Intracerebral injection of CpG oligonucleotide for patients with de novo glioblastoma—A phase II multicentric, randomised study

Publication date: March 2017
Source:European Journal of Cancer, Volume 73
Author(s): Renata Ursu, Alexandre Carpentier, Philippe Metellus, Vincent Lubrano, Florence Laigle-Donadey, Laurent Capelle, Jacques Guyotat, Olivier Langlois, Luc Bauchet, Kristell Desseaux, Annick Tibi, Olivier Chinot, Jérôme Lambert, Antoine F. Carpentier
BackgroundImmunostimulating oligodeoxynucleotides containing unmethylated cytosine-guanosine motifs (CpG-ODN) have shown a promising efficacy in several cancer models when injected locally. A previous phase II study of CpG-ODN in patients with recurrent glioblastoma (GBM) has suggested some activity and has shown a limited toxicity. This multicentre single-blinded randomised phase II trial was designed to study the efficacy of a local treatment by CpG-ODN in patients with de novo glioblastomas.Patients and methodsPatients with a newly diagnosed glioblastoma underwent large surgical resection and CpG-ODN was randomly administrated locally around the surgical cavity. The patients were then treated according to standard of care (SOC) with radiotherapy and temozolomide. The primary objective was 2-year survival. Secondary outcomes were progression free survival (PFS), and tolerance.ResultsEighty-one (81) patients were randomly assigned to receive CpG-ODN plus SOC (39 patients) or SOC (42 patients). The 2-year overall survival was 31% (19%; 49%) in the CpG-ODN arm and 26% (16%; 44%) in the SOC arm. The median PFS was 9 months in the CpG-ODN arm and 8.5 months in the SOC arm. The incidence of adverse events was similar in both arms; although fever and post-operative haematoma were more frequent in the CpG-ODN arm.ConclusionsLocal immunotherapy with CpG-ODN injected into the surgical cavity after tumour removal and followed by SOC, although well tolerated, does not improve survival of patients with newly diagnosed GBM.



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Anti-müllerian hormone levels and evolution in women of reproductive age with breast cancer treated with chemotherapy

Publication date: March 2017
Source:European Journal of Cancer, Volume 74
Author(s): T. Fréour, P. Barrière, D. Masson
BackgroundLong-term consequences of cancer treatments in young women, and especially fertility issues, are gaining attention as survival rates increase. Breast cancer is the most frequent malignancy in women of reproductive age.AimThe purpose of this review is to describe serum anti-müllerian hormone (AMH) level at diagnosis and its evolution during and after chemotherapy in women of reproductive age treated for breast cancer. Second, the impact of taxanes on AMH, the association between AMH and amenorrhea, and the comparison of AMH with other hormonal markers of ovarian reserve were studied.MethodsA systematic PubMed search was conducted on all articles, published up to April 2016 and related to AMH in women suffering from breast cancer using the following key words: AMH, müllerian-inhibiting substance, ovarian reserve, ovarian function, breast cancer, gonadotoxicity, ovarian toxicity, amenorrhea, chemotherapy, and menopause.ResultsAMH levels rapidly fall down to undetectable levels in most women during chemotherapy and generally persist at very low levels in most women after the treatment. Taxanes seem to impact negatively ovarian function, but data on ovarian reserve are scarce. AMH is a predictor of the occurrence of chemotherapy-related amenorrhea and is the most relevant hormonal marker of ovarian reserve.ConclusionSerum AMH is a relevant tool for ovarian reserve assessment and follow-up during treatment in premenopausal women with breast cancer. Further large prospective studies are necessary to determine its predictive interest for post-treatment residual fertility, and eventually use it in fertility preservation counseling before treatment initiation.



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Segmental Latissimus Dorsi Free Flap Attempting to Preserve Function at the Donor Site: Anatomical and Clinical Experiences

J reconstr Microsurg
DOI: 10.1055/s-0036-1597835

Background The purpose of the present study was to evaluate arm and shoulder function prospectively after transfer of the lateral segment of the latissimus dorsi (LD) muscle. Methods In this study, 20 specimens of LD muscles from 10 cadavers were dissected to determine the relationship between the artery and the nerve. Twenty patients were recruited and functional disability was determined by the Disabilities of Arm, Shoulder, and Hand (DASH), and muscle strength by needle electromyography (EMG) before surgery and at five different time points postoperatively. Results Two specimens (10%) had no medial branch arising from the thoracodorsal artery. The pedicle length of the lateral branch was longer than that of the medial branch (mean 10.41 vs. 9.27 cm, p = 0.03). All DASH scores and EMG amplitudes at half a month postoperative decreased compared with those preoperatively, with no significant difference at 3 months postoperative. Conclusion Lateral segmental LD muscle transfer, leaving the residual segment motor function intact, can be recommended as an alternative for moderate and small-size bone exposure wounds, especially in the lower extremities, that minimizes loss of donor-site function.
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Different mechanisms in learning different second languages: Evidence from English speakers learning Chinese and Spanish

Publication date: 1 March 2017
Source:NeuroImage, Volume 148
Author(s): Fan Cao, Bethany L. Sussman, Valeria Rios, Xin Yan, Zhao Wang, Gregory J. Spray, Ryan M. Mack
Word reading has been found to be associated with different neural networks in different languages, with greater involvement of the lexical pathway for opaque languages and greater invovlement of the sub-lexical pathway for transparent langauges. However, we do not know whether this language divergence can be demonstrated in second langauge learners, how learner's metalinguistic ability would modulate the langauge divergence, or whether learning method would interact with the language divergence. In this study, we attempted to answer these questions by comparing brain activations of Chinese and Spanish word reading in native English-speaking adults who learned Chinese and Spanish over a 2 week period under three learning conditions: phonological, handwriting, and passive viewing. We found that mapping orthography to phonology in Chinese had greater activation in the left inferior frontal gyrus (IFG) and left inferior temporal gyrus (ITG) than in Spanish, suggesting greater invovlement of the lexical pathway in opaque langauges. In contrast, Spanish words evoked greater activation in the left superior temporal gyrus (STG) than English, suggesting greater invovlement of the sublexical pathway for transparant languages. Furthermore, brain-behavior correlation analyses found that higher phonological awareness and rapid naming were associated with greater activation in the bilateral IFG for Chinese and in the bilateral STG for Spanish, suggesting greater language divergence in participants with higher meta-linguistic awareness. Finally, a significant interaction between the language and learning condition was found in the left STG and middle frontal gyrus (MFG), with greater activation in handwriting learning than viewing learning in the left STG only for Spanish, and greater activation in handwriting learning than phonological learning in the left MFG only for Chinese. These findings suggest that handwriting facilitates assembled phonology in Spanish and addressed phonology in Chinese. In summary, our study suggests different mechanisms in learning different L2s, providing important insights into neural plasticity and important implications in second language education.



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In Memoriam: Peter H. Berman, M.D. December 29, 1931 - September 1, 2016

Publication date: Available online 28 January 2017
Source:Pediatric Neurology
Author(s): Barry S. Russman, Gihan Tennekoon, Don Younkin




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In memoriam: Bruce O. Berg, M.D. January 2, 1931 - October 5, 2016

Publication date: Available online 28 January 2017
Source:Pediatric Neurology
Author(s): Kenneth F. Swaiman, Donna Ferriero




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ERCC1 polymorphisms and oxaliplatin. A review of the literature and a monocentric experience in the absence of a ‘sliding doors’ trial

Publication date: Available online 28 January 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): V. Formica, E. Doldo, F.R. Antonetti, A. Nardecchia, P. Ferroni, S. Riondino, C. Morelli, H.T. Arkenau, F. Guadagni, A. Orlandi, M. Roselli
Excision repair cross-complementation group 1 (ERCC1) is a key component in DNA repair mechanisms and may influence the tumor DNA-targeting effect of the chemotherapeutic agent oxaliplatin. Germline ERCC1 polymorphisms may alter the protein expression and published data on their predictive and prognostic value have so far been contradictory. In the present article we review available evidence on the clinical role and utility of ERCC1 polymorphisms and, in the absence of a 'perfect' trial, what we call the 'sliding doors' trial, we present the data of ERCC1 genotyping in our local patient population finding a useful predictive value for oxaliplatin-induced risk of anemia.



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Targeting HIF-2 α in clear cell renal cell carcinoma: A promising therapeutic strategy

Publication date: Available online 28 January 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Olga Martínez-Sáez, Pablo Gajate Borau, Teresa Alonso-Gordoa, Javier Molina-Cerrillo, Enrique Grande
The loss of the Von Hippel-Lindau tumor suppressor (VHL) is a key oncogenic event in the vast majority of patients with clear cell renal cell carcinoma (ccRCC). With the loss of the VHL protein (pVHL) function, the hypoxia inducible factor α (HIF-α) accumulates inside the tumor cell and dimerizes with HIF-β. The HIF-α/HIF-β complex transcriptionally activates hundreds of genes promoting the adaptation to hypoxia that is implicated in tumor development. There is growing evidence showing that HIF-2α subunit has a central role in ccRCC over HIF-1α. Thus, efforts have been made to specifically target this pathway. PT2385 and PT2399 are first-in-class, orally available, small molecule inhibitors of HIF-2 that selectively disrupt the heterodimerization of HIF-2α with HIF-1β. Preclinical and clinical data indicate that these new molecules are effective in blocking cancer cell growth, proliferation, and tumor angiogenesis characteristic in ccRCC.Treatment with HIF-2α specific antagonists, either alone or in combination with immunotherapy or other antiangiogenic agents have the potential to transform the therapeutic landscape in this tumor in the future. Herein, we summarize the molecular background behind the use of HIF-2α inhibitors in ccRCC and give an overview of the development of new agents in this setting.



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Early disturbances in multimodal evoked potentials as a prognostic factor for long-term disability in relapsing-remitting multiple sclerosis patients

Publication date: Available online 28 January 2017
Source:Clinical Neurophysiology
Author(s): Frédéric London, Souraya El Sankari, Vincent van Pesch
ObjectiveThe aim of this study was to investigate whether early alterations in evoked potentials (EP) have a prognostic value in relapsing-remitting multiple sclerosis (RRMS).MethodsWe retrospectively selected 108 early MS patients with a neurological follow-up ranging from 5 to 15 years, in whom multimodal EPs (visual, brainstem auditory, somatosensory and motor) were performed at diagnosis. A conventional ordinal score was used to quantify the observed abnormalities.ResultsThe extent of change in the composite EP score was well correlated to the Expanded Disability Status Scale (EDSS) at ten years (Y10) and up to 15 years (Y11-15) after disease onset. Analysis of the predictive value of the EP score showed an increased risk of disability progression at Y10 and Y11-15 of 60% (p < 0.0001) and 73% (p < 0.0001) respectively in patients with an EP score >4. Conversely, the risk of disability progression at Y10 and Y11-15 associated with a lower EP score (⩽ 4) was reduced to 16% and 20% respectively.ConclusionsOur data support the good predictive value for long-term disability progression of multimodal EPs performed early after disease onset in RRMS patients.SignificanceThis study, performed in a homogeneous RRMS cohort with long term follow-up, demonstrates the value of an early comprehensive neurophysiological assessment as a marker for future disability.



