Biosensors: Essentials, by Gennady Evtugyn (Lecture Notes in Chemistry Vol.84), 265 pages, Springer, 2014, ISBN 978-3-642-40240-1.

Publication date: 15 September 2018
Source:Biosensors and Bioelectronics, Volume 115
Author(s): Edwin W.H. Jager




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Editorial Board

Publication date: 15 September 2018
Source:Biosensors and Bioelectronics, Volume 115





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Gold nanorod-assisted near-infrared stimulation of bullfrog sciatic nerve

Abstract

Infrared neural stimulation (INS) is a new and developing approach for neural repair, with the advantages of being non-contact, spatially precise, and artifact-free. However, the disadvantage of infrared light is that it is difficult to stimulate deep tissue because of its weak penetrating power. Therefore, this paper introduces an improved method using near-infrared laser to stimulate bullfrog sciatic nerves because of its strong penetrating power. Meanwhile, gold nanorods (Au NRs) are injected into the nerve to increase the absorption of light. The mechanism is the instantaneous temperature rise caused by the absorption of infrared light by Au NRs. The compound muscle action potential (CMAP) associated with the irradiated sciatic nerve is recorded by a multi-channel physiological signal instrument. The peak to peak amplitude (V_pp) of CMAP for sciatic nerves injected with Au NRs increases significantly compared to the CMAP for control nerves without Au NRs. These results demonstrate INS by labeling nerves with nanoparticle exhibiting latent capacity to increase the efficiency, spatial resolution, and the neural responsivity, and especially, can increase the penetration depth and reduce the requisite radiant exposure level.

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Raman spectral feature selection using ant colony optimization for breast cancer diagnosis

Abstract

Pathology as a common diagnostic test of cancer is an invasive, time-consuming, and partially subjective method. Therefore, optical techniques, especially Raman spectroscopy, have attracted the attention of cancer diagnosis researchers. However, as Raman spectra contain numerous peaks involved in molecular bounds of the sample, finding the best features related to cancerous changes can improve the accuracy of diagnosis in this method. The present research attempted to improve the power of Raman-based cancer diagnosis by finding the best Raman features using the ACO algorithm. In the present research, 49 spectra were measured from normal, benign, and cancerous breast tissue samples using a 785-nm micro-Raman system. After preprocessing for removal of noise and background fluorescence, the intensity of 12 important Raman bands of the biological samples was extracted as features of each spectrum. Then, the ACO algorithm was applied to find the optimum features for diagnosis. As the results demonstrated, by selecting five features, the classification accuracy of the normal, benign, and cancerous groups increased by 14% and reached 87.7%. ACO feature selection can improve the diagnostic accuracy of Raman-based diagnostic models. In the present study, features corresponding to ν(C–C) αhelix proline, valine (910–940), νs(C–C) skeletal lipids (1110–1130), and δ(CH2)/δ(CH3) proteins (1445–1460) were selected as the best features in cancer diagnosis.

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The band structure control of visible-light-driven rGO/ZnS-MoS2 for excellent photocatalytic degradation performance and long-term stability

Publication date: 15 October 2018
Source:Chemical Engineering Journal, Volume 350
Author(s): Xiufen Hu, Fang Deng, Weiya Huang, Guisheng Zeng, Xubiao Luo, Dionysios D. Dionysiou
ZnS-MoS2 solid solution anchored on reduced graphene oxide sheet (rGO/ZnS-MoS2) was explored as novel visible-light-driven photocatalysts, and synthesized by solvent thermal method. The light absorption intensity of rGO/ZnS-MoS2 was greatly strengthened, and rGO/ZnS-MoS2 possess modulated continuous band gaps from 3.47 to 3.56 eV by changing the Zn/Mo ratios and rGO content. Their photocatalytic activities for 2-nitrophenol degradation are dependent on the chemical composition, and the optimal 11% rGO/ZnS-MoS2 possessed the highest photocatalytic performance, which could be attributed to the most efficient charge separation, the largest specific area, and its optimized band structure. Moreover, 11% rGO/ZnS-MoS2 can effectively treat real industrial effluent with 74.05% COD removal, and maintain long-term stability without obvious decline after five use cycle.

Graphical abstract

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Antibiotic producing endophytic Streptomyces spp. colonize above-ground plant parts and promote shoot growth in multiple healthy and pathogen-challenged cereal crops

Publication date: Available online 3 June 2018
Source:Microbiological Research
Author(s): Janki K. Patel, Sheeba Madaan, G. Archana
The Streptomyces spp. used in this work were previously isolated as diazotrophic endophytes from sorghum stems. Here, we characterize the Streptomyces spp. for their colonization ability, plant growth promotion and protection against fungal disease in three cereals. In vitro analysis by dual culture study showed inhibitory effect on the rice pathogen Magnaporthe oryzae B157 and along with inhibition of the ubiquitous phytopathogen Rhizoctonia solani by the Streptomyces spp. used in this study. The active compound responsible for fungal pathogen inhibition was extracted with ethyl acetate and tested positive against the fungal pathogens. GC-MS based identification of the active compounds responsible for fungal pathogen inhibition showed them to be 2-(chloromethyl)-2-cyclopropyloxirane, 2, 4- ditert-butylphenol and 1‐ethylthio‐3‐methyl‐1, 3‐butadiene in extracts of culture supernatants from the three different strains respectively. EGFP tagged Streptomyces strains showed profuse colonization in roots as well as aerial parts of cereal plants. Direct inhibitory action against M. oryzae B157 and R. solani correlated with the observation that upon fungal pathogen challenge, the bacterized rice, sorghum and wheat plants showed significantly good plant growth, particularly in aerial parts as compared to unbacterized controls. In addition, benefit was seen in inoculated healthy plants in terms of increase in wet weight of roots and shoots as compared to the uninoculated controls. The mechanism of biocontrol also involved induction of plant's own defense response as evidenced by the upregulation of PR10a, NPR1, PAL and LOX2 in Streptomyces colonized plants.



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Bacillus thuringiensis produces the lipopeptide thumolycin to antagonize microbes and nematodes

Publication date: Available online 3 June 2018
Source:Microbiological Research
Author(s): Dehong Zheng, Zhiyong Zeng, Bingbing Xue, Yaoyao Deng, Ming Sun, Ya-Jie Tang, Lifang Ruan
Bacillus thuringiensis has been widely used as a bio-insecticide. However, novel biological activities other than insect toxicity of B. thuringiensis are still underestimated. In this study, a new lipopeptide biosynthesis gene cluster in B. thuringiensis BMB171 was discovered by genome mining and verified by reverse genetics. Thumolycin, the lipopeptide synthesized by this gene cluster, was then isolated and purified. Mass spectrum analysis revealed the molecular mass of thumolycin is 696.51 Da with the predicted molecular formula of C38H64N8O4. Further bioactivities assay showed that thumolycin endowed B. thuringiensis BMB171 with broad spectrum antimicrobial and nematocidal activities.



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The impact of spasticity on diaphragm contraction: Electrophysiological assessment

Publication date: August 2018
Source:Clinical Neurophysiology, Volume 129, Issue 8
Author(s): Bruno Miranda, Susana Pinto, Mamede de Carvalho
ObjectiveWe aimed to evaluate diaphragm spasticity by measuring diaphragm compound muscle action potentials (CMAPs) to phrenic nerve stimulation at end-expiration (exp) and at full-inspiration (insp) in amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS) and aged-matched controls. We also compared diaphragmatic responses of ALS patients with and without spasticity.MethodsDiaphragm CMAPs were recorded from 111 ALS patients, 15 PLS patients and 36 controls. Percentage of change (%insp-exp) was calculated for each neurophysiological measure. Clinical evaluation included: functional ALS scale, spasticity and forced vital capacity.ResultsDiaphragmatic exp and insp CMAPs in ALS patients had longer latency, lower peak-to-peak amplitude and smaller negative-peak area (all p < 0.05). ANCOVA analysis for %insp-exp differences across groups, taking into account end-expiration values, revealed a group effect for peak-to-peak amplitude (all p < 0.001) and negative-peak area (all p < 0.01). For both measures, the change in ALS and PLS patients was smaller than controls (all p < 0.05). Among ALS patients, those without spasticity (74%) had longer latency, lower peak-to-peak amplitude and smaller negative-peak area (all p < 0.05).ConclusionsUpper motor neuron involvement changes physiological variability of diaphragmatic CMAPs, likely due to decreased muscle shortening and mobility.SignificanceSpasticity impacts on diaphragm electrophysiology, with potential implications in respiratory function.



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High voltage 14 Hz hippocampal discharges on stereotactic EEG underlying 14&6 Hz positive bursts on scalp EEG

Publication date: Available online 2 June 2018
Source:Clinical Neurophysiology
Author(s): Puneet Jain, Shatha Shafi, Ayako Ochi, Elizabeth Donner, Rohit Sharma, George Ibrahim, James Drake, Hiroshi Otsubo




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Neurological complications of the treatment of pediatric neoplastic disorders

Publication date: Available online 2 June 2018
Source:Pediatric Neurology
Author(s): Lisa R. Sun, Stacy Cooper
Neurological complications resulting from childhood cancer treatments are common. Treatment for childhood neoplastic disorders is often multimodal and may include procedures, cranial irradiation, chemotherapy, transplant, and immunotherapy, each of which carries distinct neurological risks. Procedures, such as lumbar punctures, are commonly used in this population for diagnostic purposes as well as intrathecal medication administration. Surgery is associated with an array of potential neurologic complications, with posterior fossa syndrome being a common cause of morbidity in pediatric brain tumor patients after neurosurgical resection. Cranial irradiation can cause late neurological sequelae such as stroke, cerebral vasculopathy, secondary malignancy, and cognitive dysfunction. Neurotoxic effects of chemotherapeutic agents are common and include neuropathy, coagulopathy causing stroke or cerebral sinovenous thrombosis, encephalopathy, seizures, cerebellar dysfunction, myelopathy, and neuropsychological difficulties. Hematopoietic stem cell transplant has a high risk of neurological complications including central nervous system infection, seizures, and stroke. Immunotherapies, including chimeric antigen receptor-modified T-cells (CAR T-cells) and immune checkpoint inhibitors, are emerging as potentially effective strategies to treat some types of childhood cancer, but may carry with them substantial neurotoxicity which is just beginning to be recognized and studied. With evolving treatment protocols, childhood cancer survivorship is increasing, and the role of the neurologist in managing both the acute and chronic neurological consequences of treatment is becoming more important. Prevention, early recognition, and treatment of therapy-associated neurotoxicity are imperative to ensuring children can remain on the most effective therapeutic regimens and to improve the neurological function and quality of life of childhood cancer survivors.



