relapse was recorded within 2 years (group 1), between 5 and 10 years (group 2), and after 10 years (group 3). In our study all established breast cancers were heavily infiltrated by CD68 positive cells. Both in PTs and in R lesions the infiltration was more abundant in the peritumoral than in the intratumoral stroma. The mean frequency of M2 marker and CD14 positive cells in the intratumoral stroma and CCL2 expressing tumor cells was higher in the Rs as compared to the corresponding PTs. In PTs, a high frequency of CD14 positive cells and a high expression of CCL2 by tumor cells was associated with an early recurrence. The findings support the current understanding of immune cell orchestrated development, progression and metastatic spread of breast cancer. Our study showed that a high frequency of CCL2 positive tumor cells and CD14 positive TAMs are significant risk factors for rapid tumor recurrence. Potential targets for intervention are discussed.

https://ift.tt/2Q086aO

Outcome of 150 Consecutive Blumgart’s Pancreaticojejunostomy After Pancreaticoduodenectomy

Abstract

Postoperative pancreatic fistula (POPF) is the most feared complication after pancreaticoduodenectomy (PD) that leads to intra-abdominal abscess, sepsis, or bleeding and remains the single most important source of morbidity and mortality after PD. To minimize this dreaded complication, various surgical techniques and modifications of pancreaticoenteric reconstruction have been proposed. However, still POPF does occur even in experienced hands. We herein describe the outcome of 150 post PD patients who underwent duct-to-mucosa (DM) pancreaticojejunostomy (PJ) using a special technique, Blumgart's "through & through" U transpancreatic sutures. The technique is described in detail. Postoperative octreotide and metoclopramide were used in all patients for 3 days. An enhanced recovery (ERAS) protocol was followed in a subset of patients. All patients were ASA grade 1 and had adenocarcinoma of the periampullary region/pancreatic head and underwent standard pylorus resecting PD after due optimization. Eighty-eight (58.7%) patients had pancreatic duct < 3 mm and pancreatic texture was soft to very soft in 112 (74.6%) patients. There was only one International Study Group of Pancreatic Surgery (ISGPS) grade C POPF with concomitant hemorrhage. Five patients developed ISGPS grade B and two grade C, delayed gastric emptying (DGE). There was no 30-day mortality. The average length of hospital stay was 7.3 ± 4.2 days with a median of 6 days in the ERAS subset of patients. Blumgart's "through & through" DMPJ technique is very helpful in reducing the POPF and other complications even in high-risk pancreas (i.e., soft with a small pancreatic duct) and is easy to learn and perform.

https://ift.tt/2SjIOG2

Phase I study of BNC105P, carboplatin and gemcitabine in partially platinum-sensitive ovarian cancer patients in first or second relapse (ANZGOG-1103)

Abstract

Purpose

The primary objective of this study was to determine the recommended dose of the vascular disrupting agent, BNC105P, in combination with gemcitabine and carboplatin in patients with ovarian cancer in first or second relapse with a minimum 4 month progression-free interval after last platinum.

Methods

Patients received carboplatin AUC4 on day 1 in combination with escalating doses of 800 or 1000 mg/m² gemcitabine on days 1 and 8 and escalating doses of 12 or 16 mg/m² BNC105P on days 2 and 9 every 21 days for a maximum for six cycles. Maintenance treatment with 16 mg/m² BNC105P treatment continued for a maximum of six additional cycles. Patients were followed for safety and anti-tumor activity.

Results

Fifteen patients were enrolled in the study. Adverse events were most commonly of hematological origin. Dose-limiting toxicities (thrombocytopenia and neutropenia) occurred in two patients at the dose level of 800 mg/m² gemcitabine, carboplatin AUC4 and 16 mg/m² BNC105P. No dose-limiting toxicities were observed at a dose level of gemcitabine 1000 mg/m², carboplatin AUC4 and BNC105P 12 mg/m². BNC105P as a single agent was well tolerated at a dose of 16 mg/m² in maintenance treatment. Ten patients (67%) achieved a complete or partial response according to CA125 and/or RECIST response criteria, four of 13 (31%) responded by RECIST alone. The median progression-free survival was 5.9 months.

Conclusions

We have established that BNC105P 12 mg/m² with gemcitabine 1000 mg/m² and carboplatin AUC4 is the recommended dose level and has an acceptable toxicity profile. Further exploration of BNC105P in the ovarian cancer setting is planned.

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Highlight: Frontiers in Proteolysis

Journal Name: Biological Chemistry
Issue: Ahead of print

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Characterization of PdCP1, a serine carboxypeptidase from Pseudogymnoascus destructans, the causal agent of White-nose Syndrome

Journal Name: Biological Chemistry
Issue: Ahead of print

https://ift.tt/2O4tAl3

Formylglycine-generating enzymes for site-specific bioconjugation

Journal Name: Biological Chemistry
Issue: Ahead of print

https://ift.tt/2yxvxS0

MiR-128/SOX7 alleviates myocardial ischemia injury by regulating IL-33/sST2 in acute myocardial infarction

Journal Name: Biological Chemistry
Issue: Ahead of print

https://ift.tt/2O9Arte

FAM134B promotes adipogenesis by increasing vesicular activity in porcine and 3T3-L1 adipocytes

Journal Name: Biological Chemistry
Issue: Ahead of print

https://ift.tt/2yEkRB2

Bacterial community structure and succession in nests of two megachilid bee genera

Abstract

Studies on honeybees have revealed bacterial taxa which adopt key functions in the hive, in terms of nutrient uptake and immune responses. Despite solitary bees providing invaluable ecological services, the contribution of their microbial communities to larval health and the development and fitness of adults is mainly unknown. To address this gap, we conducted a 16S rDNA meta-barcoding study including larvae and stored pollen in nest chambers from two different megachilid solitary bee genera. We tested how host taxonomy, environmental context and the developmental stage of larvae determined richness and composition of associated bacterial communities. A total of 198 specimens from Osmia bicornis, Osmia caerulescens, Megachile rotundata and Megachile versicolor nests were investigated. Solitary bee bacterial microbiota in the nesting environment were mostly homogeneous within species, and not significantly affected by landscape. For each bee species, we identified bacterial taxa that showed consistent occurrence in the larvae and stored pollen. For the pollen provision, we also described a community shift with progressing larval development, suggesting a reduction of imported floral bacteria.

