The selection of the most relevant molecular descriptors to describe a target variable in the context of QSAR (Quantitative Structure-Activity Relationship) modelling is a challenging combinatorial optimization problem. In this paper, a novel software tool for addressing this task in the context of regression and classification modelling is presented. The methodology that implements the tool is organized into two phases. The first phase uses a multiobjective evolutionary technique to perform the selection of subsets of descriptors. The second phase performs an external validation of the chosen descriptors subsets in order to improve reliability. The tool functionalities have been illustrated through a case study for the estimation of the ready biodegradation property as an example of classification QSAR modelling. The results obtained show the usefulness and potential of this novel software tool that aims to reduce the time and costs of development in the drug discovery process.
http://bit.ly/2IgFQkI
Σάββατο 16 Φεβρουαρίου 2019
MoDeSuS: A Machine Learning Tool for Selection of Molecular Descriptors in QSAR Studies Applied to Molecular Informatics
New Platinum(IV) and Palladium(II) Transition Metal Complexes of s-Triazine Derivative: Synthesis, Spectral, and Anticancer Agents Studies
New Pd(II) and Pt(IV) triazine complexes [Pt3(L1)2(Cl)9(H2O)3].3Cl.3H2O (1), [Pt3(L2)2(Cl)9(H2O)3].3Cl (2), [Pt3(L3)2(Cl)9(H2O)3].3Cl (3), [Pt2(L4)2(Cl)6(H2O)2] .2Cl.4H2O (4), [Pd3(L1)2(H2O)6] .3Cl2 (5), [Pd3(L2)2(H2O)6].3Cl2 (6), [Pd3(L3)2(H2O)6].3Cl2 (7), and [Pd2(L4)2(H2O)4].2Cl2 (8) were synthesized and well characterized using elemental analyses, molar conductance, IR, UV-Vis, magnetic susceptibility, 1H, 13C-NMR spectra, and thermal analyses. These analyses deduced that the L1, L2, and L3 ligands act as tridentate forming octahedral geometry with Pt(IV) metal ions and square planar geometry in case of Pd(II) complexes but the L4 ligand acts as bidentate chelate. The molar conductance values refer to the fact that all the prepared s-triazine complexes have electrolyte properties which are investigated in DMSO solvent. Surface morphology behaviors of prepared complexes have been scanned using TEM. The crystalline behavior of triazine complexes has been checked based on X-ray powder diffraction patterns. The antimicrobial activity of the free ligands and their platinum(IV) and palladium(II) complexes against the species Staphylococcus aureus (G+), Escherichia coli (G−), Aspergillus flavus, and Candida albicans has been carried out and compared with the standard one. The coordination of ligands towards metal ions makes them stronger bacteriostatic agents, thus inhibiting the growth of bacteria and fungi more than the free ligands. The cytotoxic assessment IC50 of the free ligands and its platinum(IV) complexes in vitro against human colon and lung cancer cell lines introduced a promising efficiency.
http://bit.ly/2GKaxMM
Gastroprotective Effects of Plants Extracts on Gastric Mucosal Injury in Experimental Sprague-Dawley Rats
Rubus crataegifolius (black raspberry, RF), Ulmus macrocarpa (elm, UL), and Gardenia jasminoides (cape jasmine, GJ) are well known for hundreds of years as folk medicines in China and Korea to treat various gastrointestinal disturbance. The present study evaluated the gastroprotective effects of these plants either single or in combination against HCl/EtOH-induced gastritis and indomethacin-induced ulcer in rat model. Stomach ulcer was induced by oral ingestions of HCl/EtOH or indomethacin. Treatment with RF, UL, and GJ separately or in combination was done 1 h before ulcer induction. On HCl/EtOH-induced gastritis RF, UL, and GJ at a dose of 150 mg/kg showed comparable antigastritis effect (less than 50% inhibition) with lesion index of 94.97±8.05, 108.48±11.51, and 79.10±9.77 mm compared to cimetidine (45.33±23.73 mm). However, the combination of RF, UL, and GJ at a dose of 150 mg/kg with a ratio of 50:50:50 showed remarkable antigastritis effect with 77% inhibition. The observed lesion index at a ratio of 50:50:50 was 23.34±9.11 mm similar to cimetidine (18.88±19.88 mm). On indomethacin-induced ulcer, RF and GJ showed 38.28% and 51.8% inhibition whereas UL showed around 17.73% inhibition at 150 mg/kg. Combination of RF, UL, and GJ at 150 mg/kg showed strong antigastritis effect with 83.71% inhibition. These findings suggest strong gastroprotective effect of combined extract. In addition, these plants showed significant antioxidant activity in DPPH scavenging assay and antilipid peroxidation activity. Combination of black raspberry, elm, and cape jasmine might be a significant systemic gastroprotective agent that could be utilized for the treatment and/or protection of gastritis and gastric ulcer.
http://bit.ly/2tnaYoo
The Green Synthesis of MgO Nano-Flowers Using Rosmarinus officinalis L. (Rosemary) and the Antibacterial Activities against Xanthomonas oryzae pv. oryzae
Recently, the use of herbs in the agriculture and food industry has increased significantly. In particular, Rosmarinus officinalis L. extracts have been reported to have strong antibacterial properties, which depend on their chemical composition. The present study displayed a biological method for synthesis of magnesium oxide (MgO) nano-flowers. The nano-flowers are developed without using any catalyst agent. Aqueous Rosemary extract was used to synthesize MgO nano-flowers (MgONFs) in stirring conditions and temperature at 70°C for 4 h. The mixture solution was checked by UV-Vis spectrum to confirm the presence of nanoparticles. The MgO nano-flowers powder was further characterized in this study by the X-ray diffraction, scanning electron microscopy, transmission electron microscopy, and Fourier transform infrared spectroscopy. In addition, bacteriological tests indicated that MgO nano-flowers significantly inhibited bacterial growth, biofilm formation, and motility of Xanthomonas oryzae pv. oryzae, which is the causal agent of bacterial blight disease in rice. The electronic microscopic observation showed that bacterial cell death may be mainly due to destroy of cell integrity, resulting in leakage of intracellular content. As recommended, the use of Rosemary extract is an effective and green way to produce the MgO nano-flowers, which can be widely used in agricultural fields to suppress bacterial infection.
http://bit.ly/2tnblzi
Reduced Patient-Reported Outcome Scores Associate with Level of Fibrosis in Patients with Nonalcoholic Steatohepatitis
Patient-reported outcomes (PROs) are used to measure patients' experience with their disease. However, there are few PRO data from patients with NASH. We collected data from the STELLAR clinical trials to assess PROs for NASH and advanced fibrosis.
http://bit.ly/2GMNtgv
Enrichment of CLDN18‐ARHGAP fusion gene in gastric cancers in young adults
Summary
Gastric cancer in young adults has been pointed out to comprise a subgroup associated with distinctive clinicopathological features, including an equal gender distribution, advanced disease and diffuse‐type histology. Comprehensive molecular analyses of gastric cancers have led to molecular‐based classifications and to specific and effective treatment options available. The molecular traits of gastric cancers in young adults await investigations, which should provide a clue to explore therapeutic strategies. Here we studied 146 gastric cancer patients diagnosed at the age of less than 40 years old at the Cancer Institute Hospital. Tumor specimens were examined for Helicobacter pylori infection, Epstein‐Barr virus positivity, and for the expression of mismatch repair genes to indicate microsatellite instability. Overexpression, gene amplifications and rearrangements of 18 candidate driver genes were examined by immunohistochemistry and fluorescence in situ hybridization. Besides small number of cases positive for Epstein‐Barr virus and microsatellite instability (n=2, each), we repeatedly found tumors having gene fusion between a tight‐junction protein claudin CLDN18 and a regulator of small G proteins ARHGAP in as many as 22 cases (15.1%), and RNA sequencing identified two novel types of the fusion. Notably, patients with the CLDN18‐ARHGAP fusion revealed association with aggressive disease and poor prognosis, even when grouped by their clinical stages. These observations indicate that a fusion gene between CLDN18 and ARHGAP is enriched in younger age‐onset gastric cancers, and its presence may contribute to their aggressive characteristics.
