Inhibition of hemangioma growth using polymer–lipid hybrid nanoparticles for delivery of rapamycin

Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Haitao Li, Yunfei Teng, Jin Sun, Jianyong Liu
Although infantile hemangiomas is benign, its rapid growth may induce serious complications. However, only one drug Hemangeol™ has been approved by US Food and Drug Administration (FDA) to treat infantile hemangiomas. Thus it is necessary to develop novel alternative drugs to treat infantile hemangiomas. Rapamycin is a well-know potent antiangiogenic agent, whereas the daily oral administration of rapamycin exerts undesired metabolic effects due to its inhibition of mechanistic target of rapamycin (mTOR) which is critical in cell metabolism. We hereby developed rapamycin-loaded polymer–lipid hybrid nanoparticles (Rapamycin-PLNPs) as a local controlled release system to realize local and sustained release of rapamycin, aiming to reduce the side effects and frequency of administration of rapamycin. Rapamycin-PLNPs are of a small size (129.1nm), desired drug encapsulation efficiency (63.7%), and sustained drug release for 5 days. Rapamycin-PLNPs were shown to be able to effectively bind to hemangioma endothelia cells (HemECs), induce significant proliferation inhibition and reduce expression of angiogenesis factors in HemECs. The therapeutic effect of Rapamycin-PLNPs against infantile hemangioma in vivo was superior to rapamycin, as reflected by reduced hemangioma volume, weight and microvessel density. Taken together, Rapamycin-PLNPs represent a very promising local approach in the treatment of infantile hemangiomas.

Graphical abstract

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YAP1-TEAD1-Glut1 axis dictates the oncogenic phenotypes of breast cancer cells by modulating glycolysis

Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Chunli Lin, Xiaofeng Xu
Altered energy metabolism is a universal property of most cancer cells. The Hippo signaling pathway and its principal downstream effector YAP1 are responsible for tissue homeostasis including organ size, cell proliferation, apoptosis, and differentiation. Dysregulation of the Hippo pathway leads to the activation of YAP1 and further culminates in the development of multiple human cancers. In this study, by loss-of-function assay, we demonstrated that YAP1 contributed to the glycolytic phenotype of breast cancer cells. Knockdown of YAP1 inhibited the extracellular acidification rates, glucose consumption, and lactate production of breast cancer cells. Moreover, YAP1 interacted with TEAD1, exerted their transcriptional control of the functional target, glucose transporter 1 (Glut1). Overexpression of Glut1 restored the inhibitory effects of YAP1 knockdown on glycolysis as demonstrated by glucose consumption and lactate production. Suppression of glycolysis by deprivation of glucose largely compromised the oncogenic roles of YAP1 on cell proliferation, apoptosis, and invasive potential. Taken together, our data identify a novel role of YAP1-TEAD1 pathway in cancer energy metabolism.



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Antinociceptive, anti-inflammatory and anxiolytic-like effects of the ethanolic extract, fractions and Hibalactone isolated from Hydrocotyle umbellata L. (Acariçoba) – Araliaceae

Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Thiago Levi Silva Oliveira, Sandra Ribeiro de Morais, Stone de Sá, Matheus Gabriel de Oliveira, Iziara Ferreira Florentino, Dayane Moreira da Silva, Verônica Vale Carvalho, Vinícius Barreto da Silva, Boniek Gontijo Vaz, José Ricardo Sabino, Elson Alves Costa, José Realino de Paula
Hydrocotyle umbellata Linn. (Araliaceae) is specie used in the treatment of inflammatory diseases. Crude extract (E-HU) was prepared from H. umbellata subterraneous parts and fractionated by liquid-liquid partition, resulting hexane fraction (HF-HU), dichloromethane fraction (DF-HU), ethyl acetate fraction (EAF-HU) and aqueous fraction (AF-HU). The hibalactone (HU-1) was isolated from the DF-HU and its structure was elucidated by ¹H NMR and ¹³C NMR Spectroscopy, mass spectrometry and crystallographic x-ray analysis. The formalin-induced nociception was used to evaluate antinociceptive activity; carrageenan-induced edema and pleurisy tests to evaluate anti-inflammatory activity and light-dark box to evaluate anxiolytic-like activity in mice. The acute oral treatments with E-HU (1000mg/kg), DF-HU (150mg/kg), EAF-HU (400mg/kg) and HU-1 (33mg/kg) decreased the licking time in both phases of the formalin test. In the carrageenan-induced inflammation models, the treatment with the same doses of E-HU, DF-HU, EAF-HU and HU-1 reduced the paw edema formation and leukocytes account into pleural cavity. In silico findings suggest that hibalactone present anti-inflammatory activity by interacting with the enzymes 5-lipoxygenase and cyclooxygenase-2. In the light dark box, the treatments with DF-HU, EAF-HU and HU-1 revealed an anxiolytic like effect. Thus, the E-HU and fractions of H. umbellata showed antinociceptive, anti-inflammatory and anxiolytic like activities, as also hibalactone, a possible phytoconstituent responsible for the biological effects of this specie.

Graphical abstract

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Bamboo leaf extract ameliorates cardiac fibrosis possibly via alleviating inflammation, oxidative stress and apoptosis

Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Lili Zhang, Yizhen Mao, Jiajun Pan, Shanshan Wang, Lei Chen, Jie Xiang
Previous studies have shown that inflammatory process contributes to the pathogenesis of cardiac damage induced by diabetes mellitus. However, the underlying mechanisms and strategies to alleviate inflammatory injury in the diabetic heart are not fully elucidated. In this study, we investigated the potential role and related mechanism of bamboo leaf extract (BLE) on diabetes-induced cardiac fibrosis in rats. Diabetes was induced by streptozocin (STZ) in rats, blood glucose and glycosylated hemoglobin A1c (HbAlc) were measured. Super oxide dismutase (SOD) activity and malondialdehyde (MDA) level in rat heart homogenates were tested using special kits. Cardiac function was evaluated by echocardiography, and myocardial histology was detected by hematoxylin eosin (HE) staining and Masson's trichrome staining. Furthermore, expression of transforming growth factor-β1 (TGF-β1), interleukin 6 (IL-6) and Cleaved-cysteinyl aspartate-specific proteinase-3 (Cleaved-caspase-3), and the activity of nuclear factor κB (NF-κB) were examined by western blot analysis. From the data, we found that the BLE treatment inhibits oxidative stress and improved cardiac function in STZ-induced diabetic rats. BLE treatment significantly ameliorated diabetes-induced myocardial morphological changes and cardiac inflammation. Moreover, the protein levels of TGF-β1, IL-6,Cleaved-caspase-3 and the nuclear transcription of NF-κB in the hearts were markedly reduced in diabetic rats result from BLE treatment. In conclusion, this study suggested that BLE ameliorates cardiac fibrosis in streptozotocin-induced diabetic rats, and this protective effect possibly through inhibiting inflammation, oxidative stress and apoptosis. BLE might serve as a potential therapeutic target for the treatment of the cardiac fibrosis in diabetic patients.



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Development and characterization of hyaluronic acid modified PLGA based nanoparticles for improved efficacy of cisplatin in solid tumor

Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Noor Alam, Mytre Koul, Mubashir J. Mintoo, Vaibhav Khare, Rahul Gupta, Neha Rawat, Parduman Raj Sharma, Shashank K. Singh, Dilip M. Mondhe, Prem N. Gupta
Cisplatin is a potent and widely used chemotherapeutic agent to treat a variety of tumors. However, its clinical use is associated with undesirable side effects and acquired resistance to cisplatin. In this study, cisplatin loaded hyaluronic acid (HA) functionalized poly (lactic-co-glycolic acid)–poly (ethylene glycol) nanoparticles (CP-HA-PLGA-PEG-NPs) were fabricated using double emulsion solvent evaporation method to target CD44 receptor expressed on cancerous cells. The developed nanoconstructs were characterized for various in vitro parameters, including size distribution, zeta potential, morphology, drug loading and in vitro release. The HA content on the HA-PLGA-PEG-NPs was quantified by a turbidimetric method. The in vitro anticancer study in human ovarian cancer (SKOV-3) cells showed significantly (p<0.05) higher cytotoxicity of CP-HA-PLGA-PEG NPs as compared to free cisplatin and non-targeted nanoparticles (CP-PLGA-PEG NPs). Further, laser scanning confocal microscopy revealed that there was enhanced cellular uptake of HA-PLGA-PEG NPs in CD44-over expressing ovarian cancer cell line (SKOV-3). The in vivo antitumor activity of CP-HA-PLGA-PEG-NPs was significantly (p<0.05) higher than free cisplatin and CP-PLGA-PEG-NPs in Ehrlich tumor (solid) bearing mice. The results demonstrated the potential of target specific nanoconstruct of cisplatin in the improved cancer chemotherapy.

Graphical abstract

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Mixed micelles for encapsulation of doxorubicin with enhanced in vitro cytotoxicity on breast and ovarian cancer cell lines versus Doxil®

Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Maximiliano Cagel, Ezequiel Bernabeu, Lorena Gonzalez, Eduardo Lagomarsino, Marcela Zubillaga, Marcela A. Moretton, Diego A. Chiappetta
Doxorubicin (DOX) is used as a "first-line" antineoplastic drug in ovarian and metastatic breast cancer. However, serious side effects, such as cardiotoxicity have been reported after DOX intravenous administration. Hence, we investigated different micelle-former biomaterials, as Soluplus^®, Pluronic F127, Tetronic T1107 and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) to develop a potential mixed micellar nanocarrier for DOX delivery. Since DOX hydrochloride is a poor candidate to be encapsulated inside the hydrophobic core of the mixed micelles, we assayed a hydrophobic complex between DOX and sodium deoxycholate (NaDC) as an excellent candidate to be encapsulated within polymeric micelles. The combination of T1107:TPGS (1:3, weight ratio) demonstrated the best physicochemical properties together with a high DL capacity (6.43% w/v). Particularly, DOX in vitro release was higher at acidic tumour microenvironment pH value (5.5) than at physiological counterpart (7.4). The hydrodynamic diameter of the DOX/NaDC-loaded mixed micellar system was 10.7nm (PDI=0.239). The in vitro cytotoxicity of the mixed micellar formulation resulted significantly (p<0.05) higher than Doxil^® against ovarian (SKOV-3) and triple-negative breast cancer cells (MDA-MB- 231). Further, the in vitro cellular uptake assays demonstrated a significant increment (p<0.05) of the DOX intracellular content for the mixed micelles versus Doxil^® for both, SKOV-3 (at 2, 4 and 6h of incubation) and MDA-MB-231 (at 4h of incubation) cells. These findings suggest that T1107:TPGS (1:3) mixed micelles could be employed as a potential nanotechnological platform for drug delivery of DOX.

