Predication of Different Stages of Alzheimer’s Disease Using Neighborhood Component Analysis and Ensemble Decision Tree

Publication date: Available online 24 February 2018
Source:Journal of Neuroscience Methods
Author(s): Mingwu Jin, Weishu Deng
BackgroundThere is a spectrum of the progression from healthy control (HC) to mild cognitive impairment (MCI) without conversion to Alzheimer's disease (AD), to MCI with conversion to AD (cMCI), and to AD. This study aims to predict the different disease stages using brain structural information provided by MRI data.New methodThe neighborhood component analysis (NCA) is applied to select most powerful features for prediction. The ensemble decision tree classifier is built to predict which group the subject belongs to. The best features and model parameters are determined by cross validation of the training data.ResultsOur results show that 16 out of a total of 429 features were selected by NCA using 240 training subjects, including MMSE score and structural measures in memory-related regions. The boosting tree model with NCA features can achieve prediction accuracy of 56.25% on 160 test subjects.Comparison with existing method(s)Principal component analysis (PCA) and sequential feature selection (SFS) are used for feature selection, while support vector machine (SVM) is used for classification. The boosting tree model with NCA features outperforms all other combinations of feature selection and classification methods.ConclusionsThe results suggest that NCA be a better feature selection strategy than PCA and SFS for the data used in this study. Ensemble tree classifier with boosting is more powerful than SVM to predict the subject group. However, more advanced feature selection and classification methods or additional measures besides structural MRI may be needed to improve the prediction performance.



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Blood vessel occlusion with erythrocyte aggregates causes burn injury progression: microvasculature dilation as a possible therapy

Abstract

Other than radiation, caustic strong alkali insults, and massive over-reactive inflammation (pyoderma gangrenosum), injury progression after trauma is usually secondary to ischemia from decreased blood vessel perfusion. Impeded blood flow contributes to injury progression in a variety of disorders including venous stasis ulcers, arterial ulcers, diabetic ulcers, flap and graft necrosis, sickle cell disease, cryoglobulinemia and other vasculopathies, vasculitis, post-myocardial infarction, and post stroke. The cause of impeded blood flow in these disorders/diseases is well known.

This article is protected by copyright. All rights reserved.

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An immunohistochemical panel consisting of EZH2, C-KIT, and CD205 is useful for distinguishing thymic squamous cell carcinoma from type B3 thymoma

Publication date: Available online 24 February 2018
Source:Pathology - Research and Practice
Author(s): Bo-Sung Kim, Jin Kuk Kim, Chang Hyun Kang, Young Tae Kim, Kyeong Cheon Jung, Jae-Kyung Won
Type B3 thymoma and thymic squamous cell carcinoma (SqCC) often cause a diagnostic problem due to their histological similarities. The aim of this study is to identify EZH2 as a novel and powerful biomarker that can effectively distinguish thymic SqCC from type B3 thymoma, and find optimal combinations among 11 markers. A total of 53 patients, comprising 26 with type B3 thymoma and 27 with thymic SqCC, were allocated to the discovery or validation cohorts, and immunohistochemical staining was performed and analyzed. The expression level of each marker was scored, and receiver-operator characteristic curve analysis was performed to evaluate their diagnostic accuracies. This analysis identified EZH2, C-KIT, and CD205 as useful markers for distinguishing thymic SqCC, and a combined panel approach using them further improved diagnostic accuracy in both the discovery and validation cohorts. In the combined cohorts analysis, EZH2 was the single best marker with 88.9% sensitivity and 100% specificity [area under the curve (AUC) = 0.967]. The sensitivity and specificity were 85.2% and 100% (AUC = 0.962) for C-KIT, and 100% and 73.1% (AUC = 0.844) for CD205. The combined panel had the highest sensitivity and specificity at 96.3% and 100%, which was significantly or marginally higher than those of EZH2, C-KIT, and CD205 alone (P = 0.071, 0.034, and 0.005, respectively). The present findings indicate that EZH2 is useful as a novel diagnostic marker for distinguishing thymic SqCC and that the panel approach can be used as an effective differential diagnostic tool in daily practice.



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Distribution of gonadotropin-inhibitory hormone (GnIH) in male Luchuan piglets

Publication date: Available online 24 February 2018
Source:Gene Expression Patterns
Author(s): Xiaoye Wang, Xun Li, Chuanhuo Hu
Gonadotropin inhibitory hormone (GnIH) has emerged as a novel hypothalamic neuropeptide that actively inhibits gonadotropin release in birds and mammals. Recent evidence indicates that GnIH not only acts as a key neurohormone that controls vertebrate reproduction but is also involved in stress response, food intake, and aggressive and sexual behaviors, suggesting a broad physiological role for this neuropeptide. To elucidate its multiple sites of action and potential functions, studying the detailed distribution of GnIH in different organs, except for the hypothalamus-pituitary-ovary/testis axis, is necessary. Therefore, in the present study, in different central nervous system (CNS) and peripheral organs of male Luchuan piglets, the distribution of GnIH was systemically determined using immunohistochemistry, and the expression of GnIH mRNA was investigated using semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). Our results demonstrate that GnIH immune reactive (GnIH-ir) neurons were widely distributed in the pig CNS, but the number and size of the GnIH-ir neurons varied and exhibited morphological diversity. In the peripheral organs, GnIH immunoreactive cells were observed in the respiratory tract, alimentary tract, endocrine organs, genitourinary tract and lymphatic organs. GnIH mRNA was highly expressed in the CNS, with the highest expression in the hypothalamus. In the peripheral organs, high GnIH mRNA levels were detected in the testis, while no GnIH expression was observed in the liver, lungs and heart et al. These results demonstrated that GnIH might play an important role in modulating a variety of physiological functions and provided the morphological data for further study of GnIH in pigs.



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Editorial Board

Publication date: April 2018
Source:Medical Image Analysis, Volume 45





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Cerebrovascular Network Registration via An Efficient Attributed Graph Matching Technique

Publication date: Available online 24 February 2018
Source:Medical Image Analysis
Author(s): Sepideh Almasi, Alexandra Lauric, Adel Malek, Eric L. Miller
Registration of vascular networks is an indispensable element of prognostic and diagnostic studies that require structural analysis and comparison over time, among different samples, and to a gold standard. However, vascular networks manifest low spatial texture and sparse structural content so that even small variations in their location can make the intensity-based registration inefficient and prone to errors. Motivated by geometrical graph-based models developed in our prior work, we use the shape information in the graph topology sense to enhance the registration performance. An efficient feature-based registration is presented that seeks correspondence of the bifurcations and branches in a graph matching scheme. Since the graph matching is originally posed a NP-hard quadratic assignment problem (QAP) in the literature, we have designed a node signature that incorporates edge correspondences indirectly. This allows removing the quadratic term in the QAP to recast the problem as a linear assignment problem (LAP) to relieve the computational burden. The LAP is efficiently solvable and is scalable to data with graph representation of larger size. The performance is tested and validated using clinical 3-D angiography images of the human cerebrovasculature as well as synthetic datasets. This method proves to be robust in the face of different structural and algorithm's parameters. Quality of inter-subject and multimodal matching of clinical data has also been confirmed.

Graphical abstract

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Cation distribution effect on static and dynamic magnetic properties of Co1-xZnxFe2O4 ferrite powders

Publication date: 15 June 2018
Source:Journal of Magnetism and Magnetic Materials, Volume 456
Author(s): G. Barrera, M. Coisson, F. Celegato, S. Raghuvanshi, F. Mazaleyrat, S.N. Kane, P. Tiberto
Co1-xZnxFe2O4 (0.08 ≤ x ≤ 0.56) powders prepared by a sol-gel auto-combustion method have been investigated through the combined use of structural and dc/ac-magnetization measurements under a wide range of applied magnetic field values. EDS spectra are performed to evaluate the samples chemical composition, whereas the X-ray diffraction measurements indicate the formation of the typical nanocrystalline mixed cubic spinel structure and allow to determine the cationic distribution as well as the lattice parameter and the oxygen position as function of Zn content. Magnetic characterization improves the knowledge about the correlation between the structural properties and magnetic behavior. The magnetization curves show a hysteretic behavior at room temperature and they are analyzed as function of Zn content taking in account the Yafet-Kittel's model. The replacement of non-zero magnetic moment Co²⁺ ions with zero magnetic moment Zn²⁺ ions induces a gradual reduction of magnetocrystalline anisotropy and a lowering of the magnetic coercivity. The energy lost in a static and alternating magnetic field (frequency of 69 kHz) at selected vertex field values for the studied samples has been calculated in order to evaluate their prospective usage to operate in different field conditions.

Graphical abstract

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Humoral immune responses to infection: common mechanisms and unique strategies to combat pathogen immune evasion tactics

Ismail Sebina | Marion Pepper

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Are human ATP-binding cassette transporter C11 and earwax associated with the incidence of cholesteatoma?

Publication date: Available online 24 February 2018
Source:Medical Hypotheses
Author(s): Hiroshi Nakagawa, Yu Toyoda, Tobias Albrecht, Megumi Tsukamoto, Mark Praetorius, Toshihisa Ishikawa, Kazusaku Kamiya, Takeshi Kusunoki, Katsuhisa Ikeda, Serkan Sertel
Cholesteatoma is an ear disease based on a locally destructive noncancerous conglomerate of epidermis and keratin debris. Abnormal growth of stratified keratinized squamous epithelium in the temporal bone causes destruction of the outer and middle ear, potentially leading to hearing impairment, facial palsy, vertigo, lateral sinus thrombosis, and intracranial complications. Although cholesteatoma is effectively treated by surgical resection (mastoidectomy), the lack of effective and nonsurgical therapies potentially results in fatal consequences, establishing the need for a comprehensive investigation of cholesteatoma pathogenesis. Although its etiology is still being debated, interestingly, we found that the trend associated with frequency of the 538G allele of the adenosine triphosphate-binding cassette transporter C11 (ABCC11) gene, the determinant of wet-type earwax, and ethnic groups was similar to that between the incidence of cholesteatoma and ethnic groups (countries). The incidences of cholesteatoma in Europe (Denmark, Finland, and Scotland) are higher than in East Asia (Japan), and the frequencies of the ABCC11 538G allele in African, American, and European (Finland and Scotland) populations are higher than those in East Asian populations (Japan). Additionally, a single-nucleotide polymorphism in the ABCC11 gene (rs17822931, 538G>A; Gly180Arg) is closely related to earwax morphotypes. While earwax is often beneficial to ear health, it is sometimes harmful in cases where it causes hearing impairment. Based on independent findings of associations between ABCC11 and the physiological environment of the auditory canal, we hypothesize a possible link between ABCC11, earwax, and the incidence of cholesteatoma.



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PVDF piezoelectric neural conduit incorporated pre-differentiated adipose-derived stem cells may accelerate the repair of peripheral nerve injury

Publication date: Available online 24 February 2018
Source:Medical Hypotheses
Author(s): Li Ming, Zhang Peixun, Zhang Dianying
Peripheral nerve injury is a common trauma disease which often results in sensory and motor dysfunction. However, the surgical repair for peripheral nerve injury, especially for large segmental defects, is not satisfactory. Growing evidences suggest that artificial neural conduit combined with stem cells is potential tissue engineering remediation method for peripheral nerve injury. But, selections of biomaterials and stem cells are still being debated. Based on the findings from previous studies, we hypothesize that PVDF piezoelectric neural conduit incorporated Schwann-like cells which pre-differentiated from adipose-derived stem cells may substantially promote the repair of peripheral nerve injury. This novel technique may help clinical surgeons cure the seriously injured patients better and point out a new direction for neural tissue engineering researchers select the suitable biomaterials and seed cells.