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Decreasing Seizure Treatment Time through Quality Improvement Reduces Critical Care Utilization,,✯✯✯

Publication date: Available online 2 June 2018
Source:Pediatric Neurology
Author(s): Adam P. Ostendorf, Kelsey Merison, T. Arthur Wheeler, Anup D. Patel
ObjectiveRapid, effective treatment for status epilepticus reduces associated morbidity and mortality, yet medication delivery remains slow in many hospitalized patients. We utilized quality improvement (QI) methodology to improve treatment times for hospitalized children with status epilepticus. We hypothesized rapid initial seizure treatment would decrease seizure morbidity.MethodsWe utilized QI and statistical process control analysis in a non-intensive care setting within a tertiary care pediatric hospital. We performed Plan-Do-Study-Act cycles including (1) revising the nursing process for responding to seizures; (2) emphasizing intranasal midazolam over intravenous (IV) lorazepam; (3) relocating medications and supplies; (4) developing documentation tools and reinforcing correct processes; (5) developing and disseminating an online education module for residents and nurse practitioners; and (6) completing standardization to intranasal (IN) midazolam. This resulted in reduced utilization of critical care and mitigated hospital charges.ResultsSeventeen months after start, 66 seizures were treated with a benzodiazepine in a median (p25-p75) time of 7.5 minutes (5 to10) decreased from a baseline of 14 minutes (8 to30)(p=.01). The proportion of patients receiving a benzodiazepine in 10 minutes or less improved from 39% to 79%. The proportion of patients transferred to intensive care decreased from a baseline of 39% to 9% (p<.005), resulting in an estimated $2.1 million in mitigated hospital charges. Significant harm did not occur during the implementation of these interventions.ConclusionsChildren with status epilepticus were treated with benzodiazepines more rapidly and effectively following implementation of QI methodology. These interventions reduced utilization of critical care and mitigated hospital charges.



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The Radiologically Isolated Syndrome: An Opportunity to Prevent Multiple Sclerosis in Children

Publication date: Available online 3 June 2018
Source:Pediatric Neurology
Author(s): Naila Makhani




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Hybrid Fractional Ablative and Nonablative Laser Resurfacing of Actinic Keratoses

No abstract available

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Internet of Health Things: Toward intelligent vital signs monitoring in hospital wards

Publication date: Available online 2 June 2018
Source:Artificial Intelligence in Medicine
Author(s): Cristiano André da Costa, Cristian F. Pasluosta, Björn Eskofier, Denise Bandeira da Silva, Rodrigo da Rosa Righi
BackgroundLarge amounts of patient data are routinely manually collected in hospitals by using standalone medical devices, including vital signs. Such data is sometimes stored in spreadsheets, not forming part of patients' electronic health records, and is therefore difficult for caregivers to combine and analyze. One possible solution to overcome these limitations is the interconnection of medical devices via the Internet using a distributed platform, namely the Internet of Things. This approach allows data from different sources to be combined in order to better diagnose patient health status and identify possible anticipatory actions.MethodsThis work introduces the concept of the Internet of Health Things (IoHT), focusing on surveying the different approaches that could be applied to gather and combine data on vital signs in hospitals. Common heuristic approaches are considered, such as weighted early warning scoring systems, and the possibility of employing intelligent algorithms is analyzed.ResultsAs a result, this article proposes possible directions for combining patient data in hospital wards to improve efficiency, allow the optimization of resources, and minimize patient health deterioration.ConclusionIt is concluded that a patient-centered approach is critical, and that the IoHT paradigm will continue to provide more optimal solutions for patient management in hospital wards.

Graphical abstract

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The absence of the pCO2 effect on dissolved 134Cs uptake in select marine organisms

Publication date: December 2018
Source:Journal of Environmental Radioactivity, Volume 192
Author(s): Thomas Lacoue-Labarthe, François Oberhänsli, Jean-Louis Teyssié, Marc Metian
Ocean acidification have been shown to not affect the capacity of bivalves to bioaccumulation ¹³⁴Cs in their tissue; but as this was studied on only one species to date. There is therefore a need to verify if this holds true for other bivalve species or other marine invertebrates. The present short communication confirms that in the scallop Mimachlamys varia and the prawn Penaeus japonicus, two species that supposedly have a record to preferentially concentrates this radionuclide, that bioconcentration of ¹³⁴Cs was shown not to be influenced by a decreasing pH (and thereby increasing seawater pCO2). Although the dissolved ¹³⁴Cs was taken up in a similar manner under different pH values (8.1, 7.8, and 7.5) in both species, being described by a saturation state equilibrium model, the species displayed different bioconcentration capacities of ¹³⁴Cs: CFss in the prawns was approximately 10-fold higher than in scallops. Such results suggest that the Cs bioconcentration capacity are mainly dependent of the taxa and that uptake processes are independent the physiological ones involved in the biological responses of prawns and scallops to ocean acidification.



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Everolimus Plus Exemestane vs Everolimus or Capecitabine Monotherapy for Advanced Breast Cancer

This randomized clinical trial compares treatment with everolimus plus exemestane vs everolimus or capecitabine monotherapy for estrogen receptor-positive, HER2-negative advanced breast cancer.

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Association of Exercise With Mortality in Adult Survivors of Childhood Cancer

This cohort analysis examines the association between self-reported exercise and change in exercise and mortality in adult survivors of childhood cancer.

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Air pollutant sinks on noise barriers: Where do they perform the best?

Publication date: August 2018
Source:Atmospheric Environment, Volume 187
Author(s): Amitosh Dash, Gerrit E. Elsinga
While laboratory experiments, numerical simulations as well as field tests have underlined the influence of noise barriers in dispersing vehicular emissions and reducing downwind peak concentrations, these pollutants still remain in the atmosphere. Artificial pollutant sinks (for example, particle capturing or toxic gas treating devices) installed on top of noise barriers can further alleviate this problem by eliminating the pollutants passing through it. However, it is not known how the installation of a semi-permeable pollutant sink affects the aerodynamics of the pollutants' flow. By finding an optimal position and orientation for these sinks, the mass of the pollutants reaching the sink inlet can be maximized. Scaled down water tunnel experiments have been used to investigate the effectiveness of installing such a pollutant sink, of fixed dimensions, on top of a noise barrier adjacent to a highway. It is found that installing a sink is more beneficial on top of shorter barriers and that vertically elevating the sink, only slightly, can enhance its pollutant capturing performance. Using a sink in a 'highway canyon' (two noise barriers placed symmetrically with respect to the highway) must be done cautiously as there are several flow regimes observed, which are sensitive not only to the canyon aspect ratio (ratio between canyon width and height), but also to the presence/absence of the sink. The results here not only demonstrate the effectiveness of installing pollutant sinks on noise barriers, but also provide ballpark estimates on the optimal placement, orientation and performance of these devices, prior to field tests or even large-scale installation.

Graphical abstract

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Improved photodynamic efficacy of thiophenyl sulfonated zinc phthalocyanine loaded in lipid nano-carriers as new formulation for hepatocellular carcinoma cancer cells

Publication date: Available online 2 June 2018
Source:Photodiagnosis and Photodynamic Therapy
Author(s): Doaa A. Abdel Fadeel, Ghada Muneer, Asma M. Elsharif, Suhailah S. Al-Jameel, Hanan H. Mohamed, Tamer E. Youssef
BackgroundThe aim of the present study was to modify the structural activity of zinc(II)phthalocyanine by combining it with thiophenyl groups then loaded in lipid nano-carriers and evaluates its parameters required for the structure-activity relationship (SAR) for photodynamic therapy (PDT) of cancer.MethodsTetra (4–Thiophenyl) sulphonated phthalocyaninatozinc(II) (PhS.SO3Na)4ZnPc 5 was synthesized and characterized by various spectroscopic methods as a test compound. Liver hepatocellular carcinoma (HepG2) cells were treated with the synthesized (PhS.SO3Na)4ZnPc 5 derivative loaded in lipid nano carriers to understand the effect of combined compound on liver cancer cells. Furthermore, HepG2 cells were irradiated by visible red light at 60 mW/cm² for 20 min. The phototoxicity of (PhS.SO3Na)4ZnPc 5 after being formulated in both (L) and transfersomes (T) was investigated.ResultsOverall, the results indicate that combination of thiophenyl groups substitution, in particular in the structure of sulphonated zinc phthalocyanine is able to improve the photodynamic properties of ZnPc, and (PhS.SO3Na)4ZnPc 5 loaded in lipid nano-carriers can be a promising combined PDT treatment strategy for Liver hepatocellular carcinoma (HepG2) cells.ConclusionsThe new formulation ZnPc-lipid nano-carriers will be beneficial in the upcoming clinical trials and would enhance the inhibition of tumor growth.



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Matrix metalloproteinase-2: A key regulator in coagulation proteases mediated human breast cancer progression through autocrine signaling

Publication date: September 2018
Source:Biomedicine & Pharmacotherapy, Volume 105
Author(s): Kaushik Das, Ramesh Prasad, Shabbir Ahmed Ansari, Abhishek Roy, Ashis Mukherjee, Prosenjit Sen
AimsCell invasion is attributed to the synthesis and secretion of proteolytically active matrix-metalloproteinases (MMPs) by tumor cells to degrade extracellular matrix (ECM) and promote metastasis. The role of protease-activated receptor 2 (PAR2) in human breast cancer migration/invasion via MMP-2 up-regulation remains ill-defined; hence we investigated whether TF-FVIIa/trypsin-mediated PAR2 activation induces MMP-2 expression in human breast cancer.Main methodsMMP-2 expression and the signaling mechanisms were analyzed by western blotting and RT-PCR. MMP-2 activity was measured by gelatin zymography. Cell invasion was analyzed by transwell invasion assay whereas; wound healing assay was performed to understand the cell migratory potential.Key findingsHere, we highlight that TF-FVIIa/trypsin-mediated PAR2 activation leads to enhanced MMP-2 expression in human breast cancer cells contributing to tumor progression. Knock-down of PAR2 abrogated TF-FVIIa/trypsin-induced up-regulation of MMP-2. Again, genetic manipulation of AKT or inhibition of NF-ĸB suggested that PAR2-mediated enhanced MMP-2 expression is dependent on the PI3K-AKT-NF-ĸB pathway. We also reveal that TF, PAR2, and MMP-2 are over-expressed in invasive breast carcinoma tissues as compared to normal. Knock-down of MMP-2 significantly impeded TF-FVIIa/trypsin-induced cell invasion. Further, we report that MMP-2 activates p38 MAPK-MK2-HSP27 signaling axis that leads to actin polymerization and induces cell migration. Pharmacological inhibition of p38 MAPK or MK2 attenuates MMP-2-induced cell migration.SignificanceThe study delineates a novel signaling pathway by which PAR2-induced MMP-2 expression regulates human breast cancer cell migration/invasion. Understanding these mechanistic details will certainly help to identify crucial targets for therapeutic interventions in breast cancer metastasis.

