Bioenergetic feedback between heart cell contractile machinery and mitochondrial 3D deformations

In the heart, mitochondria are arranged in pairs sandwiched between the contractile machinery, which is the major ATP consumer. Thus, in response to the contraction-relaxation cycle of the cell, the mitochondrial membrane should deform accordingly. Membrane deformations in isolated ATP synthesis or in isolated mitochondria affect ATP production. However, it is unknown whether physiological deformation of the mitochondrial membrane in response to the contraction-relaxation cycle can act as a bioenergetic signaling mechanism between ATP demand to supply.

https://ift.tt/2wPZ5cC

Time-resolved Laurdan fluorescence reveals insights into membrane viscosity and hydration levels

Membrane viscosity and hydration levels characterize the biophysical properties of biological membranes and are reflected in the rate and extent of solvent relaxation, respectively, of environmentally sensitive fluorophores such as Laurdan. Here we first developed a method for a time-resolved General Polarization (GP) analysis with fluorescence-lifetime imaging microscopy (FLIM) that captures both the extent and rate of Laurdan solvent relaxation. We then conducted time-resolved GP measurements with Laurdan-stained model membranes and cell membranes.

https://ift.tt/2oHCuKZ

Physiological Calcium Concentrations Slow Dynamics at the Lipid-Water Interface

Phospholipids can interact strongly with ions at physiological concentrations, and these interactions can alter membrane properties. Here we describe the effects of calcium ions on the dynamics in phospholipid membranes. We used a combination of time-resolved ultrafast two-dimensional infrared (2D IR) spectroscopy and molecular dynamics (MD) simulations. We found that millimolar Ca2+ concentrations lead to slower fluctuations in the local environment at the lipid-water interface of membranes with phosphatidylserine.

https://ift.tt/2CpeFkH

Peptide—Lipid Interaction Sites Affect Vesicles’ Responses to Antimicrobial Peptides

This article presents coarse-grained molecular dynamics simulations of pore-forming antimicrobial peptide melittin and its interactions with vesicles composed of a mixture of zwitterionic and anionic phospholipids. Besides creating holes in the membrane, the adsorption of melittin also induces vesicle budding, which can develop into vesiculation at high peptide concentrations, as well as vesicle invagination, which can eventually result in a corrugated membrane surface. These rich morphology changes are mediated by the curvature of the vesicles and the peptide concentration.

https://ift.tt/2CpeDJB

Effect of smoking cessation on the risk of dementia: a longitudinal study

Annals of Clinical and Translational Neurology, EarlyView.


https://ift.tt/2Coymcl

Impact of vascular disease, amputation level, and the mismatch between balance ability and balance confidence in a cross sectional study of the likelihood of falls among people with limb loss: perception versus reality

Objective Investigate impact of balance ability, Activities-specific Balance Confidence (ABC), and other self-reported and clinical factors on incidence of falls among people with lower-limb loss. Design Cross-sectional study (N=305) with multivariable logistic regression analysis Results Participants included 68.3% males with age 55.5±14.9; with 50% dysvascular and 56.8% transtibial amputations. Average ABC=2.1/4 ±1.1, balance ability=2.9/4 ±1.3 and walking speed=0.766±0.387 m/s. The final model showed fall risk was heightened for people with vascular comorbidities (odds ratio [OR]=3.46, 95% confidence interval [CI]=1.40-8.54) and better balance (OR=23.29, CI=3.19-170.23); but attenuated for people with transfemoral (OR=0.08, CI=0.01-0.82) and vascular amputations (OR=0.38, CI=0.15-0.95). Significant interactions existed between age and amputation level (OR=1.06, CI=1.02-1.11) and between balance confidence and balance ability (OR=0.27, CI=0.13-0.57). Conclusions While people with vascular amputations were less likely to fall than those with nonvascular amputations, people with concurrent vascular comorbidities were more likely to fall than those without. People with transfemoral amputations were less likely to fall—however, fall risk increased with each year of age compared to people with transtibial amputations. People with balance ability ≥3.5 fell more often than those with lower ability, but people with lower balance ability and mismatched confidence in their balance ability had 3.7 times greater fall risk. CORRESPONDING AUTHOR CONTACT INFORMATION: Christopher Kevin Wong, PT, PhD, OCS, Associate Professor, Department of Rehabilitation and Regenerative Medicine, Associate Director, Program in Physical Therapy, Columbia University Medical Center, 617 West 168th Street, The Georgian 3rd Floor, New York, NY 10032, Tel: 212-305-3781 Fax: 212-305-4569 Email: ckw7@cumc.columbia.edu DISCLOSURES: a. The authors have no conflicts of interest to report. c. Funding: Supported in part by the National Center for Injury Prevention and Control, Centers for Disease Control and Prevention (grant no. 1 R49 CE002096). Its contents are solely the responsibility of the authors and do not represent the official views of the Centers for Disease Control and Prevention or the Department of Health and Human Services. c. The authors have no potential financial benefits to report. d. Prior presentations: This work has not been presented. Related work focused on injury was presented at the International Society of Prosthetics and Orthotics, 2017 World Conference, Capetown, South Africa. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2CnUiEA

A correction to the age-adjustment of the GH-2000 score used in the detection of growth hormone misuse

The GH-2000 biomarker test has been introduced by the World Anti-Doping Agency as a method of detecting growth hormone misuse in professional sport. The test involves the measurement insulin-like growth factor...

https://ift.tt/2wIReOb

Transcranial magnetic stimulation intervention in Alzheimer’s disease: a research proposal for a randomized controlled trial

Alzheimer's disease is a major health problem in our society. To date, pharmacological treatments have obtained poor results and there is a growing interest in finding non-pharmacological interventions for thi...

https://ift.tt/2NWkJTm

A novel experimental setup for evaluating the stiffness of ankle foot orthoses

The purpose of this study was the construction of a new semi-automated experimental setup for the evaluation of the stiffness of ankle foot orthoses (AFOs) around an axis aligned to the anatomical ankle joint ...

https://ift.tt/2wOXq7r

A population based pediatric oncology registry in Southern Sweden: the BORISS registry

Abstract

A population based registry, with the acronym BORISS, was established. It contains all individuals (0–18 years of age at diagnosis) diagnosed with cancer from 1970–01–01 until 2016–12–31 in Southern Sweden. The treatment data has been entered into the registry after confirmation of the diagnosis by the Swedish national cancer registry and updates on vital status from the Swedish population registry. The number of individuals with a pediatric cancer diagnosed during these 46 years are 2928. Of these, 2065 are currently alive and 1882 individuals are 5-year survivors. Data on treatment and malignancy of the 5–year survivors has been collected from medical records and entered into the database. Treatment data contains surgical procedure, target organ of radiation therapy including dose and fractionation, and cytostatic treatment with dose (mg) per body surface area (m²) for all cytostatic agents. Data on individuals receiving stem cell treatment is included. The database is unique in that it is population based, contains all individuals and detailed treatment data on all 5-year survivors after childhood cancer in Southern Sweden since 1970. The database has contributed to several academic theses in the field of late effects after childhood cancer. BORISS also supports the Late Effect Clinic at Skåne University Hospital in Lund, Sweden with treatment details enabling a stratified surveillance.

https://ift.tt/2PBiQeU

She Looks like She’d Be an Animal in Bed: Dehumanization of Drinking Women in Social Contexts

Abstract

The purpose of the present research was to examine the perceptions of women who drink in social contexts through the lens of dehumanization (Haslam 2006). Across three experiments, we manipulated the presence of alcohol by depicting a woman at a bar with a bottle of beer or a bottle of water and measured dehumanization. As hypothesized, women were dehumanized more in the alcohol condition than in the water condition by men (Experiments 1–3) and women (Experiments 2 and 3). Notably, the presence of alcohol compared to water had no impact on dehumanization of men (Experiment 2). Also, as hypothesized, perceived intoxication emerged as a significant mediator of the link between alcohol condition and dehumanization in Experiments 1 and 2, and alcohol quantity predicted greater dehumanization in Experiment 3. Extending the present work to prior work in this area, Experiment 3 also examined the links among alcohol, perceived sexual availability, and dehumanization, revealing that perceived sexual availability mediated the link between alcohol and dehumanization. Implications for theories of dehumanization, alcohol, and social perception as well as practical implications of these findings are discussed.

https://ift.tt/2Q7o8A7

The Trials of Women Leaders in the Workforce: How a Need for Cognitive Closure can Influence Acceptance of Harmful Gender Stereotypes

Abstract

Women leaders in the workforce are adversely affected by two sets of stereotypes: women are warm and communal but leaders are assertive and competent. This mismatch of stereotypes can lead to negative attitudes toward women leaders, however, not all individuals will be equally sensitive to these stereotypes. Men and women characterized by a need for cognitive closure (the desire for stable and certain knowledge) should be particularly sensitive to these stereotypes because they can be stable knowledge sources. We hypothesized that (a) negative attitudes toward women leaders in the workforce would vary with individuals' need for closure, independent of their gender, and that (b) binding moral foundations (a concern for the larger group and its norms and standards) would mediate this association. In two studies, MTurk workers completed measures of negative attitudes toward women managers (Study 1, n = 149), stereotyped beliefs of women as not wanting or deserving high status positions in the workforce (Study 2, n = 207), as well as need for cognitive closure, moral foundations, social desirability, gender, and political orientation. Our results were consistent with our hypotheses and suggest that attitudes toward woman managers can reflect acceptance of pre-existent norms. If these norms can be changed, then changes in attitudes could follow.

https://ift.tt/2wOEnZM

Differentiated vulvar intraepithelial neoplasia (dVIN): the most helpful histological features and the utility of cytokeratins 13 and 17

Abstract

Differentiated vulvar intraepithelial neoplasia (dVIN) is the precursor lesion of HPV-negative vulvar squamous cell carcinoma (VSCC). The histopathological diagnosis of dVIN can be challenging, as it often resembles vulvar non-neoplastic epithelial disorders (NNED), especially lichen sclerosus (LS). We aimed to establish the most specific and reproducible histological features of dVIN and assessed cytokeratin 13 (CK13) and cytokeratin 17 (CK17) immunohistochemistry as a diagnostic aid. Consecutive cases of dVIN (n = 180) and LS (n = 105) from the period 2010 to 2013 were reviewed using a checklist of histological features. Each feature was recorded as 'present' or 'absent' and statistical comparison (dVIN vs LS) was made. Interobserver agreement between two pairs of pathologists was assessed for a subset of cases of dVIN (n = 31) and LS and other NNED (n = 23). Immunohistochemistry with CK13, CK17, MIB1 and p53 was performed on dVIN, LS, and other NNED cases. Macronucleoli, features of disturbed maturation and angulated nuclei were significantly more common in dVIN than LS (p < 0.001). We found 'substantial agreement' for the diagnosis of dVIN (κ = 0.71). Macronucleoli and deep keratinisation had the highest agreement. In dVIN, the mean percentage of cells staining with CK13 was 15 and with CK17, this was 74. For LS, the mean percentage of cells staining with CK13 was 31, and with CK17, this was 41. By plotting receiver operating characteristic curves (ROC), an area under the curve (AUC) of 0.52 was obtained for CK13, and an AUC of 0.87 was obtained for CK17. The most helpful histological features for diagnosing dVIN were macronucleoli, features of disturbed maturation, and angulated nuclei. Increased CK17 expression may have promise for supporting dVIN diagnosis.