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Clinical manifestations of pachychoroid may be secondary to pachysclera and increased scleral rigidity

Publication date: Available online 24 February 2018
Source:Medical Hypotheses
Author(s): Pradeep Venkatesh, Brijesh Takkar, Shreyas Temkar
Current imaging advancements have led to emergence of pachychoroid as an association of important vision threatening diseases like chronic serous chorioretinopathy and polypoidal choroidal vasculopathy. While the precise relation between thick choroid and such disorder is being investigated, the etiology behind pachychoroid remains elusive. We hypothesize pachychoroid to be a resultant of impeded vascular outflow due to thick sclera and increased scleral rigidity. We discuss our hypothesis in the perspective of other choroidal manifestations of anomalously thick scleral structure.



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SGLT2 Inhibitor- Induced Euglycaemic Diabetic Ketoacidosis May be due to Abrupt, Severe and Transient Impaired Glucose Sensing in Susceptible Individuals with a Hitherto Unrecognised Beta Cell SGLT Variant

Publication date: Available online 24 February 2018
Source:Medical Hypotheses
Author(s): F.M. Finucane
Euglycaemic diabetic ketoacidosis (EDKA) is a rare complication of treatment with SGLT2 inhibitors in patients with type 2 diabetes. Uncertainty remains about its precise mechanistic basis, but the physiological derangement is acute and profound, yet reversible with cessation of the drug. It is reminiscent of other "non type 1" presentations with DKA such as ketosis prone diabetes, except that glucose levels are usually normal. Impaired beta cell glucose sensing that mimicked a state of hypoglycaemia could theoretically lead to abrupt and transient cessation of insulin secretion. GLUT2 mediates glucose sensing in beta cells. In other tissues such as enterocytes, GLUT2 mediated glucose transport is controlled by SGLT1. Although the affinity of SGLT1 for SGLT2 inhibitors is low, hypothetically a rare variant within the SGLT family with a hitherto unrecognised role in GLUT2 mediated glucose sensing might have an affinity for the SGLT2 inhibitor ligand and thus give rise to acute, severe but reversible euglycaemic DKA in susceptible patients.



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Categorising bone defect hematomas – Enhance early bone healing

Publication date: Available online 24 February 2018
Source:Medical Hypotheses
Author(s): Xin Wang, Yi Zhang, Wenjun Ji, Jun Ao
Fracture hematoma formation describes a transitional phase that involves a dynamic and tightly choreographed interaction between the fibrin matrix, cells, and cytokines that guides the ensuing bone repair. Here we propose a novel hypothesis to explain why hematomas in conjunction with critical sized bone defects are prone to differentiate into fibrous tissues, which eventually results in non-unions of the bone. We postulate that certain hematoma qualities are triggers that influence cell biological behaviours and that the release of certain growth factors determines what pattern of remodelling will prevail: intramembranous or endochondral ossification. A detailed characterization of the structural parameters of hematomas will allow researchers to create a microenvironment that aids the migration of mesenchymal stromal cells into the hematoma where, once established, they accelerate the bone healing process. Such a strategy would be particularly useful when faced with the complications arising from large recalcitrant bone defects that often fail to heal naturally.



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Application of 3D Printing Technology in RGPCL Simulation Fitting

Publication date: Available online 24 February 2018
Source:Medical Hypotheses
Author(s): Feng Zhao, Guiyang Zhao, Fan Weijie, Lixun Chen
The rigid gas permeable contact lens (RGPCL) is an ideal choice to improve the corrective vision of patients with a high degree of refractive error, keratoconus and corneal transplantation. However, RGPCL fitting is not an easy work for those patients with extremely irregular corneal surface. Technicians or doctors often need to try many times to determine the relatively satisfied lens customization parameters. This repeated try-on process not only increases discomfort of patients, but also will increase the risks of corneal epithelial shedding or corneal infection. In order to conduct RGP fitting in a faster and safer manner, a new method of simulating RGPCL fitting in 3D printing technology was assumed. The preliminary experimental results indicated that this method could effectively reduce the number of try-on and increase patient satisfaction, while decrease the risk of epithelial shedding or infection.



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Dissecting Spontaneous Cerebrospinal Fluid Collection

Publication date: Available online 24 February 2018
Source:Medical Hypotheses
Author(s): Pierre-Olivier Champagne, Jean-Claude Decarie, Louis Crevier, Alexander G Weil
Hydrocephalus is a common condition in the pediatric population known to have many causes and presentation patterns. We report from the analysis of 2 cases the existence of a new complication of pediatric hydrocephalus. Naming this entity "dissecting intraparenchymal cerebrospinal fluid collection", we advance a hypothesis regarding its pathophysiology and discuss its clinical implications and management.



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Combining cognitive training and multi-site rTMS to improve cognitive functions in Alzheimer's disease

Publication date: Available online 24 February 2018
Source:Brain Stimulation
Author(s): Jean-Paul Nguyen, Alcira Suarez, Estelle Le Saout, Michel Meignier, Julien Nizard, Jean-Pascal Lefaucheur




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Short-term quality of life after subthalamic stimulation depends on non-motor symptoms in Parkinson's disease

Publication date: Available online 24 February 2018
Source:Brain Stimulation
Author(s): Haidar Salimi Dafsari, Luisa Weiß, Monty Silverdale, Alexandra Rizos, Prashanth Reddy, Keyoumars Ashkan, Julian Evans, Paul Reker, Jan Niklas Petry-Schmelzer, Michael Samuel, Veerle Visser-Vandewalle, Angelo Antonini, Pablo Martinez-Martin, K. Ray-Chaudhuri, Lars Timmermann
BackgroundSubthalamic nucleus (STN) deep brain stimulation (DBS) improves quality of life (QoL), motor, and non-motor symptoms (NMS) in advanced Parkinson's disease (PD). However, considerable inter-individual variability has been observed for QoL outcome.HypothesisWe hypothesized that demographic and preoperative NMS characteristics can predict postoperative QoL outcome.MethodsIn this ongoing, prospective, multicenter study (Cologne, Manchester, London) including 88 patients, we collected the following scales preoperatively and on follow-up 6 months postoperatively: PDQuestionnaire-8 (PDQ-8), NMSScale (NMSS), NMSQuestionnaire (NMSQ), Scales for Outcomes in PD (SCOPA)-motor examination, -complications, and –activities of daily living, levodopa equivalent daily dose. We dichotomized patients into "QoL responders"/"non-responders" and screened for factors associated with QoL improvement with (1) Spearman-correlations between baseline test scores and QoL improvement, (2) step-wise linear regressions with baseline test scores as independent and QoL improvement as dependent variables, (3) logistic regressions using aforementioned "responders/non-responders" as dependent variable.ResultsAll outcomes improved significantly on follow-up. However, approximately 44% of patients were categorized as "QoL non-responders". Spearman-correlations, linear and logistic regression analyses were significant for NMSS and NMSQ but not for SCOPA-motor examination. Post-hoc, we identified specific NMS (flat moods, difficulties experiencing pleasure, pain, bladder voiding) as significant contributors to QoL outcome.ConclusionsOur results provide evidence that QoL improvement after STN-DBS depends on preoperative NMS characteristics. These findings are important in the advising and selection of individuals for DBS therapy. Future studies investigating motor and non-motor PD clusters may enable stratifying QoL outcomes and help predict patients' individual prospects of benefiting from DBS.



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Neuropeptide Y as a possible homeostatic element for changes in cortical excitability induced by repetitive transcranial magnetic stimulation

Publication date: Available online 24 February 2018
Source:Brain Stimulation
Author(s): Danny Jazmati, Ute Neubacher, Klaus Funke
BackgroundRepetitive transcranial magnetic stimulation (rTMS) is able to modify cortical excitability. Rat rTMS studies revealed a modulation of inhibitory systems, in particular that of the parvalbumin-expressing (PV+) interneurons, when using intermittent theta-burst stimulation (iTBS).ObjectiveThe potential disinhibitory action of iTBS raises the questions of how neocortical circuits stabilize excitatory-inhibitory balance within a physiological range. Neuropeptide Y (NPY) appears to be one candidate.MethodsAnalysis of cortical expression of PV, NPY and vesicular glutamate transporter type 1 (vGluT1) by immunohistochemical means at the level of cell counts, mean neuropil expression and single cell pre-/postsynaptic expression, with and without intraventricular NPY-injection.ResultsOur results show that iTBS not only reduced the number of neurons with high-PV expression in a dose-dependent fashion, but also increased the cortical expression of NPY, discussed to reduce glutamatergic transmission, and this was further associated with a reduced vGluT1 expression, an indicator of glutamateric presynaptic activity. Interneurons showing a low-PV expression exhibit less presynaptic vGluT1 expression compared to those with a high-PV expression. Intraventricular application of NPY prior to iTBS prevented the iTBS-induced reduction in the number of high-PV neurons, the reduction in tissue vGluT1 level and that presynaptic to high-PV cells.ConclusionsWe conclude that NPY, possibly via a global but also slow homeostatic control of glutamatergic transmission, modulates the strength and direction of the iTBS effects, likely preventing pathological imbalance of excitatory and inhibitory cortical activity but still allowing enough disinhibition beneficial for plastic changes as during learning.



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Key steps forward for maternal immunization: Policy making in action

Publication date: 14 March 2018
Source:Vaccine, Volume 36, Issue 12
Author(s): R.H. Beigi, S.B. Omer, K.M. Thompson




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Cost-effectiveness of a potential vaccine candidate for Haemophilus influenzae serotype ‘a’

Publication date: 14 March 2018
Source:Vaccine, Volume 36, Issue 12
Author(s): Affan Shoukat, Robert Van Exan, Seyed M. Moghadas
The preceding decade has witnessed the emergence of severe community-acquired acute infections caused by Haemophilus influenzae serotype a (Hia), with alarming incidence rates in North America, particularly among indigenous populations. The remarkable success of Hib conjugate vaccine over the past 20 years signify the development of an Hia vaccine candidate as a prevention measure to reduce the incidence of invasive Hia disease. However, quantifications of the long-term epidemiologic and economic impacts of vaccination are needed to inform decision on investment in Hia vaccine development and immunization programs. We sought to evaluate the cost-effectiveness of an Hia vaccine with a similar routine infant immunization schedules currently in practice for Hib in Canada. We developed and parameterized an agent-based simulation model using age-specific incidence rates reported for Nunavut, a Canadian territory with predominantly aboriginal populations. Our results, based on statistical analyses of the incremental cost-effectiveness ratio, show that an Hia conjugate vaccine is highly cost-effective. Sustaining an immunization program with vaccine coverages of 77% for primary series and 93% for booster dose over a 10-year period reduces the incidence of invasive disease by 63.8% on average from 9.97 to 3.61 cases, per 100,000 population. The overall costs of disease management in year 10 are reduced by 53.4% from CDN $1.863 million (95% CI: $1.229–$2.519 M) to CDN $0.868 million (95% CI: $0.627–$1.120 M). The findings suggest an important role for a conjugate vaccine in managing Hia disease as a growing public health threat.