Graphical abstract

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Downregulation of MiR-1297 predicts poor prognosis and enhances gastric cancer cell growth by targeting CREB1

Publication date: September 2018
Source:Biomedicine & Pharmacotherapy, Volume 105
Author(s): Wencang Gao, Ying Cao, Piaoting Guo, Xiaoyan Bao, Hongye Zhu, Jian Zheng, Cheng Yao, Dong Chen, Shenquan Yu, Binhai Chen, Shaoling Zhou, Dexiang Pang, Weijian Chen
Dysregulation of mircoRNAs (miRs) that act as tumor suppressors or oncogenes is participated in tumorigenesis and progression. The aim of the study is to investigate the role and mechanism of miR-1297 in gastric cancer (GC). Here, we demonstrated that miR-1297 expression was significantly lower in GC tissue samples compared to adjacent normal tissue samples in 62 cases GC patients. Lower miR-1297 expression positively associated with larger tumor size, lymph node metastasis, advanced TNM stage and poor survival time of patients. Upregulation of miR-1297 significantly inhibited cell proliferation and cell colony forming abilities in vitro. However, downregulation of miR-1297 can cause the reverse biological function changes. In vivo, miR-1297 overexpression suppressed tumor growth. Luciferase reporter assay showed that CREB1 was a direct target of miR-1297 in GC. MiR-1297 inhibited the expression of CREB1 by targeting the 3'UTR of CREB1. Additionally, we demonstrated that CREB1 overexpression rescued the effects on GC cell growth induced by miR-1297. Therefore, these results indicated that miR-1297 might be a prognostic predictor for GC and potential target of GC treatment.

Graphical abstract

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Xiaokeping-induced autophagy protects pancreatic β-cells against apoptosis under high glucose stress

Publication date: September 2018
Source:Biomedicine & Pharmacotherapy, Volume 105
Author(s): Yanyang Wu, Yongquan Hu, Zhou Haiyan, Wei YunLin, Kang Xincong, Liu Dongbo
Xiaokeping (XKP), a prescribed Traditional Chinese Medicine (TCM), has been used to treat patients with type Ⅱ diabetes mellitus for many years; however, the molecular mechanism of its effects is unknown. As the only insulin producer, the pancreatic β cell plays an important role in diabetes. Whether XKP influences the viability of pancreatic β cells remains to be substantiated. In the present study, autophagy/apoptosis analyses were used to evaluate the therapeutic effect of XKP on pancreatic β-cells induced by high glucose levels and to investigate a potential causal molecular mechanism of XKP effect on the cells. The pancreatic β-cell lines MIN-6 were divided into four groups: control, high glucose (33.3 mmol/L), high glucose with XKP, high glucose with XKP and 3-Methyladenine (3-MA). Immunofluorescence assay was employed to determine autophagosome formation and flow cytometry was used to determine apoptotic rates of the β cells by the detecting expression of autophagy- and apoptosis-related proteins. High glucose increased the apoptotic rate of β-cells from 5.37% to 23.24%; however addition of XKP mitigated the rate at 10.92%. Data indicate that autophagy of β-cells was induced by XKP via the mammalian target of rapamycin (mTOR) pathway. Where the autophagy inhibitor 3-MA was added, the apoptotic rate was 23.94%, similar to the high glucose group rate. The results suggest a potential cytoprotective effect of XKP from high glucose toxicity by its induction of autophagy which may be linked to mTOR-mediated autophagy.

Graphical abstract

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TAILORx trial finds most women with early breast cancer do not benefit from chemotherapy

Findings from the TAILORx clinical trial show chemotherapy does not benefit most women with early breast cancer. The new data, released at the 2018 ASCO annual meeting, will help inform treatment decisions for many women with early-stage breast cancer.

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Potential of memory T cells in bridging preoperative chemoradiation and immunotherapy in rectal cancer

Publication date: Available online 2 June 2018
Source:Radiotherapy and Oncology
Author(s): Sven de Mey, Heng Jiang, Hui Wang, Benedikt Engels, Thierry Gevaert, Inès Dufait, Olivier Feron, Joeri Aerts, Valeri Verovski, Mark De Ridder
The management of locally advanced rectal cancer has passed a long way of developments, where total mesorectal excision and preoperative radiotherapy are crucial to secure clinical outcome. These and other aspects of multidisciplinary strategies are in-depth summarized in the literature, while our mini-review pursues a different goal. From an ethical and medical standpoint, we witness a delayed implementation of novel therapies given the cost/time consuming process of organizing randomized trials that would bridge an already excellent local control in cT3-4 node-positive disease with long-term survival. This unfortunate separation of clinical research and medical care provides a strong motivation to repurpose known pharmaceuticals that suit for treatment intensification with a focus on distant control. In the framework of on-going phase II-III IG/IMRT-SIB trials, we came across an intriguing translational observation that the ratio of circulating (protumor) myeloid-derived suppressor cells to (antitumor) central memory CD8+ T cells is drastically increased, a possible mechanism of tumor immuno-escape and spread. This finding prompts that restoring the CD45RO memory T-cell pool could be a part of integrated adjuvant interventions. Therefore, the immunocorrective potentials of modified IL-2 and the anti-diabetic drug metformin are thoroughly discussed in the context of tumor immunobiology, mTOR pathways and revised Warburg effect.



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Disease Prediction using Graph Convolutional Networks: Application to Autism Spectrum Disorder and Alzheimer’s Disease

Publication date: Available online 2 June 2018
Source:Medical Image Analysis
Author(s): Sarah Parisot, Sofia Ira Ktena, Enzo Ferrante, Matthew Lee, Ricardo Guerrero, Ben Glocker, Daniel Rueckert
Graphs are widely used as a natural framework that captures interactions between individual elements represented as nodes in a graph. In medical applications, specifically, nodes can represent individuals within a potentially large population (patients or healthy controls) accompanied by a set of features, while the graph edges incorporate associations between subjects in an intuitive manner. This representation allows to incorporate the wealth of imaging and non-imaging information as well as individual subject features simultaneously in disease classification tasks. Previous graph-based approaches for supervised or unsupervised learning in the context of disease prediction solely focus on pairwise similarities between subjects, disregarding individual characteristics and features, or rather rely on subject-specific imaging feature vectors and fail to model interactions between them. In this paper, we present a thorough evaluation of a generic framework that leverages both imaging and non-imaging information and can be used for brain analysis in large populations. This framework exploits Graph Convolutional Networks (GCNs) and involves representing populations as a sparse graph, where its nodes are associated with imaging-based feature vectors, while phenotypic information is integrated as edge weights. The extensive evaluation explores the effect of each individual component of this framework on disease prediction performance and further compares it to different baselines. The framework performance is tested on two large datasets with diverse underlying data, ABIDE and ADNI, for the prediction of Autism Spectrum Disorder and conversion to Alzheimer's disease, respectively. Our analysis shows that our novel framework can improve over state-of-the-art results on both databases, with 70.4% classification accuracy for ABIDE and 80.0% for ADNI.

Graphical abstract

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Reintroducing OPV in Israel on the journey to global polio eradication – Estimation at a low rate of contraindicated population

Publication date: 18 June 2018
Source:Vaccine, Volume 36, Issue 26
Author(s): Chen Rosenberg Danziger, Emilia Anis, Ethel-Sherry Gordon, Itamar Grotto, Yehuda L. Danon
IntroductionThe 2013 reemergence of wild poliovirus in Israel led to the reinstatement of a routine OPV vaccination. Fearing VAPP in immunocompromised, the MOH regulated contraindications for vaccination candidates and household contacts. In this study we estimate the size of the contraindicated population to OPV vaccination.MethodWe studied vaccination candidates aged 2–9 and 14–23 months and probable household contacts. Using the rate of contraindications extracted for each study group from a medical records database, a statistical model was built to estimate the probability of contraindications in candidates.Results3.9% of the 2–9-month-old study group and 4% of the 14–23-month-old group had contraindications by either self or household contacts.ConclusionA statistical model can provide an estimation of the contraindicated population and can be used in the future when devising vaccination campaigns. In contrast to concerns raised by the MOH, our findings show a smaller than anticipated contraindicated population.



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Safety and immunogenicity of fractional dose intradermal injection of two quadrivalent conjugated meningococcal vaccines

Publication date: 18 June 2018
Source:Vaccine, Volume 36, Issue 26
Author(s): Emile F.F. Jonker, Mariëtte B. van Ravenhorst, Guy A.M. Berbers, Leo G. Visser
BackgroundVaccination with conjugated meningococcal vaccines is the best way to prevent invasive meningococcal disease. Changes in serogroup epidemiology have led to the inclusion of quadrivalent vaccines in the national immunization programs of several countries, but vaccines are frequently in short supply. Intradermal administration has the potential to increase vaccine availability through dose reduction, without sacrificing efficacy. It has never before been investigated for glycoconjugate meningococcal vaccines.MethodsDifferent fractional doses of two quadrivalent meningococcal conjugate vaccines (MenACWY-CRM197 (Menveo®) and MenACWY-TT (Nimenrix®)) were administered intradermally to sequential groups of 4 participants, according to an adaptive dose escalation design, starting at 1/10th of the original dose. Booster doses were given after 4–6 months based on interim serology results using a multiplex bead-based assay (MIA). Final analyses were based on serum bactericidal antibody titers (rSBA).ResultsA total of 12 subjects were enrolled (average 25 years old, range 19–48). MenACWY-CRM197 became unavailable during the course of the study and was only evaluated for a 1/10th dose. This dose resulted in less than complete seroprotection for serogroup A but complete protection against the other serogroups. MenACWY-TT was evaluated for a 1/10th and 1/5th dose level. Both fractional doses of MenACWY-TT resulted in complete seroprotection against all vaccine serogroups. Geometric mean titers 1 month after vaccination were lower and decayed faster in the MenACWY-CRM197 group. Adverse events were mild and there were no serious adverse events.ConclusionFractional intradermal vaccination against meningococcal disease with quadrivalent conjugate vaccine appears to be safe and effective in our small dose finding study. Tetanus toxoid conjugated vaccine (Nimenrix®) shows a trend towards higher antibody levels compared to CRM197-conjugated vaccine (Menveo®). The 1/5th fractional dose of MenACWY-TT appears to result in higher antibody levels than does the 1/10th dose. These results can be used for a larger non-inferiority study.This trial was registered in clinicaltrials.gov under NCT01782066.