Graphical abstract

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In vitro, In silico and In vivo Antitumor Activity of Crude Methanolic Extract of Tetilla dactyloidea (Carter, 1869) on DEN Induced HCC in a Rat Model

Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Gowri Shankar Krishnan, Vidhya Rajagopal, Sophy Renilda Antony Joseph, Divya Sebastian, Ignacimuthu Savarimuthu, Karthick Raja Namasivayam Selvaraj, Albin Fleming Thobias
Tetilla dactyloidea (Carter, 1869) is a marine sponge classified under Demospongia and recent studies have demonstrated that active constituents of Demospongia class have exhibited several potential medical applications. However, no preliminary pharmacological studies have been reported so far. The present investigation was carried out to evaluate the zoo-chemical status, antioxidant potential and anticancer activity of Crude Methanolic Extract of Tetilla dactyloidea (CMETD). Hepatocellular Carcinoma (HCC) was induced in the liver of male Sprague Dawley (SD) rats by treating with diethylnitrosamine (DEN). Nodule incidence, body weight, liver marker enzymes, enzymatic and non-enzymatic antioxidant, phase I metabolizing and liver macromolecular damaging enzymes and immuno-histopathological changes were assessed in DEN and DEN+CMETD treated rats. Oral administration of CMETD at a dose of 400mg/kg body weight to DEN treated rats restored the above parameters to near normal levels compared to control. The biochemical results were consistent with histopathological observations suggesting marked hepatoprotective effect of CMETD in a dose dependent manner. The GCMS of CMETD analysis showed the presence of six compounds. In in silico analysis 9-Octadecenoic acid (Z)-, 2-hydroxy-1-(hydroxymethyl) ethyl ester ligand showed an effective binding energy of −7.1kcal/mol against Cox-2 receptor. The compounds showed desirable pharmacokinetic properties and significant molecular interactions with the HCC receptors. To conclude, our results clearly suggested that CMETD treatment prevented liver damage, protected the antioxidant defense system and possessed anti-carcinogenic potential in DEN induced hepatic carcinoma.



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Homoisoflavonoids as potential antiangiogenic agents for retinal neovascularization

Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Sk. Abdul Amin, Nilanjan Adhikari, Shovanlal Gayen, Tarun Jha
A number of people worldwide have been suffering from ocular neovascularization that may be treated by a variety of drugs but these may possess adverse effects. Therefore, small antiangiogenic molecules with higher potency and lower toxic effects are intended. However, homoisoflavonoids of natural origin show the potential antiangiogenic effect in ocular neovascularization. These homoisoflavonoids are judged quantitatively in terms of statistical validation through multi-chemometric modeling approaches for the betterment and refinement of their structures required for higher antiangiogenic activity targeted to ocular neovascularization. These approaches may be utilized to design better antiangiogenic homoisoflavonoids.

Graphical abstract

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The effects of β-caryophyllene oxide and trans-nerolidol on the efficacy of doxorubicin in breast cancer cells and breast tumor-bearing mice

Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Veronika Hanušová, Kateřina Caltová, Hana Svobodová, Martin Ambrož, Adam Skarka, Natálie Murínová, Věra Králová, Pavel Tomšík, Lenka Skálová
BackgroundOne approach to improve effect of chemotherapy is combination of classical cytostatic drugs with natural compounds, e. g. sesquiterpenes. In our previous study, sesquiterpenes β-caryophyllene oxide (CAO) and trans-nerolidol (NER) improved the anti-proliferative effect of doxorubicin (DOX) in intestinal cancer cell lines.PurposeThe present study was designed to evaluate the effect of CAO and NER on DOX efficacy, focusing on cell proliferation, migration, apoptosis and DOX accumulation in breast cancer cells MDA-MB-231 and MCF7 in vitro and in mice bearing solid Ehrlich tumors (EST) in vivo.MethodsThe impact of cytotoxic effect was assessed by the neutral red uptake test. The ability to migrate was tested using real-time measurement in x-CELLigence system. Expressions of molecules were examined using western blot analysis. The accumulation of DOX inside the cells using time lapse microscopy was observed. The mice with inoculated EST cells were treated repeatedly with DOX and DOX+CAO or DOX+NER and the growth of tumors were monitored. DOX concentrations in plasma and tumor were assayed using HPLC.ResultsIn MDA-MB-231, combination of DOX with CAO enhanced anti-proliferative effect and acted strongly synergistic. NER increased accumulation of DOX inside the cells; moreover combination DOX with NER suppressed migration ability in vitro. In vivo, apoptosis was activated especially in group treated with DOX and CAO. However, none of tested sesquiterpenes was able to improve DOX accumulation in tumors and DOX-mediated inhibition of tumor growth.ConclusionIn conclusion, sesquiterpenes CAO and NER increased the efficacy of DOX in breast cancer cells in vitro, but did not improve its effect in vivo, in Ehrlich solid tumor bearing mice.

Graphical abstract

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Diamine derivative anti-Trichomonas vaginalis and anti-Tritrichomonas foetus activities by effect on polyamine metabolism

Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Graziela Vargas Rigo, Márcia Rodrigues Trein, Danielle da Silva Trentin, Alexandre José Macedo, Bruno Assis de Oliveira, Angelina Maria de Almeida, Raquel Brandt Giordani, Mauro Vieira de Almeida, Tiana Tasca
Human and bovine trichomoniasis are sexually transmitted diseases (STD) caused by Trichomonas vaginalis and Tritrichomonas foetus, respectively. Human trichomoniasis is the most common non-viral STD in the world and bovine trichomoniasis causes significant economic losses to breeders. Considering the significant impact of the infections caused by these protozoa and the treatment failures, the search for new therapeutic alternatives becomes crucial. In this study the effect of diamines and amino alcohols in the in vitro viability of trichomonads was evaluated. Screening demonstrated the high activity of diamine 4 against these protozoa. Although cytotoxicity against HMVII cell line and slight hemolysis were observed in vitro, the compound showed no toxic effect on the Galleria mellonella in vivo model. Importantly, diamine 4 was active against both trichomonads species at 6h and 24h of incubation, and these effects was reverted by putrescine, a polyamine, suggesting competition for the same metabolic pathway. These findings indicate that the mechanism of action of diamine 4 is through the polyamine metabolism, a pathway distinct from that presented by metronidazole, the drug usually used to treat trichomoniasis and to which resistance is widely reported. These data demonstrate the importance of diamines as potential novel candidates as anti-T. vaginalis and anti-T. foetus agents.

Graphical abstract

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Molecular estimation of alteration in intestinal microbial composition in Hashimoto’s thyroiditis patients

Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Hafiz Muhammad Ishaq, Imran Shair Mohammad, Hui Guo, Muhammad Shahzad, Yin Jian Hou, Chaofeng Ma, Zahid Naseem, Xiaokang Wu, Peijie Shi, Jiru Xu
The gut microbiota has a crucial effect on human health and physiology. Hypothyroid Hashimoto's thyroiditis (HT) is an autoimmune disorder manifested with environmental and genetic factors. However, it is hypothesized that intestinal microbes might play a vital role in the pathogenesis of HT. The aim of current was to investigate and characterize the gut microbial composition of HT patients both quantitatively and qualitatively. The fecal samples from 29 HT patients and 12 healthy individuals were collected. The PCR-DGGE targeted V3 site of 16S rRNA gene and real time PCR for Bifidobacterium Lactobacillus, Bacteroides vulgatus and Clostridium leptum were performed. Pyrosequencing of 16S rRNA gene with V4 location was performed on 20 randomly selected samples. The comparative analysis of diversity and richness indices revealed diversification of gut microbiota in HT as compared to control. The statistical data elucidate the alterations in phyla of HT patients which was also affirmed at the family level. We observed the declined abundance of Prevotella_9 and Dialister, while elevated genera of the diseased group included Escherichia-Shigella and Parasutterella. The alteration in gut microbial configuration was also monitored at the species level, which showed an increased abundance of E. coli in HT. Therefore, the current study is in agreement with the hypothesis that HT patients have intestinal microbial dysbiosis. The taxa statistics at species-level along with each gut microbial community were modified in HT. Thus, the current study may offer the new insights into the treatment of HT patients, disease pathway, and mechanism.

Graphical abstract

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Dexmedetomidine exerts neuroprotective effect via the activation of the PI3K/Akt/mTOR signaling pathway in rats with traumatic brain injury

Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Min Shen, Shan Wang, Xin Wen, Xin-Rui Han, Yong-Jian Wang, Xiu-Min Zhou, Man-He Zhang, Dong-Mei Wu, Jun Lu, Yuan-Lin Zheng
Objective: This study aims to explore the neuroprotective effects of dexmedetomidine (Dex) in rats suffering from traumatic brain injury (TBI) via the PI3K/Akt/mTOR signaling pathway.MethodsA weight drop model was performed for TBI model establishment. A total of 150 Sprague Dawley rats were selected and assigned into control, sham, TBI, TBI+Dex, TBI+LY294002 (LY) and TBI+Dex+LY groups. Modified Neurological Severity Score (mNSS) was conducted in order to evaluate the neurological injury. The water content in brain tissues was measured. The expressions of PI3K/Akt/mTOR signaling pathway-related proteins, tight junction proteins (ZO-1 and Claudin-5) and autophagy proteins (LC3 I/II and Beclin-1) were detected using Western blot assay. A TUNEL assay was applied for cell apoptosis, immunofluorescence was employed for the detection of the positive expression of LC3, and ELISA was applied for detection of levels of inflammatory factors [tumor necrosis factor-alph (TNF-a), interleukin-1β (IL-1β), interferon-γ (INF-γ) as well as IL-6], respectively.ResultsCompared with the control group, the other four groups exhibited increased mNSS, brain water content, expression of LC3, TNF-a, IL-1β, INF-γ and IL-6, and positive expression of LC3, expression of LC3 I/II and Beclin-1, but decreased expression of pp-PI3K/t-PI3K, p-Akt/t-Akt, p-mTOR/t-mTOR, ZO-1 and Claudin-5. Compared with the TBI group, the TBI+Dex group exhibited reduced mNSS, brain water content, expression of LC3, TNF-a, IL-1β, INF-γ and IL-6, positive expression of LC3, as well as expression of LC3 I/II and Beclin-1 but demonstrated an elevated expression of pp-PI3K/t-PI3K, p-Akt/t-Akt, p-mTOR/t-mTOR, ZO-1 and Claudin-5, while opposite trends were observed in the TBI+LY group. The TBI+Dex group exhibited reduced mNSS, brain water content, expression of LC3, TNF-a, IL-1β, INF-γ and IL-6, positive expression of LC3, as well as expression of LC3 I/II and Beclin-1 but demonstrated an elevated expression of pp-PI3K/t-PI3K, p-Akt/t-Akt, p-mTOR/t-mTOR, ZO-1 and Claudin-5, while opposite trends were observed in the TBI+LY group, as compared with the TBI+Dex+LY group.ConclusionThe data shows that Dex exerts a neuroprotective effect via the activation of the PI3K/Akt/mTOR signaling pathway in rats with TBI.



