A novel conditional Aire allele enables cell specific ablation of the immune tolerance regulator Aire

http://ift.tt/2Aom7dI

Giant cell tumor of temporomandibular joint presenting as a parotid tumor: Challenges in the accurate subclassification of giant cell tumors in an unusual location

Abstract

Fine needle aspiration is frequently used as the initial diagnostic procedure in the work-up of head and neck lesions, including soft tissue masses and salivary gland neoplasms. Giant cell tumors (GCTs), both osseous and extraosseous, are benign tumors that occur, albeit rarely, in the head and neck region. Extraosseous GCTs may be further classified based on their tissue of origin and specific anatomic location. Regardless of location, giant cell tumors are morphologically similar and share cytologic and histologic diagnostic criteria. Evaluation of imaging is therefore essential to the correct classification of these tumors. Accurate diagnosis is crucial since the clinical behavior and treatment is significantly different among the subtypes of GCTs. The case presented herein illustrates the diagnostic dilemma between two uncommon entities in an unusual site: GCT of parotid gland and tenosynovial GCT.

http://ift.tt/2jxDCOc

Primary cutaneous aspergillosis, mimicking malignancy, a rare presentation in an immunocompetent patient

Aspergillus species are ubiquitous opportunistic molds that cause both allergic and invasive syndromes. A 65-year-old female, farmer by occupation, presented with left upper limb and trunk swelling for one year, associated with pain, tightening of skin, and vesicles with watery discharge. Local examination showed a diffuse swelling extending from left arm to forearm and lateral chest wall associated with edema, induration, and raised temperature. The swelling was firm to hard with superficial skin ulcers and black eschar. Hematological investigations of the patient showed raised total WBC count and peripheral blood eosinophilia. Patient had no history suggesting immunosuppression. Clinico-radiological impression was left breast carcinoma with secondary skin involvement. fine-needle aspiration cytology (FNAC) from the swelling showed inflammatory cells, necrosis, epitheloid cell granulomas, and giant cells along with branching hyphae of variable thickness, confirmed on Gomori Methenamine Silver stain as fungal hyphae. Culture was advised which identified the species as Aspergillius fumigatus. Primary cutaneous infection by A. fumigatus in an immunocompetent patient is unheard of. FNAC has an important role in resolving diagnostic dilemma in primary cutaneous aspergillosis, which may mimic malignancy as in our case.

http://ift.tt/2i4z29Y

Implementing noninvasive follicular thyroid neoplasm with papillary-like nuclear features may potentially impact the risk of malignancy for thyroid nodules categorized as AUS/FLUS and FN/SFN

Background

Noninvasive encapsulated follicular variant of papillary thyroid carcinoma (PTC) has recently been reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Implementation of the new terminology may alter the implied risk of malignancy (ROM) across the six categories of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC).

Methods

The study cohort consisted of thyroid fine needle aspiration (FNA) cases which were assessed between January 2011 and June 2016 and led to surgical resections. For each case, patient demographics as well as cytologic and corresponding histologic diagnoses were recorded. The surgical specimens diagnosed as follicular variant of PTC (FVPTC) were re-reviewed to identify cases that met the diagnostic criteria for NIFTP. The ROM with and without exclusion of NIFTP from malignant categorization, as well as the relative change in ROM were calculated for individual categories of TBSRTC.

Results

A total of 908 FNA cases with surgical follow-up were retrieved and PTC was identified in 252 (27.8%) surgical specimens. Twenty-nine of 252 (11.5%) were initially classified as FVPTC, of which 17 (6.7%) were reclassified as NIFTP. The cytologic interpretations for the majority of NIFTP cases were atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS, n = 8) or follicular neoplasm/suspicious for neoplasm/(FN/SFN, n = 4). Excluding NIFTP from malignant categorization resulted in a relative decrease in ROM in AUS/FLUS (25.8%) and FN/SFN (22.3%) categories.

Conclusion

Our institutional data demonstrates that eliminating NIFTP from malignant categorization may result in a reduction of the implied ROM for AUS/FLUS and FN/SFN categories.

http://ift.tt/2jvYlSL

Primary cutaneous mucoepidermal carcinoma

Mucoepidermal carcinoma (MEC) is a tumour having mixed components of mucus secreting and epidermoid cells. Salivary glands are the the most common site of origin. Primary cutaneous MEC is a rare presentation. We report a primary cutaneous MEC in a 98-year-old woman presenting a noduloulcerative lesion over the dorsum of the nose. Histopathology of the tumour showed nests of epidermoid cells with glandular differentiation and mucin production. The diagnosis was confirmed by immunohistochemistry.

http://ift.tt/2By0S71

Systemic thrombolysis in a patient with massive pulmonary embolism and recent glioblastoma multiforme resection

While trials of systemic thrombolysis for submassive and massive pulmonary embolism (PE) report intracranial haemorrhage (ICH) rates of 2%–3%, the risk of ICH in patients with recent brain surgery or intracranial neoplasm is unknown since these patients were excluded from these trials. We report a case of massive PE treated with systemic thrombolysis in a patient with recent neurosurgery for an intracranial neoplasm. We discuss the risks and benefits of systemic thrombolysis for massive PE in the context of previous case reports, prior cohort studies and trials, and current guidelines. There may be times when the immediate risk of death from massive PE outweighs the risk of ICH from systemic thrombolysis, even when guideline-listed major contraindications exist. This case provides an example of how the haemodynamic benefit of systemic thrombolysis outweighed the impact of ICH in a patient who had undergone recent neurosurgical resection of a glioblastoma multiforme tumour.

http://ift.tt/2kar0Rf

Lyric hearing aid: a rare cause of benign necrotising otitis externa/external ear canal cholesteatoma

An 80-year-old Caucasian man presented with an incidental and asymptomatic lesion in his right ear thought to be secondary to his use of hearing aids for presbycusis. He used Lyric hearing aids, designed for 24 hours-a-day use for 4 months at a time and had no other previous otological problems. He underwent a bony meatoplasty and vascular flap reconstruction via a retroauricular approach to remove the lesion for histological analysis and regrafting of the area. The lesion was confirmed on histopathology as an ear canal cholesteatoma.

http://ift.tt/2By0PrR

Follicular bronchiolitis in an HIV-infected individual on combination antiretroviral therapy with low CD4+ cell count but sustained viral suppression

A 36-year-old Danish man, living in Asia, was diagnosed with Pneumocystis pneumonia (PCP) and HIV in 2013 (CD4+ count: 6 cells/µL; viral load: 518 000 copies/mL). He initiated combination antiretroviral therapy. Later that year, he was also diagnosed with granulomatosis with polyangiitis and was treated with prednisolone. Despite complete viral suppression and increasing CD4+ count (162 cells/µL), he was readmitted with PCP in April 2015. Subsequently, he returned to Denmark (CD4+ count: 80 cells/µL, viral suppression). Over the following months, he developed progressive dyspnoea. Lung function tests demonstrated severely reduced lung capacity with an obstructive pattern and a moderately reduced diffusion capacity. High resolution computer tomography revealed minor areas with tree-in-bud pattern and no signs of air trapping on expiratory views. Lung biopsy showed lymphocytic infiltration surrounding the bronchioles with sparing of the alveolar septa. He was diagnosed with follicular bronchiolitis. The patient spontaneously recovered along with an improvement of the immune system.

http://ift.tt/2kaTjio

Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC

Abstract

Merkel cell carcinoma (MCC) is a highly aggressive, often lethal neuroendocrine cancer. Its carcinogenesis may be either caused by the clonal integration of the Merkel cell polyomavirus into the host genome or by UV-induced mutations. Notably, virally-encoded oncoproteins and UV-induced mutations affect comparable signaling pathways such as RB restriction of cell cycle progression or p53 inactivation. Despite its low incidence, MCC recently received much attention based on its exquisite immunogenicity and the resulting major success of immune modulating therapies. Here, we summarize current knowledge on epidemiology, biology and therapy of MCC as conclusion of the project 'Immune Modulating strategies for treatment of Merkel Cell Carcinoma', which was funded over a 5-year period by the European Commission to investigate innovative immunotherapies for MCC.

http://ift.tt/2zQ3kbN

Urine cell-free microRNA as biomarkers for transitional cell carcinoma

MicroRNA (miRNA) are short nucleotide strands with a regulatory function in the cell. Several miRNAs have been shown to be useful as biomarkers for different neoplasms. The aim of this project was to assess wh...

http://ift.tt/2kacdpA

Social media usage among health care providers

The objective of this study was to evaluate the use of social media among healthcare workers in an attempt to identify how it affects the quality of patient care.

http://ift.tt/2i2kwQ5

Experiencing physical warmth affects implicit attitudes and altruistic behavior toward outgroup in females

Experiencing physical warmth has been demonstrated to influence interpersonal warmth. However, the effects of this metaphorical link in an intergroup context is not clear. The current study aimed to investigat...

http://ift.tt/2Bx8KFY

Operational research within the national tuberculosis control programme in Benin

To document whether the placement of operational research (OR) fellows within disease control programmes in low and middle income countries leads to the implementation of operational research and improvements ...

http://ift.tt/2jxB7eK

Polymorphism rs13334190 in zinc finger protein 469 (ZNF469) is not a risk factor for keratoconus in a Saudi cohort

Polymorphism rs13334190 in the zinc finger protein 469 gene has been suggested to predispose toward a "thin" cornea, which then becomes keratoconic or is directly pathogenic. Thus, we genotyped polymorphism rs...

http://ift.tt/2i2VnF0

Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC

Abstract

Merkel cell carcinoma (MCC) is a highly aggressive, often lethal neuroendocrine cancer. Its carcinogenesis may be either caused by the clonal integration of the Merkel cell polyomavirus into the host genome or by UV-induced mutations. Notably, virally-encoded oncoproteins and UV-induced mutations affect comparable signaling pathways such as RB restriction of cell cycle progression or p53 inactivation. Despite its low incidence, MCC recently received much attention based on its exquisite immunogenicity and the resulting major success of immune modulating therapies. Here, we summarize current knowledge on epidemiology, biology and therapy of MCC as conclusion of the project 'Immune Modulating strategies for treatment of Merkel Cell Carcinoma', which was funded over a 5-year period by the European Commission to investigate innovative immunotherapies for MCC.

http://ift.tt/2zQ3kbN

Chasing Seasonal Influenza — The Need for a Universal Influenza Vaccine

As clinicians in the United States prepare for the start of another influenza season, experts have been watching the Southern Hemisphere winter for hints of what might be in store for us in the North. Reports from Australia have caused mounting concern, with record-high numbers of…

http://ift.tt/2ioKtx1

Chasing Seasonal Influenza — The Need for a Universal Influenza Vaccine

As clinicians in the United States prepare for the start of another influenza season, experts have been watching the Southern Hemisphere winter for hints of what might be in store for us in the North. Reports from Australia have caused mounting concern, with record-high numbers of…

http://ift.tt/2ioKtx1

Bayesian Diallel Analysis Reveals Mx1-Dependent and Mx1-Independent Effects on Response to Influenza A Virus in Mice