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Comparison of serum bactericidal and antibody titers induced by two Haemophilus influenzae type b conjugate vaccines: A phase III randomized double-blind study

Publication date: 14 March 2018
Source:Vaccine, Volume 36, Issue 12
Author(s): Yukihiro Akeda, Yuka Koizumi, Yohei Takanami, Shuji Sumino, Yumi Hattori, Kayoko Sugizaki, Nodoka Mitsuya, Kazunori Oishi
Haemophilus influenzae type b (Hib) conjugate vaccines have drastically reduced disease incidence worldwide. Protection against Hib infection has relied on the serum bactericidal activity (SBA) of antibodies to the Hib capsular polysaccharide (polyribosylribitol phosphate). However, licensure usually relies on measuring induction of antibodies to PRP as a surrogate for SBA. In a phase III clinical trial we compared a PRP-conjugate vaccine using the nontoxic diphtheria toxin mutant, CRM197, as carrier protein with the licensed tetanus toxoid conjugate when administered subcutaneously as a three dose primary series in Japanese infants. As an addition to the phase III study, we have now evaluated SBA and show PRP-CRM197 induces higher levels of SBA than PRP-T four weeks after the primary series, with a statistically significant correlation with anti-PRP titers. This data confirms the superior immunogenicity of PRP-CRM197 compared with PRP-T assessed as SBA following a three-dose primary series by subcutaneous administration.Clinical trial registry: Registered on ClinicalTrials.gov (NCT01379846).



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Complications of herpes zoster in immunocompetent older adults: Incidence in vaccine and placebo groups in two large phase 3 trials

Publication date: 14 March 2018
Source:Vaccine, Volume 36, Issue 12
Author(s): Martina Kovac, Himal Lal, Anthony L. Cunningham, Myron J. Levin, Robert W. Johnson, Laura Campora, Antonio Volpi, Thomas C. Heineman
BackgroundAn adjuvanted herpes zoster (HZ) subunit vaccine, HZ/su, demonstrated high efficacy against HZ and postherpetic neuralgia (PHN) in two randomized, observer-blind, placebo-controlled trials in adults aged ≥50 and ≥70 years (ZOE-50 and ZOE-70, respectively).MethodsData from ZOE-50 and ZOE-70 trials were analyzed to evaluate the efficacy of HZ/su against mortality, hospitalizations, and non-PHN complications of HZ including HZ-associated vasculitis, stroke, and disseminated, ophthalmic, neurologic, and visceral diseases.ResultsIn the pooled ZOE-50/ZOE-70 analysis, 1 of 32 HZ/su recipients (3.1%) and 16 of 477 placebo recipients (3.4%) with a confirmed HZ episode had complications other than PHN. Efficacy against HZ-related complications was 93.7% (95% confidence interval, 59.5–99.9%) in adults aged ≥50 years and 91.6% (43.3–99.8%) in adults ≥70 years. Five HZ-related hospitalizations, all in placebo recipients, and no HZ-related deaths were reported.ConclusionsHZ/su reduces the risk of HZ-associated complications in older adults (NCT01165177; NCT01165229).



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Editorial Board/Aims and Scope

Publication date: 14 March 2018
Source:Vaccine, Volume 36, Issue 12





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Hepatitis B vaccination and the putative risk of central demyelinating diseases – A systematic review and meta-analysis

Publication date: 14 March 2018
Source:Vaccine, Volume 36, Issue 12
Author(s): Julie Mouchet, Francesco Salvo, Emanuel Raschi, Elisabetta Poluzzi, Ippazio Cosimo Antonazzo, Fabrizio De Ponti, Bernard Bégaud
BackgroundThe anti-hepatitis B immunization campaigns launched in the early 1990s were a major public health breakthrough and targeted various populations (at-risk adults, newborns, adolescents). However, debate is still active about a possible link between this vaccine and central demyelination. This study provides a pooled estimate of this risk based on a comprehensive review and meta-analysis of all available epidemiologic studies.MethodsA systematic review was conducted in Medline, Embase, ISI Web of Science and the Cochrane Library from database inception to 10 May 2017. Grey literature was searched and snowballing was also undertaken. Only observational studies including a control group were retained. Primary outcome was multiple sclerosis diagnosed by recognized criteria. Study selection was performed by two independent reviewers with disagreements solved through discussion. This meta-analysis based on crude, adjusted estimates, or risks limited to the 3 months following immunization was performed using a generic inverse variance random-effect model. Heterogeneity was investigated; sensitivity and subgroup analyses were performed when necessary. This study followed the PRISMA statement and the MOOSE reporting guideline (Study protocol registered in PROSPERO: CRD42015020808).FindingsOf the 2804 references reviewed, 13 studies with a control group were analysed. None of the pooled risk estimates for either multiple sclerosis or central demyelination following HB immunization reached statistical significance. When considering adjusted risk ratios, the following non-significant figures were obtained: 1.19 (95%CI: 0.93 – 1.52) and 1.25 (95%CI: 0.97 – 1.62), for multiple sclerosis and central demyelination, respectively.ConclusionsNo evidence of an association between hepatitis B vaccination and central demyelination was found.



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Efficacy of a high quality O1/Campos foot-and-mouth disease vaccine upon challenge with a heterologous Korean O Mya98 lineage virus in pigs

Publication date: 14 March 2018
Source:Vaccine, Volume 36, Issue 12
Author(s): S. Galdo Novo, V. Malirat, E.D. Maradei, A.R. Pedemonte, A.M. Espinoza, E. Smitsaart, K.N. Lee, J.H. Park, I.E. Bergmann
In 2010 serotype O foot-and-mouth disease virus of the Mya98 lineage/SEA topotype spread into most East Asian countries. During 2010–2011 it was responsible for major outbreaks in the Republic of Korea where a monovalent O/Manisa vaccine (belonging to the ME-SA topotype) was applied to help control the outbreaks. Subsequently, all susceptible animals were vaccinated every 6 months with a vaccine containing the O/Manisa antigen. Despite vaccination, the disease re-occurred in 2014 and afterwards almost annually. This study focuses on the in vivo efficacy in pigs of a high quality monovalent commercial O1/Campos vaccine against heterologous challenge with a representative 2015 isolate from the Jincheon Province of the Republic of Korea. Initially, viral characterizations and r1 determinations were performed on six viruses recovered in that region during 2014–2015, centering on their relationship with the well characterized and widely available O1/Campos vaccine strain. Genetic and antigenic analysis indicated a close similarity among 2014–2015 Korean isolates and with the previous 2010 virus, with distinct differences with the O1/Campos strain. Virus neutralisation tests using O1/Campos cattle and pig post vaccination sera and recent Korean outbreak viruses predicted acceptable cross-protection after a single vaccination, as indicated by r1 values, and in pigs, by expectancy of protection. In agreement with the in vitro estimates, in vivo challenge with a selected field isolate indicated that O1/Campos primo vaccinated pigs were protected, resulting in a PD50 value of nearly 10. The results indicated that good quality oil vaccines containing the O1/Campos strain can successfully be used against isolates belonging to the O Mya98/SEA topotype.



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Use of a new global indicator for vaccine safety surveillance and trends in adverse events following immunization reporting 2000–2015

Publication date: 14 March 2018
Source:Vaccine, Volume 36, Issue 12
Author(s): Jiayao Lei, Madhava Ram Balakrishnan, Jane F. Gidudu, Patrick L.F. Zuber
Reporting of adverse events following immunization (AEFI) is a key component for functional vaccine safety monitoring system. The aim of our study is to document trends in the AEFI reporting ratio globally and across the six World Health Organization (WHO) regions. We describe the number of AEFI reports communicated each year through the World Health Organization/United Nations Children's Fund Joint Reporting Form on Immunization from 2000 to 2015. The AEFI reporting ratios (annual AEFI reports per 100,000 surviving infants) were calculated to identify WHO countries (n = 191 in 2000 and n = 194 by 2015) that met a minimal reporting ratio of 10, a target set by the Global Vaccine Action Plan for vaccine safety monitoring as a proxy measure for a functional AEFI reporting system. The number of countries reporting any AEFI fluctuated over time but with progress from 32 (17%) in 2000 to 124 (64%) in 2015. In 2015, the global average AEFI reporting ratio was 549 AEFI reports per 100,000 surviving infants. The number of countries with AEFI reporting ratios greater than 10 increased from 8 (4%) in 2000 to 81 (42%) in 2015. In 2015, 60% of countries in the WHO Region of the Americas reported at least 10 AEFI per 100,000 surviving infants, followed by 55% in European Region, 43% in Eastern Mediterranean Region, 33% in Western Pacific Region, 27% in South-East Asia Region and 21% in African Region. Overall, AEFI reporting has increased over the past sixteen years worldwide, but requires strengthening in a majority of low- and middle- income countries. The AEFI reporting ratio is useful for benchmarking and following trends over time; but does not provide information on the quality of the reporting system and does not guarantee capacity to detect and manage a vaccine safety problem at a national level. Additional efforts are required to ensure and improve data quality, AEFI reporting and surveillance of immunization safety in every country.



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Monoclonal antibody based in vitro potency assay as a predictor of antigenic integrity and in vivo immunogenicity of a Respiratory Syncytial Virus post-fusion F-protein based vaccine

Publication date: 14 March 2018
Source:Vaccine, Volume 36, Issue 12
Author(s): Matieyendou Didier Djagbare, Li Yu, Arun Parupudi, Jenny Sun, Melissa L. Coughlin, Benjamin S. Rush, Gautam Sanyal
The post-fusion form of Respiratory Syncytial Virus (RSV) fusion (F) protein has been used recently in clinical trials as a potential vaccine antigen with the objective of eliciting protective immune response against RSV. In this paper, in vitro antigenicity and in vivo immunogenicity of recombinant, soluble F protein of RSV (RSVsF) were evaluated by several assays. In Vitro Relative Potency (IVRP) of RSVsF was measured in a sandwich ELISA using two antibodies, each specific for epitope site A or C. Therefore, IVRP reflected the integrity of the antigen in terms of changes in antibody binding affinity of either or both of these sites. RSVsF samples with a wide range of IVRP values were generated by applying UV irradiation (photo) and high temperature (heat) induced stress for varying lengths of time. These samples were characterized in terms of stress induced modifications in primary and secondary structures as well as aggregation of RSVsF. Immunogenicity, also referred to as In vivo potency, was measured by induction of total F-protein specific IgG and RSV-neutralizing antibodies in mice dosed with these RSVsF samples. Comparison of results between IVRP and these immunogenicity assays revealed that IVRP provided a sensitive read-out of the integrity of epitope sites A and C, and a conservative and reliable evaluation of the potency of RSVsF as a vaccine antigen. This high throughput and fast turn-around assay allowed us to efficiently screen many different RSVsF antigen lots, thereby acting as an effective filter for ensuring high quality antigen that delivered in vivo potency. In vitro and in vivo potencies were further probed at the level of individual epitope sites, A and C. Results of these experiments indicated that site A was relatively resistant to stress induced loss of potency, in vitro or in vivo, compared to site C.