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When EEG is bad for you

Publication date: Available online 28 January 2017
Source:Clinical Neurophysiology
Author(s): Selim R. Benbadis, Pierre Thomas




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Subthalamic or Red Nucleus? A puzzling question arising during intraoperative recording for DBS

Publication date: Available online 28 January 2017
Source:Clinical Neurophysiology
Author(s): A. Merola, G. Mandybur, K. Biddell, T.K. Tareen, H. Wilson-Perez, A.J. Espay, A.P. Duker




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Targeting HIF-2 α in clear cell renal cell carcinoma: A promising therapeutic strategy

Publication date: Available online 28 January 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Olga Martínez-Sáez, Pablo Gajate Borau, Teresa Alonso-Gordoa, Javier Molina-Cerrillo, Enrique Grande
The loss of the Von Hippel-Lindau tumor suppressor (VHL) is a key oncogenic event in the vast majority of patients with clear cell renal cell carcinoma (ccRCC). With the loss of the VHL protein (pVHL) function, the hypoxia inducible factor α (HIF-α) accumulates inside the tumor cell and dimerizes with HIF-β. The HIF-α/HIF-β complex transcriptionally activates hundreds of genes promoting the adaptation to hypoxia that is implicated in tumor development. There is growing evidence showing that HIF-2α subunit has a central role in ccRCC over HIF-1α. Thus, efforts have been made to specifically target this pathway. PT2385 and PT2399 are first-in-class, orally available, small molecule inhibitors of HIF-2 that selectively disrupt the heterodimerization of HIF-2α with HIF-1β. Preclinical and clinical data indicate that these new molecules are effective in blocking cancer cell growth, proliferation, and tumor angiogenesis characteristic in ccRCC.Treatment with HIF-2α specific antagonists, either alone or in combination with immunotherapy or other antiangiogenic agents have the potential to transform the therapeutic landscape in this tumor in the future. Herein, we summarize the molecular background behind the use of HIF-2α inhibitors in ccRCC and give an overview of the development of new agents in this setting.



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Editorial Board Members

Publication date: 1 January 2017
Source:Advanced Drug Delivery Reviews, Volume 108





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Editorial: Editors’ Collection 2016

Publication date: 1 January 2017
Source:Advanced Drug Delivery Reviews, Volume 108
Author(s): Hamidreza Ghandehari




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Challenges and strategies in anti-cancer nanomedicine development: An industry perspective

Publication date: 1 January 2017
Source:Advanced Drug Delivery Reviews, Volume 108
Author(s): Jennifer I. Hare, Twan Lammers, Marianne B. Ashford, Sanyogitta Puri, Gert Storm, Simon T. Barry
Successfully translating anti-cancer nanomedicines from pre-clinical proof of concept to demonstration of therapeutic value in the clinic is challenging. Having made significant advances with drug delivery technologies, we must learn from other areas of oncology drug development, where patient stratification and target-driven design have improved patient outcomes. We should evolve our nanomedicine development strategies to build the patient and disease into the line of sight from the outset. The success of small molecule targeted therapies has been significantly improved by employing a specific decision-making framework, such as AstraZeneca's 5R principle: right target/efficacy, right tissue/exposure, right safety, right patient, and right commercial potential. With appropriate investment and collaboration to generate a platform of evidence supporting the end clinical application, a similar framework can be established for enhancing nanomedicine translation and performance. Building informative data packages to answer these questions requires the following: (I) an improved understanding of the heterogeneity of clinical cancers and of the biological factors influencing the behaviour of nanomedicines in patient tumours; (II) a transition from formulation-driven research to disease-driven development; (III) the implementation of more relevant animal models and testing protocols; and (IV) the pre-selection of the patients most likely to respond to nanomedicine therapies. These challenges must be overcome to improve (the cost-effectiveness of) nanomedicine development and translation, and they are key to establishing superior therapies for patients.

Graphical abstract

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Investigation of Asymmetric and Symmetric Dimethylarginine Levels after Iloprost Treatment in Patients with Buerger's Disease

Publication date: Available online 28 January 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): S. Senol, A. Senol
ObjectiveThe aim of this study was to compare the levels of acetyl-dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and the l-arginine/ADMA ratio before and after iloprost treatment in patients with Buerger's disease.MethodsBetween January 2011 and December 2015, data from 44 patients (36 males, 8 females, mean age 48.7 ± 18.1 years) with the diagnosis of Fontaine Stage III–IV Buerger's disease were included. Iloprost infusion was administered intravenously through the forearm veins for 7 days at a dose of 0.5–1.5 ng/kg/min over 16 h. Blood samples were collected before and after treatment for measurement of ADMA, SDMA, and l-arginine. ADMA, SDMA, l-arginine levels were measured using high performance liquid chromatography (HPLC).ResultsAfter iloprost treatment, ADMA and SDMA levels significantly decreased (p = .001). The increase in the l-arginine levels was not significant (p = .16). However, the l-arginine/ADMA ratio increased significantly (p = .001).ConclusionIloprost treatment decreases ADMA and SDMA, which are associated with endothelial dysfunctions in patients with Buerger's disease. Of note, the still higher than normal range of SDMA levels after iloprost treatment suggests that treatment should continue until SDMA levels are within the normal range in this patient population.



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Formulating a poorly water soluble drug into an oral solution suitable for paediatric patients; lorazepam as a model drug

Publication date: 30 March 2017
Source:European Journal of Pharmaceutical Sciences, Volume 100
Author(s): A.C. van der Vossen, I. van der Velde, O.S.N.M. Smeets, D.J. Postma, M. Eckhardt, A. Vermes, B.C.P. Koch, A.G. Vulto, L.M. Hanff
IntroductionMany drugs are unavailable in suitable oral paediatric dosage forms, and pharmacists often have to compound drugs to provide paediatric patients with an acceptable formulation in the right dose. Liquid formulations offer the advantage of dosing flexibility and ease of administration to young patients, but drug substances often show poor aqueous solubility. The objective of this work was to study different solvents and matrices to design a liquid formulation for poorly water soluble drugs, using lorazepam as model drug.MethodsThree different formulation strategies were explored to improve the solubility. Firstly, water-soluble organic solvents were used to improve the aqueous solubility directly, secondly, ionic surfactants were used to solubilise the model drug, and thirdly, complexation of lorazepam with cyclodextrin was studied. Specific attention was paid to excipients, adequate taste correction and palatability. For the final formulation, physical and chemical stability and microbiological quality were assessed for 12months.ResultsAn organic solvent based formulation, containing a mixture of polyethylene glycol and glycerol 85%, with a minimum amount of propylene glycol, proved to be physically and chemically stable. Development of the non-ionic surfactants formulation was discontinued due to taste problems. The cyclodextrin formulations were physically stable, but lorazepam content declined to 90% within five months. The final formulation contained in volume concentration (%v/v) 87% glycerol, 10% polyethylene glycol 400 and 3% propylene glycol. Orange essence was the preferred taste corrector. The formulation remained stable for 12months at 4°C, with lorazepam content remaining >95%. Related substances increased during the study period but remained below 2%. In-use stability was proven up to 4weeks.ConclusionAn organic solvent based oral formulation was shown to be superior to a non-ionic surfactant based formulation or a cyclodextrin formulation. These results may help to formulate paediatric formulations of other poorly water soluble drugs, to aid pharmacy compounding.

Graphical abstract

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American Thyroid Association (ATA) is looking for patients with hypothyroidism taking hormone treatment to complete survey

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The post American Thyroid Association (ATA) is looking for patients with hypothyroidism taking hormone treatment to complete survey appeared first on American Thyroid Association.

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Epigallocatechin gallate induces a hepatospecific decrease in the CYP3A expression level by altering intestinal flora

Publication date: 30 March 2017
Source:European Journal of Pharmaceutical Sciences, Volume 100
Author(s): Nobutomo Ikarashi, Sosuke Ogawa, Ryuta Hirobe, Risako Kon, Yoshiki Kusunoki, Marin Yamashita, Nanaho Mizukami, Miho Kaneko, Nobuyuki Wakui, Yoshiaki Machida, Kiyoshi Sugiyama
In previous studies, we showed that a high-dose intake of green tea polyphenol (GP) induced a hepatospecific decrease in the expression and activity of the drug-metabolizing enzyme cytochrome P450 3A (CYP3A). In this study, we examined whether this decrease in CYP3A expression is induced by epigallocatechin gallate (EGCG), which is the main component of GP. After a diet containing 1.5% EGCG was given to mice, the hepatic CYP3A expression was measured. The level of intestinal bacteria of Clostridium spp., the concentration of lithocholic acid (LCA) in the feces, and the level of the translocation of pregnane X receptor (PXR) to the nucleus in the liver were examined. A decrease in the CYP3A expression level was observed beginning on the second day of the treatment with EGCG. The level of translocation of PXR to the nucleus was significantly lower in the EGCG group. The fecal level of LCA was clearly decreased by the EGCG treatment. The level of intestinal bacteria of Clostridium spp. was also decreased by the EGCG treatment. It is clear that the hepatospecific decrease in the CYP3A expression level observed after a high-dose intake of GP was caused by EGCG. Because EGCG, which is not absorbed from the intestine, causes a decrease in the level of LCA-producing bacteria in the colon, the level of LCA in the liver decreases, resulting in a decrease in the nuclear translocation of PXR, which in turn leads to the observed decrease in the expression level of CYP3A.

Graphical abstract

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Endocrine Pathology Society Hubert Wolfe Award for 2016: Call for Nominations

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Targeting HIF-2 α in clear cell renal cell carcinoma: A promising therapeutic strategy

Publication date: Available online 28 January 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Olga Martínez-Sáez, Pablo Gajate Borau, Teresa Alonso-Gordoa, Javier Molina-Cerrillo, Enrique Grande
The loss of the Von Hippel-Lindau tumor suppressor (VHL) is a key oncogenic event in the vast majority of patients with clear cell renal cell carcinoma (ccRCC). With the loss of the VHL protein (pVHL) function, the hypoxia inducible factor α (HIF-α) accumulates inside the tumor cell and dimerizes with HIF-β. The HIF-α/HIF-β complex transcriptionally activates hundreds of genes promoting the adaptation to hypoxia that is implicated in tumor development. There is growing evidence showing that HIF-2α subunit has a central role in ccRCC over HIF-1α. Thus, efforts have been made to specifically target this pathway. PT2385 and PT2399 are first-in-class, orally available, small molecule inhibitors of HIF-2 that selectively disrupt the heterodimerization of HIF-2α with HIF-1β. Preclinical and clinical data indicate that these new molecules are effective in blocking cancer cell growth, proliferation, and tumor angiogenesis characteristic in ccRCC.Treatment with HIF-2α specific antagonists, either alone or in combination with immunotherapy or other antiangiogenic agents have the potential to transform the therapeutic landscape in this tumor in the future. Herein, we summarize the molecular background behind the use of HIF-2α inhibitors in ccRCC and give an overview of the development of new agents in this setting.