Influenza A virus (IAV) is a respiratory pathogen that causes substantial morbidity and mortality during both seasonal and pandemic outbreaks. Infection outcomes in unexposed populations are affected by host genetics, but this host genetic architecture is not well understood. Here we obtain a broad view of how heritable factors affect a mouse model of response to IAV infection using an 8x8 diallel of the eight inbred founder strains of the Collaborative Cross (CC). Expanding on a prior statistical framework for modeling treatment response in diallels, we explore how a range of heritable effects modify acute host response to IAV through 4 days post-infection. Heritable effects in aggregate explained about 57% of the variance in IAV-induced weight loss. Much of this was attributable to a pattern of additive effects that became more prominent through day 4 post-infection and was consistent with previous reports of anti-influenza myxovirus resistance 1 (Mx1) polymorphisms segregating between these strains; the additive effects largely recapitulated haplotype effects observed at the Mx1 locus in a previous study of the incipient CC (pre-CC), and are also replicated here in a CC recombinant intercross (CC-RIX) population. Genetic dominance of protective Mx1 haplotypes was observed to differ by subspecies origin: relative to the domesticus null Mx1 allele, musculus acts dominantly whereas castaneus acts additively. After controlling for Mx1, heritable effects, though less distinct, accounted for about 34% of the phenotypic variance. Implications for future mapping studies are discussed.

http://ift.tt/2BmlMVD

Dissecting the Genetic Architecture of Shoot Growth in Carrot (Daucus carota L.) Using a Diallel Mating Design

Carrot production suffers yield losses under weed pressure, and thus improved competitive ability is a breeding priority. However, continued improvement and in-depth genetic studies for these traits relies on knowledge of the underlying genetic architecture. This study estimated heritable and non-heritable components of carrot shoot growth from a diallel mating design using a Bayesian mixed model. Results directly contribute to improvement efforts by ranking hybrids, identifying useful tester lines, and estimating the genetic and non-genetic influences on traits for improved competitive ability in carrot.

http://ift.tt/2j3RH6R

Dependency of Heterochromatin Domains on Replication Factors

Chromatin structure regulates both genome expression and dynamics in eukaryotes where large heterochromatic regions are epigenetically silenced through the methylation of histone H3K9, histone deacetylation, and assembly of repressive complexes. Previous genetic screens with the fission yeast Schizosaccharomyces pombe have led to the identification of key enzymatic activities and structural constituents of heterochromatin. We report here on additional factors discovered by screening a library of deletion mutants for silencing defects at the edge of a heterochromatic domain bound by its natural boundary - the IR-R⁺ element - or by ectopic boundaries. We found that several components of the DNA replication progression complex (RPC) including Mrc1/Claspin, Mcl1/Ctf4, Swi1/Timeless, Swi3/Tipin and the FACT subunit Pob3 are essential to robust heterochromatic silencing, as are the ubiquitin ligase components Pof3 and Def1 that have been implicated in the removal of stalled DNA and RNA polymerases from chromatin. Moreover, the search identified the cohesin release factor Wpl1 and the forkhead protein Fkh2, both likely to function through genome organization, as well as the Ssz1 chaperone, the Fkbp39 proline cis-trans isomerase, that acts on histone H3P30 and P38 in S. cerevisiae, and the chromatin remodeler Fft3. In addition to their effects in the mating-type region, these factors take part in heterochromatic silencing in pericentromeric regions and telomeres, to various extent, revealing for many a general effect in heterochromatin. This list of factors provides precious new clues with which to study the spatio-temporal organization and dynamics of heterochromatic regions in connection with DNA replication.

http://ift.tt/2BmUH4P

Identifying Genetic Differences Between Dongxiang Blue-Shelled and White Leghorn Chickens Using Sequencing Data

The Dongxiang Blue-shelled chicken is one of the most valuable Chinese indigenous poultry breeds. However, compared to the Italian native White Leghorn, although this Chinese breed possesses numerous favorable characteristics, it also exhibits lower growth performance and fertility. We utilize genotyping sequencing data in this paper obtained via genome reduction on a sequencing platform to detect 100,114 single nucleotide polymorphisms (SNPs) and perform further biological analysis and functional annotation. We employed cross-population extended haplotype homozygosity (XP-EHH), EigenGWAS, and efficient mixed-model association eXpedited (EMMAX) methods to detect areas of the genome which are potential selected regions (PSR) in both chicken breeds, and performed gene ontology (GO) enrichment and quantitative trait loci (QTL) analyses annotating using the Kyoto Encyclopedia of Genes and Genomes (KEGG).The results of this study reveal a total of 2,424 outlier loci (p-value<0.01) of which 2,144 occur in the White Leghorn breed and 280 occur in the Dongxiang Blue-shelled chicken. These correspond to 327 and 94 potentially selected regions containing 297 and 54 genes, respectively. The most significantly selected genes in Blue-shelled chicken are TMEM141 and CLIC3, while the SLCO1B3 gene, related to eggshell color, was identified via EigenGWAS. We show that the White Leghorn genes JARID2, RBMS3, GPC3, TRIB2，ROBO1, SAMSN1, OSBP2 and IGFALS are involved in immunity, reproduction, and growth, and thus might represent footprints of the selection process. In contrast, we identified six significantly enriched pathways in the Dongxiang Blue-shelled chicken that are related to amino acid and lipid metabolism as well as signal transduction. Our results also reveal the presence of a GO term associated with cell metabolism that mainly occurs in the White Leghorn breed, while the most significant QTL regions mapped to the Chicken QTL Database (GG_4.0) for the Dongxiang Blue-shelled breed are predominantly related to lesions, bone mineral content and other related traits compared to tibia length and body weight (i.e. at 14 days, 28 days, 42 days, 70 days) in the White Leghorn. The results of this study highlight differences in growth, immunity and egg quality traits between the two breeds and provide a foundation for the exploration of their genetic mechanisms.

http://ift.tt/2j1Wrd9

Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib

Purpose: Vandetanib is well-tolerated in patients with advanced medullary thyroid carcinoma (MTC). Long-term outcomes and mechanisms of MTC progression have not been reported previously.  Experimental Design:We monitored toxicities and disease status in patients taking vandetanib for hereditary, advanced MTC. Tumor samples were analyzed for molecular mechanisms of disease progression. Results: Seventeen patients (8 male, age 13 (9-17)* years) enrolled; 16 had a RET p.Met918Thr germline mutation. The duration of vandetanib therapy was 6.1 (0.1-9.7+)* years with treatment ongoing in nine patients. Best response was partial response (PR) in ten, stable disease (SD) in six, and progressive disease (PD) in one patient. Duration of response was 7.4 (0.6-8.7+)* and 4.9 (0.6-7.8+)* years in patients with PR and SD, respectively. Six patients died 2.0 (0.4-5.7)* years after progression. Median progression free survival (PFS) was 6.7 years (95% CI: 2.3 years-undefined) and 5-year overall survival (OS) was 88.2% (95% CI 60.6-96.9%). Of 16 patients with a RET p.Met918Thr mutation, progression free survival was 6.7 years (95% CI 3.1-undefined) and 5-year overall survival was 93.8% (95% CI 63.2-99.1%). No patients terminated treatment because of toxicity. DNA sequencing of tissue samples (n=11) identified an increase in copy number alterations across the genome as a potential mechanism of drug resistance. Conclusions:This study demonstrates that vandetanib is safe and results in sustained responses in children and adolescents with hereditary MTC. Our preliminary molecular data suggest that an increase in copy number abnormalities may be associated with tumor progression in hereditary MTC patients treated with vandetanib.

http://ift.tt/2irFU4Z

Premature birth affects the degree of airway dysanapsis and mechanical ventilatory constraints

Abstract

Adult survivors of very preterm birth (≤32 weeks gestational age) without (PRE) and with bronchopulmonary dysplasia (BPD) have obstructive lung disease as evidenced by reduced expiratory airflow at rest and have significant mechanical ventilatory constraints during exercise. Airflow obstruction, under any condition, could be due to several factors including small airways. PRE and/or BPD could have smaller airways than their counterparts born at full-term (CON) due to a greater degree of dysanaptic airway development during the pre- and/or post-natal period. Thus, the purpose of the present study was to compare the dysanapsis ratio (DR), as an index of airway size, between PRE, BPD, and CON. To do so, we calculated DR in PRE (n = 21), BPD (n = 14) and CON (n = 34) individuals, as well as examined flow-volume loops at rest and during sub-maximal exercise. DR, using multiple estimates of static recoil pressure, was significantly smaller in PRE and BPD (0.16 ± 0.05 and 0.10 ± 0.03 AU) compared to CON (0.22 ± 0.04 AU; both P < 0.001) and smallest in BPD (P < 0.001). DR was significantly correlated to peak expiratory airflow at rest (r = 0.42; P < 0.001) and the extent of expiratory flow limitation during exercise (r = 0.60; P < 0.001). Our findings suggest that PRE/BPD may have anatomically smaller airways than CON, which may help explain their lower expiratory airflow rate at rest and during exercise and further our understanding of the consequences of preterm birth and neonatal O₂ therapy.

This article is protected by copyright. All rights reserved

http://ift.tt/2im3dx5

Genotypic characterization of gentamicin and cephalosporin resistant Escherichia coli isolates from blood cultures in a Norwegian university hospital 2011–2015

Cephalosporin resistance in clinical E. coli isolates is increasing internationally. The increase has been caused by virulent and often multidrug-resistant clones, especially the extended spectrum β-lactamase (ES...

http://ift.tt/2AkmRyd

Anti-inflammatory evaluation of the methanolic extract of Taraxacum officinale in LPS-stimulated human umbilical vein endothelial cells

Atherosclerosis is a chronic vascular inflammatory disease. Since even low-level endotoxemia constitutes a powerful and independent risk factor for the development of atherosclerosis, it is important to find t...

http://ift.tt/2kayh3q

Jia-Wei-Jiao-Tai-Wan ameliorates type 2 diabetes by improving β cell function and reducing insulin resistance in diabetic rats

Jia-Wei-Jiao-Tai-Wan (JWJTW), composed of Jiao-Tai-Wan (Cinnamomum cassia and Rhizoma coptidis) and other antidiabetic herbs, including Astragalus membranaceus, Herba Gynostemmatis, Radix Puerariae Lobatae, Foliu...

http://ift.tt/2iomQET

PTBP3-mediated regulation of ZEB1 mRNA stability promotes epithelial-mesenchymal transition in breast cancer

The RNA polypyrimidine tract binding protein PTBP3 is a little studied paralog of PTBP1 which has oncogenic properties. In this study, we demonstrate that PTBP3 induces epithelial-mesenchymal transition (EMT) in breast tumor cells and promotes their invasive growth and metastasis. Elevated expression of PTBP3 associated significantly with lymph node metastasis, advanced histology grade, TNM stage, and poor 5-year overall survival of patients. In human mammary epithelial cells, PTBP3 overexpression was sufficient to induce EMT and enhance cell migration, invasion, and cancer stem-like cell properties. PTBP3 regulated expression of the EMT regulatory transcription factor ZEB1 by binding the 3'UTR of its mRNA, thereby preventing its degradation. Conversely, ZEB1 ablation blocked the ability of PTBP3 to induce EMT. Overall, our findings define PTBP3 as a regulator of EMT that acts by governing expression of ZEB1, and they establish an oncogenic function of PTBP3 suggesting its candidacy as a theranostic target.

