Background: Balanced crystalloid solutions induce less hyperchloremia than normal saline, but their role as primary fluid replacement for children undergoing surgery is unestablished. We hypothesized that balanced crystalloids induce less chloride and metabolic derangements than 0.9% saline solutions in children undergoing brain tumor resection. Methods: In total, 53 patients (age range, 6 mo to 12 y) were randomized to receive balanced crystalloid (balanced group) or 0.9% saline solution (saline group) during and after (for 24 h) brain tumor resection. Serum electrolyte and arterial blood gas analyses were performed at the beginning of surgery (baseline), after surgery, and at postoperative day 1. The primary trial outcome was the absolute difference in serum chloride concentrations (post-preopΔCl−) measured after surgery and at baseline. Secondary outcomes included the post-preopΔ of other electrolytes and base excess (BE); hyperchloremic acidosis incidence; and the brain relaxation score, a 4-point scale evaluated by the surgeon for assessing brain edema. Results: Saline infusion increased post-preopΔCl (6 [3.5; 8.5] mmol/L) compared with balanced crystalloid (0 [−1.0; 3.0] mmol/L; P
https://ift.tt/2tdD1pJ
Σάββατο 16 Ιουνίου 2018
Selection of Patients’ Recumbent Position Laterality According to Physician Handedness Bias Increases the Success Rate of Lumbar Puncture: A Multicenter Study
Background: Lumbar puncture (LP) is a medical procedure required during spinal anesthesia and for obtaining cerebrospinal fluid samples in the diagnosis of neurological disorders. The aim of this study was to assess the effects of physicians' handedness bias and the laterality of patients' recumbent position on the success rate of LPs. Methods and Patients: A prospective multicenter study including 36 physicians (18 left-handed and 18 right-handed) and 7200 patients was conducted in 6 medical centers. In each center, 1200 patients were randomized into group L (LPs performed by left-handed physicians) or group R (LPs performed by right-handed physicians). Each physician performed 200 cases of LPs, of which the laterality of the recumbent position (either on the left or right side) was decided after a second randomization. A successful LP was considered when the free flow of cerebrospinal fluid was observed upon the first attempt. Results: There was no significant difference in patient characteristics between groups L and R. Right-handed physicians had a significantly higher LP success rate with patients in the left lateral recumbent position (LRP) (1595/1800 vs. 1408/1800; odds ratio, 0.539; 95% confidence interval, 0.348-0.836; P=0.006). For left-handed physicians, the LP success rate was higher when patients were in the right LRP (1424/1800 vs. 1593/1800, odds ratio, 0.449; 95% confidence interval, 0.283-0.711; P=0.001). Patients' age, sex, height, and weight were not statistically related to LP success during multivariate analyses. Conclusions: Physicians handedness bias and patient laterality of recumbent position affects the success of LPs. Right-handed physicians have a greater chance of performing successful LPs when patients are in the left LRP, and vice versa. J.-L.Z. and Y.-R.S. contributed equally. Supported by the National Natural Science Foundation of China (81471241, 81271375, and 81171133), Shanghai Municipal Science and Technology Commission project (16411955300, 18441903300 and 18695841300), and Shanghai Minhang Natural Science Foundation (2014MHZ001). The authors have no conflicts of interest to disclose. Address correspondence to: Jin Hu, MD, PhD, Department of Neurosurgery, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai 200040, P.R. China (e-mail: 286644104@qq.com). Received January 7, 2018 Accepted May 8, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved
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https://ift.tt/2MuIWQ2
The causes and consequences of variation in human cytokine production in health
Melanie Schirmer | Vinod Kumar | Mihai G Netea | Ramnik J Xavier
https://ift.tt/2LWY0oN
Existing agricultural ecosystem in China leads to environmental pollution: an econometric approach
Abstract
Sustainable agriculture ensures food security and prevents starvation. However, the need to meet the increasing food demands of the growing population has led to poor and unsustainable agricultural practices, which promote environmental degradation. Given the contributions of agricultural ecosystems to environmental pollution, we investigated the impact of the agricultural ecosystem on environmental pollution in China using time series data from 1960 to 2014. We employed several methods for econometric analysis including the unit root test, Johansen test of cointegration, Granger causality test, and vector error correction model. Evidence based on the long-run elasticity indicates that a 1% increase in the emissions of carbon dioxide (CO2) equivalent to nitrous oxide from synthetic fertilizers will increase the emissions of CO2 by 1.52% in the long run. Similarly, a 1% increase in the area of harvested rice paddy, cereal production, biomass of burned crop residues, and agricultural GDP will increase the carbon dioxide emissions by 0.85, 0.63, 0.37, and 0.22%, respectively. The estimated results indicate that there are long-term equilibrium relationships among the selected variables considered for the agricultural ecosystem and carbon dioxide emissions. In particular, we identified bidirectional causal associations between CO2 emissions, biomass of burned crop residues, and cereal production.
Graphical abstract
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https://ift.tt/2LXaM6B
A network analysis of indirect carbon emission flows among different industries in China
Abstract
Indirect carbon emissions account for a large ratio of the total carbon emissions in processes to make the final products, and this implies indirect carbon emission flow across industries. Understanding these flows is crucial for allocating a carbon allowance for each industry. By combining input–output analysis and complex network theory, this study establishes an indirect carbon emission flow network (ICEFN) for 41 industries from 2005 to 2014 to investigate the interrelationships among different industries. The results show that the ICEFN was consistent with a small-world nature based on an analysis of the average path lengths and the clustering coefficients. Moreover, key industries in the ICEFN were identified using complex network theory on the basis of degree centrality and betweenness centrality. Furthermore, the 41 industries of the ICEFN were divided into four industrial subgroups that are related closely to one another. Finally, possible policy implications were provided based on the knowledge of the structure of the ICEFN and its trend.
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Neoadjuvant Radiotherapy: Changing the Treatment Sequence to Allow Immediate Free Autologous Breast Reconstruction
J reconstr Microsurg
DOI: 10.1055/s-0038-1660871
Background Locally advanced breast cancer (LABC) is traditionally treated with a multimodal approach of chemotherapy, surgery, and postmastectomy radiotherapy (PMRT). The advantages of immediate breast reconstruction (IBR) are well described and include improved aesthetic outcomes, fewer surgical procedures, shorter treatment period, and a higher quality of life. However, this sequence makes immediate free autologous reconstruction more challenging as PMRT can have deleterious and unpredictable effects on the flap. We have reversed this treatment sequence with neoadjuvant chemotherapy and radiotherapy, followed by mastectomy and immediate free autologous reconstruction. To our knowledge, this is the first series to assess the outcomes of neoadjuvant radiotherapy on immediate free microvascular breast reconstruction. Methods A review of patients with LABC who underwent immediate free autologous breast reconstruction post neoadjuvant chemoradiotherapy between 2013 and 2017 was conducted. All reconstructions were performed by a single reconstructive team. The primary end points were flap failure and surgical complications. Secondary end points were pathological response rate and disease recurrence. Results A total of 40 women with an average age of 48.1 (36–61) and average body mass index of 25.6 (18–37) were included. The most common choice of flap was immediate deep inferior epigastric perforator (DIEP, 31), followed by transverse or diagonal upper gracilis (5), muscle-sparing transversus abdominis (3), and stacked DIEP (1). Our major complication rate was 12.5% and minor complication 15%. There were no cases of local recurrence and only three cases (7.5%) of distant disease progression. Conclusion From our experience, this treatment sequence allows patients to have an immediate gold standard reconstruction without an increase in surgical morbidity. It affords the benefits of IBR without concern in delaying adjuvant therapy and appears to be safe from an oncological perspective.
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Article in Thieme eJournals:
Table of contents | Abstract | Full text
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Preoperative radiation and complication rates after double free flap reconstruction of head and neck cancer
In this study, we explore whether preoperative external beam radiation affects complication rates in patients that have undergone double simultaneous free tissue transfer for head and neck defects.
https://ift.tt/2My7WpS
Tired and Swollen: A Mono Mimic for Angioedema
Infectious mononucleosis (IM) secondary to Epstein-Barr virus (EBV) infection classically presents as a triad of cervical lymphadenopathy, fever and pharyngitis1 that is often accompanied by persistent fatigue. An uncommon presentation of early IM that has been reported rarely in the literature is periorbital edema. Here, we present a case of a 19 year-old female referred to allergy clinic for evaluation of angioedema. She was found to have periorbital swelling mistaken for angioedema and ultimately was diagnosed with IM despite lacking symptoms of the classic triad.
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Estimation of marginal abatement costs of CO 2 in Chinese provinces under 2020 carbon emission rights allocation: 2005–2020
Abstract
The calculation of marginal abatement costs of CO2 plays a vital role in meeting China's 2020 emission reduction targets by providing reference for determining carbon tax and carbon trading pricing. However, most existing researches only used one method to discuss regional and industrial marginal abatement costs, and almost no studies predicted future marginal abatement costs from the perspective of CO2 emission efficiency. To make up for the gaps, this paper first estimates marginal abatement costs of CO2 in three major industries of 30 provinces in China from 2005 to 2015 based on three assumptions. Second, based on the principle of fairness and efficiency, China's 2020 emission reduction targets are decomposed by province. Based on the ZSG-C-DDF model, the marginal abatement costs of CO2 in all provinces in China in 2020 are estimated and compared with the marginal abatement costs of 2005 to 2015. The results show that (1) from 2005 to 2015, marginal abatement costs of CO2 in all provinces show a fluctuating upward trend; (2) compared with the marginal abatement costs of primary industry or tertiary industry, most provinces have lower marginal abatement costs for secondary industry; and (3) the average marginal abatement costs of CO2 for China in 2020 are 2766.882 Yuan/tonne for the 40% carbon intensity reduction target and 3334.836 Yuan/tonne for the 45% target, showing that the higher the emission reduction target, the higher the marginal abatement costs of CO2. (4) Overall, the average marginal abatement costs of CO2 in China by 2020 are higher than those in 2005–2015. The empirical analysis in this paper can provide multiple references for environmental policy makers.
https://ift.tt/2lfEk48
Medical Treatment of Nasal Airway Obstruction
Nasal obstruction is a common, and potentially debilitating, problem. It is caused by a combination of structural factors and/or mucosal swelling/inflammation. The medical treatment of nasal obstruction is aimed at decreasing mucosal inflammation and edema and is generally guided by the underlying cause. Several different drug classes are commonly used in the treatment of nasal obstruction, each with different indications, and pros and cons to their use. This article discusses the most commonly used therapies for nasal obstruction. Current evidence on the efficacy and side effect profile of each therapy is reviewed.
https://ift.tt/2LUkiau
Prevalence of ALK gene alterations among the spectrum of plexiform spitzoid lesions
ALK gene rearrangements have been described in spitzoid lesions with plexiform growth pattern., ALK alterations characterize a significant subset of Spitz nevi and atypical Spitz tumors and can coexist with BRAF gene mutations., ALK immunohistochemistry represents a simple and relatively inexpensive ancillary technique to classify lesions with ALK gene alterations.
https://ift.tt/2LTe2jp
Clinical and Histopathological Features of Paraneoplastic Granuloma Annulare in Association with Solid Organ Malignancies: Case Control Study
Granuloma annulare (GA) is a granulomatous skin eruption rarely reported in association with solid organ, lymphoid, and blood malignancies., The clinical and histopathological features of paraneoplastic GA associated with solid organ malignancies are similar to classic GA., Cancer screening should be considered for patients with GA who display signs or symptoms concerning for underlying malignancy.