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Instructions to Authors

Publication date: February 2017
Source:The Kaohsiung Journal of Medical Sciences, Volume 33, Issue 2





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Source:The Kaohsiung Journal of Medical Sciences, Volume 33, Issue 2





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Source:The Kaohsiung Journal of Medical Sciences, Volume 33, Issue 2





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Publication date: February 2017
Source:The Kaohsiung Journal of Medical Sciences, Volume 33, Issue 2





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Publication date: February 2017
Source:The Kaohsiung Journal of Medical Sciences, Volume 33, Issue 2





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A Deep Learning Approach for the Analysis of Masses in Mammograms with Minimal User Intervention

Publication date: Available online 28 January 2017
Source:Medical Image Analysis
Author(s): Neeraj Dhungel, Gustavo Carneiro, Andrew P. Bradley
We present an integrated methodology for detecting, segmenting and classifying breast masses from mammograms with minimal user intervention. This is a long standing problem due to low signal-to-noise ratio in the visualisation of breast masses, combined with their large variability in terms of shape, size, appearance and location. We break the problem down into three stages: mass detection, mass segmentation, and mass classification. For the detection, we propose a cascade of deep learning methods to select hypotheses that are refined based on Bayesian optimisation. For the segmentation, we propose the use of deep structured output learning that is subsequently refined by a level set method. Finally, for the classification, we propose the use of a deep learning classifier, which is pre-trained with a regression to hand-crafted feature values and fine-tuned based on the annotations of the breast mass classification dataset. We test our proposed system on the publicly available INbreast dataset and compare the results with the current state-of-the-art methodologies. This evaluation shows that our system detects 90% of masses at 1 false positive per image, has a segmentation accuracy of around 0.85 (Dice index) on the correctly detected masses, and overall classifies masses as malignant or benign with sensitivity (Se) of 0.98 and specificity (Sp) of 0.7.

Graphical abstract

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Systemic sclerosis and exposure to heavy metals: A case control study of 100 patients and 300 controls

Publication date: Available online 27 January 2017
Source:Autoimmunity Reviews
Author(s): I. Marie, J-F. Gehanno, M. Bubenheim, A-B. Duval-Modeste, P. Joly, S. Dominique, P. Bravard, D. Noël, A-F. Cailleux, J. Weber, P. Lagoutte, J. Benichou, H. Levesque, J-P. Goullé
Objective.This case control study assessed: the relationship of systemic sclerosis (SSc) related to exposure to heavy metals, the risk of SSc related to occupational exposure in male and female patients.MethodsFrom 2005 to 2008, 100 patients with a definite diagnosis of SSc were included in the study; 3 age, gender, and smoking habits matched controls were selected for each patient. All SSc patients and controls underwent detection and quantification of heavy metal traces in hair samples, using multi-element inductively coupled plasma mass spectrometry (ICP-MS).ResultsSSc patients exhibited higher median levels of the following metals: antimony (p=0.001), cadmium (p=0.0003), lead (p=0.02), mercury (p=0.02), molybdenum (p=0.04), palladium (p<0.001) and zinc (p=0.0003). A marked association between SSc and occupational exposure was further found for: 1) antimony (p=0.008) and platinum (p=0.04) in male patients; and 2) antimony (p=0.02), cadmium (p=0.001), lead (p=0.03), mercury (p=0.03), palladium (p=0.0003) and zinc (p=0.0001) in female patientsConclusionThe results show the impact of occupational risk factors in the development of SSc for: antimony, cadmium, lead, mercury, molybdenum, palladium and zinc. Thus, occupational exposure should be systematically checked in all SSc patients at diagnosis. Finally, the association between SSc and occupational exposure may be variable according to patients" gender.



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Inflammatory eye disease: pre-treatment assessment of patients prior to commencing immunosuppressive and biologic therapy: Recommendations from an expert committee

Publication date: Available online 27 January 2017
Source:Autoimmunity Reviews
Author(s): Denis Wakefield, Peter McCluskey, Gerhild Wildner, Stephan Thurau, Gregory Carr, Soon-Phaik Chee, John Forrester, Andrew Dick, Bernard Hudson, Susan Lightman, Justine Smith, Ilknur Tugal-Tutkun
AimTo outline recommendations from an expert committee on the assessment and investigation of patients with severe inflammatory eye disease commencing immunosuppressive and/or biologic therapy.MethodThe approach to assessment is based on the clinical experience of an expert committee and a review of the literature with regard to corticosteroids, immunosuppressive drug and biologic therapy and other adjunct therapy in the management of patients with severe sight-threatening inflammatory eye disease.ConclusionWe recommend a careful assessment and consultative approach by ophthalmologists or physicians experienced in the use of immunosuppressive agents for all patients commencing immunosuppressive and/or biologic therapy for sight threatening inflammatory eye disease with the aim of preventing infection, cardiovascular, metabolic and bone disease and reducing iatrogenic side effects.



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Gender balance in patients with systemic lupus erythrematosus

Publication date: Available online 27 January 2017
Source:Autoimmunity Reviews
Author(s): Audrey A Margery-Muir, Christine Bundell, Delia Nelson, David M Groth, John D Wetherall
Factors are reviewed that contribute to the contemporary view of a disproportionate prevalence and incidence SLE in females. Recent studies on the epidemiology of SLE report that global Incidences and prevalences of SLE for Caucasian and Black populations are of the order of 5.5 and 13.1 per year and 81 and 212 per 100,000 persons respectively. Both parameters displayed age dependent variation over a 90-year lifespan. The female to male (F:M) incidence of SLE varied with age, being approximately 1 during the first decade of life, followed by a sharp increase to 9 during the 4th decade, thence declining in subsequent decades before an increase during the 7th or 8th decades. A cognate review of SLE diagnosis in neonates revealed a F:M ratio of ≈1.2, consistent with the epidemiology review and the sporadic nature of SLE. Notional estimates of disease duration showed a steady increase from a base level for both males and females. The linear trend line for males was always lower than the trend line for females, supporting clinical experience that SLE is a more severe disease in males. Over a 14-year interval ending in 2012, the notional duration of SLE increased from 10 to 15years to 20–25years, probably reflecting advances in diagnosis and clinical practice.A metastudy of SLE concordance in twins revealed a 75% discordance in monozygotic twins compared to a 95% discordance in dizygotic twins confirming the importance of environmental factors in susceptibility to SLE. The elevated discordance in dizygotic SLE twins (and between siblings) suggests a role for the intrinsic genomic sexual dimorphism due to divergence of Y chromosome regulatory loci from their X chromosome homologues due to lack of recombination of mammalian sex chromosomes over evolutionary time.Estimates were made of the incidences of SLE in males and females based on population data for nine autosomal deficiency loci of major effect, plus expected male prevalence associated with Kleinfelter's syndrome and female prevalence associated with Triple X syndrome. These genetic abnormalities accounted for ≈4% of female and ≈23% of male Caucasoid prevalence and for SLE resulting in a F:M ratio of ≈0.17. It may be deduced therefore that the impressive preponderance of SLE in females arises from a combination of environmental triggers and susceptibility loci of relatively small effect acting between the interval from the mini-puberty of childhood to the peak of reproductive adulthood. It is in this cohort of females, and especially in the black population, that combinations of loci of minor effect acting together with environmental factors initiate defective apoptosis resulting in consequential autoimmune disease especially SLE. We postulate that because apoptosis is itself a very complex process, and defective apoptosis is an important contributor to SLE, there will be many combinations of susceptibility loci and environmental stimuli that can result in SLE (and other autoimmune disease(s)), of varying severity.



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Characterization of isolated retinal vasculitis. Analysis of a cohort from a single center and literature review

Publication date: Available online 27 January 2017
Source:Autoimmunity Reviews
Author(s): Laura Pelegrín, José Hernández-Rodríguez, Gerard Espinosa, Víctor Llorenç, Maite Sainz-de-la-Maza, José R. Fontenla, José A. Martínez, Maria C. Cid, Alfredo Adán
IntroductionIsolated retinal vasculitis (IRV) is an inflammatory condition of unknown etiology confined to the retinal vessels. In contrast to secondary retinal vasculitis (RV), IRV has not been well characterized.ObjectiveTo describe and characterize isolated forms of RV.MethodsWe performed a retrospective review (2006–2016) of IRV patients from a multidisciplinary Uveitis Unit. RV diagnosis was based on funduscopic and fluorescein angiography findings. To distinguish between secondary RV and IRV, evaluations included clinical assessment, laboratory inflammatory, autoimmune and microbiological markers and chest radiography. Ophthalmological features at disease onset, therapeutic interventions, ocular relapses, visual outcomes and laboratory findings were recorded. Our cases were subsequently compared with those from a literature review.ResultsAmong 192 patients with RV, 11 (5.7%) were diagnosed with IRV. Seven patients with initially presumed IRV were reclassified as secondary after further evaluation. IRV generally affected adult women. Bilateral ocular involvement and retinal phlebitis were common findings. 72% of patients presented with visual loss, which was severe in 27%. Treatments used included systemic glucocorticoids (82%), additional immunosuppressive agents (27%), intravitreal therapy (37%), panretinal photocoagulation (37%) and pars plana vitrectomy (26%). The annual relapse rate was 0.46. Although final visual acuity was considered good in 86%, 45% experienced worsening and only 27% improved.ConclusionsIRV is a rare sight-threatening condition. Despite intensive local and systemic immunosuppressive treatment, visual improvement is observed in only 27% of cases. When IRV is suspected, a differential diagnosis excluding a systemic disease is always warranted. A multidisciplinary approach and a guided clinical, laboratory and imaging evaluation has proven to be useful to distinguish retinal single-organ vasculitis from secondary forms of RV.



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Can innate and autoimmune reactivity forecast early and advance stages of age-related macular degeneration?

Publication date: Available online 28 January 2017
Source:Autoimmunity Reviews
Author(s): Grazyna Adamus
Age-related macular degeneration (AMD) is a major cause of central vision loss in persons over 55years of age in developed countries. AMD is a complex disease in which genetic, environmental and inflammatory factors influence its onset and progression. Elevation in serum anti-retinal autoantibodies, plasma and local activation of complement proteins of the alternative pathway, and increase in secretion of proinflammatory cytokines have been seen over the course of disease. Genetic studies of AMD patients confirmed that genetic variants affecting the alternative complement pathway have a major influence on AMD risk. Because the heterogeneity of this disease there is no sufficient strategy to identify the disease onset and progression sole based eye examination, thus identification of reliable serological biomarkers for diagnosis, prognosis and response to treatment by sampling patient's blood. This review provides an outline of the current knowledge on possible serological (autoantibodies, complement factors, cytokines, chemokines) and related genetic biomarkers relevant to the pathology of AMD, and discusses their application for prediction of disease activity and prognosis in AMD.