http://ift.tt/2AnA4sf

Modeling the subclonal evolution of cancer cell populations

Increasing evidence shows that tumor clonal architectures are often the consequence of a complex branching process, yet little is known about the expected dynamics and extent to which these divergent subclonal expansions occur. Here we develop and implement more than 88,000 instances of a stochastic evolutionary model simulating genetic drift and neoplastic progression. Under different combinations of population genetic parameter values, including those estimated for colorectal cancer and glioblastoma multiforme, the distribution of sizes of subclones carrying driver mutations had a heavy right tail at the time of tumor detection, with only 1-4 dominant clones present at ≥10% frequency. In contrast, the vast majority of subclones were present at <10% frequency, many of which had higher fitness than currently dominant clones. The number of dominant clones (≥10% frequency) in a tumor correlated strongly with the number of subclones (<10% of the tumor). Overall, these subclones were frequently below current standard detection thresholds, frequently harbored treatment-resistant mutations and were more common in slow-growing tumors.

http://ift.tt/2ioDOTk

HER2-driven Breast Tumorigenesis Relies upon Interactions of the Estrogen Receptor with Coactivator MED1

Studies of the estrogen receptor (ER) coactivator protein MED1 have revealed its specific roles in pubertal mammary gland development and potential contributions to breast tumorigenesis, based on co-amplification of MED1 and HER2 in certain breast cancers. In this study, we generated a mouse model of mammary tumorigenesis harboring the MMTV-HER2 oncogene and mutation of MED1 to evaluate its role in HER2-driven tumorigenesis. MED1 mutation in its ER-interacting LxxLL motifs was sufficient to delay tumor onset and impair tumor growth, metastasis and cancer stem-like cell formation in this model. Mechanistic investigations revealed that MED1 acted directly to regulate ER signaling through the downstream IGF-1 pathway but not the AREG pathway. Our findings show that MED1 is critical for HER2-driven breast tumorigenesis, suggesting its candidacy as a disease-selective therapeutic target.

http://ift.tt/2AmXs9s

LSR antibody therapy inhibits ovarian epithelial tumor growth by inhibiting lipid uptake

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy but it still lacks effective treatment options. In this study, we utilized proteomic technology to identify lipolysis-stimulated lipoprotein receptor (LSR) as a new tumor antigen of EOC. Immunohistochemical analysis of EOC tissues in conjunction with survival analysis of EOC patients showed that high expression of LSR is associated with poor prognosis. High LSR expression also occurred in tumor metastases including to the lymph node and omentum. To evaluate the possible benefits of blocking this antigen in EOC, we raised a new monoclonal antibody (mAb) to human LSR (hLSR). In mouse xenograft models of hLSR-positive EOC (cell lines or patient-derived tumors), we found that administration of anti-hLSR mAb inhibited tumor growth in a manner independent of both antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity. Mechanistic investigations showed that hLSR expression increased incorporation of very low-density lipoprotein (VLDL) into EOC cells and that anti-hLSR mAb inhibited lipid uptake in vitro and in vivo. Moreover, VLDL promoted cell proliferation in hLSR-positive EOC cells in vitro and this effect was inhibited by anti-hLSR mAb. While the anti-hLSR mAb studied cross-reacted with the mouse antigen, we observed no adverse effects on normal organs and lipid metabolism in murine hosts. Our findings suggest that hLSR plays a key functional role in EOC development and that this antigen can be therapeutically targeted by specific mAb to improve EOC treatment.

http://ift.tt/2ioDunA

Photodynamic priming mitigates chemotherapeutic selection pressures and improves drug delivery

Physiological barriers to drug delivery and selection for drug resistance limit survival outcomes in cancer patients. In this study, we present preclinical evidence that a subtumoricidal photodynamic priming (PDP) strategy can relieve drug delivery barriers in the tumor microenvironment to safely widen the therapeutic window of a nanoformulated cytotoxic drug. In orthotopic xenograft models of pancreatic cancer, combining PDP with nanoliposomal irinotecan (nal-IRI) prevented tumor relapse, reduce metastasis and increase both progression-free survival and 1-year disease-free survival. PDP enabled these durable improvements by targeting multiple tumor compartments to (1) increase intratumoral drug accumulation by >10-fold, (2) increase the duration of drug exposure above a critical therapeutic threshold, and (3) attenuate surges in CD44 and CXCR4 expression which mediate chemoresistance often observed after multi-cycle chemotherapy. Overall, our results offer preclinical proof of concept for the effectiveness of PDP to minimize risks of tumor relapse, progression and drug resistance and to extend patient survival.

http://ift.tt/2AmXePE

The E3 ligase RING1 targets p53 for degradation and promotes cancer cell proliferation and survival

As a component of the transcriptional repression complex 1 (PRC1), the ring finger protein RING1 participates in the epigenetic regulation in cancer. However, the contributions of RING1 to cancer etiology or development are unknown. In this study, we report that RING1 is a critical negative regulator of p53 homeostasis in human hepatocellular and colorectal carcinomas. RING1 acts as an E3 ubiquitin (Ub) ligase to directly interact with and ubiquitinate p53, resulting in its proteasome-dependent degradation. The RING domain of RING1 was required for its E3 Ub ligase activity. RING1 depletion inhibited the proliferation and survival of the p53 wild-type cancer cells by inducing cell cycle arrest, apoptosis and senescence, with only modest effects on p53-deficient cells. Its growth inhibitory effect was partially rescued by p53 silencing, suggesting an important role for the RING1-p53 complex in human cancer. In clinical specimens of hepatocellular carcinoma, RING1 upregulation was evident in association with poor clinical outcomes. Collectively, our results elucidate a novel PRC1-independent function of RING1 and provide a mechanistic rationale for its candidacy as a new prognostic marker and/or therapeutic target in human cancer.

http://ift.tt/2in0Ytz

PPAR{delta} elicits ligand-independent repression of Trefoil Factor Family to limit prostate cancer growth

The nuclear receptor PPAR-β/δ (PPARD) has essential roles in fatty acid catabolism and energy homeostasis as well as cell differentiation, inflammation and metabolism. However, its contributions to tumorigenesis are uncertain and have been disputed. Here we provide evidence of tumor suppressive activity of PPARD in prostate cancer through a non-canonical and ligand-independent pathway. PPARD was downregulated in prostate cancer specimens. In murine prostate epithelium, PPARD gene deletion resulted in increased cellularity. Genetic modulation of PPARD in human prostate cancer cell lines validated the tumor suppressive activity of this gene in vitro and in vivo. Mechanistically, PPARD exerted its activity in a DNA binding-dependent and ligand-independent manner. We identified a novel set of genes repressed by PPARD that failed to respond to ligand-mediated activation. Among these genes, we observed robust regulation of the secretory trefoil factor family (TFF) members, including a causal and correlative association of TFF1 to prostate cancer biology in vitro and in patient specimens. Overall, our results illuminate the oncosuppressive function of PPARD and understanding of the pathogenic molecular pathways elicited by this nuclear receptor.

http://ift.tt/2Anjrgt

Delivering type I interferon to dendritic cells empowers tumor eradication and immune combination treatments

An ideal generic cancer immunotherapy should mobilize the immune system to destroy tumor cells without harming healthy cells and remain active in case of recurrence. Furthermore, it should preferably not rely on tumor-specific surface markers, as these are only available in a limited set of malignancies. Despite approval for treatment of various cancers, clinical application of cytokines is still impeded by their multiple toxic side effects. Type I interferon (IFN) has a long history in the treatment of cancer, but its multifaceted activity pattern and complex side effects prevent its clinical use. Here we develop AcTakines (Activity-on-Target cytokines), optimized (mutated) immunocytokines that are up to 1000-fold more potent on target cells, allowing specific signaling in selected cell types only. Type I IFN-derived AcTaferon-targeting Clec9A+ dendritic cells (DC) displayed strong antitumor activity in murine melanoma, breast carcinoma, and lymphoma models and against human lymphoma in humanized mice without any detectable toxic side effects. Combined with immune checkpoint blockade, chemotherapy, or low-dose TNF, complete tumor regression and long-lasting tumor immunity were observed, still without adverse effects. Our findings indicate that DC-targeted AcTaferons provide a novel class of highly efficient, safe, and broad-spectrum off-the-shelf cancer immunotherapeutics with no need for a tumor marker.

http://ift.tt/2in0vrj

Disparities in Prostate, Lung, Breast, and Colorectal Cancer Survival and Comorbidity Status among Urban American Indians and Alaskan Natives

Cancer is the second leading cause of death among American Indians and Alaskan Natives (AIAN), although cancer survival information in this population is limited, particularly among urban AIAN. In this retrospective cohort study, we compared all-cause and prostate, breast, lung, and colorectal cancer–specific mortality among AIAN (n = 582) and non-Hispanic white (NHW; n = 82,696) enrollees of Kaiser Permanente Northern California (KPNC) diagnosed with primary invasive breast, prostate, lung, or colorectal cancer from 1997 to 2015. Tumor registry and other electronic health records provided information on sociodemographic, comorbidity, tumor, clinical, and treatment characteristics. Cox regression models were used to estimate adjusted survival curves and hazard ratios (HR) with 95% confidence intervals (CI). AIAN had a significantly higher comorbidity burden compared with NHW (P < 0.05). When adjusting for patient, disease characteristics, and Charlson comorbidity scores, all-cause mortality and cancer-specific mortality were significantly higher for AIAN than NHW patients with breast cancer (HR, 1.47; 95% CI, 1.13–1.92) or with prostate cancer (HR, 1.87; 95% CI, 1.14–3.06) but not for AIAN patients with lung and colorectal cancer. Despite approximately equal access to preventive services and cancer care in this setting, we found higher mortality for AIAN than NHW with some cancers, and a greater proportion of AIAN cancer patients with multiple comorbid conditions. This study provides severely needed information on the cancer experience of the 71% of AIANs who live in urban areas and access cancer care outside of the Indian Health Services, from which the vast majority of AIAN cancer information comes. Cancer Res; 77(23); 1–7. ©2017 AACR.

http://ift.tt/2AlIlwR

Determination of antimicrobial susceptibility patterns in Staphylococcus aureus strains recovered from patients at two main health facilities in Kabul, Afghanistan

Staphylococcus aureus (S. aureus) is a major pathogen implicated in skin and soft tissue infections, abscess in deep organs, toxin mediated diseases, respiratory tract infections, urin...

http://ift.tt/2Aovfil

Identification of pathogens for differential diagnosis of fever with jaundice in the Central African Republic: a retrospective assessment, 2008–2010

Febrile jaundice results clinically in generalized yellow coloration of the teguments and mucous membranes due to excess plasma bilirubin, accompanied by fever. Two types are found: conjugated and unconjugated...

http://ift.tt/2iliQVz

Decision tree for accurate infection timing in individuals newly diagnosed with HIV-1 infection

There is today no gold standard method to accurately define the time passed since infection at HIV diagnosis. Infection timing and incidence measurement is however essential to better monitor the dynamics of l...

http://ift.tt/2Ano0qX

Daptomycin treatment in patients with resistant staphylococcal periprosthetic joint infection

Resistant staphylococcal organisms remain a serious problem in the treatment of periprosthetic joint infection (PJI). Higher failure rates have been reported when vancomycin was used. The purpose of this study...

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Pneumatosis Cystoides Intestinalis: An Unexpected Cause of Duodenal Nodules

N/A.