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The immune response of rhesus macaques to novel vaccines comprising hepatitis B virus S, PreS1, and Core antigens

Publication date: 18 June 2018
Source:Vaccine, Volume 36, Issue 26
Author(s): Xia Chuai, Bangxiang Xie, Hong Chen, Xinyi Tan, Wen Wang, Baoying Huang, Yao Deng, Wenhui Li, Wenjie Tan
Therapeutic vaccines represent a unique approach to hepatitis B virus (HBV) treatment and have the potential to induce long-term control of infection. This study explored the immune responses of rhesus macaques to novel vaccines comprising the S, PreS1, and Core antigens of the HBV that showed promise as prophylactic and therapeutic approaches in a mouse model. The tested vaccines included two DNA vaccines (pVRC-SS1, pVRC-CS1), an HBV particle subunit (HBSS1) vaccine and the recombinant vaccinia virus- (RVJ-) based vaccines (RVJSS1 and RVJCS1) in which SS1 containing S (1–223 aa) and PreS1 (21–47 aa), CS1 containing Core (1–144 aa) and PreS1 (1–42 aa). The humoral immunity and cell-mediated immunity (CMI) induced by vaccines comprising the S, PreS1, and Core antigens of HBV were investigated in a longitudinal study that continued up to 98 weeks after the firstvaccination. In rhesus macaques, anti-PreS1 antibody was induced more rapidly than anti-S or anti-Core antibody after DNA vaccination. The antibody and cell-mediated immune responses against S, PreS1, and C were significantly enhanced in macaques boosted with RVJSS1 and RVJCS1, whereas the cell-mediated response to C was most robust and durable. The immune response to S, PreS1, and C was restored by HBSS1 boosting and detected in macaques until weeks 74 and 98 after the first vaccination. Additionally, robust neutralizing activity was detected at week 52. In conclusion, novel HBV vaccine candidates, especially those used for therapeutic applications should incorporate the PreS1 and Core antigens.



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Editorial Board/Aims and Scope

Publication date: 18 June 2018
Source:Vaccine, Volume 36, Issue 26





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Development of an opsonophagocytic killing assay for group a streptococcus

Publication date: 18 June 2018
Source:Vaccine, Volume 36, Issue 26
Author(s): Scott Jones, Nicole J. Moreland, Marta Zancolli, Jeremy Raynes, Jacelyn M.S. Loh, Pierre R. Smeesters, Shiranee Sriskandan, Jonathan R. Carapetis, John D. Fraser, David Goldblatt
Group A Streptococcus (GAS) or Streptococcus pyogenes is responsible for an estimated 500,000 deaths worldwide each year. Protection against GAS infection is thought to be mediated by phagocytosis, enhanced by bacteria-specific antibody. There are no licenced GAS vaccines, despite many promising candidates in preclinical and early stage clinical development, the most advanced of which are based on the GAS M-protein. Vaccine progress has been hindered, in part, by the lack of a standardised functional assay suitable for vaccine evaluation. Current assays, developed over 50 years ago, rely on non-immune human whole blood as a source of neutrophils and complement. Variations in complement and neutrophil activity between donors result in variable data that is difficult to interpret. We have developed an opsonophagocytic killing assay (OPKA) for GAS that utilises dimethylformamide (DMF)-differentiated human promyelocytic leukemia cells (HL-60) as a source of neutrophils and baby rabbit complement, thus removing the major sources of variation in current assays. We have standardised the OPKA for several clinically relevant GAS strain types (emm1, emm6 and emm12) and have shown antibody-specific killing for each emm-type using M-protein specific rabbit antisera. Specificity was demonstrated by pre-incubation of the antisera with homologous M-protein antigens that blocked antibody-specific killing. Additional qualifications of the GAS OPKA, including the assessment of the accuracy, precision, linearity and the lower limit of quantification, were also performed. This GAS OPKA assay has the potential to provide a robust and reproducible platform to accelerate GAS vaccine development.



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Cooperative binding of anti-tetanus toxin monoclonal antibodies: Implications for designing an efficient biclonal preparation to prevent tetanus toxin intoxication

Publication date: 18 June 2018
Source:Vaccine, Volume 36, Issue 26
Author(s): Ivana Lukic, Ana Filipovic, Aleksandra Inic-Kanada, Emilija Marinkovic, Radmila Miljkovic, Marijana Stojanovic
Oligoclonal combinations of several monoclonal antibodies (MAbs) are being considered for the treatment of various infectious pathologies. These combinations are less sensitive to antigen structural changes than individual MAbs; at the same time, their characteristics can be more efficiently controlled than those of polyclonal antibodies. The main goal of this study was to evaluate the binding characteristics of six biclonal equimolar preparations (BEP) of tetanus toxin (TeNT)-specific MAbs and to investigate how the MAb combination influences the BEPs' protective capacity. We show that a combination of TeNT-specific MAbs, which not only bind TeNT but also exert positive cooperative effects, results in a BEP with superior binding characteristics and protective capacity, when compared with the individual component MAbs. Furthermore, we show that a MAb with only partial protective capacity but positive effects on the binding of the other BEP component can be used as a valuable constituent of the BEP.

Graphical abstract

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Willingness and influential factors of parents to vaccinate their children with novel inactivated enterovirus 71 vaccines in Guangzhou, China

Publication date: 18 June 2018
Source:Vaccine, Volume 36, Issue 26
Author(s): Tiegang Li, Hui Wang, Yin Lu, Qin Li, Chun Chen, Dahu Wang, Meixia Li, Yilan Li, Jianyun Lu, Zongqiu Chen, Yu Ma, Wenhui Liu, Mengmeng Ma, Di Wu, Jiachun Lu, Zhicong Yang
Hand, foot and mouth disease (HFMD) primarily affects children younger than 5 years of age. Recently, HFMD has ranked as the top notifiable infectious disease in China. In December 2015, China approved two novel inactivated enterovirus 71 vaccines (EV71 vaccines) for HFMD. Parents' acceptance is often essential for vaccination program success. The goal of this study was to identify willingness and influential factors to vaccinate among parents of kindergarteners in Guangzhou, China. A cross-sectional survey of face-to-face interviews was conducted from March to July 2016. Fifty-five kindergartens were randomly selected from 11 districts of Guangzhou. An anonymous self-designed questionnaire was used to investigate awareness, knowledge and attitude towards HFMD and EV71 vaccines. A total of 868 parents participated in the survey. Mean(±standard deviation) knowledge score of HFMD was 6.32(±1.70). Approximately 32.03% of parents had heard of the EV71 vaccines with 22.58% receiving information before this study. Nearly 44.24% of parents showed willingness to vaccinate their children. Previously receiving EV71 vaccine-related information [adjusted odds ratio (aOR) = 1.48, 95% confidence interval (CI): 1.04–2.11], no fear of adverse effects (aOR = 4.25, 95%CI: 2.77–6.53), perceived susceptibility of children to HFMD (aOR = 2.15, 95%CI: 1.42–3.25) and children not previously diagnosed with HFMD (aOR = 1.56, 95%CI: 1.07–2.27) were positively associated with EV71 vaccination acceptability. However, parental education background (aOR = 0.54, 95%CI: 0.37–0.80) was negatively correlated with vaccination acceptability. Our study provides baseline information for future vaccination campaigns to help improve the EV71 vaccine uptake rate. Special efforts are urgently needed to improve the awareness and knowledge of EV71 vaccines in China.



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Safety, tolerability, acceptability and immunogenicity of an influenza vaccine delivered to human skin by a novel high-density microprojection array patch (Nanopatch™)

Publication date: 18 June 2018
Source:Vaccine, Volume 36, Issue 26
Author(s): Germain J.P. Fernando, Julian Hickling, Cesar M. Jayashi Flores, Paul Griffin, Christopher D. Anderson, S. Rachel Skinner, Cristyn Davies, Katey Witham, Melinda Pryor, Jesse Bodle, Steve Rockman, Ian H. Frazer, Angus H. Forster
BackgroundInjection using needle and syringe (N&S) is the most widely used method for vaccination, but requires trained healthcare workers. Fear of needles, risk of needle-stick injury, and the need to reconstitute lyophilised vaccines, are also drawbacks. The Nanopatch (NP) is a microarray skin patch comprised of a high-density array of microprojections dry-coated with vaccine that is being developed to address these shortcomings. Here we report a randomised, partly-blinded, placebo-controlled trial that represents the first use in humans of the NP to deliver a vaccine.MethodsHealthy volunteers were vaccinated once with one of the following: (1) NPs coated with split inactivated influenza virus (A/California/07/2009 [H1N1], 15 µg haemagglutinin (HA) per dose), applied to the volar forearm (NP-HA/FA), n = 15; (2) NPs coated with split inactivated influenza virus (A/California/07/2009 [H1N1], 15 µg HA per dose), applied to the upper arm (NP-HA/UA), n = 15; (3) Fluvax® 2016 containing 15 µg of the same H1N1 HA antigen injected intramuscularly (IM) into the deltoid (IM-HA/D), n = 15; (4) NPs coated with excipients only, applied to the volar forearm (NP-placebo/FA), n = 5; (5) NPs coated with excipients only applied to the upper arm (NP-placebo/UA), n = 5; or (6) Saline injected IM into the deltoid (IM-placebo/D), n = 5. Antibody responses at days 0, 7, and 21 were measured by haemagglutination inhibition (HAI) and microneutralisation (MN) assays.FindingsNP vaccination was safe and acceptable; all adverse events were mild or moderate. Most subjects (55%) receiving patch vaccinations (HA or placebo) preferred the NP compared with their past experience of IM injection with N&S (preferred by 24%). The antigen-vaccinated groups had statistically higher HAI titres at day 7 and 21 compared with baseline (p < 0.0001), with no statistical differences between the treatment groups (p > 0.05), although the group sizes were small. The geometric mean HAI titres at day 21 for the NP-HA/FA, NP-HA/UA and IM-HA/D groups were: 335 (189–593 95% CI), 160 (74–345 95% CI), and 221 (129–380 95% CI) respectively. A similar pattern of responses was seen with the MN assays. Application site reactions were mild or moderate, and more marked with the influenza vaccine NPs than with the placebo or IM injection.InterpretationInfluenza vaccination using the NP appeared to be safe, and acceptable in this first time in humans study, and induced similar immune responses to vaccination by IM injection.



