Δευτέρα, 20 Φεβρουαρίου 2017

Prospective purification and characterization of Müller glia in the mouse retina regeneration assay

Abstract

Reactive gliosis is an umbrella term for various glia functions in neurodegenerative diseases and upon injury. Specifically, Müller glia (MG) in some species readily regenerate retinal neurons to restore vision loss after insult, whereas mammalian MG respond by reactive gliosis—a heterogeneous response which frequently includes cell hypertrophy and proliferation. Limited regeneration has been stimulated in mammals, with a higher propensity in young MG, and in vitro compared to in vivo, but the underlying processes are unknown. To facilitate studies on the mechanisms regulating and limiting glia functions, we developed a strategy to purify glia and their progeny by fluorescence-activated cell sorting. Dual-transgenic nuclear reporter mice, which label neurons and glia with red and green fluorescent proteins, respectively, have enabled MG enrichment up to 93% purity. We applied this approach to MG in a mouse retina regeneration ex vivo assay. Combined cell size and cell cycle analysis indicates that most MG hypertrophy and a subpopulation proliferates which, over time, become even larger in cell size than the ones that do not proliferate. MG undergo timed differential genomic changes in genes controlling stemness and neurogenic competence; and glial markers are downregulated. Genes that are potentially required for, or associated with, regeneration and reactive gliosis are differentially regulated by retina explant culture time, epidermal growth factor stimulation, and animal age. Thus, MG enrichment facilitates cellular and molecular studies which, in combination with the mouse retina regeneration assay, provide an experimental approach for deciphering mechanisms that possibly regulate reactive gliosis and limit regeneration in mammals. © GLIA 2017

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Main Points

  • Transgenic reporter assisted purification of mouse Müller glia (MG).
  • Isolated MG facilitate studies on reactive gliosis, hypertrophy, proliferation, and regeneration.
  • Differential MG genomic response upon retinal injury: time-, EGF-, and age-dependence.


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The impact of bitter taste receptor genetics on culturable bacteria in chronic rhinosinusitis.

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The impact of bitter taste receptor genetics on culturable bacteria in chronic rhinosinusitis.

Rhinology. 2017 Feb 19;:

Authors: Rom DI, Christensen JM, Alvarado R, Sacks R, Harvey RJ

Abstract
BACKGROUND: Extra-oral bitter taste receptors have been associated with innate bacterial defence mechanisms. Genetic variation in T2R38 functionality has been shown to be associated with susceptibility to upper respiratory tract infections and chronic rhinosinusitis (CRS). We sought to independently assess the influence of bitter taste receptor genotype on the presence of culturable bacteria in the sinuses.
METHODOLOGY: A cross-sectional analysis of patients with CRS undergoing surgery was performed. Middle meatal nasal swabs were sent for microbiological evaluation at the time of the procedure. Mucosal biopsies were taken and sent for bitter taste receptor genotype analysis. Sequencing of 3 polymorphisms in the TAS2R38 gene was performed to identify genotypes as super-tasters (PAV/PAV), non-tasters (AVI/AVI) or heterozygous expression (PAV/AVI). The presence of culturable organisms and common pathogens were compared with bitter taste receptor genotypes.
RESULTS: 25 patients (age 52.4 +/- 18.28 years, 51% female) were assessed. Super-tasters comprised 16% of the group, 24% were non-tasters and 48% had heterozygous expression. A cultured pathogen was grown in 48% of patients; 32% gram-positive, 20% gram-negative, 28% grew Staphylococcus aureus and 12% Pseudomonas aeruginosa. A non-taster genotype was predictive of colonised pathogens. Tissue eosinophilia (more than 10 HPF) was seen in 48%.
CONCLUSION: Even in a small sample of patients with CRS, non-taster T2R38 genotype appears to predict the presence of culturable bacteria colonising the sinus cavity at the time of surgery for their condition. A genetic link to patients more likely to become infected is likely.

PMID: 28214914 [PubMed - as supplied by publisher]



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Assessment of efficacy and safety of the herbal medicinal product BNO 1016 in chronic rhinosinusitis.

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Assessment of efficacy and safety of the herbal medicinal product BNO 1016 in chronic rhinosinusitis.

Rhinology. 2017 Feb 19;:

Authors: Palm J, Steiner I, Abramov-Sommariva D, Ammendola A, Mitzenheim S, Steindl H, Wonnemann M, Bachert C

Abstract
BACKGROUND: The objective of this clinical trial (CRS-02) was to assess the efficacy, safety and tolerability of two dosages of the herbal medicinal product BNO 1016 (Sinupret extract) in patients with chronic rhinosinusitis (CRS).
METHODOLOGY: 929 patients suffering from CRS were enrolled in this randomised placebo-controlled trial with a treatment period of 12 weeks. The primary endpoint was the mean Major Symptom Score (MSS) in week 8 and week 12 compared to placebo. Secondary endpoints included further MSS related parameters and responder rates over time. Pharmacoeconomic endpoints were also analysed. Finally, safety and tolerability were evaluated.
RESULTS: Sinupret extract was not superior over placebo regarding the primary endpoint. However, the results of the secondary endpoints showed a clear trend towards superior efficacy. Therefore, additional post-hoc sensitivity analyses were performed in patients with a baseline MSS over 9 and persistence of disease more than 1 year diagnosed by specialists in otorhinolaryngology. Those patients significantly benefited from Sinupret extract. Therapy was superior for the primary endpoint analysis. Patients were less impaired with respect to work and daily activities. A good safety and tolerability of Sinupret extract was assured in all patients.
CONCLUSIONS: Sinupret extract can safely be administered in patients with CRS. Although the primary endpoint of the study was not significant, a post-hoc subgroup analysis in patients whose disease was diagnosed by a specialist revealed a pronounced treatment effect. Effects in that subgroup were even stronger with longer disease persistence and stronger severity.

PMID: 28214913 [PubMed - as supplied by publisher]



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Issue Information - TOC



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Bioethics in a Post-Truth Era



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Response of trabecular bone, thyroid C and follicular cells to synthetic salmon calcitonin in middle-aged orchidectomized male rats

Abstract

In contrast to studies in women, male osteoporosis is poorly understood and strictly related to advancing age. Among the first antiresorptive substances used in the prevention and treatment of osteoporosis is calcitonin (CT), a hypocalcemic hormone that potently inhibits osteoclastic bone resorption. Natural CT is produced and secreted by thyroid C-cells. The other endocrine population of thyroid cells produces thyroid hormones (TH), which also affect bone turnover. The aim of this study was to evaluate the influence of salmon CT on trabecular bone microarchitecture with special reference to effects on the structure and function of both CT- and TH-producing thyroid cells in orchidectomized (Orx) middle-aged rats. Twenty-four male Wistar rats aged 15 months were randomly divided into Orx and sham-operated (SO) groups. One group of Orx animals received (s.c.) synthetic salmon CT (Orx + CT; 100 IU kg−1 b.w.) subcutaneously every second day for 6 weeks. The second Orx group and SO rats were given the same volume of vehicle alone by the same schedule. Trabecular bone histomorphometrical parameters were: cancellous bone area (B.Ar), trabecular thickness (Tb.Th), trabecular number (Tb.N) and trabecular separation (Tb.Sp) were obtained with an ImageJ public-domain image-processing program. The peroxidase–antiperoxidase method was applied for localization of CT in C-cells. Anti-human CT antisera served as the primary antibodies. For immunohistochemical characterization of vascular endothelial growth factor (VEGF) in thyroid tissue, rabbit antisera against human VEGF, served as primary antibodies. CT-immunopositive thyroid C-cells, thyroid follicular epithelium, interstitium and colloid were evaluated morphometrically. Blood serum samples were analyzed for CT, osteocalcin (OC), and thyroxine (T4), and calcium (Ca2+) concentration was determined in urine samples. Salmon CT application significantly increased B.Ar, TbTh and TbN, but markedly decreased Tb.Sp. Administration of exogenous CT significantly decreased mean volume (Vc) and relative volume density (Vv) of thyroid C-cells in relation to both SO and Orx groups. The Vv of the colloid was higher, whereas the VV of the follicular epithelium was lower after CT treatment compared with Orx alone. CT treatment markedly elevated serum CT, whereas serum OC, T4 and urinary Ca2+ concentrations were lower than in the Orx group. These results indicate that salmon CT stimulates trabecular bone microarchitecture, strongly inhibits thyroid C-cells and changes the structure of the thyroid gland, indicating hypoactivity.



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Morphological interaction between the nasal septum and nasofacial skeleton during human ontogeny

Abstract

The nasal septal cartilage is thought to be a key growth center that contributes to nasofacial skeletal development. Despite the developmental influence of the nasal septum however, humans often exhibit a high frequency of septal deviation suggesting discordance in the growth between the septum and surrounding nasofacial skeleton. While there are numerous etiological factors that contribute to septal deviation, the surrounding nasofacial skeleton may also act to constrain the septum, resulting in altered patterns of growth. That is, while the nasal septum has a direct morphogenetic influence on aspects of the nasofacial skeleton, other nasofacial skeletal components may restrict septal growth resulting in deviation. Detailing the developmental relationship between these structures is important not only for understanding the causal determinants of nasal septal deviation, but also for developing a broader understanding of the complex interaction between the facial skeleton and chondrocranium. We selected 66 non-syndromic subjects from the University of Minnesota Orthodontic Clinic who ranged from 7 to 18 years in age and had an existing pretreatment cone-beam computed tomography (CBCT) scan. Using CBCT data, we examined the developmental relationship between nasal septal deviation and the surrounding nasofacial skeleton. We measured septal deviation as a percentage of septal volume relative to a modeled non-deviated septum. We then collected a series of coordinate landmark data in the region immediately surrounding the nasal septum in the midsagittal plane representing the nasofacial skeleton. First, we examined ontogenetic changes in the magnitude of nasal septal deviation relative to chronological age and nasofacial size. Next, using Procrustes-based geometric morphometric techniques, we assessed the morphological relationship between nasal septal deviation and nasofacial skeletal shape. Our results indicate that variation in the magnitude of nasal septal deviation was established in our earliest age group and maintained throughout ontogeny. Moreover, nasal septal deviation was correlated with non-allometric variation in nasofacial shape restricted to the region of the anterior sphenoid body. Ultimately, our results suggest that early developmental variation in midline basicranial components may act to alter or constrain patterns of nasal septal growth.