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Isolated Polycystic Liver Disease

N/A.

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Platypnea-Orthodeoxia Syndrome After Complicated Cholecystectomy: An Unsuspected Diagnosis

A 65-year-old woman with no significant prior medical history presented, in the postoperative course of a complicated cholecystectomy, several episodes of arterial desaturation. Pulmonary embolism was repeatedly suspected, but there was no evidence of pulmonary thrombus on the chest computed tomography angiographies obtained. As these episodes were mainly induced by postural changes, a platypnea-orthodeoxia syndrome was suspected. A transthoracic echocardiogram was performed and revealed a patent foramen ovale. A transesophageal echocardiography confirmed the presence of a significant right-to-left shunt exacerbated by the Valsalva manouver. The defect was repaired using a percutaneous transcatheter technique with complete resolution of the condition.

http://ift.tt/2AnzXx8

Symptomatic Hyponatremia after Bowel Preparation: Report of Two Cases and Literature Review

Introduction: Bowel preparation for colonoscopy and/or colorectal surgery can cause electrolyte imbalances. The risk of electrolyte imbalances seems to be related to the type of bowel cleansing solution, age of patients and comorbidities.
Case Report: We report two cases of symptomatic hyponatremia (focal neurological signs and coma) after bowel preparation with sodium picosulfate/magnesium citrate for colonoscopy. In both cases, symptoms related to hyponatremia rapidly disappeared after sodium level correction with intravenous administration of hypertonic saline (3% NaCl).
Discussion: Electrolyte imbalances are more common with sodium phosphate-based solutions (NaP) and sodium picosulfate/magnesium citrate, in patients older than 65, in patients treated with thiazide diuretics, angiotensin-converting-enzyme inhibitor, betablockers or antidepressants and in gastrectomized patients. These patients should use macrogol-based solutions (polyethylene glycol).
Conclusion: In patients at risk (patient > 65 years old, patients taking thiazide diuretics, angiotensin-converting-enzyme inhibitors, beta-blockers and antidepressants and with previous gastrectomy) we recommend macrogol-based solutions.

http://ift.tt/2ilCdh8

Pregnancy after Breast Cancer: State of the Art

Breast cancer survivors have given rise to several issues of major relevance from a clinical and scientific point of view. In fact, breast cancer is the most prevalent malignancy in women of reproductive age. The effect of pregnancy on overall survival and in the recurrence after treatment of breast cancer, as well as the questions related to heredity continue to be matter of the highest timeliness and scientific interest. Most recent studies seem to agree in admitting that pregnancy after breast cancer appears to be potentially safe to both the women and her offspring, although this issue remains complex. Heredity and genetics seem to play an important role in this subject, but the conclusions lack absolute and unequivocal consistency. There is a need for meta-analysis, cohort and case-control studies, translational and prospective studies extended in time, in order to obtain greater safety in the establishment of strategies and guidelines for clinicians and adequate objective information for young breast cancer patients.

http://ift.tt/2AmrXwe

Metabolic Activity in the Visceral and Subcutaneous Adipose Tissues by FDG-PET/CT in Obese Patients

Introduction: The emerging role of the 18F-fluorodeoxyglucose-positron emission tomography/computed tomography in the study of the metabolic activity and inflammation in adipose tissue indicates that it might be a reliable tool to complement the risk stratification in obesity. The aims of this study were the evaluation of 18F-fluorodeoxyglucose uptake by visceral adipose tissues and subcutaneous adipose tissues and to determine eventual differences in patients with and without obesity.
Material and Methods: Retrospective study of adult patients who underwent whole body 18F-fluorodeoxyglucose-positron emission tomography/ computed tomography scanning between July and August of 2016. Statistical analysis: SPSS™ software v.20. Statistical
significance: p < 0.05.
Results: We assessed fluorodeoxyglucose-positron emission tomography/computed tomography scans from 156 patients (58.3% of males) with a mean age of 61.0 ± 14.1 years. Half of the patients had a body mass index ≥ 25.0 kg/m2 and 15.4% (n = 24) were obese. In both groups, the mean 18F-fluorodeoxyglucose uptake was higher in visceral adipose tissues. There were no differences in 18F-fluorodeoxyglucose uptake in visceral adipose tissues between the groups. Obese patients had lower density of adipose tissue,
both in subcutaneous adipose tissues and in visceral adipose tissues. Abdominal circumference and density of visceral adipose tissues
had a positive predictive value in the mean 18F-fluorodeoxyglucose uptake in visceral adipose tissues. 
Discussion: Through a non-invasive test, this study demonstrated a significant higher metabolic activity in visceral adipose tissues in both obese and non-obese patients. According to our results, abdominal circumference was an important determinant in 18F-fluorodeoxyglucose uptake in visceral adipose tissues. We also demonstrated that obese patients had differences in adipose tissue quality.
Conclusion: Our findings reinforce the importance of the adipose tissue quality and distribution for metabolic risk stratification.

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Characterization of all Surgical Specimens Provided by a Portuguese Department of Ophthalmology over a 13 Year Period

Introduction: We intend to evaluate clinically, topographically and morphologically all surgical specimens sent by the Department of Ophthalmology of Hospital de Braga to the Department of Pathology of the same hospital.
Material and Methods: Two hundred and fifty eight surgically obtained specimens, from the Department of Ophthalmology of Hospital de Braga, analyzed in the Department of Pathology, from January 2002 to June 2015, were characterized. Data was arranged according to year, age, sex, topography and morphological diagnosis according to the SNOMED® coding system.
Results: Mean age at time of diagnosis was 54.6 years old; 52.3% were male subjects. The number of specimens was relatively stable until the year 2010, with a significant increase between 2011 and 2013. Most specimens sent corresponded to eyelid (54.7%), followed by conjunctiva (26.7%); the most common pathological diagnosis was malignant epithelial lesions (22.48%), followed by melanocytic tumours (22.09%) and benign epithelial lesions (17.05%).
Discussion: The results are distinct from previous publications presumably because of differences between the populations submitted to analysis.
Conclusion: This is the first indexed publication characterizing surgical specimens from a Department of Ophthalmology in Portugal; moreover, it also includes an extensive review of global epidemiological data about ophthalmic surgical specimens.

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Single Centre Prospective Study of Systematic Pain Evaluation in Portuguese Patients with Metastatic Prostate Cancer

Introduction: Pain is one of the most common symptoms reported by cancer patients and is associated with decreased quality of life. Assessment of pain with standardized questionnaires reduces variability in its interpretation and may increase effectiveness of medical interventions. Prostate cancer is the most frequent male neoplasm in Portugal. We designed this study to evaluate the impact of a standardized pain questionnaire on pain management in patients with metastatic prostate cancer.
Material and Methods: Single centre prospective observational study of patients with metastatic prostate cancer. The study was designed to evaluate the benefit of systematically evaluating pain with Brief Pain Inventory-Short Form prior to a scheduled medical oncology consult. Patients reporting pain were reassessed one week later by telephone. To assess the benefit two consecutive cohorts were established based on communication of questionnaire results to the treating physician.
Results: We recruited 207 patients of which 60% reported pain. Statistically significant decrease in mean pain intensity one week after the scheduled appointment was noted (3.95 vs 3.01; p < 0.001). Patients whose Brief Pain Inventory-Short Form was provided to their oncologist experienced greater reduction in pain, which was non-significant (p = 0.227). Using Brief Pain Inventory-Short Form assessment resulted in a higher probability of pain control (43.5% vs 30.9%; p = 0.193).
Discussion: The prevalence of pain founded was higher than described in the literature, probably because our sample was less selected than the published in clinical trials. After the scheduled appointment, there was a statistically significant reduction in mean pain intensity, but the explicit use of this questionnaire was not associated with a statistically significant reduction of pain.
Conclusion: Patients with metastatic prostate cancer have a high prevalence of pain. Evaluation and treatment by medical oncologists is associated with a reduction of mean pain intensity. The use of Brief Pain Inventory-Short Form was associated with a non-significant increased reduction of pain.

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Portuguese Adaptation and Input for the Validation of the Views on Inpatient Care (VOICE) Outcome Measure to Assess Service Users’ Perceptions of Inpatient Psychiatric Care

Introduction: Patient satisfaction is an important measure of health care quality. Patients' views have seldom been considered in the construction of measures addressing satisfaction with inpatient facilities in psychiatry. The Views on Inpatient Care - VOICE - is a first service-user generated outcome measure relying solely on their perceptions of acute care, representing a valuable indicator of service users' perceived quality of care. The present study aimed to contribute to the validation of the Portuguese version of VOICE.
Material and Methods: The questionnaire was translated into Portuguese and applied to a sample of eighty-five female inpatients of a psychiatric institution. Data analysis focused on assessing reliability and exploring the impact of demographic and clinical variables on participants' satisfaction.
Results: Internal consistency of the questionnaire was high (α = 0.87). Participants' age and marital status were associated with differences in scores, with older patients and patients who were married or involved in a close relationship presenting higher satisfaction levels.
Discussion: The questionnaire demonstrated good internal consistency and acceptability, as well as construct validity. Further studies should expand the analysis of the psychometric properties of this measure e.g., test-retest reliability.
Conclusion: The Portuguese version of VOICE is a promising tool to assess service users' perceptions of inpatient psychiatric care in Portugal.

http://ift.tt/2AmrsSS

Cross-Cultural and Psychometric Properties Assessment of the Exercise Self-Efficacy Scale in Individuals with Spinal Cord Injury

Introduction: The Exercise Self-Efficacy scale (ESES) is a reliable measure, in the English language, of exercise self-efficacy in individuals with spinal cord injury. The aim of this study was to culturally adjust and validate the Exercise Self-Efficacy scale in the Portuguese language.
Material and Methods: The Exercise Self-Efficacy scale was applied to 76 subjects, with three-month intervals (three applications in total). The reliability was appraised using the intra-class correlation coefficient and Bland-Altman methods, and the internal consistency was evaluated using Cronbach´s alpha. The Exercise Self-Efficacy scale was correlated with the domains of the Quality of life Questionnaire SF-36 and Functional Independence Measure and tested using the Spearman rho coefficient.
Results: The Exercise Self-Efficacy scale-Brazil presented good internal consistency (alpha 1 = 0.856; alpha 2 = 0.855; alpha 3 = 0.822) and high reliability in the test-retest (intra-class correlation coefficient = 0.97). There was a strong correlation between the Exercise Self-Efficacy scale-Brazil and the SF-36 only in the functional capacity domain (rho = 0.708). There were no changes in Exercise Self-Efficacy scale-Brazil scores between the three applications (p = 0.796).
Discussion: The validation of the Exercise Self-Efficacy scale questionnaire permits the assessor to use it reliably in Portuguese speaking countries, since it is the first instrument measuring self-efficacy specifically during exercises in individuals with spinal cord injury. Furthermore, the questionnaire can be used as an instrument to verify the effectiveness of interventions that use exercise as an outcome.
Conclusion: The results of the Brazilian version of the Exercise Self-Efficacy scale support its use as a reliable and valid measurement of exercise self-efficacy for this population.