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Conditional admission, religious exemption type, and nonmedical vaccine exemptions in California before and after a state policy change

Publication date: 18 June 2018
Source:Vaccine, Volume 36, Issue 26
Author(s): Alison M. Buttenheim, Malia Jones, Caitlin Mckown, Daniel Salmon, Saad B. Omer
Recent measles and pertussis outbreaks in the US have focused national attention on state laws governing exemptions from mandatory vaccines for school entry. After several years of increases in nonmedical exemptions in California, the state assembly passed Assembly Bill 2109 in 2012, making nonmedical exemptions more difficult to obtain by requiring parents to obtain a signature from a health care provider. We used data from the California Department of Public Health to describe changes in the overall prevalence of personal belief exemptions and compositional changes in immunization status for the school years 2012–2013 through 2015–2016. Following the implementation of Assembly Bill 2109, the statewide exemption rate declined from 3.1% in 2013 to 2.5% in 2014 and then to 2.3% in 2015, representing a 25% reduction from the 2013 peak. Continued surveillance of exemption rates and vaccine refusal are needed to monitor and protect herd immunity against vaccine-preventable diseases.



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Safety and immunogenicity of a Vi-DT typhoid conjugate vaccine: Phase I trial in Healthy Filipino adults and children

Publication date: 18 June 2018
Source:Vaccine, Volume 36, Issue 26
Author(s): Maria Rosario Capeding, Samuel Teshome, Tarun Saluja, Khalid Ali Syed, Deok Ryun Kim, Ju Yeon Park, Jae Seung Yang, Yang Hee Kim, Jiwook Park, Sue-Kyoung Jo, Yun Chon, Sudeep Kothari, Seon-Young Yang, Dong Soo Ham, Ji Hwa Ryu, Hee-Seong Hwang, Ju-Hwan Mun, Julia A. Lynch, Jerome H. Kim, Hun Kim, Jean-Louis Excler, Sushant Sahastrabuddhe
BackgroundTyphoid fever remains a major public health problem in low- and middle-income countries where children aged 2–14 years bear the greatest burden. Vi polysaccharide is poorly immunogenic in children <2 years of age, and protection in adults is modest. The limitations of Vi polysaccharide vaccines can be overcome by conjugation of the Vi to a carrier protein. A typhoid conjugate vaccine composed of Vi polysaccharide conjugated to diphtheria toxoid (Vi-DT) has been developed. The Phase I study results are presented here.MethodsThis was a randomized, observer-blinded Phase I study to assess the safety and immunogenicity of Vi-DT compared to Vi polysaccharide vaccine, conducted in Manila, Philippines. Participants enrolled in an age de-escalation manner (18–45, 6–17 and 2–5 years) were randomized between Test (Vi-DT, 25 µg) administered at 0 and 4 weeks and Comparator (Vi polysaccharide, Typhim Vi® and Vaxigrip®, Sanofi Pasteur) vaccines.ResultsA total of 144 participants were enrolled (48 by age strata, 24 in Test and Comparator groups each). No serious adverse event was reported in either group. Solicited and unsolicited adverse events were mild or moderate in both groups with the exception of a 4-year old girl in Test group with grade 3 fever which resolved without sequelae. All participants in Test group seroconverted after first and second doses of Vi-DT while the proportions in the Comparator group were 97.1% and 97.2%, after first dose of Typhim Vi® and second dose of Vaxigrip®, respectively. Vi-DT showed 4-fold higher Geometric Mean Titers (GMT) compared to Typhim Vi® (adjusted for age strata, p < 0.001). No further increase of GMT was detected after the second dose of Vi-DT. Anti-DT IgG seroresponse rates were 81.2% and 84.5% post first and second Vi-DT doses, respectively.ConclusionsVi-DT vaccine was safe, well-tolerated and immunogenic in participants aged 2–45 years.ClinicalTrials.gov registration number: NCT02645032.



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Genetic and antigenic relationship of foot–and–mouth disease virus serotype O isolates with the vaccine strain O1/BFS

Publication date: 18 June 2018
Source:Vaccine, Volume 36, Issue 26
Author(s): Wanhong Xu, Zhidong Zhang, Charles Nfon, Ming Yang
Foot–and–mouth disease serotype O viruses (FMDV/O) are responsible for the most outbreaks in FMD endemic countries. O1/BFS is one of the recommended FMD/O vaccine strains by World Reference Laboratory for FMD. In the current study, FMDV/O1 BFS vaccine strain and serotype O field isolates (45) were analyzed phylogenetically and antigenically to gain more insight into the genetic and antigenic characteristics of the vaccine strain and field isolates.O1/BFS showed similarity with 89% of the field isolates using a virus neutralization test (VNT). The P1 region encoding the FMDV capsid was sequenced and analysed for 46 strains of FMDV/O. Phylogenetic analysis showed these viruses originated from five continents and covered eight of 11 reported topotypes. Five isolates that demonstrated low antigenic similarities with O1/BFS were analyzed for their antigenic variation at the known neutralizing antigenic sites. Three of the five isolates demonstrated unique amino acid substitutions at various antigenic sites. No unique amino acid substitutions were observed for the other two unmatched isolates. Positively selected residues were identified on the surface of the FMD virus capsid supporting that it is important to continuously monitor field isolates for their antigenic and phenotypic changes.In conclusion, the vaccine strain O1/BFS is likely to confer protection against 89% of the 45 FMDV/O isolates based on VNT. Thus O1/BFS vaccine strain is still suitable for use in global FMD serotype O outbreak control. Combining data from phylogenetic, molecular and antigenic analysis can provide improvements in the process of vaccine selection.



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Production and efficacy of a low-cost recombinant pneumococcal protein polysaccharide conjugate vaccine

Publication date: 18 June 2018
Source:Vaccine, Volume 36, Issue 26
Author(s): Jenny A. Herbert, Emily J. Kay, Sian E. Faustini, Alex Richter, Sherif Abouelhadid, Jon Cuccui, Brendan Wren, Timothy J. Mitchell
Streptococcus pneumoniae is the leading cause of bacterial pneumonia. Although this is a vaccine preventable disease, S. pneumoniae still causes over 1 million deaths per year, mainly in children under the age of five. The biggest disease burden is in the developing world, which is mainly due to unavailability of vaccines due to their high costs. Protein polysaccharide conjugate vaccines are given routinely in the developed world to children to induce a protective antibody response against S. pneumoniae. One of these vaccines is Prevnar13, which targets 13 of the 95 known capsular types. Current vaccine production requires growth of large amounts of the 13 serotypes, and isolation of the capsular polysaccharide that is then chemically coupled to a protein, such as the diphtheria toxoid CRM197, in a multistep expensive procedure. In this study, we design, purify and produce novel recombinant pneumococcal protein polysaccharide conjugate vaccines in Escherichia coli, which act as mini factories for the low-cost production of conjugate vaccines. Recombinant vaccine efficacy was tested in a murine model of pneumococcal pneumonia; ability to protect against invasive disease was compared to that of Prevnar13. This study provides the first proof of principle that protein polysaccharide conjugate vaccines produced in E. coli can be used to prevent pneumococcal infection. Vaccines produced in this manner may provide a low-cost alternative to the current vaccine production methodology.



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Decline of HPV infections in Scandinavian cervical screening populations after introduction of HPV vaccination programs

Publication date: 18 June 2018
Source:Vaccine, Volume 36, Issue 26
Author(s): Joakim Dillner, Mari Nygård, Christian Munk, Maria Hortlund, Bo T. Hansen, Camilla Lagheden, Kai-Li Liaw, Susanne K. Kjaer
ObjectiveTo monitor the changes in prevalence of human papillomavirus (HPV) infections in women <50 years of age, participating in cervical screening programs of Denmark, Norway, and Sweden, before and after introduction of quadrivalent HPV (qHPV) vaccination.MethodsLiquid-based cytology samples were collected from 6538 women who attended cervical screening in Denmark, Norway, and Sweden in 2006–2008 and from 6332 similarly enrolled women in 2012–2013. Denmark started organized qHPV vaccination in 2008, Norway in 2009, and Sweden in 2012. All HPV testing and genotyping was performed using identical enrollment and analysis methods, by accredited general primer polymerase chain reaction methods with typing using the Luminex system.ResultsOverall HPV positivity declined slightly from 36.5% in 2006–2008 to 34.5% in 2012–2013. The decline was most pronounced among women 18–26 years of age: from 54.4% to 48.1% (P < 0.001). The decline was substantial for vaccine HPV types (HPV6/11/16/18: decline from 22.3% to 16.6%; P < 0.001) and was seen for both low-risk vaccine types (HPV6/11 declined from 5.0% to 2.5%) and high-risk vaccine types (HPV16/18 declined from 18.9% to 14.9%). Among women 27–50 years of age, there was no change between the time periods (22.5% and 21.6%, respectively). The significant decline in the younger age group was different in the 3 countries.ConclusionThis population-based study enrolling >12,000 women participating in cervical screening in the 3 Nordic countries before and after introduction of organized qHPV vaccination demonstrated a marked decline in HPV infection in the younger population in the 2 countries where qHPV vaccination programs started in 2008–2009, suggesting that organized HPV vaccination programs resulted in a decrease of HPV types circulating in the general population.