https://ift.tt/2MS4Y3d

Novel KHDRBS1-NTRK3 rearrangement in a congenital pediatric CD34-positive skin tumor: a case report

Abstract

Cutaneous spindle-cell neoplasms in adults as well as children represent a frequent dilemma for pathologists. Along this neoplasm spectrum, the differential diagnosis with CD34-positive proliferations can be challenging, particularly concerning neoplasms of fibrohistiocytic and fibroblastic lineages. In children, cutaneous and superficial soft-tissue neoplasms with CD34-positive spindle cells are associated with benign to intermediate malignancy potential and include lipofibromatosis, plaque-like CD34-positive dermal fibroma, fibroblastic connective tissue nevus, and congenital dermatofibrosarcoma protuberans. Molecular biology has been valuable in showing dermatofibrosarcoma protuberans and infantile fibrosarcoma that are characterized by COL1A1-PDGFB and ETV6-NTRK3 rearrangements respectively. We report a case of congenital CD34-positive dermohypodermal spindle-cell neoplasm occurring in a female infant and harboring a novel KHDRBS1-NTRK3 fusion. This tumor could belong to a new subgroup of pediatric cutaneous spindle-cell neoplasms, be an atypical presentation of a plaque-like CD34-positive dermal fibroma, of a fibroblastic connective tissue nevus, or represent a dermatofibrosarcoma protuberans with an alternative gene rearrangement.

https://ift.tt/2CoseRv

Clinical Evaluations of Toxicity and Efficacy of Nanoparticle-Mediated Gene Therapy

Human Gene Therapy, Ahead of Print.


https://ift.tt/2wLVufO

Patterns of conventional and complementary non-pharmacological health practice use by US military veterans: a cross-sectional latent class analysis

Non-pharmacological therapies and practices are commonly used for both health maintenance and management of chronic disease. Patterns and reasons for use of health practices may identify clinically meaningful ...

https://ift.tt/2NmTsMs

Predictors and interdependence of family support in a random sample of long‐term young breast cancer survivors and their biological relatives

Cancer Medicine, EarlyView.


https://ift.tt/2MTc6MD

Thoracoscopic resection of a cystic seminoma of the mediastinum

Asian Journal of Endoscopic Surgery, EarlyView.


https://ift.tt/2PIk5Jh

Trusting the Results of Model-Based Economic Analyses: Is there a Pragmatic Validation Solution?

Abstract

Models have become a nearly essential component of health technology assessment. This is because the efficacy and safety data available from clinical trials are insufficient to provide the required estimates of impact of new interventions over long periods of time and for other populations and subgroups. Despite more than five decades of use of these decision-analytic models, decision makers are still often presented with poorly validated models and thus trust in their results is impaired. Among the reasons for this vexing situation are the artificial nature of the models, impairing their validation against observable data, the complexity in their formulation and implementation, the lack of data against which to validate the model results, and the challenges of short timelines and insufficient resources. This article addresses this crucial problem of achieving models that produce results that can be trusted and the resulting requirements for validation and transparency, areas where our field is currently deficient. Based on their differing perspectives and experiences, the authors characterize the situation and outline the requirements for improvement and pragmatic solutions to the problem of inadequate validation.

https://ift.tt/2Q9qFd9

Liposarcoma in the Inguinal Canal: Challenges in Preoperative Diagnosis and Importance of Routine Pathological Examination of “Hernia Sacs”

Liposarcoma is the most common histologic subtype of soft tissue sarcoma in the retroperitoneum. The distinction of primary cord liposarcomas, which arise in and are confined to the inguinal canal, from inguinoscrotal extension of a retroperitoneal tumor is mandatory. Both can be found incidentally in inguinal hernia sac specimens. Preoperative diagnosis is essential for adequate surgery with clear margins. We present a clinicopathological correlation of two men with slowly growing right para-testicular masses diagnosed as inguinal hernias. Pathological examination revealed well-differentiated lipoma-like liposarcoma and well-differentiated liposarcoma mixed type (lipoma-like and sclerosing types), respectively. The first tumor was considered a primary cord liposarcoma with no recurrence on follow-up. The second tumor showed an unusual growth pattern of discontinuous nodules that gave the false impression of complete resection. This growth pattern may explain why inguinal liposarcomas have a high recurrence rate despite apparently negative surgical margins. A follow-up CT scan exposed a fatty tumor in the retroperitoneum of the second patient. Careful interpretation of imaging studies in patients with fatty inguinal masses is mandatory to rule out a retroperitoneal or intraperitoneal component. Although the two cases herein discussed represent less than 0.1% of the total inguinal hernia sacs examined over the past five years in our pathology department, we recommend routine examination of all "mass-containing" hernia sacs as missing the diagnosis of liposarcoma can lead to substantial morbidity and mortality.

https://ift.tt/2MPdNux

Sleep, Diet, and Cardiometabolic Health Investigations: a Systematic Review of Analytic Strategies

Abstract

Purpose of Review

Poor sleep is a risk factor for cardiometabolic morbidity. The relationship of sleep and cardiometabolic health could be confounded, mediated, or modified by diet, yet the incorporation of diet in sleep-cardiometabolic health studies is inconsistent. This rapid systematic literature review evaluates the conceptualization of diet as a confounder, mediator, or effect modifier within sleep-cardiometabolic health investigations, and the statistical approaches utilized.

Recent Findings

Of 4692 studies identified, 60 were retained (28 adult, 32 pediatric). Most studies included diet patterns, quality, or energy intake as confounders, while a few examined these dietary variables as mediators or effect modifiers. There was some evidence, mostly in pediatric studies, that inclusion of diet altered sleep-cardiometabolic health associations.

Summary

Diet plays a diverse role within sleep-cardiometabolic health associations. Investigators should carefully consider the conceptualization of diet variables in these relationships and utilize contemporary statistical approaches when applicable.

https://ift.tt/2NTYfSD

Estimating Asian Contribution to the Brazilian Population: A New Application of a Validated Set of 61 Ancestry Informative Markers

Estimates of different ancestral proportions in admixed populations are very important in population genetics studies, especially for the detection of population substructure effects in studies of case-control associations. Brazil is one of the most heterogeneous countries in the world, both from a socio-cultural and a genetic point of view. In this work, we investigated a previously developed set of 61 ancestry informative markers (AIM), aiming to estimate the proportions of four different ancestral groups (African, European, Native American and Asian) in Brazilian populations. To the best of our knowledge, this is the first study to use a set of AIM to investigate the genetic contribution of all four main parental populations to the Brazilian population, including Asian contribution. All selected markers were genotyped through multiplex PCR and capillary electrophoresis. The set was able to successfully differentiate the four ancestral populations (represented by 939 individuals) and identify their genetic contributions to the Brazilian population. In addition, it was used to estimate individual interethnic admixture of 1050 individuals from the Southeast region of Brazil and it showed that these individuals present a higher European ancestry contribution, followed by African, Asian and Native American ancestry contributions. Therefore, the 61 AIM set has proved to be a valuable tool to estimate individual and global ancestry proportions in populations mainly formed by these four groups. Our findings highlight the importance of using sets of AIM to evaluate population substructure in studies carried in admixed populations, in order to avoid misinterpretation of results.

https://ift.tt/2M1TfcQ

A Novel MCL-1 Inhibitor Combined with Venetoclax Rescues Venetoclax Resistant Acute Myelogenous Leukemia [Research Articles]

Suppression of apoptosis by expression of anti-apoptotic BCL2-family members is a hallmark of acute myeloblastic leukemia (AML). Induced myeloid leukemia cell differentiation protein (MCL-1), an anti-apoptotic BCL-2 family member, is commonly upregulated in AML cells, and is often a primary mode of resistance to treatment with the BCL-2 inhibitor, venetoclax. Here, we describe VU661013, a novel, potent, selective MCL-1 inhibitor that de-stabilizes BIM/MCL-1 association, leads to apoptosis in AML, and is active in venetoclax-resistant cells and patient derived xenografts. In addition, VU661013 was safely combined with venetoclax for synergy in murine models of AML. Importantly, BH3 profiling of patient samples, and drug sensitivity testing ex vivo accurately predicted cellular responses to selective inhibitors of MCL-1 or BCL-2, and showed benefit of the combination. Taken together, these data suggest a strategy of rationally employing BCL-2 and MCL-1 inhibitors in sequence or in combination in AML clinical trials. -

https://ift.tt/2CndDWs

Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness [Research Articles]

In many solid tumors, parasympathetic input is provided by the vagus nerve, which has been shown to modulate tumor growth. However, whether cholinergic signaling directly regulates progression of pancreatic cancer (PDAC) has not been defined. Here, we found that subdiaphragmatic vagotomy in LSL-Kras+/G12D;Pdx1-Cre (KC) mice accelerated PDAC development, whereas treatment with the systemic muscarinic agonist bethanechol restored the normal KC phenotype, thereby suppressing the accelerated tumorigenesis caused by vagotomy. In LSL-Kras+/G12D;LSL-Trp53+/R172H;Pdx1-Cre (KPC) mice with established PDAC, bethanechol significantly extended survival. These effects were mediated in part through the CHRM1, which inhibited downstream MAPK/EGFR and PI3K/AKT pathways in PDAC cells. Enhanced cholinergic signaling led to a suppression of the CSC compartment, CD11b+ myeloid cells, TNF-α levels, and metastatic growth in the liver. Therefore, these data suggest that cholinergic signaling directly and indirectly suppresses growth of PDAC cells, and therapies that stimulate muscarinic receptors may be useful in the treatment of PDAC.

https://ift.tt/2MUgFXi

Study Explains Specificity of CRISPR/Cas12a [News in Brief]

Researchers find that alternate nuclease requires a closer DNA match than Cas9.

https://ift.tt/2M1Kq2T

With GBM, T Cells May Be Stuck in Bone Marrow [News in Brief]

Sequestration driven by cell-surface S1P1 loss; findings suggest new therapeutic strategies for brain cancer.

https://ift.tt/2Np8RMi

Strategy for Tumor Selective Disruption of Androgen Receptor Function in the Spectrum of Prostate Cancer

Purpose: Testosterone suppression in prostate cancer (PC) is limited by serious side effects and resistance via restoration of androgen receptor (AR) functionality. ELK1 is required for ARdependent growth in various hormone-dependent and castration resistant PC models. The amino terminal domain of AR docks at two sites on ELK1 to co-activate essential growth genes. This study explores the ability of small molecules to disrupt the ELK1-AR interaction in the spectrum of PC, inhibiting AR activity in a manner that would predict functional tumor selectivity. Experimental design: Small molecule drug discovery and extensive biological characterization of a lead compound. Results: We have discovered a lead molecule (KCI807) that selectively disrupts ELK1-dependent promoter activation by wild-type and variant ARs without interfering with ELK1 activation by ERK. KCI807 has an obligatory flavone scaffold and functional hydroxyl groups on C5 and C3'. KCI807 binds to AR, blocking ELK1 binding, and selectively blocks recruitment of AR to chromatin by ELK1. KCI807 primarily affects a subset of AR target growth genes selectively suppressing AR-dependent growth of PC cell lines with a better inhibitory profile than enzalutamide. KCI807 also inhibits in vivo growth of castration/enzalutamide-resistant cell line-derived and patient-derived tumor xenografts. In the rodent model, KCI807 has a plasma half-life of 6h and maintenance of its antitumor effect is limited by self-induced metabolism at its 3'-hydroxyl. Conclusions: The results offer a mechanism-based therapeutic paradigm for disrupting the AR growth-promoting axis in the spectrum of prostate tumors while reducing global suppression of testosterone actions. KCI807 offers a good lead molecule for drug development.