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Reconsidering the ‘Decline’ of Dental Student Empathy within the Course in Latin America

Introduction: The controversy over the presence of empathic decline within the course in students of medicine, dentistry and health sciences in general, has not fully been studied. This controversy could be partially solved if massive studies of empathy levels are made in similar cultural, social and economic contexts.
Material and Methods: Empathy levels within the course were studied in eighteen dental schools from six countries in Latin America (2013). The mean of the empathy levels were used to study the behavior between first and fifth academic years. The values of empathy levels within the course were observed by applying the Jefferson Scale of Physician Empathy, the Spanish version. All these studies were cross-sectional. The value of means observed, were subjected to regression studies and further adjustment curves were obtained and the coefficient of determination were calculated.
Results: Six different models of behavior were observed, which found that five of them suffer empathic decline within the course, but with different final results: in some the decline persists until the fifth academic year and in others, this decline 'recovers' persistently until the fifth academic year. The sixth model is characterized by a constant and persistent increase of levels of empathy within the course until the last academic year.
Discussion: There are six different models for the behavior of means of levels of empathy within the course evaluated by a common methodology in eighteen dental schools from six countries of Latin America. These findings support the existence of variability of empathic response and a comprehensive approach is needed to find the causes that give rise to this variability.
Conclusion: In dental students of Latin America, there is variability in the behavior of the distribution in means between the academic years of the dentistry schools examined in this study.

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Readmission to an Adolescent Psychiatry Inpatient Unit: Readmission Rates and Risk Factors

Introduction: Most mental disorders have a chronic evolution and therefore a certain amount of psychiatric readmissions are inevitable. Several studies indicate that over 25% of child and adolescent inpatients were readmitted within one year of discharge. Several risk factors for psychiatric readmissions have been reported in the literature, but the history of repeated readmissions is the most consistent risk factor. Our aim is to calculate the readmission rates at 30 days and 12 months after discharge and to identify associated risk factors.
Material and Methods: The authors consulted the clinical files of patients admitted to the Inpatient Unit between 2010 and 2013, in order to calculate the readmission rates at 30 days and at 12 months. The demographic and clinical characteristics of the readmitted patients were analyzed and compared with a second group of patients with no hospital readmissions, in order to investigate possible predictors of readmission.
Results: A total of 445 patients were admitted to our inpatient unit between 2010 and 2013. Six adolescents were readmitted in a 30 days period (1.3%) and 52 were readmitted in a 12 month period after discharge (11.5%). Duration of the hospitalization and the previous number of mental health admissions were significant predictors of future hospital readmissions (p = 0.04 and p = 0.014).
Discussion: The low readmission rates may reflect the positive clinical and sociofamilial support being provided after discharge.
Conclusion: Rehospitalisation is considered a fundamental target for intervention concerning prevention and intervention in mental healthcare. Thus, knowledge regarding their minimisation is crucial.

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Breast Cancer: Value-Based Healthcare, Costs and Financing

Introduction: Breast cancer is the second most common oncological disease worldwide. To analyse the new disease specific funding programme (breast cancer) implemented at the Francisco Gentil Portuguese Institute of Oncology, Lisbon Center (Instituto Português de Oncologia de Lisboa Francisco Gentil), the actual costs of the patients were examined using activity-based costing as a costing methodology. This study addresses the following question: "How much does it cost to treat breast cancer per 'patient-month' compared to the monthly fixed 'funding envelope'?".
Materials and Methods: The study cohort consisted of 807 patients, corresponding to all the patients eligible for the new disease specific funding programme and who were enrolled during the first year of implementation. Activity-based costing was used to calculate the total real costs per stage of disease and per 'patient-month' as well as the deviation from the monthly fixed 'funding envelope'.
Results: The total costs were 6.6 M€, whereas the total funding was 5.2 M€ for a total of 5648 'patient-months'. In 2014, the balance difference between the funding obtained and the actual costs was -1.4 €M for the cohort of 807 patients.
Discussion: The extreme cases of differences in cost per 'patient-month' compared to the monthly fixed 'funding envelope' were (i) stage 0/Tis, with higher funding at 415.23 € per 'patient-month', and (ii) stage IIIC, with lower funding at 1062.79 € per 'patient-month'.
Conclusion: The 'patient-month' cost, regardless of disease stage was 1170.29 €. The median deviation per 'patient-month' was negative (241.21 €) compared to the monthly fixed 'funding envelope' of 929.08 € in the first year. Establishing activity-based costing - funding models will be crucial for the future sustainability of the healthcare sector.

http://ift.tt/2inukbl

Physician Involvement in the Activities of the European Medicines Agency

For more than two decades of activity, the European Medicines Agency has been operating as part of a network with the national medicines agencies in Europe, bringing together - in its various scientific committees and working groups - European experts on a wide range of topics related to quality assurance, safety and efficacy of medicines. The work carried out within the European Medicines Agency activities and the conclusions reached at European level affect millions of citizens. The European Medicines Agency considers that it is of great importance to maintain, in a sustainable and consistent manner, the active participation of general practitioners, as well as other medical specialists, in the process of medicines' evaluation and supervision. This article summarizes how the participation of doctors and health professionals in general is promoted in the European Medicines Agency activities.

http://ift.tt/2Amr2Mi

The Smurf transition: new insights on ageing from end-of-life studies in animal models

Purpose of review Over the past 5 years, many articles were published concerning the prediction of high risk of mortality in apparently healthy adults, echoing the first description in 2011 of the Smurf phenotype, a harbinger of natural death in drosophila. Recent findings These recent findings suggest that the end-of-life is molecularly and physiologically highly stereotyped, evolutionarily conserved and predictable. Summary Taken altogether, these results from independent teams using multiple organisms including humans draw the lines of future directions in ageing research. The ability to identify and study individuals about to die of natural causes with no apparent diseases is a game-changer in this field. In addition, the public health applications are potentially of tremendous impact in our ageing societies and raise important ethical questions.

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Editorial introductions

No abstract available

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An update on noninvasive follicular thyroid neoplasm with papillary-like nuclear features

Purpose of review Noninvasive encapsulated follicular variant of papillary thyroid carcinoma (PTC) has been established in the literature as a clinically indolent tumor. Despite this, it was traditionally treated like all other PTCs. In an attempt to reduce overtreatment of this entity, a panel of experts reclassified this entity as noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP). This reclassification has led to a flurry of literature elucidating the molecular, cytologic and clinical parameters of this 'new' entity and the implications for patient management. The purpose of this review is to examine the latest literature on this tumor and explore how its emergence has impacted our current understanding of the diagnosis, management and outcomes in this entity. Recent findings NIFTP is a low grade tumor with an indolent clinical course. Recent studies have begun to document the variable incidence of NIFTP, the ultrasound and cytologic findings, and the impact of the NIFTP terminology on established rates of malignancy in fine-needle aspiration and clinical outcome studies. Summary The recent literature on molecular, radiographic and cytologic characteristics of NIFTP are building our understanding of this neoplasm and support its indolent nature.

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Targeting the perivascular niche in brain tumors

Purpose of review Brain tumors are composed of primary tumors of the central nervous system, such us glioblastoma (GBM), and secondary metastatic tumors, such as melanoma, non-Hodgkin lymphoma as well as lung and breast cancers. Brain tumors are highly deadly, and unfortunately not many improvements have been achieved to improve the survival of patients with brain tumors. Chemoradiation resistance is one of the most clinically relevant challenges faced in patients with brain tumors. The perivascular niche is one of the most relevant microenvironment hubs in brain tumors. The understanding of the cellular crosstalk established within the brain tumor perivascular niche might provide us with key discoveries of new brain tumor vulnerabilities. Recent findings Radio and chemoresistance in GBM and brain metastases is attributed to cancer stem cells (CSCs), which intrinsically modulate several pathways that make them resistant to therapy. Growing evidence, however, highlights the perivascular space as a niche for CSC survival, resistance to therapy, progression and dissemination. Here, I review the latest discoveries on the components and features of brain tumor vascular niches and the possible therapeutic strategies aimed at targeting its vulnerabilities, thus preventing GBM and metastasis chemoradiation resistance and recurrence. Summary Recent discoveries suggest that targeting the brain perivascular niche has the potential of sensitizing brain tumors to therapies and reducing the occurrence of metastases.

http://ift.tt/2Aosfmc

An update on the status of molecular testing for the indeterminate thyroid nodule and risk stratification of differentiated thyroid cancer

Purpose of review Correct identification of malignancy in cytologically indeterminate thyroid nodules is a diagnostic challenge, leading to potentially unnecessary surgery in patients for whom final histology is benign. Similarly, many patients with differentiated thyroid cancer (DTC) undergo aggressive surgical management of tumors, which may ultimately have low-risk histologic features. Use of molecular testing strategies can aid in both the diagnosis of indeterminate thyroid nodules and preoperative risk stratification of DTC. Recent findings Validation studies of both the Afirma Gene Expression Classifier and Thyroseq Next-Generation Sequencing panel are ongoing. Both tests can be used to help rule out malignancy in indeterminate thyroid nodules. Recent additions to available molecular testing for indeterminate thyroid nodules include the Rosetta microRNA classifier and the augmentation of the ThyGenX gene panel with a microRNA reflex test (ThyraMIR). Mutational analysis of DTC shows that mutation in TERT alone, and in combination with other mutations, portends advanced disease. Summary Currently available molecular testing modalities are useful for ruling out malignancy in indeterminate thyroid nodules; however, longer-term follow-up studies are needed to confirm that test-negative nodules are truly benign. Analysis of specific gene mutations helps identify aggressive disease to guide prognostication and management, but further study is needed.

http://ift.tt/2AorwkY

Lysine methylation signaling in pancreatic cancer

Purpose of review Despite better knowledge of its genetic basis, pancreatic cancer is still highly lethal with very few therapeutic options. In this review, we discuss the potential impact of epigenetic therapies, focusing on lysine methylation signaling and its implication in pancreatic cancer. Recent findings Protein lysine methylation, a key mechanism of posttranslational modifications of histone proteins, has emerged as a major cell signaling mechanism regulating physiologic and pathologic processes including cancer. This finely tuned and dynamic signaling mechanism is regulated by lysine methyltransferases (KMT), lysine demethylases (KDM) and signal transducers harboring methyl-binding domains. Recent evidence demonstrates that overexpression of cytoplasmic KMT and resulting enhanced lysine methylation is a reversible event that enhances oncogenic signaling through the Ras and Mitogen-Activated Protein Kinases pathway in pancreatic cancer, opening perspectives for new anticancer chemotherapeutics aimed at controlling these activities. Summary The development of potent and specific inhibitors of lysine methylation signaling may represent a hitherto largely unexplored avenue for new forms of targeted therapy in cancer, with great potential for yet hard-to-treat cancers such as pancreatic cancer.

http://ift.tt/2AorpG4

Advances in understanding the molecular underpinnings of adrenocortical tumors

Purpose of review Adrenocortical tumors are divided into benign adenomas and malignant carcinomas. The former is relatively common and carries a favorable prognosis, whereas the latter is rare and frequently presents at an advanced stage, with poor outcomes. Advances in next-generation sequencing, genome analysis, and bioinformatics have allowed for high-throughput molecular characterization of adrenal tumorigenesis. Recent findings Although recent genomic, epigenomic, and transcriptomic studies in large tumor cohorts have confirmed the central roles of aberrant Wnt/ß-catenin signaling, constitutive protein kinase A pathway activation, cell cycle dysregulation, and ion channelopathies in adrenal tumorigenesis, these studies also revealed novel signature events underlying malignant differentiation of adrenocortical carcinomas. Summary Recent advances in understanding of the molecular mechanisms underlying adrenocortical tumorigenesis provide new molecular diagnostic and prognostic tools and opportunities for novel therapeutic approaches. These findings are particularly important in adrenocortical carcinoma, for which current treatment options are limited.