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Renaud Mazeron, 1977-2016

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Publication date: Available online 21 February 2017
Source:Brachytherapy





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Journal of the American College of Cardiology

Journal of the American College of Cardiology, published by American College of Cardiology, last updated on 2017-02-20, available at http://ift.tt/2hqiVCb

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JACC: Clinical Electrophysiology

JACC: Clinical Electrophysiology, published by American College of Cardiology, last updated on 2017-02-20, available at http://ift.tt/2l2dieK

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Neuronal Signaling

Neuronal Signaling, published by Portland Press Ltd, last updated on 2017-02-20, available at http://ift.tt/2l29zO5

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Adenosine A2 receptor activation ameliorates mitochondrial oxidative stress upon reperfusion through the posttranslational modification of NDUFV2 subunit of complex I in the heart

Publication date: Available online 20 February 2017
Source:Free Radical Biology and Medicine
Author(s): Jingman Xu, Xiyun Bian, Yuan Liu, Lan Hong, Tianming Teng, Yuemin Sun, Zhelong Xu
While it is well known that adenosine receptor activation protects the heart from ischemia/reperfusion injury, the precise mitochondrial mechanism responsible for the action remains unknown. This study probed the mitochondrial events associated with the cardioprotective effect of 5’-(N-ethylcarboxamido) adenosine (NECA), an adenosine A2 receptor agonist. Isolated rat hearts were subjected to 30min ischemia followed by 10min of reperfusion, whereas H9c2 cells experienced 20min ischemia and 10min reperfusion. NECA prevented mitochondrial structural damage, decreases in respiratory control ratio (RCR), and collapse of mitochondrial membrane potential (ΔΨm). Both the adenosine A2A receptor antagonist SCH58261 and A2B receptor antagonist MRS1706 inhibited the action of NECA. NECA reduced mitochondrial proteins carbonylation, H2O2, and superoxide generation at reperfusion, but did not change superoxide dismutase (SOD) activity. In support, the protective effects of NECA and Peg-SOD on ΔΨm upon reperfusion were additive, implying that NECA's protection is attributable to the reduced superoxide generation but not to the enhancement of the superoxide-scavenging capacity. NECA increased the mitochondrial Src tyrosine kinase activity and suppressed complex I activity at reperfusion in a Src-dependent manner. NECA also reduced mitochondrial superoxide through Src tyrosine kinase. Studies with liquid chromatography-mass spectrometer (LC-MS) identified Tyr118 of the NDUFV2 subunit of complex 1 as a likely site of the tyrosine phosphorylation. Furthermore, the complex I activity of cells transfected with the Y118F mutant was increased, suggesting that this site might be a negative regulator of complex I activity. In support, NECA failed to suppress complex I activity at reperfusion in cells transfected with the Y118F mutant of NDUFV2. In conclusion, NECA prevents mitochondrial oxidative stress by decreasing mitochondrial superoxide generation through inhibition of complex I via the mitochondrial Src tyrosine kinase. Phosphorylation of Tyr118 residue in NDUFV2 subunit may account for the inhibitory effect of NECA on complex I.

Graphical abstract

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Conversion to purpurogallin, a key step in the mechanism of the potent xanthine oxidase inhibitory activity of pyrogallol

Publication date: Available online 20 February 2017
Source:Free Radical Biology and Medicine
Author(s): Sari Honda, Yuya Fukuyama, Hisashi Nishiwaki, Akiko Masuda, Toshiya Masuda
In this study, the mechanism of the xanthine oxidase (XO) inhibitory activity of pyrogallol, the main inhibitor found in roasted coffee, was investigated. Pyrogallol was unstable and readily converted to purpurogallin in a pH 7.4 solution, a physiological model of human body fluids. The XO inhibitory activity of the produced purpurogallin was higher than that of pyrogallol, as evidenced by comparing their IC50 values (0.2 µmol L−1 for purpurogallin, 1.6 µmol L−1 for pyrogallol). The XO activity of pyrogallol was enhanced by pre-incubation in pH 7.4 solution. Although the initial XO inhibitory activity of 4-methylpyrogallol was weak (IC50 33.3 µmol L−1), its XO inhibitory activity was also enhanced by pre-incubation in the pH 7.4 solution. In contrast, 5-methylpyrogallol, which could not be transformed into corresponding purpurogallin derivatives, did not show XO inhibitory activity before or after incubation in pH 7.4 solution. Molecular docking simulations clarified that purpurogallins have stronger affinities for XO than corresponding pyrogallols. These results revealed that the potent XO inhibitory activity seemingly observed in pyrogallol is actually derived from its chemical conversion, under alkaline conditions, into purpurogallin.

Graphical abstract

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Erratum to: Scaling up strategies of the chronic respiratory disease programme of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Area 5)



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Wnt3α and transforming growth factor-β induce myofibroblast differentiation from periodontal ligament cells via different pathways

Publication date: Available online 20 February 2017
Source:Experimental Cell Research
Author(s): Hui Xu, Yao He, Jian Q. Feng, Rui Shu, Zhe Liu, Jingyu Li, Yating Wang, Yang Xu, Huan Zeng, Xin Xu, Zichao Xiang, Chaoran Xue, Ding Bai, Xianglong Han
Myofibroblasts are specialized cells that play a key role in connective tissue remodeling and reconstruction. Alpha-smooth muscle actin (α-SMA), vimentin and tenascin-C are myofibroblast phenotype, while α-SMA is the phenotypic marker. The observation that human periodontal ligament cells (hPDLCs) differentiate into myofibroblasts under orthodontic force has provided a new perspective for understanding of the biological and biomechanical mechanisms involved in orthodontic tooth movement. However, the cell-specific molecular mechanisms leading to myofibroblast differentiation in the periodontal ligament (PDL) remain unclear. In this study, we found that expression of Wnt3α, transforming growth factor-β1 (TGF-β1), α-SMA and tenascin-C increased in both tension and compression regions of the PDL under orthodontic load compared with unloaded control, suggesting that upregulated Wnt3α and TGF-β1 signaling might have roles in myofibroblast differentiation in response to orthodontic force. We reveal in vitro that both Wnt3α and TGF-β1 promote myofibroblast differentiation from hPDLCs. Dickkopf-1 (DKK1) impairs Wnt3α-induced myofibroblast differentiation in a β-catenin-dependent manner. TGF-β1 stimulates myofibroblast differentiation via a JNK-dependent mechanism. DKK1 has no significant effect on TGF-β1-induced myofibroblastic phenotype.



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The regulation of transcriptional repression in hypoxia

Publication date: Available online 20 February 2017
Source:Experimental Cell Research
Author(s): Miguel A.S. Cavadas, Alex Cheong, Cormac T. Taylor
A sufficient supply molecular oxygen is essential for the maintenance of physiologic metabolism and bioenergetic homeostasis for most metazoans. For this reason, mechanisms have evolved for eukaryotic cells to adapt to conditions where oxygen demand exceeds supply (hypoxia). These mechanisms rely on the modification of pre-existing proteins, translational arrest and transcriptional changes. The hypoxia inducible factor (HIF; a master regulator of gene induction in response to hypoxia) is responsible for the majority of induced gene expression in hypoxia. However, much less is known about the mechanism(s) responsible for gene repression, an essential part of the adaptive transcriptional response. Hypoxia-induced gene repression leads to a reduction in energy demanding processes and the redirection of limited energetic resources to essential housekeeping functions. Recent developments have underscored the importance of transcriptional repressors in cellular adaptation to hypoxia. To date, at least ten distinct transcriptional repressors have been reported to demonstrate sensitivity to hypoxia. Central among these is the Repressor Element-1 Silencing Transcription factor (REST), which regulates over 200 genes. In this review, written to honor the memory and outstanding scientific legacy of Lorenz Poellinger, we provide an overview of our existing knowledge with respect to transcriptional repressors and their target genes in hypoxia.



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Foxc1 and Foxc2 are necessary to maintain glomerular podocytes

Publication date: Available online 20 February 2017
Source:Experimental Cell Research
Author(s): Masaru Motojima, Tsutomu Kume, Taiji Matsusaka
Foxc1 and Foxc2 (Foxc1/2) are transcription factors involved in many biological processes. In adult kidneys, expression of Foxc1/2 is confined to the glomerular epithelial cells, i.e., podocytes.To bypass embryonic lethality of Foxc1/2 null mice, mice ubiquitously expressing inducible-Cre (ROSA26-CreERT2) or mice expressing Cre in podocytes (Nephrin-Cre) were mated with floxed-Foxc1 and floxed-Foxc2 mice. The CreERT2 was activated in adult mice by administrations of tamoxifen.Eight weeks after tamoxifen treatment, ROSA26-CreERT2; Foxc1+/flox; Foxc2flox/flox mice developed microalbuminuria, while ROSA26-Cre ERT2; Foxc1flox/flox; Foxc2+/flox mice had no microalbuminuria. The kidneys of conditional-Foxc1/2 null mice showed proteinaceous casts, protein reabsorption droplets in tubules and huge vacuoles in podocytes, indicating severe podocyte injury and massive proteinuria. Comparison of gene expression profiles revealed that Foxc1/2 maintain expression of genes necessary for podocyte function such as podocin and Cxcl12. In addition, mice with an innate podocyte-specific deletion of Foxc1/2 by Nephrin-Cre develop similar podocyte injury.These results demonstrate dose-dependence of Foxc1/2 gene in maintaining the podocyte with a more critical role for Foxc2 than Foxc1 and a critical role of Foxc1/2 in regulating expression of genes that maintain podocyte integrity.



