Reply to: Regarding complications following completion lymphadenectomy

Publication date: Available online 1 November 2017
Source:European Journal of Surgical Oncology
Author(s): J.A. Moody, D.L. Wallace, J.T. Hardwicke




http://ift.tt/2inWj6x

Management of pediatric psoriasis with acitretin: A review

Abstract

Psoriasis is a chronic inflammatory disease of the skin which can occur at any age-group. Psoriasis in childhood is not uncommon and has genetic susceptibility but usually, an environmental trigger such as infection is thought to initiate the disease process. Pediatric psoriasis has profound effects on both physical and psychosocial health of the patient. Treatment of mild psoriasis can be done with topical therapies but those which do not respond to topical therapies can be treated with phototherapy and systemic therapies. The use of systemic therapies in childhood is mainly based on the published data, case series, expert opinion and the experience as there is the lack of controlled trials in the age group. Based on the experience retinoids are probably the second line drugs for the treatment of pediatric psoriasis which do not respond to topical therapies and phototherapy. Using acitretin in a low dose and with proper physical examinations and laboratory investigations will reduce the hazard of potential serious adverse events. This article gives the review of the use of acitretin in pediatric psoriasis.

http://ift.tt/2iTw8IX

Impulsive Responding in Threat and Reward Contexts as a Function of PTSD Symptoms and Trait Disinhibition

Publication date: Available online 1 November 2017
Source:Journal of Anxiety Disorders
Author(s): Naomi Sadeh, Jeffrey M. Spielberg, Jasmeet P. Hayes
We examined current posttraumatic stress disorder (PTSD) symptoms, trait disinhibition, and affective context as contributors to impulsive and self-destructive behavior in 94 trauma-exposed Veterans. Participants completed an affective Go/No-Go task (GNG) with different emotional contexts (threat, reward, and a multidimensional threat/reward condition) and current PTSD, trait disinhibition, and risky/self-destructive behavior measures. PTSD interacted with trait disinhibition to explain recent engagement in risky/self-destructive behavior, with Veterans scoring high on trait disinhibition and current PTSD symptoms reporting the highest levels of these behaviors. On the GNG task, commission errors were also associated with the interaction of PTSD symptoms and trait disinhibition. Specifically, PTSD symptoms were associated with greater commission errors in threat vs. reward contexts for individuals who were low on trait disinhibition. In contrast, veterans high on PTSD and trait disinhibition exhibited the greatest number of commission errors in the multidimensional affective context that involved both threat and reward processing. Results highlight the interactive effects of PTSD and disinhibited personality traits, as well as threat and reward systems, as risk factors for impulsive and self-destructive behavior in trauma-exposed groups. Findings have clinical implications for understanding heterogeneity in the expression of PTSD and its association with disinhibited behavior.



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A Network Perspective on Comorbid Depression in Adolescents with Obsessive-compulsive Disorder

Publication date: Available online 1 November 2017
Source:Journal of Anxiety Disorders
Author(s): Payton J. Jones, Patrick Mair, Bradley C. Riemann, Beth L. Mugno, Richard J. McNally
People with obsessive-compulsive disorder [OCD] frequently suffer from depression, a comorbidity associated with greater symptom severity and suicide risk. We examined the associations between OCD and depression symptoms in 87 adolescents with primary OCD. We computed an association network, a graphical LASSO, and a directed acyclic graph (DAG) to model symptom interactions. Models showed OCD and depression as separate syndromes linked by bridge symptoms. Bridges between the two disorders emerged between obsessional problems in the OCD syndrome, and guilt, concentration problems, and sadness in the depression syndrome. A directed network indicated that OCD symptoms directionally precede depression symptoms. Concentration impairment emerged as a highly central node that may be distinctive to adolescents. We conclude that the network approach to mental disorders provides a new way to understand the etiology and maintenance of comorbid OCD-depression. Network analysis can improve research and treatment of mental disorder comorbidities by generating hypotheses concerning potential causal symptom structures and by identifying symptoms that may bridge disorders.

Graphical abstract

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Rescue therapy with bismuth quadruple regimen in patients with Helicobacter pylori -resistant strains

Abstract

Background

Bismuth quadruple therapy (BQT) is the recommended rescue therapy for Helicobacter pylori (H. pylori) infection. This study aimed to assess the efficacy and safety of a 10-day BQT regimen in patients who failed previous therapies and were infected with multiresistant H. pylori strains

Materials and methods

Helicobacter pylori-infected patients underwent endoscopy, culture, and susceptibility test for clarithromycin, metronidazole, and levofloxacin. Treatment with three-in-one capsule (Pylera®) four times daily and esomeprazole 20 mg twice daily for 10 days was administered. Treatment-emergent adverse events (TEAEs) were registered.

Results

A total of 116 patients with persistent H. pylori infection following at least one eradication therapy attempt were treated. Overall, resistance toward clarithromycin was detected in 80% of strains, toward metronidazole in 70%, and levofloxacin in 47.5%, with dual or triple resistance in 72.5% of cases. An eradication rate of 81.0% (95% CI: 73.0-87.1) and 87.0% (95% CI: 79.4-92.1) at ITT and PP analyses, respectively, was achieved. The cure rate remained high until it was used as fourth-line regimen, while it dropped to low values (<67%) in those patients with more than 4 therapy failures. A total of 65.7% (95% CI: 56.4-74.0) patients complained of TEAEs.

Conclusions

Our data found that bismuth-based quadruple regimen is effective as rescue therapy for curing patients infected with multiresistant H. pylori strains.

http://ift.tt/2A1xjsK

Personality biomarkers of pathological gambling: A machine learning study

Publication date: 15 January 2018
Source:Journal of Neuroscience Methods, Volume 294
Author(s): Antonio Cerasa, Danilo Lofaro, Paolo Cavedini, Iolanda Martino, Antonella Bruni, Alessia Sarica, Domenico Mauro, Giuseppe Merante, Ilaria Rossomanno, Maria Rizzuto, Antonio Palmacci, Benedetta Aquino, Pasquale De Fazio, Giampaolo R. Perna, Elena Vanni, Giuseppe Olivadese, Domenico Conforti, Gennarina Arabia, Aldo Quattrone
BackgroundThe application of artificial intelligence to extract predictors of Gambling disorder (GD) is a new field of study. A plethora of studies have suggested that maladaptive personality dispositions may serve as risk factors for GD.New methodHere, we used Classification and Regression Trees algorithm to identify multivariate predictive patterns of personality profiles that could identify GD patients from healthy controls at an individual level.Forty psychiatric patients, recruited from specialized gambling clinics, without any additional comorbidity and 160 matched healthy controls completed the Five-Factor model of personality as measured by the NEO-PI-R, which were used to build the classification model.ResultsClassification algorithm was able to discriminate individuals with GD from controls with an AUC of 77.3% (95% CI 0.65–0.88, p<0.0001). A multidimensional construct of traits including sub-facets of openness, neuroticism and conscientiousness was employed by algorithm for classification detection.Comparison with existing method(s)To the best of our knowledge, this is the first study that combines behavioral data with machine learning approach useful to extract multidimensional features characterizing GD realm.ConclusionOur study provides a proof-of-concept demonstrating the potential of the proposed approach for GD diagnosis. The multivariate combination of personality facets characterizing individuals with GD can potentially be used to assess subjects' vulnerability in clinical setting.



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Trends in breast imaging: an analysis of 21years of formal scientific abstracts at the Radiological Society of North America

Publication date: May–June 2018
Source:Clinical Imaging, Volume 49
Author(s): Samantha L. Heller, Abbas Charlie, James S. Babb, Linda Moy, Yiming Gao
PurposeTo capture shifts in breast imaging through 21years of scientific meeting abstracts.Materials and methodsRSNA meeting programs (1995–2015) were searched to identify breast imaging scientific oral abstracts. Abstract year, author gender and degree, country, state, study design, modality, topic, funding and disclosures were recorded. Spearman correlation was performed.ResultsThere was an increase in %women first authors (rs=0.81, p<0.001), in %international abstracts (rs=−0.64, p=0.0002) and in industry funding (rs=0.766, p<0.001).Conclusion%Women first author presenters and %international presence and %industry support increased over time. These areas of flux may be useful for continued tracking.



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Reexamining mechanic’s hands as a characteristic skin finding in dermatomyositis

Publication date: Available online 2 November 2017
Source:Journal of the American Academy of Dermatology
Author(s): Josef Symon S. Concha, Joseph F. Merola, David Fiorentino, Victoria P. Werth
Mechanic's hands is a poorly defined clinical finding that has been reported in a variety of rheumatologic diseases. Morphologic descriptions include hyperkeratosis on the sides of the digits that sometimes extends to the distal tips, diffuse palmar scale, and, more recently observed, linear discrete scaly papules in a similar lateral distribution. The association of mechanic's hands with dermatomyositis, although recognized, is still debatable. In this review, most studies have shown that mechanic's hands is commonly associated with dermatomyositis and displays histopathologic findings of interface dermatitis, colloid bodies and interstitial mucin which are consistent with a cutaneous connective tissue disease. A more specific definition of this entity would help to determine its usefulness in classifying and clinically identifying patients with dermatomyositis, with implications related to subsequent screening for associated comorbidities in this setting.



http://ift.tt/2z4R9nL

Cause specific mortality in adults with atopic dermatitis

Publication date: Available online 2 November 2017
Source:Journal of the American Academy of Dermatology
Author(s): Jacob P. Thyssen, Lone Skov, Alexander Egeberg
BackgroundAdult atopic dermatitis (AD) has been associated with several co-morbidities, but cause-specific mortality risk is unknown.ObjectivesTo examine cause-specific death rates and risk in adults with AD.MethodsWe performed cross-linkage of nationwide health care and cause of death registers. Adult patients with AD were matched with 10 controls per study subject. We calculated incidence rates per 1,000 person-years and hazard ratios (HRs) of cause-specific death with 95% confidence intervals (95% CIs) using Cox proportional hazards models.ResultsA total of 8,686 patients and 86,860 matched controls were studied. The risk of death, due to any cause, was significantly increased in patients with AD (HR 1.27, 95%CI 1.11-1.45). Significant causes included cardiovascular (HR 1.45; 95%CI 1.07-1.96), infectious (HR 3.71; 95% CI 1.43-9.60) and urogenital diseases (HR 5.51; 95%CI 1.54-19.80). No increased risk of death due to cancer, endocrine, neurological, psychiatric, respiratory, or gastroenterological disease was observed.LimitationsThe results might not be generalizable to patients seen exclusively by primary care physicians.ConclusionsAdults with atopic dermatitis had slightly increased risk of death during follow-up. While the risk of death from cardiovascular, urogenital, and infectious diseases was slightly elevated among patients with AD, the absolute risk was very low.