This article is protected by copyright. All rights reserved.
http://bit.ly/2SCkUJM
Validity and reliability of lower‐limb pulse‐wave velocity assessments using an oscillometric technique
NEW FINDINGS
What is the central question of this study? There is growing interest on the effects of sedentarism on central and peripheral cardiovascular health. To permit further investigation, including in larger epidemiological studies, there is a need to identify arterial health assessment tools that are valid (accurate) and reliable (precise), yet practical. What is the main finding and its importance? Lower‐limb vascular health (femoral‐ankle pulse‐wave velocity) can be determined in a supine position with accuracy and precision using an oscillometric‐based device. This technology may help further the understanding of the pathological mechanisms linking cardiovascular disease to sedentarism, including the interaction between peripheral and central vasculature.
ABSTRACT
Background
There is a growing interest in the deleterious effects of sedentary behaviour on lower‐limb arterial health. To permit further investigation, including in larger epidemiological studies, there is a need to identify lower‐limb arterial health assessment tools that are valid and reliable, yet simple to administer.
Purpose
This study sought to determine the validity and between‐day reliability of femoral‐ankle pulse‐wave velocity (faPWV) measures obtained using an oscillometric‐based device (SphygmocCor XCEL) in supine and seated positions. Doppler ultrasound (US) was used as the criterion.
Methods
A total of 47 healthy adults were recruited for validity (n = 32) and reliability (n = 15) analyses. Validity was determined by measuring faPWV in seated and supine positions using the XCEL and US devices, in a randomised order. Between‐day reliability was determined by measuring seated and supine faPWV using the XCEL on 3 different mornings, separated by a maximum of 7 days.
Results
The validity criteria (absolute standard error of estimate [aSEE] < 1.0 m s−1) was met in the supine (aSEE = 0.8 m s−1, 95% CI: 0.4‐1.0), but not the seated (aSEE = 1.2 m s−1, 95% CI: 1.1, 1.2) position. Intras‐class correlation coefficient estimates revealed the XCEL demonstrated good reliability in the supine position (ICC = 0.83, 95% CI: 0.65, 0.93), but poor reliability in the seated position (ICC = 0.29, 95% CI: 0.23, 0.63).
Conclusions
The oscillometric XCEL device can be used to determine lower‐limb PWV with acceptable validity and reliability in the conventionally recommended supine position, but not the seated position.
This article is protected by copyright. All rights reserved
http://bit.ly/2N8pzgF
Is the Mallampati Score Useful for Emergency Department Airway Management or Procedural Sedation?
We review the literature in regard to the accuracy, reliability, and feasibility of the Mallampati score as might be pertinent and applicable to emergency department (ED) airway management and procedural sedation. This 4-level pictorial tool was devised to predict difficult preoperative laryngoscopy and intubation, but is now also widely recommended as a routine screening element before procedural sedation. The literature evidence demonstrates that the Mallampati score is inadequately sensitive for the identification of difficult laryngoscopy, difficult intubation, and difficult bag-valve-mask ventilation, with likelihood ratios indicating a small and clinically insignificant effect on outcome prediction.
http://bit.ly/2DKN62X
Presenting Their Gendered Selves? How Women and Men Describe Who They Are, What They Have Done, and Why They Want the Job in Their Written Applications
Abstract
Occupational segregation is due, at least in part, to differences in what jobs women and men apply to and how they are evaluated. However, we know little about one mechanism that may relate to employers' evaluations and, therefore, to occupational segregation: how applicants present themselves to employers. Theories of gender presentation offer competing predictions of how applicants present themselves to employers and empirical studies have not fully examined the issue. We address this theoretical ambiguity and empirical gap by drawing upon 1124 randomly selected applications that U.S. women and men used to apply for the same high-status job. After conducting a content analysis, we found that women and men present themselves similarly in terms of why they want the job and what experiences they have, but differently in terms of who they are and what information they divulge. We conclude that different aspects of applications correspond to different theories of gender presentation, but that most of the evidence supports a perspective of minimal gender differences. The present study implies that one way to combat occupational segregation that occurs due to employers' essentialist beliefs is to point them to how women and men actually present themselves in their applications.
http://bit.ly/2GtryeU
Subtraction of Epstein‐Barr virus and microsatellite instability genotypes from the Lauren histotypes: combined molecular and histologic subtyping with clinicopathological and prognostic significance validated in a cohort of 1,248 cases
Limited studies investigated clinicopathological and prognostic significance of histologic and molecular subgroups of gastric cancer concurrently. We retrospectively enrolled 1,248 patients with gastric cancer who received radical gastrectomy with lymphadenectomy and classified these cases into the Epstein‐Barr virus (EBV)‐associated and microsatellite instability (MSI)‐associated subtypes by EBV‐encoded small RNA in situ hybridization and immunohistochemical stains for DNA mismatch repair proteins, respectively. The remaining cases were categorized as the Lauren intestinal and diffuse/mixed subtypes. The clinicopathological and prognostic significance of the subtypes was examined by statistical analysis. In total, 65 (5.2%), 116 (9.3%), 496 (39.7%), 431 (34.5%) and 140 (11.2%) cases were identified as EBV‐associated, MSI‐associated, intestinal, diffuse and mixed subtypes, respectively. The EBV‐associated, MSI‐associated, intestinal and diffuse/mixed subtypes exhibited distinctive clinicopathological characteristics, including differences in age, gender, stump cancer, gastric location, tumor size, TNM stage, margin involvement, lymphatic/perineural invasion, HER2 status, and recurrence pattern. The log‐rank test showed survival discrimination (P < 0.001), and the multivariate analysis identified EBV‐associated and MSI‐associated cases demonstrated better outcomes than the diffuse/mixed subtype (EBV, HR 0.464, 95% CI 0.296‐0.727, P = 0.001; MSI, HR 0.590, 95% CI 0.407‐0.856, P = 0.005). EBV‐associated lymphoepithelioma‐like carcinoma cases had the most favorable outcome (HR 0.138, 95% CI 0.033‐0.565, P = 0.006). In different clinical groups, the subtypes exhibited survival discrepancies. The EBV‐associated and D/M cases exhibited more favorable response to chemotherapy. In conclusion, this combined classification, in parallel with the molecular subtypes specified in the Cancer Genome Atlas study, have implications for the clinical management of gastric cancer.
This article is protected by copyright. All rights reserved.
http://bit.ly/2S9Tt4W
Mortality after breast cancer as a function of time since diagnosis by estrogen receptor status and age at diagnosis
Our aim was to estimate how long‐term mortality following breast cancer diagnosis depends on age at diagnosis, tumor estrogen receptor (ER) status, and the time already survived. We used the population‐based Australian Breast Cancer Family Study which followed‐up 1,196 women enrolled during 1992‐99 when aged <60 years at diagnosis with a first primary invasive breast cancer, over‐sampled for younger ages at diagnosis, for whom tumor pathology features and ER status were measured. There were 375 deaths (median follow‐up=15.7; range=0.8‐21.4, years). We estimated the mortality hazard as a function of time since diagnosis using a flexible parametric survival analysis with ER status a time‐dependent covariate. For women with ER‐negative tumors compared with those with ER‐positive tumors, 5‐year mortality was initially higher (P<.001), similar if they survived to 5 years (P=0.4), and lower if they survived to 10 years (P=0.02). The estimated mortality hazard for ER‐negative disease peaked at ~3 years post‐diagnosis, thereafter declined with time, and at 7 years post‐diagnosis became lower than that for ER‐positive disease. This pattern was more pronounced for women diagnosed at younger ages. Mortality was also associated with lymph node count (hazard ratio (HR) per 10 nodes=2.52 [95% CI:2.11‐3.01]) and tumor grade (HR per grade=1.62 [95% CI:1.34‐1.96]). The risk of death following a breast cancer diagnosis differs substantially and qualitatively with diagnosis age, ER status and time survived. For women who survive >7 years, those with ER‐negative disease will on average live longer, and more so if younger at diagnosis.