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High resolution age-structured mapping of childhood vaccination coverage in low and middle income countries

Publication date: 14 March 2018
Source:Vaccine, Volume 36, Issue 12
Author(s): C. Edson Utazi, Julia Thorley, Victor A. Alegana, Matthew J. Ferrari, Saki Takahashi, C. Jessica E. Metcalf, Justin Lessler, Andrew J. Tatem
BackgroundThe expansion of childhood vaccination programs in low and middle income countries has been a substantial public health success story. Indicators of the performance of intervention programmes such as coverage levels and numbers covered are typically measured through national statistics or at the scale of large regions due to survey design, administrative convenience or operational limitations. These mask heterogeneities and 'coldspots' of low coverage that may allow diseases to persist, even if overall coverage is high. Hence, to decrease inequities and accelerate progress towards disease elimination goals, fine-scale variation in coverage should be better characterized.MethodsUsing measles as an example, cluster-level Demographic and Health Surveys (DHS) data were used to map vaccination coverage at 1 km spatial resolution in Cambodia, Mozambique and Nigeria for varying age-group categories of children under five years, using Bayesian geostatistical techniques built on a suite of publicly available geospatial covariates and implemented via Markov Chain Monte Carlo (MCMC) methods.ResultsMeasles vaccination coverage was found to be strongly predicted by just 4–5 covariates in geostatistical models, with remoteness consistently selected as a key variable. The output 1 × 1 km maps revealed significant heterogeneities within the three countries that were not captured using province-level summaries. Integration with population data showed that at the time of the surveys, few districts attained the 80% coverage, that is one component of the WHO Global Vaccine Action Plan 2020 targets.ConclusionThe elimination of vaccine-preventable diseases requires a strong evidence base to guide strategies and inform efficient use of limited resources. The approaches outlined here provide a route to moving beyond large area summaries of vaccination coverage that mask epidemiologically-important heterogeneities to detailed maps that capture subnational vulnerabilities. The output datasets are built on open data and methods, and in flexible format that can be aggregated to more operationally-relevant administrative unit levels.



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Multi-antigenic human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity

Publication date: 14 March 2018
Source:Vaccine, Volume 36, Issue 12
Author(s): Shinu John, Olga Yuzhakov, Angela Woods, Jessica Deterling, Kimberly Hassett, Christine A. Shaw, Giuseppe Ciaramella
A cytomegalovirus (CMV) vaccine that is effective at preventing congenital infection and reducing CMV disease in transplant patients remains a high priority as no approved vaccines exist. While the precise correlates of protection are unknown, neutralizing antibodies and antigen-specific T cells have been implicated in controlling infection. We demonstrate that the immunization of mice and nonhuman primates (NHPs) with lipid nanoparticles (LNP) encapsulating modified mRNA encoding CMV glycoproteins gB and pentameric complex (PC) elicit potent and durable neutralizing antibody titers. Since the protective correlates in pregnant women and transplant recipients may differ, we developed an additional mRNA vaccine expressing the immunodominant CMV T cell antigen pp65. Administration of pp65 vaccine with PC and gB elicited robust multi-antigenic T cell responses in mice. Our data demonstrate that mRNA/LNP is a versatile platform that enables the development of vaccination strategies that could prevent CMV infection and consequent disease in different target populations.



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Genetic and subunit vaccines based on the stem domain of the equine influenza hemagglutinin provide homosubtypic protection against heterologous strains

Publication date: 14 March 2018
Source:Vaccine, Volume 36, Issue 12
Author(s): Lorena Itatí Ibañez, Cecilia Andrea Caldevilla, Yesica Paredes Rojas, Nora Mattion
H3N8 influenza virus strains have been associated with infectious disease in equine populations throughout the world. Although current vaccines for equine influenza stimulate a protective humoral immune response against the surface glycoproteins, disease in vaccinated horses has been frequently reported, probably due to poor induction of cross-reactive antibodies against non-matching strains. This work describes the performance of a recombinant protein vaccine expressed in prokaryotic cells (ΔHAp) and of a genetic vaccine (ΔHAe), both based on the conserved stem region of influenza hemagglutinin (HA) derived from A/equine/Argentina/1/93 (H3N8) virus.Sera from mice inoculated with these immunogens in different combinations and regimes presented reactivity in vitro against highly divergent influenza virus strains belonging to phylogenetic groups 1 and 2 (H1 and H3 subtypes, respectively), and conferred robust protection against a lethal challenge with both the homologous equine strain (100%) and the homosubtypic human strain A/Victoria/3/75 (H3N2) (70–100%). Animals vaccinated with the same antigens but challenged with the human strain A/PR/8/34 (H1N1), belonging to the phylogenetic group 1, were not protected (0–33%). Combination of protein and DNA immunogens showed higher reactivity to non-homologous strains than protein alone, although all vaccines were permissive for lung infection.



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Quantitative profiling reveals minor changes of T cell receptor repertoire in response to subunit inactivated influenza vaccine

Publication date: 14 March 2018
Source:Vaccine, Volume 36, Issue 12
Author(s): Anastasiia L. Sycheva, Mikhail V. Pogorelyy, Ekaterina A. Komech, Anastasia A. Minervina, Ivan V. Zvyagin, Dmitriy B. Staroverov, Dmitriy M. Chudakov, Yuri B. Lebedev, Ilgar Z. Mamedov
Vaccination against influenza is widely used to protect against seasonal flu epidemic although its effectiveness is debated. Here we performed deep quantitative T cell receptor repertoire profiling in peripheral blood of a healthy volunteer in response to trivalent subunit influenza vaccine. We did not observe significant rebuilding of peripheral blood T cell receptors composition in response to vaccination. However, we found several clonotypes in memory T cell fraction that were undetectable before the vaccination and had a maximum concentration at day 45 after vaccine administration. These cells were found in lower concentration in the course of repertoire monitoring for two years period. Our observation suggests a potential for recruitment of only a limited number of new T cells after each seasonal influenza vaccination.



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Intradermal immunization with inactivated swine influenza virus and adjuvant polydi(sodium carboxylatoethylphenoxy)phosphazene (PCEP) induced humoral and cell-mediated immunity and reduced lung viral titres in pigs

Publication date: 14 March 2018
Source:Vaccine, Volume 36, Issue 12
Author(s): Royford Magiri, Ken Lai, Alyssa Chaffey, Yan Zhou, Hyun-Mi Pyo, Volker Gerdts, Heather L. Wilson, George Mutwiri
Swine influenza virus is endemic worldwide and it is responsible for significant economic losses to the swine industry. A vaccine that stimulates a rapid and long-lasting protective immune response to prevent this infection is highly sought. Poly[di(sodium carboxylatoethylphenoxy)-phosphazene (PCEP) has demonstrated adjuvant activity when formulated as part of multiple vaccines in mice and pigs. In this study we examined the magnitude and type of immune response induced in pigs vaccinated via the intramuscular or intradermal routes with inactivated swine influenza virus (SIV) H1N1 vaccine formulated with PCEP. Intradermal administration of PCEP-adjuvanted inactivated SIV vaccine stimulated significant anti-SIV antibody titres, increased neutralizing antibodies, and significantly reduced lung virus load with limited reduction of gross lung lesions after challenge with virulent H1N1 relative to control animals. These results indicate that PCEP may be effective as a vaccine adjuvant against swine influenza viruses in pigs and should be considered a potential candidate adjuvant for future swine intradermal influenza vaccines.



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Assesssing an unmet healthcare demand: A survey of immunisation among homecare patients and their caregivers

Publication date: 14 March 2018
Source:Vaccine, Volume 36, Issue 12
Author(s): Süleyman Görpelioğlu, Canan Emiroğlu, Özlem Suvak, Cenk Aypak, Derya Akbıyık
Susceptibility of the homecare patient to vaccine preventable infections and their complications is high. Hospitalization of this patient group increases costs to the healthcare system. Therefore vaccination services are of great importance for protecting these patients from complications and hospitalization. We aimed to determine vaccination status of the patients receiving home care services from a tertiary hospital in Turkey and to reveal their vaccination needs.This cross sectional study was carried out in the Division of Home Care Services of Dışkapı Yıldırım Beyazıt Training and Research Hospital in Ankara Turkey. A questionnaire Comprised of 15 questions were administered through face to face with 336 patients and their care givers. The data obtained was analyzed with descriptive statistical methods and chi-squared test was used for comparison of proportions.A total of 86.3% of the patients and 22.6% of the caregivers were older than age 65. Approximately 45% of the patients were receiving home care due to primary neurological diagnosis such as Dementia, Parkinson's disease and Cerebrovascular Accident. In addition, 78% of the patients had at least 1 additional diagnosis other than their primary diagnosis.Although immunization indications were present among all patients included in the study and at least 22% of the care providers, only 15.2% of patients and 11.3% of care providers had been recommended to receive vaccination. Among those who had been recommended to get vaccinated, 74% of patients and 77% of care givers had been administered the recommended vaccine. This finding implied that both groups were responsive to the advice for vaccination. Moreover, since the patients receiving home care are already followed-up by a healthcare team, thus these patients can be vaccinated with very little additional logistic support.



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Immunity against measles, mumps, rubella, varicella, diphtheria, tetanus, polio, hepatitis A and hepatitis B among adult asylum seekers in the Netherlands, 2016

Publication date: 14 March 2018
Source:Vaccine, Volume 36, Issue 12
Author(s): Gudrun S. Freidl, Alma Tostmann, Moud Curvers, Wilhelmina L.M. Ruijs, Gaby Smits, Rutger Schepp, Erwin Duizer, Greet Boland, Hester de Melker, Fiona R.M. van der Klis, Jeannine L.A. Hautvast, Irene K. Veldhuijzen
Asylum seekers are a vulnerable population for contracting infectious diseases. Outbreaks occur among children and adults. In the Netherlands, asylum seeker children are offered vaccination according to the National Immunization Program. Little is known about protection against vaccine-preventable diseases (VPD) in adult asylum seekers. In this 2016 study, we assessed the immunity of adult asylum seekers against nine VPD to identify groups that might benefit from additional vaccinations. We invited asylum seekers from Syria, Iran, Iraq, Afghanistan, Eritrea and Ethiopia to participate in a serosurvey. Participants provided informed consent and a blood sample, and completed a questionnaire. We measured prevalence of protective antibodies to measles, mumps, rubella, varicella, diphtheria, tetanus, polio type 1–3 and hepatitis A and B, stratified them by country of origin and age groups. The median age of the 622 participants was 28 years (interquartile range: 23–35), 81% were male and 48% originated from Syria. Overall, seroprotection was 88% for measles (range between countries: 83–93%), 91% for mumps (81–95%), 94% for rubella (84–98%), 96% for varicella (92–98%), 82% for diphtheria (65–88%), 98% for tetanus (86–100%), 91% (88–94%) for polio type 1, 95% (90–98%) for polio type 2, 82% (76–86%) for polio type 3, 84% (54–100%) for hepatitis A and 27% for hepatitis B (anti-HBs; 8–42%). Our results indicate insufficient protection against certain VPD in some subgroups. For all countries except Eritrea, measles seroprotection was below the 95% threshold required for elimination. Measles seroprevalence was lowest among adults younger than 25 years. In comparison, seroprevalence in the Dutch general population was 96% in 2006/07. The results of this study can help prioritizing vaccination of susceptible subgroups of adult asylum seekers, in general and in outbreak situations.