https://ift.tt/2MOamEl

Smad7 Promotes Healing of Radiotherapy-Induced Oral Mucositis without Compromising Oral Cancer Therapy in a Xenograft Mouse Model

Purpose: We previously reported preventive and therapeutic effects of Smad7, a multifunctional protein, on radiation-induced mucositis in mice without promoting human oral cancer cell survival or migration in vitro. The current study aims to determine whether a Smad7-based biologic can treat existing oral mucositis during radiotherapy for oral cancer and whether this treatment compromises RT-induced cancer cell killing in neighboring oral cancer. Experimental Design: We transplanted human oral cancer cells into the tongues of mice and applied craniofacial irradiation to simultaneously kill tumor cells and induce oral mucositis, thus modeling RT and mucositis in oral cancer patients. We topically applied a recombinant human Smad7 protein fused with the cell-penetrating Tat tag (Tat-Smad7) to the oral mucosa of tumor-bearing mice post RT when oral mucositis began to develop. Results: Topically applied Tat-Smad7 penetrated cells in both the oral mucosa and oral cancer, attenuating TGFβ and NFB signaling as well as inflammation at both sites. Tat-Smad7 treatment alleviated oral mucositis with reductions in DNA damage and apoptosis in keratinocytes, but increased keratinocyte proliferation compared to vehicle-treated mucositis lesions. In contrast, adjacent oral cancer exposed to Tat-Smad7 did not show alterations in proliferation or direct DNA damage, but showed increased oxidative stress damage and apoptosis compared to tumors treated with vehicle. Conclusion: Our results suggest that short-course Tat-Smad7 application to oral mucositis promotes its healing but does not compromise the cytotoxic effect of RT on oral cancer and has context-specific effects on oral mucosa vs. oral cancer.

https://ift.tt/2NSj8xR

A Non-Invasive Blood-Based Combinatorial Proteomic Biomarker Assay to Detect Breast Cancer in Women over age 50 with BI-RADS 3, 4, or 5 Assessment

Purpose: With improvements in breast cancer (BC) imaging, there has been a corresponding increase in false-positives and avoidable biopsies. There is a need to better differentiate when a breast biopsy is warranted and determine appropriate follow-up. This study describes the design and clinical performance of a combinatorial proteomic biomarker assay (CPBA), Videssa® Breast, in women over age 50. Experimental Design: A BI-RADS 3, 4, or 5 assessment was required for clinical trial enrollment. Serum was collected prior to breast biopsy and subjects were followed for 6-12 months and clinically relevant outcomes recorded. Samples were split into training (70%) and validation (30%) cohorts with an approximate 1:4 case:control ratio in both arms. Results: A CPBA that combines biomarker data with patient clinical data was developed using a training cohort (469 women, cancer incidence: 18.5%), resulting in 94% sensitivity and 97% negative predictive value (NPV). Independent validation of the final algorithm in 194 subjects (BC incidence: 19.6%) demonstrated a sensitivity of 95% and a NPV of 97%. When combined with previously published data for women under age 50, Videssa Breast achieves a comprehensive 93% sensitivity and 98% NPV in a population of women ages 25 - 75. Had Videssa Breast results been incorporated into the clinical workflow, approximately 45% of biopsies might have been avoided. Conclusions: Videssa Breast combines serum biomarkers with clinical patient characteristics to provide clinicians with additional information for patients with indeterminate breast imaging results, potentially reducing false-positive breast biopsies.

https://ift.tt/2Nhra6g

Lobular carcinomas in situ display intra-lesion genetic heterogeneity and clonal evolution in the progression to invasive lobular carcinoma

Purpose:Lobular carcinoma in situ (LCIS) is a pre-invasive lesion of the breast. We sought to define its genomic landscape, whether intra-lesion genetic heterogeneity is present in LCIS, and the clonal relatedness between LCIS and invasive breast cancers. Experimental Design: We reanalyzed whole-exome sequencing (WES) data and performed a targeted amplicon sequencing validation of mutations identified in 43 LCIS and 27 synchronous more clinically-advanced lesions from 24 patients (nine ductal carcinomas in situ (DCIS), 13 invasive lobular carcinomas (ILCs) and five invasive ductal carcinomas (IDCs)). Somatic genetic alterations, mutational signatures, clonal composition and phylogenetic trees were defined using validated computational methods. Results: WES of 43 LCIS lesions revealed a genomic profile similar to that previously reported for ILCs, with CDH1 mutations present in 81% of the lesions. Forty-two percent (18/43) of LCIS were found to be clonally-related to synchronous DCIS and/or ILCs, with clonal evolutionary patterns indicative of clonal selection and/or parallel/branched progression. Intra-lesion genetic heterogeneity was higher among LCIS clonally-related to DCIS/ILC than in those non-clonally related to DCIS/ILC. A shift from aging to APOBEC-related mutational processes was observed in the progression from LCIS to DCIS and/or ILC in a subset of cases. Conclusions:Our findings support the contention that LCIS has a repertoire of somatic genetic alterations similar to that of ILCs, and likely constitutes a non-obligate precursor of breast cancer. Intra-lesion genetic heterogeneity is observed in LCIS and should be considered in studies aiming to develop biomarkers of progression from LCIS to more advanced lesions.

https://ift.tt/2NSj3Kz

Carapa guianensis Aublet (Andiroba) Seed Oil: Chemical Composition and Antileishmanial Activity of Limonoid-Rich Fractions

Leishmaniasis is a complex of diseases caused by protozoa of the genus Leishmania and affects millions of people around the world. Several species of plants are used by traditional communities for the treatment of this disease, among which is Carapa guianensis Aubl. (Meliaceae), popularly known as andiroba. The objective of the present work was to conduct a chemical study of C. guianensis seed oil and its limonoid-rich fractions, with the aim of identifying its secondary metabolites, particularly the limonoids, in addition to investigating its anti-Leishmania potential. The chemical analyses of the C. guianensis seed oil and fractions were obtained by electrospray ionization mass spectrometry (ESI-MS). The cytotoxic activity was tested against peritoneal macrophages, and antileishmanial activity was evaluated against promastigotes and intracellular amastigotes of Leishmania amazonensis. All the C. guianensis seed oil samples analyzed exhibited the same pattern of fatty acids, while the limonoids 7-deacetoxy-7-hydroxygedunin, deacetyldihydrogedunin, deoxygedunin, andirobin, gedunin, 11β-hydroxygedunin, 17-glycolyldeoxygedunin, 6α-acetoxygedunin, and 6α,11β-diacetoxygedunin were identified in the limonoid-rich fractions of the oil. The C. guianensis seed oil did not exhibit antileishmanial activity, and cytotoxicity was higher than 1000 μg/mL. Three limonoid-rich oil fractions demonstrated activity against promastigotes (IC50 of 10.53±0.050, 25.3±0.057, and 56.9±0.043μg/mL) and intracellular amastigotes (IC50 of 27.31±0.091, 78.42±0.086, and 352.2±0.145 μg/mL) of L. amazonensis, as well as cytotoxicity against peritoneal macrophages (CC50 of 78.55±1.406, 139.0±1.523, and 607.7±1.217 μg/mL). The anti-Leishmania activity of the limonoid-rich fractions of C. guianensis can be attributed to the limonoids 11β-hydroxygedunin and 6α,11β-diacetoxygedunin detected in the chemical analysis.

https://ift.tt/2wOYcAe

Baloxavir Superior to Placebo for Alleviating Flu Symptoms

WEDNESDAY, Sept. 5, 2018 -- The selective inhibitor of influenza cap-dependent endonuclease, baloxavir marboxil, is superior to placebo for alleviating influenza symptoms, according to a study published in the Sept. 6 issue of the New England...

https://ift.tt/2wPvkZs

Google Search for Cardiovascular Disease Peaks in Winter

WEDNESDAY, Sept. 5, 2018 -- Google search query volumes related to cardiovascular disease (CVD) follow a strong seasonal pattern, according to a study published in the September issue of the Mayo Clinic Proceedings. Nilay Kumar, M.D., from the...

https://ift.tt/2NRVeCi

130 Now Sickened by Salmonella-Tainted Honey Smacks Cereal

WEDNESDAY, Sept. 5, 2018 -- One hundred thirty people across 36 states have now fallen ill with Salmonella after eating Kellogg's Honey Smacks cereal, according to the U.S. Centers for Disease Control and Prevention. Many of the illnesses linked to...

https://ift.tt/2wLYtVF

Recent Increase in Contraception Use Noted Among U.S. Teenagers

WEDNESDAY, Sept. 5, 2018 -- Among U.S. adolescents, there were increases in contraceptive use from 2007 to 2014, including dual-method use and long-acting reversible contraception, according to a study published in the August issue of the Journal of...

https://ift.tt/2NNrIO1

Rare Shewanella spp. associated with pulmonary and bloodstream infections of cancer patients, China: a case report

Members of Shewanella species are opportunistic pathogens that are found in marine environments. Currently more than sixty species have been identified, whereas the most commonly clinical cases associated with Sh...

https://ift.tt/2wN0Lmj

Relapse of chronic melioidosis in a paediatric cystic fibrosis patient: first case report from Malaysia

Burkholderia pseudomallei is the causative agent of melioidosis, which is a potentially life threatening disease endemic in Southeast Asian countries. In Malaysia, cystic fibrosis (CF) is an uncommon condition. T...

https://ift.tt/2Q83vne

Determinants of Visfatin/NAMPT Serum Concentration and its Leukocyte Expression in Hyperthyroidism

Horm Metab Res 2018; 50: 653-660
DOI: 10.1055/a-0669-1584

We aimed to analyze the potential influence of thyroid autoimmunity on visfatin/NAMPT serum concentration and its leukocyte expression in hyperthyroid patients. This is a single-center, cross-sectional study with consecutive enrollment. All patients with newly diagnosed overt hyperthyroidism in a course of Graves' disease or toxic nodular goiter were included in the study. They underwent physical examination, laboratory investigation, body composition analysis, and thyroid ultrasound. NAMPT mRNA leukocyte expressions were measured using RT-qPCR. Of the 173 patients, 95 were enrolled in further analysis [67 patients with Graves' disease (GD) and 28 with toxic nodular goiter (TNG)]. Control group consisted of 43 healthy volunteers adjusted for age, sex, and BMI. Higher NAMPT/visfatin serum concentration was found in patients with GD comparing with patients with TNG (p=0.03855). We found significant NAMPT leukocyte overexpression in GD patients (n=32) as compared to TNG patients (n=18) and euthyroid controls (n=24) (p=0.005965). Simple linear regression analysis revealed that NAMPT/visfatin serum concentration was significantly associated with NAMPT leukocyte expression, thyroid autoimmunity, age, HOMA-IR, and fat mass percentage (FM%). NAMPT leukocyte expression was related to thyroid autoimmunity, age, and TRAb levels. The stepwise multiple regression analysis revealed FM% and HOMA-IR as independent predictors of visfatin/NAMPT serum levels. In a separate stepwise multiple regression analysis, we confirmed the association between NAMPT leukocyte expression and TRAb levels. We found that fat mass percentage together with HOMA-IR are the most significant predictors of visfatin/NAMPT serum elevation in hyperthyroid patients.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

https://ift.tt/2PGXAED

MetS Risk Score: A Clear Scoring Model to Predict a 3-Year Risk for Metabolic Syndrome

