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Παρασκευή 11 Μαΐου 2018

Fatal unexpected death due to familial hemophagocytic lymphohistiocytosis type 3

Abstract

Familial hemophagocytic lymphohistiocytosis is a rare autosomal recessive disorder of immune dysregulation associated with uncontrolled activation of cytotoxic T cells and macrophages. Herein, we report a case of a 14-month-old Chinese boy who presented with fever, abdominal distension and thrombopenia, and died within 3 days of admission to the hospital. Postmortem examination revealed pleuroperitoneal fluid, enlarged mesenteric lymph nodes and hepatosplenomegaly. Histopathological examination showed interstitial pneumonia, hepatonecrosis and hemophagocytosis. Immunohistochemical staining of the spleen, lymph node and liver specimens revealed numerous cytotoxic T cells (CD8+) and histiocytes (CD68+). EBER1-positive cells were observed in lymphocytes of the spleen, lymph node, liver and lungs by in situ hybridization. UNC13D mutation was identified, although the boy had no family history. The following medico-legal autopsy case is being reported for its rarity in the forensic setting. We addresses the need for genetic testing in addition to a thorough clinical history, appropriate laboratory tests, histological examination and immunohistochemical analysis for the rapid and accurate diagnosis of familial hemophagocytic lymphohistiocytosis.



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Risk-benefit of dexrazoxane for preventing anthracycline-related cardiotoxicity: re-evaluating the European labeling

Future Oncology, Ahead of Print.


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Prognostic value of systemic immune-inflammation index in patients with advanced non-small-cell lung cancer

Future Oncology, Ahead of Print.


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Estimating Drug Costs: How do Manufacturer Net Prices Compare with Other Common US Price References?

Abstract

Background

Drug costs are frequently estimated in economic analyses using wholesale acquisition cost (WAC), but what is the best approach to develop these estimates? Pharmaceutical manufacturers recently released transparency reports disclosing net price increases after accounting for rebates and other discounts.

Objective

Our objective was to determine whether manufacturer net prices (MNPs) could approximate the discounted prices observed by the U.S. Department of Veterans Affairs (VA).

Methods

We compared the annual, average price discounts voluntarily reported by three pharmaceutical manufacturers with the VA price for specific products from each company. The top 10 drugs by total sales reported from company tax filings for 2016 were included. The discount observed by the VA was determined from each drug's list price, reported as WAC, in 2016. Descriptive statistics were calculated for the VA discount observed and a weighted price index was calculated using the lowest price to the VA (Weighted VA Index), which was compared with the manufacturer index.

Results

The discounted price as a percentage of the WAC ranged from 9 to 74%. All three indexes estimated by the average discount to the VA were at or below the manufacturer indexes (42 vs. 50% for Eli Lilly, 56 vs. 65% for Johnson & Johnson, and 59 vs. 59% for Merck).

Conclusions

Manufacturer-reported average net prices may provide a close approximation of the average discounted price granted to the VA, suggesting they may be a useful proxy for the true pharmacy benefits manager (PBM) or payer cost. However, individual discounts for products have wide variation, making a standard discount adjustment across multiple products less acceptable.



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Flexible sigmoidoscopy in colorectal cancer screening: implications of different colonoscopy referral strategies

Abstract

Flexible sigmoidoscopy (FS) screening reduces colorectal cancer incidence and mortality. Its potential to detect proximal neoplasms depends on colonoscopy referral. We estimated diagnostic performance of sigmoidoscopy using 12 different referral criteria in detecting colorectal cancer and advanced adenomas. Colonoscopy results from 14,947 participants of screening colonoscopy in Germany were used to derive sensitivity of sigmoidoscopy for colorectal cancer, advanced adenomas (AAs), and any advanced neoplasms in the proximal colon. It was assumed that FS detects the same neoplasms as colonoscopy within its reach and that distal neoplasms would be followed by colonoscopy. In addition, numbers of colonoscopies needed (NCN) to detect one proximal advanced neoplasm were calculated. The most advanced findings during colonoscopy were colorectal cancer in 213 subjects (1.4%), AA in 1539 subjects (10.2%) and non-advanced adenomas in 2988 subjects (19.8%). Without colonoscopy referral, overall sensitivities for any colorectal cancer, advanced adenoma and any advanced neoplasm (proximal or distal) would be 79, 65 and 66%, respectively. These sensitivities could be increased to up to 86, 83 and 84% by the referral strategies investigated. Compared to referral due to advanced adenomas, referral due to non-advanced adenomas would substantially increase the NCN at a modest gain in sensitivity. Sensitivities were higher and NCNs were lower in men than in women for every strategy. In conclusion, colonoscopy referral can substantially increase sensitivity of sigmoidoscopy-based screening, but the gain by referral due to non-advanced adenomas substantially increases NCN compared to referral due to advanced neoplasms only. Major sex differences may call for sex-specific referral strategies.



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Contents



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Continuing Medical Education Exam: June 2018



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Erratum

In the October 2017 issue of Gastrointestinal Endoscopy, the article "Needle-based confocal laser endomicroscopy for the diagnosis of pancreatic cystic lesions: an international external interobserver and intraobserver study (with videos)" by Somashekar G. Krishna, et al (Gastrointest Endosc 2017;86:644-54.), contains typographical errors in Table 2. The corrected table appears below.

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The silence of the LAMS

We read with interest the single-center, retrospective study by Aburajab et al1 on EUS-guided lumen-apposing metal stents (LAMSs) for symptomatic pancreatic pseudocyst (PP) drainage. Technical success was achieved in 98% (46/47) of patients. An interim analysis of their initial 23 cases revealed high rates of cyst infection (4/23; 17.4%), which prompted them to routinely place a 10F double-pigtail (DP) stent across the LAMS in the remaining 23 cases. Overall, there was a trend toward a lower rate of infection in patients with DP through the LAMS versus LAMS alone (relative risk 0.8; 95% confidence interval, 0.7-1.0; P = .054).

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A novel method to prevent catheter dysfunction during spray cryotherapy

This letter provides data that the insufflation of CO2 gas in an endoscope working channel as depicted in Visrodia et al1 reduces the ablation power of truFreeze spray cryotherapy. An Olympus UCR insufflator routed CO2 through the vacuum fitting of an Olympus GIF-140 gastroscope into the 2.8-mm working channel alongside the truFreeze delivery catheter. Power (Fig. 1A) measured by the use of validated test tools with a 1.4-standard liters per minute (SLPM) CO2 flow rate revealed a significant drop of 64%.

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Small and diminutive hyperplastic polyps in the proximal colon: Are they innocent or guilty of a crime?

Over the past 30 years, serrated polyps (SPs) of the colorectum have gained increasing attention in relation to colorectal cancer (CRC) prevention.1 Historically, this group of lesions was called "hyperplastic polyps" (HPs), which were considered innocuous, and the term "serrated" was used to describe the "saw-toothed" architecture in their crypt epithelium.2 The heterogeneity of SPs was not recognized until 1990, when Longacre and Fenoglio-Preiser3 proposed the term "serrated adenoma" (now termed "traditional serrated adenoma," or TSA) to describe a subgroup of SPs that not only share the serrated crypt architecture of HPs but also have cytologic dysplasia.

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Editors



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Information for readers



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Focus on...



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Response:

I appreciate Matsushita et al1 for their interest in my article "A rare cause of recurrent acute pancreatitis: duodenal intussusception by a fenestrated duodenum web."2 I agree with their assertion that endoscopically treating a fenestrated duodenum web, intraluminal duodenal diverticulum, would be less invasive and effective. Although we also considered endoscopic treatment for intraluminal duodenal diverticulum in this case, we could not determine the major duodenal papilla while performing EGD before surgery, thereby posing a high risk for endoscopic treatment.

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ASGE update



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EUS-FNA giving way to fine-needle biopsy: Is it time to retire your old trusted needles?

EUS-guided tissue acquisition (EUS-TA) plays a fundamental role in the diagnosis of pancreatic masses. The ideal EUS-TA technique and device is that which will maximize diagnostic yield, specimen adequacy, and accuracy while minimizing adverse event rates and costs.1 Several factors have an impact on EUS-TA outcomes, including (1) sampling methods and techniques (use of suction, fanning, capillary technique, number of passes, methods of sample expression), (2) availability of rapid onsite evaluation (ROSE), (3) endosonographer and cytopathologist qualifications (training and experience), and (4) type of specimen and needle used.

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In upcoming issues...



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Response:

We thank Drs Yang and Draganov1 for their comments on our study2 wherein we evaluated the safety and efficacy of lumen-apposing metal stents (LAMSs) with and without simultaneously placing double-pigtail stents for draining pancreatic pseudocysts (PPs). In an unpublished multicenter study using LAMSs to drain PPs, the authors observed LAMS occlusion in 17.5% of patients at a median of 5 weeks.1 These results are similar to the results in our patients who presented with cyst cavity infection (17.4%) within 30 days after LAMSs were placed to drain PPs.

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In the expanding arena of endoscopic management for Barrett’s neoplasia, how should we fit in endoscopic submucosal dissection?

Endoscopic submucosal dissection (ESD) is increasingly being performed for different indications in the GI tract. The main advantage of ESD is that it allows for en bloc resection of lesions larger than 15 mm, for which conventional snare-based endoscopic resection (ER) techniques would require piecemeal resection.1 En bloc resection of neoplastic lesions with ESD allows for optimal histopathologic evaluation, especially regarding the radicality at the deep and lateral resection margins. Another advantage of en bloc resection is that there is no risk of residual neoplastic remnants between adjacent resections, as might occur during piecemeal resection.

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Effective endoscopic treatment for intraluminal duodenal diverticulum

We read with interest the article by Koike1 on a patient with recurrent acute pancreatitis caused by a fenestrated duodenal web: intraluminal duodenal diverticulum. On the basis of a duodenum-within-duodenum configuration on CT, a large fenestrated duodenal web on EGD, and a windsock appearance on upper GI series, duodenal intussusception caused by a fenestrated duodenal web was diagnosed. Although the duodenal web was surgically resected with a favorable outcome, we suspect that endoscopic treatment would be a safe and effective alternative.

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Per-oral endoscopic myotomy short-term outcomes are good—but the long-term results are what count

Per-oral endoscopic myotomy (POEM), introduced in 2008 by Inoue et al,1 has rapidly become an established treatment for achalasia, expanding the number of patients having surgery and demonstrating short-term to mid-term efficacy and excellent safety profiles.2 When compared with laparoscopic Heller myotomy, POEM has been shown to have comparable efficacy, with less morbidity and shorter hospital stay.

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Guidewire caliber is not important when controlled by high-caliber operators

"All the tools, techniques, and technology in the world are nothing without the head, heart, and hands to use them wisely, kindly, and mindfully."–Rasheed OgunlaruTherapeutic ERCP requires cannulation and deep guidewire access of the desired biliary duct, pancreatic duct, or both. Although cannulation is more an art than a science,1 it is instructive to consider the important general principles and the growing accumulation of data that pertain to successful and safe strategies.

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Outcome analysis in Crohn’s disease using endomicroscopy: How important and reliable is in vivo analysis of microscopic changes?