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Investigation of insulin resistance in the popularly used four rat models of type-2 diabetes

Publication date: May 2018
Source:Biomedicine & Pharmacotherapy, Volume 101
Author(s): Pin-Chun Chao, Yingxiao Li, Chin-Hong Chang, Ja Ping Shieh, Juei-Tang Cheng, Kai-Chun Cheng
Animal models are widely used to develop drugs for treating diabetes mellitus (DM). Insulin resistance (IR) is one of the main problems in type-2 DM (T2DM). Streptozotocin (STZ) is used to damage pancreatic cells for induction of DM. Many rat models were applied in research as T2DM. However, the degree of IR in each model is unknown. In the present study, IR and insulin signaling were compared in four models of type 2 diabetes: rats fed a fructose-rich chow for 8 weeks, rats feed high-fat chow for 4 weeks followed by injection with streptozotocin (35 mg/kg, i.p.), rats injected with a single low dose streptozotocin (45 mg/kg, i.p.), and rats injected with a single dose of nicotinamide followed by a single high dose of streptozotocin (60 mg/kg, i.p.). Values from these determinations in diabetic rats showing the order that insulin resistance is most marked in rats received fructose-rich chow followed by high-fat diet before STZ injection induced model (HFD/STZ rats), and rats injected with low dose of STZ but it is less marked in rats induced by nicotinamide and STZ. Additionally, insulin secretion was reduced in three rat models except the rats receiving fructose-rich chow. Western blots also showed the same changes in phosphorylation of IRS-1 or Akt using soleus muscle from each model. The obtained data suggest a lack of pronounced IR in the rats with acute diabetes induced by nicotinamide and STZ while IR is markedly identified in rats fed fructose-rich chow. However, the increase of plasma glucose levels in fructose-rich chow-fed rats was not so significant as other groups. Therefore, HFD/STZ rats is an appropriate and stable animal model which is analogous to the human T2DM through a combination of high-fat diet with multiple low-dose STZ injections.



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Crocin attenuates cyclophosphamide induced testicular toxicity by preserving glutathione redox system

Publication date: May 2018
Source:Biomedicine & Pharmacotherapy, Volume 101
Author(s): Ajay Godwin Potnuri, Lingesh Allakonda, Mangala Lahkar
Chemotherapy induced testicular toxicity is an emerging reason for azoospermia and impotency in males. Cyclophosphamide (CP) is a widely used chemotherapeutic agent to manage neoplastic and non-neoplastic autoimmune diseases. Testicular toxicity along with bladder and hepatotoxicity are its widely reported adverse effects. Crocin (CR) is the digentiobiosyl ester of crocetin, found in the fruits of gardenia (Gardenia jasminoides E.) and dried stigmas of saffron (Crocus sativus L.) possess antioxidant, anti-depressant, anti-tumor and aphrodisiac properties. In the light of these reports, the present study aimed to investigate protective effect of CR administration (10 mg/kg and 20 mg/kg per day for eight weeks) on CP induced (15 mg/kg per week for eight weeks) testicular toxicity in male Sprague dawley rats by analysing the Glutathione redox cycle, Sperm quality, spermatogenic and steroidogenesis hormonal axis, caspase 3 activity and histological investigations. Administration of CR preserved the glutathione redox cycle, sperm quality, hormonal mediators associated with sperm production. It also decreased testicular apoptosis as evident from the reduction of caspase 3 activity. These biochemical findings were well reflected on the histo-pathological investigation. Conclusively, the results of this study indicate that administration of CR can dose dependently attenuate the toxic effects of CP on testis.

Graphical abstract

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The anticonvulsant effect of a polysaccharide-rich extract from Genipa americana leaves is mediated by GABA receptor

Publication date: May 2018
Source:Biomedicine & Pharmacotherapy, Volume 101
Author(s): Dayanne Terra Tenório Nonato, Silvânia Maria Mendes Vasconcelos, Mário Rogério Lima Mota, Paulo Goberlânio de Barros Silva, Arcelina Pacheco Cunha, Nágila Maria Pontes Silva Ricardo, Maria Gonçalves Pereira, Ana Maria Sampaio Assreuy, Edna Maria Camelo Chaves
BackgroundThis study aimed to chemically characterize a polysaccharide-rich extract (PRE) obtained from Genipa americana leaves and evaluate its neuroprotective effect in the brain morphology and oxidative markers using mice behavioral models.MethodsDry powder (5 g) of G. americana leaves were submitted to depigmentation in methanol. PRE was obtained by extraction in NaOH and precipitation with absolute ethanol and characterized by infrared spectroscopy (FTIR) and nuclear magnetic resonance (¹H and ¹³C NMR). Swiss mice (25–35 g) received saline (0.9% NaCl) or PRE (1–27 mg/kg) by intraperitoneal (i.p.) route, 30 min before evaluation in behavioral models (open field, elevated plus maze, sleeping time, tail suspension, forced swimming, seizures induced by pentylenetetrazole-PTZ). Animal's brain were dissected and analyzed for histological alterations and oxidative stress.ResultsFTIR spectrum showed bands around 3417 cm⁻¹ and 2928 cm⁻¹, relative to the vibrational stretching of OH and CH, respectively. ¹H NMR spectrum revealed signals at δ 3.85 (methoxyl groups) and δ 2.4 (acetyl) ppm. ¹³C NMR spectrum revealed signals at δ 108.0 and δ 61.5 ppm, corresponding to C1 and C5 of α-L-arabinofuranosyl residues. PRE presented central inhibitory effect, increasing the latency for PTZ-induced seizures by 63% (9 mg/kg) and 55% (27 mg/kg), and the latency to death by 73% (9 mg/kg) and 72% (27 mg/kg). Both effects were reversed by the association with flumazenil.ConclusionsPRE, containing a heteropolysaccharide, presents antioxidant and anticonvulsant effect in the model of PTZ-induced seizures via gamma-aminobutyric acid (GABA), decreasing the number of hippocampal black neurons.

Graphical abstract

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Antioxidant and anti-inflammatory activities of alpha lipoic acid protect against indomethacin-induced gastric ulcer in rats

Publication date: May 2018
Source:Biomedicine & Pharmacotherapy, Volume 101
Author(s): Asmaa M.S. Gomaa, Nashwa A. Abd El-Mottaleb, Hazem A. Aamer
Little is known about the role of tumor necrosis factor-alpha (TNF-α), plasminogen activator inhibitor-1 (PAI-1), and inducible nitric oxide synthase (iNOS) in the gastric ulcer and the effect of alpha lipoic acid (ALA) in their modulation. Hence, this experimental study was designed to assess the possible protective effect of ALA against indomethacin (IND)-induced gastric ulcer in rats, as well as to determine the possible underlying mechanisms with a special focus on TNF-α, PAI-1, and iNOS. Adult male rats (n = 28) were divided into four equal groups: the control group received distilled water, the vehicle group received 0.5% carboxymethylcellulose, the ulcer group received a single oral dose of IND (50 mg/kg) and the ALA-treated group received ALA (100 mg/kg) orally for 3 days before ulcer induction. Four hours after IND administration, all rats were sacrificed. The ulcer index, and gastric tissue homogenate contents of total antioxidant capacity (TAC), malondialdehyde (MDA), TNF-α, and PAI-1 were evaluated. Immunohistochemical evaluation of iNOS protein expression and histopathological examination of gastric tissue were investigated. The results revealed that ALA pretreatment significantly decreased the ulcer index, the gastric levels of MDA, TNF-α, PAI-1, and iNOS protein expression while increased the gastric levels of TAC as well as improved the histopathological appearance of gastric tissues. In conclusion, ALA ameliorated the IND-induced gastric ulceration. This could be attributed to its antioxidant and anti-inflammatory activities via suppression of TNF-α-induced elevation of both PAI-1 level and iNOS expression in the gastric tissue.

Graphical abstract

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Editorial Board

Publication date: 2 May 2018
Source:Behavioural Brain Research, Volume 343





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Adjuvant Therapy for Revision Rhinoplasty of Contracted Nose Using Polydeoxyribonucleotide and Invasive Bipolar Radiofrequency

Summary: Most cases of severely contracted nose require revision rhinoplasty and septoplasty, wherein preoperative and/or intraoperative expansion of nasal soft tissue is necessary for tension-free revision surgery. The present study aimed to evaluate the efficacy and safety of pre- and postoperative adjuvant therapy using polydeoxyribonucleotide (PDRN) and invasive, pulsed-type, bipolar, alternating current radiofrequency (RF) for revision surgery of a contracted nose. In total, 30 patients were treated with 16 sessions (8 preoperative sessions and 8 postoperative sessions) of intralesional injection of PDRN and invasive RF treatment using microneedle electrodes at 1-week intervals. One week after the final combined pretreatment using PDRN and invasive bipolar RF, the skin of contracted noses was sufficiently softened, and nasal skin mobility was notably improved in all the patients. During revision rhinoplasty and septoplasty, the contracted nasal skin in each patient was adequately released for proper covering of the nasal tip without tension. Postoperatively, 8 sessions of adjuvant therapy elicited marked clinical improvements in persistent nasal tip dimpling and contracture, septal deviation, and warping from the incomplete recovery of nasal contracture after revision surgery. In conclusion, our pre- and postoperative adjuvant therapies using PDRN and invasive bipolar RF remarkably improved the therapeutic outcomes of revision rhinoplasty and septoplasty for contracted skin of the nose without major side effects.

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V-shaped Internal Nasal Vestibular Flap for Reconstruction of Iatrogenic Columellar Defect

Summary: Columella is an important structure in the center of the face, and its structural integrity has an important functional, social, and psychological role. Columella reconstruction can be very challenging for surgeons and the ideal technique remains elusive. This article describes a reconstruction technique in a young woman with columella necrosis due to nasal continuous positive airway pressure treatment. The method of reconstruction described here, with a V-shaped internal nasal vestibular flap and a cartilage grafts from lateral crura, is simple and easily reproducible, providing an optimal aesthetic result and in addition the donor site does not create a secondary deformity by disrupting normal anatomy.

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Tuberculous Enteritis Presenting as Acute Appendicitis and Perirectal Abscess

Mycobacterium tuberculosis has a wide variety of presentations. A rare occurrence is gastrointestinal tuberculosis. It may occur anywhere along the alimentary canal but usually occurs in the ileocecum with rare involvement of the appendix.

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Automatic procedures for the synthesis of difficult peptides using oxyma as activating reagent: a comparative study on the use of bases and on different deprotection and agitation conditions.

Publication date: Available online 24 February 2018
Source:Peptides
Author(s): A. Caporale, N. Doti, A. Monti, A. Sandomenico, M. Ruvo
Solid-Phase Peptide Synthesis (SPPS) is a rapid and efficient methodology for the chemical synthesis of peptides and small proteins. However, the assembly of peptide sequences classified as "difficult" poses severe synthetic problems in SPPS for the occurrence of extensive aggregation of growing peptide chains which often leads to synthesis failure. In this framework, we have investigated the impact of different synthetic procedures on the yield and final purity of three well-known "difficult peptides" prepared using oxyma as additive for the coupling steps. In particular, we have comparatively investigated the use of piperidine and morpholine/DBU as deprotection reagents, the addition of DIPEA, collidine and N-methylmorpholine as bases to the coupling reagent. Moreover, the effect of different agitation modalities during the acylation reactions has been investigated. Data obtained represent a step forward in optimizing strategies for the synthesis of "difficult peptides".