http://ift.tt/2AmFHXP

Paracrine interactions of cancer-associated fibroblasts, macrophages and endothelial cells: tumor allies and foes

Purpose of review Tumor stroma is composed of many cellular subtypes, of which the most abundant are fibroblasts, macrophages and endothelial cells. During the process of tissue injury, these three cellular subtypes must coordinate their activity to efficiently contribute to tissue regeneration. In tumor, this mechanism is hijacked by cancer cells, which rewire the interaction of stromal cells to benefit tumor development. The present review aims at summarizing most relevant information concerning both pro-tumorigenic and anti-tumorigenic actions implicating the three stromal cell subtypes as well as their mutual interactions. Recent findings Although stromal cells are generally regarded as tumor-supportive and at will manipulated by cancer cells, several novel studies point at many defaults in cancer cell-mediated stromal reprograming. Indeed, parts of initial tissue-protective and homeostatic functions of the stromal cells remain in place even after tumor development. Both tumor-supportive and tumor-suppressive functions have been well described for macrophages, whereas similar results are emerging for fibroblasts and endothelial cells. Summary Recent success of immunotherapies have finally brought the long awaited proof that stroma is key for efficient tumor targeting. However, a better understanding of paracrine stromal interactions is needed in order to encourage drug development not only aiming at disruption of tumor-supportive communication but also re-enforcing, existing, tumor-suppressive mechanisms.

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Revisiting tumor patterns and penetrance in germline TP53 mutation carriers: temporal phases of Li–Fraumeni syndrome

Purpose of review Germline pathogenic TP53 mutation may predispose to multiple cancers but penetrance and cancer patterns remain incompletely documented. We have analyzed international agency for research on cancer TP53 database to reevaluate age and variant-dependent tumor patterns. Recent findings Genome-wide studies suggest that germline variants are more frequent than estimated prevalence of Li–Fraumeni syndrome (LFS), suggesting that many carriers of potentially pathogenic mutations may not develop the syndrome. Carriers of a germline TP53 mutation who are detected in a clinical context have a penetrance of 80% at age 70. Penetrance varies according to age, sex and mutation type. Temporal tumor patterns show distinct phases, with childhood phase (0–15 years, 22% of all cancers) characterized by adrenal cortical carcinoma, choroid plexus carcinoma, rhabdomyosarcoma and medulloblastoma; early adulthood phase (16–50 years, 51%) including breast cancer, osteosarcoma, soft tissue sarcomas, leukemia, astrocytoma and glioblastoma, colorectal and lung cancer; late adulthood phase (51–80 years, 27%) including pancreatic and prostate cancer. Summary Germline pathogenic variants in TP53 gene have different consequences according to cell, tissue, context and age. The occurrence of frequent variants in patients with no criteria suggestive of LFS calls for attention in predicting individual risk and highlights the need of additional predictors for assigning carriers to appropriate surveillance programs.

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Mutational and epigenetic signatures in cancer tissue linked to environmental exposures and lifestyle

Purpose of review In this article, we describe how recent advances in the study of mutational and epigenetic signatures in tumours provide new opportunities to understand the role of the environment and lifestyle in cancer development. Recent findings Cancer-related mutational events have been investigated for decades but only recently the wide availability of genomic sequences and epigenomic data from thousands of cancer genomes has made it possible to identify numerous distinct mutational and epigenetic signatures through the application of advanced mathematical models. Some of these signatures have been linked to endogenous factors such as defective DNA repair or the action of APOBEC cytidine deaminases and to exogenous factors such as tobacco smoke, ultraviolet light, aflatoxins, aristolochic acid and ionizing radiation. More recently, it has been shown that exposure to factors such as tobacco smoke may also leave marks in the DNA methylation profile of both normal and tumour tissue in target organs. Summary The analysis of mutational and epigenetic signatures is a novel and useful tool to study cancer. Their application to experimental studies and to studies with detailed data on environmental exposures and lifestyle is likely to improve our understanding of how the environment and lifestyle influence cancer development and its evolution.

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The Adolescent Champion Model: Primary Care Becomes Adolescent-Centered via Targeted Quality Improvement

To evaluate the effects of implementing the Adolescent Champion model, a novel quality improvement program targeted at helping primary care sites become more adolescent-centered.

http://ift.tt/2AprgSW

Ultrasonographic Quantitative Analysis of Fatty Pancreas in Obese Children: Its Correlation with Metabolic Syndrome and Homeostasis Model Assessment of Insulin Resistance

To evaluate pancreatic echogenicity on transabdominal ultrasonography and the correlation of fatty pancreas with metabolic syndrome (MetS), as well as insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR]).

http://ift.tt/2ikE7i9

Increased Pituitary Volumes in Children after Fontan Operation: Congestion in the Other Portal Circulation

We performed brain magnetic resonance imaging in 40 patients after the Fontan procedure and 40 control subjects. Pituitary volumes in patients after Fontan were significantly larger than those in the control subjects (472 [425-527] vs 257 [182-311]; P < .0001), and were significantly related to central venous pressure.

http://ift.tt/2incQLS

Patient-Reported Outcome Measures for Fatigue in Patients on Hemodialysis: A Systematic Review

Fatigue is a prevalent and debilitating symptom in patients receiving hemodialysis. We aimed to identify and evaluate the characteristics and psychometric properties of patient-reported outcome measures for fatigue in patients receiving hemodialysis, to inform the selection of a robust and feasible measure for use in randomized trials in hemodialysis.

http://ift.tt/2inlASr

International Differences in the Location and Use of Arteriovenous Accesses Created for Hemodialysis: Results From the Dialysis Outcomes and Practice Patterns Study (DOPPS)

Vascular access practice is strongly associated with clinical outcomes. There is substantial international variation in the use of arteriovenous fistulas (AVFs) and grafts (AVGs), as well as AVF maturation time and location.

http://ift.tt/2Am6DXI

X-Linked Glomerulopathy Due to COL4A5 Founder Variant

Alport syndrome is a rare hereditary disorder caused by rare variants in 1 of 3 genes encoding for type IV collagen. Rare variants in COL4A5 on chromosome Xq22 cause X-linked Alport syndrome, which accounts for ∼80% of the cases. Alport syndrome has a variable clinical presentation, including progressive kidney failure, hearing loss, and ocular defects. Exome sequencing performed in 2 affected related males with an undefined X-linked glomerulopathy characterized by global and segmental glomerulosclerosis, mesangial hypercellularity, and vague basement membrane immune complex deposition revealed a COL4A5 sequence variant, a substitution of a thymine by a guanine at nucleotide 665 (c.T665G; rs281874761) of the coding DNA predicted to lead to a cysteine to phenylalanine substitution at amino acid 222, which was not seen in databases cataloguing natural human genetic variation, including dbSNP138, 1000 Genomes Project release version 01-11-2004, Exome Sequencing Project 21-06-2014, or ExAC 01-11-2014.

http://ift.tt/2inzHHv

Effects of platelet-rich plasma on pain and muscle strength in patients with knee osteoarthritis

Objective No studies comparing the effects of platelet-rich plasma (PRP) injection and placebo injection in bilateral knee osteoarthritis (OA) in the same patient, or discussing muscle strength after PRP injection, have been published. Design Twenty patients with bilateral knee OA were eligible, and 40 knees were randomized into two groups: PRP (knees [right or left by a coin toss] receiving a single intra-articular PRP injection) and saline group (the contralateral knee of the same patient, into which single 4-mL intra-articular injection of normal saline was administered). The primary outcome measure was Western Ontario and McMaster's Universities Osteoarthritis Index (WOMAC) and the secondary included isokinetic test results. The evaluation was at baseline and at 2 weeks, 1, 3, and 6 months post-injection. Results The PRP group showed a significant reduction in the WOMAC-pain and -total scores compared to normal saline group (p flexor) was found in the PRP group during a longer follow-up period, PRP treatment resulted in insignificant differences in muscle strength compared to normal saline. Conclusions PRP treatment significantly improves pain, stiffness, and disability in patients with knee OA compared to normal saline treatment. Additional strength training is recommended to enhance muscle strength recovery. Corresponding author: Dr. Liang-Cheng Chen, MD, MS, Department of Physical Medicine and Rehabilitation, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, No. 325, Sec. 2, Cheng-Kung Road, Neihu District, Taipei, Taiwan, Republic of China. E-mail: clctsgh@yahoo.com.tw Sources of Funding: The study is supported by the Ministry of Science and Technology, Taiwan, Republic of China (grant no. MOST 104-2314-B-016-050). Conflict of Interest/Disclosure: There is no Conflict of Interest/Disclosure in this study Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2AHvR3w

The effect of stretching combined with ultrashort wave diathermy on joint function and it’s possible mechanism in a rabbit knee contracture model

Objective The aim of this study was to investigate the therapeutic effect of stretching combined with ultrashort wave on joint contracture and explore its possible mechanism. Design Thirty-two rabbits underwent unilateral immobilization of a knee joint at full extension to cause joint contracture. At 6 weeks after immobilization, the rabbits were randomly divided into four groups: natural recovery group, stretching treatment group, ultrashort wave treatment group and combined treatment group. For comparison, eight control group animals of corresponding age were also examined. The effect of stretching and ultrashort wave treatment on joint contracture was assessed by measuring the joint range of motion (ROM), evaluating the collagen deposition of joint capsule and assessing the mRNA and protein levels for TGF-β1 in the joint capsule. Results The combined treatment group led to the best recovery of joint function. The combined treatment with stretching and ultrashort wave was more effective than stretching or ultrashort wave treatment alone against the synovial thickening of suprapatellar joint capsule, the collagen deposition of anterior joint capsule and the elevated expression of TGF-β1 in the joint capsule. Conclusions Stretching combined with ultrashort wave treatment was effective in improving joint ROM, reducing the biomechanical, histological and molecular manifestations of joint capsule fibrosis in a rabbit model of extending joint contracture. Corresponding author: Yun Zhou. Email:zhouyunanhui@sina.com Author Discosures Conflict of Interest: None. Funding: None. Ethical approval: All procedures performed in this study involving animals were approved by the Institutional Animal Care and Use Committee of Anhui Medical University. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Electrophysiological Measurement of Noxious-evoked Brain Activity in Neonates Using a Flat-tip Probe Coupled to Electroencephalography

Measuring pain in non-verbal patients is a challenge. In this study we combine EEG recording with stimulation using a flat-tip probe to detect noxious-evoked brain activity in an objective manner.

http://ift.tt/2Bw3QJ3

Drug Burden Index to Define the Burden of Medicines in Older Adults with Intellectual Disabilities: An Observational Cross-Sectional Study

Summary

Aims

The Drug Burden Index (DBI) is a dose-related measure of anticholinergic and sedative drug exposure. This cross-sectional study described DBI in older adults with intellectual disabilities (ID) and the most frequently reported therapeutic classes contributing to DBI and examined associations between higher DBI scores and potential adverse effects as well as physical function.