Endomicroscopy provides in vivo histologic analysis, functional imaging, and molecular imaging. Endomicroscopy is a unique technology, which provides in vivo histologic analysis during ongoing endoscopy. Endomicroscopy has been shown to be highly effective in defining final histologic features if used in experienced hands.1 However, there are several limitations of the technology. The grade of dysplasia cannot be assessed properly because fluorescein (a commonly used contrast agent in endomicroscopy) does not label nuclei.

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Pancreas cyst fluid viscocity assesment in the diagnosis of mucinous cyts

We read with interest the article by Krishna et al1 about the use of EUS-guided needle-based confocal laser endomicroscopy (nCLE) in differentiating between mucinous and nonmucinous pancreatic cysts. They reported a cohort of patients with 16 mucinous and 13 nonmucinous pancreas cysts to assess the performance characteristics of EUS-guided nCLE, which was found to have a high accuracy. However, in our experience, nCLE is a very expensive evaluation method for daily practice. In differentiating between mucinous and nonmucinous pancreas cysts, determination of the viscosity of the cyst fluid may be useful.

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Isolated Drain Site Metastasis After Open Resection in Ileal Adenocarcinoma—an Uncommon Site

Abstract

Although port site implants have been described after laparoscopic resection for gastrointestinal malignancies, drain site metastasis in solid intra-abdominal tumor after open resection is a rare phenomenon. Only few cases have been reported in literature describing drain site metastasis after open resection for carcinoma in the colon, stomach, cervix etc. Isolated drain site metastasis is even rare. To our knowledge, drain site recurrence after laparotomy for ileal cancer has not been published. We report a 50-year-old gentleman who had undergone laparotomy and ileal resection for distal ileal adenocarcinoma presented with an isolated drain site metastasis after 1 year of completion of chemotherapy.



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Defining mechanisms of neural plasticity after brainstem ischemia in rats

Annals of Neurology, EarlyView.


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The domino SWI2/SNF2 Gene Product Represses Cell Death in Drosophila melanogaster

The Drosophila domino locus encodes DNA-dependent ATPases of the SWI2/SNF2 class. This class of chromatin remodeler is associated with an array of cellular activities encompassing transcription, replication, repair and recombination. Moreover, domino was observed initially to maintain a repressive chromatin state via genetic interaction studies with homeotic genes. Although domino mutations were also characterized with a cell death phenotype, its association with a death pathway has not been investigated. Here we have used targeted RNA interference to depress domino function in the wing. Resultant wing damage phenotypes were found to be enhanced through overexpression of pro-apoptotic loci, and suppressed through loss of function of these loci. Loss of wing margin and blade tissue was correlated with activation of the effector Caspase Dcp-1, a marker for apoptosis. The affected wing regions also exhibited lower levels of the DIAP1 protein, an inhibitor of apoptosis. The lower level of DIAP1 protein was not correlated with an effect on the activity of a DIAP1 gene transgenic reporter (thread-LacZ), suggesting that loss of DIAP1 occurred post transcriptionally. In some cases excessive cell proliferation within the targeted tissue, measured through BrdU incorporation, was also observed. Finally, we used a transgenic reporter construct to monitor the chromatin state upstream of the proapoptotic reaper locus. In genotypes exhibiting targeted domino loss and wing phenotypes, we observed increased reporter activity only in the affected areas. These data support the conclusion that domino normally functions to maintain pro-apoptotic genes in a repressed state.



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The PVT1 Promoter Suppresses MYC Transcription to Reduce Cell Growth [Research Watch]

The PVT1 promoter is a tumor-suppressive DNA element that is recurrently mutated in human tumors.



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UTX Promotes Chromatin Remodeling to Suppress Leukemogenesis [Research Watch]

UTX-mediated suppression of myeloid leukemogenesis is independent of its demethylase activity.



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The cis-Regulatory DERARE Element Regulates Leukemogenesis [Research Watch]

DERARE methylation suppresses HOXB gene expression and leukemogenesis to maintain normal hematopoiesis.



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ARID1A Deficiency May Predict Response to Immune Checkpoint Blockade [Research Watch]

ARID1A deficiency impairs mismatch repair to increase tumor mutation load and promote tumor progression.



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CD4+ T cell-mediated rejection of MHC class II-positive tumor cells is dependent on antigen secretion and indirect presentation on host APCs

Tumor-specific CD4+ T cells have been shown to mediate efficient anti-tumor immune responses against cancer. Such responses can occur through direct binding to MHC class II (MHC II)-expressing tumor cells or indirectly via activation of professional antigen-presenting cells (APC) that take up and present the tumor antigen. We have previously shown that CD4+ T cells reactive against an epitope within the Ig light chain variable region of a murine B cell lymphoma can reject established tumors. Given the presence of MHC II molecules at the surface of lymphoma cells, we investigated whether MHC II-restricted antigen presentation on tumor cells alone was required for rejection. Variants of the A20 B lymphoma cell line that either secreted or intracellularly retained different versions of the tumor-specific antigen revealed that antigen secretion by the MHC II-expressing tumor cells was essential both for the priming and effector phase of CD4+ T cell-driven anti-tumor immune responses. Consistent with this, genetic ablation of MHC II in tumor cells, both in the case of B lymphoma and B16 melanoma, did not preclude rejection of tumors by tumor antigen-specific CD4+ T cells in vivo. These findings demonstrate that MHC class II expression on tumor cells themselves is not required for CD4+ T cell-mediated rejection, and that indirect display on host APC is sufficient for effective tumor elimination. These results support the importance of tumor-infiltrating APC as mediators of tumor cell killing by CD4+ T cells.

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NK cell editing mediates Epithelial to Mesenchymal Transition via phenotypic and proteomic changes in melanoma cell lines

Tumor cell plasticity is a major obstacle for the cure of malignancies as it makes tumor cells highly adaptable to micro-environmental changes, enables their phenotype switching among different forms, and favors the generation of pro-metastatic tumor cell subsets. Phenotype switching towards more aggressive forms involves different functional, phenotypic and morphologic changes, which are often related to the process known as Epithelial-Mesenchymal Transition (EMT). In this study, we report NK cells may increase the malignancy of melanoma cells by inducing changes relevant to EMT and, more broadly, to phenotype switching from proliferative to invasive forms. In co-culture, NK cells induced effects on tumor cells similar to those induced by EMT-promoting cytokines, including up-regulation of stemness and EMT markers, morphologic transition, inhibition of proliferation, and increased capacity for matrigel invasion. Most changes were dependent on the engagement of NKp30 or NKG2D and the release of cytokines including IFN-γ and TNF-α. Moreover, EMT induction also favored escape from NK cell attack. Melanoma cells undergoing EMT either increased NK-protective HLA-I expression on their surface or downregulated several tumor-recognizing activating receptors on NK cells. Mass spectrometry-based proteomic analysis revealed in two different melanoma cell lines a partial overlap between proteomic profiles induced by NK cells or by EMT-cytokines, indicating that various processes or pathways related to tumor progression are induced by exposure to NK cells.

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Midstream Urine Microbiome Diverse in Seniors With CKD

FRIDAY, May 11, 2018 -- Older adults with non-dialysis-dependent chronic kidney disease (CKD) have a diverse midstream voided urine microbiome, according to a study published online April 12 in International Urology and Nephrology. Holly Kramer,...

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Emotion Regulation Program Cuts Risky Sex Behaviors in Youth

FRIDAY, May 11, 2018 -- An emotion regulation intervention reduced sexual risk behaviors among at-risk middle school students, according to a study published online May 10 in Pediatrics. Christopher D. Houck, Ph.D., from Brown University in...

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Primary Care Providers Have Mixed Views on Genetic Tests

FRIDAY, May 11, 2018 -- Primary care providers view tests for genetic risks of common diseases as useful, but lack confidence in interpreting results, according to a study published in the May issue of Health Affairs. Diane Hauser, from the Icahn...

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Tobacco Cessation Support Lacking in Mental Health Facilities

FRIDAY, May 11, 2018 -- Many patients in mental health and substance abuse treatment facilities are not screened for tobacco use or offered treatments to facilitate tobacco cessation, according to research published in the May 11 issue of the U.S....

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Researchers Explore Nanofibers to Target, Treat Atherosclerosis

FRIDAY, May 11, 2018 -- Self-assembling peptide amphiphile (PA) nanofibers, incorporating an 18 amino acid sequence that retains the cholesterol efflux actions of apolipoprotein-A1 (apoA1) and a liver X receptor (LXR) agonist can target and treat...

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Classification of Pancreatic Cancer - Ready for Practical Application?

There is great interest in an ability to categorize pancreas cancer and understand and classify the significant heterogeneity that exists in this disease. Such classifications based on morphologic, genetic, and immunologic features are emerging and the application of this information to provide both prognostic and predictive information is highly desired.



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Identification and validation of radiographic enhancement for reliable differentiation of CD117(+) benign renal oncocytoma and chromophobe renal cell carcinoma

PURPOSE: The diagnostic differential for CD117/KIT(+) oncocytic renal tumor biopsies is limited to benign renal oncocytoma (RO) vs. chromophobe renal cell carcinoma (ChRCC), however further differentiation is often challenging and requires surgical resection.  We investigated clinical variables that might improve preoperative differentiation of CD117(+) RO vs. ChRCC to avoid the need for benign tumor resection. EXPERIMENTAL DESIGN: 124 nephrectomy patients from a single institute with 133 RO or ChRCC tumors were studied. Patients from 2003-2012 comprised a retrospective cohort to identify clinical/radiographic variables associated with RO versus ChRCC. Prospective validation was performed among consecutive RO/ChRCC tumors resected from 2013-2017. RESULTS: Tumor size and younger age were associated with ChRCC, and multifocality with RO, however the most reliable variable for ChRCC vs. RO differentiation was the tumor:cortex peak early-phase enhancement ratio (PEER) using multiphase computer tomography (CT). Among 54 PEER-evaluable tumors in the retrospective cohort (19 CD117(+), 13 CD117(-), 22 CD117-untested), PEER classified each correctly as RO (PEER >0.50) or ChRCC (PEER <0.50), except four misclassified CD117(-) ChRCC variants. Prospective study of PEER confirmed 100% accuracy of RO/ChRCC classification among 22/22 additional CD117(+) tumors. Prospective inter-observer reproducibility was excellent for PEER scoring (intra-class correlation coefficient, ICC=0.97) and perfect for RO/ChRCC assignment (ICC=1.0). CONCLUSIONS: In the largest clinical comparison of RO vs. ChRCC to our knowledge, we identified and prospectively validated a reproducible radiographic measure that differentiates CD117(+) RO from ChRCC with potentially 100% accuracy.  PEER may allow reliable biopsy-based diagnosis of CD117(+) RO, avoiding the need for diagnostic nephrectomy.