This article is protected by copyright. All rights reserved.
http://bit.ly/2X7MLjC
The Challenge of Accurate Spinal Growth Assessment in the Treatment of Early Onset Scoliosis with Growth-Friendly Systems
Publication date: Available online 16 February 2019
Source: The Spine Journal
Author(s): John T. Braun
http://bit.ly/2GNdbl5
Post-operative Direct Healthcare Costs of Lumbar Discectomy are Reduced with the Use of a Novel Annular Closure Device in High-Risk Patients
Publication date: Available online 15 February 2019
Source: The Spine Journal
Author(s): Jared Ament, Bart Thaci, Zhuo Yang, Adisa Kursumovic, Richard Bostelmann, Todd Lanman, J. Patrick Johnson, Susanne Fröhlich, Kee D. Kim
ABSTRACT
Background Context
Lumbar discectomy is a largely successful surgical procedure; however, reherniation rates in patients with large annular defects are as high as 27%. The expense associated with a revision surgery places significant burden on the healthcare system.
Purpose
To compare the direct healthcare costs through 5 years follow-up of conventional discectomy (Control) with those of discectomy supplemented by an adjunctive annular closure device (ACD) in high-risk patients with large annular defects.
Study Design
This was a cost-effectiveness study.
Methods
All-cause index level reoperations were reviewed from a multicenter, randomized controlled superiority trial (RCT) that allocated 554 high-risk discectomy patients with large annular defects to either control or ACD. Medicare and private insurer (Humana) direct costs were derived from a commercially available payer database to estimate costs in the U.S. healthcare system, including those associated with facility, surgeon, imaging, follow-up visits, physical therapy, and injections. A 50:50 split between Medicare and Commercial insurers was assumed for the base case analysis. The analysis was also performed on a 80:20 Commercial:Medicare payer basis. For the base case scenario, a 2-year time horizon and outpatient cost setting was established for the index procedure. Repeat discectomy was assumed to be performed on a 60:40 outpatient-to-inpatient basis. Complications requiring surgery, revisions, and/or fusion were assumed to be managed in the inpatient setting. Total costs of reoperation and per-patient costs of reoperation were compared between groups for both forms of insurers. One author received consulting fees of <$50,000 for the completion of this study, and the other eight authors did not have any financial associations with the current work. Funding for this study was provided by Intrinsic Therapeutics, but all analyses, interpretation, and writing were performed independently by the authors.
Results
At two years follow-up, use of the ACD reduced the rate of symptomatic reherniations in a large defect population to 13% compared to 25% in the control group (p < 0.001). This reduction in symptomatic reherniations in the ACD group translated to a savings of $2,802 per patient in direct healthcare costs compared to Control at 2 years and $5,315 per patient by 5 years based on 50% private and 50% public (Medicare) payer split. Under the scenario of 80:20 private:public insurance reimbursement, the estimated direct cost savings were $3,215 and $6,099 per patient at 2- and 5-years post-op, respectively, with the use of the ACD.
Conclusion
Symptomatic reherniation and reoperation rates were nearly double among control patients compared to ACD-treated patients, which translated to markedly greater per-patient healthcare costs in the control group, where the ACD was not used.
http://bit.ly/2tosJDE
Clinical Features and Prognostic Factors of Pediatric Spine Giant Cell Tumors: report of 31 clinical cases in a single center
Publication date: Available online 15 February 2019
Source: The Spine Journal
Author(s): Qi Jia, Guanghui Chen, Jiashi Cao, Xinghai Yang, Zhenhua Zhou, Haifeng Wei, Tielong Liu, Jianru Xiao
Abstract
BACKGROUND CONTEXT
Giant cell tumors (GCTs) of the bone are benign but locally aggressive. Pediatric spine giant-cell tumors (PSGCTs) have been infrequently reported in the literature because of the rarity of the disease.
PURPOSE
The purpose of this study was to define the overall occurrence rate of PSGCTs among all spinal GCTs in our center and investigate the clinical features and prognostic factors of this rare disease.
STUDY DESIGN
A retrospective review.
PATIENT SAMPLE
Thirty-one PSGCT patients, screened from 226 patients with spine GCTs who received treatment in our center between 1998 to 2017.
OUTCOME MEASURES
The clinical symptoms, neurologic status, radiologic manifestations, treatment, outcome, and complications were recorded and analyzed.
METHODS
The postoperative recurrence-free survival (RFS) rate was estimated by the Kaplan–Meier method. Factors with P values ≤0.1 were subjected to multivariate analysis for RFS by proportional hazard analysis, among which P values ≤0.5 were considered statistically significant.
RESULTS
A total of 31 (31/226, 13.7%) PSGCTs patients (9 male and 22 female) were included in the study, with a mean age of 15.9 years and a mean follow-up period of 85.1 (median 84.0; range 12–221) months. The majority of patients (80.6 %) were 14-18 years of age. Recurrence was detected in 12 (38.7%) of the 31 patients. Univariate and multivariate analyses suggested that Jaffe grade II-III was an adverse prognostic factor for RFS, while total spondylectomy and bisphosphonate treatment were positive prognostic factors.
CONCLUSIONS
Total en bloc spondylectomy (TES) is associated with excellent prognosis for PSGCTs, and total piecemeal spondylectomy is a viable alternative if TES is unfeasible. Long-term bisphosphonate administration could significantly reduce the recurrence risk of PSGCTs. Denosumab treatment is recommended, especially for advanced PSGCTs. Jaffe grade II-III is an adverse prognostic factor for recurrence.
http://bit.ly/2GKjSUV
Isolation of Embryonic Tissues and Formation of Quail-Chicken Chimeric Organs Using The Thymus Example
This article provides a method to isolate pure embryonic tissues from quail and chicken embryos that can be combined to form ex vivo chimeric organs.
http://bit.ly/2T2nc4t
Optimization, Test and Diagnostics of Miniaturized Hall Thrusters
http://bit.ly/2DK2A75
Beta-cell sensitivity to insulinotropic gut hormones is reduced after gastric bypass surgery
Objective
Postprandial hyperinsulinaemia after Roux-en Y gastric bypass (GB) has been attributed to rapid nutrient flux from the gut, and an enhanced incretin effect. However, it is unclear whether surgery changes islet cell responsiveness to regulatory factors. This study tested the hypothesis that β-cell sensitivity to glucagon like-peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) is attenuated after GB.
DesignTen non-diabetic subjects with GB, and 9 body mass index (BMI)-matched and age-matched non-surgical controls (CN) with normal glucose tolerance had blood glucose clamped at ~7.8 mM on three separate days. Stepwise incremental infusions of GLP-1 (15, 30, 60, 120 and 300 ng/LBkg/h), GIP (75, 150, 300, 600 and 1200 ng/LBkg/h) or saline were administered from 90 to 240 min and insulin secretion measured.
ResultsGB subjects had similar fasting glucose levels but lower fasting insulin compared with CN, likely due to increased insulin clearance. The average insulin secretion rates (ISRs) to 7.8 mM glucose were ~30% lower in GB relative to CN subjects. However, incretin-stimulated ISRs, adjusted for insulin sensitivity and glucose-stimulated insulin secretion, were even more attenuated in the GB subjects, by threefold to fourfold (AUCISR(90–240 min) during GLP-1 and GIP: 47±8 and 44±12 nmol in GB and 116±16 and 161±44 in CN; p<0.01).