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Survival of patients with colorectal peritoneal metastases is affected by treatment disparities among hospitals of diagnosis: A nationwide population-based study

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Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Koen P. Rovers, Geert A. Simkens, Pauline A. Vissers, Valery E. Lemmens, Victor J. Verwaal, Andre J. Bremers, Marinus J. Wiezer, Jacobus W. Burger, Patrick H. Hemmer, Henk Boot, Wilhelmina M. van Grevenstein, Wilhelmus J. Meijerink, Arend G. Aalbers, Cornelis J. Punt, Pieter J. Tanis, Ignace H. de Hingh
BackgroundIn the Netherlands, surgery for peritoneal metastases of colorectal cancer (PMCRC) is centralised, whereas PMCRC is diagnosed in all hospitals. This study assessed whether hospital of diagnosis affects treatment selection and overall survival (OS).MethodsBetween 2005 and 2015, all patients with synchronous PMCRC without systemic metastases were selected from the Netherlands Cancer Registry. Treatment was classified as cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC), systemic therapy or other/no treatment. Hospitals of diagnosis were classified as: (1) non-teaching or academic/teaching hospital and (2) HIPEC centre or referring hospital. Referring hospitals were further classified based on the frequency of CRS/HIPEC as high-, medium- or low-frequency hospital. Multivariable regression analyses were used to assess the independent influence of hospital categories on the likelihood of CRS/HIPEC and OS.ResultsA total of 2661 patients, diagnosed in 89 hospitals, were included. At individual hospital level, CRS/HIPEC and systemic therapy ranged from 0% to 50% and 6% to 67%, respectively. Hospital of diagnosis influenced the likelihood of CRS/HIPEC: 33% versus 13% for HIPEC centres versus referring hospitals (odds ratio (OR) 3.66 [2.40−5.58]) and 11% versus 17% for non-teaching hospitals versus academic/teaching hospitals (OR 0.60 [0.47–0.77]). Hospital of diagnosis affected median OS: 14.1 versus 9.6 months for HIPEC centres versus referring hospitals (hazard ratio (HR) 0.82 [0.67–0.99]) and 8.7 versus 11.5 months for non-teaching hospitals versus academic/teaching hospitals (HR 1.15 [1.06–1.26]). Compared with diagnosis in medium-frequency referring hospitals, median OS was increased in high-frequency referring hospitals (12.6 months, HR 0.82 [0.73−0.91]) and reduced in low-frequency referring hospitals (8.1 months, HR 1.12 [1.01–1.24]).ConclusionTreatment disparities among hospitals of diagnosis and their impact on survival indicate suboptimal treatment selection for PMCRC.



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Phase-II trials in osteosarcoma recurrences: A systematic review of past experience

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Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Natacha Omer, Marie-Cécile Le Deley, Sophie Piperno-Neumann, Perrine Marec-Berard, Antoine Italiano, Nadège Corradini, Carine Bellera, Laurence Brugières, Nathalie Gaspar
BackgroundThe most appropriate design of Phase-II trials evaluating new therapies in osteosarcoma remains poorly defined.ObjectiveTo study consistency in phase-II clinical trials evaluating new therapies for osteosarcoma recurrences with respect to eligibility criteria, response assessment, end-points, statistical design and reported results.MethodsSystematic review of clinical trials registered on clinicaltrials.gov, clinicaltrialsregister.eu and French National Cancer Institute website or referenced in PubMed and American Society of Clinical Oncology websites, between 2003 and 2016, using the following criteria: (osteosarcoma OR bone sarcoma) AND (Phase-II).ResultsAmong the 99 trials identified, 80 were Phase-II, 17 I/II and 2 II/III, evaluating mostly targeted therapy (n = 40), and chemotherapy alone (n = 26). Results were fully (n = 28) or partially (abstract, n = 6) published. Twenty-four trials were dedicated to osteosarcoma, 22 had an osteosarcoma stratum. Twenty-eight out of 99 trials refer to the age range observed at recurrence (28%). Overall, 65 trials were run in multicentre settings, including 17 international trials. Only 9 trials were randomised. The primary end-point was tumour response in 71 trials (response rate, n = 40 or best response, n = 31), with various definitions (complete + partial ± minor response and stable disease), mainly evaluated with RECIST criteria (n = 69); it was progression-free survival in 24 trials and OS in 3. In single-arm trials evaluating response rate, the null hypothesis tested (when available, n = 12) varied from 5% to 25%.ConclusionNo robust historical data can currently be derived from past efficacy Phase-II trials. There is an urgent need to develop international randomised Phase-II trials across all age ranges with standardised primary end-point.



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Anthropometrics at birth and risk of a primary central nervous system tumour: A systematic review and meta-analysis

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Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Marios K. Georgakis, Eleni I. Kalogirou, Athanasios Liaskas, Maria A. Karalexi, Paraskevi Papathoma, Kyriaki Ladopoulou, Maria Kantzanou, Georgios Tsivgoulis, Eleni Th. Petridou
BackgroundThe aetiology of primary central nervous system (CNS) tumours remains largely unknown, but their childhood peak points to perinatal parameters as tentative risk factors. In this meta-analysis, we opted to quantitatively synthesise published evidence on the association between birth anthropometrics and risk of primary CNS tumour.MethodsEligible studies were identified via systematic literature review; random-effects meta-analyses were conducted for the effect of birth weight and size-for-gestational-age on childhood and adult primary CNS tumours; subgroup, sensitivity, meta-regression and dose–response by birth weight category analyses were also performed.ResultsForty-one articles, encompassing 53,167 CNS tumour cases, were eligible. Birth weight >4000 g was associated with increased risk of childhood CNS tumour (OR: 1.14, [1.08–1.20]; 22,330 cases). The risk was higher for astrocytoma (OR: 1.22, [1.13–1.31]; 7456 cases) and embryonal tumour (OR: 1.16, [1.04–1.29]; 3574 cases) and non-significant for ependymoma (OR: 1.12, [0.94–1.34]; 1374 cases). Increased odds for a CNS tumour were also noted among large-for-gestational-age children (OR: 1.12, [1.03–1.22]; 10,339 cases), whereas insufficient data for synthesis were identified for other birth anthropometrics. The findings remained robust across subgroup and sensitivity analyses controlling for several sources of bias, whereas no significant heterogeneity or publication bias were documented. The limited available evidence on adults (4 studies) did not reveal significant associations between increasing birth weight (500-g increment) and overall risk CNS tumour (OR: 0.99, [0.98–1.00]; 1091 cases) or glioma (OR: 1.03, [0.98–1.07]; 2052 cases).ConclusionsThis meta-analysis confirms a sizeable association of high birth weight, with childhood CNS tumour risk, particularly astrocytoma and embryonal tumour, which seems to be independent of gestational age. Further research is needed to explore underlying mechanisms, especially modifiable determinants of infant macrosomia, such as gestational diabetes.



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Advanced breast cancer rates in the epoch of service screening: The 400,000 women cohort study from Italy

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Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Donella Puliti, Lauro Bucchi, Silvia Mancini, Eugenio Paci, Susanna Baracco, Cinzia Campari, Debora Canuti, Claudia Cirilli, Natalina Collina, Giovanni Maria Conti, Enza Di Felice, Fabio Falcini, Maria Michiara, Rossella Negri, Alessandra Ravaioli, Priscilla Sassoli de' Bianchi, Monica Serafini, Manuel Zorzi, Adele Caldarella, Luigi Cataliotti, Marco Zappa
BackgroundThe objective of this study was to evaluate if mammography screening attendance is associated with a reduction in late-stage breast cancer incidence.MethodsThe cohort included over 400,000 Italian women who were first invited to participate in regional screening programmes during the 1990s and were followed for breast cancer incidence for 13 years. We obtained individual data on their exposure to screening and correlated this with total and stage-specific breast cancer incidence. Socio-economic status and pre-screening incidence data were used to assess the presence of self-selection bias.ResultsOverall, screening attendance was associated with a 10% excess risk of in situ and invasive breast cancer (IRR = 1.10; 95% confidence interval (CI): 1.06–1.14), which dropped to 5% for invasive cancers only (IRR = 1.05; 95% CI: 1.01–1.09). There were significant reductions among attenders for specific cancer stages; we observed a 39% reduction for T2 or larger (IRR = 0.61; 95% CI: 0.57–0.66), 19% for node positives (IRR = 0.81; 95% CI: 0.76–0.86) and 28% for stage II and higher (IRR = 0.72; 95% CI: 0.68–0.76). Our data suggest that the presence of self-selection bias is limited and, overall, invited women experienced a 17% reduction of advanced cancers compared with pre-screening rates.ConclusionsComparing attenders' and non-attenders' stage-specific breast cancer incidence, we have estimated that screening attendance is associated with a reduction of nearly 30% for stages II+.



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Rationale for stimulator of interferon genes–targeted cancer immunotherapy

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Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Thaiz Rivera Vargas, Isis Benoit-Lizon, Lionel Apetoh
The efficacy of checkpoint inhibitor therapy illustrates that cancer immunotherapy, which aims to foster the host immune response against cancer to achieve durable anticancer responses, can be successfully implemented in a routine clinical practice. However, a substantial proportion of patients does not benefit from this treatment, underscoring the need to identify alternative strategies to defeat cancer. Despite the demonstration in the 1990's that the detection of danger signals, including the nucleic acids DNA and RNA, by dendritic cells (DCs) in a cancer setting is essential for eliciting host defence, the molecular sensors responsible for recognising these danger signals and eliciting anticancer immune responses remain incompletely characterised, possibly explaining the disappointing results obtained so far upon the clinical implementation of DC-based cancer vaccines. In 2008, STING (stimulator of interferon genes), was identified as a protein that is indispensable for the recognition of cytosolic DNA. The central role of STING in controlling anticancer immune responses was exemplified by observations that spontaneous and radiation-induced adaptive anticancer immunity was reduced in the absence of STING, illustrating the potential of STING-targeting for cancer immunotherapy. Here, we will discuss the relevance of manipulating the STING signalling pathway for cancer treatment and integrating STING-targeting based strategies into combinatorial therapies to obtain long-lasting anticancer immune responses.



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Can chance cause cancer? A causal consideration

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Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Mats Julius Stensrud, Susanne Strohmaier, Morten Valberg, Odd Olai Aalen
The role of randomness, environment and genetics in cancer development is debated. We approach the discussion by using the potential outcomes framework for causal inference. By briefly considering the underlying assumptions, we suggest that the antagonising views arise due to estimation of substantially different causal effects. These effects may be hard to interpret, and the results cannot be immediately compared. Indeed, it is not clear whether it is possible to define a causal effect of chance at all.