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Alternative Uses of Dermatoscopy In Daily Clinical Practice: An Update
Dermatoscopy is mainly used for the diagnosis of pigmented and non-pigmented skin tumours, The use of dermatoscopy beyond skin tumours is constantly increasing, Dermatoscopy may enhance the clinical diagnosis of various skin disorders, narrowing down the differential diagnosis and avoiding, in selected cases, unnecessary skin biopsy
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Overcoming heparin resistance in pregnant women with antithrombin deficiency: a case report and review of the literature
The risk of thromboembolic events during pregnancy in patients with antithrombin deficiency is increased. Preventing thromboembolic events during pregnancy in the case of antithrombin deficiency is still a mat...
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Differences of Cd uptake and expression of OAS and IRT genes in two varieties of ryegrasses
Abstract
Pot experiment was conducted to study the difference of cadmium uptake and OAS and IRT genes' expression between the two ryegrass varieties under cadmium stress. The results showed that with the increase of cadmium levels, the dry weights of roots of the two ryegrass varieties, and the dry weights of shoots and plants of Abbott first increased and then decreased. When exposed to 75 mg kg−1 Cd, the dry weights of shoot and plant of Abbott reached the maximum, which increased by 11.13 and 10.67% compared with the control. At 75 mg kg−1 Cd, cadmium concentrations in shoot of the two ryegrass varieties were higher than the critical value of Cd hyperaccumulator (100 mg kg−1), 111.19 mg kg−1 (Bond), and 133.69 mg kg−1 (Abbott), respectively. The OAS gene expression in the leaves of the two ryegrass varieties showed a unimodal curve, which was up to the highest at the cadmium level of 150 mg kg−1, but fell back at high cadmium levels of 300 and 600 mg kg−1. The OAS gene expression in Bond and Abbott roots showed a bimodal curve. The OAS gene expression in Bond root and Abbott stem mainly showed a unimodal curve. The expression of IRT genes family in the leaves of ryegrass varieties was basically in line with the characteristics of unimodal curve, which was up to the highest at cadmium level of 75 or 150 mg kg−1, respectively. The IRT expression in the ryegrass stems showed characteristics of bimodal and unimodal curves, while that in the roots was mainly unimodal. The expression of OAS and IRT genes was higher in Bond than that in Abbott due to genotype difference between the two varieties. The expression of OAS and IRT was greater in leaves than that in roots and stems. Ryegrass tolerance to cadmium can be increased by increasing the expression of OAS and IRT genes in roots and stems, and transfer of cadmium from roots and stems to the leaves can be enhanced by increasing expression OAS and IRT in leaves.
https://ift.tt/2LWcCo7
Intermittent micro-aeration control of methane emissions from an integrated vertical-flow constructed wetland during agricultural domestic wastewater treatment
Abstract
It is very important to control methane emissions to mitigate global warming. An intermittent micro-aeration control system was used to control methane emissions from an integrated vertical-flow constructed wetland (IVCW) to treat agricultural domestic wastewater pollution in this study. The optimized intermittent micro-aeration conditions were a 20-min aeration time and 340-min non-aeration time, 3.9 m3 h−1 aeration intensity, evenly distributed micro-aeration diffusers at the tank bottom, and an aeration period of every 6 h. Methane flux emission by intermittent micro-aeration was decreased by 60.7% under the optimized conditions. The average oxygen transfer efficiency was 26.73%. The control of CH4 emission from IVCWs was most strongly influenced by the intermittent micro-aeration diffuser distribution, followed by aeration intensity, aeration time, and water depth. Scaling up of IVCWs is feasible in rural areas by using intermittent micro-aeration control as a mitigation measure for methane gas emissions for climate change.
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Hyperthermia in cervical cancer – current status
Publication date: Available online 15 June 2018
Source:Reports of Practical Oncology & Radiotherapy
Author(s): Ewa Burchardt, Andrzej Roszak
BackgroundThis article reviews the salient features of recent results of clinical studies. It puts a special emphasis on technical aspects, mechanisms of action together with radiotherapy and chemotherapy and points out areas for additional investigation.AimTo present the current state of knowledge on hyperthermia (HT) and to highlight its role in the treatment of cervical cancer.Materials and methodsThe literature on the clinical use of combined hyperthermia for cervical cancer was analyzed. Clinical outcomes together with the technical aspects and the role of HT were also evaluated.ResultsClinically randomized trials have demonstrated benefit including survival with the addition of hyperthermia to radiation or chemotherapy in the treatment of cervical cancer without significant acute or late morbidities. The technological advances have led to an effective and safer treatment delivery, thermal treatment planning, thermal dose monitoring and online adaptive temperature modulation.ConclusionsDue to rapid development over the last decade of hyperthermia systems and new studies at the basic science and clinical level, the perception of hyperthermia as a part of multimodality treatment in cervical cancer has been changed. However, there is still a need for multicentre randomized clinical trials.
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The influence of brain iron and myelin on magnetic susceptibility and effective transverse relaxation - A biochemical and histological validation study
Source:NeuroImage, Volume 179
Author(s): Simon Hametner, Verena Endmayr, Andreas Deistung, Pilar Palmrich, Max Prihoda, Evelin Haimburger, Christian Menard, Xiang Feng, Thomas Haider, Marianne Leisser, Ulrike Köck, Alexandra Kaider, Romana Höftberger, Simon Robinson, Jürgen R. Reichenbach, Hans Lassmann, Hannes Traxler, Siegfried Trattnig, Günther Grabner
Quantitative susceptibility mapping (QSM) and effective transverse relaxation rate (R2*) mapping are both highly sensitive to variations in brain iron content. Clinical Magnetic Resonance Imaging (MRI) studies report changes of susceptibilities and relaxation rates in various neurological diseases which are often equated with changes in regional brain iron content. However, these mentioned metrics lack specificity for iron, since they are also influenced by the presence of myelin. In this study, we assessed the extent to which QSM and R2* reflect iron concentration as well as histological iron and myelin intensities. Six unfixed human post-mortem brains were imaged in situ with a 7 T MRI scanner. After formalin fixation, the brains were sliced axially and punched. 671 tissue punches were subjected to ferrozine iron quantification. Subsequently, brain slices were embedded in paraffin, and histological double-hemispheric axial brain slices were stained for Luxol fast blue (myelin) and diaminobenzidine (DAB)-enhanced Turnbull blue (iron). 3331 regions of interest (ROIs) were drawn on the histological stainings to assess myelin and iron intensities, which were compared with MRI data in corresponding ROIs. QSM more closely reflected quantitative ferrozine iron values (r = 0.755 vs. 0.738), whereas R2* correlated better with iron staining intensities (r = 0.619 vs. 0.445). Myelin intensities correlated negatively with QSM (r = −0.352), indicating a diamagnetic effect of myelin on susceptibility. Myelin intensities were higher in the thalamus than in the basal ganglia. A significant relationship was nonetheless observed between quantitative iron values and QSM, confirming the applicability of the latter in this brain region for iron quantification.
https://ift.tt/2HUqGMx
Soil arthropod composition differs between old-fields dominated by exotic plant species and remnant native grasslands
Source:Acta Oecologica, Volume 91
Author(s): Gimena Vilardo, Pedro M. Tognetti, Adelia González-Arzac, Laura Yahdjian
Secondary succession after agriculture abandonment (old-fields) is mostly dominated by exotic grass species. Non-native plant invasions may alter soil fauna, potentially inducing plant-soil feedbacks. Despite their importance in nutrient cycling and plant-soil interactions, meso and macrofauna received less attention than bacteria or fungi. Here we compared the composition of the soil arthropod community in native remnants and plant exotic-dominated old-fields grasslands in the Inland Pampa, Argentina. We sampled independent remnants and old-field grassland plots within a 100 km2 agricultural landscape to test the hypothesis that the abundance of soil arthropod organisms is related to the quality of the plant biomass, whereas the diversity of the soil biota is related to plant species richness, resulting in a different soil biota composition because of differing plant communities. When compared to non-invaded remnant grasslands, soil activity and soil food-web characteristics of the old-fields sites included: 1. Higher total arthropod abundance, particularly of Isopoda, Pseudoescorpionida and Blattaria; 2. Lower abundance of Hymenoptera and Enthomobryomorpha (Collembola); 3. Lower diversity, and evenness, but similar richness of soil organisms orders; 4. Higher soil respiration rates and soil temperature; and 5. Higher total soil N and K+content, but lower soil P content. These results illustrate that soil arthropod composition can vary widely within grasslands patches depending on plant species composition. Also, the more diverse plant community of remnant grasslands supports a more diverse soil biota, although soil activity is slower. Our results support the strong linkage between plant community and soil arthropod composition and suggest that changes in soil biota composition might promote plant-soil feedback interactions inducing the persistence of these alternative grassland states in new agricultural human-modified landscapes.