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Porcine Xenografts for Surgical Defects: A Single Center Experience with 128 Cases

Publication date: Available online 2 November 2017
Source:Journal of the American Academy of Dermatology
Author(s): Sean Marzolf, Divya Srivastava, Rajiv I. Nijhawan




http://ift.tt/2iRxXpw

A simple device for ablation of keloidal tissue and serial deposition of intralesional drugs

Publication date: Available online 2 November 2017
Source:Journal of the American Academy of Dermatology
Author(s): Savita Yadav, Somesh Gupta




http://ift.tt/2z6Yfbw

Down-regulation of Noggin and miR-138 coordinately promote osteogenesis of mesenchymal stem cells

Abstract

Mesenchymal stem cells (MSCs) can differentiate to osteocytes under suitable conditions. In recent years, micro-nucleotides have been progressively used to modulate gene expression in cells due to the consideration of safety. Our present study aimed to investigate whether co-delivery of Noggin-siRNA and antimiR-138 enhances the osteogenic effect of MSCs. Using a murine MSC line, C3H/10T1/2 cells, the delivery efficiency of Noggin-siRNA and antimiR-138 into MSCs was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). Cell phenotype and proliferation capacity was assessed by flow cytometry and MTT assay respectively. The osteogenesis of MSCs was tested by Alkaline Phosphatase (ALP) staining, qRT-PCR, and western blot analyses. Our results demonstrated that the expression of Noggin and miR-138 were significantly silenced in MSCs by Noggin-siRNA and/or antimiR-138 delivery, while the phenotype and proliferation capacity of MSCs were not affected. Down-regulation of Noggin and miR-138 cooperatively promoted osteogenic differentiation of MSCs. The ALP positive cells reached about 83.57 ± 10.18%. Compared with single delivery, the expression of osteogenic related genes, such as Alp, Col-1, Bmp2, Ocn and Runx2, were the highest in cells with co-delivery of the two oligonucleotides. Moreover, the protein level of RUNX2, and the ratios of pSMAD1/5/SMAD1/5 and pERK1/2/ERK1/2 were significantly increased. The activation of Smad, Erk signaling may constitute the underlying mechanism of the enhanced osteogenesis process. Taken together, our study provides a safe strategy for the clinical rehabilitation application of MSCs in skeletal deficiency.

http://ift.tt/2h4Tsmw

Safety, efficacy, and drug survival of biologics and biosimilars for moderate-to-severe plaque psoriasis

Abstract

Background

Real-life data on newer biologic and biosimilar agents for moderate-to-severe psoriasis are lacking.

Objectives

To examine safety, efficacy, and time to discontinuation (drug survival) of biologics (adalimumab, etanercept, infliximab, secukinumab, and ustekinumab) and compare originators with biosimilars (i.e. Enbrel with Benepali, and Remicade with Remsima).

Methods

The DERMBIO registry contains data on all Danish patients with moderate-to-severe plaque psoriasis treated with biologics. We examined patients treated between January 1^st, 2007 and March 31^st, 2017. We used Kaplan-Meier survival curves and Cox-regression to examine drug survival patterns.

Results

A total of 3495 treatment series (2161 patients) were included (adalimumab n=1332, etanercept n=579, infliximab n=333, ustekinumab n=1055, and secukinumab n=196). Secukinumab had the highest number of PASI100 respondants, but also the lowest drug survival among all biologics. Ustekinumab had the highest drug survival overall. There were no significant differences in discontinuation risk between originator and biosimilar versions of infliximab or etanercept. Treatment with higher-than-approved dosages was frequent for all drugs except for adalimumab and secukinumab. Adverse events (predominantly infections) were most frequent for secukinumab and showed an increased (albeit low) incidence of cardiovascular events compared with the other agents.

Conclusions

Ustekinumab was associated with the highest drug survival, and secukinumab with the lowest, albeit that most patients on secukinumab were non-naïve. Switching from originator to biosimilar had no significant impact on drug survival, and the safety profiles were comparable. Adverse events occurred most frequently with secukinumab. Future studies are warranted to assess the long-term safety of novel biologics for psoriasis.

This article is protected by copyright. All rights reserved.

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Population-based Clinical Practice Research Datalink study using algorithm modelling to identify the true burden of hidradenitis suppurativa

Summary

Background

Epidemiology data regarding hidradenitis suppurativa (HS) are conflicting and prevalence estimates vary 80-fold, from 0.05% in a population-based study, to 4%.

Objectives

To assess the hypothesis that previous population-based studies under-estimated true HS prevalence by missing undiagnosed cases.

Methods

We performed a population-based observational and case-control study using the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics data. Physician-diagnosed cases in CPRD were identified from specific Read codes. Algorithms identified unrecognised 'proxy' cases, with at least five Read code records for boils in flexural skin sites. Validation of proxy cases was undertaken with General Practitioner questionnaires to confirm criteria-diagnosed cases. A case-control study assessed disease associations.

Results

On 30 June 2013, 23,353 physician-diagnosed HS cases were documented in 4,364,308 research-standard records. 68,890 proxy cases were identified, reduced to 10,146 criteria-diagnosed cases after validation, extrapolated from 107 completed questionnaires (61% return rate). Overall point prevalence was 0.77% (95% CI 0.76% to 0.78%). An additional 18,417 cases had a history of 1-4 flexural skin boils.

In physician-diagnosed cases, ORs for current smoker and obesity (BMI>30) were 3.61 (95% CI 3.44 to 3.79) and 3.29 (95% CI 3.14 to 3.45). HS was associated with type 2 diabetes, Crohn's disease, hyperlipidaemia, acne and depression and not associated with ulcerative colitis or polycystic ovary syndrome.

Conclusions

Contrary to results of previous population-based studies, HS is relatively common, with a UK prevalence of 0.77%, one-third being unrecognised, criteria-diagnosed cases using the most stringent disease definition. If probable cases are included, HS prevalence rises to 1.19%.

This article is protected by copyright. All rights reserved.

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A PTX/nitinol stent combination with temperature-responsive phase-change 1-hexadecanol for magnetocaloric drug delivery: Magnetocaloric drug release and esophagus tissue penetration

Publication date: January 2018
Source:Biomaterials, Volume 153
Author(s): Zhu Jin, Keqin Wu, Jingwen Hou, Kunhong Yu, Yuanyuan Shen, Shengrong Guo
An antitumor drug/esophagus stent combination can palliatively relieve malignant esophageal stricture and exert local chemotherapy to cancer. It is vital for effective treatment of cancer to control drug release and facilitate drug penetration into deep tissue after the combination is placed in the malignant strictured esophagus part. In this study, we firstly designed and prepared a novel antitumor drug/esophagus stent combination: a magnetocaloric nitinol stent coated with a bilayered film that consisted of one ethylene-vinyl acetate copolymer (EVA) layer as drug blocking layer and one EVA layer containing 10% paclitaxel (PTX) and 30% temperature sensitive phase-change fatty alcohol (1-tetradecanol, 1-hexadecanol or 1-octadecanol). The drug release and penetration into rabbit esophagus wall from the combination were investigated. It was found that, under an alternating electromagnetic field at a power of 0.1 kW, the combination was heated to 43 °C, the PTX was faster and more released from the combination, as well as the amount of PTX in esophagus tissue or its deep muscle tissue penetrated from the combination was much higher than that without alternating electromagnetic field. The pathological data showed that the combination was biocompatible and safe after placement in rabbit esophagus even under an alternating electromagnetic field. Overall, the PTX could be magnetocalorically released and effectively penetrated into esophagus wall from the PTX/nitinol stent combination.

Graphical abstract

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Editorial board

Publication date: January 2018
Source:Biomaterials, Volume 152





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Molecular mechanism of Gd@C82(OH)22 increasing collagen expression: Implication for encaging tumor

Publication date: January 2018
Source:Biomaterials, Volume 152
Author(s): Jing Liu, Seung-gu Kang, Peng Wang, Yue Wang, Xiaonan Lv, Ying Liu, Fei Wang, Zonglin Gu, Zaixing Yang, Jeffrey K. Weber, Ning Tao, Zhihai Qin, Qing Miao, Chunying Chen, Ruhong Zhou, Yuliang Zhao
Gadolinium-containing fullerenol Gd@C82(OH)22 has demonstrated low-toxicity and highly therapeutic efficacy in inhibiting tumor growth and metastasis through new strategy of encaging cancer, however, little is known about the mechanisms how this nanoparticle regulates fibroblast cells to prison (instead of poison) cancer cells. Here, we report that Gd@C82(OH)22 promote the binding activity of tumor necrosis factor (TNFα) to tumor necrosis factor receptors 2 (TNFR2), activate TNFR2/p38 MAPK signaling pathway to increase cellular collagen expression in fibrosarcoma cells and human primary lung cancer associated fibroblasts isolated from patients. We also employ molecular dynamics simulations to study the atomic-scale mechanisms that dictate how Gd@C82(OH)22 mediates interactions between TNFα and TNFRs. Our data suggest that Gd@C82(OH)22 might enhance the association between TNFα and TNFR2 through a "bridge-like" mode of interaction; by contrast, the fullerenol appears to inhibit TNFα-TNFR1 association by binding to two of the receptor's cysteine-rich domains. In concert, our results uncover a sequential, systemic process by which Gd@C82(OH)22 acts to prison tumor cells, providing new insights into principles of designs of cancer therapeutics.



http://ift.tt/2z5ojDH

A new near-infrared persistent luminescence nanoparticle as a multifunctional nanoplatform for multimodal imaging and cancer therapy

Publication date: January 2018
Source:Biomaterials, Volume 152
Author(s): Junpeng Shi, Xia Sun, Shenghui Zheng, Jinlei Li, Xiaoyan Fu, Hongwu Zhang
Multifunctional nanoplatforms with multimodal imaging and cancer therapy capabilities have attracted attention in biomedical applications. Near-infrared persistent luminescence nanoparticles (NPLNPs) were considered one of the most promising candidates for constructing multifunctional nanoplatforms due to the absence of in situ excitation and high signal-to-noise ratios (SNRs). Here, we report a novel NPLNP mSiO2@Gd3Ga5O12:Cr³⁺, Nd³⁺ (mSiO2@GGO) as multifunctional nanoplatforms for multimodal imaging and cancer therapy. These NPs exhibited a persistent luminescence (745 nm) of more than 3 h in the first near-infrared window (NIR-I) after UV excitation, which can realize high SNRs and long-term in vivo imaging. Moreover, these NPs showed excellent NIR luminescence (1067 nm) in the second near-infrared window (NIR-II) under 808 nm excitation, which is more suitable for deep tissue imaging due to the lower photon scattering and deeper tissue penetration of NIR-II luminescence. Furthermore, the host Gd3Ga5O12 with high Gd³⁺ concentration showed a high r1 value (10.70 mM⁻¹ s⁻¹) and was suitable for T1 MR imaging. The mesoporous silica nanoparticles (mSiO2) served as a framework to control the mSiO2@GGO particle morphology and provide low toxicity and drug loading capacity for cancer therapy.