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Microglia in CNS development: shaping the brain for the future

Publication date: Available online 28 January 2017
Source:Progress in Neurobiology
Author(s): Coralie-Anne Mosser, Sofia Baptista, Isabelle Arnoux, Etienne Audinat
Microglial cells are the resident macrophages of the central nervous system (CNS) and are mainly known for their roles in neuropathologies. However, major recent developments have revealed that these immune cells actively interact with neurons in physiological conditions and can modulate the fate and functions of synapses. Originating from myeloid precursors born in the yolk sac, microglial cells invade the CNS during early embryonic development. As a consequence they can potentially influence neuronal proliferation, migration and differentiation as well as the formation and maturation of neuronal networks, thereby contributing to the entire shaping of the CNS. We review here recent evidence indicating that microglial cells are indeed involved in crucial steps of the CNS development, including neuronal survival and apoptosis, axonal growth, migration of neurons, pruning of supernumerary synapses and functional maturation of developing synapses. We also discuss current hypotheses proposing that diverting microglial cells of their physiological functions, by promoting the expression of an immune phenotype during development, may be central to neurodevelopmental disorders such as autism, schizophrenia and epilepsy.



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Practice makes perfect: Performance optimisation in ‘arboreal’ parkour athletes illuminates the evolutionary ecology of great ape anatomy

Publication date: February 2017
Source:Journal of Human Evolution, Volume 103
Author(s): Lewis G. Halsey, Samuel R.L. Coward, Robin H. Crompton, Susannah K.S. Thorpe
An animal's size is central to its ecology, yet remarkably little is known about the selective pressures that drive this trait. A particularly compelling example is how ancestral apes evolved large body mass in such a physically and energetically challenging environment as the forest canopy, where weight-bearing branches and lianas are flexible, irregular and discontinuous, and the majority of preferred foods are situated on the most flexible branches at the periphery of tree crowns. To date the issue has been intractable due to a lack of relevant fossil material, the limited capacity of the fossil record to reconstruct an animal's behavioural ecology and the inability to measure energy consumption in freely moving apes. We studied the oxygen consumption of parkour athletes while they traversed an arboreal-like course as an elite model ape, to test the ecomorphological and behavioural mechanisms by which a large-bodied ape could optimize its energetic performance during tree-based locomotion. Our results show that familiarity with the arboreal-like course allowed the athletes to substantially reduce their energy expenditure. Furthermore, athletes with larger arm spans and shorter legs were particularly adept at finding energetic savings. Our results flesh out the scanty fossil record to offer evidence that long, strong arms, broad chests and a strong axial system, combined with the frequent use of uniform branch-to-branch arboreal pathways, were critical to off-setting the mechanical and energetic demands of large mass in ancestral apes.



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The Middle Stone Age human fossil record from Klasies River Main Site

Publication date: February 2017
Source:Journal of Human Evolution, Volume 103
Author(s): Frederick E. Grine, Sarah Wurz, Curtis W. Marean
The paleoanthropological significance of Klasies River Main Site derives from its abundant Middle Stone Age (MSA) archaeological debris and the hominin fossils that have featured in discussions about modern human emergence. Despite their significance, the human remains have yet to be contextualized within the spatial, stratigraphic and geochronological framework of the site. We provide an updated overview of the stratigraphy and geochronology of the site, and review the human fossil record in this context. We also provide the first anatomical interpretations of many of the cranial vault fragments. Five hominin specimens derive from the Upper Member and six from the lowermost LBS Member. The vast majority – nearly 40 cataloged specimens – come from the SAS Member; many of these are from a single stratigraphic horizon in a relatively small area in Cave 1. There is a strong cranial bias to the sample; just over 70% of skeletal remains are from the skull. The postcranial skeleton is poorly represented. Excluding the three metatarsals, there are only three long bones in the sample – a clavicle, a proximal radius, and a proximal ulna. Remarkably, humeral, femoral and tibial diaphyses, which are the most durable elements in terms of cortical bone thickness and density, are absent. However, the proportional representation of hominin remains is reminiscent of the "Klasies Pattern" shown by the MSA large bovid skeletal parts. To some degree, this may reflect the excavation and recovery methods that were employed. The vast bulk of the human fossils represent adults. Only three undoubted juvenile individuals are represented – each by a deciduous tooth. This contrasts with other MSA sites along the southern coast of South Africa, where human remains are predominantly juvenile, usually in the form of (possibly exfoliated) deciduous teeth. However, this apparent dissimilarity may also reflect different excavation techniques.



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Clinical Thyroidology High-Impact Articles

FREE ACCESS through February 10, 2017
Read Now:

Does Meta-Analysis Prove Which Factors Predict Relapse After Antithyroid Drugs Are Discontinued?
Stephen W. Spaulding

Thyroid Cancer Overdiagnosis Is a Result of Screening Programs in South Korea
Elizabeth N. Pearce

The Increased Incidence of Thyroid Cancer Is Worldwide
Jerome M. Hershman

Lymph Node Mapping with Ultrasound Is Highly Useful in the Preoperative Workup of Patients with Thyroid Cancer
Martin Biermann

 

The post Clinical Thyroidology High-Impact Articles appeared first on American Thyroid Association.

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Nanotechnology for delivery of gemcitabine to treat pancreatic cancer

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Gebremariam Birhanu, Hamid Akbari Javar, Ehsan Seyedjafari, Ali Zandi-Karimi
Pancreatic cancer (PC) is one of the most deadly and quickly fatal human cancers with a 5-year mortality rate close to 100%. Its prognosis is very poor, mainly because of its hostile biological behavior and late onset of symptoms for clinical diagnosis; these bring limitations on therapeutic interventions. Factors contributing for the difficulties in treating PC include: high rate of drug resistance, fast metastasis to different organs, poor prognosis and relapse of the tumor after therapy. After being approved by US FDA 1997, Gemcitabine (Gem) is the first line and the gold standard drug for all stages of advanced PC till now. However, its efficacy is unsatisfactory, mainly due to; its chemical instability and poor cellular uptake, resulting in an extremely short half-life and low bioavailability. To solve this drawbacks and increase the therapeutic outcome important progress has been achieved in the field of nanotechnology and offers a promising and effective alternative. This review mainly focus on the most commonly investigated nanoparticle (NP) delivery systems of Gem for PC treatment and the latest progresses achieved. Novel nanocarriers with better tumor targeting efficiencies and maximum treatment outcome to treat this deadly due are given much attention.



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Factors Associated with the Use of Hyaluronic Acid and Corticosteroid Injections among Patients with Radiographically Confirmed Knee Osteoarthritis: A Retrospective Data Analysis

Publication date: Available online 28 January 2017
Source:Clinical Therapeutics
Author(s): Kate L. Lapane, Shao-Hsien Liu, Catherine E. Dubé, Jeffrey B. Driban, Timothy E. McAlindon, Charles B. Eaton
PurposeDespite the rapid proliferation of hyaluronate (HA) and corticosteroid (CO) injections and clinical guidelines regarding their use in osteoarthritis (OA), information on the characteristics of people receiving these injections is scarce. We describe the use of injections among adults with radiographically confirmed knee OA and identify factors associated with injection use.MethodsWe used publicly available data from the Osteoarthritis Initiative (OAI), an international collaboration sponsored by the National Institutes of Health, and included participants with ≥1 radiographically confirmed knee OA (Kellgren-Lawrence grade ≥2 [definite osteophytes and possible joint space narrowing (JSN) on anteroposterior weight-bearing radiograph]) at baseline. We matched 415 participants who received at least 1 HA and/or CO injection during the 6-month interval before 1 of the first 7 annual follow-up assessments to 1841 injection nonusers by randomly selecting a study visit to match the distribution observed in the injection users. Multinomial logistic regression models were used for identifying factors associated with injection use, including sociodemographic and clinical/functional factors.FindingsEighteen percent of the 2256 patients identified as having knee OA had received at least 1 injection (years 1–7, 16.9%, 13.7%, 16.6%, 13.5%, 15.9%, 13.5%, and 9.9%, respectively), most commonly with CO (68.4%). HA and CO were more commonly injected in those with a higher annual household income (adjusted odds ratio [aOR] [95% CI] with HA, US ≥$50,000 vs <$25,000, 3.63; [1.20–10.99]) and less commonly in black patients (HA, 0.19 [0.06–0.55]). Greater Kellgren-Lawrence grade (grade 4 vs 2) was associated with an increased likelihood (aOR [95% CI]) of having received HA (4.79 [2.47–9.30]), CO (1.56 [1.04–2.34]), or both (4.94 [1.99–12.27]).ImplicationsThe receipt of HA or CO injection may be associated with higher socioeconomic positioning and indicators of greater disease severity in patients with knee OA.



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Phosphodiesterase Type 5 Inhibitors for the Treatment of Erectile Dysfunction: Pharmacology and Clinical Impact of the Sildenafil Citrate Orodispersible Tablet Formulation

Publication date: Available online 28 January 2017
Source:Clinical Therapeutics
Author(s): Francesco Scaglione, Shaantanu Donde, Tarek A. Hassan, Emmanuele A. Jannini
PurposeThe purpose of this review is to provide an overview of the pharmacology, tolerability, and efficacy of the different phosphodiesterase type 5 (PDE5) inhibitors available for the treatment of erectile dysfunction (ED), with a special focus on the sildenafil orodispersible tablet (ODT) formulation.MethodsA literature search was performed in PubMed, EMBASE, and Cochrane Reviews using the terms erectile dysfunction, patient preference, sildenafil, and PDE5 inhibitors to identify articles published in English between May 1, 2006, and November 18, 2016. A total of 29 studies were included in this review.FindingsThere are substantial data in the literature on the use of PDE5 inhibitors for the treatment of ED. Oral PDE5 inhibitors have been found to be efficacious in the treatment of ED based on results from standard tools used to assess treatment outcomes, such as the Global Assessment Questionnaire 1. In addition, PDE5 inhibitors are defined as well tolerated because of the low occurrence of serious adverse effects or discomfort. Mild adverse reactions, compared with a placebo, include headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness, and rash. Both the film-coated tablet and ODT formulations of sildenafil with or without water have equivalent systemic exposure. However, use of a sildenafil ODT formulation offers a convenient alternative method of administration that would be advantageous for patients with ED.ImplicationsAccording to the published literature, the PDE5 inhibitors are considered an effective and well-tolerated option for the treatment of ED as determined by data generated from standard instruments used in the assessment of treatment outcomes in ED and reported types and severity of adverse effects. The sildenafil ODT formulation, which disintegrates rapidly in the mouth, is an alternative to the solid film-coated tablet formulation that offers administration benefit with the potential to improve treatment adherence, thereby enhancing the sexual health and sense of psychological well-being of patients and their partners.



http://ift.tt/2jIfs2u

Cost-effectiveness Analysis for Apixaban in the Acute Treatment and Prevention of Venous Thromboembolism in the Netherlands