https://ift.tt/2JQmBuA
Discriminating autism and language impairment and specific language impairment through acuity of musical imagery
Source:Research in Developmental Disabilities, Volume 80
Author(s): Pamela Heaton, Wai Fung Tsang, Kelly Jakubowski, Daniel Mullensiefen, Rory Allen
Deficits in auditory short-term memory have been widely reported in children with Specific Language Impairment (SLI), and recent evidence suggests that children with Autism Spectrum Disorder and co-morbid language impairment (ALI) experience similar difficulties. Music, like language relies on auditory memory and the aim of the study was to extend work investigating the impact of auditory short-term memory impairments to musical perception in children with neurodevelopmental disorders. Groups of children with SLI and ALI were matched on chronological age (CA), receptive vocabulary, non-verbal intelligence and digit span, and compared with CA matched typically developing (TD) controls, on tests of pitch and temporal acuity within a voluntary musical imagery paradigm. The SLI participants performed at significantly lower levels than the ALI and TD groups on both conditions of the task and their musical imagery and digit span scores were positively correlated. In contrast ALI participants performed as well as TD controls on the tempo condition and better than TD controls on the pitch condition of the task. Whilst auditory short-term memory and receptive vocabulary impairments were similar across ALI and SLI groups, these were not associated with a deficit in voluntary musical imagery performance in the ALI group.
https://ift.tt/2LVBJr9
MR imaging features of presumed retroclavicular and periscapular intermuscular vascular plexi – An observational, anatomic study
Source:Clinical Imaging, Volume 52
Author(s): Shivani Ahlawat, Filippo Del Grande, Laura M. Fayad
ObjectiveTo describe MR imaging features of presumed vascular plexi in the periscapular (PSC) and retroclavicular (RC) locations.Materials/methods443 consecutive MR studies performed as "brachial plexus" protocol (axialT1-W and sagittal STIR) were reviewed for presence, size and characteristics of PSC and RC plexi.ResultsPresumed PSC and RC vascular plexi were present in 10%. Both plexi more commonly occurred on the left side. Percutaneous biopsy (n = 1) yielded no vascular neoplasm.ConclusionRC and PSC vascular plexi are commonly encountered on routine brachial plexus MR imaging and may represent variant vascular networks, as they are frequently found on the contralateral asymptomatic side.
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Intracranial complications of pediatric sinusitis: Identifying risk factors associated with prolonged clinical course
Publication date: September 2018
Source:International Journal of Pediatric Otorhinolaryngology, Volume 112
Author(s): Alexander J. Schupper, Wen Jiang, Michael J. Coulter, Matthew Brigger, Javan Nation
ObjectiveIntracranial extension is one of the most serious and morbid complications of pediatric sinusitis. Managing this complication continues to be challenging even after widespread pneumococcal vaccination adoption. We aim to identify risk factors associated with complicated clinical courses, and to assess for altering microbial communities and increased antibiotic resistance.MethodsA retrospective review was conducted of sinus procedures performed at a single institution for acute sinusitis with intracranial extension, and 16 cases were identified. Variables collected included patient demographics, vaccination status, laboratory results, imaging data, antibiotic therapy, sinus and intracranial cultures, perioperative and surgical reports, and hospital course.ResultsThe average patient age was 11.9 years, and 75% were male. The dominant microbial organisms were gram positive in 93.8% (15/16) of cases and 37.5% (6/16) were anaerobic. There were no cases of resistant bacterial growth, and only one case of Streptococcus pneumoniae. Increased antibiotic therapy duration was associated with anaerobic and polymicrobial sinus cultures. A significant increase in length of hospital stay was identified in polymicrobial sinus cultures and frontal sinus involvement. Intracranial abscess re-accumulation was associated with sinus cultures positive for fusobacterium (p = 0.036), polymicrobial infections (p = 0.034), and involvement of brain parenchyma (p = 0.036). Patients with frontal sinus involvement required a greater number of surgical procedures for abscess drainage (p = 0.046). An anaerobic intracranial culture was associated with an increased number of revision craniotomies (p < 0.001). Parenchymal involvement of the infection was associated with an increased number of surgical complications.ConclusionsFrontal sinus involvement, and anaerobic and polymicrobial sinus cultures were predictive of a more severe infection requiring more surgical interventions, prolonged intravenous antibiotic treatment and overall hospital length of stay. Streptococcus pneumoniae was not prevalent in our series, and there seems to be a shift in the microbial profile of this patient subset, compared to previous studies, which can likely be attributed to the adoption of pneumococcal vaccinations. Sinus cultures were more predictive of a complicated clinical course compared to intracranial cultures, suggesting the importance of a thorough sinus debridement and obtaining directed sinus cultures.
https://ift.tt/2lf96Kp
Turkish Adaptation of the Pediatric Voice Related Quality of Life Survey: A validity and reliability study
Publication date: August 2018
Source:International Journal of Pediatric Otorhinolaryngology, Volume 111
Author(s): Rahşan Çinar, Çağıl Gökdoğan, Yusuf Kemal Kemaloğlu, Metin Yılmaz
ObjectivesChildhood voice disorders have increased in recent years reduce not only communication of the child, but also; the quality of life by affecting the socio-emotional state.MethodsIn the study, it is aimed to test validity and reliability of Pediatric Voice Related Quality of Life Survey (PVRQOL)'s Turkish adaptation. A total of 223 individuals aged between 2 years and 18 years, with and without voice problems were involved in this study.ResultsStatistically significant differences were found between study and control groups for total score and sub domain scores for PVRQOL (p < 0,001). Total score of quality of life was higher in the control group. Cronbach alpha coefficient for overall PVRQOL was 0,922; dimension of physical function was 0,894 and socio-emotional domain was 0,804. In the test-retest reliability test, overall PVRQOL was found to be 0,732; physical functional sub domain was 0,734; socio-emotional sub domain was 0,721. The validity of the questionnaire was determined by factor analysis.ConclusionThe results suggest that the Turkish version of the PVRQOL has reliability and validity, and may play a crucial role in evaluating children with voice disorders.
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Including auditory tube function on models is relevant to assess water exposure after tympanostomy tubes–Multiphase computerized fluid dynamics model
Source:International Journal of Pediatric Otorhinolaryngology, Volume 111
Author(s): Joao Subtil, Nuno Martins, Teresa Nunes, Didia Covas, Paulo Vera-Cruz, Richard Voegels, Joao Paco
IntroductionMyringotomy with tympanostomy tube is the most common otologic surgery and some patients are still advised to avoid water. However, there is no evidence supporting this, with published papers questioning the need for this advice.MethodsA Multiphase Computational Fluid Dynamics (CFD) model was created using computerized tomography images of a child's healthy ear. It was then used to study the flow of fluids through the external ear, tympanic cavity, and auditory tube, with and without submersion.ResultsThe model accurately described the behavior of the air retained in the patient's nasopharynx and tympanic cavity. A simulated elevation of pressure in the external auditory canal without submersion, without increase of pressure in the nasopharynx, demonstrated that fluids promptly crossed the tympanostomy tube into the middle ear. However, simulated elevation of pressure in the external auditory canal with concurrent elevation of air pressure in the nasopharynx during submersion did not lead to passive tube opening nor to any detectable flow through the tympanostomy tube.ConclusionsIn the model, submersion increases pressure in the nasopharynx which offsets the pressure in the external auditory canal. So, in the absence of a pressure gradient, no passive tubal opening took place, and no air or fluid flow was detected through the transtympanic tube.This model now includes the exhaust function of the auditory tube in the model and shows its relevance.
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What Is the Relationship Between Eosinophilic Esophagitis (EoE) and Aeroallergens? Implications for Allergen Immunotherapy
Abstract
Purpose of Review
Observations suggesting that aeroallergens trigger eosinophilic esophagitis (EoE) in a subset of patients raise questions about the implications this finding has on the evaluation and management of patients with EoE, including a potential role for allergen immunotherapy.
Recent Findings
The majority of studies evaluating the potential role of aeroallergens as provocateurs of EoE have addressed this issue by assessing the seasonal variation in EoE diagnosis and/or symptom onset or worsening, with mixed results. For various reasons, reaching accurate conclusions based on this methodology is potentially fraught with error. In addition, studies examining the even harder to assess role of perennial aeroallergens in triggering EoE are lacking. Although clearly not the majority, there may be a subset of patients with EoE and allergic rhinitis in whom exposure to aeroallergens to which they are sensitized contributes to esophageal eosinophilia either through direct chronic esophageal mucosal contact with pollen allergens or from repetitive exposure of the esophageal mucosa to pollen allergens, mediators, and eosinophils in swallowed nasal secretions. Therefore, evaluation for and optimal treatment of comorbid allergic rhinitis in EoE patients are clearly indicated. Recognition of the potential role of aeroallergens as triggers of EoE also raises the question of whether allergen immunotherapy might be an effective form of EoE treatment. Reports of sublingual immunotherapy (SLIT) inducing EoE support the notion that aeroallergens can trigger EoE, but negate this approach as a potential form of EoE therapy. In fact, the use of SLIT is contraindicated in patients with EoE. The literature regarding the role of subcutaneous immunotherapy (SCIT) in patients with EoE is limited. Current evidence indicates that it should not be typically recommended; however, SCIT might benefit a subset of patients with EoE and uncontrolled allergic rhinitis on conventional therapies in whom SCIT would otherwise be indicated for allergic rhinoconjunctivitis, particularly in those with sensitizations to pollens containing allergens that cross react with food allergens.