Graphical abstract

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Ultrasensitive MRI detection of spontaneous pancreatic tumors with nanocage-based targeted contrast agent

Publication date: January 2018
Source:Biomaterials, Volume 152
Author(s): Takahito Kawano, Masaharu Murata, Jeong-Hun Kang, Jing Shu Piao, Sayoko Narahara, Fuminori Hyodo, Nobuhito Hamano, Jie Guo, Susumu Oguri, Kenoki Ohuchida, Makoto Hashizume
Contrast agents with greater specificity and sensitivity are required for the diagnosis of pancreatic cancers by magnetic resonance imaging (MRI). In this study, small heat shock protein 16.5 (Hsp16.5)-based nanocages conjugated to gadolinium(III)-chelated contrast agents and iRGD peptides (which target neuropilin-1 expressed on pancreatic cancer cells) were developed. To investigate whether template size influences relaxivity, nanocages with one to four hydrophobic domains were designed. MRI data showed that larger nanocages had higher T1 relaxivity than smaller nanocages, which resulted from a reduction in molecular tumbling rates caused by an increase in nanocage size, and a robust cage structure resulting from the introduction of hydrophobic domains. For in vivo MRI studies, the engineered nanocages were evaluated using the Kras^G12D; Trp53^R172H; Pdx-1Cre (KPC) transgenic mouse models, which develop clinically relevant pancreatic tumor under normal processes of angiogenesis, immune function and inflammation. Molecular MRI with protein nanocages was enabled to detect neuropilin-1-positive cells and to produce strong signal enhancement of spontaneous pancreatic tumors in KPC genetically engineered mouse models. Novel iRGD-modified nanocages displayed potential as a specific and sensitive MRI contrast agent for the diagnosis of pancreatic tumors for clinical translation.

Graphical abstract

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Bioengineering a non-genotoxic vector for genetic modification of mesenchymal stem cells

Publication date: January 2018
Source:Biomaterials, Volume 152
Author(s): Xuguang Chen, Alireza Nomani, Niket Patel, Faranak S. Nouri, Arash Hatefi
Vectors used for stem cell transfection must be non-genotoxic, in addition to possessing high efficiency, because they could potentially transform normal stem cells into cancer-initiating cells. The objective of this research was to bioengineer an efficient vector that can be used for genetic modification of stem cells without any negative somatic or genetic impact. Two types of multifunctional vectors, namely targeted and non-targeted were genetically engineered and purified from E. coli. The targeted vectors were designed to enter stem cells via overexpressed receptors. The non-targeted vectors were equipped with MPG and Pep1 cell penetrating peptides. A series of commercial synthetic non-viral vectors and an adenoviral vector were used as controls. All vectors were evaluated for their efficiency and impact on metabolic activity, cell membrane integrity, chromosomal aberrations (micronuclei formation), gene dysregulation, and differentiation ability of stem cells. The results of this study showed that the bioengineered vector utilizing VEGFR-1 receptors for cellular entry could transfect mesenchymal stem cells with high efficiency without inducing genotoxicity, negative impact on gene function, or ability to differentiate. Overall, the vectors that utilized receptors as ports for cellular entry (viral and non-viral) showed considerably better somato- and genosafety profiles in comparison to those that entered through electrostatic interaction with cellular membrane. The genetically engineered vector in this study demonstrated that it can be safely and efficiently used to genetically modify stem cells with potential applications in tissue engineering and cancer therapy.

Graphical abstract

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A Note From the Editors

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Editorial: Innovations in Study Design—A Call for Creative Solutions

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Blood Lead, Bone Turnover, and Survival in Amyotrophic Lateral Sclerosis

Abstract

Blood lead and bone turnover may be associated with the risk of amyotrophic lateral sclerosis (ALS). We aimed to assess whether these factors were also associated with time from ALS diagnosis to death through a survival analysis of 145 ALS patients enrolled during 2007 in the National Registry of Veterans with ALS. Associations of survival time with blood lead and plasma biomarkers of bone resorption (C-terminal telopeptides of type I collagen (CTX)) and bone formation (procollagen type I amino-terminal peptide (PINP)) were estimated using Cox models adjusted for age at diagnosis, diagnostic certainty, diagnostic delay, site of onset, and score on the Revised ALS Functional Rating Scale. Hazard ratios were calculated for each doubling of biomarker concentration. Blood lead, plasma CTX, and plasma PINP were mutually adjusted for one another. Increased lead (hazard ratio (HR) = 1.38; 95% confidence interval (CI): 1.03, 1.84) and CTX (HR = 2.03; 95% CI: 1.42, 2.89) were both associated with shorter survival, whereas higher PINP was associated with longer survival (HR = 0.59; 95% CI: 0.42, 0.83), after ALS diagnosis. No interactions were observed between lead or bone turnover and other prognostic indicators. Lead toxicity and bone metabolism may be involved in ALS pathophysiology.

http://ift.tt/2zrl6kU

Comparison of Sociodemographic and Health-Related Characteristics of UK Biobank Participants With Those of the General Population

Abstract

The UK Biobank cohort is a population-based cohort of 500,000 participants recruited in the United Kingdom (UK) between 2006 and 2010. Approximately 9.2 million individuals aged 40–69 years who lived within 25 miles (40 km) of one of 22 assessment centers in England, Wales, and Scotland were invited to enter the cohort, and 5.5% participated in the baseline assessment. The representativeness of the UK Biobank cohort was investigated by comparing demographic characteristics between nonresponders and responders. Sociodemographic, physical, lifestyle, and health-related characteristics of the cohort were compared with nationally representative data sources. UK Biobank participants were more likely to be older, to be female, and to live in less socioeconomically deprived areas than nonparticipants. Compared with the general population, participants were less likely to be obese, to smoke, and to drink alcohol on a daily basis and had fewer self-reported health conditions. At age 70–74 years, rates of all-cause mortality and total cancer incidence were 46.2% and 11.8% lower, respectively, in men and 55.5% and 18.1% lower, respectively, in women than in the general population of the same age. UK Biobank is not representative of the sampling population; there is evidence of a "healthy volunteer" selection bias. Nonetheless, valid assessment of exposure-disease relationships may be widely generalizable and does not require participants to be representative of the population at large.

http://ift.tt/2zbRnfd

Prentice et al. Respond to “Improving Estimation of Sodium Intake”

http://ift.tt/2zc5gd5

Associations of Biomarker-Calibrated Sodium and Potassium Intakes With Cardiovascular Disease Risk Among Postmenopausal Women

Abstract

Studies of the associations of sodium and potassium intakes with cardiovascular disease incidence often rely on self-reported dietary data. In the present study, self-reported intakes from postmenopausal women at 40 participating US clinical centers are calibrated using 24-hour urinary excretion measures in cohorts from the Women's Health Initiative, with follow-up from 1993 to 2010. The incidence of hypertension was positively related to (calibrated) sodium intake and to the ratio of sodium to potassium. The sodium-to-potassium ratio was associated with cardiovascular disease incidence during an average follow-up period of 12 years. The estimated hazard ratio for a 20% increase in the sodium-to-potassium ratio was 1.13 (95% confidence interval (CI): 1.04, 1.22) for coronary heart disease, 1.20 (95% CI: 1.01, 1.42) for heart failure, and 1.11 (95% CI: 1.04, 1.19) for a composite cardiovascular disease outcome. The association with total stroke was not significant, but it was positive for ischemic stroke and inverse for hemorrhagic stroke. Aside from hemorrhagic stroke, corresponding associations of cardiovascular disease with sodium and potassium jointly were positive for sodium and inverse for potassium, although some were not statistically significant. Specifically, for coronary heart disease, the hazard ratios for 20% increases were 1.11 (95% CI: 0.95, 1.30) for sodium and 0.85 (95% CI: 0.73, 0.99) for potassium; and corresponding values for heart failure were 1.36 (95% CI: 1.02, 1.82) for sodium and 0.90 (95% CI: 0.69, 1.18) for potassium.

http://ift.tt/2zqMtfh

Mammographic Density Reduction as a Prognostic Marker for Postmenopausal Breast Cancer: Results Using a Joint Longitudinal-Survival Modeling Approach

Abstract

Previous studies have linked reductions in mammographic density after a breast cancer diagnosis to an improved prognosis. These studies focused on short-term change, using a 2-stage process, treating estimated change as a fixed covariate in a survival model. We propose the use of a joint longitudinal-survival model. This enables us to model long-term trends in density while accounting for dropout as well as for measurement error. We studied the change in mammographic density after a breast cancer diagnosis and its association with prognosis (measured by cause-specific mortality), overall and with respect to hormone replacement therapy and tamoxifen treatment. We included 1,740 women aged 50–74 years, diagnosed with breast cancer in Sweden during 1993–1995, with follow-up until 2008. They had a total of 6,317 mammographic density measures available from the first 5 years of follow-up, including baseline measures. We found that the impact of the withdrawal of hormone replacement therapy on density reduction was larger than that of tamoxifen treatment. Unlike previous studies, we found that there was an association between density reduction and survival, both for tamoxifen-treated women and women who were not treated with tamoxifen.

http://ift.tt/2zc5aSL

A Multinomial Regression Approach to Model Outcome Heterogeneity

Abstract

When a risk factor affects certain categories of a multinomial outcome but not others, outcome heterogeneity is said to be present. A standard epidemiologic approach for modeling risk factors of a categorical outcome typically entails fitting a polytomous logistic regression via maximum likelihood estimation. In this paper, we show that standard polytomous regression is ill equipped to detect outcome heterogeneity and will generally understate the degree to which such heterogeneity may be present. Specifically, nonsaturated polytomous regression will often a priori rule out the possibility of outcome heterogeneity from its parameter space. As a remedy, we propose to model each category of the outcome as a separate binary regression. For full efficiency, we propose to estimate the collection of regression parameters jointly using a constrained Bayesian approach that ensures that one remains within the multinomial model. The approach is straightforward to implement in standard software for Bayesian estimation.