Horm Metab Res 2018; 50: 683-689
DOI: 10.1055/a-0677-2720

Although several risk factors for metabolic syndrome (MetS) have been reported, there are few clinical scores that predict its incidence. Therefore, we created and validated a risk score for prediction of 3-year risk for MetS. Three-year follow-up data of 4395 initially MetS-free subjects, enrolled for an annual physical examination from Wenzhou Medical Center were analyzed. Subjects at enrollment were randomly divided into the training and the validation cohort. Univariate and multivariate logistic regression models were employed for model development. The selected variables were assigned an integer or half-integer risk score proportional to the estimated coefficient from the logistic model. Risk scores were tested in a validation cohort. The predictive performance of the model was tested by computing the area under the receiver operating characteristic curve (AUROC). Four independent predictors were chosen to construct the MetS risk score, including BMI (HR=1.906, 95% CI: 1.040–1.155), FPG (HR=1.507, 95% CI: 1.305–1.741), DBP (HR=1.061, 95% CI: 1.002–1.031), HDL-C (HR=0.539, 95% CI: 0.303–0.959). The model was created as –1.5 to 4 points, which demonstrated a considerable discrimination both in the training cohort (AUROC=0.674) and validation cohort (AUROC=0.690). Comparison of the observed with the estimated incidence of MetS revealed satisfactory precision. We developed and validated the MetS risk score with 4 risk factors to predict 3-year risk of MetS, useful for assessing the individual risk for MetS in medical practice.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

https://ift.tt/2wKOj7K

Panhypopituitarism Without GH Replacement: About Insulin Sensitivity, CRP Levels, and Metabolic Syndrome

Horm Metab Res 2018; 50: 690-695
DOI: 10.1055/a-0649-8010

A complete deficiency of anterior pituitary hormones from several etiologies characterizes Panhypopituitarism (PH). Despite advances in treatment, patients with PH maintain high rates of morbidity and mortality, a reason to investigate some insulin sensitivity, metabolic and inflammatory parameters that could be related to the increase of these indicators. This was a cross-sectional study comprising 41 PH patients under hormonal replacement, except for growth hormone, and 37 individuals in a control group (CG) with similar age, gender and body mass index (BMI). We assessed clinical data as age, sex, BMI, waist circumference, waist/hip ratio (WHR), history of hypertension, diabetes mellitus and dyslipidemia as well as fasting glycaemia, insulin, HOMA-IR, HbA1c, high-sensitivity CRP (hs-CRP), and lipid profile. PH patients presents lower values of glycaemia, insulin, HOMA-IR (0.88 vs 2.1) and WHR, but higher levels of hs-CRP (0.38 vs 0.16mg/dl) when compared with the CG. Although the occurrence of dyslipidemia was higher in patients with PH, the frequency of metabolic syndrome was similar between the groups. In multivariate linear regression analysis, the PH group independently predicted lower HOMA-IR and WHR values. In conclusion, this study demonstrated that patients with PH without GH replacement have lower HOMA-IR and WHR values and higher levels of hs-CRP than a CG paired by age, gender and BMI. The diagnosis of dyslipidemia was more frequent in patients with PH, but the occurrence of MS was similar to CG. Further studies are needed to confirm our findings and to better understand the metabolic characteristics of patients with PH.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

https://ift.tt/2PDmu8f

COST SAVINGS USING A TEST-BASED DE-ESCALATION STRATEGY FOR PATIENTS WITH CROHN’S DISEASE IN REMISSION ON OPTIMIZED INFLIXIMAB: A DISCRETE EVENT MODEL STUDY

Drug de-escalation is considered in Crohn's disease patients in sustained remission on optimized infliximab treatment.

https://ift.tt/2NQmkKe

Obstructive jaundice caused by myeloid sarcoma in duodenal ampulla

https://ift.tt/2wOAPaX

Infection Prevention for the Emergency Department

The emergency department (ED) presents unique challenges to infection control and prevention. Hand hygiene, transmission-based precautions, environmental cleaning, high-level disinfection and sterilization of reusable medical devices, and prevention of health care–associated infections (catheter-associated urinary tract infection, ventilator-associated pneumonia, central line–associated bloodstream infection) are key priorities in ED infection prevention. Effective and sustainable infection prevention strategies tailored to the ED are necessary and achievable. Emergency clinicians can and already play an invaluable role in infection prevention.

https://ift.tt/2Q9nB0i

Cerebellar impairment during an orthostatic challenge in patients with neurogenic orthostatic hypotension

Neurogenic Orthostatic Hypotension (NOH) is a cardinal feature of autonomic dysfunction. NOH is clinically defined as a sustained reduction in systolic blood pressure (SBP) ≥30mmHg or diastolic blood pressure of ≥15mmHg within 3 minutes of standing or head-up tilt performed at 60°(Freeman et al. 2011). NOH is unique in that the orthostatic component relates to an excessive BP drop associated with an upright/standing position and the neurogenic component highlights a failure of the autonomic nervous system to reflexively increase sympathetic outflow to counteract the BP drop.

https://ift.tt/2oI7WJ5

Approach to Transplant Infectious Diseases in the Emergency Department

The emergency department (ED) is an increasingly important site of care for patients who have undergone solid organ transplantation or hematopoietic cell transplantation. It is paramount for emergency physicians to recognize infections early on, obtain appropriate diagnostic testing, initiate empirical antimicrobial therapy, and consider specialty consultation and inpatient admission when caring for these patients. This review provides emergency physicians with an approach to the assessment of transplant patients' underlying risk for infection, formulation of a broad differential diagnosis, and initial management of transplant infectious disease emergencies in the ED.

https://ift.tt/2wNHamh

Biothreat Agents and Emerging Infectious Disease in the Emergency Department

The challenges faced by the emergency physician with recognizing and treating category A biothreat agents and emerging infectious disease are summarized and reviewed.

https://ift.tt/2wNH8Lb

Community-Acquired Pneumonia

Community-acquired pneumonia is one of the most common infections seen in emergency department patients. There is a wide spectrum of disease severity and viral pathogens are common. After a careful history and physical examination, chest radiographs may be the only diagnostic test required. The first step in management is risk stratification, using a validated clinical decision rule and serum lactate, followed by early antibiotics and fluid resuscitation when indicated. Antibiotics should be selected with attention to risk factors for multidrug-resistant respiratory pathogens. Broad use of pneumococcal vaccine in adults and children can prevent severe community-acquired pneumonia.

https://ift.tt/2Q94Pqb

Reduced Postburn Hypertrophic Scarring and Improved Physical Recovery With Yearlong Administration of Oxandrolone and Propranolol

Background: Massive burns induce a hypermetabolic response that leads to total body wasting and impaired physical and psychosocial recovery. The administration of propranolol or oxandrolone positively affects postburn metabolism and growth. The combined administration of oxandrolone and propranolol (OxProp) for 1 year restores growth in children with large burns. Here, we investigated whether the combined administration of OxProp for 1 year would reduce scarring and improve quality of life compared with control. Study Design: Children with large burns (n = 480) were enrolled into this institutional review board-approved study; patients were randomized to control (n = 226) or administration of OxProp (n = 126) for 1 year postburn. Assessments were conducted at discharge and 6, 12, and 24 months postburn. Scar biopsies were obtained for histology. Physical scar assessments and patient reported outcome measures of physical and psychosocial function were obtained. Results: Reductions in cellularity, vascular structures, inflammation, and abnormal collagen (P

https://ift.tt/2MHnC9P

Approach to Transplant Infectious Diseases in the Emergency Department

The emergency department (ED) is an increasingly important site of care for patients who have undergone solid organ transplantation or hematopoietic cell transplantation. It is paramount for emergency physicians to recognize infections early on, obtain appropriate diagnostic testing, initiate empirical antimicrobial therapy, and consider specialty consultation and inpatient admission when caring for these patients. This review provides emergency physicians with an approach to the assessment of transplant patients' underlying risk for infection, formulation of a broad differential diagnosis, and initial management of transplant infectious disease emergencies in the ED.

https://ift.tt/2wNHamh

Infection Prevention for the Emergency Department

The emergency department (ED) presents unique challenges to infection control and prevention. Hand hygiene, transmission-based precautions, environmental cleaning, high-level disinfection and sterilization of reusable medical devices, and prevention of health care–associated infections (catheter-associated urinary tract infection, ventilator-associated pneumonia, central line–associated bloodstream infection) are key priorities in ED infection prevention. Effective and sustainable infection prevention strategies tailored to the ED are necessary and achievable. Emergency clinicians can and already play an invaluable role in infection prevention.

https://ift.tt/2Q9nB0i

Biothreat Agents and Emerging Infectious Disease in the Emergency Department

The challenges faced by the emergency physician with recognizing and treating category A biothreat agents and emerging infectious disease are summarized and reviewed.

https://ift.tt/2wNH8Lb

Community-Acquired Pneumonia

Community-acquired pneumonia is one of the most common infections seen in emergency department patients. There is a wide spectrum of disease severity and viral pathogens are common. After a careful history and physical examination, chest radiographs may be the only diagnostic test required. The first step in management is risk stratification, using a validated clinical decision rule and serum lactate, followed by early antibiotics and fluid resuscitation when indicated. Antibiotics should be selected with attention to risk factors for multidrug-resistant respiratory pathogens. Broad use of pneumococcal vaccine in adults and children can prevent severe community-acquired pneumonia.

https://ift.tt/2Q94Pqb

Improved Outcomes in Preterm Infants Fed a Nonacidified Liquid Human Milk Fortifier: A Prospective Randomized Clinical Trial

To compare growth, feeding tolerance, and clinical and biochemical evaluations in human milk-fed preterm infants randomized to receive either an acidified or a nonacidified liquid human milk fortifier.

https://ift.tt/2wJSZdS

Variability in Antibiotic Prescribing for Upper Respiratory Illnesses by Provider Specialty

To evaluate variation in antibiotic prescribing between pediatric and nonpediatric providers for common upper respiratory illnesses.

https://ift.tt/2wMmomX

Advancement of Feeds in Preterm Low Birth Weight Infants

In the study by Singh et al, the included subjects were infants born preterm with birth weights between 1500 and 2000 g.1 The swallowing reflex generally is developed in these neonates; thus, feeding by spoon, breast, or bottle is possible, and often they do not require gavage feeding. It would have been of more value and relevance had neonates of very low birth weight been included in the study, as necrotizing enterocolitis is more common in these tiny babies.

https://ift.tt/2oIgEXB

Familial Risk of Appendicitis: A Nationwide Population Study

To investigate the familial risk of appendicitis in the general population.

https://ift.tt/2wJ3jlD

Reply

We thank Koestenberger and Hansmann for their interest in our article on pulmonary artery acceleration time (PAAT) measures in preterm infants.1 The true prevalence of pulmonary vascular disease (PVD) and its most severe form, pulmonary hypertension (PH), in preterm infants has been difficult to discern due to the lack of reliable noninvasive indices to account for the main components of right ventricular (RV) afterload. Pulmonary artery acceleration time (PAAT) measures are validated, reliable estimates of invasive pulmonary hemodynamics in children and infants and provide a quantitative method for defining blood flow velocity characteristics in the RV outflow tract in response to changes in ventricular mechanical performance, pulmonary vascular load, and compliance.