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The highly metastatic nature of uterine cervical/endometrial cancer displaying tumor-related leukocytosis: clinical and preclinical investigations

Purpose: The aim of this study was to investigate the metastatic potential of uterine cervical and endometrial cancer displaying tumor-related leukocytosis (TRL). Experimental Design: Clinical data on uterine cervical (N=732) and endometrial cancer (N=900) were collected, and the metastatic potential of TRL-positive cancer was evaluated in univariate and multivariate analyses. Tumor and blood samples obtained from cervical cancer patients, cervical cancer cell lines, and a mouse model of cervical cancer were employed to examine the mechanisms underlying the highly metastatic nature of TRL-positive cancer, focusing on tumor-derived granulocyte-colony stimulating factor (G-CSF) and the myeloid-derived suppressor cells (MDSC)-mediated premetastatic niche. Results: Pretreatment TRL was significantly associated with visceral organ metastasis in patients with uterine cervical or endometrial cancer. The TRL-positive cervical cancer patients displayed upregulated tumor G-CSF expression, elevated G-CSF levels, and increased MDSC frequencies in the peripheral blood compared with the TRL-negative patients. In vitro and in vivo investigations revealed that MDSC produced in response to tumor-derived G-CSF are involved in premetastatic niche formation, which promotes visceral organ metastasis of TRL-positive cancer. The depletion of MDSC attenuated this premetastatic niche formation and effectively inhibited the visceral organ metastasis of TRL-positive cancer. Conclusions: Uterine cervical/endometrial cancer displaying TRL is a distinct clinical entity with high metastatic potential. Tumor-derived G-CSF and the MDSC-mediated premetastatic niche are responsible for the highly metastatic nature of this type of cancer. MDSC-targeting therapy might represent a potential strategy for combating metastasis derived from TRL-positive uterine cancer.



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Zika virus vaccines: immune response, current status, and future challenges

Justin M Richner | Michael S Diamond

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Immunological responses to influenza vaccination: lessons for improving vaccine efficacy

Taia T .Wang | Stylianos Bournazos | Jeffrey V Ravetch

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MR1 antigen presentation to MAIT cells: new ligands, diverse pathways?

Hamish EG McWilliam | Jose A Villadangos

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Vyaire Medical AirLife Resuscitation Device & Broselow Convenience Kit by Vyaire Medical: Class I Recall - Due to Risk of Malfunction Caused by Error in Product Design

[Posted 05/11/2018] AUDIENCE: Emergency Medicine, Health Professional, Risk Manager, Patient, Pulmonology ISSUE: Vyaire Medical is recalling the AirLife Resuscitation Device & Broselow Convenience Kit due to an error in its product design that...

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Vyaire Medical AirLife Resuscitation Device & Broselow Convenience Kit by Vyaire Medical: Class I Recall - Due to Risk of Malfunction Caused by Error in Product Design

[Posted 05/11/2018] AUDIENCE: Emergency Medicine, Health Professional, Risk Manager, Patient, Pulmonology ISSUE: Vyaire Medical is recalling the AirLife Resuscitation Device & Broselow Convenience Kit due to an error in its product design that...

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Why extragastric deep-type buried bumper syndrome should (not) be a contraindication for endoscopic treatment?



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Rare Complication of Permanent Indwelling Transmural Plastic Stent



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Gastric Mucosal Metastasis of Prostate Cancer

A 65-year-old male patient who had been hospitalized in the ıntensive care unit for pneumonia presented with hematemesis and melena. He was diagnosed with metastatic adenocarcinoma of prostate (multiple bone and lung metastases), which was accompanied by diabetes mellitus, hypertension, and coronary heart disease. The hemoglobin levels decreased from 11.4 g/dL to 7.3 g/dL during follow-up. Upper endoscopy revealed widespread distribution of numerous umbilicated nodules with varying sizes (from 0.5 to 2 cm) on gastric mucosa (A, B, C).

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An atypical infection of esophagus mimicking malignancy

A 49-year-old man, who was an outdoor builder, had habitual consumption of cigarette, alcohol, and betel nut. He had dysphagia and hoarseness, accompanied with a weight loss of about 5 to 6 kg within 6 months. His esophagogastroduodenoscopy (EGD) (GIF-Q260, Olympus Medical Systems, Tokyo, Japan) demonstrated numerous granular lesions with some erosions and ulcers, mainly distributed at the middle to lower esophagus as seen by white-light imaging.

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MicroRNA-17-92 cluster promotes the proliferation and the chemokine production of keratinocytes: implication for the pathogenesis of psoriasis

MicroRNA-17-92 cluster promotes the proliferation and the chemokine production of keratinocytes: implication for the pathogenesis of psoriasis

MicroRNA-17-92 cluster promotes the proliferation and the chemokine production of keratinocytes: implication for the pathogenesis of psoriasis, Published online: 11 May 2018; doi:10.1038/s41419-018-0621-y

MicroRNA-17-92 cluster promotes the proliferation and the chemokine production of keratinocytes: implication for the pathogenesis of psoriasis

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PTBP3 contributes to the metastasis of gastric cancer by mediating CAV1 alternative splicing

PTBP3 contributes to the metastasis of gastric cancer by mediating CAV1 alternative splicing

PTBP3 contributes to the metastasis of gastric cancer by mediating CAV1 alternative splicing, Published online: 11 May 2018; doi:10.1038/s41419-018-0608-8

PTBP3 contributes to the metastasis of gastric cancer by mediating CAV1 alternative splicing

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Caspase-3 suppresses diethylnitrosamine-induced hepatocyte death, compensatory proliferation and hepatocarcinogenesis through inhibiting p38 activation

Caspase-3 suppresses diethylnitrosamine-induced hepatocyte death, compensatory proliferation and hepatocarcinogenesis through inhibiting p38 activation

Caspase-3 suppresses diethylnitrosamine-induced hepatocyte death, compensatory proliferation and hepatocarcinogenesis through inhibiting p38 activation, Published online: 11 May 2018; doi:10.1038/s41419-018-0617-7

Caspase-3 suppresses diethylnitrosamine-induced hepatocyte death, compensatory proliferation and hepatocarcinogenesis through inhibiting p38 activation

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Checkpoint suppressor 1 suppresses transcriptional activity of ERα and breast cancer cell proliferation via deacetylase SIRT1

Checkpoint suppressor 1 suppresses transcriptional activity of ERα and breast cancer cell proliferation via deacetylase SIRT1

Checkpoint suppressor 1 suppresses transcriptional activity of ERα and breast cancer cell proliferation via deacetylase SIRT1, Published online: 11 May 2018; doi:10.1038/s41419-018-0629-3

Checkpoint suppressor 1 suppresses transcriptional activity of ERα and breast cancer cell proliferation via deacetylase SIRT1

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A novel long non-coding RNA-PRLB acts as a tumor promoter through regulating miR-4766-5p/SIRT1 axis in breast cancer

A novel long non-coding RNA-PRLB acts as a tumor promoter through regulating miR-4766-5p/SIRT1 axis in breast cancer

A novel long non-coding RNA-PRLB acts as a tumor promoter through regulating miR-4766-5p/SIRT1 axis in breast cancer, Published online: 11 May 2018; doi:10.1038/s41419-018-0582-1

A novel long non-coding RNA-PRLB acts as a tumor promoter through regulating miR-4766-5p/SIRT1 axis in breast cancer

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miR-5591-5p regulates the effect of ADSCs in repairing diabetic wound via targeting AGEs/AGER/JNK signaling axis

miR-5591-5p regulates the effect of ADSCs in repairing diabetic wound via targeting AGEs/AGER/JNK signaling axis

miR-5591-5p regulates the effect of ADSCs in repairing diabetic wound via targeting AGEs/AGER/JNK signaling axis, Published online: 11 May 2018; doi:10.1038/s41419-018-0615-9

miR-5591-5p regulates the effect of ADSCs in repairing diabetic wound via targeting AGEs/AGER/JNK signaling axis

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FOXM1 contributes to taxane resistance by regulating UHRF1-controlled cancer cell stemness

FOXM1 contributes to taxane resistance by regulating UHRF1-controlled cancer cell stemness

FOXM1 contributes to taxane resistance by regulating UHRF1-controlled cancer cell stemness, Published online: 11 May 2018; doi:10.1038/s41419-018-0631-9

FOXM1 contributes to taxane resistance by regulating UHRF1-controlled cancer cell stemness

https://ift.tt/2IyDnAX

Regulation of proliferation and cell cycle by protein regulator of cytokinesis 1 in oral squamous cell carcinoma

Regulation of proliferation and cell cycle by protein regulator of cytokinesis 1 in oral squamous cell carcinoma

Regulation of proliferation and cell cycle by protein regulator of cytokinesis 1 in oral squamous cell carcinoma, Published online: 11 May 2018; doi:10.1038/s41419-018-0618-6

Regulation of proliferation and cell cycle by protein regulator of cytokinesis 1 in oral squamous cell carcinoma

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Announcements



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North Dakota selects ESO to create statewide data repository for EMS agencies

System enables collaborative data input and sharing to drive performance improvement, injury prevention and better outcomes for North Dakota communities AUSTIN — ESO, the leading data and software company serving emergency medical services (EMS), fire departments and hospitals, today announced it is partnering with North Dakota to create a data repository to collect and analyze EMS patient care ...

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Making a Difference in Low-Resource Settings

By Nathan Douthit

In February, 1999, the World Health Organization partnered with more than 20 non-governmental organizations involved in eye care to launch VISION2020: The Right to Sight. The goal of this initiative is to eliminate the main preventable and treatable causes of blindness by the year 2020. The threefold strategy involves disease control, human resource development, and infrastructure and appropriate technology development. Despite major improvements, there is still work to be done.[1]

In "Management of a rhegmatogenous retinal detachment in a low-resource setting: treatment options when there is no vitreoretinal surgeon," Emsley et all highlight the difficulty in management of opthalmological problems in low resource settings, where no subspecialists are present. The patient presented with a treatable retinal detachment and retinal tear, but, "Unfortunately, no access to any vitreoretinal trained personnel or vitrectomy equipment currently exists in Sierra Leone…. [T]he nearest facility in Ghana is 2018 km away and beyond the financial means of the patient." Despite presenting with vision acuity of 20/30 bilaterally, "At review 8 months later, the visual acuity had dropped to 6/36 and the retina had completely detached.

In the discussion, the authors present the incidence of rhegmatogenous retinal detachment in sub-Saharan Africa and Sierra Leone. Despite the growing prevalence of this disease and the "late presentation with advanced disease and secondary complications" in the developing world, only 15 subspecialty trained vitreoretinal surgeons practice in the region of Senegal to Kenya and Ethiopia to Tanzania. The lack of equipment and continued training for opthalmologic specialties is a well documented problem.[2] The need to develop a system for screening, referring and transporting patients to well-equipped tertiary care centers is also well-described.[3]

Despite steps in these directions, however, there are still countless patients suffering with no access to the necessary specialties—in this case, a vitreoretinal surgeon. Rather than forgoing any care, healthcare professionals with appropriate training can optimize the treatment with the resources they have available to them. Emsley et al excellently describe several interventions in there article that would have helped this patient without the need for a vitreoretinal surgeon. They focus on pneumatic retinopexy, "[T]he ideal treatment option for the case described above in this setting."