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Medical students "taught how to practice empathy by following clever mnemonics" - NEJM

C. Nicholas Cuneo, M.D. in the NEJM: "With every faux interaction I felt myself being forced to shed another layer of authenticity, and I quickly grew to dread the whole tedious charade.

PEARLS, it spelled out: Partnership, Empathy, Apology, Respect, Legitimization, and Support.

With a smirk, I tossed it in the trash."

Better understanding and educational approach are needed.

--

Just as a side note, here is an overview of some empathy/communication mnemonics with the corresponding references:

"PEARLS – which stands for partnership, empathy, apology/acknowledgment, respect, legitimation, and support"
https://www.mdedge.com/familypracticenews/article/88977/neurology/use-pearls-build-relationships-patients

"The NURSE mnemonic is a useful memory aid to assist you to comprehensively and appropriately respond to patients' emotions"
https://www.stepsforward.org/modules/empathetic-listening

The NURSE mnemonic has been reproduced from Back A, Arnold R, Tulsky J. Mastering communication with seriously ill patients: balancing honesty with empathy and hope. Cambridge University Press; 2009 Mar 2.

"The 4 C's"
https://defenceupdate.mdanational.com.au/Articles/empathic-communication

"BATHE Mnemonic"
https://fpnotebook.com/Psych/Exam/BthTchnq.htm

Communicate with H.E.A.R.T®
https://my.clevelandclinic.org/departments/patient-experience/depts/experience-partners/training/communicate-with-heart

The H.E.A.R.T. program consists of 3 training modules: S.T.A.R.T. with Heart® focuses on nine key expected services behaviors to use in every interaction with patient, families and other employees. Respond with H.E.A.R.T.® is an innovative model for service recovery providing employees with tools to help consistently address patient concerns. Answer with H.E.A.R.T.® delivers training for exceptional phone service and crucial factors for de-escalating challenging calls.

R.E.D.E. to Communicate
https://my.clevelandclinic.org/departments/patient-experience/depts/experience-partners/training/rede-to-communicate

References:

https://www.nejm.org/doi/full/10.1056/NEJMp1808397

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Safety of intradiscal delivery of triamcinolone acetonide by a poly(esteramide) microsphere platform in a large animal model of intervertebral disc degeneration

Publication date: Available online 26 October 2018

Source: The Spine Journal

Author(s): Imke Rudnik-Jansen, Anna R. Tellegen, Martijn Beukers, Fetullah C. Öner, Nina Woike, George Mihov, Jens Thies, Björn P. Meij, Marianna A. Tryfonidou, Laura B. Creemers

Abstract

Background Context

Local corticosteroids have been used to relieve symptoms of chronic low back pain, although treatment effects have been shown to wear off relatively fast. Prolonging corticosteroid presence by controlled release from biomaterials may allow for longer pain relief while circumventing adverse effects such as high bolus dosages.

Purpose

The purpose of this study was to evaluate the safety and efficacy of intradiscal controlled release of triamcinolone acetonide (TAA) by poly(esteramide) microspheres in a canine degenerated intervertebral disc (IVD) model.

Study Design

In a preclinical experimental large animal model the effect of prolonged glucocorticoid exposure on disc degeneration was evaluated.

Methods

Degeneration was accelerated by nucleotomy of lumbar IVDs of Beagle dogs. After 4 weeks, microspheres loaded with 8.4 µg TAA and 0.84 mg TAA were administered to the degenerated IVDs by intradiscal injection (n=6 per group). Empty microspheres (n=6) and all adjacent non-nucleotomized non-injected IVDs were included as controls (n=24). Immediately prior to TAA administration and after 12 weeks, magnetic resonance imaging was performed. Degenerative changes were evaluated by disc height index, Pfirrmann grading, T1ρ and T2 mapping values, post mortem CT scans, macroscopic and microscopic grading and biochemical/immunohistochemical analysis of inflammation and extracellular matrix content. In addition, nerve growth factor (NGF) protein expression, a biomarker for pain, was scored in nucleus pulposus (NP) tissues. The study was funded by a research grant from Health Holland (1.3 million euros = 1.5 million U.S. dollars).

Results

Macroscopic evaluation and CT images post mortem were consistent with mild disc degeneration. Other abnormalities were not observed. Nucleotomy-induced degeneration and inflammation was mild, reflected by moderate Pfirrmann grades and PGE₂ levels. Regardless of TAA dosage, local sustained delivery did not affect disc height index nor Pfirrmann grading, T1ρ and T2 mapping values, PGE₂ tissue levels, collagen, GAG and DNA content. However, the low dosage of TAA microspheres significantly reduced NGF immunopositivity in degenerated NP tissue.

Conclusions

This is the first in vivo application in a preclinical large animal model of a controlled release formulation of corticosteroids in mild IVD degeneration. Sustained release of TAA locally in the IVD appeared safe and reduced NGF expression, suggesting its potential applicability for pain relief, although beneficial effects were absent on tissue degeneration.

Clinical Significance

The present platform seems to be promising in extending the local controlled delivery of TAA with the potency to provide long standing analgesia in the subset of LBP patients suffering from discogenic pain.

Graphical Abstract

Image, graphical abstract

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Incidence of tuberculosis and the need of prophylactic treatment in persons living with HIV in Stockholm during the era of anti-retroviral therapy 1996–2013

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Mixed Blessings from a Cambridge Union, Elizabeth N Anionwu

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Food-grade gene transformation system constructed in Lactobacillus plantarum using a GlmS-encoding selection marker

Abstract

Food-grade gene expression systems in lactic acid bacteria enable production of functional proteins or product testing without antibiotic requirement. Here, we expanded the available selection markers by developing a novel food-grade genetic transformation system for Lactobacillus plantarum WCFS1 using the glucosamine-6-phosphate synthase gene (glmS1). A glmS-vector pSIPH497 was constructed by replacing the erythromycin resistance gene (erm) with L. plantarum glmS1 under control of the PldhL promoter from WCFS1. The selection efficiency and stability of the glmS-vector were shown to be comparable to those of the erm-based plasmid. Moreover, using mCherry expression as a reporter gene, we showed the feasibility of the system for producing foreign proteins. This food-grade host/vector system will provide an effective and safe technique for the application of lactic acid bacteria in the food and medical industries. Furthermore, this study provides a useful strategy for developing food-grade selection markers in other host/vector systems.