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Maslinic acid inhibits impairment of endothelial functions induced by high glucose in HAEC cells through improving insulin signaling and oxidative stress

Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Feng Li, Qingxian Li, Xianai Shi, Yanghao Guo
Impaired endothelial functions are closely associated with many chronic vascular-related diseases. Maslinic acid (MA), a natural pentacyclic triterpene compound, has received more and more attentions in recent years due to a variety of bioactivities. In the present study, we investigated the effect of MA on impaired endothelial functions in human aortic endothelial cells (HAEC) induced by high glucose treatment and discussed its possible mechanism. We showed that MA decreased the ROS level, inhibited the inflammatory cytokines expression, facilitated insulin-mediated IRS-1/PI3K/Akt/eNOS signaling and suppressed the cellular apoptosis ratio induced by high glucose. The molecular docking results showed that MA may regulate multiple targets to improve the endothelial dysfunction in HAECs exposed to high glucose. These results revealed potential application of MA in improving endothelia dysfunction.



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Hormonal and genetic factors interact to control aromatase expression in the developing brain

Abstract

The brain expression of the enzyme P450-aromatase has been extensively studied. Since the aromatization hypothesis established brain aromatase as a key factor to convert gonadal testosterone to oestradiol, several studies have investigated the regulation of aromatase during the critical period of brain sexual differentiation. Here, we review previous and recent findings concerning regulation of aromatase. The role of gonadal hormones, sex chromosome genes and neurosteroids is analysed in term of their contribution to aromatase expression and the implications for the organizational effect of steroids during development.

This article is protected by copyright. All rights reserved.

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The changing landscape of dermatology practice: melanoma and pump-probe laser microscopy

Abstract

To present current melanoma diagnosis, staging, prognosis, and treatment algorithms and how recent advances in laser pump-probe microscopy will fill in the gaps in our clinical understanding. Expert opinion and significantly cited articles identified in SCOPUS were used in conjunction with a pubmed database search on Melanoma practice guidelines from the last 10 years. Significant advances in melanoma treatment have been made over the last decade. However, proper treatment algorithm and prognostic information per melanoma stage remain controversial. The next step for providers will involve the identification of patient population(s) that can benefit from recent advances. One method of identifying potential patients is through new laser imaging techniques. Pump-probe laser microscopy has been shown to correctly identify nevi from melanoma and furthermore stratify melanoma by aggressiveness. The recent development of effective adjuvant therapies for melanoma is promising and should be utilized on appropriate patient populations that can potentially be identified using pump-probe laser microscopy.

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Effect of hydrophobicity of pharmaceuticals and personal care products for adsorption on activated carbon: Adsorption isotherms, kinetics and mechanism

Abstract

Adsorption of three pharmaceuticals and personal care products (PPCPs), namely caffeine, ibuprofen and triclosan on commercial powdered activated carbon was examined in aqueous medium. The contaminants were chosen based on their diverse log K_ow (octanol-water partition coefficient) viz. − 0.07 for caffeine, 3.97 for ibuprofen and 4.76 for triclosan to examine the role of hydrophobicity on adsorption process. The adsorbent characterisation was achieved using BET surface area, SEM, pore size distribution studies and FTIR. Influence of mass of PAC, contact time, solution pH and initial concentration on adsorption capacity of PAC was studied. Adsorption isotherms and kinetics were applied to establish the mechanism of adsorption. The kinetics followed pseudo-second order with physisorption occurring through particle diffusion. The Freundlich model fitted best among the isotherm models. The adsorption capacity increased in the order CFN < IBU < TCS which correlates with increasing hydrophobicity (log K_ow), molecular weight and decreasing water solubility, respectively. We conclude that micro-pollutant hydrophobicity contributes towards adsorption on activated carbon.

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Hyperirritable stomach as a cause of obstructive symptoms after sleeve gastrectomy: clinical and radiographic findings

Publication date: Available online 10 September 2017
Source:Clinical Imaging
Author(s): Amelia M. Wnorowski, Marc S. Levine, Stephen E. Rubesin, Noel N. Williams, Kristoffel R. Dumon
PurposeTo characterize clinical and radiographic features of a hyperirritable stomach after sleeve gastrectomy.Materials/methodsRadiology reports revealed that 10/76 patients (13%) with obstructive symptoms after sleeve gastrectomy had a hyperirritable stomach.ResultsAll 10 patients presented with nausea, vomiting, and/or regurgitation. All 10 had emesis on barium studies in the absence of gastric outlet obstruction, gastroparesis, or small bowel obstruction/ileus. Five had extraintestinal causes of nausea/vomiting. Eight had improvement/resolution of symptoms on medical treatment.ConclusionIn 13% of patients with nausea/vomiting after sleeve gastrectomy, barium studies revealed a hyperirritable stomach, which likely is multifactorial and self-limited in most patients.



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The new targeted therapy in systemic lupus erythematosus: Is the glass half-full or half-empty?

Publication date: Available online 9 September 2017
Source:Autoimmunity Reviews
Author(s): Andrea Doria, Ricard Cervera, Mariele Gatto, Gamal Chehab, Matthias Schneider
Biologic therapy is still limited in lupus, where chronic steroid exposure and wide-spectrum immunosuppression are major triggers of organ damage.In this viewpoint, the authors summarize their views for a "half-full or half-empty" glass on targeted therapy in SLE.The are several reasons for seeing the glass half-empty and in this section the authors propose a critical reflection on scarceness of novel targeted lupus therapies. They show how hard it is to identify suitable biological and clinical targets and to choose the patients that may best fit those targets, as well as to stratify patients according to disease subtype and response, all contributing to the final outcome.On the other hand, reasons are emerging to see the glass half-full, including the growing evidence that disease activity and damage can both be hindered by the proper use of novel drugs and that promising molecules are upcoming. In this section, the authors contextualize potentials and failures of new drugs, providing a critical reading of disappointing results and underlining the concrete benefits obtainable through a wise use of available treatments.Indeed, combining medications with new therapeutic strategies such as the treat-to-target seems the right approach to add some water to a filling glass.



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Can we withdraw anticoagulation in patients with antiphospholipid syndrome after seroconvertion?

Publication date: Available online 9 September 2017
Source:Autoimmunity Reviews
Author(s): S. Sciascia, E. Coloma-Bazán, M. Radin, M.L. Bertolaccini, C. López-Pedrera, Gerard Espinosa, P.L. Meroni, R. Cervera, M.J. Cuadrado
The current mainstay of treatment in patients with thrombotic antiphospholipid syndrome (APS) is long-term anticoagulation, mainly with Vitamin K antagonist agents. Some recently available studies have created new ground for discussion about the possible discontinuation of anticoagulation therapy in patients with a history of thrombotic APS in whom antiphospholipid antibodies (aPL) are not detected any longer (i.e. aPL seroconversion).We report the main points discussed at the last CORA Meeting regarding the issue whether or not anticoagulation can be stopped after aPL seroconversion. In particular, we systematically reviewed the available evidence investigating the clinical outcome of APS patients with aPL seroconversion in whom anticoagulation was stopped when compared to those in whom therapy was continued regardless the aPL profile. Furthermore, the molecular basis for the aPL pathogenicity, the available evidence of non-criteria aPL and their association with thrombosis are addressed.To date, available evidence is still limited to support the indication to stop oral anticoagulation therapy in patients with a previous diagnosis of thrombotic APS who subsequently developed a negative aPL profile. The identification of the whole risk profile for cardiovascular manifestations and possibly of a second level aPL testing in selected patients with aPL might support the eventual clinical decision but further investigation is warranted.



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Neutrophil extracellular traps (NETs) in autoimmune diseases: A comprehensive review

Publication date: Available online 9 September 2017
Source:Autoimmunity Reviews
Author(s): Keum Hwa Lee, Andreas Kronbichler, David Duck-Young Park, YoungMin Park, Hanwool Moon, Hyungdo Kim, Jun Hyug Choi, YoungSeo Choi, Songjoo Shim, Il Suk Lyu, Byung Hwan Yun, Yeonseung Han, Donghee Lee, Sang Yoon Lee, Byung Hun Yoo, Kyung Hwan Lee, Tai Lim Kim, Heonki Kim, Joo Sung Shim, Wonseok Nam, Heesung So, SooYeon Choi, Sangmok Lee, Jae Il Shin
The structures named neutrophil extracellular traps (NETs) are fibrous networks which protrude from the membrane of activated neutrophils. NETs are found in a variety of conditions, such as infection, malignancy, atherosclerosis, and autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), psoriasis, and gout. The impact of NETs on the development mechanisms of autoimmune diseases are proposed to arise from an imbalance between "NETosis" which is a process of NET formation and NET degradation. Neutrophils, interleukin-8, ANCA and other many inflammatory molecules are considered to play a key role in NET formation. In this way, prolonged exposure to these abnormal cascade of NETs affect autoimmunity and increase the chance of systemic organ damage. In this review, we will discuss the specific roles of various inflammatory molecules in relationship to NETs. We will also provide evidence of the importance of NETs in the pathogenesis of autoimmune diseases and furthermore highlight the potential that target therapies may influence NET formation and associated molecules.



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Humanistic and cost burden of systemic sclerosis: A review of the literature

Publication date: Available online 9 September 2017
Source:Autoimmunity Reviews
Author(s): Aryeh Fischer, Evelina Zimovetz, Caroline Ling, Dirk Esser, Nils Schoof
BackgroundSystemic sclerosis (SSc), or systemic scleroderma, is a chronic multisystem autoimmune disease characterised by widespread vascular injury and progressive fibrosis of the skin and internal organs. Patients with SSc have decreased survival, with pulmonary involvement as the main cause of death. Current treatments for SSc manage a range of symptoms but not the cause of the disease. Our review describes the humanistic and cost burden of SSc.MethodsA structured review of the literature was conducted, using predefined search strategies to search PubMed, Embase, and the Cochrane Library. Grey literature searches also were conducted.ResultsIn total, 2226 articles were identified in the databases and 52 were included; an additional 10 sources were included from the grey literature. The review identified six studies reporting relevant cost estimates conducted in five different countries and four studies that assessed the humanistic burden of SSc. Total direct annual medical costs per patient for Europe varied from €3544 to €8452. For Canada, these costs were reported to be from Can$5038 to Can$10,673. In the United States, the total direct health care costs were reported to be US$17,365 to US$18,396. Different key drivers of direct costs were reported, including hospitalisations, outpatients, and medication. The total annual costs per patient were reported at Can$18,453 in Canada and varied from €11,074 to €22,459 in Europe. Indirect costs represented the largest component of the total costs. EQ-5D utility scores were lower for patients with SSc than those observed in the general population, with reported mean values of 0.49 and 0.68, respectively. The average value of the Health Assessment Questionnaire for patients with SSc was significantly higher than the control population (0.94), and the average value of the SF-36 was significantly lower than the control population: 49.99 for the physical dimension and 58.42 for the mental dimension.ConclusionsOverall, there is a paucity of information on the burden of SSc. Nonetheless, our review indicates that the quality of life of patients with SSc is considerably lower than that of the general population. In addition, SSc places a considerable economic burden on health care systems and society as a whole.



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Is PET/CT essential in the diagnosis and follow-up of temporal arteritis?