BMJ Case Reports invites authors to submit global health case reports that describe feasible interventions that could alleviate disease in low-resource settings. These cases could focus on:

  •  Interventions that have been successfully instituted in a low-resource area
  •  Potential interventions to help a vulnerable population
  •  Challenges to instituting an intervention in a low-resource setting
  •  Low-resource interventions that have aided individual patients

Manuscripts may be submitted by students, physicians, nurses and allied health professionals to BMJ Case Reports via the submission system. For more information, review our guidance on how to write a global health case report and look through our online collection.

To read more about interventions in low resource settings at BMJ Case Reports, please review:

To read more about opthalmologic care in the developing world, please review:

[1] World Health Organization. What is VISION 2020? [internet] Prevention of Blindness and Visual Impairment. WHO 2018. Accessed from: http://www.who.int/blindness/partnerships/vision2020/en/ on 3 May 2018

[2] Courtright P, Ndegwa L, Msosa J, Banzi J. Use of our existing eye care human resources: assessment of the productivity of cataract surgeons trained in eastern Africa. Archives of ophthalmology. 2007 May 1;125(5):684-7.

[3] Sommer A, Taylor HR, Ravilla TD, West S, Lietman TM, Keenan JD, Chiang MF, Robin AL, Mills RP. Challenges of ophthalmic care in the developing world. JAMA ophthalmology. 2014 May 1;132(5):640-4.

Competing Interests

None Declared



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Making a Difference with Individual Patients-Health Equity, Power, and Dignity

By Nathan Douthit

   At another session of CUGH's Annual Meeting, Richard Horton, Editor in Chief of the Lancet, debated Cheryl Heaton, director of New York University's Global Institute of Public Health, on the subject: Equity is the defining objective of global health in the 21st century. Heaton argued in favour of the motion, saying that our past neglect has created high reservoirs of need around the world. She made the point that equity creates hope and optimism in vulnerable populations, which turn motivate their ability to bring about change.

   While Horton agreed that equity is a valuable and admirable goal, he argued that global health, as it is currently framed, makes this impossible to achieve. He argued that global health "is not about equity; it is about power", with power held by the privileged. He continued "before there can be equity, individuals must have liberty and power over their lives." Further, liberty requires that all humans be recognized for their dignity. Dignity affirms that every individual is an end unto themselves; not a means to our ends. "Without dignity, there can be no equity." Horton concluded that our obligation is to challenge authorities that deny liberty. We must discharge this obligation if we are to see the dignity of individual patients recognized.

   BMJ Case Reports is committed to recognizing the dignity and worth of individual patients. Our case reports focus on patients at the center of clinical medicine and global health. While our clinical case reports highlight the challenges of dealing with disease, our global health case reports shed light on the determinants of health and disease: the environments in which patients live and work; education and financial well-being; access to healthcare; local and national politics; instability and conflict; the practice of corporations and industry; and, ethnic and cultural histories. Our authors argue for better living conditions and improvements in health at the level of the individual – working towards global health one patient at a time. Each patient is an end unto themselves. We encourage our authors to work with their patients in writing each global health case report and want to be not merely a repository of global health problems and solutions but a repository of patient voices from across the world.

   BMJ Case Reports invites authors to submit global health case reports that give voice to individual patients and uphold their dignity. These reports should examine the determinants of health:

  • The effects of culture and environment
  • Education and literacy
  • How occupation may exacerbate or cause disease
  • The effects of conflict, disaster, migration and poverty
  • Access to healthcare
  • The interventions and innovations put into place in global health to treat individual patients.
  • The disproportional effect of social determinants of health on vulnerable communities

   Manuscripts may be submitted by students, physicians, nurses and allied health professionals to BMJ Case Reports via the submission system. For more information, review our guidance on how to write a global health case report and look through our online collection.

Competing Interests

None Declared



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Anthracycline Use for Early Stage Breast Cancer in the Modern Era: a Review

Opinion statement

Anthracycline-based regimens have been an important treatment component for patients with breast cancer. As demonstrated in the last Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis, anthracycline-based regimens decrease breast cancer mortality by 20–30%. Anthracycline toxicities include the rare—but potential morbid—cardiotoxicity or leukemogenic effect, and the almost universal—but very distressing—alopecia. Due to potential toxicities, and large number of patients being exposed, several worldwide trials have re-examined the role of anthracycline-based regimens in the management of breast cancer. Current literature supports that anthracyclines are not required for all patients with breast cancer and should be avoided in those with high cardiac risk. Recent results from the ABC trials suggest that anthracyclines should not be spared for patients with triple negative breast cancer (regardless of axillary node involvement) or HER2−/ER+ with significant node involvement. Based on current literature, for HER2-negative patients with low-risk breast cancer, anthracyclines could be spared with regimens such as cyclophosphamide, methotrexate, and fluorouracil (CMF) or docetaxel and cyclophosphamide (TC). Patients with intermediate or high-risk breast cancer should be considered for anthracycline-based regimens based on other factors such as age, comorbidities, tumor grade, lymphovascular invasion, and genomic profiling. Patients with HER2-positive breast cancer with low risk could be treated with paclitaxel and trastuzumab. For the remaining patients with HER2 overexpression, while docetaxel, carboplatin, and trastuzumab (TCH) has demonstrated to improve disease-free survival (DFS), anthracycline-containing regimens should be discussed, especially for those with very high-risk breast cancer. Although several biomarkers, such as topoisomerase II (TOP2A) and chromosome 17 centromeric duplication (Ch17CEP) have been proposed to predict benefit from anthracycline regimens, further research is required to delineate their proper utility in the clinical setting.



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Visualization of Motor Axon Navigation and Quantification of Axon Arborization In Mouse Embryos Using Light Sheet Fluorescence Microscopy

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Here, we describe a protocol for visualizing motor neuron projection and axon arborization in transgenic Hb9::GFP mouse embryos. After immunostaining for motor neurons, we used light sheet fluorescence microscopy to image embryos for subsequent quantitative analysis. This protocol is applicable to other neuron navigation processes in the central nervous system.

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Evaluation of Exon Inclusion Induced by Splice Switching Antisense Oligonucleotides in SMA Patient Fibroblasts

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Various antisense oligonucleotides (AONs) have been shown to induce exon inclusion (splice modulation) and rescue SMN expression for spinal muscular atrophy (SMA). Here, we describe a protocol for AON lipotransfection to induce exon inclusion in the SMN2 gene and the evaluation methods to determine the efficacy in SMA patient fibroblasts.

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Surface Functionalization of Hepatitis E Virus Nanoparticles Using Chemical Conjugation Methods

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We have engineered the capsid protein of hepatitis E virus as a theranostic nanoparticle (HEVNP). HEVNP self-assembles into a stable icosahedral cage in mucosal delivery. Here, we describe the modification of HEVNPs for tumor targeting by mutating surface-exposed residues to cysteines, which conjugate synthetic ligands that specifically bind tumor cells.

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Influence of incomplete neoadjuvant chemotherapy on esophageal carcinoma

Abstract

Background

Neoadjuvant chemotherapy (NAC) involving two cycles of cisplatin plus fluorouracil is recommended in Japan as a standard treatment for resectable, locally advanced esophageal squamous cell carcinoma (ESCC). We have encountered patients who were administered incomplete chemotherapy because of adverse events or the patient's refusal of treatment. Here, we retrospectively investigated the influence on perioperative outcomes and long-term prognosis of patients with ESCC who underwent complete (two cycles) or incomplete (one cycle) NAC.

Methods

We retrospectively investigated 133 patients with locally advanced ESCC of the thoracic esophagus who underwent NAC. We compared the perioperative results and prognoses of patients who underwent complete or incomplete NAC because of adverse events or the patient's refusal of treatment.

Results

Of 133 patients, 37 patients did not receive the second cycle of NAC; the remaining 96 patients received the second cycle of NAC as scheduled. There were no significant differences in the clinical backgrounds, surgical results, or operative morbidity rates between the groups. Patients in both groups were similarly administered postoperative chemotherapy regimens. There was no significant difference in disease-free survival or overall survival.

Conclusions

We suggest that perioperative outcomes and long-term prognosis of patients with locally advanced ESCC were not significantly influenced, even if the patients did not receive a complete cycle of NAC. When certain adverse events occur after the first cycle of NAC, we believe that it is nevertheless possible to discontinue chemotherapy.



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Association of body mass index and outcomes following lobectomy for non-small-cell lung cancer

Abstract

Background

Obesity and overweight have become increasingly prevalent, but no consensus has been reached regarding the effect of body mass index (BMI) on surgical outcomes. In this study, we sought to examine the influence of BMI on perioperative outcomes in a large cohort of patients with non-small-cell lung cancer (NSCLC) who underwent lobectomy.

Methods

A retrospective study was conducted in 1198 patients who underwent lobectomy for primary NSCLC at Shandong Provincial Hospital between November 2006 and January 2017. BMI was calculated using measured height and weight on admission and categorized as obese (≥ 30 kg/m2), overweight (25 to 29.9 kg/m2), normal (18.5 to 24.9 kg/m2), or underweight (< 18.5 kg/m2). Patients' baseline characteristics and outcomes were abstracted from medical records following institutional review board approval. Endpoints included operative mortality, perioperative complications, and length of stay (LOS). Complications were divided into four groups as respiratory, cardiovascular, other, and overall. Logistic regression models were constructed to assess the association between BMI and adverse outcomes.

Results

When compared with normal BMI, obesity and overweight did not increase the risk of complications in any category, operative mortality, or prolonged LOS. In fact, the incidence of operative mortality and respiratory complications tended to be lower in overweight patients than in normal weight patients (P = 0.047 and P = 0.041, respectively). Conversely, underweight patients experienced significantly more operative mortality, respiratory complications, and prolonged LOS (P = 0.004, P = 0.011, and P = 0.003, respectively).

Conclusions

Obesity and overweight did not confer adverse surgical outcomes. Underweight patients presented increased risk of respiratory complications, perioperative death, and prolonged LOS. Thus, overweight and obesity should not be a relative contraindication for lobectomy. Meanwhile, nurses and surgeons should focus on perioperative management of underweight patients.



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Harnessing the evolutionary information on oxygen binding proteins through Support Vector Machines based modules

The arrival of free oxygen on the globe, aerobic life is becoming possible. However, it has become very clear that the oxygen binding proteins are widespread in the biosphere and are found in all groups of org...

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Ruptured caesarean scar ectopic pregnancy: a diagnostic dilemma in a resource-limited setting

Caesarean scar pregnancy (CSP) remains a very rare form of ectopic pregnancy associated with serious life threatening obstetric complications and even death in case of late diagnosis and treatment.

https://ift.tt/2rAMSGh

Prevalence and antimicrobial susceptibility patterns of methicillin-resistant Staphylococcus aureus among janitors of Mekelle University, North Ethiopia

The objective of this study was to determine the prevalence of methicillin-resistant Staphylococcus aureus and antimicrobial susceptibility patterns among janitors working at Mekelle University, Tigray, Northern ...

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Level of insulin adherence among diabetes mellitus patients in Felege Hiwot Referral Hospital, Bahir Dar, Northwest Ethiopia, 2017: a cross-sectional study

The objective of this study was to know the level of insulin adherence and to identify factors affecting insulin adherence among diabetes mellitus patients in Felege Hiwot Referral Hospital, Bahir Dar, Northwe...