Methods

This study analysed data from Wave 2 (2013/2014) of the Intellectual Disability Supplement to the Irish Longitudinal Study on Ageing (IDS-TILDA), a representative study on the ageing of people with ID in Ireland. Self- and objectively-reported data was collected on medication use and physical health, including health conditions. The Barthel Index was the physical function measure.

Results

The study examined 677 individuals with ID, of which 644 (95.1%) reported taking medication and 78.6% (n = 532) were exposed to medication with anticholinergic and/or sedative activity. 54.2% (n = 367) were exposed to high DBI score (≥1). Adjusted multivariate regression analysis revealed no significant association between DBI score and daytime dozing, constipation or falls. After adjusting for confounders (gender, age, level of ID, comorbidities, behaviours that challenge, history of falls), DBI was associated with significantly higher dependence in the Barthel Index (p = 0.002).

Conclusions

This is the first time DBI has been described in older adults with ID. Scores were much higher than those observed in the general population and higher scores were associated with higher dependence in Barthel Index activities of daily living.

http://ift.tt/2jwOsE5

Mammalian Cell Division in 3D Matrices via Quantitative Confocal Reflection Microscopy

This protocol efficiently studies mammalian cell division in 3D collagen matrices by integrating synchronization of cell division, monitoring of division events in 3D matrices using live-cell imaging technique, time-resolved confocal reflection microscopy and quantitative imaging analysis.

http://ift.tt/2Ag3Q1Z

Optical Screening of Novel Bacteria-specific Probes on Ex Vivo Human Lung Tissue by Confocal Laser Endomicroscopy

This technique describes an efficient screening process for evaluating bacteria-specific optical imaging agents within ex vivo human lung tissue, by fibered confocal fluorescence microscopy for the rapid identification of small molecule chemical probe-candidates with translatable potential.

http://ift.tt/2zPZrUk

Uterus transplantation: A Rapidly Expanding Field

No abstract available

http://ift.tt/2AlKDfy

AFM and Microrheology in the Zebrafish Embryo Yolk Cell

The lack of tools to measure material properties and tensional parameters in vivo prevents validating their roles during development. We employed atomic force microscopy (AFM) and nanoparticle-tracking to quantify mechanical features on the intact zebrafish embryo yolk cell during epiboly. These methods are reliable and widely applicable avoiding intrusive interventions.

http://ift.tt/2ik7eC8

Phlebotomy as a preventive measure for crocidolite-induced mesothelioma in male rats

Summary

Malignant mesothelioma (MM) is a rare but socially important neoplasm due to its association with asbestos exposure. While MM is difficult to diagnose at an early stage, there are no particularly effective treatments available at the advanced stage, thus necessitating efficient strategies to prevent MM in individuals already exposed to asbestos. We previously showed that persistent oxidative damage caused by foreign body reaction and affinity of asbestos both to hemoglobin and histones is one of the major pathogeneses. Accordingly, as an effective strategy to prevent asbestos-induced MM, we undertook the use of an iron chelator, deferasirox, which decreased the epithelial-mesenchymal transition in a crocidolite-induced rat MM model. However, this agent may exhibit adverse effects. Here, we studied the effects of iron removal by phlebotomy as a realistic measure on the same rat model. We injected a total of 5 mg of crocidolite intraperitoneally to F1 hybrid rats between the Fischer-344 and Brown-Norway strains at the age of 6 weeks. We repeated weekly or biweekly phlebotomy of 6 to 8 ml/kg/time from 10 to 60 weeks of age. The animals were observed until 120 weeks. In male rats, phlebotomy significantly decreased the weight and nuclear grade of MM, and modestly reduced the associated ascites and the fraction of more malignant sarcomatoid subtype. Weekly phlebotomy prolonged the long-term survival. Our results indicate that appropriate phlebotomy may be a practical preventive measure to attenuate the initiation and promotion capacity of asbestos towards MM by reducing iron in individuals exposed to asbestos.

This article is protected by copyright. All rights reserved.

http://ift.tt/2ilA4SP

Phosphoinositol-4,5-Bisphosphate Regulates Auditory Hair-Cell Mechanotransduction-Channel Pore Properties and Fast Adaptation

Membrane proteins, such as ion channels, interact dynamically with their lipid environment. Phosphoinositol-4,5-bisphosphate (PIP₂) can directly or indirectly modify ion-channel properties. In auditory sensory hair cells of rats (Sprague Dawley) of either sex, PIP₂ localizes within stereocilia, near stereocilia tips. Modulating the amount of free PIP₂ in inner hair-cell stereocilia resulted in the following: (1) the loss of a fast component of mechanoelectric-transduction current adaptation, (2) an increase in the number of channels open at the hair bundle's resting position, (3) a reduction of single-channel conductance, (4) a change in ion selectivity, and (5) a reduction in calcium pore blocking effects. These changes occur without altering hair-bundle compliance or the number of functional stereocilia within a given hair bundle. Although the specific molecular mechanism for PIP₂ action remains to be uncovered, data support a hypothesis for PIP₂ directly regulating channel conformation to alter calcium permeation and single-channel conductance.

SIGNIFICANCE STATEMENT How forces are relayed to the auditory mechanoelectrical transduction (MET) channel remains unknown. However, researchers have surmised that lipids might be involved. Previous work on bullfrog hair cells showed an effect of phosphoinositol-4,5-bisphosphate (PIP₂) depletion on MET current amplitude and adaptation, leading to the postulation of the existence of an underlying myosin-based adaptation mechanism. We find similar results in rat cochlea hair cells but extend these data to include single-channel analysis, hair-bundle mechanics, and channel-permeation properties. These additional data attribute PIP₂ effects to actions on MET-channel properties and not motor interactions. Further findings support PIP₂'s role in modulating a fast, myosin-independent, and Ca²⁺-independent adaptation process, validating fast adaptation's biological origin. Together this shows PIP₂'s pivotal role in auditory MET, likely as a direct channel modulator.

http://ift.tt/2neZqDw

Autocrine Interleukin-10 Mediates Glucagon-Like Peptide-1 Receptor-Induced Spinal Microglial {beta}-Endorphin Expression

The glucagon-like peptide-1 (GLP-1) receptor agonist exenatide stimulates microglial β-endorphin expression and subsequently produces neuroprotection and antinociception. This study illustrated an unrecognized autocrine role of IL-10 in mediation of exenatide-induced β-endorphin expression. Treatment with exenatide in cultured primary spinal microglia concentration dependently stimulated the expression of the M2 microglial markers IL-10, IL-4, Arg 1, and CD206, but not the M1 microglial markers TNF-α, IL-1β, IL-6, or CD68. Intrathecal exenatide injection also significantly upregulated spinal microglial expression of IL-10, IL-4, Arg 1, and CD206, but not TNF-α, IL-1β, IL-6, or CD68. Intrathecal injection of exenatide stimulated spinal microglial expression of IL-10 and β-endorphin in neuropathic rats. Furthermore, treatment with IL-10 (but not IL-4) stimulated β-endorphin expression in cultured primary microglia, whereas treatment with β-endorphin failed to increase IL-10 expression. The IL-10-neutralizing antibody entirely blocked exenatide-induced spinal microglial expression of β-endorphin in vitro and in vivo and fully blocked exenatide mechanical antiallodynia in neuropathic rats. Moreover, specific cAMP/PKA/p38 signal inhibitors and siRNA/p38β, but not siRNA/p38α, completely blocked exenatide-induced IL-10 expression in cultured primary microglia. Knock-down of IL-10 receptor-α mRNA using siRNA fully inhibited exenatide-induced spinal microglial β-endorphin expression and mechanical antiallodynia in neuropathy. Exenatide also markedly stimulated phosphorylation of the transcription factor STAT3 in cultured primary microglia and β-endorphin stimulation was completely inhibited by the specific STAT3 activation inhibitor. These results revealed that IL-10 in microglia mediated β-endorphin expression after GLP-1 receptor activation through the autocrine cAMP/PKA/p38β/CREB and subsequent IL-10 receptor/STAT3 signal pathways.

SIGNIFICANCE STATEMENT Activation of GLP-1 receptors specifically and simultaneously stimulates the expression of anti-inflammatory cytokines IL-10 and IL-4, as well as the neuroprotective factor β-endorphin from microglia. GLP-1 receptor agonism induces β-endorphin expression and antinociception through autocrine release of IL-10. Activation of GLP-1 receptors stimulates IL-10 and β-endorphin expression subsequently through the Gs-cAMP/PKA/p38β/CREB and IL-10/IL-10 receptor-α/STAT3 signal transduction pathways.

http://ift.tt/2zyJopz

Protease-Mediated Suppression of DRG Neuron Excitability by Commensal Bacteria

Peripheral pain signaling reflects a balance of pronociceptive and antinociceptive influences; the contribution by the gastrointestinal microbiota to this balance has received little attention. Disorders, such as inflammatory bowel disease and irritable bowel syndrome, are associated with exaggerated visceral nociceptive actions that may involve altered microbial signaling, particularly given the evidence for bacterial dysbiosis. Thus, we tested whether a community of commensal gastrointestinal bacteria derived from a healthy human donor (microbial ecosystem therapeutics; MET-1) can affect the excitability of male mouse DRG neurons. MET-1 reduced the excitability of DRG neurons by significantly increasing rheobase, decreasing responses to capsaicin (2 μm) and reducing action potential discharge from colonic afferent nerves. The increase in rheobase was accompanied by an increase in the amplitude of voltage-gated K⁺ currents. A mixture of bacterial protease inhibitors abrogated the effect of MET-1 effects on DRG neuron rheobase. A serine protease inhibitor but not inhibitors of cysteine proteases, acid proteases, metalloproteases, or aminopeptidases abolished the effects of MET-1. The serine protease cathepsin G recapitulated the effects of MET-1 on DRG neurons. Inhibition of protease-activated receptor-4 (PAR-4), but not PAR-2, blocked the effects of MET-1. Furthermore, Faecalibacterium prausnitzii recapitulated the effects of MET-1 on excitability of DRG neurons. We conclude that serine proteases derived from commensal bacteria can directly impact the excitability of DRG neurons, through PAR-4 activation. The ability of microbiota-neuronal interactions to modulate afferent signaling suggests that therapies that induce or correct microbial dysbiosis may impact visceral pain.