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Validation of reference genes for reverse transcription real-time quantitative PCR analysis in the deep-sea bacterium Shewanella psychrophila WP2

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Can I still eat it? Using problem-based learning to test the 5-second rule and promote scientific literacy

Abstract

Defining appropriate student learning outcomes for general education science courses is a daunting task. We must ask ourselves how to best prepare our students to understand the role of science in their lives and in society at large. In the era of social media and armchair experts, life-changing scientific advancements such as vaccination are being dismissed or actively resisted, emphasizing the critical need to teach science literacy skills. One active classroom method known as problem-based learning promotes self-motivated learning and synthesis skills that, when applied in a science-literacy context, can provide students with the ability to generate informed opinions on new scientific advances throughout their lifetime. This piece describes one such problem-based course, designed to tackle the scientific basis (or lack thereof) of the 5-second rule for eating food dropped on the floor. In this course, first year students experimentally engage this issue, while also applying their developing skill set to sort out scientific controversies such as vaccine safety and genetically modified foods.

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N-acetylmannosamine (ManNAc) supports the growth of Borrelia burgdorferi in the absence of N-acetylglucosamine (GlcNAc)

Abstract

Borrelia burgdorferi, the causative agent of Lyme disease, lacks the ability to biosynthesize many essential nutrients de novo, including N-acetylglucosamine (GlcNAc). This amino sugar is required for cell wall synthesis, and is a component of the complex growth medium used for in vitro propagation. When cultured without free GlcNAc, B. burgdorferi cells exhibit a unique biphasic growth pattern. We hypothesized that genes involved in the GlcNAc starvation response would be differentially expressed when compared to cells cultured in complete medium, and investigated this using transcriptomics. Twenty-one genes were differentially regulated in wild-type and starvation-adapted cells cultured without GlcNAc compared to wild-type cells cultured with GlcNAc. Of those, three genes involved in carbohydrate utilization were upregulated: bbb04 (chbC) encoding a subunit of the chitobiose transporter, bb0629 (fruA-2) encoding a putative carbohydrate transporter and bb0644 (nanE) encoding a putative GlcNAc-6-phosphate-2-epimerase predicted to catalyze the conversion of N-acetylmannosamine-6-phosphate (ManNAc-6-P) to GlcNAc-6-P. Quantitative RT-PCR was used to confirm differential expression of select genes, and substitution of free GlcNAc with free ManNAc resulted in growth to high cell density, suggesting B. burgdorferi cells can utilize free ManNAc for cell wall synthesis and energy production.

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Aggressive treatment in paediatric or young patients with drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is associated with future development of type III polyglandular autoimmune syndrome

We experienced a 6-year-old case of drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) with subsequent development autoimmune thyroiditis (Hashimoto's thyroiditis), type 1 diabetes with antithyroglobulin, thyroid peroxidase, insulinoma-associated antigen and anti-insulin antibodies at 4 months, alopecia at 7 months, vitiligo, uveitis due to Vogt-Koyanagi-Harada disease at 8 months after clinical resolution of the DiHS/DRESS. He was diagnosed as type III polyglandular autoimmune syndrome (PASIII) after DiHS/DRESS. Prompted by this case, we sought to determine which triggering factors were responsible for later development of PASIII in previously published cases with autoimmune sequelae. In the literature review, five patients with DIHS/DRESS were found to develop autoimmune sequelae consistent with PASIII. All cases with PASIII were much younger than those without them. Four out of the five patients were treated with intravenous immunoglobulin or pulsed prednisolone in the acute stage, although effective in short-term outcomes.

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Lemierres syndrome: a life-threatening sore throat

Description

A 25-year-old previously healthy Japanese man presented to our emergency department with a 1-day history of dyspnoea, following a sore throat in the previous week. Physical examination revealed acute exudative tonsillitis and right-sided diminished breath sounds. The laboratory analysis revealed a significantly elevated C reactive protein level of 30.67 mg/dL. A CT scan with contrast revealed a thrombophlebitis of the left internal jugular vein, a right-sided empyema and bilateral septic pulmonary emboli (figure 1).

Figure 1

Axial CT scan with contrast of the neck (left) and the chest (right). A thrombus in the left internal jugular vein (arrow, left), empyema (asterisks) and septic pulmonary emboli (arrow, right) are depicted.

In addition to thoracocentesis, curettage and irrigation of the right-sided thoracic cavity were performed with video-assisted thoracoscopic surgery. Gram staining of the purulent pleural fluid showed Gram-negative rods with abundant polymorphonuclear leukocytes....

https://ift.tt/2PskdQW

When things are not quite what they seem!

Description

A 61-year-old man presented with recurrent presyncope, 12-lead ECG and echocardiographic features of a right ventricular (RV) cardiomyopathy, and non-sustained ventricular tachycardia on Holter monitoring. During defibrillator implant for presumed arrhythmogenic RV cardiomyopathy, ventricular pacing parameters were satisfactory and the following images were obtained (figure 1). The implantable cardioverter defibrillator lead appeared well sited in the RV apex on posterior-anterior fluoroscopy (figure 1A). However, screening in the left anterior oblique (LAO) projection raised doubts about the true lead position (figure 1B). On-table echocardiography and 12-lead ECG confirmed lead placement within the left ventricle (LV). Pullback of the lead, while screening, suggested passage to the systemic circulation via an atrial septal defect (ASD; figure 2A–D and video 1). Attempts to reposition the lead by advancing it from the superior vena cava (SVC) revealed an anomalous connection to a right pulmonary...

https://ift.tt/2JjGxXi

Pleural tuberculosis: a key differential diagnosis for pleural thickening, even without obvious risk factors for tuberculosis in a low incidence setting

We report the case of a 64-year-old woman, presenting with pleuritic chest pain and weight loss. She had a previous history of breast malignancy and no clear risk factors for tuberculosis (TB). Initial investigations showed a right-sided pleural effusion and pleural thickening suggestive of malignancy, which would have been in keeping with the clinical presentation. Initial pleural biopsy showed features suggestive of possible TB infection, though no growth on cultures. A repeat biopsy was negative on initial microscopy, but was culture positive for Mycobacterium tuberculosis, also identifying isoniazid resistance. This case highlights that TB remains an important differential even in the absence of classical risk factors, and illustrates the diagnostic challenges it poses. It also highlights the value of culture positivity in identification of drug resistance and facilitation of appropriate treatment.

https://ift.tt/2JjH5wk

Health literacy, cognitive ability and smoking: a cross-sectional analysis of the English Longitudinal Study of Ageing

Objectives

We used logistic regression to investigate whether health literacy and cognitive ability independently predicted whether participants have ever smoked and, in ever smokers, whether participants still smoked nowadays.