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An innovative medical school curriculum to address human papillomavirus vaccine hesitancy

Publication date: 18 June 2018
Source:Vaccine, Volume 36, Issue 26
Author(s): Abigail M. Schnaith, Erica M. Evans, Caleb Vogt, Andrea M. Tinsay, Thomas E. Schmidt, Katelyn M. Tessier, Britt K. Erickson
BackgroundVaccination rates against Human Papillomavirus (HPV) in the US remain alarmingly low. Physicians can significantly influence a parent's decision to vaccinate their children. However, medical education often lacks training on specific strategies for communicating with vaccine hesitant parents.MethodsWe created an innovative curriculum designed to teach medical students how to address HPV vaccine hesitancy. The curriculum consisted of (1) a presentation on the epidemiology, biology, and disease morbidity associated with HPV, (2) a video that teaches specific communication strategies and (3) role-playing simulations. This curriculum was delivered to medical students at two separate sites. Medical students were surveyed before and after completing the educational curriculum. The surveys assessed student comfort talking to HPV vaccine hesitant parents and their likelihood to recommend the HPV vaccine.ResultsPre- and post-intervention surveys were completed by 101 of the 132 participants (77% response rate). After the intervention, student awareness of the benefits of the HPV vaccine increased by a mean of 0.82 points (Likert scale 1–5, p < 0.01) and student comfort talking to vaccine hesitant parents increased by a mean of 1.37 points (p < 0.01). Prior to the intervention, students more strongly recommended the HPV vaccine to females compared to males, but this gender disparity was eliminated after the intervention (p < 0.01). Personal vaccination status was independately associated with a higher likelihood of recommending the HPV vaccine both before and after the intervention.ConclusionOur innovative curriculum improved medical student comfort level discussing HPV vaccination with hesitant parents and increased the perceived likelihood of recommending HPV vaccination. The intervention is easy to implement, scalable, and requires minimal resources. Educating future providers on this important topic has the potential to improve vaccination rates nationwide and thus should be considered for all medical students.



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Determinants of cost of routine immunization programme in India

Publication date: 18 June 2018
Source:Vaccine, Volume 36, Issue 26
Author(s): Susmita Chatterjee, Arpita Ghosh, Palash Das, Nicolas A. Menzies, Ramanan Laxminarayan
The costs of delivering routine immunization services in India vary widely across facilities, districts and states. Understanding the factors influencing this cost variation could help predict future immunization costs and suggest approaches for improving the efficiency of service provision.We examined determinants of facility cost for immunization services based on a nationally representative sample of sub-centres and primary health centres (99 and 89 facilities, respectively) by regressing logged total facility costs, both including and excluding vaccine cost, against several explanatory variables. We used a multi-level regression model to account for the multi-stage sampling design, including state- and district-levelrandom effects.We found that facility costs were significantly associated with total doses administered, type of facility, salary of the main vaccinator, number of immunization sessions, and the distance of the facility from the nearest cold chain point.Use of pentavalent vaccine by the state was an important determinant of total facility cost including vaccine cost. India is introducing several new vaccines including some supported by Gavi. Therefore, the government will have to ensure that additional resources will be made available after the support from Gavi ceases.



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Comparison of reproductive protection against bovine viral diarrhea virus provided by multivalent viral vaccines containing inactivated fractions of bovine viral diarrhea virus 1 and 2

Publication date: 18 June 2018
Source:Vaccine, Volume 36, Issue 26
Author(s): Paul H. Walz, Kay P. Riddell, Benjamin W. Newcomer, John D. Neill, Shollie M. Falkenberg, Victor S. Cortese, Daniel W. Scruggs, Thomas H. Short
Bovine viral diarrhea virus (BVDV) is an important viral cause of reproductive disease, immune suppression and clinical disease in cattle. The objective of this study was to compare reproductive protection in cattle against the impacts of bovine viral diarrhea virus (BVDV) provided by three different multivalent vaccines containing inactivated BVDV. BVDV negative beef heifers and cows (n = 122) were randomly assigned to one of four groups. Groups A-C (n = 34/group) received two pre-breeding doses of one of three commercially available multivalent vaccines containing inactivated fractions of BVDV 1 and BVDV 2, and Group D (n = 20) served as negative control and received two doses of saline prior to breeding. Animals were bred, and following pregnancy diagnosis, 110 cattle [Group A (n = 31); Group B (n = 32); Group C (n = 31); Group D (n = 16)] were subjected to a 28-day exposure to cattle persistently infected (PI) with BVDV (1a, 1b and 2a). Of the 110 pregnancies, 6 pregnancies resulted in fetal resorption with no material for testing. From the resultant 104 pregnancies, BVDV transplacental infections were demonstrated in 73 pregnancies. The BVDV fetal infection rate (FI) was calculated at 13/30 (43%) for Group A cows, 27/29 (93%) for Group B cows, 18/30 (60%) for Group C cows, and 15/15 (100%) for Group D cows. Statistical differences were observed between groups with respect to post-vaccination antibody titers, presence and duration of viremia in pregnant cattle, and fetal infection rates in offspring from BVDV-exposed cows. Group A vaccination resulted in significant protection against BVDV infection as compared to all other groups based upon outcome measurements, while Group B vaccination did not differ in protection against BVDV infection from control Group D. Ability of inactivated BVDV vaccines to provide protection against BVDV fetal infection varies significantly among commercially available products; however, in this challenge model, the inactivated vaccines provided unacceptable levels of BVDV FI protection.



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Facilitators of and barriers to HPV vaccination among sexual and gender minority patients at a Boston community health center

Publication date: 18 June 2018
Source:Vaccine, Volume 36, Issue 26
Author(s): Kaan Z. Apaydin, Holly B. Fontenot, Derri Shtasel, Sannisha K. Dale, Christina P.C. Borba, Christopher S. Lathan, Lori Panther, Kenneth H. Mayer, Alex S. Keuroghlian
BackgroundYoung sexual minority individuals have lower human papillomavirus (HPV) vaccine completion rates than the general population, and little is known about how gender minority people perceive HPV vaccination. The aim of this study was to qualitatively identify patient-, provider-, and systems-level barriers and facilitators for HPV vaccination among sexual and gender minority (SGM) people.MethodsFifteen SGM-identified individuals, ages 23–26, were recruited at an urban community health center in Boston, MA, that specializes in care for SGM. Participants were enrolled in a study that utilized surveys and in-person focus groups. During focus groups, participants were asked to describe their perceived barriers and facilitators for completion of HPV vaccination.ResultsFourteen participants reported having a sexual minority identity, and five participants reported having a gender minority identity. Participants described the following factors influencing HPV vaccination: (1) at the patient level, low HPV-related knowledge and lack of engagement in care were associated with less vaccination, whereas fear of HPV-related disease motivated vaccination; (2) at the provider level, knowledge and SGM cultural-competence related to HPV was associated with patient willingness to be vaccinated; (3) at the systems level, SGM identity-affirming healthcare settings were associated with increased vaccination, whereas historical trends in HPV vaccine marketing selectively for cisgender women and lack of public awareness of HPV-related disease among SGM were associated with decreased vaccincation.ConclusionOur study identified internal and external barriers for HPV vaccination related among SGM patients. These findings highlight the need to increase public awareness about the risks of HPV-related disease among SGM and educate SGM youth about HPV-related disease and vaccine importance. Finally, this study supports the need for future interventions to cultivate SGM-competent providers and SGM identity-affirming healthcare settings as a way to increase HPV vaccination.



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Epidemiology, clinical presentation, risk factors, intensive care admission and outcomes of invasive meningococcal disease in England, 2010–2015

Publication date: 18 June 2018
Source:Vaccine, Volume 36, Issue 26
Author(s): Sydel R. Parikh, Helen Campbell, Stephen J. Gray, Kazim Beebeejaun, Sonia Ribeiro, Ray Borrow, Mary E. Ramsay, Shamez N. Ladhani
The epidemiology of invasive meningococcal disease (IMD) is constantly changing as new strains are introduced into a population and older strains are removed through vaccination, population immunity or natural trends. Consequently, the clinical disease associated with circulating strains may also change over time. In England, IMD incidence has declined from 1.8/100,000 in 2010/2011 to 1.1/100,000 in 2013/2014, with a small increase in 2014/2015 to 1.3/100,000. Between 01 January 2011 and 30 June 2015, MenB was responsible for 73.0% (n = 2489) of 3411 laboratory-confirmed IMD cases, followed by MenW (n = 371, 10.9%), MenY (n = 373, 10.9%) and MenC (n = 129, 3.8%); other capsular groups were rare (n = 49, 1.4%). Detailed questionnaires were completed for all 3411 laboratory-confirmed cases. Clinical presentation varied by capsular group and age. Atypical presentations were uncommon (244/3411; 7.2%), increasing from 1.2% (41/3411) in children to 3.5% (120/3411) in older adults. Known IMD risk factors were rare (18/3411; 0.5%) and included complement deficiency (n = 11), asplenia (n = 6) or both (n = 1). Nearly a third of cases required intensive care (1069/3411; 31.3%), with rates highest in adults. The 28-day CFR was 6.9% (n = 237), with the lowest rates in 0–14 year-olds (85/1885, 4.5%) and highest among 85+ year-olds (30/94, 31.9%). These observations provide a useful baseline for the current burden of IMD in a European country with enhanced national surveillance.



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Hepatocellular Carcinoma Tumor Dose Response following 90Y-radioembolization with glass microspheres using 90Y-SPECT/CT based Voxel Dosimetry

Publication date: Available online 2 June 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): S.Cheenu Kappadath, Justin Mikell, Anjali Balagopal, Veera Baladandayuthapani, Ahmed Kaseb, Armeen Mahvash
PurposeTo investigate hepatocellular carcinoma (HCC) tumor dose-response characteristics based on voxel-level absorbed doses (D) and biological effective doses (BED) using quantitative ⁹⁰Y-SPECT/CT after ⁹⁰Y-radioembilization with glass-microspheres. We also investigated the relationship between normal liver D and toxicities.Methods⁹⁰Y-radioembolization activity distributions for 34 patients were based on quantitative ⁹⁰Y-bremsstrahlung SPECT/CT. D maps were generated using a local-deposition algorithm. Contrast-enhanced CTs or MRIs of the liver were registered to ⁹⁰Y-SPECT/CT and all tumor larger than 2.5 cm diameter (53 tumors) were segmented. Tumor mean D and BED (Dmean and BEDmean) and dose volume coverage from 0-100% in 10% steps (D0-D100 and BED0-BED100) were extracted. Tumor response was evaluated on follow-up using WHO, RECIST, and mRECIST. Differences in dose metrics for responders and non-responders were assessed using Mann-Whitney U test. Univariate logistic regression model was used to determine tumor dose metrics that correlated with tumor response. Correlations between tumor size, tumor Dmean, and tumor dose heterogeneity (defined as the coefficient of variation) were assessed.ResultsThe objective response rates were 14/53, 15/53, and 30/53 for WHO, RECIST, and mRECIST criteria, respectively. WHO and RECIST response statuses did not correlate with D or BED. D and BED between mRECIST responders and non-responders were significantly different for Dmean, D20-D80, BEDmean, and BED0-BED80. Threshold doses (and the 95% confidence interval) for 50% probability of mRECIST response (D50%) were 160 Gy (123-196 Gy) for Dmean and 214 Gy (146-280 Gy) for BEDmean. Tumor dose heterogeneity significantly correlated with tumor volume. No statistically significant association between Dmean to normal liver and complications related to bilirubin, albumin, or ascites was observed.ConclusionsHCC tumor dose-response curves following ⁹⁰Y-radioembolization with glass-microspheres showed Dmean of 160 Gy and BEDmean of 214 Gy for D50% with PPV of ∼70% and NPV of ∼62%. No complications were observed in our patient cohort for normal liver Dmean less than 44 Gy.