Summary
The purpose of this review is to discuss the current literature examining the role of aeroallergens in triggering EoE with a focus on the potential clinical implications of this finding on managing patients with EoE.
https://ift.tt/2t2aNzd
Synthesis of axially disubstituted silicon phthalocyanines and investigation of photodynamic effects on HCT-116 colorectal cancer cell line
Source:Photodiagnosis and Photodynamic Therapy, Volume 23
Author(s): Ceren Sarı, Figen Celep Eyüpoğlu, İsmail Değirmencioğlu, Rıza Bayrak
Photodynamic therapy is one of the hot topics in cancer studies. Photosensitizing chemical substrates are stimulated by light having a specific wavelength to cause fatal effect on different kinds of targets.In this study, axially 4-{[(1E)-2-furylmethylene]amino}phenol, 4-{[(1E)-2-thienylmethylene]amino}phenol and 4-{[(1E)-(4-nitro-2-thienyl)methylene]amino}phenol disubstituted silicon phthalocyanines were synthesized as Photosensitizers for photodynamic therapy in cancer treatment. The structural characterizations of these novel compounds were performed by a combination of FT-IR, 1H-NMR, UV–vis and mass. All these newly prepared compounds did not show aggregation at the concentration range of 2 × 10−6−12 × 10−6 M in tetrahydrofurane and also did not show aggregation in different organic solvents at 2 × 10−6 M concentration.Phthalocyanines synthesized in this study were tested on HCT-116 colorectal cancer cells and stimulated by light has wavelength of 680 nm. The toxic effects on cancer cells which are caused by different concentrations of photosensitizing molecules have been examined and compared with the toxic effects on cancer cells that were kept in the dark. It is confirmed that these molecules caused toxic effects on colorectal cancer cells when they were stimulated by light but there was no toxic effect in the dark.
https://ift.tt/2t34dIz
Learning How Professionalism Evolves
Source:Academic Radiology
Author(s): Richard B. Gunderman, Mark J. Mutz
https://ift.tt/2t34uLB
Body mass estimates of the earliest possible hominins and implications for the last common ancestor
Source:Journal of Human Evolution
Author(s): Mark Grabowski, Kevin G. Hatala, William L. Jungers
Many hypotheses regarding the paleobiology of the earliest possible hominins, Orrorin tugenensis and Ardipithecus ramidus, are dependent upon accurate body mass estimates for these taxa. While we have previously published body mass predictions for Orrorin and Ardipithecus, the accuracies of those estimates depend on the assumption that the postcranial skeletal dimensions and body masses of these taxa followed scaling patterns that were similar to those observed in modern humans. This assumption may not be correct because certain aspects of postcranial morphology in Orrorin and Ardipithecus differ from modern humans, and suggest that their overall body plans might be unique but more similar to modern non-human great apes than to modern humans. Here we present individual body mass predictions for O. tugenensis and Ar. ramidus assuming that they followed postcranial scaling patterns similar to those of chimpanzees. All estimates include individual prediction intervals as measures of uncertainty. In addition, we provide equations for predicting body mass from univariate postcranial measurements based on the largest sample (n = 25) yet compiled of common chimpanzee skeletons with known body masses, which is vital for calculating prediction intervals for individual fossils. Our results show that estimated body masses in Orrorin and Ardipithecus are generally larger when derived from a chimpanzee-like scaling pattern compared to estimates that assume a human-like pattern, though the prediction intervals of the two sets of estimates overlap. In addition, the more complete of the two known Orrorin femora has an overall scaling pattern that is more similar to common chimpanzees than to modern humans, supporting the application of a non-human great ape comparative model. Our new estimates fall near the male (Ardipithecus) average and in between the male and female averages (Orrorin) for wild-caught common chimpanzees. If a chimpanzee-like pattern of scaling between postcranial dimensions and body mass did exist in these earliest hominins, our results suggest the large body masses found in some early australopiths were already present in taxa near the origins of our lineage, and perhaps also in the Pan-Homo last common ancestor.
https://ift.tt/2lfr9QK
Oncogenic drivers in 11q13 associated with prognosis and response to therapy in advanced oropharyngeal carcinomas
Source:Oral Oncology, Volume 83
Author(s): M.C. Barros-Filho, L.A. Reis-Rosa, M. Hatakeyama, F.A. Marchi, T. Chulam, C. Scapulatempo-Neto, U.R. Nicolau, A.L. Carvalho, C.A.L. Pinto, S.A. Drigo, L.P. Kowalski, S.R. Rogatto
ObjectivesTo identify potential molecular drivers associated with prognosis and response to treatment in advanced oropharyngeal squamous cell carcinomas (OPSCC).Materials and methodsThirty-three OPSCC biopsies from untreated Brazilian patients were evaluated for human papilloma virus genotyping, genome wide copy number alterations and gene expression profiling. Data were integrated using CONEXIC algorithm. Validation with TCGA dataset and confirmation by RT-qPCR of candidate genes were performed.ResultsHigh-risk HPV positive cases, detected in 55% of advanced OPSCC, were associated with better outcome. Losses of 8p11.23-p11.22, 14q11.1-q11.2 and 15q11.2, and gains of 11q13.2 and 11q13.2-q13.3 were detected as recurrent alterations. Gains of 3q26.31 and 11q13.2 and losses of 9p21.3 were exclusively detected in HPV-negative tumors. Two clusters of expression profiles were observed, being one composed mostly by HPV positive cases (83%). HPV-positive enriched cluster showed predominantly immune response-related pathways. Integrative analysis identified 10 modulators mapped in 11q13, which were frequently cancer-related. These 10 genes showed copy number gains, overexpression and an association with worse survival, further validated by TCGA database analyses. Overexpression of four genes (ORAOV1, CPT1A, SHANK2 and PPFIA1) evaluated by RT-qPCR confirmed their association with poor survival. Multivariate analysis showed that PPFIA1 overexpression and HPV status are independent prognostic markers. Moreover, SHANK2 overexpression was significantly associated with incomplete response to treatment.ConclusionThe integrative genomic and transcriptomic data revealed potential driver genes mapped in 11q13 associated with worse prognosis and response to treatment, giving fundamentals for the identification of novel therapeutic targets in OPSCC.
https://ift.tt/2lb4vss
Risk of plate removal in free flap reconstruction of the mandible
Source:Oral Oncology, Volume 83
Author(s): C. Burton Wood, Justin R. Shinn, Shaunak N. Amin, Sarah L. Rohde, Robert J. Sinard
ObjectivesTo evaluate the factors associated with need for removal of fixation plates in mandibular free flap reconstruction.MethodsThis retrospective cohort analysis reviews patients undergoing mandibular free flap reconstruction at a tertiary care center from 2005 to 2016. Patients requiring removal of fixation plates were identified through electronic medical records. Factors including demographics, adjuvant therapy, surgical site infection (SSI) and fistula rates were compared. Removal rates based on flap type were determined.ResultsBetween 2004 and 2016, 307 patients underwent osteocutaneous mandibular free flap reconstruction. 83 required removal of their fixation plates (27%). Age, tobacco use, and BMI were similar between patients requiring removal versus not requiring removal. Primary indications for removal were plate exposure (n = 41), and/or chronic drainage (n = 31), infection (n = 25), and pain (n = 17). Patients undergoing removal were significantly more likely to have had adjuvant radiation therapy (OR 2.09, CI 1.82–3.81), surgical site infection (OR 13.9, CI 5.15–43.2), and post-operative fistula (OR 13.0, 6.85–24.8). 35% of all fibula flaps (n = 52), 21% of osteocutaneous radial forearm (n = 21), and 11% of osteocutaneous scapular flaps (n = 6) required removal. 90% of patients (n = 75) had resolution of their symptoms following hardware removal.ConclusionSurgical site infection and fistula are strongly associated with the need for plate removal. Fibular free flaps carry the highest rate of plate removal. Plate removal leads to resolution of plate-associated symptoms in a majority of cases.
https://ift.tt/2JYHRSj
Urban residential indoor volatile organic compounds in summer, Beijing: Profile, concentration and source characterization
Publication date: September 2018
Source:Atmospheric Environment, Volume 188
Author(s): Lihui Huang, Hui Qian, Shunxi Deng, Jifeng Guo, Yanpeng Li, Weiping Zhao, Yang Yue
Residential indoor exposure to volatile organic compounds (VOCs) is a major public health concern. However, the relevant pollution sources have not been well characterized in China. In this study, the 24-h integrated concentrations of 55 VOC species in 27 urban residences, Beijing were measured in the summer. The sources were characterized with positive matrix factorization (PMF) and general linear model (GLM). The most abundant species in terms of geometric mean concentration were formaldehyde (55.1 μg/m3), acetaldehyde (18.7 μg/m3), acetone (14.8 μg/m3), toluene (14.1 μg/m3), hexanal (13.8 μg/m3), n-hexadecane (8.9 μg/m3) and n-pentadecane (8.5 μg/m3). PMF generated 7 factors associated with VOC sources, including aldehydes from ozone-initiated secondary reactions, butyraldehyde from hydrolysis of building materials and furniture, wood flooring emission, wooden furniture emission, wall coverings emission, mobile emission and halogenated hydrocarbons of miscellaneous outdoor origin. GLM identified leather sofa as another source of indoor terpenes and formaldehyde. GLM also found composite wood flooring had stronger emission of VOCs than solid wood flooring, except 1,4-dichlorobenzene. A comparison with multiple studies across the world suggested that: (1) more intensive ozone-initiated secondary reactions resulted in the significantly higher indoor carbonyl concentrations in Beijing than in Japan and USA in the summer; (2) the indoor concentrations of benzene and C12-C17 alkanes were much higher in Beijing, due to the traffic conditions and prevalent use of wood flooring varnishing.
https://ift.tt/2MyLxZw
Adsorption and diffusion of lithium on heteroatom-doped monolayer molybdenum disulfide
Publication date: 15 October 2018
Source:Applied Surface Science, Volume 455
Author(s): Xiaoli Sun, Zhiguo Wang
In this work, heteroatom doping in monolayer MoS2 by substitution of S with nonmetal elements (N, P, As, F, Cl, and I) and substitution of Mo with metal elements (Fe, Co, Ni, Cu, and Zn) was investigated using density functional theory. The adsorption and diffusion of Li on the heteroatom-doped MoS2 monolayer were also studied. Results showed that heteroatom doping can be realized by controlling the synthesis condition, and can enhance the adsorption of Li on monolayer MoS2, especially for p-type doped monolayers. The diffusion energy barriers were slightly decreased as Li diffused towards the doping site, whereas they were increased for the diffusion around the doping site. The maximum values of the diffusion energy barriers were 0.82, 0.62, and 0.72 eV for Ni, Cu, and Cu dopants, respectively, with others around 0.25 eV. The diffusion was not affected by the doping for sites far from the doping position. Thus, heteroatom-doped monolayer MoS2 can be used as an anode material for lithium ion batteries.