ConclusionAfter GB, the sensitivity of insulin secretion to both glucose and incretins is diminished.
http://bit.ly/2NbnYGL
Effective therapeutic regimens in two South Asian countries with high resistance to major Helicobacter pylori antibiotics
Nepal and Bangladesh have a high prevalence of Helicobacter pylori with high resistance rates to clarithromycin, metronidazole, and levofloxacin. Here, we evaluated the susceptibility and genetic mutations of 5 a...
http://bit.ly/2X7nYw7
Extended-spectrum beta-lactamase production and multi-drug resistance among Enterobacteriaceae isolated in Addis Ababa, Ethiopia
The global emergence and spread of extended-spectrum beta-lactamases (ESBLs) producing Enterobacteriaceae have been threatening the ability to treat an infection. Hence, this study aimed to determine the prevalen...
http://bit.ly/2X5Nbae
Reproductive health services utilization and its associated factors among secondary school youths in Woreta town, South Gondar, North West Ethiopia: a cross sectional study
The aim of this study was to assess reproductive health service utilization and its associated factors among secondary school students in Woreta town, South Gondar, North east Ethiopia 2018.
http://bit.ly/2Efd93D
Elastic intramedullary nailing of the femur fracture in patients affected by osteogenesis imperfecta type 3: Indications, limits and pitfalls
Publication date: Available online 15 February 2019
Source: Injury
Author(s): Pietro Persiani, Lorena Martini, Filippo Maria Ranaldi, Anna Zambrano, Mauro Celli, Luca Celli, Patrizia D'Eufemia, Ciro Villani
ABSTRACT
Introduction
Patients with Osteogenesis Imperfecta (OI) Type 3 may exhibit both primitive deformities and secondary fracture malunions on a femoral level. The orthopaedic surgeon's objective is to cure the deformities in order to prevent fractures and to treat the fractures in order to prevent deformities, by using telescopic nails as the gold standard method of fixation. However, the titanium elastic nail (TEN) is indicated as a possible alternative in certain selected cases.
Materials and methods
The Centre for Congenital Osteodystrophy of the Sapienza University of Rome follows 485 patients with osteogenesis imperfecta. For the purpose of this study, we selected 36 patients with OI type 3 (15 females and 21 males), aged between 2 and 10 years old, who were surgically treated for femur fractures with Titanium Elastic Nail (TEN) from January 2007 to December 2009. In 12 cases a single TEN was implanted, while 24 of the cases were treated by implanting 2 TENs with the Sliding Nail (SN) technique. A retrospective evaluation was carried out by analysing the data from the medical charts and dossiers related to pain symptoms, knee and hip Range of Motion (ROM), any possible complications that could cause implant revisions (infections, nail slide failure, nail migration, traumatic events following surgery, delayed consolidation, epiphysiodesis).
Results
At the 60th post-surgical month, the revision rate was 75%, mostly due to migration, osteolysis, nail slide failure and nail fracture. The Kaplan-Meier's survival curve analysis showed a coefficient of 0.25 to 60 months (confidence interval -0.31 and 0.81).
Discussion
The percentage of complications and the high rate of revisions recorded in our sample confirm that telescopic nail is the gold standard in the treatment of femoral fractures in patients with OI type 3.
Conclusions
In patients under the age of 4, with narrow medullary canals, low life expectancy, few to nil rehabilitative prospectives or severe comorbidities, the use of TEN may be considered as a less invasive approach compared to telescopic nail surgery, however only temporarily, as it will still most probably require a surgical revision a few years down the line.
http://bit.ly/2DIvJzM
Nationwide epidemiology of carbapenem resistant Klebsiella pneumoniae isolates from Greek hospitals, with regards to plazomicin and aminoglycoside resistance
To evaluate the in vitro activities of plazomicin and comparator aminoglycosides and elucidate the underlying aminoglycoside resistance mechanisms among carbapenemase-producing K. pneumoniae isolates collected du...
http://bit.ly/2SDAtko
First case report of thyroid abscess caused by Helicobacter cinaedi presenting with thyroid storm
Helicobacter cinaedi is a microaerobic Gram-negative spiral-shaped bacterium that causes enteritis, cellulitis, and bacteremia in both immunocompromised and immunocompetent patients. While there have been increas...
http://bit.ly/2SBM2sv
A superiority of viral load over CD4 cell count when predicting mortality in HIV patients on therapy
CD4 cell count has been identified to be an essential component in monitoring HIV treatment outcome. However, CD4 cell count monitoring sometimes fails to predict virological failure resulting in unnecessary s...
http://bit.ly/2DJG3Yj
Etiology of acute otitis media and phenotypic-molecular characterization of Streptococcus pneumoniae isolated from children in Liuzhou, China
The etiology and epidemiology of acute otitis media (AOM) are poorly understood in China. This study aimed to describe the etiology of AOM and the phenotypic and molecular characteristics of AOM-causing Streptoco...
http://bit.ly/2DPqPkC
Cancers, Vol. 11, Pages 234: Exploring lncRNA-Mediated Regulatory Networks in Endometrial Cancer Cells and the Tumor Microenvironment: Advances and Challenges
Cancers, Vol. 11, Pages 234: Exploring lncRNA-Mediated Regulatory Networks in Endometrial Cancer Cells and the Tumor Microenvironment: Advances and Challenges
Cancers doi: 10.3390/cancers11020234
Authors: Peixin Dong Ying Xiong Junming Yue Sharon J. B. Hanley Noriko Kobayashi Yukiharu Todo Hidemichi Watari
Recent studies have revealed both the promise and challenges of targeting long non-coding RNAs (lncRNAs) to diagnose and treat endometrial cancer (EC). LncRNAs are upregulated or downregulated in ECs compared to normal tissues and their dysregulation has been linked to tumor grade, FIGO stage, the depth of myometrial invasion, lymph node metastasis and patient survival. Tumor suppressive lncRNAs (GAS5, MEG3, FER1L4 and LINC00672) and oncogenic lncRNAs (CCAT2, BANCR, NEAT1, MALAT1, H19 and Linc-RoR) have been identified as upstream modulators or downstream effectors of major signaling pathways influencing EC metastasis, including the PTEN/PI3K/AKT/mTOR, RAS/RAF/MEK/ERK, WNT/β-catenin and p53 signaling pathways. TUG1 and TDRG1 stimulate the VEGF-A pathway. PCGEM1 is implicated in activating the JAK/STAT3 pathway. Here, we present an overview of the expression pattern, prognostic value, biological function of lncRNAs in EC cells and their roles within the tumor microenvironment, focusing on the influence of lncRNAs on established EC-relevant pathways. We also describe the emerging classification of EC subtypes based on their lncRNA signature and discuss the clinical implications of lncRNAs as valuable biomarkers for EC diagnosis and potential targets for EC treatment.
http://bit.ly/2TMKkAV
Incidence and malignancy rates of indeterminate pediatric thyroid nodules
Background
The American Thyroid Association guidelines task force currently recommends definitive thyroidectomy or lobectomy after an indeterminate thyroid biopsy in children. This recommendation is based on evidence of a greater incidence and a higher risk of malignancy compared with adults in earlier pediatric studies. Such management may lead to overtreatment and unnecessary surgery for many children in the United States.
Methods
The objective of the current study was to re‐evaluate pediatric thyroid nodules and assess the overall percentages and malignancy rates for indeterminate thyroid biopsies in children. In total, 302 pediatric thyroid fine‐needle aspirations (FNAs) were analyzed retrospectively (2001‐2018). Distribution percentages and malignancy rates were calculated for each category of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC).
Results
Two indeterminate TBSRTC groups (atypia of undetermined significance/follicular lesion of undetermined significance and follicular neoplasm/suspicious for a follicular neoplasm) had much lower distribution percentages and malignancy rates compared with earlier pediatric series and American Thyroid Association guidelines. A meta‐analysis further supported these findings and demonstrated distinctly different malignancy rates for the indeterminate groups (atypia of undetermined significance/follicular lesion of undetermined significance, follicular neoplasm/suspicious for a follicular neoplasm, and suspicious for malignancy), suggesting the need for TBSRTC category‐specific management recommendations rather than a nondiscriminatory, up‐front surgical approach.