Publication date: Available online 9 September 2017
Source:Autoimmunity Reviews
Author(s): Carlo Salvarani, Alessandra Soriano, Francesco Muratore, Yehuda Shoenfeld, Daniel Blockmans
The increasing availability and improvement of imaging techniques are deeply influencing diagnosis and work-up of patients affected with vasculitis, particularly those with large vessel vasculitis (LVV). Fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET), especially when integrated with computed tomography (CT), is taking hold as a useful diagnostic technique to examine the aorta and the other large vessels in giant cell arteritis (GCA) with concomitant large vessel involvement (LV-GCA). In this paper we examined the progresses performed in this field in the last twenty years and the evidence available so far according to two different points of view ('pros' and 'cons'), in order to give a comprehensive answer to a still open question about the role of PET/CT in the diagnosis and follow-up of GCA.



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Should we treat congenital heart block with fluorinated corticosteroids?

Publication date: Available online 9 September 2017
Source:Autoimmunity Reviews
Author(s): Antonio Brucato, Angela Tincani, Micaela Fredi, Silvia Breda, Veronique Ramoni, Nathalie Morel, Nathalie Costedoat-Chalumeau




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Bone mineral density and vitamin D status in systemic lupus erythematosus (SLE): A systematic review

Publication date: Available online 9 September 2017
Source:Autoimmunity Reviews
Author(s): Tarek Carlos Salman-Monte, Vicenç Torrente-Segarra, Ana Leticia Vega Vidal, Patricia Corzo, F. Castro-Dominguez, F. Ojeda, Jordi Carbonell Abelló
Despite the improvement in the quality of life of patients with SLE due to scientific and technological advances, SLE remains a disease that over the years may produce irreversible damage to patients. Osteoporosis and secondary bone fractures are two of the major causes of irreparable injury in patients with SLE. Vitamin D insufficiency may play a vital role both in reduced Bone Mineral Density (BMD) and in the appearance of fractures, although its mechanisms of action are still unclear. We performed a systematic review of the literature in order to determine the prevalence and predictors of reduced vitamin D plasma levels, bone loss and the presence of fractures in SLE patients. Our review encompassed all English-language publications using Medline and EMBase electronic databases from their inception (1966 and 1980, respectively) to December 2016. We included all intervention studies and observational studies in which vitamin D plasma levels, BMD and bone loss were measured and applied to patients with SLE. Previous studies suggested an increase in bone loss and fracture in patients with SLE compared with general population and although there is a high prevalence of vitamin D insufficiency in the general population, previous studies had demonstrated lower vitamin D levels in patients with SLE compared to age-matched controls. The etiology of reduced bone mass and reduced vitamin D plasma levels in SLE is multifactorial and includes a variety of intrinsic factors related to the disease itself and treatment side effects. SLE patients are at risk for developing these two comorbidities (reduced vitamin D plasma levels and low BMD) and it is therefore essential to study, monitor, prevent and treat bone metabolism disorders in SLE patients.



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Is ACPA positivity the main driver for rheumatoid arthritis treatment? Pros and cons

Publication date: Available online 9 September 2017
Source:Autoimmunity Reviews
Author(s): Stefano Alivernini, Mauro Galeazzi, Hagit Peleg, Barbara Tolusso, Elisa Gremese, Gianfranco Ferraccioli, Yaakov Naparstek
Rheumatoid Arthritis (RA) is an autoimmune chronic disease that is characterized by the positivity of various antibodies, the most specific being autoantibodies against citrullinated antigens (ACPA). Despite ACPA are not arthritogenic by themselves, ACPA positive individuals have high risk of RA development and ACPA positivity is associated with severe erosive phenotype and higher mortality rate compared to seronegative RA. Moreover, ACPA status is associated with favorable response to biologics targeting pathways involving autoantibody producing cells as B lymphocytes. In the current review we have discussed the pros and cons on the available scientific evidences, regarding the diagnostic, prognostic and management implications of ACPAs in RA.



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The role of nuclear NS1 protein in highly pathogenic H5N1 influenza viruses

Publication date: Available online 10 September 2017
Source:Microbes and Infection
Author(s): Bobo Wing-Yee Mok, Honglian Liu, Pin Chen, Siwen Liu, Siu-Ying Lau, Xiaofeng Huang, Yen-Chin Liu, Pui Wang, Kwok-Yung Yuen, Honglin Chen
The non-structural protein (NS1) of influenza A viruses (IAV) performs multiple functions during viral infection. NS1 contains two nuclear localization signals (NLS): NLS1 and NLS2. The NS1 protein is located predominantly in the nucleus during the early stages of infection and subsequently exported to the cytoplasm. A nonsense mutation that results in a large deletion in the carboxy-terminal region of the NS1 protein that contains the NLS2 domain was found in some IAV subtypes, including highly pathogenic avian influenza (HPAI) H7N9 and H5N1 viruses. We introduced different mutations into the NLS domains of NS1 proteins in various strains of IAV, and demonstrated that mutation of the NLS2 region in the NS1 protein of HPAI H5N1 viruses severely affects its nuclear localization pattern. H5N1 viruses expressing NS1 protein that is unable to localize to the nucleus are less potent in antagonizing cellular antiviral responses than viruses expressing wild-type NS1. However, no significant difference was observed with respect to viral replication and pathogenesis. In contrast, the replication and antiviral defenses of H1N1 viruses are greatly attenuated when nuclear localization of the NS1 protein is blocked. Our data reveals a novel functional plasticity for NS1 proteins among different IAV subtypes.



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Highly conserved M2e and hemagglutinin epitope-based recombinant proteins induce protection against influenza virus infection

Publication date: Available online 10 September 2017
Source:Microbes and Infection
Author(s): Yan Guo, Lei He, Nianping Song, Pei Li, Shihui Sun, Guangyu Zhao, Wanbo Tai, Shibo Jiang, Lanying Du, Yusen Zhou
Highly pathogenic influenza viruses continue to cause serious threat to public health due to their pandemic potential, calling for an urgent need to develop effective, safe, convenient, and universal vaccines against influenza virus infection. In this study, we constructed two recombinant protein vaccines, 2H5M2e-2H7M2e-H5FP-H7FP (hereinafter M2e-FP-1) and 2H5M2e-H5FP-2H7M2e-H7FP (hereinafter M2e-FP-2), by respectively linking highly conserved sequences of two molecules of ectodomain of M2 (M2e) and one molecule of fusion peptide (FP) epitope of hemagglutinin (HA) of H5N1 and H7N9 influenza viruses in different orders. The E.coli-expressed M2e-FP-1 and M2e-FP-2 proteins induced similarly high-titer M2e-FP-specific antibodies in the immunized mice. Importantly, both proteins were able to prevent lethal challenge of heterologous H1N1 influenza virus, with significantly reduced viral titers and alleviated pathological changes in the lungs, as well as increased body weight and complete survivals, in the challenge mice. Taken together, our study demonstrates that highly conserved M2e and FP epitope of HA of H5N1 and H7N9 influenza viruses can be used as important targets for development of safe and economical universal influenza vaccines, and that the position of H7N9 M2e and H5N1 HA epitope sequences in the vaccine components had no significant effects on the immunogenicity and efficacy of M2e-FP-based subunit vaccines.



http://ift.tt/2wRjVty

Complete sequence of the ATP6 and ND3 mitochondrial genes in breast cancer tissue of postmenopausal women with different body mass indexes

Publication date: Available online 10 September 2017
Source:Annals of Diagnostic Pathology
Author(s): Mónica Martínez-Ramírez, Ramón Mauricio Coral-Vázquez, Alberto Tenorio, Juan Pablo Méndez, Jesús Benítez-Granados, Antonio Maffuz Asis, Sergio Rodríguez Cuevas, Carlos Domínguez Reyes, Aura Erazo-Valle, Patricia Canto
Due to the fact that mitochondrial defects and oxidative stress have been related with obesity and breast cancer is more aggressive in women with obesity, we investigated if postmenopausal Mexican-Mestizo women with breast cancer presented somatic mutations in the sequence of the ATP6 and/or ND3 genes. Twenty one postmenopausal Mexican-Mestizo women with breast cancer who underwent mastectomy or breast conserving surgery were studied. Height and weight were used to calculate body mass index. DNA from tumor tissue samples and blood leukocytes was amplified by polymerase chain reaction and sequenced the ATP6 and ND3 mitochondrial genes. Ages ranged from 46 to 82. According to World Health Organization criteria among the 21 women, 7 had a normal BMI, 7 were overweight and 7 had obesity. In regard to the molecular study, after sequencing the coding region of ATP6 and ND3 genes of the DNA obtained from both leukocytes and tumor tissue, we did not find somatic mutations. All of the changes that we found in both genes were polymorphisms: in ATP6, we identified in ten patients 3 non-synonymous nucleotide changes and in ND3 we observed that six patients presented polymorphisms, three of them were synonymous and two non-synonymous.To our knowledge, this constitutes the first report where the complete sequence of the ATP6 and ND3 genes has been analyzed in postmenopausal Mexican-Mestizo women with breast cancer and diverse BMI. Our results differ with those reported in Caucasian and Asian populations, possibly due to ethnic differences.



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1-D and 2-D morphology of metal cation co-doped (Zn, Mn) TiO2 and investigation of their photocatalytic activity

Publication date: 1 January 2018
Source:Applied Surface Science, Volume 427, Part B
Author(s): Poonam Benjwal, Bibekananda De, Kamal K. Kar
Morphology and electronic bandgap of titania (TiO2) are considered to be the primary factors for determining the photocatalytic efficiency, as they determine the number of active sites for the photocatalytic reactions. In the present study, two different morphologies of TiO2 (nanosphere and nanorod) with varying Zn and Mn co-doping were synthesized by solvothermal and hydrothermal methods to examine their photocatalytic efficiency by methylene blue degradation. The co-doped photocatalysts were characterized by XRD, XPS, SEM, TEM, Raman, FTIR and UV–vis DRS. Further, a comparison has been made with co-doped TiO2 nanospheres and TiO2 nanorods, where Zn, Mn co-doped TiO2 nanorods show higher photocatalytic activity compared to nanospheres. This higher photocatalytic activity of co-doped TiO2 is attributed to its polymorphic phases, as they act as heterojunctions for TiO2. Further, being 1-D nanostructure, the TiO2 nanorods exhibit the straight diffusion path for charge carriers, which reduces the recombination possibilities. The obtained results suggest that the photocatalysis efficiency of TiO2 can be significantly enhanced by tailoring the shape and co-doping concentration, which enforce a new concept for developing the new nanostructures of TiO2.