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Misdiagnosis of pulmonary tuberculosis and associated factors in peripheral laboratories: a retrospective study, Addis Ababa, Ethiopia

Sputum smear microscopy reading errors are likely to result in failure to detect persons with infectious TB. This study was intended to review misdiagnosis of pulmonary TB and associated factors in peripheral ...

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Chronic Transcranial Electrical Stimulation and Intracortical Recording in Rats

This detailed protocol describes transcranial stimulation electrode placement on the temporal bone in order to investigate the short- and long-term effects of transcranial electrical stimulation in freely moving rats.

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Peripheral vascular disease assessment in the lower limb: a review of current and emerging non-invasive diagnostic methods

Worldwide, at least 200 million people are affected by peripheral vascular diseases (PVDs), including peripheral arterial disease (PAD), chronic venous insufficiency (CVI) and deep vein thrombosis (DVT). The h...

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Screening Blood Donations for Zika Virus Is Costly, Low Yield

FRIDAY, May 11, 2018 -- Screening blood donations for Zika virus (ZIKV) in the United States is costly with low yield, according to a study published in the May 10 issue of the New England Journal of Medicine. Paula Saá, Ph.D. from the American Red...

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Fx Risk Should Be Monitored in Bisphosphonate Drug Holiday

FRIDAY, May 11, 2018 -- For patients with osteopenia or osteoporosis, taking a bisphosphonate (BP) drug holiday is associated with increased risk of fracture for patients with lower femoral neck bone mineral density (BMD) or T scores, according to a...

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Many Dispensaries in CO Proffer Marijuana for Morning Sickness

FRIDAY, May 11, 2018 -- More than two-thirds of Colorado cannabis dispensaries recommend cannabis products to treat nausea during the first trimester of pregnancy, according to a study published online May 7 in Obstetrics & Gynecology. Betsy...

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CKAP4 Is Novel Serodiagnostic Marker for Lung Cancer

FRIDAY, May 11, 2018 -- Cytoskeleton-associated protein 4 (CKAP4) appears to be a novel serodiagnostic marker for lung cancer, with increased levels in lung cancer patients versus healthy controls, according to a study published online May 8 in The...

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Hemorrhage Control Training Is Beneficial for Laypersons

FRIDAY, May 11, 2018 -- Hemorrhage control training for laypersons is the most efficacious method for controlling hemorrhaging, according to a study published online May 9 in JAMA Surgery. Eric Goralnick, M.D., from Brigham and Women's Hospital in...

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Objective Measures Needed for Assessing Nasal Obstruction

FRIDAY, May 11, 2018 -- The Nasal Obstruction Symptom Evaluation (NOSE) scale is an adequate subjective measure for assessing nasal airway obstruction (NAO), but more objective measures are required for diagnosis and treatment of NAO, according to a...

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Sofosbuvir Improves Renal Safety in Patients With Chronic Hep C

FRIDAY, May 11, 2018 -- Sofosbuvir-based treatment appears to guarantee renal safety for patients with chronic hepatitis C virus over one year of follow-up, according to a study published online May 7 in the Journal of Clinical Pharmacy and...

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Malnutrition Is Associated With Poor Prognosis in Heart Failure

FRIDAY, May 11, 2018 -- Patients with heart failure frequently have malnutrition, which is associated with increased mortality, according to a study published online May 9 in JACC: Heart Failure. Shirley Sze, M.B.B.S., from Hull York Medical School...

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Resistance Exercise May Reduce Depressive Symptoms in Adults

FRIDAY, May 11, 2018 -- Resistance exercise training (RET) is associated with reduced depressive symptoms among adults, according to a meta-analysis published online May 9 in JAMA Psychiatry. Brett R. Gordon, from the University of Limerick in...

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Initiative Cuts Overuse of Tests, Treatments for Bronchiolitis

FRIDAY, May 11, 2018 -- A multidisciplinary improvement initiative can reduce overuse of interventions for bronchiolitis, according to a study published online May 11 in Pediatrics. In an effort to reduce overuse of interventions for children with a...

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Physical interaction of STAT1 isoforms with TGF-β receptors leads to functional crosstalk between two signaling pathways in epithelial ovarian cancer

Abstract

Background

The signal transducer and activator of transcription (STAT) and transforming growth factor-β (TGF-β) signaling pathways play important roles in epithelial ovarian cancer (EOC). However, the mechanism of crosstalk between two pathways is not completely understood.

Methods

The expression of STAT1 protein was detected by tissue microarray and immunoblotting (IB). The interaction of STAT1 isoforms with TGF-β receptors was confirmed by immunoprecipitation and IB. The effect of TGF-β signaling on STAT1 activation was examined in EOC and non-tumorous HOSEpiC cells treated with TGF-β1 in the presence or absence of the inhibitor of TGF-β type I receptor. The gain-of-function and loss-of-function approaches were applied for detecting the role of STAT1 on EOC cell behaviours.

Results

The high level of STAT1 was observed in patients with high-grade serous EOC. STAT1 expression was higher in ovarian cancer cells than noncancerous cells. TGF-β1 activated the STAT1 pathway by inducing the phosphorylation of STAT1α on S727 residue. The full-length STAT1α and the truncated STAT1β directly interacted with TGF-β receptors (ALK1/ALK5 and TβRII), which was mediated by TGF-β1. STAT1α and STAT1β blocked the activation of the TGF-β1 signaling pathway in EOC cells by reducing Smad2 phosphorylation. STAT1 overexpression induced EOC cell proliferation, migration, and invasion; whereas its inhibition enhanced TGF-β1-induced phospho-Smad2 and suppressed EOC cell proliferation, migration, and invasion.

Conclusions

Our data unveil a novel insight into the molecular mechanism of crosstalk between the STAT1 and TGF-β signaling pathways, which affected the cancer cell behavior. Suppression of STAT1 may be a potential therapeutic strategy for targeting ovarian cancer.



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A cross-sectional and longitudinal study evaluating brain volumes, RNFL, and cognitive functions in MS patients and healthy controls

The principal biomarker of neurodegeneration in multiple sclerosis (MS) is believed to be brain volume, which is associated with cognitive functions and retinal nerve fibre layer (RNFL). A cross-sectional and ...

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The Role of Adiposity in the Association between Muscular Fitness and Cardiovascular Disease

To test the associations of muscular fitness and body mass index (BMI), individually and combined, with clustered cardiovascular disease risk factors in children and adolescents and to analyze the mediator role of BMI in the association between muscular fitness and clustered cardiovascular disease risk factors.

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Differences in Prehospital Patient Assessments for Pediatric Versus Adult Patients

To evaluate whether completion of vital signs assessments in pediatric transports by emergency medical services (EMS) differs by patient age.

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Methicillin-Resistant Staphylococcus aureus: The Effects Are More Than Skin Deep

To assess the psychosocial effects of a methicillin-resistant Staphylococcus aureus (MRSA) diagnosis on the households of children with MRSA skin and soft tissue infection (SSTI).

https://ift.tt/2G5uh9K

Mechanisms of immune evasion in breast cancer

Abstract

Tumors develop multiple mechanisms of immune evasion as they progress, with some cancer types being inherently better at 'hiding' than others. With an increased understanding of tumor immune surveillance, immunotherapy has emerged as a promising treatment strategy for breast cancer, despite historically being thought of as an immunologically silent neoplasm. Some types of cancer, such as melanoma, bladder, and renal cell carcinoma, have demonstrated a durable response to immunotherapeutic intervention, however, breast neoplasms have not shown the same efficacy. The causes of breast cancer's immune silence derive from mechanisms that diminish immune recognition and others that promote strong immunosuppression. It is the mechanisms of immune evasion in breast cancers that are poorly defined. Thus, further characterization is critical for the development of better therapies. This brief review will seek to provide insight into the possible causes of weak immunogenicity and immune suppression mediated by breast cancers and highlight current immunotherapies being used to restore immune responses to breast cancer.



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Antiproliferative and apoptotic effect of LY2090314, a GSK-3 inhibitor, in neuroblastoma in vitro

Abstract

Background

Neuroblastoma (NB) is a devastating disease. Despite recent advances in the treatment of NB, about 60% of high-risk NB will have relapse and therefore long-term event free survival is very minimal. We have reported that targeting glycogen synthase kinase-3 (GSK-3) may be a potential strategy to treat NB. Consequently, investigating LY2090314, a clinically relevant GSK-3 inhibitor, on NB cellular proliferation and may be beneficial for NB treatment.

Methods

The effect of LY2090314 was compared with a previously studied GSK-3 inhibitor, Tideglusib. Colorimetric, clonogenic, and live-cell image confluency assays were used to study the proliferative effect of LY2090314 on NB cell lines (NGP, SK-N-AS, and SH-SY-5Y). Western blotting and caspase glo assay were performed to determine the mechanistic function of LY2090314 in NB cell lines.

Results

LY2090314 treatment exhibited significant growth reduction starting at a 20 nM concentration in NGP, SK-N-AS, and SH-SY-5Y cells. Western blot analysis indicated that growth suppression was due to apoptosis as evidenced by an increase in pro-apoptotic markers cleaved PARP and cleaved caspase-3 and a reduction in the anti-apoptotic protein, survivin. Further, treatment significantly reduced the level of cyclin D1, a key regulatory protein of the cell cycle and apoptosis. Functionally, this was confirmed by an increase in caspase activity. LY2090314 treatment reduced the expression levels of phosphorylated GSK-3 proteins and increased the stability of β-catenin in these cells.

Conclusions

LY2090314 effectively reduces growth of both human MYCN amplified and non-amplified NB cell lines in vitro. To our knowledge, this is the first study to look at the effect of LY2090314 in NB cell lines. These results indicate that GSK-3 may be a therapeutic target for NB and provide rationale for further preclinical analysis using LY2090314.



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Prevalence of the potentially inappropriate Kampo medications to be used with caution among elderly patients taking any prescribed Kampo medications at a single centre in Japan: a retrospective cross-sectional study

Few studies have investigated the prevalence and characteristics of potentially inappropriate Kampo medication use among elderly ambulatory patients taking any prescribed Kampo medications.

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Use of Two Intracorporeal Ventricular Assist Devices As a Total Artificial Heart

Here, we present a protocol using two centrifugal pumps as a total artificial heart replacement.

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Regulatory mechanism of microRNA-377 on CDH13 expression in the cell model of Alzheimer’s disease

OBJECTIVE: To explore whether microRNA-377 could participate in the development of Alzheimer's disease (AD) by regulating CDH13.

MATERIALS AND METHODS: In this research, AD model was constructed by the SH-SY5Y cells. The expression levels of microRNA-377 and CDH13 in the AD model were detected by quantitative Real-time polymerase chain reaction (qRT-PCR). The cell viability and apoptosis after knockdown of microRNA-377 and CDH13 were measured by cell counting kit-8 (CCK-8) assay and flow cytometry, respectively. The regulatory mechanism of microRNA-377 on CDH13 was confirmed by dual-luciferase reporter gene assay, qRT-PCR and Western blot.