Conclusions
Adult patients with indeterminate preoperative thyroid cytopathology are followed by repeat biopsy and possibly molecular testing before undergoing definitive surgery. However, in children, the guidelines are considerably more aggressive and recommend definitive surgery after the first indeterminate thyroid biopsy. Here, the largest pediatric cohort to date with meta‐analysis is presented, and the authors propose a re‐evaluation of this up‐front approach to pediatric thyroid care.
http://bit.ly/2tmPesK
Antenatal care utilisation among Syrian refugees in Tehran: A respondent driven sampling method
Publication date: Available online 15 February 2019
Source: Women and Birth
Author(s): Mohsen Abbasi-Kangevari, Kamal Amin, Ali-Asghar Kolahi
Abstract
Aim
To assess the antenatal care utilisation among Syrian refugees in Tehran.
Methods
This cross-sectional study was performed in 2016 in Tehran. As the refugees live in the city, we used Respondent Driven Sampling method for finding participants. Data were collected from interviews by a newly graduated Syrian general practitioner.
Findings
In total, 231 women participated in the study. The mean (standard deviation) number of antenatal care visits was 3.73 (1.41) and 131(56.7%) women received at least four visits. The mean (standard deviation) number of antenatal care visits was higher among women with four or more living children compared with those with four or more: 3.47 (1.35); 95% confidence interval 3.28 to 3.66 vs. 2.82 (1.64); 95% confidence interval 2.25 to 3.40, p = 0.01. The mean (standard deviation) number of antenatal care visits was higher among women whose spouses had academic degrees compared with those with lower education: 4.13 (1.37); 95% confidence interval 3.86–4.40 vs. 3.28 (1.31); 95% confidence interval 3.05–3.52, p < 0.001.
Conclusions
Antenatal care utilisation of Syrian women in Tehran complied with neither national guidelines of Iran nor the recommendations of World Health Organization. However, antenatal care utilisation of Syrian women in Tehran was higher than the main destinations of Syrian refugees. Syrian women kept their own cultural behaviour in terms of antenatal care utilisation.
http://bit.ly/2GHtsrH
Cancers, Vol. 11, Pages 233: Comparison of Diagnosis-Specific Survival Scores for Patients with Small-Cell Lung Cancer Irradiated for Brain Metastases
Cancers, Vol. 11, Pages 233: Comparison of Diagnosis-Specific Survival Scores for Patients with Small-Cell Lung Cancer Irradiated for Brain Metastases
Cancers doi: 10.3390/cancers11020233
Authors: Dirk Rades Heinke C. Hansen Stefan Janssen Steven E. Schild
Diagnosis-specific survival scores including a new score developed in 157 patients with brain metastases from small-cell lung cancer (SCLC) receiving whole-brain radiotherapy (WBRT) with 30 Gy in 10 fractions (WBRT-30-SCLC) were compared. Three prognostic groups were designed based on the 6-month survival probabilities of significant or almost significant factors, (age, performance score, number of brain metastases, extra-cerebral metastasis). Six-month survival rates were 6% (6–11 points), 44% (12–14 points) and 86% (16–19 points). The WBRT-30-SCLC was compared to three disease-specific scores for brain metastasis from SCLC, the original and updated diagnosis-specific graded prognostic assessment DS-GPA classifications and the Rades-SCLC. Positive predictive values (PPVs) used to correctly predict death ≤6 months were 94% (WBRT-30-SCLC), 88% (original DS-GPA), 88% (updated DS-GPA) and 100% (Rades-SCLC). PPVs to predict survival ≥6 months were 86%, 75%, 76% and 100%. For WBRT-30-SCLC and Rades-SCLC, differences between poor and intermediate prognoses groups and between intermediate and favorable prognoses groups were significant. For both DS-GPA classifications, only the difference between poor and intermediate prognoses groups was significant. Of these disease-specific tools, Rades-SCLC appeared to be the most accurate in identifying patients dying ≤6 months and patients surviving ≥6 months after irradiation, followed by the new WBRT-30-SCLC and the DS-GPA classifications.
http://bit.ly/2SEuImn
Predicting the dose of vancomycin in ICU patients receiving different types of RRT therapy: a model‐based meta‐analytic approach
Aim
Previous pharmacokinetic (PK) studies have proposed various dosing regimens for vancomycin in intensive care unit (ICU) patients undergoing renal replacement therapy (RRT), but all are restricted to specific RRT modalities. To be useful in practice, a population PK model would need to predict vancomycin clearance during any RRT modality. Development of such a model is feasible using meta‐analysis of published summarised estimates of vancomycin PK parameters. Our aims were: i) to develop and validate a population PK model for vancomycin that takes into account any RRT modalities and ii) to predict vancomycin dosing for RRT patients in ICU.
Methods
Vancomycin pharmacokinetics were assumed to be two‐compartmental, total body clearance being the sum of non‐RRT clearance and RRT‐induced clearance. Drug disposition and non‐RRT clearance parameters were estimated by systematic review and meta‐analysis of previously published parameter estimates. The relationship between RRT‐induced clearance and RRT flowrate settings was assessed using a model‐based meta‐analysis. Prediction performances of the PK model were assessed using external data.
Results
The meta‐analyses of disposition parameters, non‐RRT clearance and RRT‐induced clearance included 11, 6 and 38 studies (84 RRT clearance measurements) respectively. The model performed well in predicting external individual PK data. Individual vancomycin concentrations during RRT were accurately predicted using Bayesian estimation based solely on pre‐RRT measurements.
Conclusions
The pharmacokinetic model allowed accurate prediction of the vancomycin pharmacokinetics during RRT in ICU patients. Based on the model of RRT‐induced clearance, an appropriate adjustment of the vancomycin dosing regimen could be proposed for any kind of flowrate settings.
http://bit.ly/2T1dzmA
Angiotensin–Neprilysin Inhibition in Acute Decompensated Heart Failure
New England Journal of Medicine, Ahead of Print.
http://bit.ly/2DKLczj
Neuro-Oncology Diet and risk of glioma
| Estimating survival for renal cell carcinoma patients with brain metastases: an update of the Renal Graded Prognostic Assessment tool Abstract Background Brain metastases are a common complication of renal cell carcinoma (RCC). Our group previously published the Renal Graded Prognostic Assessment (GPA) tool. In our prior RCC study (n = 286, 1985–2005), we found marked heterogeneity and variation in outcomes. In our recent update in a larger, more contemporary cohort, we identified additional significant prognostic factors. The purpose of this study is to update the original Renal-GPA based on the newly identified prognostic factors.Methods A multi-institutional retrospective institutional review board–approved database of 711 RCC patients with new brain metastases diagnosed from January 1, 2006 to December 31, 2015 was created. Clinical parameters and treatment were correlated with survival. A revised Renal GPA index was designed by weighting the most significant factors in proportion to their hazard ratios and assigning scores such that the patients with the best and worst prognoses would have a GPA of 4.0 and 0.0, respectively.Results The 4 most significant factors were Karnofsky performance status, number of brain metastases, extracranial metastases, and hemoglobin. The overall median survival was 12 months. Median survival for GPA groups 0–1.0, 1.5–2.0, 2.5–3, and 3.5–4.0 (% n = 25, 27, 30 and 17) was 4, 12, 17, and 35 months, respectively.Conclusion The updated Renal GPA is a user-friendly tool that will help clinicians and patients better understand prognosis, individualize clinical decision making and treatment selection, provide a means to compare retrospective literature, and provide more robust stratification of future clinical trials in this heterogeneous population. To simplify use of this tool in daily practice, a free online application is available at brainmetgpa.com.