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Comparative analysis of PD-L1 expression between primary and metastatic pulmonary adenocarcinomas

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Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Sehui Kim, Jaemoon Koh, Dohee Kwon, Bhumsuk Keam, Heounjeong Go, Young A Kim, Yoon Kyung Jeon, Doo Hyun Chung
Programmed death-ligand 1 (PD-L1) expression in pulmonary adenocarcinomas (pADCs) was implicated in predicting anti-PD-1/PD-L1 therapy efficacy. However, the differential expression of PD-L1 between primary and metastatic pADC remains unclear. Thus, we addressed this issue. In total, 161 paired primary and metastatic tumour tissues from 146 patients with pADC were collected. Most of the cases had regional nodal metastasis (134/161, 83.2%). PD-L1 expression was categorised based on the proportion of immunostained tumour cells using cutoff values of 1%, 5%, 10% and 50%. In primary tumours, PD-L1 positivity was observed in 28.1% (41/146), 27.4% (40/146), 22.6% (33/146) and 13.0% (19/146) of cases using cutoff values of 1%, 5%, 10% and 50%, respectively. The overall concordance rate for PD-L1 expression between primary and metastatic tumours was 75.2% (121/161). The concordance rate in primary tumours expressing PD-L1 in <1% or ≥50% of tumour cells was 87.2% (102/117) or 70% (14/20), respectively. In contrast, the concordance rate in tumours expressing PD-L1 in ≥1% to <50% of cells was only 20.8% (5/24). After dichotomising the cases using cutoff values of 1% and 50%, the concordance rate increased to 80.1% (129/161) and 90.7% (146/161) in all paired cases and to 70.4% (19/27) and 85.2% (23/27) in cases with distant metastases, respectively. This study demonstrates that the concordance of PD-L1 expression between primary and metastatic pADC is high when using cutoff values of 1% and 50%. Thus, evaluation of PD-L1 in either primary or metastatic tumours would be helpful for guiding anti–PD-1/PD-L1 immunotherapy in patients with advanced pADC.



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A Rare Presentation of Sarcoidosis as a Pancreatic Head Mass

Sarcoidosis is a multisystem granulomatous syndrome of unknown etiology with noncaseating epithelioid granulomas being the pathognomonic pathological finding. Sarcoidosis most commonly involves the lungs and involvement of the gastrointestinal (GI) tract is uncommon. Pancreatic sarcoidosis is very rare, especially when it is the presenting feature of sarcoidosis and can masquerade as pancreatic cancer. Tissue infiltration in pancreatic sarcoidosis can lead to either a diffuse nodular appearance or a mass-like lesion. We present an interesting case of a 47-year-old woman with a 10-pack-year history of smoking who presented with sharp epigastric pain, weight loss, and elevated lipase level. CT and MRI imaging showed a 4 cm × 5 cm heterogeneous pancreatic mass with a dilated pancreatic duct and peripancreatic lymphadenopathy. Endoscopic ultrasound guided FNA revealed noncaseating granulomas with no evidence of malignancy or atypical infection. CT of the chest revealed bilateral mediastinal and hilar adenopathy with calcification, without any parenchymal abnormalities, and her angiotensin-converting enzyme level was elevated at 170 U/L. The clinical picture pointed to the diagnosis of pancreatic sarcoidosis. Given the severity of gastrointestinal symptoms related to pancreatic sarcoidosis, prednisone therapy at 0.5 mg/kg/day was initiated with complete resolution of symptoms at 8 weeks.

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Paranasal Rosai-Dorfman Disease with Osseous Destruction

Rosai-Dorfman disease is a rare histiocytic proliferative disorder of unknown etiology typically characterized by cervical lymphadenopathy. Extranodal involvement often manifests in the head and neck region. We present a 10-year-old male who presented to our hospital with left epiphora from an aggressive paranasal mass invading the left orbit with osseous destruction. The mass was surgically biopsied and debulked with histopathological examination revealing Rosai-Dorfman disease. Although rarely found in the sinuses, Rosai-Dorfman disease should be considered when evaluating sinonasal masses.

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ANA IIF Automation: Moving towards Harmonization? Results of a Multicenter Study

Background. Our study aimed to investigate whether the introduction of automated anti-nuclear antibody (ANA) indirect immunofluorescence (IIF) analysis decreases the interlaboratory variability of ANA titer results. Method. Three serum samples were sent to 10 laboratories using the QUANTA-Lyser® in combination with the NOVA View®. Each laboratory performed the ANA IIF analysis 10x in 1 run and 1x in 10 different runs and determined the endpoint titer by dilution. One of the three samples had been sent in 2012, before the era of ANA IIF automation, by the Belgian National External Quality Assessment (EQA) Scheme. Harmonization was evaluated in terms of variability in fluorescence intensity (LIU) and ANA IIF titer. Results. The evaluation of the intra- and interrun LIU variability revealed a larger variability for 2 laboratories, due to preanalytical and analytical problems. Reanalysis of the EQA sample resulted in a lower titer variability. Diluted endpoint titers were similar to the estimated single well titer and the overall median titer as reported by the EQA in 2012. Conclusion. The introduction of automated microscopic analysis allows more harmonized ANA IIF reporting, provided that this totally automated process is controlled by a thorough quality assurance program, covering the total ANA IIF process.

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Periodontal Ligament Stem Cells in the Periodontitis Microenvironment Are Sensitive to Static Mechanical Strain

During orthodontic treatment, periodontium remodeling of periodontitis patients under mechanical force was abnormal. We have previously confirmed the function impairment of periodontal ligament stem cells (PDLSCs) in the periodontitis microenvironment which might be involved in this pathological process. However, the response of PDLSCs in periodontitis microenvironment to mechanical force remains unclear. Therefore, in the present study, we introduced a Flexcell tension apparatus and investigated the response of PDLSCs obtained from periodontal tissues of periodontitis patients (PPDLSCs) and of those obtained from healthy periodontal tissues (HPDLSCs) to different magnitudes of static mechanical strain (SMS). PPDLSCs showed increased proliferation, decreased osteogenic activity, activated osteoclastogenesis, and greater secretion of inflammatory cytokines. Different magnitudes of SMS exerted distinct effects on HPDLSCs and PPDLSCs. An SMS of 12% induced optimal effects in HPDLSCs, including the highest proliferation, the best osteogenic ability, the lowest osteoclastogenesis, and the lowest secretion of inflammatory cytokines, while the optimal SMS for PPDLSCs was 8%. Excessive SMS damaged PPDLSCs function, including decreased proliferation, an imbalance between osteogenesis and osteoclastogenesis, and an activated inflammatory response. Our data suggest that PPDLSCs are more sensitive and less tolerant to SMS, and this may explain why mechanical force results in undesirable effects in periodontitis patients.

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Fatigue Properties of Plain Concrete under Triaxial Tension-Compression-Compression Cyclic Loading

Fatigue tests were performed on plain concrete under triaxial tension-compression-compression (T-C-C) cyclic loading with constant and variable amplitude using a large multiaxial machine. Experimental results show that, under constant amplitude fatigue loads, the development of residual strain in the fatigue loading direction depends mostly on the lateral compressive stress ratio and is nearly independent of stress level. Under variable amplitude fatigue loads, the fatigue residual strain is related to the relative fatigue cycle and lateral compressive stress ratio but has little relationship with the loading process. To model this system, the relative residual strain was defined as the damage variant. Damage evolutions for plain concrete were established. In addition, fatigue damage analysis and predictions of fatigue remaining life were conducted. This work provides a reference for multistage fatigue testing and fatigue damage evaluation of plain concrete under multiaxial loads.

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Progressive Pseudorheumatoid Dysplasia or JIA?

Progressive pseudorheumatoid dysplasia (PPD) or spondyloepiphyseal dysplasia tarda with progressive arthropathy (SEDT-PA) is a rare arthropathy of childhood involving the axial skeleton as well as small peripheral joints. A 10-year-old boy was referred by a general practitioner with pain and deformity in the fingers of hands and limping gait. There was no joint synovitis although the finger joints were bulky on examination with mild flexion deformity. Patient had exaggerated kyphosis and lumbar lordosis with pigeon chest and restricted hip joint movements. Anteroposterior X-rays of the hip joints revealed widened and flattened epiphyses of the femoral heads with narrow and irregular joint spaces. Hand X-rays revealed periarticular osteopenia, significant narrowing of the joint spaces of proximal interphalangeal, and distal interphalangeal joints, together with osseous enlargement of the basis of metacarpal bones and phalanges. Spinal X-rays revealed generalized platyspondyly and anterior beaking of vertebral bodies. There was a clear mega os trigonum in his feet images. All blood investigations were normal with no evidence of inflammation and thyroid hormone levels were normal. The diagnosis of PPD was favored by imaging studies and normal inflammatory markers and the patient was treated with physiotherapy, family counseling, and anti-inflammatory medications.

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An Analysis of Impact Factors for Positioning Performance in WLAN Fingerprinting Systems Using Ishikawa Diagrams and a Simulation Platform

Many factors influence the positioning performance in WLAN RSSI fingerprinting systems, and summary of these factors is an important but challenging job. Moreover, impact analysis on nonalgorithm factors is significant to system application and quality control but little research has been conducted. This paper analyzes and summarizes the potential impact factors by using an Ishikawa diagram considering radio signal transmitting, propagating, receiving, and processing. A simulation platform was developed to facilitate the analysis experiment, and the paper classifies the potential factors into controllable, uncontrollable, nuisance, and held-constant factors considering simulation feasibility. It takes five nonalgorithm controllable factors including APs density, APs distribution, radio signal propagating attenuation factor, radio signal propagating noise, and RPs density into consideration and adopted the OFAT analysis method in experiment. The positioning result was achieved by using the deterministic and probabilistic algorithms, and the error was presented by RMSE and CDF. The results indicate that the high APs density, signal propagating attenuation factor, and RPs density, with the low signal propagating noise level, are favorable to better performance, while APs distribution has no particular impact pattern on the positioning error. Overall, this paper has made great potential contribution to the quality control of WLAN fingerprinting solutions.