SIGNIFICANCE STATEMENT Commercially available probiotics have the potential to modify visceral pain. Here we show that secretory products from gastrointestinal microbiota derived from a human donor signal to DRG neurons. Their secretory products contain serine proteases that suppress excitability via activation of protease-activated receptor-4. Moreover, from this community of commensal microbes, Faecalibacterium prausnitzii strain 16-6-I 40 fastidious anaerobe agar had the greatest effect. Our study suggests that therapies that induce or correct microbial dysbiosis may affect the excitability of primary afferent neurons, many of which are nociceptive. Furthermore, identification of the bacterial strains capable of suppressing sensory neuron excitability, and their mechanisms of action, may allow therapeutic relief for patients with gastrointestinal diseases associated with pain.

http://ift.tt/2nezmYZ

Trafficking of Kv2.1 Channels to the Axon Initial Segment by a Novel Nonconventional Secretory Pathway

Kv2.1 is a major delayed-rectifier voltage-gated potassium channel widely expressed in neurons of the CNS. Kv2.1 localizes in high-density cell-surface clusters in the soma and proximal dendrites as well as in the axon initial segment (AIS). Given the crucial roles of both of these compartments in integrating signal input and then generating output, this localization of Kv2.1 is ideal for regulating the overall excitability of neurons. Here we used fluorescence recovery after photobleaching imaging, mutagenesis, and pharmacological interventions to investigate the molecular mechanisms that control the localization of Kv2.1 in these two different membrane compartments in cultured rat hippocampal neurons of mixed sex. Our data uncover a unique ability of Kv2.1 channels to use two molecularly distinct trafficking pathways to accomplish this. Somatodendritic Kv2.1 channels are targeted by the conventional secretory pathway, whereas axonal Kv2.1 channels are targeted by a nonconventional trafficking pathway independent of the Golgi apparatus. We further identified a new AIS trafficking motif in the C-terminus of Kv2.1, and show that putative phosphorylation sites in this region are critical for the restricted and clustered localization in the AIS. These results indicate that neurons can regulate the expression and clustering of Kv2.1 in different membrane domains independently by using two distinct localization mechanisms, which would allow neurons to precisely control local membrane excitability.

SIGNIFICANCE STATEMENT Our study uncovered a novel mechanism that targets the Kv2.1 voltage-gated potassium channel to two distinct trafficking pathways and two distinct subcellular destinations: the somatodendritic plasma membrane and that of the axon initial segment. We also identified a distinct motif, including putative phosphorylation sites, that is important for the AIS localization. This raises the possibility that the destination of a channel protein can be dynamically regulated via changes in post-translational modification, which would impact the excitability of specific membrane compartments.

http://ift.tt/2njKJiH

EM Nerd-The Case of Corporeal Clock

How exactly do trialists proceed when deciding upon the appropriate acronyms for their soon-to-be blockbuster trial? Is the proper etiquette to follow a traditional prospective process, utilizing the first letter of each word in a trial's longer title? Or is the selection of an acronym based on its ability to inspire and only then, retrospectively […]

EMCrit by Rory Spiegel.

http://ift.tt/2ikAZTy

A survival analysis using physique-adjusted tumor size of non-small cell lung cancer

Abstract

Background

Differences in individual body sizes have not been well considered when analyzing the survival of patients with non-small cell lung cancer (NSCLC). We hypothesized that physique-adjusted tumor size is superior to actual tumor size in predicting the prognosis.

Methods

Eight hundred and forty-two patients who underwent R0 resection of NSCLC between 2005 and 2012 were retrospectively reviewed, and overall survival (OS) was evaluated. The physique-adjusted tumor size was defined as: x-adjusted tumor size = tumor size × mean value of x/individual value of x [x = height, weight, body surface area (BSA), or body mass index (BMI)]. Tumor size category was defined as ≤2, 2–3, 3–5, 5–7, and >7 cm. The separation index (SEP), which is the weighted mean of the absolute value of estimated regression coefficients over the subgroups with respect to a reference group, was used to measure the separation of subgroups.

Results

The mean values of height, weight, BSA, and BMI were 160.7 cm, 57.6 kg, 1.59 m², and 22.2 kg/m², respectively. The 5-year survival rates ranged from 88−59% in the non-adjusted tumor size model (SEP 1.937), from 90−57% in the height-adjusted model (SEP 2.236), from 91−52% in the weight-adjusted model (SEP 2.146), from 90−56% in the BSA-adjusted model (SEP 2.077), and from 91−51% in the BMI-adjusted model (SEP 2.169).

Conclusions

The physique-adjusted tumor size can separate the survival better than the actual tumor size.

http://ift.tt/2ily2C7

Frontal Eye Field Inactivation Diminishes Superior Colliculus Activity, But Delayed Saccadic Accumulation Governs Reaction Time Increases

Stochastic accumulator models provide a comprehensive framework for how neural activity could produce behavior. Neural activity within the frontal eye fields (FEFs) and intermediate layers of the superior colliculus (iSC) support such models for saccade initiation by relating variations in saccade reaction time (SRT) to variations in such parameters as baseline, rate of accumulation of activity, and threshold. Here, by recording iSC activity during reversible cryogenic inactivation of the FEF in four male nonhuman primates, we causally tested which parameter(s) best explains concomitant increases in SRT. While FEF inactivation decreased all aspects of ipsilesional iSC activity, decreases in accumulation rate and threshold poorly predicted accompanying increases in SRT. Instead, SRT increases best correlated with delays in the onset of saccade-related accumulation. We conclude that FEF signals govern the onset of saccade-related accumulation within the iSC, and that the onset of accumulation is a relevant parameter for stochastic accumulation models of saccade initiation.

SIGNIFICANCE STATEMENT The superior colliculus (SC) and frontal eye fields (FEFs) are two of the best-studied areas in the primate brain. Surprisingly, little is known about what happens in the SC when the FEF is temporarily inactivated. Here, we show that temporary FEF inactivation decreases all aspects of functionally related activity in the SC. This combination of techniques also enabled us to relate changes in SC activity to concomitant increases in saccadic reaction time (SRT). Although stochastic accumulator models relate SRT increases to reduced rates of accumulation or increases in threshold, such changes were not observed in the SC. Instead, FEF inactivation delayed the onset of saccade-related accumulation, emphasizing the importance of this parameter in biologically plausible models of saccade initiation.

http://ift.tt/2ndVyCy

Stimulation of the Locus Ceruleus Modulates Signal-to-Noise Ratio in the Olfactory Bulb

Norepinephrine (NE) has been shown to influence sensory, and specifically olfactory processing at the behavioral and physiological levels, potentially by regulating signal-to-noise ratio (S/N). The present study is the first to look at NE modulation of olfactory bulb (OB) in regards to S/N in vivo. We show, in male rats, that locus ceruleus stimulation and pharmacological infusions of NE into the OB modulate both spontaneous and odor-evoked neural responses. NE in the OB generated a non-monotonic dose–response relationship, suppressing mitral cell activity at high and low, but not intermediate, NE levels. We propose that NE enhances odor responses not through direct potentiation of the afferent signal per se, but rather by reducing the intrinsic noise of the system. This has important implications for the ways in which an animal interacts with its olfactory environment, particularly as the animal shifts from a relaxed to an alert behavioral state.

SIGNIFICANCE STATEMENT Sensory perception can be modulated by behavioral states such as hunger, fear, stress, or a change in environmental context. Behavioral state often affects neural processing via the release of circulating neurochemicals such as hormones or neuromodulators. We here show that the neuromodulator norepinephrine modulates olfactory bulb spontaneous activity and odor responses so as to generate an increased signal-to-noise ratio at the output of the olfactory bulb. Our results help interpret and improve existing ideas for neural network mechanisms underlying behaviorally observed improvements in near-threshold odor detection and discrimination.

http://ift.tt/2ndVyT4

Neuromedin B Expression Defines the Mouse Retrotrapezoid Nucleus

The retrotrapezoid nucleus (RTN) consists, by definition, of Phox2b-expressing, glutamatergic, non-catecholaminergic, noncholinergic neurons located in the parafacial region of the medulla oblongata. An unknown proportion of RTN neurons are central respiratory chemoreceptors and there is mounting evidence for biochemical diversity among these cells. Here, we used multiplexed in situ hybridization and single-cell RNA-Seq in male and female mice to provide a more comprehensive view of the phenotypic diversity of RTN neurons. We now demonstrate that the RTN of mice can be identified with a single and specific marker, Neuromedin B mRNA (Nmb). Most (~75%) RTN neurons express low-to-moderate levels of Nmb and display chemoreceptor properties. Namely they are activated by hypercapnia, but not by hypoxia, and express proton sensors, TASK-2 and Gpr4. These Nmb-low RTN neurons also express varying levels of transcripts for Gal, Penk, and Adcyap1, and receptors for substance P, orexin, serotonin, and ATP. A subset of RTN neurons (~20–25%), typically larger than average, express very high levels of Nmb mRNA. These Nmb-high RTN neurons do not express Fos after hypercapnia and have low-to-undetectable levels of Kcnk5 or Gpr4 transcripts; they also express Adcyap1, but are essentially devoid of Penk and Gal transcripts. In male rats, Nmb is also a marker of the RTN but, unlike in mice, this gene is expressed by other types of nearby neurons located within the ventromedial medulla. In sum, Nmb is a selective marker of the RTN in rodents; Nmb-low neurons, the vast majority, are central respiratory chemoreceptors, whereas Nmb-high neurons likely have other functions.

SIGNIFICANCE STATEMENT Central respiratory chemoreceptors regulate arterial PCO₂ by adjusting lung ventilation. Such cells have recently been identified within the retrotrapezoid nucleus (RTN), a brainstem nucleus defined by genetic lineage and a cumbersome combination of markers. Using single-cell RNA-Seq and multiplexed in situ hybridization, we show here that a single marker, Neuromedin B mRNA (Nmb), identifies RTN neurons in rodents. We also suggest that >75% of these Nmb neurons are chemoreceptors because they are strongly activated by hypercapnia and express high levels of proton sensors (Kcnk5 and Gpr4). The other RTN neurons express very high levels of Nmb, but low levels of Kcnk5/Gpr4/pre-pro-galanin/pre-pro-enkephalin, and do not respond to hypercapnia. Their function is unknown.

http://ift.tt/2neFjFn

Orientation Tuning of Correlated Activity in the Developing Lateral Geniculate Nucleus

Neural circuits and the cells that comprise them undergo developmental changes in the spatial organization of their connections and in their temporal response properties. Within the lateral geniculate nucleus (LGN) of the dorsal thalamus, these changes have pronounced effects on the spatiotemporal receptive fields (STRFs) of neurons. An open and unresolved question is how STRF maturation affects stimulus-evoked correlated activity between pairs of LGN neurons during development. This is an important question to answer because stimulus-evoked correlated activity likely plays a role in establishing the specificity of thalamocortical connectivity and the receptive fields (RFs) of postsynaptic cortical neurons. Using multielectrode recording methods and white noise stimuli, we recorded neural activity from ensembles of LGN neurons in cats across early development. As expected, there was a progressive maturation of the spatial and temporal properties of visual responses. Using drifting bar stimuli and cross-correlation analysis, we also determined the orientation-tuning bandwidth of correlated activity between pairs of LGN neurons at different stages of development (Sillito and Jones, 2002; Andolina et al., 2007; Stanley et al., 2012; Kelly et al., 2014). Despite the larger RFs and slower responses of immature LGN neurons compared with mature neurons, our results show that correlated activity in the LGN was as tightly tuned for orientation early in development as it was in the adult. Closer examination revealed this age-invariant orientation tuning of correlated activity likely involves cellular mechanisms related to spike fatigue in young animals and a progressive decrease in response latency with development.

SIGNIFICANCE STATEMENT Orientation tuning is a fundamental property of neurons in primary visual cortex. An important and unresolved question is how orientation tuning emerges during brain development. This study explores a potential mechanism for the establishment of orientation tuning based on correlated activity patterns among ensembles of maturing neurons in the lateral geniculate nucleus (LGN) of the thalamus. Results show that correlated activity between pairs of LGN neurons is more tightly tuned than predictions based simply on receptive field size, indicating that correlated activity has the properties needed to play an important role in the development of geniculocortical circuits and the emergence of cortical orientation tuning.

http://ift.tt/2nfV0fC