Design

Cross-sectional study.

Setting

This study used data from Wave 2 (2004–05) of the English Longitudinal Study of Ageing, which is a cohort study of adults who live in England and who, at baseline, were aged 50 years and older.

Participants

8734 (mean age=65.31 years, SD=10.18) English Longitudinal Study of Ageing participants who answered questions about their current and past smoking status, and completed cognitive ability and health literacy tests at Wave 2.

Primary and secondary outcome measures

The primary outcome measures were whether participants reported ever smoking at Wave 2 and whether ever smokers reported still smoking at Wave 2.

Results

In models adjusting for age, sex, age left full-time education and occupational social class, limited health literacy (OR=1.096, 95% CI 0.988 to 1.216) and higher general cognitive ability (OR=1.000, 95% CI 0.945 to 1.057) were not associated with reporting ever smoking. In ever smokers, limited compared with adequate health literacy was associated with greater odds of being a current smoker (OR=1.194, 95% CI 1.034 to 1.378) and a 1 SD higher general cognitive ability score was associated with reduced odds of being a current smoker (OR=0.878, 95% CI 0.810 to 0.951), when adjusting for age, sex, age left full-time education and occupational social class.

Conclusions

When adjusting for education and occupation variables, this study found that health literacy and cognitive ability were independently associated with whether ever smokers continued to smoke nowadays, but not with whether participants had ever smoked.

https://ift.tt/2CH9afS

Using the National Early Warning Score (NEWS) outside acute hospital settings: a qualitative study of staff experiences in the West of England

Objectives

Early warning scores were developed to improve recognition of clinical deterioration in acute hospital settings. In England, the National Early Warning Score (NEWS) is increasingly being recommended at a national level for use outside such settings. In 2015, the West of England Academic Health Science Network supported the roll-out of NEWS across a range of non-acute-hospital healthcare sectors. Research on the use of NEWS outside acute hospitals is limited. The objective of this study was to explore staff experiences of using NEWS in these new settings.

Design

Thematic analysis of qualitative semi-structured interviews with purposefully sampled healthcare staff.

Setting

West of England healthcare settings where NEWS was being used outside acute hospitals—primary care, ambulance, referral management, community and mental health services.

Participants

Twenty-five healthcare staff interviewed from primary care (9), ambulance (3), referral management/acute interface (5), community (4) and mental health services (3), and service commissioning (1).

Results

Participants reported that NEWS could support clinical decision-making around escalation of care, and provide a clear means of communicating clinical acuity between clinicians and across different healthcare organisations. Challenges with implementing NEWS varied—in primary care, clinicians had to select patients for NEWS and adopt different methods of clinical assessment, whereas for paramedics it fitted well with usual clinical practice and was used for all patients. In community services and mental health, modifications were 'needed' to make the tool relevant to some patient populations.

Conclusions

This study demonstrated that while NEWS can work for staff outside acute hospital settings, the potential for routine clinical practice to accommodate NEWS in such settings varied. A tailored approach to implementation in different settings, incorporating guidance supported by further research on the use of NEWS with specific patient groups in community settings, may be beneficial, and enhance staff confidence in the tool.

https://ift.tt/2qffbc6

Psychometric properties of gross motor assessment tools for children: a systematic review

Objective

Gross motor assessment tools have a critical role in identifying, diagnosing and evaluating motor difficulties in childhood. The objective of this review was to systematically evaluate the psychometric properties and clinical utility of gross motor assessment tools for children aged 2–12 years.

Method

A systematic search of MEDLINE, Embase, CINAHL and AMED was performed between May and July 2017. Methodological quality was assessed with the COnsensus-based Standards for the selection of health status Measurement INstruments checklist and an outcome measures rating form was used to evaluate reliability, validity and clinical utility of assessment tools.

Results

Seven assessment tools from 37 studies/manuals met the inclusion criteria: Bayley Scale of Infant and Toddler Development-III (Bayley-III), Bruininks-Oseretsky Test of Motor Proficiency-2 (BOT-2), Movement Assessment Battery for Children-2 (MABC-2), McCarron Assessment of Neuromuscular Development (MAND), Neurological Sensory Motor Developmental Assessment (NSMDA), Peabody Developmental Motor Scales-2 (PDMS-2) and Test of Gross Motor Development-2 (TGMD-2). Methodological quality varied from poor to excellent. Validity and internal consistency varied from fair to excellent (α=0.5–0.99). The Bayley-III, NSMDA and MABC-2 have evidence of predictive validity. Test–retest reliability is excellent in the BOT-2 (intraclass correlation coefficient (ICC)=0.80–0.99), PDMS-2 (ICC=0.97), MABC-2 (ICC=0.83–0.96) and TGMD-2 (ICC=0.81–0.92). TGMD-2 has the highest inter-rater (ICC=0.88–0.93) and intrarater reliability (ICC=0.92–0.99).

Conclusions

The majority of gross motor assessments for children have good-excellent validity. Test–retest reliability is highest in the BOT-2, MABC-2, PDMS-2 and TGMD-2. The Bayley-III has the best predictive validity at 2 years of age for later motor outcome. None of the assessment tools demonstrate good evaluative validity. Further research on evaluative gross motor assessment tools are urgently needed.

https://ift.tt/2CGdDiV

Real-world effectiveness evaluation of budesonide/formoterol Spiromax for the management of asthma and chronic obstructive pulmonary disease in the UK

Objectives

Budesonide/formoterol (BF) Spiromax ^® is an inhaled corticosteroid/long-acting β₂-agonist fixed-dose combination (FDC) inhaler, designed to minimise common inhaler errors and provide reliable and consistent dose delivery in asthma and chronic obstructive pulmonary disease (COPD). We evaluated non-inferiority of BF Spiromax after changing from another FDC inhaler, compared with continuing the original inhaler.