Graphical abstract

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Design and evaluation of novel natriuretic peptide derivatives with improved pharmacokinetic and pharmacodynamic properties

Publication date: Available online 9 September 2017
Source:Peptides
Author(s): Naomi Morozumi, Seiji Sato, Sayaka Yoshida, Yuriko Harada, Mayumi Furuya, Yoshiharu Minamitake, Kenji Kangawa
C-type natriuretic peptide (CNP) and its receptor, natriuretic peptide receptor B (NPR-B), are potent positive regulators of endochondral bone growth, making the CNP pathway one of the most promising therapeutic targets for the treatment of growth failure. However, the administration of exogenous CNP is not fully effective, due to its rapid clearance in vivo. Modification of CNP to potentially druggable derivatives may result in increased resistance to proteolytic degradation, longer plasma half-life (T1/2), and better distribution to target tissues. In the present study, we designed and evaluated CNP/ghrelin chimeric peptides as novel CNP derivatives. We have previously reported that the ghrelin C-terminus increases peptide metabolic stability. Therefore, we combined the 17-membered, internal disulfide ring portion of CNP with the C-terminal portion of ghrelin. The resultant peptide displayed improved biokinetics compared to CNP, with increased metabolic stability and longer plasma T1/2. Repeated subcutaneous administration of the chimeric peptide to mice resulted in a significant acceleration in longitudinal growth, whereas CNP(1-22) did not. These results suggest that the ghrelin C-terminus improves the stability of CNP, and the chimeric peptide may be useful as a novel therapeutic agent for growth failure and short stature.



http://ift.tt/2wiGGSD

Patterns of trunk muscle activation during walking and pole walking using statistical non-parametric mapping

Publication date: Available online 9 September 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Luca Zoffoli, Massimiliano Ditroilo, Ario Federici, Francesco Lucertini
This study used surface electromyography (EMG) to investigate the regions and patterns of activity of the external oblique (EO), erector spinae longissimus (ES), multifidus (MU) and rectus abdominis (RA) muscles during walking (W) and pole walking (PW) performed at different speeds and grades. Eighteen healthy adults undertook W and PW on a motorized treadmill at 60% and 100% of their walk-to-run preferred transition speed at 0% and 7% treadmill grade. The Teager-Kaiser energy operator was employed to improve the muscle activity detection and statistical non-parametric mapping based on paired t-tests was used to highlight statistical differences in the EMG patterns corresponding to different trials. The activation amplitude of all trunk muscles increased at high speed, while no differences were recorded at 7% treadmill grade. ES and MU appeared to support the upper body at the heel-strike during both W and PW, with the latter resulting in elevated recruitment of EO and RA as required to control for the longer stride and the push of the pole. Accordingly, the greater activity of the abdominal muscles and the comparable intervention of the spine extensors supports the use of poles by walkers seeking higher engagement of the lower trunk region.



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Female rats exhibit less avoidance than male rats of a cocaine-, but not a morphine-paired, saccharin cue

Publication date: Available online 9 September 2017
Source:Brain Research Bulletin
Author(s): Christopher B. Jenney, Jinju Dasalla, Patricia S. Grigson
Rats avoid intake of an otherwise palatable taste cue when paired with drugs of abuse (Grigson and Twining, 2002). In male rats, avoidance of drug-paired taste cues is associated with conditioned blunting of dopamine in the nucleus accumbens (Grigson and Hajnal, 2007), conditioned elevation in circulating corticosterone (Gomez et al., 2000), and greater avoidance of the drug-paired cue predicts greater drug-taking (Grigson and Twining, 2002; Twining et al., 2009). While female rats generally are more responsive to drug than male rats, in this self-administration model, female rats consume more of a cocaine-paired saccharin cue and take less drug than males (Cason and Grigson, 2013). What is not known, however, is whether the same is true when a saccharin cue predicts availability of an opiate, particularly when the amount of drug experienced is held constant via passive administration by the experimenter. Here, avoidance of a saccharin cue was evaluated following pairings with experimenter delivered cocaine or morphine in male and female rats. Results showed that males and females avoided intake of a taste cue when paired with experimenter administered morphine or cocaine, and individual differences emerged whereby some male and female rats exhibited greater avoidance of the drug-paired cue than others. Female rats did not drink more of the saccharin cue than males when paired with morphine in Experiment 1, however, they did drink more of the saccharin cue than male rats when paired with cocaine in Experiment 2. While no pattern with estrous cycle emerged, avoidance of the cocaine-paired cue, like avoidance of a morphine-paired cue (Gomez et al., 2000), was associated with a conditioned elevation in corticosterone in both male and female rats.



http://ift.tt/2wT8ZJC

Once is too much: Early development of the opponent process in taste reactivity behavior is associated with later escalation of cocaine self-administration in rats

Publication date: Available online 9 September 2017
Source:Brain Research Bulletin
Author(s): Elizabeth M. Colechio, Danielle N. Alexander, Caesar G. Imperio, Kelsey Jackson, Patricia S. Grigson
Evidence suggests that the addiction process may begin immediately in some vulnerable subjects. Specifically, some rats have been shown to exhibit aversive taste reactivity (gapes) following the intraoral delivery of a cocaine-predictive taste cue after as few as 1 to 2 taste-drug pairings. After only 3 to 4 trials, the number of gapes becomes a reliable predictor of later cocaine self-administration. Given that escalation of drug-taking behavior over time is recognized as a key feature of substance use disorder (SUD) and addiction, the present study examined the relationship between early aversion to the cocaine-predictive flavor cue and later escalation of cocaine self-administration in an extended-access paradigm. The data show that rats who exhibit the greatest conditioned aversion early in training to the intraorally delivered cocaine-paired cue exhibit the greatest escalation of cocaine self-administration over 15 extended-access trials. This finding suggests that early onset of the conditioned opponent process (i.e., the near immediate shift from ingestion to rejection of the drug-paired cue) is a reliable predictor of future vulnerability and resilience to cocaine addiction-like behavior. Future studies must determine the underlying neural mechanisms associated with this early transition and, hence, with early vulnerability to the later development of SUD and addiction. In so doing, we shall be in position to discover novel diagnostics and novel avenues of prevention and treatment.



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MicroRNA-137 and its downstream target LSD1 inversely regulate anesthetics-induced neurotoxicity in dorsal root ganglion neurons

Publication date: Available online 9 September 2017
Source:Brain Research Bulletin
Author(s): Lingyang Chen, Xiaodan Wang, Wenguang Huang, Tingting Ying, Minjuan Chen, Jianbin Cao, Mingcang Wang
PurposeAnesthetic reagents, such as bupivacaine (Bv), induce significant neurotoxicity in dorsal root ganglion neurons (DRGNs). In this study, we investigated the expression, function and cross-association of microRNA-137-3p (miR-137-3p) and lysine (K)-specific demethylase 1A (LSD1) in a murine model of Bv-induced neural injury in DRGNs.MethodsMurine DRGNs were culture in vitro and treated with Bv. QPCR was used to evaluate miR-137-3p expression in Bv-injured DRGNs. MiR-137-3p was genetically downregulated to evaluate its rescuing effect on Bv-induced DRGN apoptosis and neurite retraction. The association of miR-137-3p on its downstream target, LSD1 coding gene KDM1A, was evaluated by dual-luciferase activity assay and qPCR. In miR-137-3p-downregulated DRGNs, KDM1A was inhibited to evaluate its involvement in miR-137-3p-mediated modulation on Bv-induced DRGN neurotoxicity. Furthermore, KDM1A expression in Bv-injured DRGN was evaluated by qPCR, and LSD1 was overexpressed in DRGN to evaluate its direct effect on Bv-induced neurotoxicity.ResultsMiR-137-3p was upregulated in Bv-injured DRGNs. MiR-137-3p downregulation rescued Bv-induced DRGN apoptosis and neurite retraction. LSD1 was demonstrated to be downstream to, and inversely modulated by miR-137-3p in DRGN. In Bv-injured DRGNs, LSD1 downregulation reversed miR-137-3p-downregualtion-induced neural protection. Furthermore, LSD1 upregulation directly rescued Bv-induced apoptosis and neurite retraction in DRGNs.ConclusionsMiR-137-3p and its downstream target LSD1 are inversely associated to regulate anesthetics-induced neurotoxicity in DRGN. This signaling pathway may be a therapeutic candidate to reduce anesthetics-induced neurological damage in human patients.



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Passive, health center-based assessment of adverse events following oral cholera immunization in Nampula city, Mozambique

Publication date: Available online 9 September 2017
Source:Vaccine
Author(s): Florentina Rafael, Sergio Chicumbe, Philippe Cavailler, Américo Barata, José Paulo M. Langa




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What is ‘confidence’ and what could affect it?: A qualitative study of mothers who are hesitant about vaccines

Publication date: Available online 9 September 2017
Source:Vaccine
Author(s): Judith A. Mendel-Van Alstyne, Glen J. Nowak, Ann L. Aikin
BackgroundPublic confidence in immunization is critical to maintaining high vaccine-coverage rates needed to protect individuals and communities from vaccine-preventable diseases. Recent attention has been placed on factors influencing confidence in vaccination in the US and globally, but comprehensive understanding of what drives or hinders confidence in childhood vaccination is yet to be reached. As such, assessing parents' confidence in childhood vaccination and the ways in which educational materials affect confidence is needed.ObjectiveWe sought to (1) learn how mothers who are hesitant about vaccination characterize confidence in health-related products for young children, including the recommended vaccines; (2) gain insights on what influences vaccine confidence beliefs; and (3) assess whether short, education materials affect parental confidence in childhood vaccinations.MethodsEight moderator-lead focus groups (n=61), stratified by socioeconomic status, were undertaken with mothers of children 5years of age of less who are hesitant about vaccines. Four of the groups were held in the Philadelphia, PA area and four were held in the San Francisco/Oakland, CA area. Three educational material pairs, each consisting of a 2–3min video and an infographic poster about an immunization-related topic, were reviewed and assessed for influence on confidence.ResultsQualitative data analysis was used to identify overarching themes across the focus groups. Themes, insights, and illustrative quotes were identified and provided for each of the major discussion areas: primary health concerns for young children; confidence beliefs and perceptions, including for recommended vaccines; facilitators and barriers to confidence; and reactions to the educational materials.ConclusionsResults provide helpful insights into how mothers who are hesitant about vaccines perceive confidence in childhood vaccines and health-related products, suggestions for how to improve confidence, and support for the value and use of short videos as part of vaccination education efforts. Findings can aid those developing vaccination education materials and resources designed to foster vaccine confidence.



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A novel approach to a rabies vaccine based on a recombinant single-cycle flavivirus vector

Publication date: Available online 9 September 2017
Source:Vaccine
Author(s): Maryann Giel-Moloney, Alexander A. Rumyantsev, Fred David, Monica Figueiredo, Brad Feilmeier, Teshome Mebatsion, Mark Parrington, Harry Kleanthous, Konstantin V. Pugachev
The RepliVax® vaccine (RV) platform is based on flavivirus genomes that are rationally attenuated by deletion. These single-cycle RV vaccine candidates targeting flavivirus pathogens have been demonstrated to be safe, highly immunogenic, and efficacious in animal models, including non-human primates. Here we show utility of the technology for delivery of a non-flavivirus immunogen by engineering several West Nile-based RV vectors to express full-length rabies virus G protein. The rabies virus G protein gene was incorporated in place of different West Nile structural protein gene deletions. The resulting RV-RabG constructs were demonstrated to replicate to high titers (8 log10 infectious particles/ml) in complementing helper cells. Following infection of normal cells, they provided efficient rabies virus G protein expression, but did not spread to surrounding cells. Expression of rabies virus G protein was stable and maintained through multiple rounds of in vitro passaging. A sensitive neurovirulence test in 2–3 day old neonatal mice demonstrated that RV-RabG candidates were completely avirulent indicative of high safety. We evaluated the RV-RabG variants in several animal models (mice, dogs, and pigs) and demonstrated that a single dose elicited high titers of rabies virus-neutralizing antibodies and protected animals from live rabies virus challenge (mice and dogs). Importantly, dogs were protected at both one and two years post-immunization, demonstrating durable protective immunity. The data demonstrates the potential of the RepliVax® technology as a potent vector delivery platform for developing vaccine candidates against non-flavivirus targets.