|
| Highlights from the Literature |
| Forthcoming Meetings Edited by Albert H. Kim and Jennie W. Taylor |
| Glioblastoma: a prognostic value of AMT-PET? See the article by John et al, pp. 264–273. |
| Old meet new—the path to combination treatments in pediatric low-grade gliomas See the article by Poore et al, pp. 252–263. |
| Disparities along the glioblastoma clinical trials landscape We read with interest the recent work by Vanderbeek et al1 regarding the current clinical trials landscape for glioblastoma (GBM) patients. An unexplored dimension of their analysis centers on disparities and demographic discrepancies between clinical trial participants and the broader GBM population. We therefore examined clinical trials with published results as highlighted by the authors, totaling 51 trials.1 While most of these trials reported details regarding patient age (48/51, 94%) and gender (47/51, 92%), only 14 trials (27%) provided information regarding ethnicity and/or race in either peer-reviewed publications or ClinicalTrials.gov. The rate of reporting ethnicity/race was particularly low among phase I/II studies (9/43, 21%) compared with phase III trials (5/8, 63%, chi-squared test P = 0.02). |
| Multimodal imaging-defined subregions in newly diagnosed glioblastoma: impact on overall survival Abstract Background Although glioblastomas are heterogeneous brain-infiltrating tumors, their treatment is mostly focused on the contrast-enhancing tumor mass. In this study, we combined conventional MRI, diffusion-weighted imaging (DWI), and amino acid PET to explore imaging-defined glioblastoma subregions and evaluate their potential prognostic value.Methods Contrast-enhanced T1, T2/fluid attenuated inversion recovery (FLAIR) MR images, apparent diffusion coefficient (ADC) maps from DWI, and alpha-[11C]-methyl-L-tryptophan (AMT)-PET images were analyzed in 30 patients with newly diagnosed glioblastoma. Five tumor subregions were identified based on a combination of MRI contrast enhancement, T2/FLAIR signal abnormalities, and AMT uptake on PET. ADC and AMT uptake tumor/contralateral normal cortex (T/N) ratios in these tumor subregions were correlated, and their prognostic value was determined.Results A total of 115 MRI/PET-defined subregions were analyzed. Most tumors showed not only a high-AMT uptake (T/N ratio > 1.65, N = 27) but also a low-uptake subregion (N = 21) within the contrast-enhancing tumor mass. High AMT uptake extending beyond contrast enhancement was also common (N = 25) and was associated with low ADC (r = −0.40, P = 0.05). Higher AMT uptake in the contrast-enhancing tumor subregions was strongly prognostic for overall survival (hazard ratio: 7.83; 95% CI: 1.98–31.02, P = 0.003), independent of clinical and molecular genetic prognostic variables. Nonresected high-AMT uptake subregions predicted the sites of tumor progression on posttreatment PET performed in 10 patients.Conclusions Glioblastomas show heterogeneous amino acid uptake with high-uptake regions often extending into non-enhancing brain with high cellularity; nonresection of these predict the site of posttreatment progression. High tryptophan uptake values in MRI contrast-enhancing tumor subregions are a strong, independent imaging marker for longer overall survival. |
| Supratotal resection in glioma: a systematic review Abstract Background Emerging evidence suggests survival benefit from resection beyond all MRI abnormalities present on T1-enhanced and T2‒fluid attenuated inversion recovery (FLAIR) modalities in glioma (supratotal resection); however, the quality of evidence is unclear. We addressed this question via systematic review of the literature.Methods EMBASE, MEDLINE, Scopus, and Web of Science databases were queried. Case studies, reviews or editorials, non-English, abstract-only, brain metastases, and descriptive works were excluded. All others were included.Results Three hundred and nine unique references yielded 41 studies for full-text review, with 7 included in the final analysis. Studies were mostly of Oxford Center for Evidence-Based Medicine Level 4 quality. A total of 88 patients underwent supratotal resection in a combined cohort of 492 patients (214 males and 278 females, age 18 to 82 years). Fifty-one supratotal resections were conducted on high-grade gliomas, and 37 on low-grade gliomas. Karnofsky performance status, overall survival, progression-free survival, neurological deficits postoperatively, and anaplastic transformation were the main measured outcomes. No randomized controlled trials were identified. Preliminary low-quality support was found for supratotal resection in increasing overall survival and progression-free survival for both low-grade and high-grade glioma.Conclusion The literature suggests insufficient evidence for carte blanche application of supratotal resection, particularly in lower-grade gliomas where neurological deficits can result in long-term disability. While the preliminary studies discussed here, containing data from only a few centers, have reported increased progression-free and overall survival, these claims require validation in prospective research studies involving larger patient populations with clearly defined appropriate outcome metrics in order to reduce potential bias. |
| Uncommon low-grade brain tumors Abstract The 2016 World Health Organization (WHO) classification of primary central nervous system (CNS) tumors includes numerous uncommon (representing ≤1% of tumors) low-grade (grades I–II) brain neoplasms with varying clinical behaviors and outcomes. Generally, gross tumor or maximal safe resection is the primary treatment. Adjuvant treatments, though their exact role is unknown, may be considered individually based on pathological subtypes and a proper assessment of risks and benefits. Targetable mutations such as BRAF (proto-oncogene B-Raf), TRAIL (tumor necrosis factor apoptosis inducing ligand), and PDGFR (platelet derived growth factor receptor) have promising roles in future management. |
| Outcomes following stereotactic radiosurgery for small to medium-sized brain metastases are exceptionally dependent upon tumor size and prescribed dose Abstract Background At our institution, we have historically treated brain metastasis (BM) ≤2 cm in eloquent brain with a radiosurgery (SRS) lower prescription dose (PD) to reduce the risk of radionecrosis (RN). We sought to evaluate the impact of this practice on outcomes.Methods We analyzed a prospective registry of BM patients treated with SRS between 2008 and 2017. Incidences of local failure (LF) and RN were determined and Cox regression was performed for univariate and multivariate analyses (MVAs).Results We evaluated 1533 BM ≤2 cm. Median radiographic follow-up post SRS was 12.7 months (1.4–100). Overall, the 2-year incidence of LF was lower for BM treated with PD ≥21 Gy (9.3%) compared with PD ≤15 Gy (19.5%) (sub–hazard ratio, 2.3; 95% CI: 1.4–3.7; P = 0.0006). The 2-year incidence of RN was not significantly higher for the group treated with PD ≥21 Gy (9.5%) compared with the PD ≤15 Gy group (7.5%) (P = 0.16). MVA demonstrated that PD (≤15 Gy) and tumor size (>1 cm) were significantly correlated (P < 0.05) with higher rates of LF and RN, respectively. For tumors ≤1 cm, when comparing PD ≤15 Gy with ≥21 Gy, the risks of LF and RN are equivalent. However, for lesions >1 cm, PD ≥21 Gy is associated with a lower incidence of LF without significantly increasing the risk of RN.Conclusion Our results indicate that rates of LF or RN following SRS for BM are strongly correlated with size and PD. Based on our results, we now, depending upon the clinical context, consider increasing PD to 21 Gy for BM in eloquent brain, excluding the brainstem. |
| Sex difference of mutation clonality in diffuse glioma evolution Abstract Background Sex differences in glioma incidence and outcome have been previously reported but remain poorly understood. Many sex differences that affect the cancer risk were thought to be associated with cancer evolution.Methods In this study, we used an integrated framework to infer the timing and clonal status of mutations in ~600 diffuse gliomas from The Cancer Genome Atlas (TCGA) including glioblastomas (GBMs) and low-grade gliomas (LGGs), and investigated the sex difference of mutation clonality.Results We observed higher overall and subclonal mutation burden in female patients with different grades of gliomas, which could be largely explained by the mutations of the X chromosome. Some well-established drivers were identified showing sex-biased clonality, such as CDH18 and ATRX. Focusing on glioma subtypes, we further found a higher subclonal mutation burden in females than males in the majority of glioma subtypes, and observed opposite clonal tendency of several drivers between male and female patients in a specific subtype. Moreover, analysis of clinically actionable genes revealed that mutations in genes of the mitogen-activated protein kinase (MAPK) signaling pathway were more likely to be clonal in female patients with GBM, whereas mutations in genes involved in the receptor tyrosine kinase signaling pathway were more likely to be clonal in male patients with LGG.Conclusions The patients with diffuse glioma showed sex-biased mutation clonality (eg, different subclonal mutation number and different clonal tendency of cancer genes), highlighting the need to consider sex as an important variable for improving glioma therapy and clinical care. |
Angiotensin–Neprilysin Inhibition in Acute Decompensated Heart Failure
New England Journal of Medicine, Ahead of Print.