Graphical abstract

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Guiding Mitotic Progression by Crosstalk between Post-translational Modifications

Publication date: Available online 24 February 2018
Source:Trends in Biochemical Sciences
Author(s): Sabine A.G. Cuijpers, Alfred C.O. Vertegaal
Cell division is tightly regulated to disentangle copied chromosomes in an orderly manner and prevent loss of genome integrity. During mitosis, transcriptional activity is limited and post-translational modifications (PTMs) are responsible for functional protein regulation. Essential mitotic regulators, including polo-like kinase 1 (PLK1) and cyclin-dependent kinases (CDK), as well as the anaphase-promoting complex/cyclosome (APC/C), are members of the enzymatic machinery responsible for protein modification. Interestingly, communication between PTMs ensures the essential tight and timely control during all consecutive phases of mitosis. Here, we present an overview of current concepts and understanding of crosstalk between PTMs regulating mitotic progression.



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Unravelling the Mechanisms of RNA Helicase Regulation

Publication date: Available online 24 February 2018
Source:Trends in Biochemical Sciences
Author(s): Katherine E. Sloan, Markus T. Bohnsack
RNA helicases are critical regulators at the nexus of multiple pathways of RNA metabolism, and in the complex cellular environment, tight spatial and temporal regulation of their activity is essential. Dedicated protein cofactors play key roles in recruiting helicases to specific substrates and modulating their catalytic activity. Alongside individual RNA helicase cofactors, networks of cofactors containing evolutionarily conserved domains such as the G-patch and MIF4G domains highlight the potential for cross-regulation of different aspects of gene expression. Structural analyses of RNA helicase–cofactor complexes now provide insight into the diverse mechanisms by which cofactors can elicit specific and coordinated regulation of RNA helicase action. Furthermore, post-translational modifications (PTMs) and long non-coding RNA (lncRNA) regulators have recently emerged as novel modes of RNA helicase regulation.



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Transthyretin uptake in placental cells is regulated by the high-density lipoprotein receptor, scavenger receptor class B member 1

Publication date: Available online 24 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Kelly A. Landers, Huika Li, Robin H. Mortimer, Donald S.A. McLeod, Michael C. d'Emden, Kerry Richard
Transfer of thyroid hormone into cells is critical for normal physiology and transplacental transfer of maternal thyroid hormones is essential for normal fetal growth and development. Free thyroid hormone is known to enter cells through specific cell surface transport proteins, and for many years this uptake of unbound thyroid hormones was assumed to be the only relevant mechanism. Recently, evidence has emerged of alternate pathways for hormone entry into cells that are dependent on hormone binding proteins. In this study we identify the high-density lipoprotein receptor Scavenger Receptor class B member 1 (SR-B1) as important in the uptake and transport of transthyretin-bound thyroid hormone by placental trophoblast cells. High-density lipoprotein increases expression of SR-B1 in placental cells but also reduces uptake of transthyretin-thyroid hormone through the SR-B1 transporter. SR-B1 is expressed in many cells and this study suggests that SR-B1 may be universally important in thyroid hormone uptake. Further investigation of SR-B1-TTR interactions may fundamentally change our understanding of hormone biology and have important clinical consequences.



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Endogenous H2S resists mitochondria-mediated apoptosis in the adrenal glands via ATP5A1 S-sulfhydration in male mice

Publication date: Available online 24 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Changnan Wang, Jiankui Du, Shufang Du, Yujian Liu, Dongxia Li, Xiaoyan Zhu, Xin Ni
In a previous study, we showed that endogenous hydrogen sulfide (H2S) plays a key role in the maintenance of intact adrenal cortex function via the protection of mitochondrial function during endoxemia. We further investigated whether mitochondria-mediated apoptosis is involved in H2S protection of adrenal function. LPS treatment resulted in mitochondria-mediated apoptosis in the adrenal glands of male mice, and these effects were prevented by the H2S donor GYY4137. In the model of Y1 cells, the LPS-induced mitochondria-mediated apoptosis and blunt response to ACTH were rescued by GYY4137. The H2S-generating enzyme cystathionine-β-synthase (CBS) knockout heterozygous (CBS^+/-) mice showed mitochondria-mediated apoptosis in the adrenal gland and adrenal insufficiency. GYY4137 treatment restored adrenal function and eliminated mitochondria-mediated apoptosis. Maleimide assay combined with mass spectrometry analysis showed that a number of proteins in mitochondria were S-sulfhydrated in the adrenal gland. ATP5A1 was further confirmed as S-sulfhydrated using a modified biotin switch assay. The level of S-sulfhydrated ATP5A1 was decreased in the adrenal gland of endotoxemic and CBS^+/- mice, which was restored by GYY4137. ATP5A1 was identified as sulfhydrated at cysteine 244 by H2S. Overexpression of the cysteine 244 mutant ATP5A1 in Y1 cells resulted in a loss of LPS-induced mitochondria-mediated apoptosis and GYY4137 restoration of LPS-induced hyporesponsiveness to ACTH. Collectively, the present study revealed that decreased H2S generation leads to mitochondrial-mediated apoptosis in the adrenal cortex and a blunt response to ACTH. S-sulfhydration of ATP5A1 at cysteine 244 is an important molecular mechanism by which H2S maintains mitochondrial function and steroidogenesis in the adrenal glands.



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Androgens and androgen receptor: Above and beyond

Publication date: Available online 24 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Douglas A. Gibson, Philippa T.K. Saunders, Iain J. McEwan




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SIRT1 suppresses high glucose and palmitate-induced osteoclast differentiation via deacetylating p66Shc

Publication date: Available online 24 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Bo Qu, Kai Gong, Hongsheng Yang, Yugang Li, Tao Jiang, Zhimou Zeng, Zongrui Cao, Xianming Pan
Findings concerning the role of diabetes mellitus (DM) in osteoclast differentiation are contradictory in vivo and in vitro. Sirtuin 1 (SIRT1) can inhibit RANKL-induced osteoclastogenesis and deacetylate p66Shc suppress its phosphorylation in high glucose (HG)-stimulated human umbilical vein endothelial cells. This study aimed to investigate the role and mechanism of SIRT1 in DM-related osteoclast differentiation. Osteoclast precursors were cultured with HG and palmitate (PA), with or without resveratrol/sirtinol. TRAP staining was used to evaluate osteoclast formation. The expression of SIRT1, RANK, RANKL, OPG, NFATc1, TRAP, c-fos, p66Shc, phospho-p66Shc (S36), phospho-NF-κBp65 (p-p65), and IκB was determined by real-time PCR or western blotting. Lysine acetylation of p66Shc was assayed by immunoprecipitation. Reactive oxygen species (ROS) production was analyzed by DCFH-DA fluorescence. p66Shc siRNA and PDTC were used to confirm the mechanism of SIRT1 in osteoclastogenesis. We found HG and PA enhanced osteoclast differentiation, decreased SIRT1 and OPG expression, and increased levels of RANK, RANKL, NFATc1, TRAP, and c-fos. Upregulation of SIRT1 by resveratrol inhibited HG- and PA-induced osteoclast differentiation, whereas sirtinol further enhanced it. Resveratrol suppressed lysine acetylation and S36 phosphorylation of p66Shc, ROS production, and NF-κB activation induced by HG and PA, while sirtinol boosted these processes. p66Shc siRNA abrogated HG- and PA-induced ROS production and NF-κB activation. In addition, p66Shc siRNA and PDTC greatly suppressed the expression of RANK and RANKL induced by HG and PA. In conclusion, this study confirms the role of DM in osteoclast differentiation in vitro. SIRT1 suppresses HG- and PA-induced osteoclast differentiation via p66Shc/ROS/NF-κB signaling.



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Comparison of the antimicrobial efficacy of photodynamic therapy with two mediators against Lactobacillus acidophilus in vitro

Publication date: March 2018
Source:Photodiagnosis and Photodynamic Therapy, Volume 21
Author(s): Arash Azizi, Shiva Mousavian, Soudabeh Taheri, Shirin Lawaf, Elnaz Gonoudi, Arash Rahimi
Background and objectivesLactobacillus is a cariogenic microorganism. Different therapeutic approaches including photodynamic therapy (PDT) have been suggested for treatment of bacterial infection. The purpose of the current study was to compare the effects of PDT with Indocyanine green (ICG) and Methylene blue (MB) photosensitizers (PSs) on Lactobacillus acidophilus (L. acidophilus).Materials and methodsIn this in-vitro experimental study, 84 samples of L. acidophilus (1 McFarland standard) were compared in 14 experimental groups including: MB, ICG, 660-nm laser, 808-nm laser (pulsed, 74s/continuous-wave, 37s), different combinations of lasers and PSs, Chlorhexidine (CHX) 0.2%, sodium hypochlorite (NaOCl) 2.5%, penicillin 6.3.3 and control groups. The samples were cultured in microplates containing blood agar culture medium. After incubation at 37 °C for 48 h, the colony forming units (CFUs) of L. acidophilus were counted and compared before and after therapeutic interventions. Data were analyzed using SPSS19 software program according to one-way ANOVA test.ResultsThis study showed that the separate use of ICG, 660- and 808-nm lasers (pulsed, 74s/continuous-wave, 37s), and the combined use of 808-nm laser (pulsed, 74s/continuous-wave, 37s) and ICG have no significant inhibitory effect on L. acidophilus colonies (P > 0.05), whereas the separate use of MB and the combined use of 660-nm laser (continuous-wave, 37s/pulsed, 74s) and MB significantly inhibited the growth of L. acidophilus in comparison with the control group (p < 0.05). Likewise, CHX 0.2%, NaOCl 2.5% and penicillin 6.3.3 significantly inhibited the bacterial growth (p < 0.05).ConclusionThe results showed that separate use of MB and combined use of 660-nm laser and MB have a significant inhibitory effect on L. acidophilus growth.



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Antimicrobial efficacy of photodynamic therapy and light-activated disinfection on contaminated zirconia implants: An in vitro study

Publication date: March 2018
Source:Photodiagnosis and Photodynamic Therapy, Volume 21
Author(s): Bleron Azizi, Ana Budimir, Ivona Bago, Blerim Mehmeti, Suzana Jakovljević, Jeta Kelmendi, Aleksandra Presecki Stanko, Dragana Gabrić
BackgroundWe aimed to evaluate the antimicrobial efficacy of photodynamic therapy (PDT) and light-activated disinfection (LAD) on zirconia dental implants contaminated with three bacterial species and investigate if the PDT and LAD cause implant surface alterations.MethodsSeventy-two zirconia dental implants were contaminated with a bacterial suspension of Prevotella intermedia, Actinomyces actinomycetemcomitans, and Porphyromonas gingivalis. The implants were subsequently randomly divided into four groups (n = 12 dental implants/each) according to the decontamination protocol: Group 1 (PDT1) – PDT (660 nm, 100 mW) with toluidine blue; Group 2 (PDT2) – PDT (660 nm, 100 mW) with phenothiazine chloride dye; Group 3 (LAD) – light emitting diode (LED) with toluidine blue; and Group 4 (TB) – toluidine blue without the application of light. Implants in the positive control (PC) group were treated with a 0.2% chlorhexidine-based solution, and implants assigned to the negative control (NC) group did not undergo any treatment. Each implant was then placed in tubes containing phosphate buffered saline (PBS) and vortexed for 60 s to remove the remaining bacteria from the implant surface. After 10-fold serial dilutions, 30 μl of the suspension was plated on Brucella agar plates. After 72 h, the colony forming units (CFU) were counted. Distinctive colonies were confirmed with MALDI Biotyper. The implants were analyzed using scanning electron microscope (SEM) to evaluate the possible surface alterations due to PDT or LAD.ResultsAll study groups had significant reductions in the number of CFUs compared with the NC (p < 0.05). PDT1, the PDT2, and the LAD groups had the largest bacterial reduction with respect to each bacterial species separately and the total bacterial count, and they were more efficient compared with the TB group (p < 0.05). SEM analysis did not reveal any alterations of the implant surface after the treatment procedures.ConclusionBoth PDT protocols and LAD showed high and equal effectiveness in decontamination of zirconia dental implants.