Methods

Patients with asthma and/or COPD who switched to BF Spiromax were matched (1:3) with non-switchers. Data were obtained from the Optimum Patient Care Research Database and Clinical Practice Research Datalink in the UK. The primary end point was the proportion of patients achieving disease control (using the risk domain control (RDC) algorithm); secondary end points were: exacerbation rate, short-acting β₂-agonist (SABA) use and treatment stability (achieved RDC; no maintenance treatment change). Non-inferiority was defined as having 95% CI lower bound above –10%, using conditional logistic regression and adjusted for relevant confounders.

Results

Comparing 385 matched patients (asthma 253; COPD 132) who switched to BF Spiromax with 1091 (asthma 743; COPD 348) non-switchers, non-inferiority of BF Spiromax in RDC was demonstrated (adjusted difference: +6.6%; 95% CI –0.3 to 13.5). Among patients with asthma, switchers to BF Spiromax versus BF Turbuhaler^® reported fewer exacerbations (adjusted rate ratio (RR) 0.76;95% CI 0.60 to 0.99; p=0.044); were less likely to use high daily doses of SABA (adjusted OR 0.71;95% CI 0.52 to 0.98; p=0.034); used fewer SABA inhalers (adjusted RR 0.92;95% CI 0.86 to 0.99; p=0.019); and were more likely to achieve treatment stability (adjusted OR 1.44;95% CI 1.02 to 2.04; p=0.037). No significant differences in these end points were seen among patients with COPD.

Conclusions

Among UK patients with asthma and COPD, real-world use of BF Spiromax was non-inferior to BF Turbuhaler in terms of disease control. Among patients with asthma, switching to BF Spiromax was associated with reduced exacerbations, reduced SABA use and improved treatment stability versus continuing on BF Turbuhaler.

https://ift.tt/2qbQTzE

Assessing C reactive protein/albumin ratio as a new biomarker for polycystic ovary syndrome: a case-control study of women from Bahraini medical clinics

Objective

Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting approximately one in seven women who experience androgen excess, menstrual cycle irregularities, frequent anovulation and a tendency for central obesity and insulin resistance. Chronic subclinical inflammation is now recognised as being common in the context of PCOS, which led to the postulation that PCOS may fundamentally be an inflammatory process. This study aimed to: (1) evaluate serum C reactive protein (CRP)/albumin ratio as a potential predictive biomarker for PCOS; (2) compare the relationship between CRP/albumin and PCOS to variables classically associated with the syndrome.

Design

Case–control study.

Setting

Adult obstetrics/gynaecology, endocrinology and outpatient clinics; university hospital in Bahrain.

Participants

200 premenopausal women with a diagnosis of PCOS, and 119 ethnically matched eumenorrheic premenopausal women.

Main outcome measures

CRP/albumin ratio, anthropometric measures, insulin resistance, androgen excess.

Results

Independent of body mass index (BMI), receiver operating characteristic curve for CRP/albumin ratio as a selective biomarker for PCOS was 0.865 (95% CI 0.824 to 0.905), which was more sensitive than CRP alone. Binary regression analysis showed that CRP/albumin ratio outperformed classical correlates, Free Androgen Index and insulin resistance, in predicting PCOS for every BMI category.

Conclusion

CRP/albumin ratio, a marker for inflammation related to metabolic dysfunction, was found to have a stronger association with PCOS than either androgen excess or insulin resistance. Inflammation is known to be influenced by adiposity, but relative to controls, women with PCOS have higher levels of CRP/albumin irrespective of BMI. These findings support the view that inflammation plays a central role in the pathophysiology of PCOS.

https://ift.tt/2CIaRcR

Adapting the ToyBox obesity prevention intervention for use in Scottish preschools: protocol for a feasibility cluster randomised controlled trial

Introduction

There is an increasing need for the adoption of effective preschool obesity prevention interventions to combat the high levels of early-childhood obesity in the UK. This study will examine the feasibility and acceptability of the adapted version of the ToyBox intervention—a preschool obesity prevention programme—for use in Scotland (ToyBox-Scotland). This will inform the design of a full-scale cluster randomised controlled trial (RCT).

Methods and analysis

The ToyBox-Scotland intervention will be evaluated using a feasibility cluster RCT, which involves children aged 3–5 years at six preschools in Glasgow, three randomly assigned to the intervention group and three to the usual-care control group. The original ToyBox intervention was adapted for the Scottish context using a coproduction approach. Within the 18-week intervention, physical activity and sedentary behaviour will be targeted in the preschool through environmental changes to the classroom, physical activity sessions and movement breaks. Parents will receive home activity packs every 3 weeks containing sticker incentives and interactive parent–child games that target sedentary behaviour, physical activity, eating/snacking and water consumption. As this is a feasibility study, parameters such as recruitment rates, attrition rates and SDs of outcome measures will be obtained which will inform a power calculation for a future RCT. Additional variables to be assessed include accelerometer-measured physical activity, sedentary behaviour and sleep, body mass index, home screen time, eating/snacking and water consumption. Outcomes will be assessed at baseline and 14–17 weeks later. Intervention fidelity will be assessed using questionnaires and interviews with parents and practitioners, observation and session delivery records.

Ethics and dissemination

This study was granted ethical approval by the University of Strathclyde's School of Psychological Sciences and Health Ethics Committee. Results will be disseminated through publication in peer-reviewed journals, presentation at conferences and in lay summaries provided to participants.

Trial registration number

ISRCTN12831555.

https://ift.tt/2qdUDkt

Age, health and other factors associated with return to work for those engaging with a welfare-to-work initiative: a cohort study of administrative data from the UKs Work Programme

Objectives

To investigate the role of individual factors (including age, health and personal circumstances) and external factors associated with clients having a job start while engaging with the Work Programme and variations by benefit type.

Setting

The UK Government's main return to work initiative (The Work Programme) in Scotland.