http://bit.ly/2DKLczj
CNOT2 as the critical gene for phenotypes of 12q15 microdeletion syndrome
Chromosome 12q15 microdeletion syndrome is characterized by intellectual disability and dysmorphic facial features, but the associations between each of the deleted genes and the phenotypes of 12q15 microdeletion syndrome remain unclear. Recently, the smallest region of overlap in 16 previously reported patients was used to define three candidate genes for the 12q15 microdeletion syndrome: CNOT2, KCNMB4, and PTPRB. Among these three candidate genes, CNOT2 maintains the structural integrity of the carbon catabolite repressor 4 (CCR4)‐negative on TATA (NOT) complex, which plays a key role in regulating global gene expression, and is essential for the enzymatic activity of the CCR4‐NOT complex. Disruption of the CCR4‐NOT complex results in dysregulation of global gene expression, and is associated with various human disease processes, including neuronal diseases. Therefore, CNOT2 haploinsufficiency might account for the neurological features of the 12q15 microdeletion syndrome. Herein, we document a 12‐year‐old female patient with mild intellectual disability and multiple structural abnormalities including cleft lip and palate and 2–3 toe syndactyly. She exhibited dysmorphic facial features such as upslanting and short palpebral fissures, micrognathia, low‐set ears, and hypoplastic antihelix. A microarray analysis showed a de novo 1.32‐Mb deletion within 12q15 that included CNOT2 and 14 other genes. Remapping of the 12q15 deletion region in the 16 previously reported patients together with that in the newly identified patient indicated that CNOT2 is the only gene that is commonly deleted. These findings suggest that CNOT2 is the prime candidate for the neurological phenotypes of the 12q15 microdeletion syndrome.
http://bit.ly/2ttkyG9
So the doctor is burned out: What does it mean for patient care?
Abstract
The current state of physician burnout has become an increasingly popular topic of discussion and concern. Depending on how it is defined and measured by researchers, the prevalence of physician burnout ranges anywhere from 0 to 80%.1 Emergency medicine is often cited as the specialty with some of the highest reported levels of physician burnout.2 Regardless of what the "true" prevalence of physician burnout may be, most of these studies suggest the presence of a crisis. The detrimental impact of burnout on physicians is certainly of interest to physicians. What is missing from these discussions is the impact of burnout on patients, their families, and objective clinical outcomes.
This article is protected by copyright. All rights reserved.
http://bit.ly/2N8lOHW
Involvement of the Na,K‐ATPase isoforms in control of cerebral perfusion
New Findings
What is the topic of this review? This review considers the role of the Na,K‐ATPase in cerebrovascular function and how it might be changed in familial hemiplegic migraine type 2 (FHM2). The primary focus will be involvement of the Na,K‐ATPase isoforms in regulation of cerebrovascular tone. What advances does it highlight? The review discusses three overall distinct mechanisms whereby the Na,K‐ATPase might be capable of regulating cerebrovascular tone. Furthermore, it discusses how changes in the Na,K‐ATPase in cerebral arteries might affect brain perfusion and thereby be involved in the FHM2 pathology.
Abstract
FHM2 has been characterized by biphasic changes in cerebral blood flow during a migraine attack; initial hypoperfusion followed by abnormal hyperperfusion of the affected hemisphere. We suggested that FHM2‐associated loss‐of‐function mutation(s) in the Na,K‐ATPase α2 isoform may be responsible for these biphasic changes in several ways. We found that reduced expression of the α2 isoform leads to sensitization of the contractile machinery to intracellular Ca2+ ([Ca2+]i) via Src kinase dependent signal transduction. This change in sensitivity may be the underlying mechanism for both abnormally potentiated vasoconstriction and exaggerated vasorelaxation. Moreover, functional significance of the Na,K‐ATPase α2 isoform in astrocytes provides for the possibility of elevated extracellular potassium signaling from astrocytic endfeet to the vascular wall in neurovascular coupling.
This article is protected by copyright. All rights reserved
http://bit.ly/2TRW31h
Identification of novel HLA‐A*11:01‐restricted CTL epitopes derived from the osteosarcoma antigen PBF
Abstract
Osteosarcoma is the most common malignancy of bone that affects young people. Neoadjuvant chemotherapy and surgery have significantly improved the prognosis. However, the prognosis of non‐responders to chemotherapy is still poor. To develop peptide‐based immunotherapy for osteosarcoma, we previously identified CTL epitopes derived from papillomavirus binding factor (PBF) in the context of HLA‐A2, HLA‐A24 and HLA‐B55. In the present study, we identified two novel CTL epitopes, QVT (QVTVWLLEQK) and LSA (LSALPPPLHK), in the context of HLA‐A11 using a sequence of screenings based on the predicted affinity of peptides, in vitro folding ability of a peptide/HLA‐A11 complex, reactivity of a peptide/HLA‐A11 tetramer and IFN‐γ production of T cells that was induced by mixed lymphocyte peptide culture under a limiting dilution condition. CTL clones directed to QVT and LSA peptides showed specific cytotoxicity against HLA‐A11+PBF+ osteosarcoma (HOS‐A11) cells. On the other hand, another epitope, ASV (ASVLSRRLGK), could highly induce cognate tetramer‐positive CTLs. This might be because the ASV peptide mimics the peptide ASV (R6Q) (ASVLSQRLGK) derived from bacterial polypeptides, ROK family proteins. However, ASV‐induced CTLs did not show cytokine production against the cognate peptide. In conclusion, the CTL epitopes QVT and LSA peptides might be useful for the development of immunotherapy targeting PBF for patients with osteosarcoma.
This article is protected by copyright. All rights reserved.
http://bit.ly/2BzH18X
Rap1 signal modulators control the maintenance of hematopoietic progenitors in bone marrow and adult long‐term hematopoiesis
Summary
Adult long‐term hematopoiesis depends on sustaining hematopoietic stem/progenitor cells (HSPCs) in bone marrow (BM) niches, where their balance of quiescence, self‐renewal, and hematopoietic differentiation is tightly regulated. While various BM stroma cells that produce niche factors have been identified, regulation of the intrinsic responsiveness of HSPCs to the niche factors remains elusive. We previously reported that mice deficient for Sipa1, a Rap1 GTPase‐activating protein, develop diverse hematopoietic disorders of late onset. Here we demonstrated that the transplantation of BM cells expressing membrane‐targeted C3G (C3G‐F), a Rap1 GTP/GDP exchanger, resulted in the progressive decline of the numbers of HSPC repopulated in BM with time and impaired long‐term hematopoiesis of all cell lineages. The C3G‐F/HSPCs were sustained for months in spleen retaining hematopoietic potential, but these cells inefficiently contributed to the overall hematopoietic reconstitution. C3G‐F/HSPCs exhibited enhanced proliferation and differentiation with accelerated progenitor cell exhaustion in response to stem cell factor (SCF). Using a Ba/F3 cell line, we confirmed that the increased basal Rap1GTP levels with C3G‐F expression caused a markedly prolonged activation of c‐Kit receptor and downstream signalling via SCF ligation. A minor population of C3G‐F/HSPCs also exhibited the enhanced proliferation in the presence of thrombopoietin (TPO) compared to Vect/HSPCs. Current results suggest an important role of the basal Rap1 activation status of HSPCs in their maintenance in BM sustaining long‐term adult hematopoiesis.