https://ift.tt/2oIo7Gn

Persistent Hypoglycemia in Children: Targeted Gene Panel Improves the Diagnosis of Hypoglycemia due to Inborn Errors of Metabolism

To evaluate the role of next generation sequencing in genetic diagnosis of pediatric patients with persistent hypoglycemia.

https://ift.tt/2CloFvg

High-flow nasal oxygen versus noninvasive ventilation in adult patients with cystic fibrosis: a randomized crossover physiological study

Noninvasive ventilation (NIV) is the first-line treatment of adult patients with exacerbations of cystic fibrosis (CF). High-flow nasal oxygen therapy (HFNT) might benefit patients with hypoxemia and can reduc...

https://ift.tt/2MPUuRS

Anti-inflammatory and antioxidant activity of Thai mango ( Mangifera indica Linn.) leaf extracts

Abstract

Mango (Mangifera indica Linn.) has been widely studied as a folk medicines and it has become a common ingredient in cosmeceutical products. However, there was no report on the efficacy of Thai mango leaf extracts against inflammation. Thus, the aim of this study was to ascertain the anti-inflammatory and antioxidant activities of methanol (MeOH) and aqueous (Aq) extracts from the leaves of three mango varieties: Keaw Morakot, Nam Doc Mai, and Mahajanaka. To assay in vitro anti-inflammatory activity, the amount of nitric oxide (NO) released from macrophage cells was indirectly measured. Since free radicals play an important role in the inflammatory process, the antioxidant activity of M. indica leaf extracts was measured by ABTS and DPPH radical scavenging, ascorbic acid, and total phenolic assays. Mangiferin was also analyzed by HPLC. The most effective extract was selected and tested for anti-inflammatory activity in an animal model, an acute ear edema test in albino rats. The MeOH extract of Mahajanaka (M-MeOH) reduced nitric oxide production by LPS-stimulated macrophage cell lines RAW 264.7. M-MeOH showed the strongest antioxidant activity and it was, therefore, selected for an in vivo anti-inflammatory assay. An acute ear edema test in albino rats showed that M-MeOH exhibited significant anti-inflammatory activity compared to the control; ethyl phenylpropiolate-induced ear edema (P < 0.05). Moreover, mangiferin, a bioactive compound in M. indica leaves was detected in MeOH and Aq extracts. We concluded that the MeOH extract of M. indica leaves exhibits an anti-inflammatory property, both in vitro and in vivo, due to the presence of efficacious antioxidants.

https://ift.tt/2wLrzV6

EGR1-mediated transcription of lncRNA-HNF1A-AS1 promotes cell cycle progression in gastric cancer

Long noncoding RNAs (lncRNAs) are dysregulated in various human cancers and control tumor development and progression. However, the upstream mechanisms underlying their dysregulation remain unclear. Here we demonstrate that the expression of hepatocyte nuclear factor 1 homeobox A antisense RNA 1 (HNF1A-AS1) is significantly upregulated in gastric cancer (GC) tissues. Overexpression of HNF1A-AS1 enhanced cell proliferation and promoted cell cycle progression, whereas knockdown of HNF1A-AS1 elicited the opposite effects. Early growth response protein 1 (EGR1) directly bound the HNF1A-AS1 promoter region and activated its transcription. Overexpression of EGR1 enhanced cell proliferation and promoted cell cycle promotion, similar to the function of HNF1A-AS1. HNF1A-AS1 functioned as competing endogenous RNA (ceRNA) by binding to miR-661, upregulating the expression of cell division cycle 34 (CDC34), which is a direct target of miR-661. EGR1 and HNF1A-AS1 enhanced the expression of cyclin-dependent kinase 2 (CDK2), CDK4, and cyclin E1 but inhibited the expression of p21 by promoting CDC34-mediated ubiquitination and degradation of p21. Taken together, these findings suggest that EGR1-activated HNF1A-AS1 regulates various pro- and anti-growth factors to promote the development of GC, implicating it as a possible target for therapeutic intervention in this disease.

https://ift.tt/2wGkhky

Induction of paracrine signaling in metastatic melanoma cells by PPAR{gamma} agonist rosiglitazone activates stromal cells and enhances tumor growth

In addition to improving insulin sensitivity in type 2 diabetes, the thiazolidinedione family of compounds and the pharmacologic activation of their best characterized target PPARγ has been proposed as a therapeutic option for cancer treatment. In this study, we reveal a new mode of action for the thiazolidinedione rosiglitazone that can contribute to tumorigenesis. Rosiglitazone activated a tumorigenic paracrine communication program in a subset of human melanoma cells that involves the secretion of cytokines, chemokines, and angiogenic factors. This complex blend of paracrine signals activated non-malignant fibroblasts, endothelial cells, and macrophages in a tumor-friendly way. In agreement with these data, rosiglitazone promoted human melanoma development in xenografts, and tumors exposed to rosiglitazone exhibited enhanced angiogenesis and inflammation. Together, these findings establish an important tumorigenic action of rosiglitazone in a subset of melanoma cells. While studies conducted on cohorts of diabetic patients report overall benefits of thiazolidinediones in cancer prevention, our data suggest that exposure of established tumors to rosiglitazone may be deleterious.

https://ift.tt/2Q6Zrni

VEGFC antibody therapy drives differentiation of AML

High expression of vascular endothelial growth factor C (VEGFC) predicts adverse prognosis in acute myeloid leukemia (AML). We therefore explored VEGFC targeting efficacy as an AML therapy using a VEGFC monoclonal antibody. VEGFC antibody therapy enforced myelocytic differentiation of clonal CD34+ AML blasts. Treatment of CD34+ AML blasts with the antibody reduced expansion potential by 30-50% and enhanced differentiation via FOXO3A suppression and inhibition of MAPK/ERK proliferative signals. VEGFC antibody therapy also accelerated leukemia cell differentiation in a systemic humanized AML mouse model. Collectively, these results define a regulatory function of VEGFC in CD34+ AML cell fate decisions via FOXO3A and serve as a new potential differentiation therapy for AML patients.

https://ift.tt/2M6HBxK

CDK8 selectively promotes the growth of colon cancer metastases in the liver by regulating gene expression of TIMP3 and matrix metalloproteinases

Unresectable hepatic metastases of colon cancer respond poorly to existing therapies and are a major cause of colon cancer lethality. In this study, we evaluated the therapeutic viability of targeting the Mediator kinase CDK8, an early clinical stage drug target, as a means to suppress metastasis of colon cancer. CDK8 was amplified or overexpressed in many colon cancers and CDK8 expression correlated with shorter patient survival. Knockdown or inhibition of CDK8 had little effect on colon cancer cell growth but suppressed metastatic growth of mouse and human colon cancer cells in the liver. This effect was due in part to inhibition of already established hepatic metastases, indicating therapeutic potential of CDK8 inhibitors in the metastatic setting. In contrast, knockdown or inhibition of CDK8 had no significant effect on the growth of tumors implanted subcutaneously, intrasplenically, or orthotopically in the cecum. CDK8 mediated colon cancer growth in the liver through downregulation of matrix metalloproteinase (MMP) inhibitor TIMP3 via TGFβ/SMAD-driven expression of a TIMP3-targeting microRNA, miR-181b, along with induction of Mmp3 in murine or MMP9 in human colon cancer cells via Wnt/beta-catenin-driven transcription. These findings reveal a new mechanism for negative regulation of gene expression by CDK8 and a site-specific role for CDK8 in colon cancer hepatic metastasis. Our results indicate the utility of CDK8 inhibitors for the treatment of colon cancer metastases in the liver and suggest that CDK8 inhibitors may be considered in other therapeutic settings involving TGFbeta/SMAD or Wnt/beta-catenin pathway activation.

https://ift.tt/2Q5dwS9

Pooled analysis of nine cohorts reveals breast cancer risk factors by tumor molecular subtype

Various subtypes of breast cancer defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) exhibit etiological differences in reproductive factors, but associations with other risk factors are inconsistent. To clarify etiological heterogeneity, we pooled data from nine cohort studies. Multivariable, joint Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for molecular subtypes. Of 606,025 women, 11,741 invasive breast cancers with complete tissue markers developed during follow-up: 8,700 luminal A-like (ER+ or PR+/HER2-), 1,368 luminal B-like (ER+ or PR+/ HER2+), 521 HER2-enriched (ER-/PR-/HER2+), and 1,152 triple-negative (ER-/PR-/HER2-) disease. Ever parous compared to never was associated with lower risk of luminal A-like (HR=0.78, 95% CI 0.73 - 0.83) and luminal B-like (HR=0.74, 95% CI 0.64 - 0.87) as well as a higher risk of triple negative disease (HR=1.23, 95% CI 1.02 - 1.50; p-value for overall tumor heterogeneity <0.001). Direct associations with luminal-like, but not HER2-enriched or triple negative, tumors were found for age at first birth, years between menarche and first birth, and age at menopause (p-value for overall tumor heterogeneity <0.001). Age-specific associations with baseline body mass index differed for risk of luminal A-like and triple-negative breast cancer (p-value for tumor heterogeneity=0.02). These results provide the strongest evidence for etiological heterogeneity of breast cancer to date from prospective studies.

https://ift.tt/2M6HzG8

Dual inhibition of DNA and histone methyltransferases increases viral mimicry in ovarian cancer cells

Ovarian cancer ranks as the most deadly gynecologic cancer and there is an urgent need to develop more effective therapies. Previous studies have shown that G9A, a histone methyltransferase that catalyzes mono- and di-methylation of histone H3 lysine9, is highly expressed in ovarian cancer tumors, and its overexpression is associated with poor prognosis. Here we report that pharmacological inhibition of G9A in ovarian cancer cell lines with high levels of G9A expression induces synergistic anti-tumor effects when combined with the DNA methylation inhibitor (DNMTi) 5-aza-2'-deoxycytidine (5-aza-CdR). These anti-tumor effects included upregulation of endogenous retroviruses (ERV), activation of the viral defense response, and induction of cell death, which have been termed "viral mimicry" effects induced by DNMTi. G9Ai treatment further reduced H3K9me2 levels within the long terminal repeat (LTR) regions of ERV, resulting in further increases of ERV expression and enhancing "viral mimicry" effects. In contrast, G9Ai and 5-aza-CdR were not synergistic in cell lines with low basal G9A levels. Taken together, our results suggest that the synergistic effects of combination treatment with DNMTi and G9Ai may serve as a novel therapeutic strategy for ovarian cancer patients with high levels of G9A expression.

https://ift.tt/2Q8a4X2

HORMAD1 is a negative prognostic indicator in lung adenocarcinoma and specifies resistance to oxidative and genotoxic stress

Cancer testis antigens (CTA) are expressed in testis and placenta and anomalously activated in a variety of tumors. The mechanistic contribution of CTAs to neoplastic phenotypes remains largely unknown. Using a chemigenomics approach, we find that the CTA, HORMAD1, correlates with resistance to the mitochondrial complex I inhibitor piericidin A in non-small cell lung cancer (NSCLC). Resistance was due to a reductive intracellular environment that attenuated the accumulation of free radicals. In human lung adenocarcinoma (LUAD) tumors, patients expressing high HORMAD1 exhibited elevated mutational burden and reduced survival. HORMAD1 tumors were enriched for genes essential for homologous recombination (HR), and HORMAD1 promoted RAD51-filament formation, but not DNA resection, during HR. Accordingly, HORMAD1 loss enhanced sensitivity to gamma-irradiation and PARP inhibition, and HORMAD1 depletion significantly reduced tumor growth in vivo. These results suggest that HORMAD1 expression specifies a novel subtype of LUAD, which has adapted to mitigate DNA damage. In this setting, HORMAD1 could represent a direct target for intervention to enhance sensitivity to DNA damaging agents or as an immunotherapeutic target in patients.