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Shigellosis Caused by CTX-M Type ESBL Producing Shigella flexneri in Two Siblings of Rural Nepal: First Case Report from the Country

Shigellosis is an acute infectious disease characterized as severe bloody diarrhea (dysentery) and is accountable for a significant burden of morbidity and mortality especially in children under the age of 5 years. Antimicrobial therapy is required in the cases of severe dysentery associated with Shigella. However, emergence of multidrug resistant (MDR) strains of Shigella spp. over the last two decades has restricted the use of common therapeutic antimicrobials. In MDR strains, the third-generation cephalosporins have been used for the treatment, but, unfortunately, emerging reports of enzyme mediated β-lactam resistance among Shigella isolates from various parts of the world have greatly compromised the therapy of pediatric dysentery. In Nepal, drug resistant strains of Shigella spp. have been reported, but MDR and extended spectrum β-lactamase (ESBL) producing strains were previously unknown. Here, we report two Shigella flexneri isolates harboring ESBL genotype-CTX-M associated with acute dysentery in two siblings which were presented and treated in a tertiary care teaching hospital of Kathmandu, Nepal.

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A Perplexing Case of Abdominal Pain That Led to the Diagnosis of Zollinger-Ellison Syndrome

Zollinger-Ellison syndrome (ZES) is a rare clinical disorder, characterized by hypersecretion of gastric acid and multiple ulcers distal to the duodenal bulb. This occurs via the release of gastrin by neuroendocrine tumors known as gastrinomas. Patients with ZES present with nonspecific GI symptoms, which often leads to a delay in diagnosis. Our patient is a 55-year-old female with chronic abdominal pain, nausea, and diarrhea. She underwent EGD, EUS, MRCP, CT scans, and cholecystectomy, which did not reveal the cause of her symptoms. Repeat EGD showed a cratered ulcer in the second portion of the duodenum, suspicious for ZES. Serum gastrin was initially only moderately elevated while on PPI therapy, but chromogranin A was also elevated. Repeat gastrin level after stopping PPI therapy was 1639 pg/mL. Somatostatin receptor scintigraphy was obtained, which showed two small lesions in the gastrinoma triangle. She subsequently underwent a Whipple pancreaticoduodenectomy and pathology was positive for four microscopic foci of a neuroendocrine tumor. She reported improvement in her symptoms after surgery. This case highlights the need for increased awareness of ZES in patients with unexplained GI complaints and emphasizes the use of multiple modalities in the diagnosis of ZES.

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A New and Efficient Boundary Element-Free Method for 2-D Crack Problems

An efficient boundary element-free method is established for 2-D crack problems by combining a pair of boundary integral equations and the moving-least square approximation. The displacement boundary integral equation is collated on the on-crack boundary, and a new traction boundary integral equation is applied on the crack surface without the separate consideration of the upper and lower sides. In virtue of integration by parts, only singularity in order is involved in the integral kernels of new traction boundary integral equation, which brings convenience to the numerical implementation. Meanwhile, the integration by parts produces the new variables, the displacement density, and displacement dislocation density, and they are the coexisting unknowns along with the displacement and displacement dislocation. With the high-order continuity of the moving-least square approximation, these new variables are directly approximated with the nodal displacement or displacement dislocation, and the final system of equations contains the unknowns of nodal displacements and displacement dislocations only. The boundary element-free computational scheme is established, and several examples show the efficiency and flexibility of the proposed method.

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High Fat Diet Alters Gut Microbiota and the Expression of Paneth Cell-Antimicrobial Peptides Preceding Changes of Circulating Inflammatory Cytokines

Obesity is an established risk factor for many diseases including intestinal cancer. One of the responsible mechanisms is the chronic inflammation driven by obesity. However, it remains to be defined whether diet-induced obesity exacerbates the intestinal inflammatory status by cytokines produced in adipose tissue or the high fat diet first alters the gut microbiota and then drives intestinal inflammation. To address this question, we fed C57BL/6 mice with a high fat diet (HF, 60%) and sacrificed them sequentially after 8, 12, and 16 weeks, and then compositions of gut microbiota and expressions of antimicrobial peptides were determined. The compositions of gut microbiota were altered at 8 wk HF feeding, followed with reduced Paneth antimicrobial peptides lysozyme and Reg IIIγ after 12 and 16 wk HF feeding (), whereas elevations of circulating inflammatory cytokines IFNγ and TNF-α were observed until feeding a HF diet for 16 weeks (). These results indicated that high fat diet may stimulate intestinal inflammation via altering gut microbiota, and it occurs prior to the potential influence by circulating inflammatory cytokines. These findings emphasized the importance of microbiota, in addition to adipose tissue per se, in driving intestinal inflammation, which may thereafter promote intestinal tumorigenesis.

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Clinical Outcomes and Safety of Partial Full-Thickness Myotomy versus Circular Muscle Myotomy in Peroral Endoscopic Myotomy for Achalasia Patients

Background. Here we aimed to evaluate and compare the efficacy and safety between partial full-thickness myotomy and circular muscle myotomy during POEM procedure in achalasia patients. Methods. Clinical data of achalasia of cardia (AC) patients who underwent POEM in our center during January 2014 to January 2015 was collected (34 cases). 19 patients who received partial full-thickness myotomy were assigned to group A and 14 patients who received circular muscle myotomy were assigned to group B. The procedure-related parameters between the two groups were compared. Symptom relief rate and postprocedure manometry outcomes were compared to evaluate the efficacy. Procedure-related adverse events and complications were compared to evaluate the safety. Results. () Mean operation times were significantly shorter in group A than group B ( vs  min, ). () Symptom relief rate and postprocedure manometry outcomes had no statistical differences when compared between the two groups (all ). () Comparison of procedure-related adverse events and complications had no statistical differences (all ). Conclusion. Partial full-thickness myotomy had no significant differences in efficacy or safety with circular myotomy, but partial full-thickness myotomy significantly reduced the procedure time.

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Quantitative Thermal Testing Profiles as a Predictor of Treatment Response to Topical Capsaicin in Patients with Localized Neuropathic Pain

There are no reliable predictors of response to treatment with capsaicin. Given that capsaicin application causes heat sensation, differences in quantitative thermal testing (QTT) profiles may predict treatment response. The aim of this study was to determine whether different QTT profiles could predict treatment outcomes in patients with localized peripheral neuropathic pain (PeLNP). We obtained from medical records QTT results and treatment outcomes of 55 patients treated between 2010 and 2013. Warm sensation threshold (WST) and heat pain threshold (HPT) values were assessed at baseline at the treatment site and in the asymptomatic, contralateral area. Responders were defined as those who achieved a > 30% decrease in pain lasting > 30 days. Two distinct groups were identified based on differences in QTT profiles. Most patients (27/31; 87.1%) with a homogenous profile were nonresponders. By contrast, more than half of the patients (13/24, 54.2%) with a nonhomogenous profile were responders (). A nonhomogenous QTT profile appears to be predictive of response to capsaicin. We hypothesize patients with a partial loss of cutaneous nerve fibers or receptors are more likely to respond. By contrast, when severe nerve damage or normal cutaneous sensations are present, the pain is likely due to central sensitization and thus not responsive to capsaicin. Prospective studies with larger patient samples are needed to confirm this hypothesis.

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Children’s Behavioral Pain Cues: Implicit Automaticity and Control Dimensions in Observational Measures

Some pain behaviors appear to be automatic, reflexive manifestations of pain, whereas others present as voluntarily controlled. This project examined whether this distinction would characterize pain cues used in observational pain measures for children aged 4–12. To develop a comprehensive list of cues, a systematic literature search of studies describing development of children’s observational pain assessment tools was conducted using MEDLINE, PsycINFO, and Web of Science. Twenty-one articles satisfied the criteria. A total of 66 nonredundant pain behavior items were identified. To determine whether items would be perceived as automatic or controlled, 277 research participants rated each on multiple scales associated with the distinction. Factor analyses yielded three major factors: the “Automatic” factor included items related to facial expression, paralinguistics, and consolability; the “Controlled” factor included items related to intentional movements, verbalizations, and social actions; and the “Ambiguous” factor included items related to voluntary facial expressions. Pain behaviors in observational pain scales for children can be characterized as automatic, controlled, and ambiguous, supporting a dual-processing, neuroregulatory model of pain expression. These dimensions would be expected to influence judgments of the nature and severity of pain being experienced and the extent to which the child is attempting to control the social environment.

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Recommending Locations Based on Users’ Periodic Behaviors

The research of location recommendation system is an important topic in the field of LBSN (Location-Based Social Network). Recently, more and more researchers began focusing on researching how to recommend locations based on user’s life behavior. In this paper, we proposed a new model recommending locations based on user’s periodic behaviors. In view of multiple periodic behaviors existing in time series, an algorithm which can mine all periods in time series is proposed in this paper. Based on the periodic behaviors, we recommend locations using item-based collaborative filtering algorithm. In this paper, we will also introduce our recommendation system which can collect users’ GPS trajectory, mine user’s multiple periods, and recommend locations based user’s periodic behavior.

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Medical Image Fusion Based on Feature Extraction and Sparse Representation

As a novel multiscale geometric analysis tool, sparse representation has shown many advantages over the conventional image representation methods. However, the standard sparse representation does not take intrinsic structure and its time complexity into consideration. In this paper, a new fusion mechanism for multimodal medical images based on sparse representation and decision map is proposed to deal with these problems simultaneously. Three decision maps are designed including structure information map (SM) and energy information map (EM) as well as structure and energy map (SEM) to make the results reserve more energy and edge information. SM contains the local structure feature captured by the Laplacian of a Gaussian (LOG) and EM contains the energy and energy distribution feature detected by the mean square deviation. The decision map is added to the normal sparse representation based method to improve the speed of the algorithm. Proposed approach also improves the quality of the fused results by enhancing the contrast and reserving more structure and energy information from the source images. The experiment results of 36 groups of CT/MR, MR-T1/MR-T2, and CT/PET images demonstrate that the method based on SR and SEM outperforms five state-of-the-art methods.

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Resource Leveling Based on Backward Controlling Activity in Line of Balance

The line of balance method that provides continuous and uninterrupted use of resources is one of the best methods for repetitive project resource management. This paper develops a resource leveling algorithm based on the backward controlling activity in line of balance. The backward controlling activity is a kind of special activity, and if its duration is prolonged the project duration could be reduced. It brings two advantages to the resource leveling: both the resource allocated on the backward activity and the project duration are reduced. A resource leveling algorithm is presented which permits the number of crews of the backward controlling activity to be reduced until the terminal situation is reached, where the backward controlling activity does not exist or the number of crews cannot be reduced. That adjustment enables the productivity of all activities to be consistent. An illustrative pipeline project demonstrates the improvement in resource leveling. And this study designed a MATLAB program to execute the design algorithm. The proposed model could help practitioners to achieve the goals of both resource leveling and project duration reduction without increasing any resource.