Graphical abstract
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Interfacial microstructures and mechanical properties of Mg/Al bimetal produced by a novel liquid-liquid compound casting process
Publication date: November 2018
Source:Journal of Materials Processing Technology, Volume 261
Author(s): Zailiang Jiang, Zitian Fan, Wenming Jiang, Guangyu Li, Yao Wu, Feng Guan, Haixiao Jiang
In the present work, a novel method was proposed to produce Mg/Al bimetal using the lost foam casting (LFC) liquid-liquid compound process with a Zn interlayer, and the interfacial microstructures and mechanical properties of the Mg/Al bimetal were investigated for the first time. Obtained results reveal that a compact metallurgical interface was formed between the AZ91D magnesium alloy substrate and the A356 aluminum alloy substrate. The metallurgical interface included two reaction layers. The reaction layer adjacent to the AZ91D substrate was composed of α-Mg, Al5Mg11Zn4 and MgZn phases, and the reaction layer adjacent to the A356 substrate consisted of α-Al, Mg32(Al, Zn)49 and Mg2Si phases. The addition of the Zn interlayer not only prevented different liquid metals from directly mixing, but also restrained the formation of Mg-Al intermetallics. The microhardnesses of the reaction layers were much higher than those of the substrates, and the reaction layer close to the A356 substrate had the highest microhardness. The shear strength of the Mg/Al bimetal was about 10.91 MPa, and the fracture surface of the Mg/Al bimetal exhibited a brittle fracture nature.
Graphical abstract
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Effect of alkaline earth metal oxide (MO) Cu/MO/Al2O3 catalysts on methanol synthesis activity and selectivity via CO2 reduction
Publication date: 1 December 2018
Source:Fuel, Volume 233
Author(s): Venkata D.B.C. Dasireddy, Neja Strah Štefančič, Matej Huš, Blaž Likozar
Heterogeneous copper/alumina catalysts with MgO, CaO, SrO, and BaO were prepared by co-precipitation synthesis method and characterized by means of N2-sorption, X-ray powder diffraction (XRD), scanning electron microscopy (SEM), and subsequent H2 temperature-programmed reduction (H2 TPR) and H2/CO2 temperature-programmed desorption (H2 and CO2 TPD). The incorporation of oxides increases the metallic Cu surface area, as follows: Mg > Sr > Zn > Ca > Ba. These metal oxides thus increased the interaction between CuO and Al, resulting weaker reducibility of CuO. MgO increased the number of carbon dioxide and hydrogen adsorption active sites, whereas Ba augmented the basicity of the material. The activity with respect to methanol production matched the increase of Cu surface. As CH3OH selectivity monotonically decreased with the temperature, CO increased proportionally. Among the examined catalytic materials, Cu/MgO/Al2O3 exhibited a higher reactant conversion than the pelletized commercial analogues. Hydrogenation performance of the catalysts thus depended on both, the Cu surface site availability and the interaction between copper–metal oxides. While the industrial Cu/ZnO/Al2O3 has been extensively employed for quite some time, it is demonstrated herein that even upon the application of inexpensive non-critical raw material resources, such as MgO, an increment in bifunctional catalysis performance is attained. The Cu/Mg/Al catalyst showed a turnover frequency of 11.9 × 10−4 s−1, which is higher than the commercial HFR120 and LURGI catalysts.
Graphical abstract
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Classification of organic olives based on chemometric analysis of elemental data
Publication date: November 2018
Source:Microchemical Journal, Volume 142
Author(s): Melisa J. Hidalgo, María T. Pozzi, Octavio J. Furlong, Eduardo J. Marchevsky, Roberto G. Pellerano
The aim of this study was to discriminate organic from conventional olive samples based on the levels of macro and trace elements, combined with chemometric techniques. Ten elements (Na, K, Ca, Fe, Mg, Cu, Zn, Se, S and P) were determined in organic (n = 30) and conventional (n = 30) olive samples by inductively coupled plasma optical emission spectrometry analysis (ICP-OES). The classification of samples was performed by using a well-known chemometric techniques, linear discriminant analysis (LDA), partial least square-discriminant analysis (PLS-DA), support vector machine-discriminant analysis (SVM-DA), k-nearest neighbors (k-NN) and random forest (RF). The k-NN technique showed the best performance in discriminating organic from conventional samples (Accuracy: 94%) using all chemical variables. After variable reduction, an accuracy of 83% was found by using only the elements K and P. The use of a fingerprint based on multielemental levels associated with classification chemometric techniques may be used as a simple method to authenticate organic olive samples.
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Design of a difunctional Zn-Ti LDHs supported PdAu catalyst for selective hydrogenation of phenylacetylene
Publication date: 31 October 2018
Source:Applied Surface Science, Volume 456
Author(s): Yongli Shen, Kangjuan Yin, Cuihua An, Zihui Xiao
To suppress hydrogenation of alkene at complete alkyne conversion, a difunctional Zn-Ti layered double hydroxides (LDHs) supported bimetallic PdAu alloy catalyst with alkalinity was designed and prepared by a photochemical reduction method. On the basic of TEM and XPS results, the formation of Pd-Au alloy was determined. The alloy nanoparticles had incorporated into the interlayer region of LDHs, giving a strong interaction between them. As expected, the PdAu/ZnTi catalysts exhibited excellent styrene selectivity (over 90%) even when the reaction time was prolonged (6 h) after full conversion of phenylacetylene. Such excellent selectivity is attributed to the synergistic effect between bimetallic alloy nanoparticles and Zn-Ti LDHs. The selective formation of polar hydrogen species derived from the heterolytic dissociation of H2 at the interface between PdAu alloy and basic sites of Zn-Ti LDHs is more favorably reactive to alkyne compared with alkene. Moreover, the Zn-Ti LDHs supported PdAu catalyst exhibited great recyclability. The difunctional catalyst is expected to be potentially promising for industrial applications.
Graphical abstract
https://ift.tt/2JSea1Z
Tunable morphologies of ZnO films via the solution precursor plasma spray process for improved photocatalytic degradation performance
Publication date: 15 October 2018
Source:Applied Surface Science, Volume 455
Author(s): Zexin Yu, Hatem Moussa, Meimei Liu, Bilel Chouchene, Raphaël Schneider, Weize Wang, Michel Moliere, Hanlin Liao
The Solution Precursor Plasma Spray (SPPS) process is a novel, versatile and one-step route for building photocatalytic films. Herein, the influence of the precursor solution composition on the microstructure and on the properties of ZnO films prepared via the SPPS process was studied. Nanostructured ZnO particles (i.e. nanorods (NRs) and nanowires (NWs)) were obtained by using a solution of pure Zn(OAc)2 rather than pure Zn(NO3)2. Upon adding urea to the Zn(NO3)2 solution, NRs structured ZnO films were formed as well. The addition of acetic acid into the Zn(OAc)2 solution led to a damage of the nanostructured morphologies likely due to the inhibition of the zinc-containing clusters formation. UV–visible analyses demonstrate that all samples exhibit narrower bandgaps than pure ZnO. The A02 and N03 samples prepared from Zn(OAc)2 and Zn(NO3)2 solutions, respectively, exhibit photodegradation efficiency up to 100% under UV light irradiation. Moreover, A02 and N03 samples were able to bleach 46.2% and 54.6% of the Orange II dye under visible light, respectively. Trapping experiments revealed that hydroxyl radicals (OH), holes (h+) and electrons (e−) play a key role in the photodegradation of Orange II. This study highlights the versatility of the SPPS process and demonstrates that the final nanostructured morphologies of ZnO can easily be controlled by adjusting the precursor solution composition. This result further revealed the potential strategy for optimizing the microstructure and photocatalytic performances of other metal oxide films.
Graphical abstract
https://ift.tt/2MwTzCb
Combustion of energetic iodine-rich coordination polymer – Engineering of new biocidal materials
Publication date: 15 October 2018
Source:Chemical Engineering Journal, Volume 350
Author(s): Ajay Kumar Chinnam, Avital Shlomovich, Olga Shamis, Nathan Petrutik, Dheeraj Kumar, Kangcai Wang, Eswaravara Prasadarao Komarala, Daniel Shem Tov, Muhamed Sućeska, Qi Long Yan, Michael Gozin
Development and molecular engineering of new highly-efficient energetic biocidal materials is a significant challenge and of a great importance. Until now this type of materials included mostly halogen-rich nano-thermites and iodine-rich organic materials. So far, no energetic coordination polymers were reported as precursors for combustion-generated biocidal agents. Here, we demonstrate for the first time the synthesis of uniquely-structured three-dimensional energetic coordination polymer (ECP3) containing Zn metal centers and iodine- and nitrogen-rich bridging ligand (2). Upon its combustion, ECP3 is capable of generating gaseous reactive iodine species and elemental iodine-coated ZnO particles. ECP3 presents a novel approach for the design of efficient biocidal agents.