RESULTS: Downregulated microRNA-377 and upregulated CDH13 were observed after successful construction of the AD model. Cell viability in the AD model group was significantly reduced compared with that of the control group. Moreover, downregulated microRNA-377 could further inhibit the cell viability, which was reversed by CDH13 knockdown. Cell apoptosis in the AD model group was enhanced after microRNA-377 knockdown, which was rescued by decreasing the expression level of CDH13. MicroRNA-377 was confirmed to regulate the expression level of CDH13 by dual-luciferase reporter gene assay, qRT-PCR and Western blot.

CONCLUSIONS: MicroRNA-377 could regulate the expression level of CDH13 by promoting cell proliferation and inhibiting cell apoptosis, thus participating in the occurrence of the Alzheimer's disease.

L'articolo Regulatory mechanism of microRNA-377 on CDH13 expression in the cell model of Alzheimer's disease sembra essere il primo su European Review.



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Ptprj-as1 mediates inflammatory injury after intracerebral hemorrhage by activating NF-κB pathway

OBJECTIVE: We aimed at investigating the expression of long non-coding RNA (lncRNA) Ptprj-as1 and the role of lncRNAPtprj-as1 in inflammatory cells after intracerebral hemorrhage and its potential mechanism.

MATERIALS AND METHODS: The rat model of intracerebral hemorrhage was established. Expressions of Ptprj-as1 and inflammatory cytokines in inflammatory cells were detected by quantitative Real-time PCR (qRT-PCR). After BV2 cells were transfected with lentivirus, cell proliferation, migrative ability and apoptosis were detected by cell counting kit-8 (CCK-8) assay, transwell chamber and flow cytometry, respectively. Immunofluorescence was used to explore the ratio of M1 and M2 glial cells. The detection of tumor necrosis factor alpha (TNF-α) expression was performed using enzyme-linked immunosorbent assay (ELISA). Moreover, the expressions of key genes in NF-κB pathway were evaluated using Western blot.

RESULTS: Ptprj-as1 was highly expressed in inflammatory tissues caused by intracerebral hemorrhage (ICH). Overexpressed Ptprj-as1 promoted the migration of BV2 cells and expression levels of inflammatory cytokines such as TNF-α, interleukin-1β (IL-1β), interleukin-6 (IL-6), iNOS and NO. Meanwhile, Ptprj-as1 enhanced the proportion of M1 glial cells, the mechanism of which might be related to the activation of NF-κB pathway.

CONCLUSIONS: Ptprj-as1 activates NF-κB pathway in microglia and promotes the secretion of inflammatory cytokines, which is involved in inflammatory injury caused by intracerebral hemorrhage.

L'articolo Ptprj-as1 mediates inflammatory injury after intracerebral hemorrhage by activating NF-κB pathway sembra essere il primo su European Review.



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Study of molecular mechanisms of learning and memory impairment in neonatal rats post intrauterine distress via the pathway of Tau protein hyperphosphorylation

OBJECTIVE: To explore the reversion of the excitatory amino acid receptor antagonists against the impairment of learning-memory and the hyperphosphorylation of protein Tau induced by fetal intrauterine distress in neonatal rats.

MATERIALS AND METHODS: The analysis of variance of factorial design set up two intervention factors, fetal intrauterine distress (two levels: no fetal intrauterine distress and a course of fetal intrauterine distress) and the excitatory amino acid receptor antagonists (three levels: Saline; NMDA receptor antagonist MK-801; astragalosides). Forty-eight pregnant rats were randomly divided into six experimental groups (n=8, in each group). After the end of the fetal intrauterine distress, the pregnant rats continued until the birth of newborn rats. When the neonatal rats grow to 12W, the Morris water maze test started in order to evaluate learning-memory. The hippocampus was removed from newborn rats within 1 day after the Morris water maze test finished. The content of glutamate in the hippocampus of rats was detected by high performance liquid chromatography. Besides, the content of protein Tau including Tau5 (total protein Tau), p-PHF1Ser396/404, p-AT8Ser199/202, p-12E8Ser262 in the hippocampus of rats, was examined with the method of immunohistochemistry (IHC) staining (SP).

RESULTS: Fetal intrauterine distress and the glutamate ionic receptor blockers could induce the impairment of learning-memory in neonatal rats, extending the evasive latency time and shorten the space exploration time. Both influences present subtract effect. Fetal intrauterine distress could significantly up-regulate the content of glutamate in the hippocampus of neonatal rats, which was not affected by the glutamate ionic receptor blockers. Fetal intrauterine distress and the glutamate ionic receptor blockers did not affect the total protein Tau in the hippocampus of rats. Moreover, fetal intrauterine distress could increase the hyperphosphorylation of protein Tau in the hippocampus of neonatal rats, which were reduced by the glutamate ionic receptor blockers. Both influences presented subtract effect.

CONCLUSIONS: We showed that fetal intrauterine distress upregulates the content of glutamate in the hippocampus of neonatal rats, up-regulating the hyperphosphorylation of protein Tau and inducing the impairment of learning-memory in neonatal rats.

L'articolo Study of molecular mechanisms of learning and memory impairment in neonatal rats post intrauterine distress via the pathway of Tau protein hyperphosphorylation sembra essere il primo su European Review.



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MicroRNA-23a-3p promotes the perihematomal edema formation after intracerebral hemorrhage via ZO-1

OBJECTIVE: To explore the relationship between microRNA-23a-3p expression and perihematomal edema (PHE) in patients with acute intracerebral hemorrhage (ICH) and its underlying mechanism.

PATIENTS AND METHODS: Clinical data and blood samples on the 3rd day after ICH onset were collected. Head CT was performed in each subject when admitted. Serum expressions of microRNAs were detected by quantitative real-time PCR (qRT-PCR). The relationship between hematoma volume and perihematomal edema was analyzed by correlation analysis. The direct binding of microRNA-23a-3p and zonula occludens-1 (ZO-1) was verified by luciferase activity assay and Western blot, respectively. Moreover, in vitro experiments were carried out by flow cytometry and CCK-8 assay, respectively.

RESULTS: Serum levels of microRNA-23a-3p and microRNA-130a in ICH patients were remarkably higher than those in the control group, microRNA-26a and microRNA-146a, however, were significantly decreased. A positive correlation was observed between the microRNA-23a-3p expression and the volume of relative perihematomal edema (rPHE) on the 3rd day after ICH (r2=0.3985; p=0.0002). Up-regulation of microRNA-23a-3p significantly decreased ZO-1 expression in hCMEC/D3 cells. Results of luciferase activity assay further indicated that microRNA-23a-3p directly targets the wild-type of ZO-1. In vitro results suggested that microRNA-23a-3p expression markedly affects the proliferation and apoptosis of hCMEC/D3 cells. Similar results were obtained after overexpression or knockdown of ZO-1.

CONCLUSIONS: Up-regulated microRNA-23a-3p in ICH patients promotes the apoptosis of cerebral vascular endothelial cells by down-regulatingZO-1, thus participating in the perihematomal edema formation after intracerebral hematoma.

L'articolo MicroRNA-23a-3p promotes the perihematomal edema formation after intracerebral hemorrhage via ZO-1 sembra essere il primo su European Review.



https://ift.tt/2I9e3Cs

LncRNA MEG3 participates in neuronal cell injury induced by subarachnoid hemorrhage via inhibiting the Pi3k/Akt pathway

OBJECTIVE: To explore the effect of LncRNA MEG3 in the subarachnoid hemorrhage (SAH) and its underlying mechanism.

PATIENTS AND METHODS: The expressions of lncRNA MEG3 in SAH patients and animal model were detected by quantitative real-time PCR (qRT-PCR). After LncRNA MEG3 was overexpressed in neurons by lentivirus, viability and apoptosis abilities were detected by cell counting kit-8 (CCK-8) assay, flow cytometry, and TUNEL assay, respectively. The apoptosis-related genes and Pi3k/Akt pathway-related proteins were further detected by a Western blot.

RESULTS: The expressions of lncRNA MEG3 in SAH patients were remarkably higher than normal controls, which were positively correlated with SAH severity. After lncRNA MEG3 overexpression, neuronal cell activity was decreased and cell apoptosis was increased. Moreover, the expressions of Bax, p53, and cleaved Caspase-3 were increased, whereas the expression of Bcl-2 and Pi3k/Akt pathway-related proteins were decreased after lncRNA MEG3 overexpression.

CONCLUSIONS: LncRNA MEG3 is up-regulated in SAH, which may promote SAH-induced neuronal cell injury via inhibition of the Pi3k/Akt pathway.

L'articolo LncRNA MEG3 participates in neuronal cell injury induced by subarachnoid hemorrhage via inhibiting the Pi3k/Akt pathway sembra essere il primo su European Review.



https://ift.tt/2rAiR8J

Correlations of neuronal apoptosis with expressions of c-Fos and c-Jun in rats with post-ischemic reconditioning damage

OBJECTIVE: Transcription factors (c-Fos and c-Jun) have been considered to play roles in the initiation of programmed nerve cell death. However, the roles of c-Fos and c-Jun protein expressions in neuronal apoptosis of rats with post-ischemic reconditioning damage were not clarified. Therefore, the aim of this study was to investigate the correlations of protein expressions of c-Fos and c-Jun with neuronal apoptosis of rats with post-ischemic reconditioning damage.

MATERIALS AND METHODS: Rat models of post-ischemic reconditioning were established firstly. Then, apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) assay, and the gene expression levels of apoptosis-related proteins [cytochrome c (Cyt c), B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax)] were detected by reverse transcription-polymerase chain reaction (RT-PCR). Lastly, Western blotting was used to determine the protein expression levels of c-Fos and c-Jun, and the expressions of c-Fos and c-Jun in brain tissues of models were measured by immunohistochemistry.

RESULTS: Treatment group had significantly increased malonaldehyde (MDA) level and significantly decreased superoxide dismutase (SOD) activity in rat cortex compared with those in control group (p<0.05). The number of TUNEL positive cells in the right cortex of rats in the treatment group was clearly higher than that in control group. Among them, post-ischemic reperfusion group had reduced level of Bax in the cytoplasm, but increased Bax level in the mitochondrion, and lowered expression level of Bcl-2 in both mitochondrion and cytoplasm in comparison with control group. Dynamic detection results of c-Jun were in synchronization with those of apoptosis proteins, and maximum expression occurred at 24 h after treatment.

CONCLUSIONS: c-Jun may play a role in the initiation of apoptotic cell death in these neurons.

L'articolo Correlations of neuronal apoptosis with expressions of c-Fos and c-Jun in rats with post-ischemic reconditioning damage sembra essere il primo su European Review.



https://ift.tt/2KVxhJy

Works on heart, how about brain? Effect of hyperkalemia on focal cerebral ischemia/reperfusion injury in rats

OBJECTIVE: To investigate the effects of hyperkalemia on the brain after I/R in h transient middle cerebral artery occlusion (tMCAO) model.