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Influenza A haemagglutinin specific IgG responses in children and adults after seasonal trivalent live attenuated influenza vaccination

Publication date: Available online 9 September 2017
Source:Vaccine
Author(s): Shahinul Islam, Kristin Greve-Isdahl Mohn, Florian Krammer, Mari Sanne, Geir Bredholt, Åsne Jul-Larsen, Sarah M. Tete, Fan Zhou, Karl Albert Brokstad, Rebecca Jane Cox
Influenza is a major respiratory pathogen and vaccination is the main method of prophylaxis. In 2012, the trivalent live attenuated influenza vaccine (LAIV3) was licensed in Europe for use in children. Vaccine-induced antibodies directed against the main viral surface glycoprotein, haemagglutinin (HA), play an important role in virus neutralization through different mechanism. The objective of this study was to dissect the HA specific antibody responses induced after LAIV3 immunization to the influenza A viruses in children and adults.Plasma was collected from 20 children and 20 adults pre- and post-LAIV3 vaccination (up to ayear) and analysed by the haemagglutination inhibition (HI) and ELISA assays. We found that LAIV3 boosted the HA specific IgG response against the head and the full-length of H3N2 in children, but not adults. Adults had higher levels of pre-existing stalk antibodies (towards H3N2 and H1N1), but these were not boosted by LAIV3. Importantly, we observed a trend in boosting of H1N1 HA stalk specific antibodies in children after LAIV3. Whereas, heterosubtypic H5 and H7 full-length HA specific antibodies were not boosted in either children or adults. In conclusion, LAIV3 elicited H3-head and low levels of H1 stalk specific antibody responses in children, supporting the prophylactic use of LAIV in children.



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Targeting and Isolation of Cancer Cells Using Micro/Nanomotors

Publication date: Available online 9 September 2017
Source:Advanced Drug Delivery Reviews
Author(s): Weiwei Gao, Berta Esteban-Fernández de Ávila, Liangfang Zhang, Joseph Wang
Micro/nanomotors distinguish themselves with in situ energy conversion capability for autonomous movement, a feature that confers remarkable potential to improve cancer treatment. In this review article, three areas are highlighted where micro/nanomotors have established themselves with unique contributions, including propelled navigation to promote cancer cell targeting, powered cell membrane penetration to enhance intracellular delivery, and steered isolation of circulating cancer cells for detection. Progress made in these areas has offered promising inspiration and opportunities aimed for enhancing the efficiency and precision of drug targeting to cancer cells, improving the capability of delivering anticancer drug into cytoplasm for bioactivity, and enabling more rapid and sensitive cancer cell detection. Herein, we review each area with highlights of the current and forthcoming micro/nanomotor techniques in advancing cancer diagnosis and treatment.

Graphical abstract

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Neurophysiological localisation of ulnar neuropathy at the elbow: validation of diagnostic criteria developed by a taskforce of the Danish Society of Clinical Neurophysiology

Publication date: Available online 9 September 2017
Source:Clinical Neurophysiology
Author(s): K. Pugdahl, S. Beniczky, B. Wanscher, B. Johnsen, E.Qerama, M. Ballegaard, K. Benedek, A. Juhl, M. Ööpik, P. Selmar, J. Sønderborg, D. Terney, A. Fuglsang-Frederiksen
ObjectiveThis study validates consensus criteria for localisation of ulnar neuropathy at elbow (UNE) developed by a taskforce of the Danish Society of Clinical Neurophysiology and compares them to the existing criteria from the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM). The Danish criteria are based on combinations of conduction slowing in the segments of the elbow and forearm expressed in Z-scores, and difference between the segments in m/s. Examining fibres to several muscles and sensory fibres can increase the certainty of the localisation.MethodsDiagnostic accuracy for UNE was evaluated on 181 neurophysiological studies of the ulnar nerve from 171 peer-reviewed patients from a mixed patient-group. The diagnostic reference standard was the consensus diagnosis based on all available clinical, laboratory, and electrodiagnostic information reached by a group of experienced Danish neurophysiologists.ResultsThe Danish criteria had high specificity (98.4%) and positive predictive value (PPV) (95.2%) and fair sensitivity (76.9%). Compared to the AANEM criteria, the Danish criteria had higher specificity (p < 0.001) and lower sensitivity (p=0.02).ConclusionsThe Danish consensus criteria for UNE are very specific and have high PPV.SignificanceThe Danish criteria for UNE are reliable and well suited for use in different centres as they are based on Z-scores.



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Testing the effects of adolescent alcohol use on adult conflict-related theta dynamics

Publication date: Available online 9 September 2017
Source:Clinical Neurophysiology
Author(s): Jeremy Harper, Stephen M. Malone, William G. Iacono
ObjectiveAdolescent alcohol use (AAU) is associated with brain anomalies, but less is known about long-term neurocognitive effects. Despite theoretical models linking AAU to diminished cognitive control, empirical work testing this relationship with specific cognitive control neural correlates (e.g., prefrontal theta-band EEG dynamics) remains scarce. A longitudinal twin design was used to test the hypothesis that greater AAU is associated with reduced conflict-related EEG theta-band dynamics in adulthood, and to examine the genetic/environmental etiology of this association.MethodsIn a large (N = 718) population-based prospective twin sample, AAU was assessed at ages 11/14/17. Twins completed a flanker task at age 29 to elicit EEG theta-band medial frontal cortex (MFC) power and medial–dorsal prefrontal cortex (MFC-dPFC) connectivity. Two complementary analytic methods (cotwin control analysis; biometric modeling) were used to disentangle the genetic/shared environmental risk towards AAU from possible alcohol exposure effects on theta dynamics.ResultsAAU was negatively associated with adult cognitive control-related theta-band MFC power and MFC-dPFC functional connectivity. Genetic influences primarily underlie these associations.ConclusionsFindings provide strong evidence that genetic factors underlie the comorbidity between AAU and diminished cognitive control-related theta dynamics in adulthood.SignificanceConflict-related theta-band dynamics appear to be candidate brain-based endophenotypes/mechanisms for AAU.



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Adaptation of feedforward movement control is abnormal in patients with cervical dystonia and tremor

Publication date: Available online 9 September 2017
Source:Clinical Neurophysiology
Author(s): Laura Avanzino, Andrea Ravaschio, Giovanna Lagravinese, Gaia Bonassi, Giovanni Abbruzzese, Elisa Pelosin
ObjectiveIt is under debate whether the cerebellum plays a role in dystonia pathophysiology and in the expression of clinical phenotypes. We investigated a typical cerebellar function (anticipatory movement control) in patients with cervical dystonia (CD) with and without tremor.MethodsTwenty patients with CD, with and without tremor, and 17 healthy controls were required to catch balls of different load: 15 trials with a light ball, 25 trials with a heavy ball (adaptation) and 15 trials with a light ball (post-adaptation). Arm movements were recorded using a motion capture system. We evaluated: i) the anticipatory adjustment (just before the impact); ii) the extent and rate of the adaptation (at the impact) and (iii) the aftereffect in the post-adaptation phase.ResultsThe anticipatory adjustment was reduced during adaptation in CD patients with tremor respect to CD patients without tremor and controls. The extent and rate of adaptation and the aftereffect in the post-adaptation phase were smaller in CD with tremor than in controls and CD without tremor.ConclusionPatients with cervical dystonia and tremor display an abnormal predictive movement control.SignificanceOur findings point to a possible role of cerebellum in the expression of a clinical phenotype in dystonia.



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Enzyme-crosslinked Gene-activated Matrix for the Induction of Mesenchymal Stem Cells in Osteochondral Tissue Regeneration

Publication date: Available online 9 September 2017
Source:Acta Biomaterialia
Author(s): Yi-Hsuan Lee, Hsi-Chin Wu, Chia-Wei Yeh, Chen-Hsiang Kuan, Han-Tsung Liao, Horng-Chaung Hsu, Jui-Che Tsai, Jui-Sheng Sun, Tzu-Wei Wang
The development of osteochondral tissue engineering is an important issue for the treatment of traumatic injury or aging associated joint disease. However, the different compositions and mechanical properties of cartilage and subchondral bone show the complexity of this tissue interface, making it challenging for the design and fabrication of osteochondral graft substitute. In this study, a bilayer scaffold is developed to promote the regeneration of osteochondral tissue within a single integrated construct. It has the capacity to serve as a gene delivery platform to promote transfection of human mesenchymal stem cells (hMSCs) and the functional osteochondral tissues formation. For the subchondral bone layer, the bone matrix with organic (type I collagen, Col) and inorganic (hydroxyapatite, Hap) composite scaffold has been developed through mineralization of hydroxyapatite nanocrystals oriented growth on collagen fibrils. We also prepare multi-shell nanoparticles in different layers with a calcium phosphate core and DNA/calcium phosphate shells conjugated with polyethyleneimine to act as non-viral vectors for delivery of plasmid DNA encoding BMP2 and TGF-β3, respectively. Microbial transglutaminase is used as a cross-linking agent to crosslink the bilayer scaffold. The ability of this scaffold to act as a gene-activated matrix is demonstrated with successful transfection efficiency. The results show that the sustained release of plasmids from gene-activated matrix can promote prolonged transgene expression and stimulate hMSCs differentiation into osteogenic and chondrogenic lineages by spatial and temporal control within the bilayer composite scaffold. This improved delivery method may enhance the functionalized composite graft to accelerate healing process for osteochondral tissue regeneration.Significance of this research study:In this study, a gene-activated matrix (GAM) to promote the growth of both cartilage and subchondral bone within a single integrated construct is developed. It has the capacity to promote transfection of human mesenchymal stem cells (hMSCs) and the functional osteochondral tissues formation. The results show that the sustained release of plasmids including TGF-beta and BMP-2 from GAM could promote prolonged transgene expression and stimulate hMSCs differentiation into the osteogenic and chondrogenic lineages by spatial control manner. This improved delivery method should enhance the functionalized composite graft to accelerate healing process in vitro and in vivo for osteochondral tissue regeneration.