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Automated instead of manual treatment planning? A plan comparison based on dose-volume statistics and clinical preference

Publication date: Available online 2 June 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Barbara Vanderstraeten, Bruno Goddeeris, Katrien Vandecasteele, Marc van Eijkeren, Carlos De Wagter, Yolande Lievens
Purpose/ObjectiveAutomated planning aims to speed up treatment planning and improve plan quality. We compared manual to automated planning for lung stereotactic body radiation therapy (SBRT) based on dose-volume histogram (DVH) statistics and clinical preference.Methods and MaterialsManual (MP) and automated (AP) intensity-modulated radiation therapy (IMRT) plans were generated for 56 patients using in-house developed software and Pinnacle 9.10 Auto-Planning, respectively. Optimization times were measured in 10 patients and the impact of AP on the total treatment cost was estimated. For the remaining 46 patients each plan was checked against our clinical objectives and a pairwise DVH comparison was performed. Three experienced radiation oncologists (ROs) evaluated each plan and indicated their preference.ResultsAP reduced the average optimization time by 77.3% but only affected the total treatment cost by 3.6%. 3 AP / 0 MP failed our clinical objectives, while 13 AP / 9 MP showed a minor deviation. AP significantly reduced D2% for the spinal cord, esophagus, heart, aorta and main stem bronchus (p<0.05), while preserving target coverage. The ROs found over 75% of the AP clinically acceptable without any further fine tuning.ConclusionsAP may help to create satisfactory treatment plans fast and effectively. As the critical appraisal by qualified professionals remains necessary, there is no such thing as "fully automated" planning yet.

Teaser

Automated planning aims to improve the efficiency of the treatment planning process as well as the final plan quality. We compared automated plans to manual plans for 56 patients based on clinical objectives, DVH metrics and a blind clinical assessment by three experienced radiation oncologists. We observed a statistically significant reduction in OAR dose while maintaining PTV coverage for the automated plans. Clinically, however, the automated plans were not always preferred over their manual counterparts.


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Low-cost electromyography – Validation against a commercial system using both manual and automated activation timing thresholds

Publication date: Available online 2 June 2018
Source:Journal of Electromyography and Kinesiology
Author(s): Sophie Heywood, Yonghao Pua, Jodie McClelland, Paula Geigle, Ann Rahmann, Kelly Bower, Ross Clark
Widespread use of electromyography (EMG) as an assessment and biofeedback method may be limited by costly commercial systems. Low-cost devices are available; however their validity is unknown. This study determined the concurrent validity of a low-cost EMG on a microchip compared with a commercially available system during isometric and dynamic muscle contractions. Inter-tester, intra-session reliability of manual data extraction during data processing compared to a simple, automatic thresholding method using the Teager-Kaiser energy operator (TKEO) was also evaluated. 10 healthy women (age 28.1±6.8yrs, height 162.1±6.8cm, mass 60.3±10.2kg) were assessed simultaneously with a commercially available EMG system (Telemyo DTS) and a custom low-cost EMG system (Myoware Muscle Sensor) during voluntary isometric contractions, knee extension, squatting, stepping and jumping. Two surface electrode sets (connected to the low-cost and the commercial system) were placed end to end along the same Vastus Lateralis muscle fibre line. Peak and mean contraction intensity, and contraction duration were analysed. Overall the relative agreement between systems was excellent for peak muscle activation (ICC 0.77-0.96) and modest to excellent for mean muscle activation (ICC 0.68-0.95) and contraction duration (ICC 0.65-0.99). Inter-tester, intra-session reliability was excellent for peak contraction intensity (ICC>0.99) and modest to excellent for mean contraction intensity, with the TKEO method primarily recording stronger agreement than the manual method. Poor to excellent inter-tester reliability occurred for contraction duration. Our findings indicate that a low-cost EMG system is comparable to a commercial system for assessing muscle activation, and that using the TKEO improved the reliability of timing related variables.



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Characterizing the SEMG Patterns with Myofascial Pain Using a Multi-Scale Wavelet Model through Machine Learning Approaches

Publication date: Available online 2 June 2018
Source:Journal of Electromyography and Kinesiology
Author(s): Yu-Ching Lin, Nan-Ying Yu, Ching-Fen Jiang, Shao-Hsia Chang
In this paper, we introduce a newly developed multi-scale wavelet model for the interpretation of surface electromyography (SEMG) signals and validate the model's capability to characterize changes in neuromuscular activation in cases with myofascial pain syndrome (MPS) via machine learning methods. The SEMG data collected from normal (N=30; 27 women, 3 men) and MPS subjects (N=26; 22 women, 4 men) were adopted for this retrospective analysis. SMEGs were measured from the taut-band loci on both sides of the trapezius muscle on the upper back while he/she conducted a cyclic bilateral backward shoulder extension movement within 1 minute. Classification accuracy of the SEMG model to differentiate MPS patients from normal subjects was 77% using template matching and 60% using K-means clustering. Classification consistency between the two machine learning methods was 87% in the normal group and 93% in the MPS group. The 2D feature graphs derived from the proposed multi-scale model revealed distinct patterns between normal subjects and MPS patients. The classification consistency using template matching and K-means clustering suggests the potential of using the proposed model to characterize interference pattern changes induced by MPS.



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Prognostic predictive value of TLR4 polymorphisms in Han Chinese population with hypertrophic cardiomyopathy

Publication date: Available online 2 June 2018
Source:The Kaohsiung Journal of Medical Sciences
Author(s): Ke Han, Yan-Ping Li
Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease and is an important cause of sudden death in patients of all ages. The aim of this study was to find out whether Toll-like receptor-4 (TLR4) polymorphism is associated with HCM. To explore the association between TLR4 gene polymorphisms and HCM, 486 HCM patients and 214 healthy controls were enrolled in a case–control study of Chinese Han population. Two single nucleotide polymorphisms (SNPs) in the promoter region of TLR4 gene, −728G > C (rs11536865) and −2081G > A (rs10983755), were genotyped by PCR restriction fragment length polymorphism (PCR-RFLP). The associations between TLR4 SNPs and overall survival (OS) of HCM patients were analyzed by the Kaplan–Meier estimation method and Cox proportional hazards regression analysis. Serum TLR4 level was determined by ELISA. Our results showed that the C allelic frequency of −728G > C and A allelic frequency of −2081G > A were higher in HCM patients than those in controls (P < 0.001). The ratios of genotype frequencies for both SNPs were associated with HCM susceptibility under three genetic models (P < 0.01). Two SNPs were also associated with the OS in HCM patients (P < 0.001). The CC genotype of −728G > C and AA genotype of −2081G > A were associated with poor prognosis of HCM (P < 0.001). Moreover, HCM patients had a higher serum TLR4 level compared with the controls (242.6 pg/ml versus 135.7 pg/ml, P = 0.027). In addition, significant associations were observed between CC genotype of −728G > C or AA genotype of −2081G > A and plasma TLR4 level (P < 0.01). The results of this study indicated that TLR4 polymorphisms may be a genetic susceptibility factor for HCM in the Han Chinese population.



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Structural data of DNA binding and molecular docking studies of dihydropyrimidinone transition metal complexes

Publication date: August 2018
Source:Data in Brief, Volume 19
Author(s): P. Vijayakrishnan, S. Arul Antony, D. Velmurugan
A series of some novel copper complexes derived from Biginelli condensation of DHPHS. The ligand and its transition metal complexes show more antimicrobial activities which was substantiated by molecular docking studies. Transition metal complexes four possess antioxidant properties supported by the DNA-binding, cleavage, and viscosity measurement (Prasad et al., 2011) [1]. The in Silicon DNA binding reveals copper complex is bound to be Minor groove and other manganese, cobalt, nickel complexes are bound to the Major groove portion of DNA through hydrogen bonds and hence copper (II), manganese (II), cobalt (II), nickel (II) complexes are called Minor groove and Major groove binder respectively. The DNA cleavage studies of metal complexes presented more protruding activity in the attendance of H2O2 associated to that in the absence of H2O2. In continuance of our ongoing research on DNA binding and cleavage happenings of transition metal complexes, in this paper we obtainable the synthesis, characterization and DNA cleavage activities.

Graphical abstract

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Synthesis and characterization data of monocationic and dicationic ionic liquids or molten salts

Publication date: August 2018
Source:Data in Brief, Volume 19
Author(s): M.G. Montalbán, G. Víllora, P. Licence
Data presented in this article are related with the research paper entitled "Ecotoxicity assessment of dicationic versus monocationic ionic liquids as a more environmentally friendly alternative" [1]. The present article describes the synthesis steps and characterization data of a set of twenty-six imidazolium, pyrrolidinium and pyridinium-based ionic liquids (ILs) or molten salts: nine monocationic and seventeen dicationic. Specifically, the chemical structure of the compounds was confirmed by ¹H NMR, ¹³C NMR and ¹⁹F NMR spectroscopy and mass spectrometry (MS). Other data such as physical state at room temperature, melting point temperature (for solids at room temperature) and thermal decomposition temperature (when melting was not reached before decomposition) of the ILs or molten salts are also reported here.