MATERIALS AND METHODS: A total of 120 adult male SD rats were randomly assigned to four groups: (1) hyperkalemia 80 µg/g (HK80) group; (2) hyperkalemia 40 µg/g (HK40) group; (3) normal saline (NS) group; (4) sham (SH) group. The concentration of serum K+ was elevated in HK80 and HK40 groups. The transient middle cerebral artery occlusion (tMCAO) model was used to assess the effect of hyperkalemia on the brain after I/R. After 24 h reperfusion, the infarct volume and cell damage of rat's I/R brain tissue sections were analyzed. The concentration of K+, Ca2+ and calmodulin (CaM), the activity of Ca-ATPase, the expression of Western blot of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and Na+/Ca2+ exchanger 1 (NCX1), were also measured.

RESULTS: After 24 h reperfusion, compared with NS group, the two-hyperkalemia groups (HK80 and HK40) were with less infarct volume and cell damage, higher concentration of K+ but lower Ca2+ and CaM compared with NS group. The activity of Ca-ATPase was also elevated, the expression of CaMK II and NCX1 were down-regulated in the two hyperkalemia groups.

CONCLUSIONS: Hyperkalemia could also ameliorate the brain I/R injury by alleviating calcium overload inhibiting the activity of NCX1, lowering the concentration of Ca2+.

L'articolo Works on heart, how about brain? Effect of hyperkalemia on focal cerebral ischemia/reperfusion injury in rats sembra essere il primo su European Review.



https://ift.tt/2rBAx3I

A new framework for conceptualizing symptoms in frontotemporal dementia: from animal models to the clinic

Abstract
Behavioural-variant frontotemporal dementia is characterized by a number of ostensibly disparate clinical features, which have largely been considered independently. This Update proposes an integrated conceptual framework for these symptoms, by bringing together findings from animal studies, functional neuroimaging and behavioural neurology. The combined evidence indicates that many of the clinical symptoms––such as altered eating behaviour; overspending and susceptibility to scams; reduced empathy and socially inappropriate behaviour; apathy and stereotyped/ritualistic behaviour––can be conceptualized as a common underlying deficiency in goal-directed behaviour and the concomitant emergence of habits. This view is supported by similarities between the characteristic patterns of frontostriatal and insular atrophy in behavioural-variant frontotemporal dementia and the circuitry of homologous brain regions responsible for goal-directed and habitual behaviour in animals. Appreciating the impact of disturbance in goal-directed behaviour provides a new, integrated understanding of the common mechanisms underpinning prototypical clinical symptoms in behavioural-variant frontotemporal dementia. Furthermore, by drawing parallels between animal and clinical research, this translational approach has important implications for the development and evaluation of novel therapeutic treatments, from animal models through to behavioural interventions and clinical trials in humans.

https://ift.tt/2rznDTK

PSMA-PET based radiotherapy: a review of initial experiences, survey on current practice and future perspectives

Abstract

68Gallium prostate specific membrane antigen (PSMA) ligand positron emission tomography (PET) is an increasingly used imaging modality in prostate cancer, especially in cases of tumor recurrence after curative intended therapy. Owed to the novelty of the PSMA-targeting tracers, clinical evidence on the value of PSMA-PET is moderate but rapidly increasing. State of the art imaging is pivotal for radiotherapy treatment planning as it may affect dose prescription, target delineation and use of concomitant therapy.

This review summarizes the evidence on PSMA-PET imaging from a radiation oncologist's point of view. Additionally a short survey containing twelve examples of patients and 6 additional questions was performed in seven mayor academic centers with experience in PSMA ligand imaging and the findings are reported here.



https://ift.tt/2jQWfgQ

Stereotactic radiosurgery practice patterns for brain metastases in the United States: a national survey

Abstract

Background

Stereotactic radiosurgery (SRS) has emerged as an important modality for the treatment of intracranial metastases. There are currently few established guidelines delineating indications for SRS use and fewer still regarding plan evaluation in the treatment of multiple brain metastases.

Methods

An 18 question electronic survey was distributed to radiation oncologists at National Cancer Institute (NCI) designated cancer centers in the USA (60). Centers without radiation oncologists were excluded. Physicians who indicated that they do not prescribe SRS were excluded from the remaining survey questions. Sign test and Chi-square test were used to determine if responses differed significantly from random distribution.

Results

One hundred sixteen of the 697 radiation oncologists surveyed completed the questionnaire, representing 51 institutions. Sixty-two percent reported treating patients with brain metastases using SRS. Radiation oncologists prescribing SRS most commonly treat CNS (66.2%) and lung (49.3%) malignancies. SRS was used more frequently for < 10 brain metastases (73.7%; p < 0.0001) and whole brain radiation therapy (WBRT) for > 10 brain metastases (82.5%; p < 0.0001). The maximum number of lesions physicians were willing to treat with SRS without WBRT was 1–4 (40.4%) and 5–10 (42.4%) (p < 0.0001 compared to 11–15, 16–20 and no limit). The most important criteria for choosing SRS or WBRT were number of lesions (p < 0.0001) and performance status (p = 0.016). The most common margin for SRS was 0 mm (49.1%; p = 0.0021). The most common dose constraints other than critical structure was conformity index (84.2%) and brain V12 (61.4%). The LINAC was the most common treatment modality (54.4%) and mono-isocenter technique for multiple brain metastases was commonly used (43.9%; p = 0.23). Most departments do not have a policy for brain metastases treatment (64.9%; p = 0.024).

Conclusions

This is one of the first national surveys assessing the use of SRS for brain metastases in clinical practice. These data highlight some clinical considerations for physicians treating brain metastases with SRS.



https://ift.tt/2KhsZe3

Inhibition of glutamate oxaloacetate transaminase 1 in cancer cell lines results in altered metabolism with increased dependency of glucose

Abstract

Background

Glutamate oxaloacetate transaminase 1 (GOT1) regulates cellular metabolism through coordinating the utilization of carbohydrates and amino acids to meet nutrient requirements. KRAS mutated cancer cells were recently shown to rely on GOT1 to support long-term cell proliferation. The aim of the present study was to address the role of GOT1 in the metabolic adaption of cancer cells.

Methods

GOT1-null and knockdown cell lines were established through CRISPR/Cas9 and shRNA techniques. The growth properties, colony formation ability, autophagy and selected gene expression profiles were analysed. Glucose deprivation decreased the viability of the GOT1-null cells and rescue experiments were conducted with selected intermediates. The redox NADH/NAD+ homeostasis as well as lactate secretion were determined. GOT1 expression levels and correlation with survival rates were analysed in selected tumor databases.

Results

Inhibition of GOT1 sensitized the cancer cells to glucose deprivation, which was partially counteracted by oxaloacetate and phosphoenol pyruvate, metabolic intermediates downstream of GOT1. Moreover, GOT1-null cells accumulated NADH and displayed a decreased ratio of NADH/NAD+ with nutrient depletion. The relevance of GOT1 as a potential target in cancer therapy was supported by a lung adenocarcinoma RNA-seq data set as well as the GEO:GSE database of metastatic melanoma where GOT1 expression was increased. High levels of GOT1 were further linked to poor survival as analysed by the GEPIA web tool, in thyroid and breast carcinoma and in lung adenocarcinoma.

Conclusions

Our study suggests an important role of GOT1 to coordinate the glycolytic and the oxidative phosphorylation pathways in KRAS mutated cancer cells. GOT1 is crucial to provide oxaloacetate at low glucose levels, likely to maintain the redox homeostasis. Our data suggest GOT1 as a possible target in cancer therapy.



https://ift.tt/2wx8uIy

Uptake of three doses of HPV vaccine by primary school girls in Eldoret, Kenya; a prospective cohort study in a malaria endemic setting

Abstract

Background

All women are potentially at risk of developing cervical cancer at some point in their life, yet it is avoidable cause of death among women in Sub- Saharan Africa with a world incidence of 530,000 every year. It is the 4th commonest cancer affecting women worldwide with over 260,000 deaths reported in 2012. Low resource settings account for over 75% of the global cervical cancer burden. Uptake of HPV vaccination is limited in the developing world. WHO recommended that 2 doses of HPV vaccine could be given to young girls, based on studies in developed countries. However in Africa high rates of infections like malaria and worms can affect immune responses to vaccines, therefore three doses may still be necessary. The aim of this study was to identify barriers and facilitators associated with uptake of HPV vaccine.

Methods

A cross-sectional survey was conducted at Eldoret, Kenya involving 3000 girls aged 9 to 14 years from 40 schools. Parents/guardians gave consent through a questionnaire.

Results

Of all 3083 the school girls 93.8% had received childhood vaccines and 63.8% had a second HPV dose, and 39.1% had a third dose. Administration of second dose and HPV knowledge were both strong predictors of completion of the third dose. Distance to the hospital was a statistically significant risk factor for non-completion (P: 0.01).

Conclusions

Distance to vaccination centers requires a more innovative vaccine-delivery strategy and education of parents/guardians on cervical screening to increase attainment of the HPV vaccination.



https://ift.tt/2rA5JkI

Discovering novel SNPs that are correlated with patient outcome in a Singaporean cancer patient cohort treated with gemcitabine-based chemotherapy

Abstract

Background

Single Nucleotide Polymorphisms (SNPs) can influence patient outcome such as drug response and toxicity after drug intervention. The purpose of this study is to develop a systematic pathway approach to accurately and efficiently predict novel non-synonymous SNPs (nsSNPs) that could be causative to gemcitabine-based chemotherapy treatment outcome in Singaporean non-small cell lung cancer (NSCLC) patients.

Methods

Using a pathway approach that incorporates comprehensive protein-protein interaction data to systematically extend the gemcitabine pharmacologic pathway, we identified 77 related nsSNPs, common in the Singaporean population. After that, we used five computational criteria to prioritize the SNPs based on their importance for protein function. We specifically selected and screened six candidate SNPs in a patient cohort with NSCLC treated with gemcitabine-based chemotherapy.

Result

We performed survival analysis followed by hematologic toxicity analyses and found that three of six candidate SNPs are significantly correlated with the patient outcome (P < 0.05) i.e. ABCG2 Q141K (rs2231142), SLC29A3 S158F (rs780668) and POLR2A N764K (rs2228130).

Conclusions

Our computational SNP candidate enrichment workflow approach was able to identify several high confidence biomarkers predictive for personalized drug treatment outcome while providing a rationale for a molecular mechanism of the SNP effect.

Trial registration

NCT00695994. Registered 10 June, 2008 'retrospectively registered'.



https://ift.tt/2Kgwq4R

Prognostic value of total number of lymph nodes retrieved differs between left-sided colon cancer and right-sided colon cancer in stage III patients with colon cancer

Abstract

Background

The consensus is that a minimum of 12 lymph nodes should be analyzed at colectomy for colon cancer. However, right colon cancer and left colon cancer have different characteristics, and this threshold value for total number of lymph nodes retrieved may not be universally applicable.

Methods

The data of 63,243 patients with colon cancer treated between 2004 and 2012 were retrieved from the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Multivariate Cox regression analysis was used to determine the predictive value of total number of lymph nodes for survival after adjusting for lymph nodes ratio. The predictive value in left-sided colon cancer and right-sided colon cancer was compared. The optimal total number of lymph nodes cutoff value for prediction of overall survival was identified using the online tool Cutoff Finder. Survival of patients with high total number of lymph nodes (≥12) and low total number of lymph nodes (< 12) was compared by Kaplan–Meier analysis.