http://ift.tt/2zpLHz8

Correcting the Standard Errors of 2-Stage Residual Inclusion Estimators for Mendelian Randomization Studies

Abstract

Mendelian randomization studies use genotypes as instrumental variables to test for and estimate the causal effects of modifiable risk factors on outcomes. Two-stage residual inclusion (TSRI) estimators have been used when researchers are willing to make parametric assumptions. However, researchers are currently reporting uncorrected or heteroscedasticity-robust standard errors for these estimates. We compared several different forms of the standard error for linear and logistic TSRI estimates in simulations and in real-data examples. Among others, we consider standard errors modified from the approach of Newey (1987), Terza (2016), and bootstrapping. In our simulations Newey, Terza, bootstrap, and corrected 2-stage least squares (in the linear case) standard errors gave the best results in terms of coverage and type I error. In the real-data examples, the Newey standard errors were 0.5% and 2% larger than the unadjusted standard errors for the linear and logistic TSRI estimators, respectively. We show that TSRI estimators with modified standard errors have correct type I error under the null. Researchers should report TSRI estimates with modified standard errors instead of reporting unadjusted or heteroscedasticity-robust standard errors.

http://ift.tt/2zbcdey

Comprehensive Analysis of Prevalence, Epidemiologic Characteristics, and Clinical Characteristics of Monoinfection and Coinfection in Diarrheal Diseases in Children in Tanzania

Abstract

The role of interactions between intestinal pathogens in diarrheal disease is uncertain. From August 2010 to July 2011, we collected stool samples from 723 children admitted with diarrhea (cases) to 3 major hospitals in Dar es Salaam, Tanzania, and from 564 nondiarrheic children (controls). We analyzed the samples for 17 pathogens and assessed interactions between coinfections in additive and multiplicative models. At least one pathogen was detected in 86.9% of the cases and 62.8%, of the controls. Prevalence of coinfections was 58.1% in cases and 40.4% in controls. Rotavirus, norovirus genogroup II, Cryptosporidium, and Shigella species/enteroinvasive Escherichia coli were significantly associated with diarrhea both as monoinfections and as coinfections. In the multiplicative interaction model, we found 2 significant positive interactions: rotavirus + Giardia (odds ratio (OR) = 23.91, 95% confidence interval (CI): 1.21, 470.14) and norovirus GII + enteroaggregative E. coli (OR = 3.06, 95% CI: 1.17, 7.98). One significant negative interaction was found between norovirus GII + typical enteropathogenic E. coli (OR = 0.09, 95% CI: 0.01, 0.95). In multivariate analysis, risk factors for death were presence of blood in stool and severe dehydration. In conclusion, coinfections are frequent, and the pathogenicity of each organism appears to be enhanced by some coinfections and weakened by others. Severity of diarrhea was not affected by coinfections.

http://ift.tt/2zpKKGU

Sex Differences in the Association Between Pain and Injurious Falls in Older Adults: A Population-Based Longitudinal Study

Abstract

We investigated whether there are sex differences in the association between pain and incident injurious falls. A total of 2,934 people (ages ≥60 years) from the population-based Swedish National Study on Aging and Care in Kungsholmen (2001–2004) participated. Participants were followed up for 3 and 10 years for falls leading to hospitalization or outpatient care. Data were analyzed with flexible parametric survival models that adjusted for potential confounders. During the first 3 years of follow-up, 67 men and 194 women experienced an injurious fall, and over 10 years of follow up, 203 men and 548 women experienced such a fall. In men, the presence of pain, having pain that was at least mild, having pain that affected several daily activities, and having daily pain all significantly increased the likelihood of incurring an injurious fall during the 3-year follow-up period. The multivariate-adjusted hazard ratios ranged from 1.78 (95% confidence interval: 1.00, 3.15) for the presence of pain to 2.89 (95% confidence interval: 1.41, 5.93) for several daily activities' being affected by pain. Results for the 10-year follow-up period were similar. No significant associations were detected in women. Although pain is less prevalent in men than in women, its impact on risk of injurious falls seems to be greater in men.

http://ift.tt/2zbca2m

Quantitative Serum Nuclear Magnetic Resonance Metabolomics in Large-Scale Epidemiology: A Primer on -Omic Technologies

Abstract

Detailed metabolic profiling in large-scale epidemiologic studies has uncovered novel biomarkers for cardiometabolic diseases and clarified the molecular associations of established risk factors. A quantitative metabolomics platform based on nuclear magnetic resonance spectroscopy has found widespread use, already profiling over 400,000 blood samples. Over 200 metabolic measures are quantified per sample; in addition to many biomarkers routinely used in epidemiology, the method simultaneously provides fine-grained lipoprotein subclass profiling and quantification of circulating fatty acids, amino acids, gluconeogenesis-related metabolites, and many other molecules from multiple metabolic pathways. Here we focus on applications of magnetic resonance metabolomics for quantifying circulating biomarkers in large-scale epidemiology. We highlight the molecular characterization of risk factors, use of Mendelian randomization, and the key issues of study design and analyses of metabolic profiling for epidemiology. We also detail how integration of metabolic profiling data with genetics can enhance drug development. We discuss why quantitative metabolic profiling is becoming widespread in epidemiology and biobanking. Although large-scale applications of metabolic profiling are still novel, it seems likely that comprehensive biomarker data will contribute to etiologic understanding of various diseases and abilities to predict disease risks, with the potential to translate into multiple clinical settings.

http://ift.tt/2zpKDes

Activation of CRF/CRFR1 signaling in the basolateral nucleus of the amygdala contributes to chronic forced swim-induced depressive-like behaviors in rats

Publication date: 15 February 2018
Source:Behavioural Brain Research, Volume 338
Author(s): Lin Chen, Song Li, Jie Cai, Tian-Jiao Wei, Ling-Yu Liu, Hong-Yan Zhao, Bo-Heng Liu, Hong-Bo Jing, Zi-Run Jin, Min Liu, You Wan, Guo-Gang Xing
The basolateral nucleus of the amygdala (BLA) plays a key role in processing stressful events and affective disorders. Previously we have documented that exposure of chronic forced swim (FS) to rats produces a depressive-like behavior and that sensitization of BLA neurons is involved in this process. In the present study, we demonstrated that chronic FS stress (CFSS) could activate corticotrophin-releasing factor (CRF)/CRF receptor type 1 (CRFR1) signaling in the BLA, and blockade of CRF/CRFR1 signaling by intra-BLA injection of NBI27914 (NBI), a selective CRFR1 antagonist, could prevent the CFSS-induced depressive-like behaviors in rats, indicating that activation of CRF/CRFR1 signaling in the BLA is required for CFSS-induced depression. Furthermore, we discovered that exposure of chronic FS to rats could reinforce long-term potentiation (LTP) at the external capsule (EC)-BLA synapse and increase BLA neuronal excitability, and that all these alterations were inhibited by CRFR1 antagonist NBI. Moreover, we found that application of exogenous CRF also may facilitate LTP at the EC-BLA synapse and sensitize BLA neuronal excitability in normal rats via the activation of CRFR1. We conclude that activation of CRF/CRFR1 signaling in the BLA contributes to chronic FS-induced depressive-like behaviors in rats through potentiating synaptic efficiency at the EC-BLA pathway and sensitizing BLA neuronal excitability.



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Modified single prolonged stress reduces cocaine self-administration during acquisition regardless of rearing environment

Publication date: 15 February 2018
Source:Behavioural Brain Research, Volume 338
Author(s): Rebecca S. Hofford, Mark A. Prendergast, Michael T. Bardo
Until recently, there were few rodent models available to study the interaction of post-traumatic stress disorder (PTSD) and drug taking. Like PTSD, single prolonged stress (SPS) produces hypothalamic-pituitary-adrenal (HPA) axis dysfunction and alters psychostimulant self-administration. Other stressors, such as isolation stress, also alter psychostimulant self-administration. However, it is currently unknown if isolation housing combined with SPS can alter the acquisition or maintenance of cocaine self-administration. The current study applied modified SPS (modSPS; two hours restraint immediately followed by cold swim stress) to rats raised in an isolation condition (Iso), enrichment condition (Enr), or standard condition (Std) to measure changes in cocaine self-administration and HPA markers. Regardless of rearing condition, rats exposed to modSPS had greater corticosterone (CORT) release and reduced cocaine self-administration during initial acquisition compared to non-stressed controls. In addition, during initial acquisition, rats that received both Iso rearing and modSPS showed a more rapid increase in cocaine self-administration across sessions compared to Enr and Std rats exposed to modSPS. Following initial acquisition, a dose response analysis showed that Iso rats were overall most sensitive to changes in cocaine unit dose; however, modSPS had no effect on the cocaine dose response curve. Further, there was no effect of either modSPS or differential rearing on expression of glucocorticoid receptor (GR) in hypothalamus, medial prefrontal cortex, amygdala, or nucleus accumbens. By using modSPS in combination with Iso housing, this study identified unique contributions of each stressor to acquisition of cocaine self-administration.