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Effect of Constituent Units, Type of Interflavan Bond, and Conformation on the Antioxidant Properties of Procyanidin Dimers: A Computational Outlook

Procyanidin (PC) dimers are powerful antioxidants, abundant in plant tissues, and also bioavailable. However, the role of the molecular structure of PCs on their antioxidant properties is still a controversial and not fully understood issue that needs to be addressed in a more specific way. The objective of this study was to analyze the effect of the constituent units, type of interflavan bond, and conformation on the antioxidant properties of PC dimers including PB3, PB4, PB5, PB6, PB7, and PB8, using the density functional theory (DFT) computational method. The analysis was performed in function of parameters that allow determining the ability of the molecules to transfer or to capture electrons, among which the chemical potential, bond dissociation enthalpy (BDE), gap energy, Fukui indices, and charge distribution of HOMO-LUMO orbitals. The factors that showed the most notable effects on the antioxidant properties of the PC dimers were the type of interflavan bond and the conformation. The antioxidant ability of the dimers PB3 and PB4 containing the interflavan bond C4–C8, in their Compact conformation, was very similar to each other but greater than those of dimers PB5, PB6, PB7, and PB8 containing the C4–C6 interflavan bond. PB8 showed the lowest antioxidant ability.

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Role of Estrogens in the Size of Neuronal Somata of Paravaginal Ganglia in Ovariectomized Rabbits

We aimed to determine the role of estrogens in modulating the size of neuronal somata of paravaginal ganglia. Rabbits were allocated into control (C), ovariectomized (OVX), and OVX treated with estradiol benzoate (OVX + EB) groups to evaluate the neuronal soma area; total serum estradiol (E2) and testosterone (T) levels; the percentage of immunoreactive (ir) neurons anti-aromatase, anti-estrogen receptor (ERα, ERβ) and anti-androgen receptor (AR); the intensity of the immunostaining anti-glial cell line-derived neurotrophic factor (GDNF) and the GDNF family receptor alpha type 1 (GFRα1); and the number of satellite glial cells (SGCs) per neuron. There was a decrease in the neuronal soma size for the OVX group, which was associated with low T, high percentages of aromatase-ir and neuritic AR-ir neurons, and a strong immunostaining anti-GDNF and anti-GFRα1. The decrease in the neuronal soma size was prevented by the EB treatment that increased the E2 without affecting the T levels. Moreover, there was a high percentage of neuritic AR-ir neurons, a strong GDNF immunostaining in the SGC, and an increase in the SGCs per neuron. Present findings show that estrogens modulate the soma size of neurons of the paravaginal ganglia, likely involving the participation of the SGC.

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Identification of Significant Pathways Induced by PAX5 Haploinsufficiency Based on Protein-Protein Interaction Networks and Cluster Analysis in Raji Cell Line

PAX5 encodes a transcription factor essential for B-cell differentiation, and PAX5 haploinsufficiency is involved in tumorigenesis. There were few studies on how PAX5 haploinsufficiency regulated genes expression to promote tumorigenesis. In this study, we constructed the cell model of PAX5 haploinsufficiency using gene editing technology in Raji cells, detected differentially expressed genes in PAX5 haploinsufficiency Raji cells, and used protein-protein interaction networks and cluster analysis to comprehensively investigate the cellular pathways involved in PAX5 haploinsufficiency. The clusters of gene transcription, inflammatory and immune response, and cancer pathways were identified as three important pathways associated with PAX5 haploinsufficiency in Raji cells. These changes hinted that the mechanism of PAX5 haploinsufficiency promoting tumorigenesis may be related to genomic instability, immune tolerance, and tumor pathways.

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Epidemiology of basal cell carcinoma: scholarly review

Summary

Basal cell carcinoma (BCC) is the most common cancer in white-skinned individuals with increasing incidence rates worldwide. Patients with BCC place a large burden on healthcare systems, because of the high incidence and the increased risk of synchronous and metachronous BCCs and other ultraviolet radiation (UVR) related skin cancers (i.e. field cancerization). As a result, the disability-adjusted life years and healthcare costs have risen significantly in recent decades. BCC is a complex disease, in which the interplay between UVR, phenotype (UVR-sensitive) and genotype (somatic mutations and germline mutations/polymorphisms) fulfils a key role in the aetiopathogenesis. Prevention programmes with continual refinements and improvements could be of major importance in tackling the growing skin cancer problem. To provide the most appropriate BCC care, physicians should engage in shared decision-making and choose their treatments wisely.



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Diagnostic accuracy of ultrasound imaging in Hashimoto's thyroiditis

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Anuradha Kapali, Jaipal Beerappa, P Raghuram, Ravindra Bangar

Thyroid Research and Practice 2017 14(1):28-31

Context: There are studies describing the ultrasound (USG) features of Hashimoto's thyroiditis in literature; however, we have not come across studies determining the accuracy of USG in diagnosing Hashimoto's thyroiditis. Aims: We evaluated the cases referred to our institute with suspected thyroid abnormalities and studied in them the accuracy of USG in diagnosing Hashimoto's thyroiditis and also studied the associated malignancies and their USG characteristics. Settings and Design: The patients referred to our department with suspected thyroid abnormalities were included in the prospective study. The study period was of 1 year; we included 28 patients with Hashimoto's thyroiditis. Materials and Methods: We evaluated the USG features of the cases namely echogenicity, echotexture, micronodules, and increased vascularity and followed them up for final diagnosis by fine needle aspiration cytology, histopathology, or antithyroglobulin and thyroid peroxidase tests, other 60 cases were used as a control. The results were analyzed. Statistical Analysis Used: Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. Results: Hashimoto's thyroiditis was present in 28 patients. The most sensitive parameter in diagnosing Hashimoto's thyroiditis was hypoechogenicity and increased vascularity. The most specific parameter was micronodules. Nodules were seen in 13 patients, out of which malignant nodules was present in six patients. Microcalcification, thick halo, and internal vascularity increase the likelihood of nodules being malignant. Conclusions: The most sensitive parameter in diagnosing Hashimoto's thyroiditis was hypoechogenicity and increased vascularity. The most specific parameter was micronodules. Coarsened echo texture had an intermediate sensitivity and specificity. The USG is a specific modality for diagnosing Hashimoto's thyroiditis with a good sensitivity. Microcalcification, thick halo, and internal vascularity also increase the likelihood of nodules being malignant in the background of Hashimoto's thyroiditis. Hence, these nodules must be subject to FNA.

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Study on quantification of drain in intracapsular thyroidectomies

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UP Santosh, KB Prashanth, K Swetha, KR Sumanth

Thyroid Research and Practice 2017 14(1):3-7

Introduction: Disease of the thyroid gland is common with prevalence of 4–7% in the general population. The incidence being higher in endemic areas. Thyroidectomy is an important procedure done for majority of thyroid swellings, after which drains are placed. Our study aims to assess the postoperative drain fluid amount in thyroidectomies done using intracapsular dissection technique. Materials and Methods: Retrospective study of 170 patients who underwent hemi/subtotal/total thyroidectomies using intracapsular dissection in Chigateri District Hospital and Bapuji Hospital, Teaching Hospitals, attached to JJM Medical College, Davangere during March 2009 to July 2015. All patients fulfilling inclusive criteria are included in the study. The drain was removed after 48 h of surgery. The amount of drain present was measured before removal of the drain. Results: Total number of 170 cases were analyzed. We found that the drain fluid amount was drastically less when compared with thyroidectomies done using other techniques. Conclusion: Drain fluid amount was minimal with thyroidectomies done using intracapsular dissection technique.

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Rashtriya Bal Swasthya Karyakram: Bringing thyroid to center-stage

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Naresh Kardwal, Mudita Dhingra, Sanjay Kalra

Thyroid Research and Practice 2017 14(1):1-2



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Spectrum of extrathyroidal congenital malformations in a cohort of North Indian children with permanent primary congenital hypothyroidism

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Devi Dayal, Rajendra Prasad, Savita Bhunwal, Rakesh Kumar, Rohit Manoj Kumar, Kushaljit Singh Sodhi

Thyroid Research and Practice 2017 14(1):8-11

Background: Children with permanent primary congenital hypothyroidism (CH) are at increased risk for extrathyroidal congenital malformations (ECMs) as compared to normal child population. A wide variation in the prevalence of ECMs in CH has been reported previously with the reports from Turkey and India indicating a much higher prevalence (48%–59%) as compared to reports from other countries (2.1%–10.5%). Setting and Design: Pediatric Endocrinology Clinic of a large multispecialty hospital located in Northwest India. Retrospective study. Materials and Methods: Children diagnosed as permanent primary CH underwent evaluation for associated ECMs using echocardiography and abdominal and pelvic ultrasonography if clinically indicated. Results: The etiological diagnoses in 106 children (52 girls and 54 boys) with permanent CH were thyroid agenesis in 70 (66%), ectopia in 9 (8.5%), hypoplasia in 6 (5.5%), hypothyroidism with eutopic gland in 5 (4.7%), and dyshormonogenesis in 16 (15%) patients. Seven (7.42%) patients had associated ECMs. The majority (4, 3.7%) of ECMs were cardiac (ventricular septal defect in two patients and patent ductus arteriosus and transposition of great arteries in one each), while skeletal (congenital talipes equinovarus in two and hemivertebra in one patient) and genitourinary (splitting of the pelvicalyceal system in two patients) anomalies were seen in 3 (2.8%) and 2 (1.8%) patients, respectively. Conclusion: The prevalence of ECMs in children with permanent CH was much lower as compared to other cohorts from India. Further studies are needed to determine the underlying genetic and environmental factors to explain the drastic regional differences in the prevalence of ECMs in CH.