Graphical abstract
https://ift.tt/2tamlQ4
Formononetin inhibits neuroinflammation and increases estrogen receptor beta (ERβ) protein expression in BV2 microglia
Source:International Immunopharmacology, Volume 61
Author(s): Abdelmeniem El-Bakoush, Olumayokun A. Olajide
Formononetin is a bioactive non-steroidal polyphenol found in a variety of plants. In this study we evaluated the effects of formononetin on neuroinflammation in LPS-stimulated BV2 microglia. Results showed that formononetin significantly reduced the production of TNF-α, IL-6 and IL-1β, nitrite and PGE2, as well as protein levels of iNOS and COX-2. Reporter gene assays showed that formononetin produced inhibition of NF-κB luciferase activity in HEK293 cells stimulated with TNF-α. Immunoblotting experiments revealed an inhibition of IKKα phosphorylation, with the resultant attenuation of phosphorylation and degradation of IκBα following LPS stimulation. Formononetin also produced an inhibition of nuclear translocation and DNA binding by NF-κB following LPS stimulation. RNAi experiments showed that transfection of BV2 microglia with ERβ siRNA resulted in the loss of anti-inflammatory action of formononetin. MTT assay and MAP2 immunoreactivity experiments showed that formononetin produced significant neuroprotective activity by preventing BV2 microglia conditioned media-induced toxicity to HT22 neurons. Investigations on the effect of formononetin on MCF7 breast cancer cells revealed that, while the compound significantly increased ER-luciferase activity, its effects on proliferation were modest. This study has established that formononetin inhibits neuroinflammation by targeting NF-κB signalling pathway in BV2 microglia, possibly through mechanisms involving ERβ. Formononetin appears to modulate ERβ in MCF7 breast cancer cells with limited proliferative effect. Formononetin could therefore serve as a chemical scaffold for the development of novel compounds which have selective neuroprotective actions in the brain.
https://ift.tt/2HUUd8Q
Heat treatment improves the immunomodulatory and cellular antioxidant behavior of a natural flavanone: Eriodictyol
Publication date: August 2018
Source:International Immunopharmacology, Volume 61
Author(s): Rihab Khlifi, Zaineb Dhaouefi, Mouna Maatouk, Aicha Sassi, Najet Boudhiba, Irina Ioannou, Kamel Ghedira, Leila Chekir-Ghedira, Soumaya Kilani-Jaziri
Plants and natural molecules are generally consumed not in raw state but after different processing conditions (heating, mechanical agitation or cooking). The understanding of the chemistry and biological outcome of thermal treatment is still scarce. In the current study, Eriodictyol, a natural flavanone, has undergone heat treatment, generating hence three different products ((3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid, (3-(3,4-dihydroxyphenyl) propanal) and an unidentified component).The consequences of aforementioned treatment on the immunomodulatory behavior of resulted molecules were evaluated. The amount of nitric oxide production and the lysosomal enzyme activity were determined in vitro on mouse peritoneal macrophages. The kinetic of cellular antioxidant activity in splenocytes and macrophages was measured. The present investigation demonstrates that heat-processed eriodictyol significantly enhanced the proliferation of lymphocytes B and T compared to native eriodictyol. Indeed, this compound showed an important improvement on cytotoxic T lymphocyte (CTL) and natural killer (NK) activities. In addition, the production of nitric oxide (NO) and suppression of phagocytic activity of activated macrophages have been increasingly important after thermal processing. Furthermore, it was also revealed that heat-treated Erio in comparison with the native (non heat-treated) molecule has a highest cellular anti-oxidant activity in splenocytes and macrophages cells. These findings highlight the importance of heat-process as feasible and effective strategy to improve the immunomodulatory and the antioxidant efficiency of an known flavanone Eriodictyol.
Graphical abstract
https://ift.tt/2JUalN3
Molecular modeling, synthesis, antibacterial and cytotoxicity evaluation of sulfonamide derivatives of benzimidazole, indazole, benzothiazole and thiazole
Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Farha Naaz, Ritika Srivastava, Anuradha Singh, Nidhi Singh, Rajesh Verma, Vishal K. Singh, Ramendra K. Singh
A new series of heterocyclic molecules bearing sulfonamide linkage has been synthesized and screened for antibacterial activity. During antibacterial screening using broath dilution method, molecules were found to be highly active (MIC value 50–3.1 µg/mL) against different human pathogens, namely B. cerus, S. aureus, E. coli and P. aeruginosa, and most effective against E. coli. A great synergistic effect was observed during determination of FIC where molecules were used in combination with reference drugs chloramphenicol and sulfamethoxazole. The MIC value of the combination – varying concentration of test compounds and ½ MIC of reference drugs or varying concentration of reference drugs and ½ MIC of test compounds, was reduced up to 1/4 or 1/32 of the original value, indicating thereby the combination was 4–32 times more potent than the test molecule. The molecules also showed low degree of cytotoxicity against PBM, CEM and VERO cell lines. The results positively indicated towards the development of lead antibacterials using the combination approach.
Graphical abstract
https://ift.tt/2HTveTn
Exploiting polarity and chirality to probe the Hsp90 C-terminus
Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Leah K. Forsberg, Rachel E. Davis, Virangika K. Wimalasena, Brian S.J. Blagg
Inhibition of the Hsp90 C-terminus is an attractive therapeutic approach for the treatment of cancer. Novobiocin, the first Hsp90 C-terminal inhibitor identified, contains a synthetically complex noviose sugar that has limited the generation of structure-activity relationships for this region of the molecule. The work described herein utilizes various ring systems as noviose surrogates to explore the size and nature of the surrounding binding pocket.
Graphical abstract
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Synthesis and characterization of radioiodinated 3-phenethyl-2-indolinone derivatives for SPECT imaging of survivin in tumors
Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Natsumi Ishikawa, Takeshi Fuchigami, Tatsuya Mizoguchi, Sakura Yoshida, Mamoru Haratake, Morio Nakayama
Survivin, overexpressed in most cancers, is associated with poor prognosis and resistance to radiation therapy and chemotherapy. Herein, we report the synthesis of three 3-phenethyl-2-indolinone derivatives and their application as in vivo imaging agents for survivin. Of these, 3-(2-(benzo[d][1,3]dioxol-5-yl)-2-oxoethyl)-3-hydroxy-5- iodoindolin-2-one (IPI-1) showed the highest binding affinity (Kd = 68.3 nM) to recombinant human survivin, as determined by quartz crystal microbalance (QCM). In vitro studies demonstrated that the [125I]IPI-1 binding in survivin-positive MDA-MB-231 cells was significantly higher than that in survivin-negative MCF-10A cells. In addition, uptake of [125I]IPI-1 by MDA-MB-231 cells decreased in a dose-dependent manner in the presence of the high-affinity survivin ligand S12; this is indicative of specific binding of [125I]IPI-1 to cellular survivin protein in vitro. Biodistribution studies in MDA-MB-231 tumor-bearing mice demonstrated the moderate uptake of [125I]IPI-1 in the tumor tissue (1.37% ID/g) at 30 min that decreased to 0.32% ID/g at 180 min. Co-injection of S12 (2.5 mg/kg) slightly reduced tumor uptake and the tumor/muscle ratio of [125I]IPI-1. Although further structural modifications are necessary to improve pharmacokinetic properties, our results indicate that PI derivatives may be useful as tumor-imaging probes targeting survivin.
Graphical abstract
https://ift.tt/2HTvcLf
Design, synthesis and evaluation of vilazodone-tacrine hybrids as multitarget-directed ligands against depression with cognitive impairment
Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Wenwen Liu, Huan Wang, Xiaokang Li, Yixiang Xu, Jian Zhang, Wei Wang, Qi Gong, Xiaoxia Qiu, Jin Zhu, Fei Mao, Haiyan Zhang, Jian Li
Depression, a severe mental disease, is greatly difficult to treat and easy to induce other neuropsychiatric symptoms, the most frequent one is cognitive impairment. In this study, a series of novel vilazodone-tacrine hybrids were designed, synthesized and evaluated as multitarget agents against depression with cognitive impairment. Most compounds exhibited good multitarget activities and appropriate blood-brain barrier permeability. Specifically, compounds 1d and 2a exhibited excellent 5-HT1A agonist activities (1d, EC50 = 0.36 ± 0.08 nM; 2a, EC50 = 0.58 ± 0.14 nM) and 5-HT reuptake inhibitory activities (1d, IC50 = 20.42 ± 6.60 nM; 2a, IC50 = 22.10 ± 5.80 nM). In addition, they showed moderate ChE inhibitory activities (1d, AChE IC50 = 1.72 ± 0.217 μM, BuChE IC50 = 0.34 ± 0.03 μM; 2a, AChE IC50 = 2.36 ± 0.34 μM, BuChE IC50 = 0.10 ± 0.01 μM). Good multitarget activities with goodt blood-brain barrier permeability of 1d and 2a make them good lead compounds for the further study of depression with cognitive impairment.
Graphical abstract
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Editorial Board
Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
https://ift.tt/2HTvced
Osteoblastic differentiation on hydrogels fabricated from Ca2+-responsive self-assembling peptides functionalized with bioactive peptides
Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Hiroshi Tsutsumi, Megumi Kawamura, Hisakazu Mihara
We recently developed an amphiphilic peptide, E1Y9 (Ac-E-YEYKYEYKY-NH2), that self-assembles into nanofibers and forms a hydrogel in the presence of Ca2+ ion. Four E1Y9-derivatives (E1Y9-ALK, E1Y9-DGR, E1Y9-PRG and E1Y9-RGD) were designed as conjugates of E1Y9 with bioactive peptide sequences named as ALK (ALKRQGRTLYGF), DGR (DGRDSVAYG), PRG (PRGDSGYRGDS) and RGD (RGDS), respectively, and stimulated osteoblast cells growth as well as differentiation. In this study, E1Y9/E1Y9-derivative mixed hydrogels were constructed to serve as scaffolds for osteoblastic differentiation of MC3T3-E1 cells. E1Y9 and E1Y9-derivatives co-assembled into networked nanofibers and formed hydrogels in response to Ca2+ ion. The pre-osteoblast cell line MC3T3-E1 was cultured and differentiated on mixed hydrogels. An E1Y9/E1Y9-ALK mixed hydrogel exhibited the highest cell proliferation and differentiation activity among the peptide hydrogels. The peptide sequence ALK promoted expression of RUNX2 and osteopontin, a key transcription factor and bone tissue matrix protein, respectively, during the differentiation stage. During the later stage, localization of RUNX2 and osteopontin was regulated in the cytosol and extracellularly, respectively, indicating that the E1Y9/E1Y9-ALK mixed hydrogel controlled the differentiation of MC3T3-E1 cells. Thus, the E1Y9/E1Y9-ALK mixed hydrogel developed in this study showed potential for the culture and regulation of differentiation of osteoblast cells for bone regeneration.