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Lesions within the head direction system reduce retrosplenial c-fos expression but do not impair performance on a radial-arm maze task

Publication date: 15 February 2018
Source:Behavioural Brain Research, Volume 338
Author(s): Seralynne D. Vann
The lateral mammillary nuclei are a central structure within the head direction system yet there is still relatively little known about how these nuclei contribute to spatial performance. In the present study, rats with selective neurotoxic lesions of the lateral mammillary nuclei were tested on a working memory task in a radial-arm maze. This task requires animals to distinguish between eight radially-oriented arms and remember which arms they have entered within a session. Even though it might have been predicted that this task would heavily tax the head direction system, the lesion rats performed equivalently to their surgical controls on this task; no deficit emerged even when the task was made more difficult by rotating the maze mid-way through testing in order to reduce reliance on intramaze cues. Rats were subsequently tested in the dark to increase the use of internally generated direction cues but the lesion rats remained unimpaired. In contrast, the lateral mammillary nuclei lesions were found to decrease retrosplenial c-Fos levels. These results would suggest that the head direction system is not required for the acquisition of the standard radial-arm maze task. It would also suggest that small decreases in retrosplenial c-Fos are not sufficient to produce behavioural impairments.



http://ift.tt/2xMeglM

Autologous breast reconstruction using the immediately lipofilled extended latissimus dorsi flap

–The latissimus dorsi flap is a popular choice for autologous breast reconstruction. To dramatically improve volume, we report our experience of using the immediately lipofilled extended latissimus dorsi flap and show it is a valid option for autologous breast reconstruction.

http://ift.tt/2gW2ZIE

Optimizing donor site closure following bilateral breast reconstruction with abdominal-based free flaps

The abdomen is the primary donor site for autologous free flap breast reconstruction, but violation of the rectus abdominus complex can result in significant morbidity.1, 2 Abdominal hernias and bulges are the most concerning donor site complications in the long term, but early wound complications also contribute to significant morbidity during the initial postoperative period. In order to minimize the risk of hernias and bulges, reinforcement of the abdominal wall with placement of mesh may be necessary particularly in the setting of bilateral breast reconstruction.

http://ift.tt/2imDKPX

Rectus femoris branch: an alternative blood supply for a distally based anterolateral thigh flap

Successful raising of a distally-based anterolateral thigh (dALT) flap mainly depends on a well-developed lateral circumflex femoral artery (LCFA) descending branch and an intact vascular connection between the descending branch and the vascular network of the knee. However, in some clinical scenarios, the descending branch is hypoplastic or the vascular connection of the knee is compromised. We present six cases of using dALT flaps in soft tissue defect reconstruction of the knee with either of the above-mentioned conditions.

http://ift.tt/2gVso5r

Distally based sural neuro-fasciocutaneous perforator flap for foot and ankle reconstruction: surgical modifications for flap pedicle and donor site closure without skin graft

The conventional procedure of the sural neuro-fasciocutaneous flap enables the supply of blood and venous drainage by increasing the width of the adipofascial tissue and preserving tiny venous return routes. Moreover, skin graft is a common method for donor site closure, which may lead to some complications and influence the aesthetic appearance. We report modifications for a distally based sural neuro-fasciocutaneous perforator flap and a relaying flap for donor site closure without skin graft.

http://ift.tt/2im5btj

Importance of sentinel lymphatic node biopsy in detection of early micrometastases in patients with cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (CSCC) is the second most common malignant skin cancer with a tendency to spread via lymphogenic pathway. Metastases are found in 2% - 6 % of cases. The aim of this study was to determine CSCC micrometastases when non-invasive examination methods do not detect them.

http://ift.tt/2gSJQr3

A systematic review of near-infrared spectroscopy in flap monitoring: current basic and clinical evidence and prospects

Recently, near-infrared spectroscopy (NIRS) has been reported to be a reliable non-invasive modality for free flap monitoring; however, the history of its application in flap monitoring is short, and there is no definite consensus regarding its use at present.

http://ift.tt/2im4P5X

Retrobulbar hematoma: a systematic review of factors related to outcomes

Retrobulbar hematoma (RBH), a rare but serious condition, can result in permanent vision loss. Although it is a known complication following trauma or facial fracture reduction, sinus surgery, or blepharoplasty, factors related to patient outcomes are not well-defined. A systematic review was performed to determine the relation of patient/treatment factors to outcomes.

http://ift.tt/2gSJzEx

A flap based on the plantar digital artery arch branch to improve appearance of reconstructed fingers: anatomical and clinical application

To investigate blood supply features of the flap based on the plantar digital artery arch and arch branch artery, and the treatment of outcomes of reconstructed fingers by the plantar digital artery arch branch island flap.

http://ift.tt/2imDErz

Hormone-dependent medial preoptic/lumbar spinal cord/autonomic coordination supporting male sexual behaviors

Publication date: Available online 31 October 2017
Source:Molecular and Cellular Endocrinology
Author(s): Donald W. Pfaff, Michael J. Baum
Testosterone (T) can act directly through neural androgen receptors (AR) to facilitate male sexual behavior; however, T's metabolites also can play complicated and interesting roles in the control of mating. One metabolite, dihydrotestosterone (DHT) binds to AR with significantly greater affinity than that of T. Is that important behaviorally? Another metabolite, estradiol (E), offers a potential alternative route of facilitating male mating behavior by acting through estradiol receptors (ER). In this review we explore the roles and relative importance of T as well as E and DHT at various levels of the neuroaxis for the activation of male sex behavior in common laboratory animals and, when relevant research findings are available, in man.



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Molecular endocrinology of female reproductive behavior

Publication date: Available online 31 October 2017
Source:Molecular and Cellular Endocrinology
Author(s): D.W. Pfaff, K. Gagnidze, R.G. Hunter
Epigenetic methodologies address mechanisms of estrogenic effects on hypothalamic and preoptic neurons, as well as mechanisms by which stress can interfere with female reproductive behaviors. Recent results are reviewed.



http://ift.tt/2iSTQFd

Fe3O4 and metal–organic framework MIL-101(Fe) composites catalyze luminol chemiluminescence for sensitively sensing hydrogen peroxide and glucose

Publication date: 1 March 2018
Source:Talanta, Volume 179
Author(s): Xue Qian Tang, Yi Dan Zhang, Zhong Wei Jiang, Dong Mei Wang, Cheng Zhi Huang, Yuan Fang Li
In this work, Fe3O4 and metal–organic framework MIL-101(Fe) composites (Fe3O4/MIL-101(Fe)) was demonstrated to possess excellent catalytic property to directly catalyze luminol chemiluminescence without extra oxidants. We utilized Fe3O4/MIL-101(Fe) to develop a ultra-sensitive quantitative analytical method for H2O2 and glucose. The possible mechanism of the chemiluminescence reaction had been investigated. Under optimal conditions, the relative chemiluminescence intensity was linearly proportional to the logarithm of H2O2 concentration in the range of 5–150nM with a limit of detection of 3.7nM (signal-to-noise ratio = 3), and glucose could be linearly detected in the range from 5 to 100nM and the detection limit was 4.9nM (signal-to-noise ratio = 3). Furthermore, the present approach was successfully applied to quantitative determination of H2O2 in medical disinfectant and glucose in human serum samples.

Graphical abstract

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Synthesis, spectral characterization and computed optical analysis of potent triazole based compounds

Publication date: 5 February 2018
Source:Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, Volume 190
Author(s): Sajjad H. Sumrra, Fazila Mushtaq, Muhammad Khalid, Muhammad Asam Raza, Muhammad Faizan Nazar, Bakhat Ali, Ataualpa A.C. Braga
Biologically active triazole Schiff base ligand (L) and metal complexes [Fe(II), Co(II), Ni(II), Cu(II) and Zn(II)] are reported herein. The ligand acted as tridentate and coordinated towards metallic ions via azomethine-N, triazolic-N moiety and deprotonated-O of phenyl substituents in an octahedral manner. These compounds were characterized by physical, spectral and analytical analysis. The synthesized ligand and metal complexes were screened for antibacterial pathogens against Chromohalobacter salexigens, Chromohalobacter israelensi, Halomonas halofila and Halomonas salina, antifungal bioassay against Aspergillus niger and Aspergellus flavin, antioxidant (DPPH, phosphomolybdate) and also for enzyme inhibition [butyrylcholinesterase (BChE) and acetylcholinesterase (AChE)] studies. The results of these activities indicated the ligand to possess potential activity which significantly increased upon chelation. Moreover, vibrational bands, frontier molecular orbitals (FMOs) and natural bond analysis (NBO) of ligand (1) were carried out through density functional theory (DFT) with B3lYP/6-311++G (d,p) approach. While, UV–Vis analysis was performed by time dependent TD-DFT with B3lYP/6-311++G (d,p) method. NBO analysis revealed that investigated compound (L) contains enormous molecular stability owing to hyper conjugative interactions. Theoretical spectroscopic findings showed good agreement to experimental spectroscopic data. Global reactivity descriptors were calculated using the energies of FMOs which indicated compound (L) might be bioactive. These parameters confirmed the charge transfer phenomenon and reasonable correspondence with experimental bioactivity results.

Graphical abstract

http://ift.tt/2z6rZrf

XPA is primarily cytoplasmic but is transported into the nucleus upon UV damage in a cell cycle dependent manner

Publication date: December 2017
Source:DNA Repair, Volume 60
Author(s): Phillip R. Musich, Zhengke Li, Steven M. Shell, Yue Zou




http://ift.tt/2zoV6a9

Electronic structure, vibrational assignments and simulation studies with A/T rich DNA duplex of an aromatic bis-amidine derivative

Publication date: December 2017
Source:DNA Repair, Volume 60
Author(s): Umesh Yadava, Sanjai Kumar Yadav, Ramesh Kumar Yadav
In this paper, computational investigations have been carried out on an aromatic bis-amidine which is considered to be crucial due to its peculiar properties including anti-Pneumocystis carinii pneumonia(PCP), anti-inflammatory and anticancer activities. The raw structure of an aromatic bis-amidine namely; 2,5-bis[4-(N-cyclohexyl-amidino)phenyl]furan was retrieved, optimized and geometrical parameters were computed. The computational results have been compared with those of reported experimental values. In order to check its binding capability, we pave the way a step further by the interaction of the molecule with DNA duplex, 5′(CGCGAATTCGCG)3′, which consisted of A/T base pairs in its central region. In addition to geometrical, MEP, HOMO-LUMO analyses and IR assignments, molecular docking with DNA has also been performed. The best docked complex was subjected to molecular dynamics simulation for 50ns using AMBER force field. Free energy of binding has been calculated using MM/PBSA method. The outcomes demonstrate that the molecule recognizes both the strands of DNA duplex through hydrogen bonding within the minor groove side, preferably at A/T rich region and remains stable during the course of dynamics. It may be concluded that the compound shows better binding capability with duplex under study and may be used as a drug lead against Pneumocystis carinii pneumonia.