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Encephalopathy associated with autoimmune thyroid disease in an 11-year-old girl, a rare clinical presentation

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Meenakshi Cheripady Nayanar, Shakil Vadalivala, Tabrez Noorani, Hiral Shah

Thyroid Research and Practice 2017 14(1):38-40

Encephalopathy associated with autoimmune thyroid disease (EAATD) is a rare clinical presentation in pediatric age group whose exact prevalence has not been precisely elucidated. EAATD is characterized by neurological and psychiatric symptoms, high levels of antithyroid antibodies, increased cerebrospinal fluid (CSF) protein concentration, nonspecific electroencephalogram abnormalities, and responsiveness to the corticosteroid treatment. We present a case of an 11-year-old female patient who presented with acute history of fever, irritability, double vision, altered behavior, and unsteady gait which progressed to altered sensorium with drowsiness, tremors, and ataxia. The child had exophthalmos which was long standing in view of which thyroid profile was sent. Preliminary work-up, CSF analysis, and neuroimaging with magnetic resonance imaging of the brain proved normal. Thyroid profile was high with positive thyroperoxidase antibody. Thus, we came to the diagnosis of EAATD. EAATD still requires a better definition of its pathophysiology, the diagnostic criteria, and the most appropriate management including the long-term follow-up of patients.

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Study of epicardial fat thickness as a marker of visceral adiposity in patients with hypothyroidism

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Ritu Karoli, Nikhil Gupta, Jalees Fatima, Zeba Siddiqi

Thyroid Research and Practice 2017 14(1):12-17

Introduction: Hypothyroidism has adverse effects on the cardiovascular system. Visceral adiposity, the fat deposited around the internal organs, is recognized as an important risk factor. Hence, the present study was undertaken to investigate the presence of visceral adiposity, epicardial fat thickness (EFT), and nonalcoholic fatty liver disease (NAFLD) in patients with hypothyroidism as compared to matched euthyroid controls. Materials and Methods: In a case–control hospital-based study, 100 patients of hypothyroidism and equal number of age-, gender-, and body mass index-matched euthyroid controls were enrolled. They were studied for EFT and the presence of NAFLD along with anthropometric and biochemical parameters. Results: Among the hypothyroid patients, 67% had serum thyroid-stimulating hormone (TSH) varying 4.5–10 mIU/L and 33% had serum TSH >10 mIU/L. Patients with hypothyroidism had higher waist circumference (92.4 ± 8.6 cm vs. 84 ± 6.2 cm, P = 0.002) and diastolic blood pressure (88 ± 4 mmHg vs. 72 ± 10 mmHg, P = 0.01) than controls. The hypothyroid patients had significantly higher levels of triglycerides, low-density lipoprotein cholesterol homeostasis model assessment of insulin resistance, and prevalence of metabolic syndrome (22% vs. 8%). Markers of visceral adiposity were significantly higher in hypothyroid patients, and EFT had positive correlation with serum TSH levels. Conclusion: We observed higher EFT in patients with hypothyroidism and a significant correlation between EFT and serum TSH levels. Whether increased epicardial thickness as a marker of visceral adiposity may be associated with the potential cardiovascular adverse effects of hypothyroidism warrants further research.

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Histologic pattern of thyroid disorders in Southern Kerala

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Jayasree Geothe, KP Poulose

Thyroid Research and Practice 2017 14(1):25-27

Since the implementation of universal salt iodization in 1986, India is said to be in the transition phase from iodine deficiency to iodine sufficiency, and this is expected to change the spectrum of thyroid disorders in the country. Materials and Methods: A retrospective study of 246 biopsy specimens of subtotal/total/hemi thyroidectomy cases done during a period of 6 years from 2007 to 2012 at a tertiary hospital in Trivandrum, Kerala, is analyzed. Results: Thyroidectomy specimens accounted for 3.2% of the total surgical specimens received during the study period. Among the 246 thyroidectomy specimens, nodular colloid goiter (NCG) with or without other associated thyroid lesions outnumbered other disorders accounting for a total of 142 cases (58%) followed by 90 cases of autoimmune thyroiditis (AIT) with or without other thyroid lesions (37%). Dual lesions such as AIT with colloid goiter (7 cases, 3%), AIT with tumors (45 cases, 18%), and NCG with tumors (40 cases 16%) were also noted. The presence of tumors was found in 106 cases (43%). The overall incidence of malignancy was 36%. Forty-one cases of AIT and 36 cases of NCG were associated with papillary thyroid carcinoma (PTC) (46% and 25%, respectively); the difference was statistically significant (P = 0.01). Conclusions: This study showed that the incidence of AIT and associated PTC is high, and the role of iodine or any other goitrogens in triggering or enhancing the onset and development of AIT in this area deserves further study.

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Ophthalmic manifestation as adverse factor for cure in radioiodine treatment of Graves' disease

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Yetunde A Onimode, Kayode S Adedapo, Magbagbeola D Dairo

Thyroid Research and Practice 2017 14(1):18-21

Context: Figures from several states indicate the prevalence of primary hyperthyroidism as 1.5%–5.4%. Goiters (including Graves' disease [GD]) and diabetes mellitus are the most common presentations at Nigerian endocrine clinics. Aim: This study aims to assess the efficacy of radioactive iodine-131 therapy (RAIT) of GD, evaluate factors affecting its outcome, and to find the impact of ophthalmic symptoms on response of GD to RAIT. Participants and Methods: A retrospective review of RAI-naϊve GD patients treated from 2006 to 2016 was performed. Results: Eighty-one treatments were made in this period to 75 patients; of these, 51 patients had had no prior RAI treatment. Overall, 41 patients (78.8%) were cured by mean time to cure 4.5 ± 2.36 months. Fourteen patients (26.9%) were cured by 3 months, an additional 19 (36.5%) by 6 months, an additional 5 (9.6%) by 9 months, and 1 more by 14 months, and 2 were cured later. Cure comprised euthyroidism in 14 patients (26.9%) and outright hypothyroidism in 27 (51.9%). Graves' ophthalmopathy (GO) is associated with less likelihood of cure (P = 0.025). Those with GO were ten times less likely to be cured than those without GO (odds ratio = 0.105, confidence interval = 0.11–0.979, P = 0.048). Conclusions: Findings suggest that GO is an adverse factor in RAIT for GD (as was found in an earlier study from this center) and also suggest that patients with GO will benefit from larger doses of RAI.

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Thyroid dysfunction in patients of ischemic cerebrovascular accidents

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Apurva Pande, Vijay Kumar Goel, Amit Rastogi, Abhinav Gupta

Thyroid Research and Practice 2017 14(1):32-37

Introduction: Thyroid dysfunction has been associated with cerebrovascular accidents (CVAs) and is an area of active research in the present times. Materials and Methods: In the present study we tried to establish a relation between the variation in thyroid profile and ischemic CVAs in 75 patients who were admitted to our hospital within 48 hours of the event. Results: Of the 75 patients, 43 had nonthyroidal illness syndrome (NTIS), 13 were euthyroid, 6 were hyperthyroid, 9 were subclinical hypothyroid, and 4 were hypothyroid. Conclusion: In ischemic cases, high mortality rates were observed in euthyroid patients followed by patients with NTIS. A low FT3 level was associated with unfavorable outcome as accessed by the Glasgow Coma Scale and the Scandinavian Stroke Scale scoring.

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Study of anemia in primary hypothyroidism

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Ram Prakash Patel, Atishay Jain

Thyroid Research and Practice 2017 14(1):22-24

Context: Thyroid hormones directly or indirectly, through erythropoietin, stimulate growth of erythroid colonies. In the deficiency of thyroid hormones, anemia frequently develops and may be normocytic, hypochromic-microcytic, or macrocytic. Aims: In this study, we evaluated the types of anemia and its causes in patients with untreated primary hypothyroidism. Settings and Design: This is an observational study conducted at department of general medicine of a tertiary care center. The duration of study was 1 year, November 2015–October 2016. Subjects and Methods: Four hundred and seventy-two patients of overt hypothyroidism or subclinical hypothyroidism were evaluated for possible inclusion in this study. Out of these 112 participants were recruited for the study after fulfilling inclusion criteria. Statistical Analysis Used: Microsoft Excel® and SPSS® 20 for Windows® were used for data storage and analysis. The qualitative data were expressed in percentages, and quantitative data were expressed as mean ± standard deviation. Student's t-test and Chi-square test were used to determine statistical difference between variables. Results: In our study, anemia frequency was 18% in the subclinical hypothyroid patients and 11% in the overt hypothyroid group. In the subgroup analysis of the hypothyroid patients, anemia of chronic disease was most common anemia in patients with overt and subclinical hypothyroidism. Conclusions: Anemia is a common finding in overt hypothyroidism, but anemia is not listed among the consequences of untreated subclinical hypothyroidism. Type and cause of anemia is also different in overt and subclinical hypothyroid patients. Therefore, anemia in hypothyroidism needs to be properly evaluated because treatment varies with etiology of anemia.

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Undiagnosed juvenile hypothyroidism and resultant irreversible brain damage: Cannot we do anything?

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Partha Pratim Chakraborty, Sugata Narayan Biswas

Thyroid Research and Practice 2017 14(1):41-42



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Kaempferol Attenuates Cardiac Hypertrophy via Regulation of ASK1/MAPK Signaling Pathway and Oxidative Stress

Planta Med
DOI: 10.1055/s-0043-103415

Kaempferol has been demonstrated to provide benefits for the treatment of atherosclerosis, coronary heart disease, hyperlipidemia, and diabetes through its antioxidant and anti-inflammatory properties. However, its role in cardiac hypertrophy remains to be elucidated. The aim of our study was to investigate the effects of kaempferol on cardiac hypertrophy and the underlying mechanism. Mice subjected to aorta banding were treated with or without kaempferol (100 mg/kg/d, p. o.) for 6 weeks. Echocardiography was performed to evaluate cardiac function. Mice hearts were collected for pathological observation and molecular mechanism investigation. H9c2 cardiomyocytes were stimulated with or without phenylephrine for in vitro study. Kaempferol significantly attenuated cardiac hypertrophy induced by aorta banding as evidenced by decreased cardiomyocyte areas and interstitial fibrosis, accompanied with improved cardiac functions and decreased apoptosis. The ASK1/MAPK signaling pathways (JNK1/2 and p38) were markedly activated in the aorta banding mouse heart but inhibited by kaempferol treatment. In in vitro experiments, kaempferol also inhibited the activity of ASK1/JNK1/2/p38 signaling pathway and the enlargement of H9c2 cardiomyocytes. Furthermore, our study revealed that kaempferol could protect the mouse heart and H9c2 cells from pathological oxidative stress. Our investigation indicated that treatment with kaempferol protects against cardiac hypertrophy, and its cardioprotection may be partially explained by the inhibition of the ASK1/MAPK signaling pathway and the regulation of oxidative stress.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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



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Quantitative morphological analysis of 2D images of complex-shaped branching biological growth forms: the example of branching thalli of liverworts

Many organisms such as plants can be characterized as complex-shaped branching forms. The morphological quantification of the forms is a support for a number of areas such as the effects of environmental facto...