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Effect of aPDT on Streptococcus mutans and Candida albicans present in the dental biofilm: Systematic review

Publication date: March 2018
Source:Photodiagnosis and Photodynamic Therapy, Volume 21
Author(s): Ana Caroline Fumes, Paloma Dias da Silva Telles, Silmara Aparecida Milori Corona, Maria Cristina Borsatto
To evaluate the effect of aPDT on S. mutans and C. albicans present in the dental biofilm, using methylene blue as a photosensitizer in different pre-irradiation times. The searches were made on Pubmed, Web of Science, Bireme, Scopus and Cochrane Library, and were complemented by screening the references of selected articles in the attempt to find any article that did not appear in the database search. The searches were performed by two researchers and limited to studies involving human subjects published in the English language. Inclusion criteria included in vitro studies with aPDT; studies that used methylene blue as a photosensitizer; studies that used low power laser; studies that evaluated S. mutans or C. albicans. Studies published in a non-English language, patents, in vivo or in situ studies; case reports, serial case, reviews and animal studies were not included. Studies published before 1996 were also not included. Initially, the search resulted in 68 published studies. 16 records were excluded because they were duplicated. The analysis of titles and abstracts resulted in the exclusion of 48 of the published studies, resulting in 4 studies included in the systematic review. The aPDT was effective in three of the four papers selected for the systematic review and the pre-irradiation time used was 5 or 15 min. This therapy had satisfactory results in both C. albicans and S. mutans when using methylene blue as a photosensitizer.



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Curcumin-mediated Photodynamic Therapy for the treatment of oral infections—A review

Publication date: March 2018
Source:Photodiagnosis and Photodynamic Therapy, Volume 21
Author(s): Carolina Santezi, Bárbara Donadon Reina, Lívia Nordi Dovigo
BackgroundRecent evidences show the promising applications of Curcumin (CUR) against different diseases, including some of the main oral pathologies. The objective of this review paper was to catalog articles that investigated the photodynamic effect of CUR for oral diseases in the last 15 years.MethodsThe establishment of defined criteria for data collection was proposed and a total of 173 articles were identified, but only 26 were eligible for full text reading. Their main findings were critically reviewed to provide a state-of-the-art overview of the use of CUR in Dentistry.ResultsAntimicrobial potential of CUR was the subject of the majority of the articles. CUR showed great potential for photodynamic action against oral bacteria, fungi, and strains resistant to conventional drugs. Some authors indicated the efficacy of CUR-mediated Photodynamic Therapy to reduce tumor cells while others observed low cytotoxicity in mammalian cells and healthy oral mucosa. However, CUR solubility and stability is still a problem for the photodynamic technique, and to overcome these drawbacks, biocompatible vehicles need to be better explored.ConclusionsInvestigations have used different CUR concentrations and formulations, as well as different light parameters. This fact, together with the lack of in vivo studies, clearly shows that clinical protocols have not been established yet. Investigations are necessary in order to establish the best concentrations and safe vehicles to be used for this technique.



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An experimental study for rapid detection and quantification of endodontic microbiota following photo-activated disinfection via new multiplex real-time PCR assay

Publication date: March 2018
Source:Photodiagnosis and Photodynamic Therapy, Volume 21
Author(s): Maryam Pourhajibagher, Reza Raoofian, Roghayeh Ghorbanzadeh, Abbas Bahador
BackgroundThe infected root canal system harbors one of the highest accumulations of polymicrobial infections. Since the eradication of endopathogenic microbiota is a major goal in endodontic infection therapy, photo-activated disinfection (PAD) can be used as an alternative therapeutic method in endodontic treatment. Compared to cultivation-based approaches, molecular techniques are more reliable for identifying microbial agents associated with endodontic infections. The purpose of this study was to evaluate the ability of designed multiplex real-time PCR protocol for the rapid detection and quantification of six common microorganisms involved in endodontic infection before and after the PAD.Materials and methodsSamples were taken from the root canals of 50 patients with primary and secondary/persistent endodontic infections using sterile paper points. PAD with toluidine blue O (TBO) plus diode laser was performed on root canals. Resampling was then performed, and the samples were transferred to transport medium. Then, six target microorganisms were detected using multiplex real-time PCR before and after the PAD.ResultsVeillonella parvula was found using multiplex real-time PCR to have the highest frequency among samples collected before the PAD (29.4%), followed by Porphyromonas gingivalis (23.1%), Aggregatibacter actinomycetemcomitans (13.6%), Actinomyces naeslundii (13.0%), Enterococcus faecalis (11.5%), and Lactobacillus rhamnosus (9.4%). After TBO-mediated PAD, P. gingivalis strains, the most resistance microorganisms, were recovered in 41.7% of the samples using molecular approach (P > 0.05).ConclusionAs the results shown, multiplex real-time PCR as an accurate detection approach with high-throughput and TBO-mediated PAD as an efficient antimicrobial strategy due to the significant reduction of the endopathogenic count can be used for detection and treatment of microbiota involved in infected root canals, respectively.



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Early choriocapillaris changes after half-fluence photodynamic therapy in chronic central serous chorioretinopathy evaluated by optical coherence tomography angiography: Preliminary results

Publication date: March 2018
Source:Photodiagnosis and Photodynamic Therapy, Volume 21
Author(s): Ali Demircan, Ceren Yesilkaya, Zeynep Alkin
BackgroundThe purpose of this study is to examine the choridal perfusion in patients with chronic central serous chorioretinopathy (CSC) after half-fluence photodynamic therapy (PDT) in the early post-treatment period.MethodsThis retrospective study included patients with chronic CSC. Indocyanine green angiography (ICGA) guided half-fluence PDT was applied to the all eyes. Best corrected visual acuity (BCVA) was assessed by Snellen chart and central retinal thickness (CRT) and subfoveal choroidal thickness (SFCT) was measured by spectral domain optical coherence tomography (SD-OCT) before PDT and at 3 and 30 days following the therapy. Optical coherence tomography angiography (OCTA) was performed to evaluate choriocapillaris perfusion in all patients before PDT and 3 and 30 days of therapy.ResultsOf the patients participating in this study, the mean age was 49.8 ± 14.1 years. BCVA remained stable in all eyes during follow-up period. CRT was 360 ± 148 μm at baseline, 327 ± 133 μm at day 3 and 203 ± 40 μm at day 30 after treatment. Subretinal fluid totally resolved at day 30 in all eyes. The mean SFCT was 493 ± 67 μm at baseline, 498 ± 71 μm at day 3 and 450 ± 63 μm at day 30. At day 3, OCTA revealed markedly decreased choriocapillaris flow limited to the site of PDT spot. The choriocapillaris perfusion appeared to be normal in all eyes in OCTA images at day 30.ConclusionsOCTA is a noninvasive imaging tool for detecting choroidal vascular changes after PDT in CSC. In this preliminary study of a limited number of CSC patients, choroiocapillaris perfusion seemed to decreased in very early period following half-fluence PDT and then returned to normal until 30 days of therapy.



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Effect of LaF3: Ag fluorescent nanoparticles on photodynamic efficiency and cytotoxicity of Protoporphyrin IX photosensitizer

Publication date: March 2018
Source:Photodiagnosis and Photodynamic Therapy, Volume 21
Author(s): F. Tavakkoli, M. Zahedifar, E. Sadeghi
LaF3: Ag nanoparticles (NPs) were synthesized by the co-precipitation method. The produced NPs were characterized by X-ray diffraction (XRD) pattern, scanning electron microscope (SEM), dynamic light scattering (DLS) and Fourier transform infrared spectroscopy (FTIR). The emission spectrum of LaF3:Ag NPs is mostly overlapped with the absorption band of protoporphyrin IX (PpIX) and their conjugation was confirmed by studying fluorescence resonance energy transfer (FRET) from LaF3:Ag donor to protoporphyrin IX acceptor. The energy transfers from LaF3:Ag NPs to photosensitizer molecules is very efficient. So, the produced LaF3:Ag NPs can be recommended as light source for photodynamic therapy (PDT). The thiol group of cysteine was bound to LaF3:Ag NPs in order to conjugate LaF3:Ag NPs and protoporphyrin IX. UVC light source was used to excite fluorescent LaF3:Ag NPs. The reactive oxygen species (ROS) produced by photosensitizer was identified using special fluorescent probes (anthracene, methylene blue and methyl orange) as detectors.



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Dose-dependent photochemical/photothermal toxicity of indocyanine green-based therapy on three different cancer cell lines

Publication date: March 2018
Source:Photodiagnosis and Photodynamic Therapy, Volume 21
Author(s): Mustafa Kemal Ruhi, Ayşe Ak, Murat Gülsoy
The Food and Drug Administration-approved Indocyanine Green can be used as a photosensitizer to kill cancer cells selectively. Although indocyanine green is advantageous as a photosensitizer in terms of strong absorption in the near-infrared region, indocyanine green-based cancer treatment is still not approved as a clinical method. Some reasons for this are aggregation at high concentrations, rapid clearance of the photosensitizer from the body, low singlet oxygen quantum yield, and the uncertainty concerning its action mechanism. This in vitro study focuses on two of these points: "what is the cell inhibition mechanism of indocyanine green-based therapy?" and "how the dose-dependent aggregation problem of indocyanine green alters its cell inhibition efficiency?" The following experiments were conducted to provide insight into these points.Nontoxic doses of indocyanine green and near-infrared laser were determined. The aggregation behavior of indocyanine green was verified through experiments. The singlet oxygen quantum yield of indocyanine green at different concentrations were calculated. Various indocyanine green and energy densities of near-infrared light were applied to prostate cancer, neuroblastoma, and colon cancer cells. An MTT assay was performed at the end of the first, second, and third days following the treatments to determine the cell viability. Temperature changes in the medium during laser exposure were recorded. ROS generation following the treatment was verified by using a Total Reactive Oxygen Species detection kit. An apoptosis detection test was performed to establish the cell death mechanism and, finally, the cellular uptakes of the three different cells were measured. According to the results, indocyanine green-based therapy causes cell viability decrease for three cancer cell lines by means of excessive reactive oxygen species production. Different cells have different sensitivities to the therapy possibly because of the differentiation level and structural differences. The singlet oxygen generation of indocyanine green decreases at high concentrations because of aggregation. Nevertheless, better cancer cell killing effect was observed at higher photosensitizer concentrations. This result reveals that the cellular uptake of indocyanine green was determinant for better cancer cell inhibition.