Design

Piecewise Poisson regression to calculate incident rate ratios using administrative data from 2013 to 2016 to identify factors associated with job start.

Participants

4322 Employment and Support Allowance (ESA) clients not in work due to poor health and 8996 Jobseeker's Allowance (JSA) clients, aged 18–64 years, referred to the Work Programme between April 2013 and July 2014.

Main outcome measures

Starting a job and the time to first job start after entering the Work Programme.

Results

JSA clients (62%) were more likely to return to work (RTW) than ESA clients (20%). There is a strong negative relationship between age and the predicted probability of having a job start during the 2-year engagement with the programme for both JSA and ESA clients. JSA clients were most likely to RTW in the first 3 months, while for ESA clients the predicted probability of having a first job start was fairly constant over the 2 years. Health, including the number of health conditions, length of unemployment, client perception of job start and other individual factors were associated with job starts for both groups.

Conclusions

Age plays an important role in influencing RTW; however, important potentially modifiable factors include the length of unemployment, the management of multimorbidity and the individual's perception of the likelihood of job start. Future welfare-to-work programmes may be improved by providing age-specific interventions which focus on health and biopsychosocial factors to enable more people to realise the potential health benefits of RTW.

https://ift.tt/2CJ0Wnp

Generalised anxiety disorder and hospital admissions: findings from a large, population cohort study

Objective

Generalised anxiety disorder (GAD) is the most common anxiety disorder in the general population and has been associated with high economic and human burden. However, it has been neglected in the health services literature. The objective of this study is to assess whether GAD leads to hospital admissions using data from the European Prospective Investigation of Cancer-Norfolk. Other aims include determining whether early-onset or late-onset forms of the disorder, episode chronicity and frequency, and comorbidity with major depressive disorder (MDD) contribute to hospital admissions.

Design

Large, population study.

Setting

UK population-based cohort.

Participants

30 445 British participants were recruited through general practice registers in England. Of these, 20 919 completed a structured psychosocial questionnaire used to identify presence of GAD. Anxiety was assessed in 1996–2000, and health service use was captured between 1999/2000 and 2009 through record linkage with large, administrative health databases. 17 939 participants had complete data on covariates.

Main outcome measure

Past-year GAD defined according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition.

Results

In this study, there were 2.2% (393/17 939) of respondents with GAD. Anxiety was not independently associated with hospital admissions (incidence rate ratio (IRR)=1.04, 95% CI 0.90 to 1.20) over 9 years. However, those whose anxiety was comorbid with depression showed a statistically significantly increased risk for hospital admissions (IRR=1.23, 95% CI 1.02 to 1.49).

Conclusion

People with GAD and MDD comorbidity were at an increased risk for hospital admissions. Clinicians should consider that meeting criteria for a pure or individual disorder at one point in time, such as past-year GAD, does not necessarily predict deleterious health outcomes; rather different forms of the disorder, such as comorbid cases, might be of greater importance.

https://ift.tt/2CHDKGi

Cell cycle inhibitors protect motor neurons in an organoid model of Spinal Muscular Atrophy

Cell cycle inhibitors protect motor neurons in an organoid model of Spinal Muscular Atrophy

Cell cycle inhibitors protect motor neurons in an organoid model of Spinal Muscular Atrophy, Published online: 27 October 2018; doi:10.1038/s41419-018-1081-0

Cell cycle inhibitors protect motor neurons in an organoid model of Spinal Muscular Atrophy

https://ift.tt/2JknRH2

CD90 determined two subpopulations of glioma-associated mesenchymal stem cells with different roles in tumour progression

CD90 determined two subpopulations of glioma-associated mesenchymal stem cells with different roles in tumour progression

CD90 determined two subpopulations of glioma-associated mesenchymal stem cells with different roles in tumour progression, Published online: 27 October 2018; doi:10.1038/s41419-018-1140-6

CD90 determined two subpopulations of glioma-associated mesenchymal stem cells with different roles in tumour progression

https://ift.tt/2Pmowxb

CRISPR/Cas9 can mediate high-efficiency off-target mutations in mice in vivo

CRISPR/Cas9 can mediate high-efficiency off-target mutations in mice in vivo

CRISPR/Cas9 can mediate high-efficiency off-target mutations in mice in vivo, Published online: 27 October 2018; doi:10.1038/s41419-018-1146-0

CRISPR/Cas9 can mediate high-efficiency off-target mutations in mice in vivo

https://ift.tt/2JnNpDe

A new synthetic derivative of cryptotanshinone KYZ3 as STAT3 inhibitor for triple-negative breast cancer therapy

A new synthetic derivative of cryptotanshinone KYZ3 as STAT3 inhibitor for triple-negative breast cancer therapy

A new synthetic derivative of cryptotanshinone KYZ3 as STAT3 inhibitor for triple-negative breast cancer therapy, Published online: 27 October 2018; doi:10.1038/s41419-018-1139-z

A new synthetic derivative of cryptotanshinone KYZ3 as STAT3 inhibitor for triple-negative breast cancer therapy

https://ift.tt/2PncIuC

Cancers, Vol. 10, Pages 404: Oncolytic Viruses for Canine Cancer Treatment

Cancers, Vol. 10, Pages 404: Oncolytic Viruses for Canine Cancer Treatment

Cancers doi: 10.3390/cancers10110404

Authors: Diana Sánchez Gabriela Cesarman-Maus Alfredo Amador-Molina Marcela Lizano

Oncolytic virotherapy has been investigated for several decades and is emerging as a plausible biological therapy with several ongoing clinical trials and two viruses are now approved for cancer treatment in humans. The direct cytotoxicity and immune-stimulatory effects make oncolytic viruses an interesting strategy for cancer treatment. In this review, we summarize the results of in vitro and in vivo published studies of oncolytic viruses in different phases of evaluation in dogs, using PubMed and Google scholar as search platforms, without time restrictions (to date). Natural and genetically modified oncolytic viruses were evaluated with some encouraging results. The most studied viruses to date are the reovirus, myxoma virus, and vaccinia, tested mostly in solid tumors such as osteosarcomas, mammary gland tumors, soft tissue sarcomas, and mastocytomas. Although the results are promising, there are issues that need addressing such as ensuring tumor specificity, developing optimal dosing, circumventing preexisting antibodies from previous exposure or the development of antibodies during treatment, and assuring a reasonable safety profile, all of which are required in order to make this approach a successful therapy in dogs.