http://ift.tt/2zarUCM

TDP1 is required for efficient non-homologous end joining in human cells

Publication date: December 2017
Source:DNA Repair, Volume 60
Author(s): Jing Li, Matthew Summerlin, Karin C. Nitiss, John L. Nitiss, Leslyn A. Hanakahi
Tyrosyl-DNA phosphodiesterase 1 (TDP1) can remove a wide variety of 3′ and 5′ terminal DNA adducts. Genetic studies in yeast identified TDP1 as a regulator of non-homologous end joining (NHEJ) fidelity in the repair of double-strand breaks (DSBs) lacking terminal adducts. In this communication, we show that TDP1 plays an important role in joining cohesive DSBs in human cells. To investigate the role of TDP1 in NHEJ in live human cells we used CRISPR/cas9 to produce TDP1-knockout (TDP1-KO) HEK-293 cells. As expected, human TDP1-KO cells were highly sensitive to topoisomerase poisons and ionizing radiation. Using a chromosomally-integrated NHEJ reporter substrate to compare end joining between wild type and TDP1-KO cells, we found that TDP1-KO cells have a 5-fold reduced ability to repair I-SceI-generated DSBs. Extracts prepared from TDP1-KO cells had reduced NHEJ activity in vitro, as compared to extracts from wild type cells. Analysis of end-joining junctions showed that TDP1 deficiency reduced end-joining fidelity, with a significant increase in insertion events, similar to previous observations in yeast. It has been reported that phosphorylation of TDP1 serine 81 (TDP1-S81) by ATM and DNA-PK stabilizes TDP1 and recruits TDP1 to sites of DNA damage. We found that end joining in TDP1-KO cells was partially restored by the non-phosphorylatable mutant TDP1-S81A, but not by the phosphomimetic TDP1-S81E. We previously reported that TDP1 physically interacted with XLF. In this study, we found that XLF binding by TDP1 was reduced 2-fold by the S81A mutation, and 10-fold by the S81E phosphomimetic mutation. Our results demonstrate a novel role for TDP1 in NHEJ in human cells. We hypothesize that TDP1 participation in human NHEJ is mediated by interaction with XLF, and that TDP1-XLF interactions and subsequent NHEJ events are regulated by phosphorylation of TDP1-S81.



http://ift.tt/2zoUcua

High homology is not required at the site of strand invasion during recombinational double-strand break repair in mammalian chromosomes

Publication date: December 2017
Source:DNA Repair, Volume 60
Author(s): Kristina M. Chapman, Megan M. Wilkey, Kendall E. Potter, Barbara C. Waldman, Alan S. Waldman
We investigated the impact of sequence divergence on DNA double-strand break (DSB) repair occurring via recombination in cultured thymidine kinase deficient mouse fibroblasts. We stably transfected cells with a DNA construct harboring a herpes thymidine kinase (tk) gene (the "recipient") rendered nonfunctional by insertion of an oligonucleotide containing the recognition site for endonuclease I-SceI. The construct also contained a closely linked truncated "donor" tk sequence. The donor could potentially restore function to the recipient gene via recombination provoked by induction of a DSB at the I-SceI site in the recipient. Repair events were recoverable by selection for tk-positive clones. The donor contained 33 mismatches relative to the recipient. The mismatches were clustered, forming a localized segment of DNA sequence displaying about 20% divergence relative to the recipient, and the mismatched segment was surrounded by regions of high homology. When the donor was aligned with the recipient, the DSB site in the recipient aligned opposite the mismatched segment, allowing us to potentially capture recombinational repair events initiating between diverged sequences. Previous work demonstrated that mammalian cells effectively avoid recombination between 20% diverged sequences. In the current study we asked whether flanking regions of high homology would enable genetic exchange between highly diverged sequences or, instead, would rejection of exchange between diverged sequences remain unchanged. We found that by surrounding mismatches with high homology, suppression of recombination between diverged sequences was overcome. Strikingly, we recovered a high frequency of gene conversion tracts positioned entirely within the mismatched sequences. We infer that such events were enabled by homologous pairing interactions between sequences surrounding the site of strand invasion. Our results suggest a search for high homology prior to recombination that is not mediated by an invading DNA terminus.

Graphical abstract

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Defects in recombination activity caused by somatic and germline mutations in the multimerization/BRCA2 binding region of human RAD51 protein

Publication date: December 2017
Source:DNA Repair, Volume 60
Author(s): Michelle C. Silva, Katie E. Bryan, Milagros D. Morrical, April M. Averill, Julie Dragon, Adrian P. Wiegmans, Scott W. Morrical
The human RAD51 recombinase possesses DNA pairing and strand exchange activities that are essential for the error-free, homology-directed repair of DNA double-strand breaks. The recombination activities of RAD51 are activated upon its assembly into presynaptic filaments on single-stranded DNA at resected DSB ends. Defects in filament assembly caused by mutations in RAD51 or its regulators such as BRCA2 are associated with human cancer. Here we describe two novel RAD51 missense variants located in the multimerization/BRCA2 binding region of RAD51. F86L is a breast tumor-derived somatic variant that affects the interface between adjacent RAD51 protomers in the presynaptic filament. E258A is a germline variant that maps to the interface region between the N-terminal and RecA homology domains of RAD51. Both variants exhibit abnormal biochemistry including altered DNA strand exchange activity. Both variants inhibit the DNA strand exchange activity of wild-type RAD51, suggesting a mechanism for negative dominance. The inhibitory effect of F86L on wild-type RAD51 is surprising since F86L alone exhibits robust DNA strand exchange activity. Our findings indicate that even DNA strand exchange-proficient variants can have negative functional interactions with wild-type RAD51. Thus heterozygous F86L or E258 mutations in RAD51 could promote genomic instability, and thereby contribute to tumor progression.



http://ift.tt/2zp627p

DNA polymerase β: A missing link of the base excision repair machinery in mammalian mitochondria

Publication date: Available online 28 October 2017
Source:DNA Repair
Author(s): Rajendra Prasad, Melike Çağlayan, Da-Peng Dai, Cristina A. Nadalutti, Ming-Lang Zhao, Natalie R. Gassman, Agnes K. Janoshazi, Donna F. Stefanick, Julie K. Horton, Rachel Krasich, Matthew J. Longley, William C. Copeland, Jack D. Griffith, Samuel H. Wilson
Mitochondrial genome integrity is fundamental to mammalian cell viability. Since mitochondrial DNA is constantly under attack from oxygen radicals released during ATP production, DNA repair is vital in removing oxidatively generated lesions in mitochondrial DNA, but the presence of a strong base excision repair system has not been demonstrated. Here, we addressed the presence of such a system in mammalian mitochondria involving the primary base lesion repair enzyme DNA polymerase (pol) β. Pol β was localized to mammalian mitochondria by electron microscopic-immunogold staining, immunofluorescence co-localization and biochemical experiments. Extracts from purified mitochondria exhibited base excision repair activity that was dependent on pol β. Mitochondria from pol β-deficient mouse fibroblasts had compromised DNA repair and showed elevated levels of superoxide radicals after hydrogen peroxide treatment. Mitochondria in pol β-deficient fibroblasts displayed altered morphology by electron microscopy. These results indicate that mammalian mitochondria contain an efficient base lesion repair system mediated in part by pol β and thus pol β plays a role in preserving mitochondrial genome stability.



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Natural product β-thujaplicin inhibits homologous recombination repair and sensitizes cancer cells to radiation therapy

Publication date: Available online 24 October 2017
Source:DNA Repair
Author(s): Lihong Zhang, Yang Peng, Ivan P. Uray, Jianfeng Shen, Lulu Wang, Xiangdong Peng, Powel H. Brown, Wei Tu, Guang Peng
Investigation of natural products is an attractive strategy to identify novel compounds for cancer prevention and treatment. Numerous studies have shown the efficacy and safety of natural products, and they have been widely used as alternative treatments for a wide range of illnesses, including cancers. However, it remains unknown whether natural products affect homologous recombination (HR)-mediated DNA repair and whether these compounds can be used as sensitizers with minimal toxicity to improve patients' responses to radiation therapy, a mainstay of treatment for many human cancers. In this study, in order to systematically identify natural products with an inhibitory effect on HR repair, we developed a high-throughput image-based HR repair screening assay and screened a chemical library containing natural products. Among the most interesting of the candidate compounds identified from the screen was β-thujaplicin, a bioactive compound isolated from the heart wood of plants in the Cupressaceae family, can significantly inhibit HR repair. We further demonstrated that β-thujaplicin inhibits HR repair by reducing the recruitment of a key HR repair protein, Rad51, to DNA double-strand breaks. More importantly, our results showed that β-thujaplicin can radiosensitize cancer cells.Additionally, β-thujaplicin sensitizes cancer cells to PARP inhibitor in different cancer cell lines. Collectively, our findings for the first time identify natural compound β-thujaplicin, which has a good biosafety profile, as a novel HR repair inhibitor with great potential to be translated into clinical applications as a sensitizer to DNA-damage-inducing treatment such as radiation and PARP inhibitor. In addition, our study provides proof of the principle that our robust high-throughput functional HR repair assay can be used for a large-scale screening system to identify novel natural products that regulate DNA repair and cellular responses to DNA damage-inducing treatments such as radiation therapy.



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Incidence of Overuse Musculoskeletal Injuries in Military Service Members with Traumatic Lower Limb Amputation

Publication date: Available online 31 October 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Shawn Farrokhi, Brittney Mazzone, Susan Eskridge, Kaeley Shannon, Owen T. Hill
ObjectiveTo describe the incidence of overuse musculoskeletal injuries in service members with combat-related lower limb amputation.DesignRetrospective cohort study.SettingMilitary treatment facilities.ParticipantsA total of 791 service members with deployment-related lower limb injury: 496 with a major lower limb amputation and 295 with a mild lower limb injury.InterventionsNot applicable.Main Outcome MeasuresThe outcomes of interest were clinical diagnosis codes (International Classification of Diseases, Ninth Revision [ICD-9]) associated with musculoskeletal overuse injuries of the lumbar spine, upper limb, and lower limb regions one year before and one year after injury.ResultsThe overall incidence of developing at least one musculoskeletal overuse injury within the first year after lower limb amputation was between 59-68%. Service members with unilateral lower limb amputation were almost twice as likely to develop an overuse lower or upper limb injury as compared to those with mild combat-related injury. Additionally, service members with bilateral lower limb amputation were more than twice as likely to develop a lumbar spine injury and four times more likely to develop an upper limb overuse injury within the first year after amputation as compared to those with mild combat-related injury.ConclusionsIncidence of secondary overuse musculoskeletal injury is elevated in service members with lower limb amputation and warrants focused research efforts towards developing preventive interventions.