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Photodynamic therapy using 5-aminolevulinic acid triggered DNA damage of adenocarcinoma breast cancer and hepatocellular carcinoma cell lines

Publication date: March 2018
Source:Photodiagnosis and Photodynamic Therapy, Volume 21
Author(s): Mona A.M. Abo-Zeid, Mahmoud T. Abo-Elfadl, Shady M. Mostafa
Targeting cancer cells with photosensitizer (PS) excited by appropriate laser irradiation to release singlet oxygen as a photodynamic therapy (PDT) remains a challenge. This research aimed to assess the cytogenetic potential of 5-aminolevulinic acid (5-ALA) activated with laser irradiation (5-ALA/PDT) to damage the intact DNA of adenocarcinoma breast cancer cell line (MCF-7) and hepatocellular carcinoma cell line (HepG2). Cancer cells were treated with 0.5 and 1 mM 5-ALA for 4 h, the precursor of the photochemical protoporphyrin IX (PpIX), and then exposed to laser irradiation at 633 nm and 0.25 W for 4 min before incubation for 24 h. Cytotoxicity of cancer cells was assessed using trypan blue exclusion assay. Genotoxicity was recorded by micronucleus test and comet assay. Both 5-ALA and laser irradiation, separately, were nontoxic on cancer cell lines, however, 5-ALA/PDT enhanced cell death in a concentration-dependent manner. Also, 5-ALA/PDT generated high percentages of micronuclei in MCF-7 and HepG2 cell lines as recorded in binucleated cells. Similarly, the mean percentages of DNA damage and tail moment ratio were intensified extremely in cancer cell lines treated with 5-ALA/PDT rather than non-treated cells or cells treated by 5-ALA or laser irradiation separately. In conclusion, the singlet oxygen of 5-ALA targets DNA of cancer cells when activated by laser irradiation. Therefore, photodynamic therapy is an applicable process to damage DNA effectively during M-phase and prohibit cancer cells proliferation.



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Assessment of safety of 5-aminolevulinic acid–mediated photodynamic therapy in rat brain

Publication date: March 2018
Source:Photodiagnosis and Photodynamic Therapy, Volume 21
Author(s): Seigo Kimura, Toshihiko Kuroiwa, Naokado Ikeda, Naosuke Nonoguchi, Shinji Kawabata, Yoshinaga Kajimoto, Toshihisa Ishikawa
BackgroundOral 5-aminolevulinic acid (ALA) induces biosynthesis/accumulation of the natural photo-sensitizer protoporphyrin IX (PpIX) in cancer cells. ALA is used widely in photodynamic diagnosis (PDD) and therapy (PDT) during malignant glioma surgery, but few studies have examined the effects of photodynamics plus ALA on normal brain tissue in vivo. We investigated the effects of ALA-mediated PDD and PDT on normal brain tissue.MethodsWe established a rat model in which the brain surface was irradiated through the skull by light-emitting diode (635 nm) after ALA administration. Using this model, we investigated the effects of various amounts of light irradiation with various ALA doses on brain tissue.ResultsNeurological symptoms developed with administration of ALA at 240 or 120 mg/kg accompanied by irradiation at 100 or 400 J/cm², respectively. Dye leakage occurred due to disruption of the blood–brain barrier (BBB) at 90 mg/kg and 100 J/cm², respectively. Thickness of the cortex increased significantly at 240 mg/kg and 400 J/cm², respectively. The number of neurons appeared to decrease at 200 mg/kg plus 400 J/cm², respectively, and there was an increase in the number of cells that were positive for terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling (TUNEL) staining.ConclusionsALA-mediated PDT is safe at doses of 90 mg/kg or less followed by light irradiation of 100 J/cm² in rat brains. At doses above this threshold, ALA-PDT led to irreversible BBB and brain damage in rats.



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Effect of an oral health education program based on the use of quantitative light-induced fluorescence technology in Uzbekistan adolescents

Publication date: March 2018
Source:Photodiagnosis and Photodynamic Therapy, Volume 21
Author(s): Bakhtinur Khudanov, Hoi In Jung, Dono Kahharova, Jeong-Woo Lee, Ilhom Hamidov, Eun-Song Lee, Baek-Il Kim
ObjectivesThe aim of this study was to determine whether an oral health education program using a Qscan device based on quantitative light-induced fluorescence (QLF) technology could improve the oral hygiene status and oral health literacy of adolescents.Materials and methodsOne hundred adolescents aged 14–16 years attending a school in Tashkent city were included in this study. The participants were assigned to the following two groups using permuted block randomization technique: (i) control group (traditional learning) and (ii) experimental group (Qscan device-based learning). The participants included in the experimental group received additional education and training on dental plaque removal using the Qscan device. The accumulated levels of plaque were assessed in all participants, who also completed questionnaires about their oral health status, oral health knowledge, attitude, and behavior during an 8-week period.ResultsThere were statistically significant improvements in the experimental group compared to the control group in the plaque index (0.46 vs 0.07, p < .05), oral health knowledge (19.4 vs 28.8, p < .05), attitude (16.7 vs 20.2, p < .05), and behavior (19.9 vs 30.5, p < .05).ConclusionsThis study has demonstrated that an oral health education program based on the use of QLF technology could be useful for improving the oral hygiene status and oral health literacy of adolescents in Uzbekistan.



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An update of the Worldwide Integrated Assessment (WIA) on systemic insecticides. Part 3: alternatives to systemic insecticides

Abstract

Over-reliance on pesticides for pest control is inflicting serious damage to the environmental services that underpin agricultural productivity. The widespread use of systemic insecticides, neonicotinoids, and the phenylpyrazole fipronil in particular is assessed here in terms of their actual use in pest management, effects on crop yields, and the development of pest resistance to these compounds in many crops after two decades of usage. Resistance can only be overcome in the longterm by implementing methods that are not exclusively based on synthetic pesticides. A diverse range of pest management tactics is already available, all of which can achieve efficient pest control below the economic injury level while maintaining the productivity of the crops. A novel insurance method against crop failure is shown here as an example of alternative methods that can protect farmer's crops and their livelihoods without having to use insecticides. Finally, some concluding remarks about the need for a new framework for a truly sustainable agriculture that relies mainly on natural ecosystem services instead of chemicals are included; this reinforcing the previous WIA conclusions (van der Sluijs et al. Environ Sci Pollut Res 22:148-154, 2015).

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A tRNA's fate is decided at its 3′ end: Collaborative actions of CCA-adding enzyme and RNases involved in tRNA processing and degradation

Publication date: Available online 31 January 2018
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Karolin Wellner, Heike Betat, Mario Mörl
tRNAs are key players in translation and are additionally involved in a wide range of distinct cellular processes. The vital importance of tRNAs becomes evident in numerous diseases that are linked to defective tRNA molecules. It is therefore not surprising that the structural intactness of tRNAs is continuously scrutinized and defective tRNAs are eliminated. In this process, erroneous tRNAs are tagged with single-stranded RNA sequences that are recognized by degrading exonucleases. Recent discoveries have revealed that the CCA-adding enzyme – actually responsible for the de novo synthesis of the 3′-CCA end – plays an indispensable role in tRNA quality control by incorporating a second CCA triplet that is recognized as a degradation tag. In this review, we give an update on the latest findings regarding tRNA quality control that turns out to represent an interplay of the CCA-adding enzyme and RNases involved in tRNA degradation and maturation. In particular, the RNase-induced turnover of the CCA end is now recognized as a trigger for the CCA-adding enzyme to repeatedly scrutinize the structural intactness of a tRNA. This article is part of a Special Issue entitled: SI: Regulation of tRNA synthesis and modification in physiological conditions and disease edited by Dr. Boguta Magdalena.



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HMGB1-mediated DNA bending: Distinct roles in increasing p53 binding to DNA and the transactivation of p53-responsive gene promoters

Publication date: March 2018
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1861, Issue 3
Author(s): Michal Štros, Martin Kučírek, Soodabeh Abbasi Sani, Eva Polanská
HMGB1 is a chromatin-associated protein that has been implicated in many important biological processes such as transcription, recombination, DNA repair, and genome stability. These functions include the enhancement of binding of a number of transcription factors, including the tumor suppressor protein p53, to their specific DNA-binding sites. HMGB1 is composed of two highly conserved HMG boxes, linked to an intrinsically disordered acidic C-terminal tail. Previous reports have suggested that the ability of HMGB1 to bend DNA may explain the in vitro HMGB1-mediated increase in sequence-specific DNA binding by p53. The aim of this study was to reinvestigate the importance of HMGB1-induced DNA bending in relationship to the ability of the protein to promote the specific binding of p53 to short DNA duplexes in vitro, and to transactivate two major p53-regulated human genes: Mdm2 and p21/WAF1. Using a number of HMGB1 mutants, we report that the HMGB1-mediated increase in sequence-specific p53 binding to DNA duplexes in vitro depends very little on HMGB1-mediated DNA bending. The presence of the acidic C-terminal tail of HMGB1 and/or the oxidation of the protein can reduce the HMGB1-mediated p53 binding. Interestingly, the induction of transactivation of p53-responsive gene promoters by HMGB1 requires both the ability of the protein to bend DNA and the acidic C-terminal tail, and is promoter-specific. We propose that the efficient transactivation of p53-responsive gene promoters by HMGB1 depends on complex events, rather than solely on the promotion of p53 binding to its DNA cognate sites.



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Suppression of gluconeogenic gene transcription by SIK1-induced ubiquitination and degradation of CRTC1

Publication date: March 2018
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1861, Issue 3
Author(s): Wei-Wei Gao, Hei-Man Vincent Tang, Yun Cheng, Ching-Ping Chan, Chi-Ping Chan, Dong-Yan Jin
CRTCs are a group of three transcriptional coactivators required for CREB-dependent transcription. CREB and CRTCs are critically involved in the regulation of various biological processes such as cell proliferation, metabolism, learning and memory. However, whether CRTC1 efficiently induces gluconeogenic gene expression and how CRTC1 is regulated by upstream kinase SIK1 remain to be understood. In this work, we demonstrated SIK1-induced phosphorylation, ubiquitination and degradation of CRTC1 in the context of the regulation of gluconeogenesis. CRTC1 protein was destabilized by SIK1 but not SIK2 or SIK3. This effect was likely mediated by phosphorylation at S155, S167, S188 and S346 residues of CRTC1 followed by K48-linked polyubiquitination and proteasomal degradation. Expression of gluconeogenic genes such as that coding for phosphoenolpyruvate carboxykinase was stimulated by CRTC1, but suppressed by SIK1. Depletion of CRTC1 protein also blocked forskolin-induced gluconeogenic gene expression, knockdown or pharmaceutical inhibition of SIK1 had the opposite effect. Finally, SIK1-induced ubiquitination of CRTC1 was mediated by RFWD2 ubiquitin ligase at a site not equivalent to K628 in CRTC2. Taken together, our work reveals a regulatory circuit in which SIK1 suppresses gluconeogenic gene transcription by inducing ubiquitination and degradation of CRTC1. Our findings have implications in the development of new antihyperglycemic agents.



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