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A computational protocol to evaluate the effects of protein mutants in the kinase gatekeeper position on the binding of ATP substrate analogues

The determination of specific kinase substrates in vivo is challenging due to the large number of protein kinases in cells, their substrate specificity overlap, and the lack of highly specific inhibitors. In t...

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Plasmon Resonances in Self-Assembled Two-Dimensional Au Nanocrystal Metamolecules

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.6b08189
ancac3?d=yIl2AUoC8zA


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Microfluidization of Graphite and Formulation of Graphene-Based Conductive Inks

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.6b07735
ancac3?d=yIl2AUoC8zA


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Positive and Negative Signals in Mast Cell Activation

Publication date: Available online 20 February 2017
Source:Trends in Immunology
Author(s): Silvia Bulfone-Paus, Gunnar Nilsson, Petr Draber, Ulrich Blank, Francesca Levi-Schaffer
Mast cells are powerful immune modulators of the tissue microenvironment. Within seconds of activation, these cells release a variety of preformed biologically active products, followed by a wave of mediator synthesis and secretion. Increasing evidence suggests that an intricate network of inhibitory and activating receptors, specific signaling pathways, and adaptor proteins governs mast cell responsiveness to stimuli. Here, we discuss the biological and clinical relevance of negative and positive signaling modalities that control mast cell activation, with an emphasis on novel FcεRI regulators, immunoglobulin E (IgE)-independent pathways [e.g., Mas-related G protein-coupled receptor X2 (MRGPRX2)], tetraspanins, and the CD300 family of inhibitory and activating receptors.



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IL-17 Signaling: The Yin and the Yang

Publication date: Available online 20 February 2017
Source:Trends in Immunology
Author(s): Nilesh Amatya, Abhishek V. Garg, Sarah L. Gaffen
Interleukin (IL)-17 is the founding member of a novel family of inflammatory cytokines. While the proinflammatory properties of IL-17 are key to its host-protective capacity, unrestrained IL-17 signaling is associated with immunopathology, autoimmune disease, and cancer progression. In this review we discuss both the activators and the inhibitors of IL-17 signal transduction, and also the physiological implications of these events. We highlight the surprisingly diverse means by which these regulators control expression of IL-17-dependent inflammatory genes, as well as the major target cells that respond to IL-17 signaling.



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Real-world Evidence for the Antianginal Efficacy of Trimetazidine from the Russian Observational CHOICE-2 Study

Abstract

Introduction

The guidelines recommend a beta-blocker or calcium channel blocker as the first-line medication for angina, supplemented by other agents for additional symptoms. One such agent is trimetazidine (TMZ), which has been shown to reduce the frequency of anginal episodes and improve exercise performance without affecting haemodynamic parameters. However, extensive real-world evidence for its efficacy in combination with first-line therapies has been lacking.

Methods

The aim of this large-scale, Russian, multicentre, 6-month, open-label, prospective observational study was to assess the effect of adding TMZ modified release 35 mg bid to background antianginal therapy in the real-world clinical setting.

Results

The study included 896 patients: 54% women, aged 29–90 years (42.6% >65 years), 63% with class II angina, and receiving beta-blockers alone or in combination (93%). Add-on TMZ reduced angina frequency and short-acting nitrate use within 2 weeks (both p < 0.0001) regardless of background therapy and maintained this effect over 6 months. It increased the proportion of patients with class I angina sixfold while decreasing that of class 3 angina almost fourfold. It also improved walking distance and well-being at 6 months (both p < 0.0001). Treatment was well tolerated.

Conclusion

Add-on TMZ is a safe and rapidly effective treatment for reducing angina attacks and nitrate use in the real-world clinical setting. It also increases exercise capacity and well-being. These effects are observed within 2 weeks and persist for at least 6 months.



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Epidemiology of sepsis in Catalonia: analysis of incidence and outcomes in a European setting

Up-to-date identification of local trends in sepsis incidence and outcomes is of considerable public health importance. The aim of our study was to estimate annual incidence rates and in-hospital mortality tre...

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Antithrombin use and 28-day in-hospital mortality among severe-burn patients: an observational nationwide study

Previous studies have suggested that antithrombin may be beneficial for treating coagulopathy in patients with severe burns. However, robust evidence for this idea is lacking. We examined the hypothesis that a...

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A new look at the origins of gibbon ape leukemia virus

Abstract

Is the origin of gibbon ape leukemia virus (GALV) human after all? When GALV was discovered and found to cause neoplastic disease in gibbons, it stimulated a great deal of research including investigations into the origins of this virus. A number of publications have suggested that the GALV progenitor was a retrovirus present in one of several species of South East Asian rodents that had close contact with captive gibbons. However, there are no published retroviral sequences from any South East Asian species to support this view. Here we present an alternative hypothesis that the origin of GALV is a virus closely related to Melomys burtoni retrovirus, and that this virus infected human patients in Papua New Guinea from whom biological material was obtained or in some way contaminated these samples. This material we propose contained infectious MbRV-related virus that was then unwittingly introduced into gibbons which subsequently developed GALV infections.



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Steady-State Therapy with Azithromycin or Low-Dose Prednisolone in Paediatric Cystic Fibrosis Patients: Inflammatory Markers and Disease Progression

Background: Anti-inflammatory therapy is a logical approach to slowing the inevitable lung function deterioration in cystic fibrosis (CF) patients. This study's aim was to evaluate inflammatory markers and disease progression in paediatric CF patients chronically treated with azithromycin or low-dose prednisolone. Methods: The study included 204 patients with CF and 100 healthy controls; 102 CF patients were treated with basic therapy only (without anti-inflammatory treatment; WAT), and 102 individuals received basic therapy along with azithromycin (n = 59) or low-dose prednisolone (n = 43). The median duration of therapy was 24 months (range 12-82) with azithromycin and 31 months (range 12-180) with prednisolone. A cross-sectional analysis of plasma and sputum biomarkers was performed. Results: Compared with the healthy controls, the WAT group showed elevated IFN-#x03B3;, IL-10 (total), and TGFβ1 concentrations, and decreased TNFα (total) and adrenocorticotropic hormone (ACTH) levels (all p Conclusions: Steady-state anti-inflammatory treatments may have a sustained immunomodulatory action at systemic and local levels in CF patients. Further investigations are needed to assess the effects of supportive azithromycin therapy on the hypothalamic-pituitary-adrenal axis and the incidence of non-pulmonary CF complications.
Int Arch Allergy Immunol 2017;172:45-54

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Human Allergen-Specific IgG Subclass Antibodies Measured Using ImmunoCAP Technology

Background: Knowledge of human IgG subclass antibody responses to various allergens has been hampered by a lack of reliable standardized assays. The aim here was to develop quantitative immunoassays for human IgG1, IgG2, and IgG3 antibodies using ImmunoCAP® technology and to evaluate their application. Methods: Enzyme conjugates with isotype-specific monoclonal antibodies and calibrators composed of purified myeloma paraproteins were developed for each assay and used together with other standardized assay reagents for the Phadia® 100 instrument. The calibrators were adjusted to the international reference preparation IRP 67/86. The assays were characterized and used together with other standard ImmunoCAP assays to measure antibodies to various allergens in preliminary studies. Results: The new assays had limits of quantitation of 1.0 (IgG1), 4.6 (IgG2), and 0.04 mgA/L (IgG3), and coefficients of variation of Conclusions: The new research assays are valuable tools for immunological studies, enabling the characterization of antibody profiles using a standardized approach, and facilitating data interpretation and the comparison of results across studies.
Int Arch Allergy Immunol 2017;172:1-10

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Altered Expression of Genes Encoding Cornulin and Repetin in Atopic Dermatitis

Background: It is assumed that beside alterations in the filaggrin gene (FLG), disturbances within genes encoding other cornified envelope proteins are also involved in atopic dermatitis (AD). To identify new potential markers of AD, we studied the polymorphisms of genes encoding repetin (RPTN), cornulin (CRNN), and their expression in the skin of AD patients. Methods: Polymorphisms in CRNN (rs941934), RPTN (rs284544, rs28441202, rs3001978, and rs12117644), and FLG mutations (R2447X, S3247X) were analyzed by TaqMan genotyping assay and by PCR-RFLP in the blood samples of 159 AD patients and 108 healthy subjects. The expression levels of CRNN and RPTN were determined by qRT-PCR in 34 AD skin samples (17 lesional and 17 nonlesional) and in 27 skin biopsies from healthy volunteers. The AD patients were recruited from the clinic of the university hospital between 2012 and 2014. Results:CRNN rs941934 (A allele) was associated with AD (OR 2.095, p = 0.008), a severe course of disease (p = 0.041), elevated IgE levels (p = 0.047), eosinophilia (p = 0.018), and concomitant asthma (p = 0.004). The mRNA level of CRNN was decreased in the AD skin (p = 0.041). In the AD patients without FLG mutations, the CC genotype of RPTN rs3001978 was associated with AD (OR 0.39, p = 0.037), early age at onset (p = 0.033), pruritus (p = 0.021), severity of AD (p = 0.045), and concomitant asthma (p = 0.041). The elevated mRNA levels of RPTN in lesional (p p = 0.017) AD skin were observed. Conclusions: The single-nucleotide polymorphisms of CRNN (rs941934) and RPTN (rs3001978, rs28441202) may contribute to AD development, but further studies on a larger group of AD patients are needed to verify this assumption.
Int Arch Allergy Immunol 2017;172:11-19

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