Publication date: Available online 28 January 2017
Source:Clinical Therapeutics
Author(s): Lisa A. de Jong, Evgeni Dvortsin, Kristel J. Janssen, Maarten J. Postma
PurposeLow-molecular weight heparin (LMWH) followed by vitamin K antagonists (VKAs) are the current standard treatment of acute venous thromboembolism (VTE) and prevention of recurrent VTE. The direct oral anticoagulant apixaban was recently found noninferior in efficacy and superior in preventing major bleeding compared with LMWH/VKAs in the AMPLIFY (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy) trial. The objective of this study was to calculate the cost-effectiveness of apixaban compared with LMWH/VKA in the treatment of acute VTE and prevention of recurrent VTE in the Netherlands.MethodsA Markov model was designed to simulate a cohort of 1,000 VTE patients receiving either apixaban or LMWH/VKA. Transition probabilities, costs, and utilities were obtained from the AMPLIFY trial and other literature. The incremental cost-effectiveness ratio (ICER) was calculated from the societal perspective; therefore, the model included both direct (inside and outside the health care sector) and indirect costs. In the univariate and probabilistic sensitivity analyses (PSAs) the robustness of the results was tested, and various additional scenario analyses were conducted.FindingsIn the base-case analysis, apixaban saved €236 and 0.044 quality-adjusted life years (QALYs) and 0.039 LYs were gained compared with LMWH/VKA. In the univariate sensitivity analysis the model appeared to be robust. The results of 2,000 iterations in the PSA found that the probability of apixaban being cost-effective at a willingness-to-pay threshold of €20,000/QALY was 100% and cost-saving was 94%. The scenario of 18-month treatment duration was the only scenario not indicating cost-savings with an ICER of €425/QALY.ImplicationsIn acute anticoagulation use apixaban was found to be cost-saving. A longer anticoagulation period (18 months) resulted in a higher difference in drug costs, indicating a higher ICER. The cost-effectiveness of long-term or life-long use should be examined in future research.



http://ift.tt/2kdOnr9

Photoactive materials based on semiconducting nanocarbons-A challenge opening new possibilities for photocatalysis

Publication date: Available online 28 January 2017
Source:Journal of Energy Chemistry
Author(s): Siglinda Perathoner, Claudio Ampelli, Shiming Chen, Rosalba Passalacqua, Dangsheng Su, Gabriele Centi
This perspective paper introduces the concept that nanocarbons and related materials such as carbon dots are an interesting intrinsic photocatalytic semiconducting material, and not only a modifier of the existing (semiconducting) materials to prepare hybrid materials. The semiconducting properties of the nanocarbons, and the possibility to have the band gap within the visible-light region through defect band engineering, introduction of light heteroatoms and control/manipulation of the curvature or surface functionalization are discussed. These materials are conceptually different from the "classical" semiconducting photocatalysts, because semiconductor domains with tuneable characteristics are embedded in a conductive carbon matrix, with the presence of various functional groups (as C=O groups) enhancing charge separation by trapping electrons. These nanocarbons open a range of new possibilities for photocatalysis both for energetic and environmental applications. The use of nanocarbons as quantum dots and photoluminescent materials was also analysed.

Graphical abstract

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Dynamic versus Isometric Electromechanical Delay in Non-Fatigued and Fatigued Muscle: A Combined Electromyographic, Mechanomyographic, and Force Approach

Publication date: Available online 27 January 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Cory M. Smith, Terry J. Housh, Ethan C. Hill, Glen O. Johnson, Richard J. Schmidt
This study used a combined electromyographic, mechanomyographic, and force approach to identify electromechanical delay (EMD) from the onsets of the electromyographic to force signals (EMDE-F), onsets of the electromyographic to mechanomyogrpahic signals (EMDE-M), and onsets of mechanomyographic to force signals (EMDM-F). The purposes of the current study were to examine: 1) the differences in EMDE-F, EMDE-M, and EMDM-F from the vastus lateralis during maximal, voluntary dynamic (1 repetition maximum [1-RM]) and isometric (maximal voluntary isometric contraction [MVIC]) muscle actions; and 2) the effects of fatigue on EMDE-F, EMDM-F, and EMDE-M. Ten men performed pretest and posttest 1-RM and MVIC leg extension muscle actions. The fatiguing workbout consisted of 70% 1-RM dynamic constant external resistance leg extension muscle actions to failure. The results indicated that there were no significant differences between 1-RM and MVIC EMDE-F, EMDE-M, or EMDM-F. There were, however, significant fatigue-induced increases in EMDE-F (94% and 63%), EMDE-M (107%), and EMDM-F (63%) for both the 1-RM and MVIC measurements. Therefore, these findings demonstrated the effects of fatigue on EMD measures and supported comparisons among studies which examined dynamic or isometric EMD measures from the vastus lateralis using a combined electromyographic, mechanomyographic, and force approach.



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A comparison of gluteus medius, gluteus minimus and tensor facia latae muscle activation during gait in post-menopausal women with and without greater trochanteric pain syndrome

Publication date: Available online 27 January 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Charlotte Ganderton, Tania Pizzari, Tanya Harle, Jill Cook, Adam Semciw
The effect of greater trochanteric pain syndrome (GTPS) on gluteus medius (GMed) and minimus (GMin) activation in post-menopausal women is unknown. The aim of this study was to compare segmental muscle activation and variability of the GMed, GMin and tensor fascia latae (TFL) during gait in post-menopausal women with and without GTPS.Intramuscular electrodes were inserted into segments of GMin (x2) and GMed (x3) and a surface electrode placed on TFL. Ten control participants and 8 with GTPS completed six walking trials. Peak amplitude, average amplitude and time to peak from each phase of the gait cycle (0-30%, 30%- toe off (TO), total stance and swing) were compared between groups using independent t-tests and effect-size (ES) calculations. Variability of muscle activation was calculated using the mean coefficient of variation (CV). Reversal of anterior GMin electromyographic burst pattern and greater average muscle activity was found in the GTPS group compared to controls: 0-TO for anterior GMin (p<0.05), anterior and middle GMed (p<0.01); 0-30% for posterior GMin and GMed. No significant differences were identified in TFL. Overall, this study found increased segmental gluteal muscle activation, decreased hip abduction strength, and reduced variability in muscle activation in post-menopausal women with GTPS, compared with controls.



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The effect of asymmetrical body orientation during simulated forward falls on the distal upper extremity impact response of healthy people

Publication date: Available online 27 January 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Timothy A. Burkhart, Evan Brydges, Jennifer Stefanczyk, David M. Andrews
The occurrence of distal upper extremity injuries resulting from forward falls (approximately 165,000 per year) has remained relatively constant for over 20 years. Previous work has provided valuable insight into fall arrest strategies, but only symmetric falls in body postures that do not represent actual fall scenarios closely have been evaluated. This study quantified the effect of asymmetric loading and body postures on distal upper extremity response to simulated forward falls. Twenty participants were suspended from the Propelled Upper Limb fall ARest Impact System (PULARIS) in different torso and leg postures relative to the ground and to the sagittal plane (0°, 30° and 45°). When released from PULARIS (hands 10 cm above surface, velocity 1 m/s), participants landed on two force platforms, one for each hand. Right forearm impact response was measured with distal (radial styloid) and proximal (olecranon) tri-axial accelerometers and bipolar EMG from seven muscles. Overall, the relative height of the torso and legs had little effect on the forces, or forearm response variables. Muscle activation patterns consistently increased from the start to the peak activation levels after impact for all muscles, followed by a rapid decline after peak. The impact forces and accelerations suggest that the distal upper extremity is loaded more medial-laterally during asymmetric falls than symmetric falls. Altering the direction of the impact force in this way (volar-dorsal to medial-lateral) may help reduce distal extremity injuries caused when landing occurs symmetrically in the sagittal plane as it has been shown that volar-dorsal forces increase the risk of injury.



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Management of food and vegetable processing waste spiked with buffalo waste using earthworms ( Eisenia fetida )

Abstract

The present investigation was focused on the vermicomposting of food and vegetable processing waste (VW) mixed with buffalo dung (BW) under laboratory condition employing Eisenia fetida earthworm species. Four different proportions of VW and BW were prepared and subjected to vermicomposting after 3 weeks of pre-composting. After vermicomposting, nitrogen (7.82–20.73 g/kg), total available phosphate (4.80–11.74 g/kg) and total potassium (7.43–12.75 g/kg) content increased significantly as compared to initial feed stocks. Significant reduction was observed in pH (7.56 to 6.55), total organic carbon (48.25–23.54%) and organic matter (83.18–40.68%). Metal content (Fe, Cu, Zn and Ni) was higher in all the vermicomposts than feedstocks. Data on growth and reproduction of earthworm revealed that the highest biomass gain and fecundity of worms were attained in 100% BW followed by [BW75% + VW25%] > [BW50% + VW50%] > [BW25% + VW75%] feedstocks. Results evidenced the suitability of VW (up to 50%) spiked with BW for increasing earthworm population and in providing potent organic manure for agricultural applications.

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Calcium Pill Aspiration: A Case Report

Publication date: Available online 27 January 2017
Source:The Journal of Emergency Medicine
Author(s): David Clark Brewer, Mark Regala, Jamie Hess




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Recurrent extracranial internal carotid artery vasospasm associated with recreational marijuana use

Publication date: May–June 2017
Source:Clinical Imaging, Volume 43
Author(s): Prasann Vachhani, Michael Phipps, Prashant Raghavan




http://ift.tt/2k3fwuR

Long-term outcome of phase I/II prospective study of dose-escalated proton therapy for early-stage non-small cell lung cancer

Publication date: Available online 28 January 2017
Source:Radiotherapy and Oncology
Author(s): Joe Y. Chang, Wencheng Zhang, Ritsuko Komaki, Noah C. Choi, Shen Chan, Daniel Gomez, Michael O'Reilly, Melenda Jeter, Michael Gillin, Xiaorong Zhu, Xiaodong Zhang, Radhe Mohan, Stephen Swisher, Stephen Hahn, James D. Cox
PurposeThe aim of this phase I/II study was to assess the long-term clinical benefits and toxicities of proton beam therapy for medically inoperable early-stage non-small cell lung cancer (NSCLC).Patients and methodsFrom June 2006 to September 2011, 35 patients with medically inoperable T1N0M0 (central or superior location, 12 patients) or T2-3N0M0 (any location, 23 patients) NSCLC were treated with 87.5Gy at 2.5Gy/fraction of proton therapy. Toxicities were scored according to the Common Terminology Criteria for Adverse Events, version 4.0.ResultsThe median follow-up time was 83.1months (95% CI: 69.2–97.1months). For all 35 patients, the 1, 3, and 5-year overall survival rates were 85.7%, 42.9%, and 28.1%, respectively. The 5-year local recurrence-free, regional recurrence-free, and distant metastasis-free survival rates were 85.0%, 89.2%, and 54.4%, respectively. Different T stages had no effect on local and regional recurrence (p=0.499, p=1.00). However, with the increase in T stages, the distant metastasis rate increased significantly (p=0.006). The most common adverse effects were dermatitis (grade 2, 51.4%; grade 3, 2.9%) and radiation pneumonitis (grade 2, 11.4%; grade 3, 2.9%). Other grade 2 toxicities included esophagitis (2.9%), rib fracture (2.9%), heart toxicities (5.7%), and chest wall pain (2.9%).ConclusionsAccording to our long-term follow-up data, proton therapy with ablative doses is well tolerated and effective in medically inoperable early-stage NSCLC. Systemic therapy should be considered to reduce the rate of distant metastasis in cases of T2 and T3 lesions.