http://ift.tt/2ymuBSD

Volumetric MRI Analysis of Plexiform Neurofibromas in Neurofibromatosis Type 1

Publication date: Available online 31 October 2017
Source:Academic Radiology
Author(s): Wenli Cai, Seth M. Steinberg, Miriam A. Bredella, Gina Basinsky, Bhanusupriya Somarouthu, Scott R. Plotkin, Jeffrey Solomon, Brigitte C. Widemann, Gordon J. Harris, Eva Dombi
ObjectivesPlexiform neurofibromas (PNs) are complex, histologically benign peripheral nerve sheath tumors that are challenging to measure by simple line measurements. Computer-aided volumetric segmentation of PN has become the recommended method to assess response in clinical trials directed at PN. Different methods for volumetric analysis of PN have been developed. The goal of this study is to test the level of agreement in volume measurements and in interval changes using two separate methods of volumetric magnetic resonance imaging analysis.MethodsThree independent volume measurements were performed on 15 PN imaged at three time-points using 3DQI software at Massachusetts General Hospital (MGH) and National Cancer Institute (NCI) and MEDx software at NCI.ResultsMedian volume differences at each time-point comparing MGH-3DQI and NCI-3DQI were −0.5, −4.2, and −19.9 mL; comparing NCI-3DQI and NCI-MEDx were −21.0, −47.0, and −21.0 mL; comparing MGH-3DQI and NCI-MEDx were −10.0, −70.3, and −29.9 mL. Median differences in percentage change over time comparing MGH-3DQI and NCI-3DQI were −1.7, 1.1, and −1.0%; comparing NCI-3DQI and NCI-MEDx were −2.3, 3.3, and −1.1%; comparing MGH-3DQI and NCI-MEDx were −0.4, 2.0, and −1.5%. Volume differences were <20% of the mean of the two measurements in 117 of 135 comparisons (86.7%). Difference in interval change was <20% in 120 of the 135 comparisons (88.9%), while disease status classification was concordant in 115 of 135 comparisons (85.2%).ConclusionsThe volumes, interval changes, and progression status classifications were in good agreement. The comparison of two volumetric analysis methods suggests no systematic differences in tumor assessment. A prospective comparison of the two methods is planned.



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Epidermal Growth Factor Receptor Overexpression and Outcomes in Early Breast Cancer: A Systematic Review and a Meta-analysis

Publication date: Available online 31 October 2017
Source:Cancer Treatment Reviews
Author(s): Galileo A. Gonzalez-Conchas, Laura Rodriguez-Romo, David Hernandez Barajas, Juan F. Gonzalez-Guerrero, Ivan A. Rodriguez-Fernandez, Adrian Verdines-Perez, Arnoud J. Templeton, Alberto Ocana, Bostjan Seruga, Ian F. Tannock, Eitan Amir, Francisco E. Vera-Badillo
BackgroundThe epidermal growth factor receptor (EGFR) is a member of the ErbB family of membrane tyrosine-kinase receptors. Studies exploring the prognostic role of EGFR-overexpression in early breast cancer have shown variable results, and the true prognostic value of EGFR is unknown.MethodsA systematic review of identified publications exploring the association between EGFR-overexpression (as defined from different techniques and cut-offs) and outcomes [disease-free (DFS) and, overall survival (OS)] in women with early breast cancer. The hazard ratios (HR) for DFS and OS were weighted and pooled in a meta-analysis using generic inverse variance and random effects modeling.ResultsFifty-three studies comprising 21,418 women were included. EGFR-overexpression was found in 27% of the patients. Primary analysis included studies reporting HRs from multivariable analyses (10 studies including 4,857 patients with HRs for OS and 17 studies comprising 8,747 patients with HRs for DFS), EGFR-overexpression was associated with worse OS (HR 1.98, 95% CI: 1.59-2.47, p<0.001) and DFS (HR 1.59, 95% CI 1.30–1.95, p<0.001). The influence of EGFR overexpression on DFS was greater in women with triple negative tumors compared to women with non-triple negative tumors (HR 2.35 versus HR 1.45, respectively; p= 0.01). Analysis looking at odd ratios for both 5-year and 10-year for DFS and OS showed similar results.ConclusionEGFR-overexpression appears to be associated with reduced OS and DFS in women with early breast cancer. Patients with triple negative and EGFR-overexpression have poorer OS and DFS than those with triple negative tumors and normal EGFR expression.



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Trait Anxiety and Probabilistic Learning: Behavioral and Electrophysiological Findings

Publication date: Available online 31 October 2017
Source:Biological Psychology
Author(s): Donghong Jiang, Dandan Zhang, Yuming Chen, Zhenhong He, Qiufeng Gao, Ruolei Gu, Pengfei Xu
Anxiety is a negative emotion that affects various aspects of people's daily life. To explain why individuals with high anxiety tend to make suboptimal decisions, we suggest that their learning ability might play an important role. Regarding that anxiety modulates both outcome expectation and attention allocation, it is reasonable to hypothesize that the function of feedback learning should be sensitive to individual level of anxiety. However, previous studies that directly examined this hypothesis were scarce. In this study, forty-two Chinese participants were assigned to a high-trait anxiety (HTA) group or a low-trait anxiety (LTA) group according to their scores in the Trait form of Spielberger's State-Trait Anxiety Inventory (STAI-T). Both groups finished a reward learning task in which two options were associated with different winning probabilities. The event-related potential (ERP) elicited by outcome feedback during the task was recorded and analyzed. Behavioral results revealed that, when the winning probability was 80% for one option and 20% for another, the HTA group chose the 80% winning option less often than the LTA group at the initial stage (i.e., first 20 trials) of the task, but there was no between-group difference in total number of choice. In addition, HTA participants took more time to make decisions in the 80/20 condition than in the 50/50 condition, but this effect was insignificant in the LTA group. ERP results indicated that anxiety affects learning in two ways. First, compared to their LTA counterparts, HTA participants showed a smaller feedback-related negativity (FRN) in response to negative feedback, indicating the impact of anxiety on outcome expectation. Second, HTA participants showed a larger P3 component in the 80/20 condition than in the 50/50 condition, indicating the impact of anxiety on attention allocation. Accordingly, we suggest that individuals' ability of feedback learning could be negatively modulated by anxiety.



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Emotional eating and instructed food-cue processing in adolescents: An ERP study

Publication date: Available online 31 October 2017
Source:Biological Psychology
Author(s): Jia Wu, Cynthia J. Willner, Claire Hill, Pasco Fearon, Linda C. Mayes, Michael J. Crowley
We examined the P3 (250 to 500ms) and Late Positive Potential (LPP; 500 to 2000ms) event-related potentials (ERPs) to food vs. nonfood cues among adolescents reporting on emotional eating (EE) behavior. Eighty-six adolescents 10-17 years old were tested using an instructed food versus nonfood cue viewing task (imagine food taste) during high-density EEG recording. Self-report data showed that EE increased with age in girls, but not in boys. Both P3 and LPP amplitudes were greater for food vs. nonfood cues (food-cue bias). Exploratory analyses revealed that, during the LPP time period, greater EE was associated with a more positive food-cue bias in the fronto-central region. This heightened fronto-central food-cue bias LPP is in line with a more activated prefrontal attention system. The results suggest that adolescents with higher EE may engage more top-down cognitive resources to regulate their automatic emotional response to food cues, and/or they may exhibit greater reward network activation to food cues than do adolescents with lower EE, even in the absence of an emotional mood induction.



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Bevacizumab in Breast Cancer: A Targeted Therapy Still in Search of a Target Population

Publication date: Available online 31 October 2017
Source:Seminars in Oncology
Author(s): Douglas K. Marks, Kevin Kalinsky




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Intra-vermis H4 receptor agonist impairs performance in anxiety- and fear-mediated models

Publication date: Available online 31 October 2017
Source:Brain Research Bulletin
Author(s): C.E.M. Fernandes, K.R. Serafim, A.C.L. Gianlorenco, R. Mattioli
The neural histaminergic system modulates cognitive performance in various animal models. However, little is known about the effects of the H4 histaminergic receptor in the central nervous system. The purpose of this study was to investigate the effect of histaminergic H4 agonist VUF-8430 microinjection into the cerebellar vermis on the consolidation of emotional memory in mice subjected to the elevated plus maze (EPM) and inhibitory avoidance task (IAT). All experiments were performed on two consecutive days: exposure (T1 and D1) and 24h after, which we called re-exposure (T2 and D2). The animals received saline (SAL) or VUF (0.15 nmol; 0.49 nmol; 1.48 nmol/0.1μl) administered post-exposure. Experiment 1 was conducted in the EPM, and the animals were free to explore the maze for 5min. In T1, immediately after exposure, the pharmacological treatment was given; in T2, there was only re-exposure to the EPM. Experiment 2 involved the IAT, and the pharmacological treatment was provided post-D1; in D2, the animals were only re-exposed to the IAT. In Experiment 1, increased open arm exploration (% open arm entries and % open arms time) for 0.49 and 1.48nmol of VUF were recorded in T2 compared to T1. In Experiment 2, a significant decrease in consolidation latency was recorded for the group that received 1.48nmol of VUF compared to the SAL group in D2. These results indicate that a 1.48nmol VUF microinjection into the cerebellar vermis impaired performance in both models, even though one model was anxiety-mediated (EPM) and the other was fear-mediated (IAT).



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An exploration of sarcasm detection in children with attention hyperactivity deficit disorder

Publication date: November–December 2017
Source:Journal of Communication Disorders, Volume 70
Author(s): Amanda K. Ludlow, Eleanor Chadwick, Alice Morey, Rebecca Edwards, Roberto Gutierrez
The present research explored the ability of children with ADHD to distinguish between sarcasm and sincerity. Twenty-two children with a clinical diagnosis of ADHD were compared with 22 age and verbal IQ matched typically developing children using the Social Inference–Minimal Test from The Awareness of Social Inference Test (TASIT, McDonald, Flanagan, & Rollins, 2002). This test assesses an individual's ability to interpret naturalistic social interactions containing sincerity, simple sarcasm and paradoxical sarcasm. Children with ADHD demonstrated specific deficits in comprehending paradoxical sarcasm and they performed significantly less accurately than the typically developing children. While there were no significant differences between the children with ADHD and the typically developing children in their ability to comprehend sarcasm based on the speaker's intentions and beliefs, the children with ADHD were found to be significantly less accurate when basing their decision on the feelings of the speaker, but also on what the speaker had said. Results are discussed in light of difficulties in their understanding of complex cues of social interactions, and non-literal language being symptomatic of children with a clinical diagnosis of ADHD. The importance of pragmatic language skills in their ability to detect social and emotional information is highlighted.