Graphical abstract

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Multivalent interactions between streptavidin-based pretargeting fusion proteins and cell receptors impede efficient internalization of biotinylated nanoparticles

Publication date: Available online 9 September 2017
Source:Acta Biomaterialia
Author(s): Christina L. Parker, Qi Yang, Bing Yang, Justin D. McCallen, Steven I. Park, Samuel K. Lai
Pretargeting represents a promising strategy to enhance delivery of nanoparticles. The strategy involves first introducing bispecific antibodies or fusion proteins (BFP) that can bind specific epitopes on target cells with one arm, and use the other arm to capture subsequently administered effector molecules, such as radionuclides or drug-loaded nanoparticles. Nevertheless, it remains unclear whether BFP that bind slowly- or non-internalizing epitopes on target cells can facilitate efficient intracellular delivery. Here, we investigated the cellular uptake of biotin-functionalized nanoparticles with streptavidin-scFv against TAG-72, a membrane protein on Jurkat T-cell leukemia cells. Unlike conventional active-targeted nanoparticles, we found that pretargeting resulted in preferential retention of ∼100nm nanoparticles at the plasma membrane rather than internalization into cells. We found no improvement in nanoparticle internalization by simply reducing nanoparticle concentration or surface biotin density. Interestingly, by adding both the BFP and a monoclonal antibody against TAG-72, we observed a twofold improvement in internalization of pretargeted nanoparticles. Our work illustrates that the cellular fate of pretargeted nanoparticles can be controlled by carefully tuning the interactions between pretargeting molecules and nanoparticles on the cell surface.Statement of SignificancePretargeting is a multi-step strategy that utilizes bispecific proteins that recognize both cellular epitopes and subsequently administered therapeutic molecules. This approach has been extensively studied for radiotherapy of blood cancers; however, pretargeting remains largely underexplored for nanoparticle targeting, including whether pretargeting can facilitate efficient intracellular delivery. Here, we found that high density of targeting proteins on the cell surface can effectively limit internalization of pretargeted nanoparticles. Our work underscores the need to carefully assess specific cell-pretargeting molecule pairs for applications requiring intracellular delivery, and the key design requirements for such bispecific pretargeting molecules.

Graphical abstract

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Small Molecule Adjuvants that Suppress Both Chromosomal and mcr-1 Encoded Colistin-Resistance and Amplify Colistin Efficacy in Polymyxin-Susceptible Bacteria.

Publication date: Available online 9 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): William T. Barker, Sara E. Martin, Courtney E. Chandler, T.Vu. Nguyen, Tyler L. Harris, Christopher Goodell, Roberta J. Melander, Yohei Doi, Robert K. Ernst, Christian Melander
Bacterial resistance to polymyxin antibiotics has taken on a new and more menacing form. Common are genomically-encoded resistance mechanisms to polymyxins, specifically colistin (polymyxin E), however, the plasmid-borne mobile colistin resistance–1 (mcr-1) gene has recently been identified and poses a new threat to global public health. Within six months of initial identification in Chinese swine in November 2015, the first human clinical isolation in the US was reported (Apr. 2016). Herein we report successful reversion of mcr-1-driven colistin resistance in Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli with adjuvants we previously reported as modulators of chromosomally-encoded colistin resistance. Further screening of our in-house library of nitrogen-dense heterocycles has identified additional chemical scaffolds that actively attenuate colistin resistance. Ultimately, we present a diverse cohort of adjuvants that both sensitize colistin-resistant and colistin-susceptible bacteria to this antibiotic, thus providing a potential avenue to both reduce colistin dosage and toxicity, and overcome colistin resistance.

Graphical abstract

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Eudesmane sesquiterpenes from Chinese liverwort are substrates of Cdrs and display antifungal activity by targeting Erg6 and Erg11 of Candida albicans.

Publication date: Available online 9 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Siwen Li, Hongzhuo Shi, Wenqiang Chang, Yi Li, Ming Zhang, Yanan Qiao, Hongxiang Lou
We isolated twelve sesquiterpenes from Chinese liverwort Tritomaria quinquedentata (Huds.) Buch., including four new compounds. Among them, five eudesmane sesquiterpenes were ineffective against Candida albicans wild strain SC5314 but active towards efflux pumps-deficient strain DSY654 using Alamar blue assay. Further test of the most active agent of ent-isoalantolactone (8, ent-iLL) showed that it also inhibited the yeast-to-hyphal switch of DSY654 cells. The intracellular content measurement using high performance liquid chromatography revealed that ent-iLL was intracellularly accumulated in C. albicans when efflux pumps were deficient or inhibited by Cdrs inhibitor riccardin D, suggesting that the activity of ent-iLL was compromised by efflux pumps Cdrs. Moreover, ent-iLL potentially inhibited the activity of Erg11 and Erg6 of DSY654 and thereby resulted in the alteration of sterol composition by decreasing ergosterol contents and increasing zymosterol and lanosterol accumulation. Our study demonstrated that eudesmane sesquiterpenes, as the substrates of Cdrs, could interfere with sterol synthesis of C. albicans to exert antifungal activity when co-applied with Cdrs inhibitors.

Graphical abstract

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Therapeutic Peptides for CNS indications: progress and challenges

Publication date: Available online 9 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Bruce H. Morimoto
Attacking neurodegeneration and promoting neuroprotection have been the holy grail in neurology for almost 20 years and represent an area of high unmet medical need. However, indications like Alzheimer's disease and stroke are areas in drug development fraught with failure. This review will highlight three CNS peptide programs which are tackling targets and indications in which traditional small molecule approaches have been difficult and challenging. The targets for these potential peptide therapeutics include the NMDA receptor, γ-secretase, and cyclin-dependent kinase in which direct inhibition has resulted in on-target (not compound related) problems. For example, direct inhibition of γ-secretase has resulted in gastrointestinal abnormalities and inhibition of the NMDA receptor can result in hallucinations, dizziness, out-of-body sensations, and nightmares. When confronted with show-stopping side effects, the CNS peptide programs profiled in this review strike the problem with intervention and disruption of selective protein-protein interactions. The goal of these peptide programs is to produce selective therapeutics with a better safety profile.

Graphical abstract

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Alternate dosing regimens of brentuximab vedotin for CD30+ cutaneous T-cell lymphoma: reply from authors

Abstract

We thank the authors Lewis, Kim, and Duvic, for their reaction to our article.

The increasingly personalised medicine should also take into account individual tumour entities and their inter-individual pathways.

Therefore, we can only welcome and sustain the comments. As described in our article, it is possible, in some patients, to reduce the dose and interval frequency of Brentuximab Vedotin (BV), while continuing to have good efficacy.

This article is protected by copyright. All rights reserved.

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Chronic actinic dermatitis: successful treatment with PUVA photochemotherapy

Abstract

Chronic actinic dermatitis (CAD) is a debilitating photodermatosis. First line therapy consists of strict photoprotection and topical corticosteroids. Second line therapy uses systemic immunosuppression. However an alternative is needed for patients with severe CAD who cannot use systemic immunosuppressants.^1,2 Case reports and small case series suggest that PUVA may be effective.^3-6

This article is protected by copyright. All rights reserved.+

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Alternate dosing regimens of brentuximab vedotin for CD30+ cutaneous T-cell lymphoma

Abstract

Stranzenbach et al. propose alternate dosing regimens of brentuximab vedotin (BV) for CD30+ cutaneous T-cell lymphomas (CTCLs) such as mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL).¹ They emphasize that lower doses or less frequent dosing schedules for CTCL may be equally effective while limiting adverse events.

The authors indicate that CTCLs may require less aggressive therapy than systemic lymphomas such as systemic ALCL (sALCL) or Hodgkin lymphoma (HL).

This article is protected by copyright. All rights reserved.

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The value and pitfalls of biologics registries for psoriasis

Abstract

We are pleased that our initial perspective article in the BJD have sparked discussions. As indicated in our initial paper, our main critical point is the exponential growth in publications relating to drug survival as an efficacy assessment based on non-randomized registry data (Figure 1). Indeed, we ourselves have performed such drug survival analyses.¹ While we agree that methods such as propensity score matching could even out some of the between-drug variations in patient characteristics, propensity score matching is a rare sight in drug survival studies.

This article is protected by copyright. All rights reserved.

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Registries as a real-world cohort studies that are useful and necessary in the pyramid of evidence

Abstract

Egeberg et al¹ enriched us by describing the limitations of registries in psoriasis, but focusing their critical perspective on a misguided outcome measure such as "drug survival". We agree that clinicians and researchers should be cautious when using that proxy measure.^2,3However, the frequent use of this poor outcome should not cast doubts over all the capabilities of registries.

This article is protected by copyright. All rights reserved.

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The role of non-endothelial cells on the penetration of nanoparticles through the blood brain barrier

Publication date: Available online 9 September 2017
Source:Progress in Neurobiology
Author(s): Rui Pedro Moura, Andreia Almeida, Bruno Sarmento
The blood brain barrier (BBB) is a well-established cell-based membrane that circumvents the central nervous system (CNS), protecting it from harmful substances. Due to its robustness and cell integrity, it is also an outstanding opponent when it comes to the delivery of several therapeutic agents to the brain, which requires the crossing through its highly-organized structure. This regulation and cell-cell communications occur mostly between astrocytes, pericytes and endothelial cells. Therefore, alternative ways to deliver drugs to the CNS, overcoming the BBB are required, to improve the efficacy of brain target drugs. Nanoparticles emerge here as a promising drug delivery strategy, due to their ability of high drug loading and the capability to exploit specific delivery pathways that most drugs are unable to when administered freely, increasing their bioavailability in the CNS. Thus, further attempts to assess the possible influence of non-endothelial may have on the BBB translocation of nanoparticles are here revised. Furthermore, the use of macrophages and/or monocytes as nanoparticle delivery cells are also approached. Lastly, the temporarily disruption of the overall organization and normal structure of the BBB to promote the penetration of nanoparticles aimed at the CNS is described, as a synergistic path.



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Peripheral nerve pathology at fixed stage in spinal muscular atrophy with respiratory distress type 1

Publication date: Available online 9 September 2017
Source:Brain and Development
Author(s): Azusa Ikeda, Sumimasa Yamashita, Yu Tsuyusaki, Mio Tanaka, Yukichi Tanaka, Akihiro Hashiguchi, Hiroshi Takashima, Tomohide Goto
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is characterized by severe respiratory failure due to diaphragmatic paralysis and distal muscular weakness in early infancy. After an initial decline in respiratory state and motor function until 1–2years of age, residual capabilities reach a plateau.We report the peripheral neuropathological findings of a patient with SMARD1 at 1year and 1month of age, when his muscle strength and respiratory symptoms had deteriorated and then stabilized for several months. Peripheral nerve biopsy revealed severely progressed axonal degeneration. This finding suggests the rapid progression of peripheral axonal neuropathy in SMARD1 that leads to its characteristic clinical course of respiratory failure and paralysis in the early infantile period.



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Semantic incongruity attracts attention at a pre-conscious level: evidence from a TMS study

Publication date: Available online 9 September 2017
Source:Cortex
Author(s): Javier Ortiz-Tudela, Elisa Martín-Arévalo, Ana B. Chica, Juan Lupiáñez
Unpredicted objects, i.e., those that do not fit in a specific context, have been shown to quickly attract attention as a mean of extracting more information about potentially relevant items. Whether the required semantic processing triggering the attraction of attention can occur independently of participants' awareness of the object is still a highly debated topic. In the present study we make use of a change detection task in which we manipulate the semantic congruity between the to-be-detected object and the background scene. We applied inhibitory repetitive Transcranial Magnetic Stimulation (rTMS) over the right temporo-parietal junction (right TPJ) and a control location (vertex) to test the causal role of the former in the processing of objects at a pre-conscious level. Our results clearly show that semantic congruity can impact detection and identification processes in opposite ways, even when low level features are controlled for. Incongruent objects are quickly detected but poorly identified. rTMS over the right TPJ effectively diminishes contextual guidance effects on attention. These results suggest that at least some high order category processing takes place before conscious detection to direct attention towards the most informative regions of space. Moreover, here we show that rTMS over right TPJ also impacts object identification, which calls for a re-evaluation of right TPJ's role on object processing.