Graphical abstract
https://ift.tt/2JWhxbf
Straightforward hit identification approach in fragment-based discovery of bromodomain-containing protein 4 (BRD4) inhibitors
Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Petro Borysko, Yurii S. Moroz, Oleksandr V. Vasylchenko, Vasyl V. Hurmach, Anastasia Starodubtseva, Natalia Stefanishena, Kateryna Nesteruk, Sergey Zozulya, Ivan S. Kondratov, Oleksandr O. Grygorenko
A combination approach of a fragment screening and "SAR by catalog" was used for the discovery of bromodomain-containing protein 4 (BRD4) inhibitors. Initial screening of 3695-fragment library against bromodomain 1 of BRD4 using thermal shift assay (TSA), followed by initial hit validation, resulted in 73 fragment hits, which were used to construct a follow-up library selected from available screening collection. Additionally, analogs of inactive fragments, as well as a set of randomly selected compounds were also prepared (3 × 3200 compounds in total). Screening of the resulting sets using TSA, followed by re-testing at several concentrations, counter-screen, and TR-FRET assay resulted in 18 confirmed hits. Compounds derived from the initial fragment set showed better hit rate as compared to the other two sets. Finally, building dose-response curves revealed three compounds with IC50 = 1.9–7.4 μM. For these compounds, binding sites and conformations in the BRD4 (4UYD) have been determined by docking.
Graphical abstract
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Structure-activity relationship investigation of Phe-Arg mimetic region of human glutaminyl cyclase inhibitors
Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Van T.H. Ngo, Van-Hai Hoang, Phuong-Thao Tran, Nguyen Van Manh, Jihyae Ann, Eunhye Kim, Minghua Cui, Sun Choi, Jiyoun Lee, Hee Kim, Hee-Jin Ha, Kwanghyun Choi, Young-Ho Kim, Jeewoo Lee
Glutamyl cyclase (QC) is a promising therapeutic target because of its involvement in the pathogenesis of Alzheimer's disease. In this study, we developed novel QC inhibitors that contain 3-aminoalkyloxy-4-methoxyphenyl and 4-aminoalkyloxyphenyl groups to replace the previously developed pharmacophore. Several potent inhibitors were identified, showing IC50 values in a low nanomolar range, and were further studied for in vitro toxicity and in vivo activity. Among these, inhibitors 51 and 53 displayed the most potent AβN3pE−40-lowering effects in in vivo acute model with reasonable BBB penetration, without showing cytotoxicity and hERG inhibition. The molecular modeling analysis of 53 indicated that the salt bridge interaction and the hydrogen bonding in the active site provided a high potency. Given the potent activity and favorable BBB penetration with low cytotoxicity, we believe that compound 53 may serve as a potential candidate for anti-Alzheimer's agents.
Graphical abstract
https://ift.tt/2JQprTR
Novel leucine ureido derivatives as aminopeptidase N inhibitors using click chemistry
Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Jiangying Cao, Chunhua Ma, Jie Zang, Shuai Gao, Qianwen Gao, Xiujie Kong, Yugang Yan, Xuewu Liang, Qin'ge Ding, Chunlong Zhao, Binghe Wang, Wenfang Xu, Yingjie Zhang
The over-expression of aminopeptidase N on diverse malignant cells is associated with the tumor angiogenesis and metastasis. In this report, one new series of leucine ureido derivatives containing the triazole moiety was designed, synthesized and evaluated as APN inhibitors. Among them, compound 13v showed the best APN inhibition with an IC50 value of 0.089 ± 0.007 μM, which was two orders of magnitude lower than that of bestatin (IC50 = 9.4 ± 0.5 μM). Compound 13v also showed dose-dependent anti-angiogenesis activities. Even at the lower concentration (10 μM), compound 13v presented similar anti-angiogenesis activity compared with bestatin at 100 μM in both the human umbilical vein endothelial cells (HUVECs) capillary tube formation assay and the rat thoracic aorta rings test. Moreover, compared with bestatin, 13v exhibited comparable, if not better in vivo anti-metastasis activity in a mouse H22 pulmonary metastasis model.
Graphical abstract
https://ift.tt/2HURpsf
Novel amidrazone derivatives: Design, synthesis and activity evaluation
Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Hua Zhou, Zhi Sen Wang, Xin Hua Liu, Fei Hu Chen
A series of new 6-styryl-naphthalene-2-amidrazone derivatives were synthesized and evaluated as potential ASIC1a inhibitors. Among them, compound 5e showed the most activity to inhibit [Ca2+]i. elevation in acid-induced articular chondrocytes. Together with the important role of ASIC1a in the pathogenesis of tissue acidification diseases including rheumatoid arthritis, these results might provide a meaningful hint or inspiration in developing drugs targeting at tissue acidification diseases.
Graphical abstract
https://ift.tt/2JQptuX
Synthesis, antimycobacterial activity and influence on mycobacterial InhA and PknB of 12-membered cyclodepsipeptides
Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Katja Laqua, Marcel Klemm, Melissa Richard-Greenblatt, Adrian Richter, Linda Liebe, Tingting Huang, Shuangjun Lin, Ana Guardia, Esther Pérez-Herran, Lluís Ballell, Yossef Av-Gay, Peter Imming
In recent years, several small natural cyclopeptides and cyclodepsipeptides were reported to have antimycobacterial activity. Following this lead, a synthetic pathway was developed for a small series of 12-membered ring compounds with one amide and two ester bonds (cyclotridepsipeptides). Within the series, the ring system proved to be necessary for growth inhibition of Mycobacterium smegmatis and Mycobacterium tuberculosis in the low micromolar range. Open-chain precursors and analogues were inactive. The compounds modulated autophosphorylation of the mycobacterial protein kinase B (PknB). PknB inhibitors were active at µM concentration against mycobacteria while inducers were inactive. PknB regulates the activity of the mycobacterial reductase InhA, the target of isoniazid. The activity of the series against Mycobacterium bovis BCG InhA overexpressing strains was indistinguishable from that of the parental strain suggesting that they do not inhibit InhA. All substances were not cytotoxic (HeLa > 5 µg/ml) and did not show any significant antiproliferative effect (HUVEC > 5 µg/ml; K-562 > 5 µg/ml). Within the scope of this study, the molecular target of this new type of small cyclodepsipeptide was not identified, but the data suggest interaction with PknB or other kinases may partly cause the activity.
Graphical abstract
https://ift.tt/2HTvbHb
Novel 8-hydroxyquinoline derivatives targeting β-amyloid aggregation, metal chelation and oxidative stress against Alzheimer’s disease
Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Xuelian Yang, Pei Cai, Qiaohong Liu, Jiajia Wu, Yong Yin, Xiaobing Wang, Lingyi Kong
A series of multitargeted 8-hydroxyquinoline derivatives were designed and synthesized for the treatment of Alzheimer's disease (AD). In vitro studies indicated that most of the prepared compounds exhibited significant inhibitory effects against self-induced Aβ1−42 aggregation and potential antioxidant properties especially compound 5b (IC50 = 5.64 μM for self-induced Aβ aggregation; the oxygen radical absorbance capacity using fluorescein (ORAC-FL) value is 2.63 Trolox equivalents). Notably, 5b can chelate biometals and inhibit Cu2+/Zn2+-induced Aβ1−42 aggregation. The cell assays showed that 5b had excellent protective effects against oxidative toxin H2O2 and presented low neurotoxicity in PC12 cells. Furthermore, 5b could penetrate the blood–brain barrier (BBB) in vitro and did not show any acute toxicity in mice at doses up to 2000 mg/kg in vivo. Our findings provide a rationale for the potential application of compound 5b as a lead compound in AD therapy.
Graphical abstract
https://ift.tt/2JWhyMl
Structure-activity relationship of clovamide and its related compounds for the inhibition of amyloid β aggregation
Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Tatsuhiko Tsunoda, Mio Takase, Hideyuki Shigemori
Alzheimer's disease (AD), a neurodegenerative disorder, is characterized by aggregation of amyloid β-protein (Aβ). Aβ aggregates through β-sheet formation and induces cytotoxicity against neuronal cells. Inhibition of Aβ aggregation by naturally occurring compounds is thus a promising strategy for the treatment of AD. We have already reported that caffeoylquinic acids and phenylethanoid glycosides, which possess two or more catechol moieties, strongly inhibited Aβ aggregation. Clovamide (1) containing two catechol moieties, isolated from cacao beans (Theobroma cacao L.), is believed to exhibit preventive effects on Aβ aggregation. To investigate the structure-activity relationship of clovamide (1) for the inhibition of Aβ aggregation, we synthesized 1 and related compounds 2–11 through reaction between l-DOPA, d-DOPA, l-tyrosine, or l-phenylalanine and caffeic acid, p-coumaric acid, or cinnamic acid, and compounds 12 and 13 were derived from 1. Among tested compounds 1–13, those containing one or two catechol moieties exhibited potent anti-aggregation activity, whereas the non-catechol-type related compounds showed little or no activity. This suggests that at least one catechol moiety is essential for inhibition of Aβ42 aggregation, and this activity increases depending on the number of catechol moieties. Consequently, clovamide (1) and its related compounds may be a promising therapeutic option for inhibiting Aβ-mediated pathology in AD.
Graphical abstract
https://ift.tt/2HTIQya
Lipophilic methylene blue analogues enhance mitochondrial function and increase frataxin levels in a cellular model of Friedreich’s ataxia
Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Omar M. Khdour, Indrajit Bandyopadhyay, Sandipan Roy Chowdhury, Nishant P. Visavadiya, Sidney M. Hecht
Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder resulting from reduced expression of the protein frataxin (FXN). Although its function is not fully understood, frataxin appears to help assemble iron sulfur clusters; these are critical for the function of many proteins, including those needed for mitochondrial energy production. Finding ways to increase FXN levels has been a major therapeutic strategy for this disease. Previously, we described a novel series of methylene violet analogues and their structural optimization as potential therapeutic agents for neurodegenerative and mitochondrial disorders. Presently, a series of methylene blue analogues has been synthesized and characterized for their in vitro biochemical and biological properties in cultured Friedreich's ataxia lymphocytes. Favorable methylene blue analogues were shown to increase frataxin levels and mitochondrial biogenesis, and to improve aconitase activity. The analogues were found to be good ROS scavengers, and able to protect cultured FRDA lymphocytes from oxidative stress resulting from inhibition of complex I and from glutathione depletion. The analogues also preserved mitochondrial membrane potential and augmented ATP production. Our results suggest that analogue 5, emerging from the initial structure of the parent compound methylene blue (MB), represents a promising lead structure and lacks the cytotoxicity associated with the parent compound MB.