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Campaigns with oral polio vaccine may lower mortality and create unexpected results

Publication date: Available online 27 January 2017
Source:Vaccine
Author(s): C.S. Benn, L.H. Jacobsen, A.B. Fisker, A. Rodrigues, E. Sartono, N. Lund, H.C. Whittle, P. Aaby
Three studies from Guinea-Bissau found conflicting effects of OPV-at-birth (OPV0) on child survival. One study from 2004 suggested excess male mortality among children receiving OPV0 compared with children receiving NoOPV0 during a period of shortage of OPV. However, two subsequent studies showed beneficial effects of OPV0. In 2004, two national OPV-campaigns had been conducted in Guinea-Bissau. In a reanalysis of the 2004-study, in a survival analysis the age-adjusted mortality rate of study participants was 67% (95% CI=42–81%) lower after the OPV-campaigns than before the campaigns. In the OPV0 group only 22% (655/3031 person-years (pyrs)) of follow-up time was "after" the OPV-campaigns whereas 55% (473/859 pyrs) of the time in the NoOPV0 group was post-campaign (p<0.0001, Chi²). Censoring for OPV-campaigns in the original study removed excess male mortality and made the three studies more homogeneous. Overall, there is now considerable evidence that OPV, like other live vaccines, has important beneficial non-specific effects.



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Comment on “Preliminary assessment of modified borosilicate glasses for chromium and ruthenium immobilization”, by Farid and Rahman

Publication date: 1 May 2017
Source:Materials Chemistry and Physics, Volume 192
Author(s): Neil C. Hyatt, Claire L. Corkhill, Daniel J. Bailey, Adam J. Fisher, Russell J. Hand
Farid and Rahman recently reported an investigation of the microstructure and alteration of borosilicate glasses designed for the immobilisation of UK radioactive wastes [Preliminary assessment of modified borosilicate glasses for chromium and ruthenium immobilization, Materials Chemistry and Physics, 186 (2017) 462–469]. The authors draw conclusions concerning the partitioning of elements within two devitrified spinel phases, at variance with previous studies of these materials. The authors also present solution chemistry and surface analysis data for alteration of these glasses, and postulate micro-cracks apparent in the gel layer of the altered glass to govern the extent of alteration. From analysis of data presented by Farid and Rahman, and comparison with previous studies, we show that their data are consistent with the presence of a single spinel phase of complex chemical composition, (Mg,Zn,Ni)(Cr,Fe,Al)2O4. We show the chemistry and surface analysis data presented by Farid and Rahman to be contradictory, in terms of the relative alteration behaviour of these glasses, as verified by previous studies, and deduce that an alternative explanation is required to rationalise their observations. We also comment on other aspects of the report which require clarification.

Graphical abstract

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Evaluation of the slurry management strategy and the integration of the composting technology in a pig farm – Agronomical and environmental implications

Publication date: 1 May 2017
Source:Journal of Environmental Management, Volume 192
Author(s): José A. Sáez, Rafael Clemente, M. Ángeles Bustamante, David Yañez, M. Pilar Bernal
The changes in livestock production systems towards intensification frequently lead to an excess of manure generation with respect to the agricultural land available for its soil application. However, treatment technologies can help in the management of manures, especially in N-surplus areas. An integrated slurry treatment system based on solid-liquid separation, aerobic treatment of the liquid and composting the solid fraction was evaluated in a pig farm (sows and piglets) in the South of Spain. Solid fraction separation using a filter band connected to a screw press had low efficiency (38%), which was greatly improved incorporating a rotatory sieve (61%). The depuration system was very efficient for the liquid, with total removal of 84% total solids, 87% volatile solids, and 98% phosphorus. Two composting systems were tested through mechanical turning of: 1- a mixture of solid fraction stored for 1 month after solid-liquid separation and cereal straw; 2- recently-separated solid fraction mixed with cotton gin waste. System 2 was recommended for the farm, as it exhibited a fast temperature rise and a long thermophilic phase to ensure compost sanitisation, and high recovery of nutrients (TN 77%, P and K > 85%) and organic matter (45%). The composts obtained were mature, stable and showed a high degree of humification of their organic matter, absence of phytotoxicity and concentrations of nutrients similar to other composts from pig manure or separated slurry solids. However, the introduction of slurry from piglets into the solid-liquid separation system should be avoided in order to reduce the content of Zn in the compost, which lowers its quality. The slurry separation followed by composting of the solid fraction using a passive windrow system, and aeration of the liquid phase, was the most recommendable procedure for the reduction of GHG emissions on the farm.

Graphical abstract

http://ift.tt/2kdAdGh

Interaction of plasma proteins with ZnSe and ZnSe@ZnS core-shell quantum dots

Publication date: 5 May 2017
Source:Colloids and Surfaces A: Physicochemical and Engineering Aspects, Volume 520
Author(s): Irshad Ahmad Mir, Kamla Rawat, H.B. Bohidar
Herein, we report, interaction of water-soluble ZnSe core only (size=3.60±0.12nm, zeta potential=−45mV), and ZnSe@ZnS core-shell (size=4.80±0.20nm, zeta potential=–38mV) quantum dots (QDs) with three globular plasma proteins (Human Serum Albumin (HSA), Bovine Serum Albumin (BSA) and β-lactoglobulin (β-Lg)). It was found that QDs effectively quenched the fluorescence of proteins that was size-dependent. The nature of quenching was static which resulted from the generation of QDs-Protein complexes. It was found that the binding affinity followed: BSA>HSA>β-Lg for both ZnSe and ZnSe@ZnS samples. Interestingly, the secondary and tertiary structure of proteins remained unaffected after interactions.

Graphical abstract

http://ift.tt/2kdkF5q

Vasopressin Bolus Protocol Compared to Desmopressin (DDAVP) for Managing Acute, Postoperative Central Diabetes Insipidus and Hypovolemic Shock.

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Vasopressin Bolus Protocol Compared to Desmopressin (DDAVP) for Managing Acute, Postoperative Central Diabetes Insipidus and Hypovolemic Shock.

Case Rep Endocrinol. 2017;2017:3052102

Authors: Shukla A, Alqadri S, Ausmus A, Bell R, Nattanmai P, Newey CR

Abstract
Introduction. Management of postoperative central diabetes insipidus (DI) can be challenging from changes in volume status and serum sodium levels. We report a case successfully using a dilute vasopressin bolus protocol in managing hypovolemic shock in acute, postoperative, central DI. Case Report. Patient presented after bifrontal decompressive craniotomy for severe traumatic brain injury. He developed increased urine output resulting in hypovolemia and hypernatremia. He was resuscitated with intravenous fluids including a dilute vasopressin bolus protocol. This protocol consisted of 1 unit of vasopressin in 1 liter of 0.45% normal saline. This protocol was given in boluses based on the formula: urine output minus one hundred. Initial serum sodium was 148 mmol/L, and one-hour urine output was 1 liter. After 48 hours, he transitioned to 1-desamino-8-D-arginine vasopressin (DDAVP). Pre-DDAVP serum sodium was 149 mmol/L and one-hour urine output 320 cc. Comparing the bolus protocol to the DDAVP protocol, the average sodium was 143.8 ± 3.2 and 149.6 ± 3.2 mmol/L (p = 0.0001), average urine output was 433.2 ± 354.4 and 422.3 ± 276.0 cc/hr (p = 0.90), and average specific gravity was 1.019 ± 0.009 and 1.016 ± 0.01 (p = 0.42), respectively. Conclusion. A protocol using dilute vasopressin bolus can be an alternative for managing acute, central DI postoperatively, particularly in setting of hypovolemic shock resulting in a consistent control of serum sodium.

PMID: 28127476 [PubMed]

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Staphylococcus aureus nasal colonization among HIV-infected adults in Botswana: prevalence and risk factors.

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Staphylococcus aureus nasal colonization among HIV-infected adults in Botswana: prevalence and risk factors.

AIDS Care. 2017 Jan 27;:1-5

Authors: Reid MJ, Steenhoff AP, Mannathoko N, Muthoga C, McHugh E, Brown EL, Fischer RS

Abstract
We sought to determine the clinical and epidemiologic determinants of Staphylococcus aureus nasal colonization in HIV-infected individuals at two outpatient centers in southern Botswana. Standard microbiologic techniques were used to identify S. aureus and methicillin-resistant S. aureus (MRSA). In a sample of 404 HIV-infected adults, prevalence of S. aureus nasal carriage was 36.9% (n = 152) and was associated with domestic overcrowding and lower CD4 cell count. MRSA prevalence was low (n = 13, 3.2%), but more common among individuals with asthma and eczema. The implications of these findings for HIV management are discussed.

PMID: 28127988 [PubMed - as supplied by publisher]

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High durability and low toxicity antimicrobial coatings fabricated by quaternary ammonium silane copolymers.

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High durability and low toxicity antimicrobial coatings fabricated by quaternary ammonium silane copolymers.

Biomater Sci. 2016 Feb;4(2):299-309

Authors: Li H, Bao H, Bok KX, Lee CY, Li B, Zin MT, Kang L

Abstract
Adhesion and subsequent growth of microorganisms on material surfaces are a major concern in many biomedical applications. Currently, various polymers are immobilized on material surfaces to prevent microbial colonization. However, there are several challenges with regard to the coating materials, including their inability to kill microorganisms, complexity of surface grafting, limited durability and toxicity towards humans. To address these challenges, we synthesize a novel quaternary ammonium silane (QAS) antimicrobial copolymer to confer the antimicrobial effect via a simple thermal-curing coating process. The QAS copolymers were less toxic to 3 human cell lines than a commercial antimicrobial QAS monomeric agent, namely, dimethyloctadecyl[3-(trimethoxysilyl) propyl]ammonium chloride (DTPAC). Moreover, the QAS coatings demonstrated superior antimicrobial efficacy and durability than those of the DTPAC coatings. In conclusion, the novel QAS copolymers are useful to prevent substrates from microbial infections, yet with low toxicity to humans and long durability. In addition, the synthetic process is potentially scalable for industrial applications.