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Central fractalkine stimulates central prostaglandin E2 production and induces systemic inflammatory responses

Publication date: Available online 2 June 2018
Source:Brain Research Bulletin
Author(s): Clarissa M.D. Mota, José Antunes-Rodrigues, Luiz G.S. Branco
Fractalkine (FKN; CX3CL1) belongs to gamma-chemokine family and binds to CX3CR1 receptors. Currently, the mechanisms involving FKN-induced inflammatory mediators are research targets in an attempt to study immune diseases mechanisms. Besides, FKN seems to modulate inflammation in the nervous system by inducing the secretion of pro-inflammatory mediators such as prostaglandin E2 (PGE2). PGE2 is a classic and important mediator of fever that activates warm-responsive neurons in the anteroventral preoptic region of the hypothalamus (AVPO). Here, we tested the hypothesis that central FKN modulates febrigenic signaling both centrally and peripherally. We performed intracerebroventricular (icv) microinjections of saline (1 μL) or FKN (doses of 5, 50, 500 pg/μL) in rats and measured body temperature (Tb) besides assessing tail skin temperature (Tsk) as a thermoeffector indicator used to calculate the heat loss index (HLI). We also measured the time course changes in AVPO PGE2, besides plasma corticosterone (CORT) and interleukin-6 (IL-6) levels. FKN induced a long lasting febrile response in which the highest dose (500 pg/μL) induced a marked rise on Tb that was accompanied by a reduced Tsk and HLI, consequently. FKN increased AVPO PGE2 production in a time-dependent manner besides increasing plasma CORT and IL-6 levels. Our data consistently indicate that FKN increases AVPO PGE2 production and Tb, accompanied by raised plasma IL-6 levels and activation of the hypothalamus-pituitary-adrenal axis.



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Human African trypanosomiasis: How do the parasites enter and cause dysfunctions of the nervous system in murine models?

Publication date: Available online 2 June 2018
Source:Brain Research Bulletin
Author(s): Willias Masocha, Krister Kristensson
In this review we describe how Trypanosoma brucei brucei, a rodent pathogenic strain of African trypanosomes, can invade the nervous system, first by localization to the choroid plexus, the circumventricular organs (CVOs) and peripheral ganglia, which have fenestrated vessels, followed by crossing of the blood-brain barrier (BBB) into the white matter, hypothalamus, thalamus and basal ganglia. White blood cells (WBCs) pave the way for the trypanosome neuroinvasion. Experiments with immune deficient mice show that the invasion of WBCs is initiated by the toll-like receptor 9, followed by an augmentation phase that depends on the cytokine IFN-γ and the chemokine CXCL10. Nitric oxide (NO) derived from iNOS then prevents a break-down of the BBB and non-regulated passage of cells. This chain of events is relevant for design of better diagnostic tools to distinguish the different stages of the disease as well as for better understanding of the pathogenesis of the nervous system dysfunctions, which include circadian rhythm changes with sleep pattern disruption, pain syndromes, movement disorders and mental disturbances including dementia.



https://ift.tt/2kK7YxV

Locomotor activity, emotionality, sensori-motor gating, learning and memory in the APPswe/PS1dE9 mouse model of Alzheimer’s disease

Publication date: Available online 2 June 2018
Source:Brain Research Bulletin
Author(s): Timothy P. O'Leary, Ahmed T. Hussin, Rhian K. Gunn, Richard E. Brown
The APPswe/PS1dE9 mouse (line 85) is a double transgenic model of Alzheimer's disease (AD) with familial amyloid precursor protein and presenilin-1 mutations. These mice develop age-related behavioral changes reflective of the neuro-psychiatric symptoms (altered anxiety-like behaviour, hyperactivity) and cognitive dysfunction (impaired learning and memory) observed in AD. The APPswe/PS1dE9 mouse has been used to examine the efficacy of therapeutic interventions on behaviour, despite previous difficulties in replicating behavioural phenotypes. Therefore, the purpose of this study was to establish the reliability of these phenotypes by further characterizing the behaviour of male APPswe/PS1dE9 and wild-type mice between 7 and 14 months of age. Mice were tested on the open-field over 5-days to examine emotionality, locomotor activity and inter-session habituation. Mice were also tested on the repeated-reversal water maze task and spontaneous alternation on the Y-maze to assess working memory. Sensori-motor gating was examined with acoustic startle and pre-pulse inhibition. Lastly contextual and cued (trace) memory was assessed with fear conditioning. The results show that among non-cognitive behaviours, APPswe/PS1dE9 mice have normal locomotor activity, anxiety-like behavior, habituation and sensori-motor gating. However, APPswe/PS1dE9 mice show impaired working memory on the repeated-reversal water-maze and impaired memory in contextual but not trace-cued fear conditioning. These results indicate that the APPswe/PS1dE9 (line 85) mice have deficits in some types of hippocampal-dependent learning and memory and, at the ages tested, APPswe/PS1dE9 mice model cognitive dysfunction but not neuro-psychiatric symptoms.



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Driven to Decay: Excitability and Synaptic Abnormalities in Amyotrophic Lateral Sclerosis

Publication date: Available online 2 June 2018
Source:Brain Research Bulletin
Author(s): Matthew J. Fogarty
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease and is clinically characterised by the death of corticospinal motor neurons (CSMNs), spinal and brainstem MNs and the degeneration of the corticospinal tract. Degeneration of CSMNs and MNs leads inexorably to muscle wastage and weakness, progressing to eventual death within 3-5 years of diagnosis. The CSMNs, located within layer V of the primary motor cortex, project axons constituting the corticospinal tract, forming synaptic connections with brainstem and spinal cord interneurons and MNs. Clinical ALS may be divided into familial (~10% of cases) or sporadic (~90% of cases), based on apparent random incidence. The emergence of transgenic murine models, expressing different ALS-associated mutations has accelerated our understanding of ALS pathogenesis, although precise mechanisms remain elusive. Multiple avenues of investigation suggest that cortical electrical abnormalities have pre-eminence in the pathophysiology of ALS. In addition, glutamate-mediated functional and structural alterations in both CSMNs and MNs are present in both sporadic and familial forms of ALS. This review aims to promulgate debate in the field with regard to the common aetiology of sporadic and familial ALS. A specific focus on a nexus point in ALS pathogenesis, namely, the synaptic and intrinsic hyperexcitability of CSMNs and MNs and alterations to their structure are comprehensively detailed. The association of extramotor dysfunction with neuronal structural/functional alterations will be discussed. Finally, the implications of the latest research on the dying-forward and dying-back controversy are considered.



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Scholar : These new articles for Aphasiology are available online

The online platform for Taylor & Francis Online content New for Aphasiology and online now on Taylor & Francis Online: Original Articles Validation of the Italian version of the Kagan scales for people with aphasia and their conversation partners Rossella Muò, Marta Rinaudo, Giulia Rabino, Ermelinda Massari, Antonio Schindler, Patrizia Steni & Tiziana Iacomussi Pages: 1-20 | DOI: 10.1080/02687038.2018.1482402 2018 Future Directions Forum JOIN US at the 2018 Future Directions Forum for Journal of Clinical Child & Adolescent Psychology - June 15-16, 2018 To update which email alerts you receive, manage your alerts within the My Account area. Unsubscribe from new content alerts for this journal (both new issue and latest article notifications) with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Ca2+-Triggered Synaptic Vesicle Fusion Initiated by Release of Inhibition

Publication date: Available online 26 April 2018
Source:Trends in Cell Biology
Author(s): Axel T. Brunger, Jeremy Leitz, Qiangjun Zhou, Ucheor B. Choi, Ying Lai
Recent structural and functional studies of the synaptic vesicle fusion machinery suggest an inhibited tripartite complex consisting of neuronal soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs), synaptotagmin, and complexin prior to Ca²⁺-triggered synaptic vesicle fusion. We speculate that Ca²⁺-triggered fusion commences with the release of inhibition by Ca²⁺ binding to synaptotagmin C2 domains. Subsequently, fusion is assisted by SNARE complex zippering and by active membrane remodeling properties of synaptotagmin. This additional, inhibitory role of synaptotagmin may be a general principle since other recent studies suggest that Ca²⁺ binding to extended synaptotagmin C2 domains enables lipid transport by releasing an inhibited state of the system, and that Munc13 may nominally be in an inhibited state, which is released upon Ca²⁺ binding to one of its C2 domains.



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The Lung and Esophagus: Developmental and Regenerative Overlap

Publication date: Available online 2 June 2018
Source:Trends in Cell Biology
Author(s): Edward E. Morrisey, Anil K. Rustgi
Lung and esophageal development and organogenesis involve a complex interplay of signaling pathways and transcriptional factors. Once the lung and esophagus do separate, their epithelial proliferation and differentiation programs share certain common properties that may fuel adaptive responses to injury and subsequent regeneration. Lung and esophageal tissue organogenesis and regeneration provide perspectives on squamous cell cancers and adenocarcinomas in each tissue.



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Editorial Board and Contents

Publication date: June 2018
Source:Trends in Cell Biology, Volume 28, Issue 6





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Microtubule-Targeting Agents: Strategies To Hijack the Cytoskeleton

Publication date: Available online 2 June 2018
Source:Trends in Cell Biology
Author(s): Michel O. Steinmetz, Andrea E. Prota
Microtubule-targeting agents (MTAs) such as paclitaxel and the vinca alkaloids are among the most important medical weapons available to combat cancer. MTAs interfere with intracellular transport, inhibit eukaryotic cell proliferation, and promote cell death by suppressing microtubule dynamics. Recent advances in the structural analysis of MTAs have enabled the extensive characterization of their interactions with microtubules and their building block tubulin. We review here our current knowledge on the molecular mechanisms used by MTAs to hijack the microtubule cytoskeleton, and discuss dual inhibitors that target both kinases and microtubules. We further formulate some outstanding questions related to MTA structural biology and present possible routes for future investigations of this fascinating class of antimitotic agents.



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Ub and Down: Ubiquitin Exercise for the Elderly

Publication date: Available online 25 April 2018
Source:Trends in Cell Biology
Author(s): Jörg Höhfeld, Thorsten Hoppe
Conjugation of ubiquitin onto proteins generates a degradation signal or exerts degradation-independent regulatory functions. Ubiquitylation is governed by the antagonistic action of ubiquitin ligases and deubiquitylating enzymes (DUBs). Several recent publications illustrate a balanced interplay of ligases and DUBs at signaling hubs that are central to longevity and protein homeostasis (proteostasis). In addition, stress-induced alterations of ubiquitin conjugation are emerging as key events that drive aging and contribute to the pathology of age-related diseases. This physiological role of dynamic ubiquitylation further extends its well-known function in protein regulation and quality control at the cellular level. Recent work thus significantly advances our understanding of the aging process both at the molecular and organismal level.



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