https://ift.tt/2wOsTFI

Large-scale Three-dimensional Imaging of Cellular Organization in the Mouse Neocortex

Here we describe a procedure for tissue clearing, fluorescent labeling, and large-scale imaging of mouse brain tissue which, thereby, enables visualization of the three-dimensional organization of cell types in the neocortex.

https://ift.tt/2MQOTuG

Surface Functionalization of Metal-Organic Frameworks for Improved Moisture Resistance

Robust functional catechol coatings were produced in one step by direct reaction of the material known as HKUST with synthetic catechols under anaerobic conditions. The formation of homogeneous coatings surrounding the entire crystal is ascribed to the biomimetic catalytic activity of Cu(II) dimers on the external surface of the crystals.

https://ift.tt/2PGIvmz

Bioindication Testing of Stream Environment Suitability for Young Freshwater Pearl Mussels Using In Situ Exposure Methods

In situ bioindications enable determination of the suitability of an environment for endangered mussel species. We describe two methods based on the juvenile exposure of freshwater pearl mussels in cages to oligotrophic river habitats. Both methods are implemented in variants for open water and hyporheic water environments.

https://ift.tt/2MQOHvs

Generation of High-Throughput Three-Dimensional Tumor Spheroids for Drug Screening

Across a wide variety of disease indications, more physiologically relevant models are being developed and implemented into drug discovery programs. The new model system described here demonstrates how three-dimensional tumor spheroids can be cultured and screened in a high-throughput 1536-well plate-based system to search for new oncology drugs.

https://ift.tt/2PI81rP

Design and Use of an Apparatus for Quantifying Bivalve Suspension Feeding at Sea

A flow-through device for using the biodeposition method to quantify filtration and feeding behavior of bivalve mollusks was modified for shipboard use. A two-dimensional gimbal table built around the device isolates the apparatus from boat motion, thereby allowing the accurate quantification of bivalve filtration variables at offshore shellfish aquaculture sites.

https://ift.tt/2Ni8OlI

Phase Contrast Magnetic Resonance Imaging in the Rat Common Carotid Artery

The overall goal of this procedure is to measure the blood flow in the rat common carotid artery by using noninvasive phase contrast magnetic resonance imaging.

https://ift.tt/2PGHpHE

The Cutting and Floating Method for Paraffin-embedded Tissue for Sectioning

Here, we present a protocol to improve paraffin sectioning. This method combines cutting and floating using a simple thermostatic chamber to avoid the transfer process required by the conventional method. As a result, the efficiency and the number of intact paraffin sections were greatly improved.

https://ift.tt/2MRf1FJ

Evolution of Staircase Structures in Diffusive Convection

Diffusive convection (DC) widely occurs in natural processes and engineering applications, characterized by a series of staircases with homogeneous convecting layers and stratified interfaces. An experimental procedure is described to simulate the evolution process of the DC staircase structure, including the generation, development and disappearance, in a rectangular tank.

https://ift.tt/2NOhgpO

Cognitive Function 3 and 12 Months After ICU Discharge—A Prospective Cohort Study

Objectives: Studies have shown impaired cognitive function after ICU discharge. We aimed to describe long-term cognitive function in Danish ICU patients. Design: Prospective cohort study. Setting: Single-center ICU at Zealand University Hospital, Køge, Denmark. Patients: Adult patients admitted for over 24 hours. Intervention: Three and 12 months after discharge, the patients were visited at home and tested with the Repeatable Battery for the Assessment of Neuropsychological Status. Measurements and Main Results: We included 161 patients, 79 patients had a 3-month and 53 a 12-month follow-up visit. The primary reasons for not being visited at 3-month were death (44 patients), decline (26 patients), or transferal to another ICU (6 patients). Visited patients were median 67 years old (interquartile range, 59–73), had a median Acute Physiology and Chronic Health Evaluation score of 20 (interquartile range, 16–26), 58% were on a ventilator, and 30% were surgical patients. The mean Repeatable Battery for the Assessment of Neuropsychological Status score was 67 (SD, 21), compared with a normal value of 100 (15). A total of 57% had Repeatable Battery for the Assessment of Neuropsychological Status scores corresponding to moderate traumatic brain injury, 46% scored corresponding to light Alzheimer's disease, and 73% corresponding to mild cognitive impairment. After 12 months, the Repeatable Battery for the Assessment of Neuropsychological Status was still reduced (71 [25]). We examined protective and risk factors using multiple linear regression and found protective effects of being employed before admission (p = 0.0005) or being admitted from a surgical ward (p = 0.019). Conclusions: In this prospective cohort study of Danish ICU patients, we found significantly reduced cognitive function for intensive care patients 3 and 12 months after discharge. Supported, in part, by Aase and Ejnar Danielsens Fund, The Danish Society for Anaesthesiology and Intensive Care Medicine's research initiative, and the Intensive Care Symposium Hindsgavl. Drs. Estrup's, Kjer's, Vilhelmsen's, and Mathiesen's institution received funding from Aase og Ejnar Danielsens fund, The Danish Society for Anaesthesiology and Intensive Care Medicine's Research Initiative, and Intensive Care Symposium Hindsgavl. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: sed@regionsjaelland.dk Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

https://ift.tt/2CnOCKS

Seizure Identification by Critical Care Providers Using Quantitative Electroencephalography

Objectives: To compare the performance of critical care providers with that of electroencephalography experts in identifying seizures using quantitative electroencephalography display tools. Design: Diagnostic accuracy comparison among healthcare provider groups. Setting: Multispecialty quaternary children's hospital in Canada. Subjects: ICU fellows, ICU nurses, neurophysiologists, and electroencephalography technologists. Intervention: Two-hour standardized one-on-one training, followed by a supervised individual review of 27 continuous electroencephalography recordings with the task of identifying individual seizures on eight-channel amplitude-integrated electroencephalography and color density spectral array displays. Measurements and Main Results: Each participant reviewed 27 continuous electroencephalograms comprising 487 hours of recording containing a total of 553 seizures. Performance for seizure identification was compared among groups using a nested model analysis with adjustment for interparticipant variability within groups and collinearity among recordings. Using amplitude-integrated electroencephalography, sensitivity for seizure identification was comparable among ICU fellows (83.8%), ICU nurses (73.1%), and neurophysiologists (81.5%) but lower among electroencephalographic technologists (66.7%) (p = 0.003). Using color density spectral array, sensitivity was comparable among ICU fellows (82.4%), ICU nurses (88.2%), neurophysiologists (83.3%), and electroencephalographic technologists (73.3%) (p = 0.09). Daily false-positive rates were also comparable among ICU fellows (2.8 for amplitude-integrated electroencephalography, 7.7 for color density spectral array), ICU nurses (4.2, 7.1), neurophysiologists (1.2, 1.5), and electroencephalographic technologists (0, 0) (p = 0.41 for amplitude-integrated electroencephalography; p = 0.13 for color density spectral array). However, performance varied greatly across individual electroencephalogram recordings. Professional background generally played a greater role in determining performance than individual skill or electroencephalogram recording characteristics. Conclusions: Following standardized training, critical care providers and electroencephalography experts displayed similar performance for identifying individual seizures using both amplitude-integrated electroencephalography and color density spectral array displays. Although these quantitative electroencephalographic trends show promise as a tool for bedside seizure screening by critical care providers, these findings require confirmation in a real-world ICU environment and in daily clinical use. 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/29S62lw). Supported, in part, by research grants from the Physicians' Services Incorporated Foundation, The Hospital for Sick Children Foundation, and the Canadian Institutes of Health Research. Dr. Hahn's institution received funding from Physician's Services Incorporated Foundation, Canadian Institutes of Health Research, and the Hospital for Sick Children Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: cecil.hahn@sickkids.ca Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

https://ift.tt/2MT7s1l

Pulse Pressure: A Risk Factor for Renal Transplant Failure or a Useful Therapeutic Target?

No abstract available

https://ift.tt/2Q87Jvd

Does teething cause a baby to vomit?

Vomiting and fever may sometimes accompany teething. Teething is a normal part of a child's development that may cause some discomfort. However, it is unlikely that teething is a direct cause of vomiting. In this article, we suggest other possible causes of vomiting and discuss how to relieve the symptoms of teething.

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Pulse Pressure and Outcome in Kidney Transplantation: Results From the Collaborative Transplant Study

Background Systolic (SBP) and diastolic blood pressure (DBP) are important predictors of graft and patient survival in renal transplantation. Pulse pressure (PP), the difference between systolic and diastolic pressure, has been associated with cardiovascular and renal morbidity in nontransplant epidemiological studies and clinical trials. Methods In this large retrospective analysis of prospectively collected data, transplant recipients from 1995 to 2015 were examined for patient and death-censored graft survival. Results In 43 006 recipients a higher 1-year PP was significantly associated with inferior 10-year patient and death-censored graft survival. In patients aged ≥60 SBP but not DBP was associated with 10-year survival, an effect that was pronounced in patients with a normal SBP of

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How Far can we Expand Donor Age Criteria for Pancreas Transplantation?

No abstract available

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Reply to “How Far can we Expand Donor Age Criteria for Pancreas Transplantation?”

No abstract available

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Radiology trainees forum survey report on workplace satisfaction, ESR education, mobility and stress level

Abstract

Objectives

The Radiology Trainees Forum (RTF) of the European Society of Radiology (ESR) conducted a survey among radiologists in training to gather and evaluate data on workplace satisfaction, ESR educational initiatives, mobility of professionals and stress levels.

Methods

A questionnaire was forwarded to radiologists in training across Europe. The subject of the questionnaire was related to: (1) the working place, (2) safety of the working environment, (3) satisfaction at the working place, (4) familiarity with educational initiatives within the ESR and (5) reasons and motivation for mobility. Results were obtained and analysed.

Results

Invitations to participate were sent by the ESR office to radiologists in training across Europe. A total of 1045 radiologists responded to the questionnaire; 77.8% were trainees and 22.2% were certified radiologists. Of the responders 65.3% considered the working place safe. Only 25.7% considered themselves involved in management, 43.9% would consider working in another country, and 52.3% were moderately satisfied with their working place. Of the responders 46.8% did not have any teaching responsibilities; 59.7% knew the European Diploma in Radiology (EDiR) and 69.7% were not aware of the content of the ESR European Training Curriculum (ETC).

Conclusion

The level of training in aspects related to management safety and quality is low among trainees. The level of satisfaction at work is adequate but not sufficient. The degree of responsibility in training tasks is scarce. A small percentage is familiar with the ESR educational initiatives. As for the mobility the main reservation is lack of confidence in the training acquired.

Main Messages

• For satisfaction levels to improve, it is vital to include more creative aspects of the profession, such as research and teaching, in balance with the routine aspects of radiology.

• Furthermore, a greater involvement of radiologists in patient care is also essential in radiology training.