This article is protected by copyright. All rights reserved.
http://bit.ly/2TRVYuv
Indoleamine 2,3‐dioxygenase 1 deletion promotes Theiler's virus–induced seizures in C57BL/6J mice
Summary
Objective
Viral encephalitis increases the risk for developing seizures and epilepsy. Indoleamine 2,3‐dioxygenase 1 (Ido1) is induced by inflammatory cytokines and functions to metabolize tryptophan to kynurenine. Kynurenine can be further metabolized to produce kynurenic acid and the N‐methyl‐d‐aspartate receptor agonist quinolinic acid (QuinA). In the present study, we sought to determine the role of Ido1 in promoting seizures in an animal model of viral encephalitis.
Methods
C57BL/6J and Ido1 knockout mice (Ido1‐KO) were infected with Theiler's murine encephalomyelitis virus (TMEV). Quantitative real‐time polymerase chain reaction was used to evaluate hippocampal expression of proinflammatory cytokines, Ido1, and viral RNA. Body weights and seizure scores were recorded daily. Elevated zero maze was used to assess differences in behavior, and hippocampal pathology was determined by immunohistochemistry.
Results
Infected C57BL/6J mice up‐regulated proinflammatory cytokines, Ido1, and genes encoding the enzymatic cascade responsible for QuinA production in the kynurenine pathway prior to the onset of seizures. Seizure incidence was elevated in Ido1‐KO compared to C57BL/6J mice. Infection increased locomotor activity in Ido1‐KO compared to C57BL/6J mice. Furthermore, the occurrence of seizures was associated with hyperexcitability. Neither expression of proinflammatory cytokines nor viral RNA was altered as a result of genotype. Immunohistochemical analysis revealed increased hippocampal pathology in Ido1‐KO mice.
Significance
Our findings suggest that Ido1 deletion promotes seizures and neuropathogenesis during acute TMEV encephalitis.
http://bit.ly/2BDVPnc
Rates and outcomes of total knee replacement for rheumatoid arthritis compared to osteoarthritis
This study shows that the use of primary total knee replacement (TKR) for rheumatoid arthritis (RA) is declining. The rate of revision after TKR in RA patients is lower than those with osteoarthritis, but patients with RA are at increased risk of infection, particularly the male group. For patients diagnosed with RA undergoing TKR, the rate of revision varies with gender but not with age.
Background
Total knee replacement (TKR) has been shown to perform differently in patients with rheumatoid arthritis (RA) when compared to osteoarthritis (OA). In this study, we compare the survivorship between these two groups and examine patient and prosthesis factors that impact the revision rate.
Methods
All RA and OA patients undergoing TKR in Australia from 1 September 1999 to 31 December 2016 were included. Revision rates were assessed using Kaplan–Meier estimates of survivorship. The cumulative percent revision analysed age, gender, prosthesis constraint and revision for infection.
Results
There were 541 744 TKR procedures performed including 7542 patients with RA. RA declined as the primary diagnosis from 2.4% of all TKR in 2003 to 0.9% in 2016. Male sex was an independent revision risk in RA patients (hazard ratio (HR) = 1.66, P < 0.001) and OA patients (3.5 years+: HR = 1.09 (1.04–1.15), P < 0.001). Male RA patients had a higher revision rate for infection than females (HR = 3.14, P < 0.001). Females with RA had a lower cumulative percent revision compared to OA females, but males showed no difference between diagnoses. Revision in RA patients was not influenced by age. Compared to OA, RA patients had a decreased revision rate for those aged <65 years, but not for patients aged ≥65 years.
Conclusion
The rate of revision after TKR in RA patients is lower than those with OA, but patients with RA are at increased risk of infection, particularly the male group. Prosthesis constraint had no influence on revision rate. Mortality in those undergoing TKR with RA was higher than in those with OA.
http://bit.ly/2IekKU9
The impact of psychosocial stress and stress management on immune responses in patients with cancer
The range of psychosocial stress factors/processes (eg, chronic stress, distress states, coping, social adversity) were reviewed as they relate to immune variables in cancer along with studies of psychosocial interventions on these stress processes and immune measures in cancer populations. The review includes molecular, cellular, and clinical research specifically examining the effects of stress processes and stress‐management interventions on immune variables (eg, cellular immune function, inflammation), which may or may not be changing directly in response to the cancer or its treatment. Basic psychoneuroimmunologic research on stress processes (using animal or cellular/tumor models) provides leads for investigating biobehavioral processes that may underlie the associations reported to date. The development of theoretically driven and empirically supported stress‐management interventions may provide important adjuncts to clinical cancer care going forward.
http://bit.ly/2DUi1Kj
“You probably can’t feel as safe as normal women”: Hispanic women’s reactions to breast density notification
Background
Patient advocacy has led to state‐level legislative mandates for the release of personal mammographic breast density information to women undergoing screening mammography. More research is needed to understand the impact of this information on women's perceptions and mammography screening behavior.
Methods
Semistructured interviews were conducted in English and Spanish with 24 self‐identified Hispanic women who had undergone at least 1 mammogram since breast density notification was enacted in New York State. The women ranged in age from 43 to 63 years. Women were asked about their understanding and perceptions of the communication of New York State‐mandated breast density information, and any actions they have taken or would take in response to this information. A content analysis of the qualitative data from the translated and transcribed interviews was conducted.
Results
The majority of participants had no prior knowledge of breast density and expressed confusion and apprehension regarding the meaning of dense breasts when presented with the notification information. Many participants understood having dense breasts to be a serious and abnormal condition, and reported feelings of worry and vulnerability. Participants mostly expressed a strong interest in learning about breast density and obtaining additional and more frequent breast cancer screening tests. These behavioral intentions were consistent with participants' overall favorable view of breast cancer screening and a belief that their faith, as well as regular screening, can help to protect them from breast cancer morbidity and mortality.
Conclusions
Hispanic women conveyed proactive breast cancer screening intentions in response to breast density notification, despite inadequate comprehension of this information and negative emotional responses.
http://bit.ly/2SHOs8L
Association between primary language, a lack of mammographic screening, and later stage breast cancer presentation
Background
Health determinants are known to influence the stage of breast cancer presentation, but it is unclear to what extent language affects stage. This study investigates whether non–English‐speaking (NES) patients present at a later stage than their English‐speaking (ES) counterparts and whether language is associated with mammographic screening.
Methods
This study was a retrospective, single‐institution cohort analysis of women undergoing breast radiotherapy from 2012 to 2017 (n = 1057). Patients were categorized as ES (n = 904) or NES (n = 153). Ordinal logistic regression analysis identified variables associated with later stage presentation, including language, race/ethnicity, and age. A subcohort analysis investigated the influence of mammographic screening on stage for NES patients.
Results
NES patients had greater odds of later stage disease than ES patients (odds ratio, 1.47; 95% confidence, 1.001‐2.150). This association persisted across all races/ethnicities. An additional analysis examined age categories associated with mammographic screening. For women eligible for screening (ie, those 40‐50 years old or older than 50 years), there was a significant association between language and stage. NES patients older than 50 years were twice as likely to present at an advanced stage in comparison with ES patients (16.19% vs 8.11%; P = .0082). An additional subset analysis accounted for mammograms. NES patients who did not undergo screening had a higher probability of stage III disease (40.3% of NES patients vs 12.7% of ES patients). There was no difference in stage between NES and ES patients who did undergo screening.
Conclusions
Language is independently associated with later stage breast cancer for NES patients, regardless of race/ethnicity. NES patients may have difficulty in accessing the health care system. Future interventions should seek to reduce language barriers for mammographic screening and diagnosis.
http://bit.ly/2DIW80n
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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