PMID: 26535418 [PubMed - indexed for MEDLINE]

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Hyaluronate synthase-2 overexpression alters estrogen dependence and induces histone deacetylase inhibitor-like effects on ER-driven genes in MCF7 breast tumor cells

Publication date: Available online 28 January 2017
Source:Molecular and Cellular Endocrinology
Author(s): Marion Vanneste, Vincent Hanoux, Mohammed Bouakka, Pierre-Jacques Bonnamy
In breast carcinoma cells, high levels of hyaluronan (HA) and its CD44 receptor are frequently associated with alteration in estrogen signaling. We demonstrate that stable hyaluronate synthase 2 (HAS2) overexpression in estrogen receptor α (ERα) -positive MCF7 cells oppositely altered estrogen dependence of cell growth and its sensitivity towards antiestrogens. Albeit without effect on ERα expression and estradiol binding properties, HAS2 overexpression increased ERα Ser118 phosphorylation as well as transcriptional activity of estrogen in an ERE-luciferase reporter gene assay. However, HAS2 overexpression induced partial silencing of E2 driven-genes without affecting the magnitude of regulation by estradiol. This effect was associated with half-reduction in the activity of nuclear histone deacetylases (HDACs) through a post-translational mechanism likely consecutive to the enhanced expression of the histone acetyl-transferase EP300. In conclusion, increase in HA/CD44 interactions may contribute, through an HDAC inhibitor-like and ER-independent mechanism, to the silencing of estrogen–driven genes in breast carcinoma.

Graphical abstract

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Regulation of miR-29b-1/a transcription and identification of target mRNAs in CHO-K1 cells

Publication date: Available online 28 January 2017
Source:Molecular and Cellular Endocrinology
Author(s): Penn Muluhngwi, Kirsten Richardson, Joshua Napier, Eric C. Rouchka, Justin L. Mott, Carolyn M. Klinge
miR-29b and miR-29a transcript levels were reported to increase in exponentially growing CHO-K1 cells. Here, we examine the regulation of miR-29b-1/a in CHO-K1 cells. We observed that 4-hydroxytamoxifen (4-OHT) increased pri-miR-29b-1 and pri-miR-29a transcription in CHO-K1 cells by activating endogenous estrogen receptor α (ERα). DICER, an established, bona fide target of miR-29b-1/a, was shown to be regulated by 4-OHT in CHO-K1 cells. We showed that miR-29b-1 and miR-29a serve a repressive role in cell proliferation, migration, invasion, and colony formation in CHO-K1 cells. To identify other targets of miR-29b-1 and miR-29a, RNA sequencing was performed by transfecting cells with anti-miR-29a, which inhibits both miR-29a and miR-29b-1, pre-miR-29b-1, and/or pre-miR-29a. In silico network analysis in MetaCore™ identified common and unique putative gene targets of miR-29b-1 and miR-29a. Pathway analysis of identified putative miR-29 targets were related to cell adhesion, cytoskeletal remodeling, and development. Further inquiry revealed regulation of pathways mediating responses to growth factor stimulus and cell cycle regulation.



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Nutrition and fasting mimicking diets in the prevention and treatment of autoimmune diseases and immunosenescence

Publication date: Available online 28 January 2017
Source:Molecular and Cellular Endocrinology
Author(s): In Young Choi, Changhan Lee, Valter D. Longo
Complex and coordinated signals are necessary to initiate and sustain the activation, proliferation, and differentiation of lymphocytes. These signals, which are known to determine T-cell fate and function, also depend on the metabolic state of the organism. Recent studies indicate that both the type and levels of nutrients can influence the generation, survival and function of lymphocytes and therefore can affect several autoimmune diseases. Here, we review the dysregulation of lymphocytes during autoimmunity and aging, the mechanisms associated with loss of immune function, and how fasting mimicking diets and other dietary interventions affect autoimmunity and immunosenescence.



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Selective deletion of Pten in theca-interstitial cells leads to androgen excess and ovarian dysfunction in mice

Publication date: Available online 28 January 2017
Source:Molecular and Cellular Endocrinology
Author(s): Zi-Jian Lan, M.S. Krause, S.D. Redding, X. Li, G.Z. Wu, H.X. Zhou, H.C. Bohler, C. Ko, A.J. Cooney, Junmei Zhou, Z.M. Lei
Theca cell-selective Pten mutation (tPtenMT) in mice resulted in increases in PDK1 and Akt phosphorylation, indicating an over-activation of PI3K signaling in the ovaries. These mice displayed elevated androgen levels, ovary enlargement, antral follicle accumulation, early fertility loss and increased expression of Lhcgr and genes that are crucial to androgenesis. These abnormalities were partially reversed by treatments of PI3K or Akt inhibitor. LH actions in Pten deficient theca cells were potentiated. The phosphorylation of Foxo1 was increased, while the binding of Foxo1 to forkhead response elements in the Lhcgr promoter was reduced in tPtenMT theca cells, implying a mechanism by which PI3K/Akt-induced upregulation of Lhcgr in theca cells might be mediated by reducing the inhibitory effect of Foxo1 on the Lhcgr promoter. The phenotype of tPtenMT females is reminiscent of human PCOS and suggests that dysregulated PI3K cascade in theca cells may be involved in certain types of PCOS pathogenesis.



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Chemical Exchange Saturation Transfer imaging: Advances and applications by Michael T. McMahon, Assaf A. Gilad, Jeff W. M. Bulte, and Peter C.M. van Zijl Publisher: Pan Stanford Publishing Pte. Ltd., Singapore

Publication date: May 2017
Source:Magnetic Resonance Imaging, Volume 38
Author(s): Daniel F Gochberg




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Synergistic activity of N-hydroxy-7-(2-naphthylthio) heptanomide and sorafenib against cancer stem cells, anaplastic thyroid cancer

Publication date: March 2017
Source:Neoplasia, Volume 19, Issue 3
Author(s): Ki Cheong Park, Seok-Mo Kim, Jeong Yong Jeon, Bup-Woo Kim, Hyeung Kyoo Kim, Ho Jin Chang, Yong Sang Lee, Soo Young Kim, Seung Hoon Choi, Cheong Soo Park, Hang-Seok Chang
Anaplastic thyroid carcinoma (ATC) although rare is the most deadly form of thyroid cancer. The fatality rate for ATC is high-pitched, the survival rate at 1 year after diagnosis is <20%. Control of ATC is severely hard and widespread with unpredictability. We Previous proved that histone gene reviser and epigenetic changes role significant parts in papillary and anaplastic thyroid cancer tumorigenesis. Herein, the goal of this study was to investigate the anti-tumor activities of a HDAC inhibitor, HNHA alone and in combination with sorafenib in ATC cells in vitro and in vivo and to explore its effects on apoptotic cell death pathways. Three ATC cell lines were exposed to sorafenib in the presence or absence of HNHA, and cell viability was determined by MTT assay. Effects of combined treatment on cell cycle and intracellular signaling pathways were assessed by flow cytometry and western blot analysis. The ATC cell lines xenograft model was used to examine the anti-tumor activity in vivo. Our data showed that HNHA and sorafenib synergistically decreased cell viability in ATC cells, and also significantly increased apoptotic cell death in these cells, as proved by the cleavage of caspase-3 and DNA fragmentation. HNHA and sorafenib combination was reduced anti-apoptotic factor in ATC. Thus, combination therapy with HNHA and sorafenib significantly decreased vessel density, and most significantly reduced tumor volume and increased survival in ATC xenografts.These results propose that HNHA in combination with sorafenib has significant anti-cancer activity in preclinical models, potentially suggesting a new clinical approach for patients of advanced thyroid cancer type.



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Isotopic ratios of nitrate in aerosol samples from Mt. Lulin, a high-altitude station in Central Taiwan

Publication date: April 2017
Source:Atmospheric Environment, Volume 154
Author(s): Tania Guha, C.T. Lin, S.K. Bhattacharya, A.S. Mahajan, Chang-Feng Ou-Yang, Yi-Ping Lan, S.C. Hsu, Mao-Chang Liang
The importance of Asian countries towards increase of atmospheric pollutants is being examined critically in recent times. In this context, we carried out analysis of nitrates separated from aerosol samples collected during 2010 from Mt. Lulin (NOAA code: LLN), Taiwan, located at an altitude of 2 862 m above sea level. Large temporal variations are seen in δ¹⁵N, δ¹⁸O and Δ¹⁷O values of the nitrate, with day-to-day variations comparable to the seasonal amplitude. The δ¹⁵N values of nitrate are found to be higher in spring months (March–April; −1±3‰) and lower in summer (June–September; −5±3‰). Similarly, the δ¹⁸O (69 ± 15‰ versus 32 ± 13‰) and Δ¹⁷O (23 ± 5‰ versus 12 ± 4‰) values are higher in spring and lower in summer. The lowest δ¹⁸O value observed was 10.8‰. The higher values of δ¹⁵N in spring could be attributed to enhanced contribution from fossil fuel combustions, especially burning of coal in nearby Asian countries like China, with the resultant pollutants being brought to the Lulin station by long-range transport. An alternative explanation is the isotopic exchange reaction between N2O5 and HNO3 that elevates the δ¹⁵N value in nitrate. The oxygen isotope variability is explained by changes in contribution from two major pathways of nitrate formation from its precursor NOx molecules. During spring time, nitrate formation via the N2O5 pathway is dominant, resulting in higher values of both δ¹⁸O and Δ¹⁷O. In contrast, during summer, formation involving HO2/RO2 radicals becomes important, producing lower values of δ¹⁸O and Δ¹⁷O. A chemistry box model was used to study the nitrate formation pathways through oxidation of NO and NO2 via formation of NO2 and NO3⁻/HNO3. Both the model results and observations suggest that for the formation of NO2 from NO, the pathway via O3 is more active in spring, whereas in summer the pathway via HO2/RO2 radicals predominates. For the subsequent formation of NO3⁻ and HNO3, the OH pathway is more active in summer than in spring. These suggestions are supported by a wind rose diagram and back trajectory analysis of air masses bringing the precursor NOx to the sampling site.



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Discovery and Dimeric Approach of Novel Natriuretic Peptide Receptor A (NPR-A) Agonists

Publication date: Available online 28 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Takehiko Iwaki, Yoshiaki Oyama, Toshiyuki Tomoo, Taisaku Tanaka, Yoshihiko Okamura, Masako Sugiyama, Akira Yamaki, Mayumi Furuya
Novel agonists of the Natriuretic Peptide Receptor A (NPR-A) were obtained through random screening and subsequent structural modification of triazine derivatives. The key structural feature to improve in vitro activity was the dimerization of triazine monomer derivatives. The non peptide derivative 7c and 13a showed highly potent NPR-A agonistic activity in vitro and diuretic activity in vivo. These results implied that non-peptidic small molecules open the possibility of new therapy for congestive heart failure.

Graphical abstract

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Simplifying Nature: Towards The Design of Broad Spectrum Kinetoplastid Inhibitors, Inspired by Acetogenins

Publication date: Available online 28 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Eoin R. Gould, Elizabeth F.B. King, Stefanie K. Menzies, Andrew L. Fraser, Lindsay B. Tulloch, Marija K. Zacharova, Terry K. Smith, Gordon J. Florence
The need for new treatments for the neglected tropical diseases African sleeping sickness, Chagas disease and Leishmaniasis remains urgent with the diseases widespread in tropical regions, affecting the world's very poorest. We have previously reported bis-tetrahydropyran 1,4-triazole analogues designed as mimics of the annonaceous acetogenin natural product chamuvarinin, which maintained trypanocidal activity. Building upon these studies, we here report related triazole compounds with pendant heterocycles, mimicking the original butenolide of the natural product. Analogues were active against T. brucei, with a nitrofuran compound displaying nanomolar trypanocidal activity. Several analogues also showed strong activity against T. cruzi and L. major. Importantly, select compounds gave excellent selectivity over mammalian cells with a furan-based analogue highly selective while remaining active against all three cell lines, thus representing a potential lead for a new broad spectrum kinetoplastid inhibitor.