• To facilitate mobility, it is important to standardise training across European countries through universal programmes and training controls such as the EDiR and the ETC.

https://ift.tt/2NhH54C

The ESR Audit Tool (Esperanto): genesis, contents and pilot

Abstract

Clinical audit is a powerful tool to improve patient care, experience and outcome. It consists of measuring a clinical outcome or procedure against predefined standards, identifying differences between current practice and the standards, and changing practice where necessary to facilitate meeting the standards, followed by re-audit (the audit cycle). The recently implemented European Council Basic Safety & Standards (BSS) Directive (2013/59/Euratom) emphasises that carrying out clinical audit is compulsory in the EU "in accordance with national requirements". In 2017, the ESR published a Clinical Audit Tool booklet (Esperanto), consisting of an explanation of clinical audit, guidance on how to start a program in a radiology department, and 17 sample audit templates which could guide departments through the process of performing audits. A sample of key audits from these templates was performed by participating EuroSafe Imaging Star departments as a pilot project, with participants providing feedback on the audit process, and their experience of using the templates. Responses showed that the chosen topics were relevant, the audit process and templates were straightforward and easy to use, and that the audit process was time-efficient. Following this successful pilot, the Audit Tool has been made available for all potential users through the ESR website.

Key Points

• Clinical audit is the process of assessing one's practice against defined standards, altering practice if necessary to meet standards, and re-assessing following changes to confirm improvement

• Clinical audit should be part of practice in all radiology departments

• Under European Council Directive 2013/59/Euratom, clinical audit is compulsory in the EU "in accordance with national requirements"

• The ESR has developed a Clinical Audit Tool (Esperanto) to explain the process and guide departments through sample audit templates

• This Clinical Audit Tool was successfully piloted in 2017, and is now available to all users on the ESR website

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Intracortical Microstimulation Modulates Cortical Induced Responses

Recent advances in cortical prosthetics relied on intracortical microstimulation (ICMS) to activate the cortical neural network and convey information to the brain. Here we show that activity elicited by low-current ICMS modulates induced cortical responses to a sensory stimulus in the primary auditory cortex (A1). A1 processes sensory stimuli in a stereotyped manner, encompassing two types of activity: evoked activity (phase-locked to the stimulus) and induced activity (non-phase-locked to the stimulus). Time-frequency analyses of extracellular potentials recorded from all layers and the surface of the auditory cortex of anesthetized guinea pigs of both sexes showed that ICMS during the processing of a transient acoustic stimulus differentially affected the evoked and induced response. Specifically, ICMS enhanced the long-latency-induced component, mimicking physiological gain increasing top-down feedback processes. Furthermore, the phase of the local field potential at the time of stimulation was predictive of the response amplitude for acoustic stimulation, ICMS, as well as combined acoustic and electric stimulation. Together, this was interpreted as a sign that the response to electrical stimulation was integrated into the ongoing cortical processes in contrast to substituting them. Consequently, ICMS modulated the cortical response to a sensory stimulus. We propose such targeted modulation of cortical activity (as opposed to a stimulation that substitutes the ongoing processes) as an alternative approach for cortical prostheses.

SIGNIFICANCE STATEMENT Intracortical microstimulation (ICMS) is commonly used to activate a specific subset of cortical neurons, without taking into account the ongoing activity at the time of stimulation. Here, we found that a low-current ICMS pulse modulated the way the auditory cortex processed a peripheral stimulus, by supra-additively combining the response to the ICMS with the cortical processing of the peripheral stimulus. This artificial modulation mimicked natural modulations of response magnitude such as attention or expectation. In contrast to what was implied in earlier studies, this shows that the response to electrical stimulation is not substituting ongoing cortical activity but is integrated into the natural processes.

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Correlations Between Primary Motor Cortex Activity with Recent Past and Future Limb Motion During Unperturbed Reaching

Many studies highlight that human movements are highly successful yet display a surprising amount of variability from trial to trial. There is a consistent pattern of variability throughout movement: initial motor errors are corrected by the end of movement, suggesting the presence of a powerful online control process. Here, we analyze the trial-by-trial variability of goal-directed reaching in nonhuman primates (five male Rhesus monkeys) and demonstrate that they display a similar pattern of variability during reaching, including a strong negative correlation between initial and late hand motion. We then demonstrate that trial-to-trial neural variability of primary motor cortex (M1) is positively correlated with variability of future hand motion ( = ~160 ms) during reaching. Furthermore, the variability of M1 activity is also correlated with variability of past hand motion ( = ~90 ms), but in the opposite polarity (i.e., negative correlation). Partial correlation analysis demonstrated that M1 activity independently reflects the variability of both past and future hand motions. These findings provide support for the hypothesis that M1 activity is involved in online feedback control of motor actions.

SIGNIFICANCE STATEMENT Previous studies highlight that primary motor cortex (M1) rapidly responds to either visual or mechanical disturbances, suggesting its involvement in online feedback control. However, these studies required external disturbances to the motor system and it is not clear whether a similar feedback process addresses internal noise/errors generated by the motor system itself. Here, we introduce a novel analysis that evaluates how variations in the activity of M1 neurons covary with variations in hand motion on a trial-to-trial basis. The analyses demonstrate that M1 activity is correlated with hand motion in both the near future and the recent past, but with opposite polarity. These results suggest that M1 is involved in online feedback motor control to address errors/noise within the motor system.

https://ift.tt/2wJNw6G

Evaluating the Columnar Stability of Acoustic Processing in the Human Auditory Cortex

Using ultra-high field fMRI, we explored the cortical depth-dependent stability of acoustic feature preference in human auditory cortex. We collected responses from human auditory cortex (subjects from either sex) to a large number of natural sounds at submillimeter spatial resolution, and observed that these responses were well explained by a model that assumes neuronal population tuning to frequency-specific spectrotemporal modulations. We observed a relatively stable (columnar) tuning to frequency and temporal modulations. However, spectral modulation tuning was variable throughout the cortical depth. This difference in columnar stability between feature maps could not be explained by a difference in map smoothness, as the preference along the cortical sheet varied in a similar manner for the different feature maps. Furthermore, tuning to all three features was more columnar in primary than nonprimary auditory cortex. The observed overall lack of overlapping columnar regions across acoustic feature maps suggests, especially for primary auditory cortex, a coding strategy in which across cortical depths tuning to some features is kept stable, whereas tuning to other features systematically varies.

SIGNIFICANCE STATEMENT In the human auditory cortex, sound aspects are processed in large-scale maps. Invasive animal studies show that an additional processing organization may be implemented orthogonal to the cortical sheet (i.e., in the columnar direction), but it is unknown whether observed organizational principles apply to the human auditory cortex. Combining ultra-high field fMRI with natural sounds, we explore the columnar organization of various sound aspects. Our results suggest that the human auditory cortex contains a modular coding strategy, where, for each module, several sound aspects act as an anchor along which computations are performed while the processing of another sound aspect undergoes a transformation. This strategy may serve to optimally represent the content of our complex acoustic natural environment.

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Central Amygdala Circuits Mediate Hyperalgesia in Alcohol-Dependent Rats

Alcohol withdrawal symptoms contribute to excessive alcohol drinking and relapse in alcohol-dependent individuals. Among these symptoms, alcohol withdrawal promotes hyperalgesia, but the neurological underpinnings of this phenomenon are not known. Chronic alcohol exposure alters cell signaling in the central nucleus of the amygdala (CeA), and the CeA is implicated in mediating alcohol dependence-related behaviors. The CeA projects to the periaqueductal gray (PAG), a region critical for descending pain modulation, and may have a role in alcohol withdrawal hyperalgesia. Here, we tested the roles of (1) CeA projections to PAG, (2) CeA melanocortin signaling, and (3) PAG μ-opioid receptor signaling in mediating thermal nociception and alcohol withdrawal hyperalgesia in male Wistar rats. Our results demonstrate that alcohol dependence reduces GABAergic signaling from CeA terminals onto PAG neurons and alters the CeA melanocortin system, that CeA-PAG projections and CeA melanocortin signaling mediate alcohol withdrawal hyperalgesia, and that μ-opioid receptors in PAG filter CeA effects on thermal nociception.

SIGNIFICANCE STATEMENT Hyperalgesia is commonly seen in individuals with alcohol use disorder during periods of withdrawal, but the neurological underpinnings behind this phenomenon are not completely understood. Here, we tested whether alcohol dependence exerts its influence on pain modulation via effects on the limbic system. Using behavioral, optogenetic, electrophysiological, and molecular biological approaches, we demonstrate that central nucleus of the amygdala (CeA) projections to periaqueductal gray mediate thermal hyperalgesia in alcohol-dependent and alcohol-naive rats. Using pharmacological approaches, we show that melanocortin receptor-4 signaling in CeA alters alcohol withdrawal hyperalgesia, but this effect is not mediated directly at synaptic inputs onto periaqueductal gray-projecting CeA neurons. Overall, our findings support a role for limbic influence over the descending pain pathway and identify a potential therapeutic target for treating hyperalgesia in individuals with alcohol use disorder .

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EMCrit 232 – SteelMan Debate – EMS Field Decisions in Cardiac Arrest with Howie Mell

Stay or Go with Cardiac Arrest in the Field?

EMCrit Project by Scott Weingart.

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S1PR3 Mediates Itch and Pain via Distinct TRP Channel-Dependent Pathways

Sphingosine 1-phosphate (S1P) is a bioactive signaling lipid associated with a variety of chronic pain and itch disorders. S1P signaling has been linked to cutaneous pain, but its role in itch has not yet been studied. Here, we find that S1P triggers itch and pain in male mice in a concentration-dependent manner, with low levels triggering acute itch alone and high levels triggering both pain and itch. Ca²⁺ imaging and electrophysiological experiments revealed that S1P signals via S1P receptor 3 (S1PR3) and TRPA1 in a subset of pruriceptors and via S1PR3 and TRPV1 in a subset of heat nociceptors. Consistent with these findings, S1P-evoked itch behaviors are selectively lost in mice lacking TRPA1, whereas S1P-evoked acute pain and heat hypersensitivity are selectively lost in mice lacking TRPV1. We conclude that S1P acts via different cellular and molecular mechanisms to trigger itch and pain. Our discovery elucidates the diverse roles that S1P signaling plays in somatosensation and provides insight into how itch and pain are discriminated in the periphery.

SIGNIFICANCE STATEMENT Itch and pain are major health problems with few effective treatments. Here, we show that the proinflammatory lipid sphingosine 1-phosphate (S1P) and its receptor, S1P receptor 3 (S1PR3), trigger itch and pain behaviors via distinct molecular and cellular mechanisms. Our results provide a detailed understanding of the roles that S1P and S1PR3 play in somatosensation, highlighting their potential as targets for analgesics and antipruritics, and provide new insight into the mechanistic underpinnings of itch versus pain discrimination in the periphery.

https://ift.tt/2wLAQw8

ED Plays Critical Role in Caring for Patients With Opioid Use Disorder

WEDNESDAY, Sept. 5, 2018 -- Emergency department providers need evidence-based strategies to identify and manage patients with opioid use disorder, according to a review published in the Annals of Emergency Medicine. Herbert C. Duber, M.D., M.P.H.,...