Results

After stratifying by lymph nodes ratio status, total number of lymph nodes≥12 remained an independent predictor of survival in the whole cohort and in right-sided colon cancer, but not in left-sided colon cancer. The optimal cutoff value for total number of lymph nodes was determined to be 11. Low total number of lymph nodes (< 11) was associated with significantly poorer survival after adjusting for lymph nodes ratio in all subgroups except in the subgroup with high lymph nodes ratio (0.5–1.0).

Conclusions

Previous reports of the prognostic significance of total number of lymph nodes on node-positive colon cancer were confounded by lymph nodes ratio. The 12-node standard for total number of lymph nodes may not be equally applicable in right-sided colon cancer and left-sided colon cancer.



https://ift.tt/2rGCnRZ

A Prospective Observational Study of Technical Difficulty With GlideScope-Guided Tracheal Intubation in Children

BACKGROUND: The GlideScope Cobalt is one of the most commonly used videolaryngoscopes in pediatric anesthesia. Although visualization of the airway may be superior to direct laryngoscopy, users need to learn a new indirect way to insert the tracheal tube. Learning this indirect approach requires focused practice and instruction. Identifying the specific points during tube placement, during which clinicians struggle, would help with targeted education. We conducted this prospective observational study to determine the incidence and location of technical difficulties using the GlideScope, the success rates of various corrective maneuvers used, and the impact of technical difficulty on success rate. METHODS: We conducted this observational study at our quaternary pediatric hospital between February 2014 and August 2014. We observed 200 GlideScope-guided intubations and documented key intubation–related outcomes. Inclusion criteria for patients were

https://ift.tt/2I7EoRf

Rates of Perioperative Respiratory Adverse Events Among Caucasian and African American Children Undergoing General Anesthesia

BACKGROUND: Perioperative respiratory adverse events (PRAEs) account for the major cause of morbidity and mortality in children undergoing general anesthesia. In our institutional clinical practice, we suspected that African American children experienced untoward respiratory events more frequently than other racial groups. Identification of high-risk groups can guide decision making in the perioperative period, and aggressive optimization of specific care can enhance safety and improve outcomes. METHODS: Data came from a retrospective chart review for records from August 2013 to December 2013. The primary aim was to compare the incidence of PRAEs among racial groups of young children at a single institution. We also analyzed factors that are potentially associated with a higher risk of PRAEs. There were 1148 records that met the inclusion criteria. Racial identities, PRAEs, and risk factors were identified. Logistic regression analysis was performed to evaluate differences in PRAEs among racial groups controlling for confounding variables. RESULTS: Of all 1148 patients, 62 (5.4%) had a PRAE. African American children had significantly higher incidences of PRAE (26/231, 11.4%) compared to Caucasian (27/777, 3.5%; P

https://ift.tt/2Ih2tRP

Burnout, Fatigue, Exhaustion: An Interdisciplinary Perspective on a Modern Affliction

No abstract available

https://ift.tt/2jNKuYp

Feasibility of Fully Automated Hypnosis, Analgesia, and Fluid Management Using 2 Independent Closed-Loop Systems During Major Vascular Surgery: A Pilot Study

Automated titration of intravenous anesthesia and analgesia using processed electroencephalography monitoring is no longer a novel concept. Closed-loop control of fluid administration to provide goal-directed fluid therapy has also been increasingly described. However, simultaneously combining 2 independent closed-loop systems together in patients undergoing major vascular surgery has not been previously detailed. The aim of this pilot study was to evaluate the clinical performance of fully automated hypnosis, analgesia, and fluid management using 2 independent closed-loop controllers in patients undergoing major vascular surgery before implementation within a larger study evaluating true patient outcomes. Accepted for publication March 30, 2018. Funding: Departmental. Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). A. Joosten and V. Jame contributed equally and share first authorship. Institutional review board: This study was approved by our Institutional Review Board (IRB) of Erasme Hospital (808 Route de Lennik, 1070 Bruxelles, Belgium). E-mail: helene.francois@erasme.ulb.ac.be. Reprints will not be available from the authors. Address correspondence to Alexandre Joosten, MD, Hopital ERASME, 808, Rt de Lennik, 1070 Brussels, Belgium. Address e-mail to Alexandre.Joosten@erasme.ulb.ac.be; joosten-alexandre@hotmail.com. © 2018 International Anesthesia Research Society

https://ift.tt/2IgEG47

Manual of Neuroanesthesia: The Essentials

No abstract available

https://ift.tt/2jOxz8z

Propensity Score Methods: Theory and Practice for Anesthesia Research

Observational data are often readily available or less costly to obtain than conducting a randomized controlled trial. With observational data, investigators may statistically evaluate the relationship between a treatment or therapy and outcomes. However, inherent in observational data is the potential for confounding arising from the nonrandom assignment of treatment. In this statistical grand rounds, we describe the use of propensity score methods (ie, using the probability of receiving treatment given covariates) to reduce bias due to measured confounders in anesthesia and perioperative medicine research. We provide a description of the theory and background appropriate for the anesthesia researcher and describe statistical assumptions that should be assessed in the course of a research study using the propensity score. We further describe 2 propensity score methods for evaluating the association of treatment or therapy with outcomes, propensity score matching and inverse probability of treatment weighting, and compare to covariate-adjusted regression analysis. We distinguish several estimators of treatment effect available with propensity score methods, including the average treatment effect, the average treatment effect for the treated, and average treatment effect for the controls or untreated, and compare to the conditional treatment effect in covariate-adjusted regression. We highlight the relative advantages of the various methods and estimators, describe analysis assumptions and how to critically evaluate them, and demonstrate methods in an analysis of thoracic epidural analgesia and new-onset atrial arrhythmias after pulmonary resection. Accepted for publication February 16, 2018. Funding: None. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Edward J. Mascha, PhD, Departments of Quantitative Health Sciences and Outcomes Research, Cleveland Clinic, 9500 Euclid Ave, P77-007, Cleveland, OH 44195. Address e-mail to maschae@ccf.org. © 2018 International Anesthesia Research Society

https://ift.tt/2IgF1np

Trainability of Cricoid Pressure Force Application: A Simulation-Based Study

BACKGROUND: Aspiration of gastric contents is a leading cause of airway management–related mortality during anesthesia practice. Cricoid pressure (CP) is widely used during rapid sequence induction to prevent aspiration. National guidelines for CP suggest a target force of 10 N before and 30 N after loss of consciousness. However, few studies have rigorously assessed whether clinicians can be trained to consistently achieve these levels of force. We hypothesized that clinicians can be trained effectively to deliver 10–30 N during application of CP. METHODS: Clinicians (attending anesthesiologist, anesthesiology residents, certified registered nurse anesthetists, or operating room nurses) applied CP on a Vernier force plate simulator with measurements taken at 4 time points over 60 seconds, 2 measurements before and 2 measurements after loss of consciousness. A successful cycle required all 4 time points to be within the target range (10 ± 5 and 30 ± 5 N, respectively). After baseline assessment (n = 100 clinicians), a subset of 40 participants volunteered for education on recommended force targets, underwent self-regulated practice, and then performed 30 1-minute cycles of high-frequency simulation analyzed by cumulative sum analysis to assess their change in performance. RESULTS: At baseline, 5 cycles (1.3% [confidence interval {CI}, 0.3%–2.50%]) out of 400 were successful. Performance improved after education and self-regulated practice (16% successful cycles [CI, 7.8%–25%]), and performance during the last 4 of 30 cycles was 45% (CI, 33%–58%). The odds of success increased over time (odds ratio, 1.1; P

https://ift.tt/2jOVODF

Should Total Intravenous Anesthesia Be Used to Prevent the Occupational Waste Anesthetic Gas Exposure of Pregnant Women in Operating Rooms?

No abstract available

https://ift.tt/2IgEOR9

Impact of 2 Distinct Levels of Mean Arterial Pressure on Near-Infrared Spectroscopy During Cardiac Surgery: Secondary Outcome From a Randomized Clinical Trial

BACKGROUND: Near-infrared spectroscopy (NIRS) is used worldwide to monitor regional cerebral oxygenation (rScO2) during cardiopulmonary bypass (CPB). Intervention protocols meant to mitigate cerebral desaturation advocate to increase mean arterial pressure (MAP) when cerebral desaturation occurs. However, the isolated effect of MAP on rScO2 is uncertain. The aim of the present study was in a randomized, blinded design to elucidate the effect of 2 distinct levels of MAP on rScO2 values during CPB. We hypothesized that a higher MAP would be reflected in higher rScO2 values, lower frequency of patients with desaturation, and a less pronounced cerebral desaturation load. METHODS: This is a substudy of the Perfusion Pressure Cerebral Infarct trial, in which we investigated the impact of MAP levels during CPB on ischemic brain injury after cardiac surgery. Deviation in rScO2 was a predefined outcome in the Perfusion Pressure Cerebral Infarct trial. Patients were randomized to low MAP (LMAP; 40–50 mm Hg) or high MAP (HMAP; 70–80 mm Hg) during CPB. CPB pump flow was fixed at 2.4 L/min/m2, and MAP levels were targeted using norepinephrine. Intraoperatively, NIRS monitoring was performed in a blinded fashion, with sensors placed on the left and right side of the patient's forehead. NIRS recordings were extracted for offline analysis as the mean value of left and right signal during prespecified periods. Mean rScO2 during CPB was defined as the primary outcome in the present study. RESULTS: The average MAP level during CPB was 67 mm Hg ± SD 5.0 in the HMAP group (n = 88) and 45 mm Hg ± SD 4.4 in the LMAP group (n = 88). Mean rScO2 was significantly lower in the HMAP group during CPB (mean difference, 3.5; 95% confidence interval, 0.9–6.1; P = .010). There was no difference in rScO2 values at specified time points during the intraoperative period between the 2 groups. Significantly more patients experienced desaturation below 10% and 20% relative to rScO2 baseline in the HMAP group (P = .013 and P = .009, respectively), and the cerebral desaturation load below 10% relative to rScO2 baseline was more pronounced in the HMAP group (P = .042). CONCLUSIONS: In a randomized blinded study, we observed that a higher MAP induced by vasopressors, with a fixed CPB pump flow, leads to lower mean rScO2 and more frequent and pronounced cerebral desaturation during CPB. The mechanism behind these observations is not clear. We cannot exclude extracranial contamination of the NIRS signal as a possible explanation. However, we cannot recommend increasing MAP by vasoconstrictors during cerebral desaturation because this is not supported by the findings of the present study. Accepted for publication March 27, 2018. Funding: None. The authors declare no conflicts of interest. Clinicaltrial.gov identifier for main study (Perfusion Pressure Cerebral Infarct trial): NCT02185885. Reprints will not be available from the authors. Address correspondence to Frederik Holmgaard, BMSc, Department of Cardiothoracic Anesthesiology, Heart Centre, Rigshospitalet, University of Copenhagen, Blegdamsvej 9 – DK-2100, Copenhagen, Denmark. Address e-mail to frederik.holmgaard@regionh.dk. © 2018 International Anesthesia Research Society

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