Graphical abstract

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Synthesis and biological evaluation of 4 arylcoumarin analogues as tubulin-targeting antitumor agents

Publication date: Available online 27 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Peggoty Mutai, Gilles Breuzard, Alessandra Pagano, Diane Allegro, Vincent Peyrot, Kelly Chibale
The synthesis of twenty-six 4-arylcoumarin analogues of combretastatin A-4 (CA-4) led to the identification of two new compounds (25 and 26) with strong cytotoxic activity. Both compounds had a high cytotoxic effect on a CA-4-resistant colon adenocarcinoma cell line (HT29D4). The compounds affected cell cycle progression characterized by a mitotic block. The activity of these compounds against microtubules both in vitro and in cells was examined and both compounds were found to potently inhibit in vitro microtubule formation via a sub-stoichiometric mode like CA-4. By immunofluorescence, it was observed that both compounds induced strong microtubule network disruption. Our results provide a strong experimental basis to develop new potent anti-tubulin molecules targeting CA-4-resistant cancer cells.

Graphical abstract

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Synthesis of new derivatives of 21-imidazolyl-16-dehydropregnenolone as inhibitors of 5α-reductase 2 and with cytotoxic activity in cancer cells

Publication date: Available online 27 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Aylin Viviana Silva-Ortiz, Eugene Bratoeff, Teresa Ramírez-Apan, Yvonne Heuze, Juan Soriano, Isabel Moreno, Marisol Bravo, Lucero Bautista, Marisa Cabeza
The aim of this study was to synthesize several 16-dehydropregnenolone derivatives containing an imidazole ring at C-21 and a different ester moiety at C-3 as inhibitors of 5α-reductase 1 and 2 isoenzymes. Their binding capacity to the androgen receptor (AR) was also studied.Additionally, we evaluated their pharmacological effect in a castrated hamster model and their cytotoxic activity on a panel of cancer cells (PC-3, MCF7, SK-LU-1).The results showed that only the derivatives with an alicyclic ester at C-3 showed 5α-R2 enzyme inhibition activity, the most potent of them being 21-(1H-imidazol-1-yl)-20-oxopregna-5,16-dien-3β-yl-cyclohexanecarboxylate with an IC50 of 29 nM. This is important because prostatic benign hyperplasia is directly associated with the presence of 5α-R2. However, all the derivatives failed to inhibit 5α-R1 or bind to the AR. These alicyclic ester derivatives decreased the weight and size of androgen-dependent glands in the hamster, indicating they are very active in vivo and are not toxic. In addition, the 21-(1H-imidazol-1-yl)-20-oxopregna-5,16-dien-3β-yl-acetate derivative showed the highest cytotoxic activity on the three cancer cell lines studied.It is therefore important in the synthesis of steroidal compounds to consider the size of the ester moiety at C-3 of the steroid skeleton, which is key in obtaining biological activity, as observed in this experiment.

Graphical abstract

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Cytotoxic and Apoptotic Effects of the Combination of Palladium (II) 5,5-diethylbarbiturate Complex with bis(2-pyridylmethyl)amine and Curcumin on Non Small Lung Cancer Cell Lines

Publication date: Available online 28 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Duygu Tunc, Egemen Dere, Didem Karakas, Buse Cevatemre, Veysel Turan Yilmaz, Engin Ulukaya
Metal-based chemotherapeutics such as cisplatin are widely used treatment of lung cancer which is the major cause of cancer-related mortality worldwide. Recent studies demonstrated that novel metal-based compounds have strong cytotoxic activity in a similar way as cisplatin. Therefore, metal-based compounds have been synthesized and investigated in order to determine their cytotoxic activities. It has been also reported curcumin, which has been derived from turmeric plant, has powerful cytotoxic effect on various cancer cell lines. In the light of these data, it has been investigated the cytotoxic effects of combination of curcumin (0.78-100 μM) and palladium (II) 5,5-diethylbarbiturate complex with bis(2-pyridylmethyl)amine [Pd(II) complex] (0.39-50 μM) against non small lung cancer cell lines, A549 and H1299. It has been found that combination of Pd(II) complex and curcumin enhanced the cytotoxic activity and apoptotic cell death at 48 h, compared to single use of each agent, only in H1299 cell line (combination index<1). Apoptosis was evident by annexin v staining positivity, increased caspase 3/7 activity and the presence of pyknotic nuclei. Pro-apoptotic genes of TNFRSF10A and HRK were found to be involved in apoptotic cell death. In conclusion, the application of this combination may be regarded as a novel and effective approach for the treatment of lung cancer due to its promising cytotoxic and apoptotic effect.

Graphical abstract

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Differential Gene Expression by 1,25(OH)2D3 in an Endometriosis Stromal Cell Line

Publication date: Available online 28 January 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Sue Ann Ingles, Liang Wu, Benjamin T. Liu, Yibu Chen, Chun-Yeh Wang, Claire Templeman, Doerthe Bruggmann
Endometriosis is a common female reproductive disease characterized by invasion of endometrial cells into other organs, frequently causing pelvic pain and infertility. Alterations of the vitamin D system have been linked to endometriosis incidence and severity. To shed light on the potential mechanism for these associations, we examined the effects of 1,25(OH)2D3 on gene expression in endometriosis cells. Stromal cell lines derived from endometriosis tissue were treated with 1,25(OH)2D3, and RNA-seq was used to identify genes differentially expressed between treated and untreated cells. Gene ontology and pathway analyses were carried out using Partek Flow and Ingenuity software suites, respectively. We identified 1627 genes that were differentially expressed (886 down-regulated and 741 up-regulated) by 1,25(OH)2D3. Only one gene, CYP24A1, was strongly up-regulated (369-fold). Many genes were strongly down-regulated. 1,25(OH)2D3 treatment down-regulated several genetic pathways related to neuroangiogenesis, cellular motility, and invasion, including pathways for axonal guidance, Rho GDP signaling, and matrix metalloprotease inhibition. These findings support a role for vitamin D in the pathophysiology of endometriosis, and provide new targets for investigation into possible causes and treatments.



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Attention-deficit/hyperactivity disorder symptoms and loneliness among adults in the general population

Publication date: March 2017
Source:Research in Developmental Disabilities, Volume 62
Author(s): Andrew Stickley, Ai Koyanagi, Hidetoshi Takahashi, Vladislav Ruchkin, Yoko Kamio
BackgroundResearch on the association between adult attention-deficit/hyperactivity disorder (ADHD) and loneliness is scarce even though factors which have been previously linked to loneliness, such as divorce and poorer mental health may be more prevalent among adults with ADHD. This study investigated the relation between ADHD symptoms/symptom severity and loneliness in the general adult population.MethodsData from the Adult Psychiatric Morbidity Survey 2007 (N=7403, aged ≥16years) were analyzed. ADHD symptoms and common mental disorders (CMDs) were assessed with the Adult ADHD Self-Report Scale (ASRS) Screener and the Clinical Interview Schedule Revised, respectively. Loneliness was measured with a question from the Social Functioning Questionnaire. Multivariable logistic regression analysis was used to examine the associations.ResultsIn the fully adjusted model, an ASRS score ≥14 was strongly associated with loneliness (OR=2.48 95%CI=1.83–3.36). ADHD symptom severity was related to loneliness in a dose-response fashion. Over one-third of the association between ADHD symptoms and loneliness was explained by CMDs.ConclusionsAdults with more ADHD symptoms are at an increased risk of feeling lonely. Future research should determine how ADHD symptoms are linked to loneliness and if loneliness is affecting well-being.



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An improved method for growing neurons: comparison with standard protocols

Publication date: Available online 27 January 2017
Source:Journal of Neuroscience Methods
Author(s): Diletta Pozzi, Jelena Ban, Federico Iseppon, Vincent Torre
BackgroundSince different culturing parameters – such as media composition or cell density – lead to different experimental results, it is important to define the protocol used for neuronal cultures. The vital role of astrocytes in maintaining homeostasis of neurons – both in vivo and in vitro – is well established: the majority of improved culturing conditions for primary dissociated neuronal cultures rely on astrocytes.New MethodOur culturing protocol is based on a novel serum-free preparation of astrocyte – conditioned medium (ACM). We compared the proposed ACM culturing method with other two commonly used methods Neurobasal/B27- and FBS- based media. We performed morphometric characterization by immunocytochemistry and functional analysis by calcium imaging for all three culture methods at 1, 7, 14 and 60days in vitro (DIV).ResultsACM-based cultures gave the best results for all tested criteria, i.e. growth cone's size and shape, neuronal outgrowth and branching, network activity and synchronization, maturation and long-term survival. The differences were more pronounced when compared with FBS-based medium. Neurobasal/B27 cultures were comparable to ACM for young cultures (DIV1), but not for culturing times longer than DIV7.Comparison with Existing Method(s)ACM-based cultures showed more robust neuronal outgrowth at DIV1. At DIV7 and 60, the activity of neuronal network grown in ACM had a more vigorous spontaneous electrical activity and a higher degree of synchronization.ConclusionsWe propose our ACM-based culture protocol as an improved and more suitable method for both short- and long-term neuronal cultures.

Graphical abstract

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Autologous Fat Grafting for Treating Blepharoplasty-induced Lower Eyelid Retraction

Summary: Autologous fat grafting for blepharoplasty-induced lower eyelid retraction offers potential for a long-term solution while avoiding the morbidity associated with posterior lamellar spacer grafts. By combining traditional methods of lifting the retracted lower eyelid with autologous fat grafting, both functional and aesthetic concerns can be successfully addressed in these patients.

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Functional and Quantitative MRI Mapping of Somatomotor Representations of Human Supralaryngeal Vocal Tract

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Speech articulation requires precise control of and coordination between the effectors of the vocal tract (e.g., lips, tongue, soft palate, and larynx). However, it is unclear how the cortex represents movements of and contact between these effectors during speech, or how these cortical responses relate to inter-regional anatomical borders. Here, we used phase-encoded fMRI to map somatomotor representations of speech articulations. Phonetically trained participants produced speech phones, progressing from front (bilabial) to back (glottal) place of articulation. Maps of cortical myelin proxies (R₁= 1/T₁) further allowed us to situate functional maps with respect to anatomical borders of motor and somatosensory regions. Across participants, we found a consistent topological map of place of articulation, spanning the central sulcus and primary motor and somatosensory areas, that moved from lateral to inferior as place of articulation progressed from front to back. Phones produced at velar and glottal places of articulation activated the inferior aspect of the central sulcus, but with considerable across-subject variability. R₁ maps for a subset of participants revealed that articulator maps extended posteriorly into secondary somatosensory regions. These results show consistent topological organization of cortical representations of the vocal apparatus in the context of speech behavior.</span>

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