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Fostamatinib Seems Effective for Immune Thrombocytopenia

WEDNESDAY, Sept. 5, 2018 -- Fostamatinib produces clinically meaningful responses in adults with immune thrombocytopenia (ITP), according a study published in the July issue of the American Journal of Hematology. James Bussel, M.D., from Weill...

https://ift.tt/2Nlz8eu

CDC: HPV Vaccination Rates Increasing Among Adolescents

WEDNESDAY, Sept. 5, 2018 -- Human papillomavirus (HPV) vaccination coverage increased 5.1 percentage points from 2016 to 2017, and there was also an increase in the number of adolescents up to date with HPV vaccinations, according to research...

https://ift.tt/2M0GAaf

~3,000 Excess Deaths Estimated Due to Hurricane Maria

WEDNESDAY, Sept. 5, 2018 -- The total excess mortality attributed to Hurricane Maria is estimated at 2,975 deaths, according to a report issued by George Washington University. Researchers from the Milken Institute School of Public Health at the...

https://ift.tt/2MPekg4

Revascularization Beats Amputation for Limb Ischemia

WEDNESDAY, Sept. 5, 2018 -- For patients with critical limb ischemia, long-term survival and costs are similar for endovascular and surgical revascularization techniques, with longer survival and lower costs versus major amputation, according to a...

https://ift.tt/2LZfWyw

WHO Issues Recommendations for Tx Intensification in T2DM

WEDNESDAY, Sept. 5, 2018 -- Recommendations have been developed by the World Health Organization for treatment intensification in type 2 diabetes. The recommendations were published online Sept. 4 in the Annals of Internal Medicine. Gojka Roglic,...

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Public Service Loan Forgiveness Program Has Uncertain Future

WEDNESDAY, Sept. 5, 2018 -- Uncertainty surrounds the future of the Public Service Loan Forgiveness (PSLF) program, according to an Ideas and Opinions article published online Aug. 28 in the Annals of Internal Medicine. Justin A. Grischkan, M.D.,...

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Immune Cells' Gene Expression May Predict Flu Susceptibility

WEDNESDAY, Sept. 5, 2018 -- KLRD1-expressing natural killer cells may be a biomarker for influenza susceptibility, according to a study published recently in Genome Medicine. Erika Bongen, from the Stanford University School of Medicine in...

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Child Participation in Medicaid, CHIP Up From 2013 to 2016

WEDNESDAY, Sept. 5, 2018 -- From 2013 to 2016 there was an increase in children's participation in Medicaid and the Children's Health Insurance Program (CHIP), according to a report published in the August issue of Health Affairs. Jennifer M. Haley,...

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Out-of-Pocket Costs Similar for Infliximab, Infliximab-Dyyb

WEDNESDAY, Sept. 5, 2018 -- Under Medicare Part D, out-of-pocket costs are similar for infliximab and its biosimilar infliximab-dyyb, according to a research letter published in the Sept. 4 issue of the Journal of the American Medical...

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On-Site Treatment of Snow Avalanche Victims: From Bench to Bedside

High Altitude Medicine &Biology, Ahead of Print.


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Table of Contents

Publication date: August 2018

Source: The Spine Journal, Volume 18, Issue 8

Author(s):

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Table of Contents

Publication date: August 2018

Source: The Spine Journal, Volume 18, Issue 8

Author(s):

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Table of Contents

Publication date: August 2018

Source: The Spine Journal, Volume 18, Issue 8

Author(s):

https://ift.tt/2CmKsCX

Table of Contents

Publication date: August 2018

Source: The Spine Journal, Volume 18, Issue 8

Author(s):

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Editorial Board

Publication date: August 2018

Source: The Spine Journal, Volume 18, Issue 8

Author(s):

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Meetings Calendar

Publication date: August 2018

Source: The Spine Journal, Volume 18, Issue 8

Author(s):

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Advancing imaging technologies for patients with spinal pain: with a focus on whiplash injury

Publication date: August 2018

Source: The Spine Journal, Volume 18, Issue 8

Author(s): James M. Elliott, Mark J. Hancock, Rebecca J. Crawford, Andrew C. Smith, David M. Walton

Abstract

Background Context

Radiological observations of soft-tissue changes that may relate to clinical symptoms in patients with traumatic and non-traumatic spinal disorders are highly controversial. Studies are often of poor quality and findings are inconsistent. A plethora of evidence suggests some pathoanatomical findings from traditional imaging applications are common in asymptomatic participants across the life span, which further questions the diagnostic, prognostic, and theranostic value of traditional imaging. Although we do not dispute the limited evidence for the clinical importance of most imaging findings, we contend that the disparate findings across studies may in part be due to limitations in the approaches used in assessment and analysis of imaging findings.

Purpose

This clinical commentary aimed to (1) briefly detail available imaging guidelines, (2) detail research-based evidence around the clinical use of findings from advanced, but available, imaging applications (eg, fat and water magnetic resonance imaging and magnetization transfer imaging), and (3) introduce how evolving imaging technologies may improve our mechanistic understanding of pain and disability, leading to improved treatments and outcomes.

Study Design/Setting

A non-systematic review of the literature is carried out.

Methods

A narrative summary (including studies from the authors' own work in whiplash injuries) of the available literature is provided.

Results

An emerging body of evidence suggests that the combination of existing imaging sequences or the use of developing imaging technologies in tandem with a good clinical assessment of modifiable risk factors may provide important diagnostic information toward the exploration and development of more informed and effective treatment options for some patients with traumatic neck pain.

Conclusions

Advancing imaging technologies may help to explain the seemingly disconnected spectrum of biopsychosocial signs and symptoms of traumatic neck pain.

https://ift.tt/2CotO62

The potential and perils of prognosticating persistent post-traumatic problems from a postpositivist perspective

Publication date: August 2018

Source: The Spine Journal, Volume 18, Issue 8

Author(s): David M. Walton, Paul Phares

Abstract

Background Context

Predicting recovery after traumatic neck pain has become an active area of research but is moving in several different directions with currently little consensus on the important outcomes to predict or relevant variables to predict them.

Purpose

This editorial explores the current state of prognostic (risk)-based tools or algorithms for predicting the likelihood of chronic problems after acute axial trauma, with a focus on traumatic neck pain (ie, whiplash-associated disorder).

Study Design/Setting

This paper has an editorial study design.

Method

This is a narrative commentary.

Results

Prognostic efforts have value in guiding clinical decision-making and optimizing resource allocation to those at highest risk while minimizing iatrogenic disability for those at lower risk, but there are also several important caveats that should be observed when applying and interpreting the results of such tools. These include the biases associated with predicting outcomes based on findings from a single administration of a tool, inappropriate assumptions of causality, assumptions of linear relationships, and inability to consider the unique individual traits and contexts of patients that likely interact with clinical variables to influence the actual degree of risk they impart.

Conclusions

The paper concludes with a brief overview of trends that are likely to dramatically change the field, including creation of large clinical databases and big data analytics.

https://ift.tt/2wU4dNd

Predictors before and after multimodal rehabilitation for pain acceptance and engagement in activities at a 1-year follow-up for patients with whiplash-associated disorders (WAD)—a study based on the Swedish Quality Registry for Pain Rehabilitation (SQRP)

Publication date: August 2018

Source: The Spine Journal, Volume 18, Issue 8

Author(s): Anne Söderlund, Monika Löfgren, Britt-Marie Stålnacke

Abstract

Background Context

Studies have shown that pain acceptance strategies related to psychological flexibility are important in the presence of chronic musculoskeletal pain. However, the predictors of these strategies have not been studied extensively in patients with whiplash-associated disorders (WAD).

Purpose

The purpose of this study was to predict chronic pain acceptance and engagement in activities at 1-year follow-up with pain intensity, fear of movement, perceived responses from significant others, outcome expectancies, and demographic variables in patients with WAD before and after multimodal rehabilitation (MMR).

Study design

The design of this investigation was a cohort study with 1-year postrehabilitation follow-up.

Study setting

The subjects participated in MMR at a Swedish rehabilitation clinic during 2009–2015.

Patient sample

The patients had experienced a whiplash trauma (WAD grade I–II) and were suffering from pain and reduced functionality. A total of 386 participants were included: 297 fulfilled the postrehabilitation measures, and 177 were followed up at 1 year after MMR.

Outcome measures

Demographic variables, pain intensity, fear of movement, perceived responses from significant others, and outcome expectations were measured at the start and after MMR. Chronic pain acceptance and engagement in activities were measured at follow-up.

Methods

The data were obtained from a Swedish Quality Registry for Pain Rehabilitation (SQRPR).

Results

Outcome expectancies of recovery, supporting and distracting responses of significant others, and fear of (re)injury and movement before MMR were significant predictors of engagement in activities at follow-up. Pain intensity and fear of (re)injury and movement after MMR significantly predicted engagement in activities at follow-up. Supporting responses of significant others and fear of (re)injury and movement before MMR were significant predictors of pain acceptance at the 1-year follow-up. Solicitous responses of significant others and fear of (re)injury and movement at postrehabilitation significantly predicted pain acceptance at follow-up.

Conclusion

For engagement in activities and pain acceptance, the fear of movement appears to emerge as the strongest predictor, but patients' perceived reactions from their spouses need to be considered in planning the management of WAD.

https://ift.tt/2Cn8qOn

Both positive and negative beliefs are important in patients with spine pain: findings from the Occupational and Industrial Orthopaedic Center registry

Publication date: August 2018

Source: The Spine Journal, Volume 18, Issue 8

Author(s): Maria M. Wertli, Ulrike Held, Angela Lis, Marco Campello, Sherri Weiser

Abstract

Background Context

Negative beliefs are known to influence treatment outcome in patients with spine pain (SP). The impact of positive beliefs is less clear.

Purpose

We aimed to assess the influence of positive and negative beliefs on baseline and treatment responses in patients with SP.

Study Design/Setting

A retrospective cross-sectional and longitudinal analysis of prospectively collected data of outpatient physical therapy patients with SP was carried out. Questionnaires administered before and during treatment included the STarT Back distress scale (negative beliefs), and expectation and self-efficacy questions (positive beliefs).

Patient Sample

Patients with SP with a baseline assessment and follow-up assessment comprised the study sample.

Outcome Measure

Perceived disability was measured using the Oswestry Disability Index (ODI) or the Neck Disability Index (NDI). A clinical meaningful change (minimum clinically important difference [MCID]) was defined as decrease in ODI or NDI of ≥30%.

Methods

We used the Akaike Information Criterion from the first imputed dataset of the prediction model to select predictor variables. Prediction models were fitted to the outcome variables.

Results

In the cross-sectional analysis, 1,695 low back pain (LBP) episodes and 487 neck pain (NP) episodes were analyzed. STarT Back Screening Tool (SBST)-distress was positively associated with perceived disability in both LBP (beta 2.31, 95% confidence interval [CI] 1.75–2.88) and NP (beta 2.57, 95% CI 1.47–3.67). Lower self-efficacy was negatively associated with more perceived disability for LBP (beta 0.50, 95% CI 0.29–0.72) but not for NP, whereas less positive expectations was associated with more perceived disability in NP (beta 0.57, 95% CI 0.02–1.12) but not in LBP. In the longitudinal analysis, 607 LBP episodes (36%) and 176 (36%) NP episodes were included. SBST-distress did not predict treatment outcome in spine patients. In LBP, patients with a lower positive expectation were less likely to experience an MCID in perceived disability (odds ratio [OR] per point increase 0.89, 95% CI 0.83–0.96), and there was a similar trend in NP (OR per point increase 0.90, 95% CI 0.79–1.03). In patients with LBP, lower self-efficacy at baseline was associated with a higher likelihood that an MCID was achieved (OR per point increase 1.09, 95% CI 1.01–1.19). In NP, self-efficacy was not included in the final model.

Conclusions

Our study demonstrates that both negative and positive beliefs are associated with perceptions of disability. However, in this study, only positive beliefs were associated with treatment outcome.

https://ift.tt/2oJO2O0