https://ift.tt/2D8u1K3

LOXL3 novel mutation causing a rare form of autosomal recessive Stickler syndrome

Clinical Genetics, Volume 0, Issue ja, -Not available-.

https://ift.tt/2yDztAL

A simulated patient evaluation of pharmacist’s performance in a men’s mental health program

The Headstrong program, a pharmacy based men's mental health promotion program, was designed to enhance pharmacists' care of men with mental illness and addictions and was focused on six conditions. A simulate...

https://ift.tt/2EZngMz

Neurologic challenges in 22q11.2 deletion syndrome

American Journal of Medical Genetics Part A, EarlyView.

https://ift.tt/2Slhffz

Intravenous Iron in Patients Undergoing Maintenance Hemodialysis

New England Journal of Medicine, Ahead of Print.

https://ift.tt/2z3cFK6

PAPD5/7 are novel host factors that are required for Hepatitis B virus RNA stabilization

Hepatology, Volume 0, Issue ja, -Not available-.

https://ift.tt/2yFaTPQ

Magnetic Resonance Imaging Is Cost‐Effective for Hepatocellular Carcinoma Surveillance in High Risk Patients with Cirrhosis

Hepatology, Volume 0, Issue ja, -Not available-.

https://ift.tt/2O8Pl3h

Single‐cell RNA‐seq analysis reveals the platinum resistance gene COX7B and the surrogate marker CD63

Cancer Medicine, EarlyView.

https://ift.tt/2yAZNeC

Intravenous Iron in Patients Undergoing Maintenance Hemodialysis

New England Journal of Medicine, Ahead of Print.

https://ift.tt/2z3cFK6

Understanding Detrimental and Beneficial Grain Boundary Effects in Halide Perovskites

Advanced Materials, EarlyView.

https://ift.tt/2O7J6N7

Rational Design of Carbon‐Rich Materials for Energy Storage and Conversion

Advanced Materials, EarlyView.

https://ift.tt/2yAQXh4

Topotactic Transformations in an Icosahedral Nanocrystal to Form Efficient Water‐Splitting Catalysts

Advanced Materials, EarlyView.

https://ift.tt/2O7IHdz

Effect of dietary inclusions of bitter kola seed on geotactic behavior and oxidative stress markers in Drosophila melanogaster

Food Science &Nutrition, EarlyView.

https://ift.tt/2OeMOEM

IFITM proteins drive type 2 T helper cell differentiation and exacerbate allergic airway inflammation

European Journal of Immunology, Volume 0, Issue ja, -Not available-.

https://ift.tt/2CIYxsN

18 F-FDG PET/CT detects Metastatic Renal Cell Carcinoma Masquerading as Primary Breast Malignancy

Abstract

We present the case of a 36-year-old woman who underwent ¹⁸F-FDG PET/CT with suspicion of a primary breast malignancy. However, PET/CT detected an occult renal cell carcinoma with metastases to the thyroid, breast, lungs and lymph nodes. Thyroid and breast metastases are atypical metastatic sites of renal cell carcinoma. Breast metastases from extra mammary tissue are extremely rare, more so from renal cell carcinoma. Histopathologic confirmation of the breast lesions is imperative to avoid unnecessary mastectomy and imaging can help in raising the suspicion of metastatic involvement versus primary breast malignancy.

https://ift.tt/2SpYdVc

Lowry-Wood syndrome: further evidence of association with RNU4ATAC , and correlation between genotype and phenotype

Abstract

Lowry-Wood syndrome (LWS) is a skeletal dysplasia characterized by multiple epiphyseal dysplasia associated with microcephaly, developmental delay and intellectual disability, and eye involvement. Pathogenic variants in RNU4ATAC, an RNA of the minor spliceosome important for the excision of U12-dependent introns, have been recently associated with LWS. This gene had previously also been associated with microcephalic osteodysplastic primordial dwarfism (MOPD) and Roifman syndrome (RS), two distinct conditions which share with LWS some skeletal and neurological anomalies. We performed exome sequencing in two individuals with Lowry-Wood syndrome. We report RNU4ATAC pathogenic variants in two further patients. Moreover, an analysis of all RNU4ATAC variants reported so far showed that FitCons scores for nucleotides mutated in the more severe MOPD are higher than RS or LWS and that they were more frequently located in the 5′ Stem–Loop of the RNA critical for the formation of the U4/U6.U5 tri-snRNP complex, whereas the variants are more dispersed in the other conditions. We are thus confirming that RNU4ATAC is the gene responsible for LWS and provide a genotype–phenotype correlation analysis.

https://ift.tt/2Pouqxv

Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1–PPP1CB complexes

Abstract

RASopathies are a group of developmental disorders caused by mutations in genes that regulate the RAS/MAPK pathway and include Noonan syndrome (NS), Costello syndrome, cardiofaciocutaneous syndrome and other related disorders. Whole exome sequencing studies recently identified LZTR1, PPP1CB and MRAS as new causative genes in RASopathies. However, information on the phenotypes of LZTR1 mutation-positive patients and functional properties of the mutations are limited. To identify variants of LZTR1, PPP1CB, and MRAS, we performed a targeted next-generation sequencing and reexamined previously analyzed exome data in 166 patients with suspected RASopathies. We identified eight LZTR1 variants, including a de novo variant, in seven probands who were suspicious for NS and one known de novo PPP1CB variant in a patient with NS. One of the seven probands had two compound heterozygous LZTR1 variants, suggesting autosomal recessive inheritance. All probands with LZTR1 variants had cardiac defects, including hypertrophic cardiomyopathy and atrial septal defect. Five of the seven probands had short stature or intellectual disabilities. Immunoprecipitation of endogenous LZTR1 followed by western blotting showed that LZTR1 bound to the RAF1–PPP1CB complex. Cells transfected with a small interfering RNA against LZTR1 exhibited decreased levels of RAF1 phosphorylated at Ser259. These are the first results to demonstrate LZTR1 in association with the RAF1–PPP1CB complex as a component of the RAS/MAPK pathway.

https://ift.tt/2Ji2xSj

Genioglossus activation during maximal sniff manoeuvres: Is upper airway function relevant in the clinical assessment of inspiratory and expiratory muscle strength?