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Is procedural memory enhanced in Tourette syndrome? Evidence from a sequence learning task

Publication date: Available online 9 September 2017
Source:Cortex
Author(s): Ádám Takács, Andrea Kóbor, Júlia Chezan, Noémi Éltető, Zsanett Tárnok, Dezso Nemeth, Michael T. Ullman, Karolina Janacsek
Procedural memory, which is rooted in the basal ganglia, underlies the learning and processing of numerous automatized motor and cognitive skills, including in language. Not surprisingly, disorders with basal ganglia abnormalities have been found to show impairments of procedural memory. However, brain abnormalities could also lead to atypically enhanced function. Tourette syndrome (TS) is a candidate for enhanced procedural memory, given previous findings of enhanced TS processing of grammar, which likely depends on procedural memory. We comprehensively examined procedural learning, from memory formation to retention, in children with TS and typically developing (TD) children, who performed an implicit sequence learning task over two days. The children with TS showed sequence learning advantages on both days, despite a regression of sequence knowledge overnight to the level of the TD children. This is the first demonstration of procedural learning advantages in any disorder. The findings may further our understanding of procedural memory and its enhancement. The evidence presented here, together with previous findings suggesting enhanced grammar processing in TS, underscore the dependence of language on a system that also subserves visuomotor sequencing.



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Grasp preparation modulates early visual processing of size and detection of local/global stimulus features

Publication date: Available online 9 September 2017
Source:Cortex
Author(s): Xavier E. Job, José van Velzen, Jan W. de Fockert
Preparing to grasp objects facilitates visual processing of object location, orientation and size, compared to preparing actions such as pointing. This influence of action on perception reflects mechanisms of selection in visual perception tuned to current action goals, such that action relevant sensory information is prioritized relative to less relevant information. In three experiments, rather than varying movement type (grasp vs. point), the magnitude of a prepared movement (power vs. precision grasps) was manipulated while visual processing of object size, as well as local/global target detection was measured. Early event-related potentials elicited by task-irrelevant visual probes were enhanced for larger probes during power grasp preparation and smaller probes during precision grasp preparation. Local targets were detected faster following precision, relative to power grasp cues. The results demonstrate a direct influence of grasp preparation on sensory processing of size and suggest that the hierarchical dimension of objects may be a relevant perceptual feature for grasp programming. To our knowledge, this is the first evidence that preparing different magnitudes of the same basic action has systematic effects on visual processing.



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The functional effects of prior motion imagery and motion perception

Publication date: Available online 9 September 2017
Source:Cortex
Author(s): Shuai Chang, Joel Pearson
The functional sensory effects and commonalties between mental imagery of different visual features such as color, form or motion remains largely unknown. Mental imagery of static visual features, including color and orientation, can have a facilitative, priming effect on subsequent perception. However, whether motion imagery can have a similar effect remains unknown. Here we used the binocular rivalry method as a measure of motion mental imagery. After imagining or viewing motion of a particular direction, participants were required to report the dominant motion direction in a brief motion rivalry stimulus. We found that motion imagery can have a facilitative priming effect on subsequent motion rivalry perception, and this effect can be attenuated by concurrent expanding and contracting perceptual motion, but not by static or flickering uniform luminance. Unlike color or orientation imagery, the effect of motion imagery on subsequent rivalry was location independent. We also observed this facilitative priming effect with prior low-contrast perceptual motion, but prior high-contrast motion induced a suppressive effect. Simultaneous imagery and perceptual motion in opposite directions induced priming, while congruent directions did not. Counter to prior findings, these results suggest motion imagery can have a priming effect on perception and that the rivalry method can be used to assess visual motion imagery. These results provide evidence for visual imagery as a multi-feature structure.



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“The role of premotor and parietal cortex during monitoring of involuntary movement: a combined TMS and tDCS study.”

Publication date: Available online 9 September 2017
Source:Cortex
Author(s): Valentina Bruno, Carlotta Fossataro, Nadia Bolognini, Luca Zigiotto, Giuseppe Vallar, Anna Berti, Francesca Garbarini
Converging evidence on voluntary actions underlays the existence of a motor monitoring system, able to compare the predicted and the actual consequences of our movements. In this context, both the premotor cortex (PMC) and the posterior parietal cortex (PPC) play a role in action monitoring and awareness. The present study explores the role of PMC and PPC in monitoring involuntary muscle contractions induced by Transcranial Magnetic Stimulation (TMS) over the hand motor area. To this aim, the effects of transcranial Direct Current Stimulation (tDCS) over PMC and PPC were examined. Thirty-six healthy subjects were asked to perform a motor monitoring task (i.e. to verbally report hand twitches induced by TMS) after 10 minutes of tDCS. Through three experiments, the effects of cathodal, anodal and sham tDCS over the left and the right hemispheres were compared. Our results show that cathodal tDCS over the right PMC does not affect the monitoring of involuntary movements. By contrast, tDCS over both the right and the left PPC affects motor monitoring, depending on the current polarity: while cathodal tDCS increases the feeling of phantom-like movements (which actually did not occur), anodal tDCS impairs the ability to detect involuntary hand twitches (which actually took place). These findings show that the PMC is not involved in motor monitoring of involuntary movements; rather, the PPC, where multisensory stimuli converge and are processed, seems to play a crucial role.



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Assessment of active bacteria metabolizing phenolic acids in the peanut (Arachis hypogaea L.) rhizosphere

Publication date: Available online 9 September 2017
Source:Microbiological Research
Author(s): Jinguang Liu, Xingxiang Wang, Taolin Zhang, Xiaogang Li
Phenolic acids can enhance the mycotoxin production and activities of hydrolytic enzymes related to pathogenicity of soilborne fungus Fusarium oxysporum. However, characteristics of phenolic acid-degrading bacteria have not been investigated. The objectives of this study were to isolate and characterize bacteria capable of growth on benzoic and vanillic acids as the sole carbon source in the peanut rhizosphere. Twenty-four bacteria were isolated, and the identification based on 16S rRNA gene sequencing revealed that pre-exposure to phenolic acids before sowing shifted the dominant culturable bacterial degraders from Arthrobacter to Burkholderia stabilis-like isolates. Both Arthrobacter and B. stabilis-like isolates catalysed the aromatic ring cleavage via the ortho pathway, and Arthrobacter isolates did not exhibit higher C12O enzyme activity than B. stabilis-like isolates. The culture filtrate of Fusarium sp. ACCC36194 caused a strong inhibition of Arthrobacter growth but not B. stabilis-like isolates. Additionally, Arthrobacter isolates responded differently to the culture filtrates of B. stabilis-like isolates. The Arthrobacter isolates produced higher indole acetic acid (IAA) levels than B. stabilis-like isolates, but B. stabilis-like isolates were also able to produce siderophores, solubilize mineral phosphate, and exert an antagonistic activity against peanut root rot pathogen Fusarium sp. ACCC36194. Results indicate that phenolic acids can shift their dominant culturable bacterial degraders from Arthrobacter to Burkholderia species in the peanut rhizosphere, and microbial interactions might lead to the reduction of culturable Arthrobacter. Furthermore, increasing bacterial populations metabolizing phenolic acids in monoculture fields might be a control strategy for soilborne diseases caused by Fusarium spp.



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Traumatic brain injury and aggression: A systematic review and future directions using community samples

Publication date: Available online 9 September 2017
Source:Aggression and Violent Behavior
Author(s): Lisa Buckley, Sherrie-Anne Kaye, Ryan P. Stork, Justin E. Heinze, James T. Eckner
Aggression is widespread and a significant community burden, with violence-related injury deaths representing a significant public health problem. We explore aggression relative to a possible associated factor, traumatic brain injury (TBI). Our focus is on a less well studied population, those recruited through the community who may not have had hospital care or contact with the criminal justice system (e.g. were recruited in schools). This study provides a critical review of the potential relationship between aggression and traumatic brain injury. We undertook a systematic search of published literature of studies recruited through the community and found seven studies examining aggression and TBI. All studies identified a relationship between reports of TBI and aggression, however only two studies were longitudinal in design. The study focuses on the limitations of the current body of research, including in definitions of constructs, the need to understand mediating and moderating factors, and improvements needed in the overall research design of studies.



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Mastectomy Flap Thickness and Complications in Nipple-Sparing Mastectomy: Objective Evaluation using Magnetic Resonance Imaging

Background: Ischemic complications after nipple-sparing mastectomy (NSM) have been associated with numerous variables. However, the impact of NSM flap thickness has been incompletely evaluated. Methods: NSM flap thickness was determined for all NSMs from 2006 to 2016 with available pre- or postoperative breast magnetic resonance imaging (MRIs). Demographics and outcomes were stratified by those with and without ischemic complications. Results: Of 1,037 NSM reconstructions, 420 NSMs had MRI data available, which included 379 preoperative MRIs and 60 postoperative MRIs. Average total preoperative skin/subcutaneous tissue NSM flap thickness was 11.4 mm. Average total postoperative NSM flap thickness was 8.7 mm. NSMs with ischemic complications were found to have significantly thinner overall postoperative NSM flap thickness compared with those without ischemic complications (P = 0.0280). Average overall postoperative NSM flap thickness less than 8.0 mm was found to be an independent predictor of ischemic complications (odds ratio, 6.5263; P = 0.026). In NSMs with both pre- and postoperative MRIs, the overall average postoperative NSM flap thickness was 68.2% of preoperative measurements. Average overall postoperative NSM flap thickness was significantly less than average overall preoperative NSM flap thickness (P

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Rebuilding Chromosomes After Catastrophe: Emerging Mechanisms of Chromothripsis

Publication date: Available online 9 September 2017
Source:Trends in Cell Biology
Author(s): Peter Ly, Don W. Cleveland
Cancer genome sequencing has identified chromothripsis, a complex class of structural genomic rearrangements involving the apparent shattering of an individual chromosome into tens to hundreds of fragments. An initial error during mitosis, producing either chromosome mis-segregation into a micronucleus or chromatin bridge interconnecting two daughter cells, can trigger the catastrophic pulverization of the spatially isolated chromosome. The resultant chromosomal fragments are religated in random order by DNA double-strand break repair during the subsequent interphase. Chromothripsis scars the cancer genome with localized DNA rearrangements that frequently generate extensive copy number alterations, oncogenic gene fusion products, and/or tumor suppressor gene inactivation. Here we review emerging mechanisms underlying chromothripsis with a focus on the contribution of cell division errors caused by centromere dysfunction.



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