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Relationship between frequency spectrum of heart rate variability and autonomic nervous activities during sleep in newborns

Publication date: Available online 31 October 2017
Source:Brain and Development
Author(s): Tsunenori Takatani, Yukihiro Takahashi, Ryota Yoshida, Ryuko Imai, Takao Uchiike, Masaharu Yamazaki, Midori Shima, Toshiya Nishikubo, Yoshito Ikada, Shinichi Fujimoto
IntroductionWe analyzed the frequency spectrum of two neonatal sleep stages, namely active sleep and quiet sleep, and the relationship between these sleep stages and autonomic nervous activity in 74 newborns and 16 adults as a comparison.MethodActive and quiet sleep were differentiated by electroencephalogram (EEG) patterns, eye movements, and respiratory wave patterns; autonomic activity was analyzed using the RR interval of simultaneously recorded electrocardiogram (ECG) signals. Power values (LFa, absolute low frequency; HFa, absolute high frequency), LFa/HFa ratio, and the values of LFn (normalized low frequency) and HFn (normalized high frequency) were obtained. Synchronicity between the power value of HFa and the LFa/HFa ratio during active and quiet sleep was also examined by a new method of chronological demonstration of the power values of HFa and LFa/HFa.ResultsWe found that LFa, HFa and the LFa/HFa ratio during active sleep were significantly higher than those during quiet sleep in newborns; in adults, on the other hand, the LFa/HFa ratio during rapid eye movement (REM) sleep, considered as active sleep, was significantly higher than that during non-REM sleep, considered as quiet sleep, and HFa values during REM sleep were significantly lower than those during non-REM sleep. LFn during quiet sleep in newborns was significantly lower than that during active sleep. Conversely, HFn during quiet sleep was significantly higher than that during active sleep. Analysis of the four classes of gestational age groups at birth indicated that autonomic nervous activity in a few preterm newborns did not reach the level seen in full-term newborns. Furthermore, the power value of HFa and the LFa/HFa ratio exhibited reverse synchronicity.ConclusionThese results indicate that the autonomic patterns in active and quiet sleep of newborns are different from those in REM and non-REM sleep of adults and may be develop to the autonomic patterns in adults, and that parasympathetic activity is dominant during quiet sleep as compared to active sleep from the results of LFn and HFn in newborns. In addition, in some preterm infants, delayed development of the autonomic nervous system can be determined by classifying the autonomic nervous activity pattern of sleep stages.



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Essential role of radiation therapy for the treatment of pancreatic cancer

Abstract

Background

Pancreatic cancer is one of the most aggressive human tumors and the incidence has increased over the last 6 years. In the majority of cases the disease is already in an advanced stage at the time of diagnosis where surgery, the only curative treatment, is no longer an option and explains the still abysmal overall survival. The role of radiation therapy as treatment option for patients with pancreatic cancer is controversially discussed although radiation oncology has emerged as a central pillar in the combined oncological treatment.

Purpose

The present manuscript gives an overview of advanced radiotherapeutic strategies in the context of chemotherapy and surgery according to the current American Society of Clinical Oncology (ASCO) guidelines in comparison with the German guidelines and to elucidate the role of radiation therapy for the treatment of pancreatic cancer.

Conclusion

Advanced modern radiotherapeutic techniques in combination with individualized high-precision radiation concepts are new therapeutic approaches for pancreatic cancer in a multimodal setting with tolerable side effects. Several clinical studies together with experimental approaches are in process, to deliver further evidence and ultimately allow true personalized medicine.

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Recurrent allograft C3 glomerulonephritis and unsuccessful eculizumab treatment

Publication date: Available online 31 October 2017
Source:Clinical Immunology
Author(s): Kati Kaartinen, Leena Martola, Anne Räisänen-Sokolowski, Seppo Meri
There is a great lack of efficient treatments for membranoproliferative glomerulonephritis (MPGN) and recently emerged complement therapies have been proposed to be useful. We report a patient with a complement-mediated MPGN having recurrencies in kidney allografts and an unsuccessful treatment with complement inhibitor, eculizumab (anti-C5 monoclonal antibody). Nephritic factor (C3Nef), an autoantibody against C3bBb, in the patient serum activated C3 but not C5 showing that major damage was mediated by C3 activation with clearly less involvement of C5 explaining unresponsiveness to eculizumab. Analyzing C3Nef-mediated C3 and C5 activation separately could help in choosing the right patients for eculizumab therapy.



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Editorial Board

Publication date: October 2017
Source:Clinical Immunology, Volume 183





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Publication date: Available online 1 November 2017 Source:American Journal of Infection Control ...

Publication date: Available online 1 November 2017
Source:American Journal of Infection Control
Author(s): Nicolette Dixon, Margie Morgan, Ozlem Equils, Ozlem Equils




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Scholar : These new articles for Atmospheric and Oceanic Science Letters are available online

The online platform for Taylor & Francis Online content New for Atmospheric and Oceanic Science Letters and online now on Taylor & Francis Online: Original Articles Amplified winter Arctic tropospheric warming and its link to atmospheric circulation changes | Xian-Ting HUANG, Yi-Na DIAO & De-Hai LUO Pages: 1-11 | DOI: 10.1080/16742834.2017.1394159 Reviews A generic methodological framework for accurately quantifying greenhouse gas footprints of crop cultivation systems | Xunhua ZHENG & Shenghui HAN Pages: 1-14 | DOI: 10.1080/16742834.2018.1393309 Hoping to have your article read by anyone, anywhere and at any time? Find out more about publishing open access with Ecosystem Health and Sustainability. To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Scholar : These new articles for Corrections are available online

The online platform for Taylor & Francis Online content New for Corrections and online now on Taylor & Francis Online: Original Articles After Release: A Qualitative Investigation into the Financial Lives of Previously Incarcerated Individuals Katherine Mielitz, Meghaan Lurtz, Joy Clady & Kristy Archuleta Pages: 1-16 | DOI: 10.1080/23774657.2017.1383215 Systems Thinking, System Justification, and the Death Penalty: Thirty-Eight Years of Capital Punishment Legislation in Texas Alexander H Updegrove & Dennis R Longmire Pages: 1-18 | DOI: 10.1080/23774657.2017.1382401 Images of God, Religious Involvement, and Prison Misconduct among Inmates Sung Joon Jang, Byron R Johnson, Joshua Hays, Grant Duwe & Michael Hallett Pages: 1-21 | DOI: 10.1080/23774657.2017.1384707 To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Outdoor Life During Summer in Russia: Varicose Veins Don't Stand a Chance!

Publication date: Available online 31 October 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Marie Josee E. van Rijn, Catherine van Montfrans




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Commentary on “Determinants of Acute Kidney Injury and Renal Function Decline after Endovascular Abdominal Aortic Aneurysm Repair”

Publication date: Available online 31 October 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Stavros K. Kakkos, Evangelos C. Papachristou




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Association Between Diverticular Disease and Abdominal Aortic Aneurysms: Pooled Analysis of Two Population Based Screening Cohorts

Publication date: Available online 31 October 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Anders Mark-Christensen, Jes Sanddal Lindholt, Axel Diederichsen, Flemming Hald Steffensen, Martin Busk, Lars Frost, Grazina Urbonaviciene, Jess Lambrechtsen, Kenneth Egstrup, Søren Laurberg
BackgroundThe aetiology of abdominal aortic aneurysms (AAA) is multifactorial, and many risk factors are shared with diverticular disease. It is unknown whether an independent association exists between these conditions.MethodsIndividuals enrolled in two Danish population based randomised AAA screening trials and assigned to cross sectional screening and evaluation of cardiovascular risk factors were identified. Diagnoses of diverticular disease were interrogated from a national patient registry covering the period from 1977 to the screening date. Adjusted odds ratios (aOR) and hazard ratios (aHR) with 95% CI were calculated as risk measures.Results24,632 individuals (median age, 69 years) were included. At screening, 687 patients had pre-existing diverticular disease. Patients with diverticular disease were more likely to have AAA at screening compared with those without diverticular disease (5.2% vs. 3.3%) (OR 1.61, 95% CI 1.14–2.27). This association persisted after adjusting for potential confounders (aOR 1.49, 95% CI 1.04–2.12) and on sensitivity analyses. The association was most pronounced for those with a diagnosis of diverticular disease for at least 10 years (aOR 2.56, 95% CI 1.49–4.38). Following screening, 6.2% of patients with diverticular disease and AAA experienced aneurysm rupture, compared with 2.2% of patients with AAA without diverticular disease (aHR 4.1, 95% CI 1.6–10.8).ConclusionAn association was found between diverticular disease and AAA in a large population based cohort. Biological causality remains to be established, and a potential impact of diverticular disease on the natural history of AAA needs to be explored further.



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Impact of radiotherapy modalities on outcomes in the adjuvant management of uterine carcinosarcoma: A National Cancer Database analysis

Publication date: Available online 31 October 2017
Source:Brachytherapy
Author(s): William A. Stokes, Bernard L. Jones, Tracey E. Schefter, Christine M. Fisher
PurposeIn the postoperative management of uterine carcinosarcoma (UCS), the roles of individual radiotherapy (RT) modalities, chiefly external-beam radiotherapy (EBRT) and brachytherapy (BT), remain undefined. We analyzed the survival impact of EBRT and BT using the National Cancer Database.Methods and materialsWe abstracted women diagnosed with UCS from 2004 to 2012 who received hysterectomy and had complete RT information. Cox multivariate analysis and propensity-score matched analyses were used to compare survival among radiotherapeutic approaches.ResultsWe identified 1229 women receiving no radiotherapy, 472 receiving EBRT alone, 331 receiving BT alone, and 271 receiving EBRT+BT. On multivariate analysis of the entire analytic cohort, survival was significantly improved among patients receiving EBRT+BT combination (hazard ratio [HR] 0.72, 95% confidence interval [CI] = 0.58–0.89, p < 0.01), but not among those receiving EBRT alone (HR 0.93, 95% CI = 0.79–1.10, p = 0.41) or BT alone (HR 0.84, 95% CI = 0.68–1.03, p = 0.09). These results were confirmed on propensity-score matches for EBRT vs. no RT (HR 0.89, 95% CI = 0.73–1.07, p = 0.34), BT vs. no RT (HR 0.80, 95% CI = 0.63–1.03, p = 0.09), and EBRT+BT vs. no RT (HR 0.74, 95% CI = 0.58–0.96, p = 0.02).ConclusionsEBRT+BT combination is associated with an overall survival advantage in UCS and warrants consideration in the adjuvant management of this disease.



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