Experimental Physiology, Volume 0, Issue ja, -Not available-.

https://ift.tt/2CGmKjs

EM Nerd-An Addendum to the Case of the Non-inferior Inferiority

An-Addendum-to-the-Case-of-the-Non-infer

Until recently the management of acute appendicitis has lay squarely in the hands of the surgeon. But there is a growing body of evidence examining the use of antibiotics alone in uncomplicated appendicitis. Most of the data exploring this question has found that the majority of patients treated with antibiotics alone will avoid surgery in […]

EMCrit Project by Rory Spiegel.

https://ift.tt/2RkeeLo

IBCC chapter & cast: Acute pancreatitis

Management of severe pancreatitis has remained in a state of controlled chaos and persistent debate for years (mirroring evolution in our treatment of septic shock). This confusion shows no signs of abating in the near future. This chapter explores a reasonable approach to pancreatitis, with the caveat that there is very little evidence available to guide our combat against this challenging foe.

EMCrit Project by Josh Farkas.

https://ift.tt/2RgJPO0

Tox and Hound – Dust To Dust

greller.jpg?resize=150%2C150

by Howard Greller Sudden sniffing death and myocardial sensitization I will show you fear in a handful of dust. – T.S. Eliot Little Johnny was having a hard time. Dumped by his girlfriend of eight glorious weeks, he was despondent. There wasn't any alcohol in the house, and he didn't have a fake ID or the […]

EMCrit Project by Tox & Hound.

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PulmCrit- Ketamine for alcohol withdrawal?

wallpaper.wiki-Acid-Trip-Wallpaper-HD-PI

Recent publications have explored the role of ketamine in alcohol withdrawal. Ketamine undoubtedly has some outstanding properties, which make it well suited for this task. The challenge is integrating ketamine into a unified, coherent treatment strategy.

EMCrit Project by Josh Farkas.

https://ift.tt/2Rjb4HA

EM Nerd-The Case of the Inferior Superiority

A perfect trial would require minimal statistical tools to assist in its analysis. Such a trial would be so large that the sample approached the true likeness of the broader population it intended to emulate, thus the risk of sampling error would be minimal. The confidence intervals surrounding the point estimates would be so minute, […]

EMCrit Project by Rory Spiegel.

https://ift.tt/2RgJRp6

EMCrit #235 – Cardiac Arrest Science with Zack Shinar

Cardiac Arrest Science

EMCrit Project by Scott Weingart.

https://ift.tt/2RgJRW8

IBCC chapter & cast: severe heart failure & cardiogenic shock

Management of severe heart failure and cardiogenic shock is difficult. There is a notable lack of high-quality evidence regarding the sickest patients. Treatment strategies validated among more stable patients may not be applicable to the most unstable heart failure patients.

EMCrit Project by Josh Farkas.

https://ift.tt/2RgJSta

Tox and Hound – Oh, the Nerve!

dan.jpg?resize=150%2C150

by Dan Rusyniak OK, I am going to dive into this whole Russia controversy. Now before you go getting all political on me, I am not talking about the Muller probe. I am talking about the recent suspected poisoning of a former Russian Spy in England. While Russia has been the prime culprit […]

EMCrit Project by Tox & Hound.

https://ift.tt/2Rhpxnc

IBCC chapter & cast – Hypoglycemia

Severe hypoglycemia can be scary, especially when the patient isn't responding to front-line therapies (e.g. IV dextrose). However, some unconventional tools and an organized approach can make this extremely manageable.

EMCrit Project by Josh Farkas.

https://ift.tt/2RgJT0c

Tox and Hound – Toxicology’s Shapeshifter: Synthetic Cannabinoids

jeff.jpg?resize=150%2C150

by Jeff Lapoint July, 2010. 3:14 am. "Jeff, I got a liddle case for ya", said the voice of Lou (named changed), the very New York C-SPI from the Poison Center. "917-555-. . ." He continued to rattle off a phone number. "Dude, give me more than that", I begged. I was a new fellow, […]

EMCrit Project by Tox & Hound.

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Tox and Hound – The Dantastic Mr. Tox & Howard – S02E04 – The Bloody Mess

17F58B0C-8AEA-442B-A787-9174998C4174.jpe

The synthetic cannabinoid / brodifacoum outbreak with Dr. Steve Aks Join Dan (@drusyniak) &Howard (@heshiegreshie) as they chat with Dr. Steve Aks as they talk about one of the more concerning toxicologic outbreaks in recent memory – the exposure to brodifacoum through synthetic cannabinoid use. Although still ongoing, this crisis highlights the importance of teamwork […]

EMCrit Project by Tox & Hound.

https://ift.tt/2RkBRmY

PulmCrit- Alcohol Withdrawal: One order to sedate them all

lor.jpg?resize=1140%2C333

I should do a formal retrospective cohort study on this, but I don't have time. Fortunately, the ICU group at Northshore/Long Island Jewish has done exactly that.

EMCrit Project by Josh Farkas.

https://ift.tt/2RjAKUC

EMCrit 234 – Pardon Me, I Couldn’t Help but Overhear or How to go from being an Ass-hole to an AYS-hole on Twitter

Are you saying?...

EMCrit Project by Scott Weingart.

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IBCC chapter & cast: Bradycardia

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Bradycardia emergencies are uncommon, but these cases can go sideways fast. An appropriately aggressive approach is needed to avoid cardiac arrest. Sometimes the answer is as simple as the appropriate epinephrine dose.

EMCrit Project by Josh Farkas.

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Tox and Hound – Snakes! Why’d it have to be SNAKES?

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by Meghan Spyres Unless you suffer the over appreciated and never-ending summer of southern California, the warm weather season is winding down and fall is settling in. Though many will lament the end of iced coffees, sunny beaches, and carefree summer attire, for many toxicologists, we will quietly lament the end of snake season. Perhaps […]

EMCrit Project by Tox & Hound.

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IBCC chapter & cast: community-onset pneumonia

Sir William Osler called pneumonia "the captain of the men of death." Over a century later, pneumonia remains the leading cause of infectious death in the developed world.

EMCrit Project by Josh Farkas.

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