Graphical abstract
https://ift.tt/2JVrHsR
Applications of a novel biodetection system to saliva using protein fingerprints with data processing
Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Yuki Tominaga, Kenji Usui, Akiyoshi Hirata, Hiro-O Ito, Kiyoshi Nokihara
A fundamental method has been developed focusing on a facile and rapid examination of periodontal disease. Periodontal disease is an oral disease thought to affect 80% of adults, and early detection with treatment is desirable for the improvement of the quality of life. Unfortunately conventional methods are not consistent as the disease is caused by a number of undefined bacteria and detection relies on the skills of the dentist. Thus an objective detection system is required. We have performed an experiment on saliva using a novel biodetection system, designated PepTenChip®. A disease model for saliva was prepared using a specimen from a healthy subject and a mixture of hemoglobin (f-Hb) and lactate dehydrogenase (LDH), which is used as a periodontal disease marker protein with healthy saliva. PepTenChip® is a peptide microarray in which fluorescent labelled structured peptides are immobilized on a novel amorphous carbon substrate. Since the peptides used as capture molecules are fluorescently labelled, labeling of analytes is not necessary. The fluorescence intensity change before and after application of analytes are detected rather than the ON/OFF detection common to conventional microarrays using a set of antigen–antibody. The fluorescence intensity value changes according to the concentration of captured protein allowing the generation of protein fingerprint (PFP) and dendrograms. The present method does not rely on a "one to one" interaction, unlike conventional biodetection, and advantages can be envisaged in the case of an undefined or unknown cause of disease. The statistical analyses, such as multivariate analyses, allow classification of the type of proteins added in saliva as mimetics of disease. PepTenChip® system is useful and convenient for examination of periodontal disease in health care.
Graphical abstract
https://ift.tt/2HT2R7Y
Synthesis and biological evaluation of 2,4-disubstituted phthalazinones as Aurora kinase inhibitors
Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Wei Wang, Xiu Feng, Huan-Xiang Liu, Shi-Wu Chen, Ling Hui
A series of 2,4-disubstituted phthalazinones were synthesized and their biological activities, including antiproliferation, inhibition against Aurora kinases and cell cycle effects were evaluated. Among them, N-cyclohexyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-1-oxophthalazin-2(1H)-yl) methyl) benzamide (12c) exhibited the most potent antiproliferation against five carcinoma cell lines (HeLa, A549, HepG2, LoVo and HCT116 cells) with IC50 values in range of 2.2–4.6 μM, while the IC50 value of reference compound VX-680 was 8.5–15.3 μM. Moreover, Aurora kinase assays exhibited that compound 12c was potent inhibitor of AurA and AurB kinase with the IC50 values were 118 ± 8.1 and 80 ± 4.2 nM, respectively. Molecular docking studies indicated that compound 12c forms better interaction with both AurA and AurB. Furthermore, compound 12c induced G2/M cell cycle arrest in HeLa cells by regulating protein levels of cyclinB1 and cdc2. These results suggested that 12c is a promising pan-Aurora kinase inhibitor for the potential treatment of cancer.
Graphical abstract
https://ift.tt/2JYZnpm
An SAR study of hydroxy-trifluoromethylpyrazolines as inhibitors of Orai1-mediated store operated Ca2+ entry in MDA-MB-231 breast cancer cells using a convenient Fluorescence Imaging Plate Reader assay
Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Ralph J. Stevenson, Iman Azimi, Jack U. Flanagan, Marco Inserra, Irina Vetter, Gregory R. Monteith, William A. Denny
The proteins Orai1 and STIM1 control store-operated Ca2+ entry (SOCE) into cells. SOCE is important for migration, invasion and metastasis of MDA-MB-231 human triple negative breast cancer (TNBC) cells and has been proposed as a target for cancer drug discovery. Two hit compounds from a medium throughput screen, displayed encouraging inhibition of SOCE in MDA-MB-231 cells, as measured by a Fluorescence Imaging Plate Reader (FLIPR) Ca2+ assay. Following NMR spectroscopic analysis of these hits and reassignment of their structures as 5-hydroxy-5-trifluoromethylpyrazolines, a series of analogues was prepared via thermal condensation reactions between substituted acylhydrazones and trifluoromethyl 1,3-dicarbonyl arenes. Structure-activity relationship (SAR) studies showed that small lipophilic substituents at the 2- and 3-positions of the RHS and 2-, 3- and 4-postions of the LHS terminal benzene rings improved activity, resulting in a novel class of potent and selective inhibitors of SOCE.
Graphical abstract
https://ift.tt/2HUH3sy
Discovery of tetrahydroindazoles as a novel class of potent and in vivo efficacious gamma secretase modulators
Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Kai Gerlach, Scott Hobson, Christian Eickmeier, Ulrike Groß, Clemens Braun, Peter Sieger, Michel Garneau, Stefan Hoerer, Niklas Heine
The identification and optimization of a novel series of centrally efficacious gamma secretase modulators (GSMs) offering an alternative to the privileged aryl imidazole motif is described. Chiral bicyclic tetrahydroindazolyl amine substituted triazolopyridines were identified as structurally distinct novel series of GSMs. Representative compound BI-1408 ((R)-42) was demonstrated to be centrally efficacious in rats at a 30 mg/kg oral dose.
Graphical abstract
https://ift.tt/2JW2heI
Design, synthesis and biological evaluation of phosphopeptides as Polo-like kinase 1 Polo-box domain inhibitors
Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Tong-yuan Lin, Hong-ping Min, Cheng Jiang, Miao-miao Niu, Fang Yan, Li-li Xu, Bin Di
Polo-like kinase 1 (Plk1) is an anti-cancer target due to its critical role in mitotic progression. A growing body of evidence has documented that Peptide-Plk1 inhibitors showed high Plk1 binding affinity. However, phosphopeptides-Plk1 inhibitors showed poor cell membranes permeability, which limits their clinical applications. In current study, nine candidate phosphopeptides consisting of non-natural amino acids were rationally designed and then successfully synthesized using an Fmoc-solid phase peptide synthesis (SPPS) strategy. Moreover, the binding affinities and selectivity were evaluated via fluorescence polarization (FP) assay. The results confirmed that the most promising phosphopeptide 6 bound to Plk1 PBD with the IC50 of 38.99 nM, which was approximately 600-fold selectivity over Plk3 PBD (IC50 = 25.44 μM) and nearly no binding to Plk2 PBD. Furthermore the intracellular activities and the cell membrane permeability of phosphopeptide 6 were evalutated. Phosphopeptide 6 demonstrated appropriate cell membrane permeability and arrested HeLa cells cycle in G2/M phase by regulating CyclinB1-CDK1. Further, phosphopeptide 6 showed typical apoptotic morphology and induced caspase-dependent apoptosis. In conclusion, we expect our discovery can provide new insights into the further optimization of Plk1 PBD inhibitors.
Graphical abstract
https://ift.tt/2HRUXeR
Design, synthesis and evaluation of benzoheterocycle analogues as potent antifungal agents targeting CYP51
Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Shizhen Zhao, Peng Wei, Mengya Wu, Xiangqian Zhang, Liyu Zhao, Xiaolin Jiang, Chenzhou Hao, Xin Su, Dongmei Zhao, Maosheng Cheng
To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compound 1, a series of benzoheterocycle analogues were designed, synthesized and evaluated for their in vitro antifungal activity. The most promising compounds 13s and 14a exhibited excellent antifungal activity against C. albicans, C. neoformans, A. fumigatus and fluconazole-resistant C. albicans strains, that was superior or comparable to those of the reference drugs fluconazole and voriconazole. GC–MS analyses suggested that the novel compound 13s might have a similar mechanism to fluconazole by inhibiting fungal lanosterol 14α-demethylase (CYP51). Furthermore, compounds 13s and 14a exhibited low inhibition profiles for various human cytochrome P450 isoforms as well as excellent blood plasma stability.
Graphical abstract
https://ift.tt/2JXYPQw
Sustained Activation of Postsynaptic 5-HT2A Receptors Gates Plasticity at Prefrontal Cortex Synapses
Abstract
The prefrontal cortex (PFC) plays a key role in many high-level cognitive processes. It is densely innervated by serotonergic neurons originating from the dorsal and median raphe nuclei, which profoundly influence PFC activity. Among the 5-HT receptors abundantly expressed in PFC, 5-HT2A receptors located in dendrites of layer V pyramidal neurons control neuronal excitability and mediate the psychotropic effects of psychedelic hallucinogens, but their impact on glutamatergic transmission and synaptic plasticity remains poorly characterized. Here, we show that a 20-min exposure of mouse PFC slices to serotonin or the 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) produces a long-lasting depression of evoked AMPA excitatory postsynaptic currents in layer V pyramidal neurons. DOI-elicited long-term depression (LTD) of synaptic transmission is absent in slices from 5-HT2A receptor-deficient mice, is rescued by viral expression of 5-HT2A receptor in pyramidal neurons and occludes electrically induced long-term depression. Furthermore, 5-HT2A receptor activation promotes phosphorylation of GluA2 AMPA receptor subunit at Ser880 and AMPA receptor internalization, indicating common mechanisms with electrically induced LTD. These findings provide one of the first examples of LTD gating under the control of a G protein-coupled receptor that might lead to imbalanced synaptic plasticity and memory impairment following a nonphysiological elevation of extracellular serotonin.https://ift.tt/2tdTSbV
Altered Cortical and Hippocampal Excitability in TgF344-AD Rats Modeling Alzheimer’s Disease Pathology
Abstract
Current findings suggest that accumulation of amyloid-β (Aβ) and hyperphosphorylated tau in the brain disrupt synaptic function in hippocampal–cortical neuronal networks leading to impairment in cognitive and affective functions in Alzheimer's disease (AD). Development of new disease-modifying AD drugs are challenging due to the lack of predictive animal models and efficacy assays. In the present study we recorded neural activity in TgF344-AD rats, a transgenic model with a full array of AD pathological features, including age-dependent Aβ accumulation, tauopathy, neuronal loss, and cognitive impairments. Under urethane anesthesia, TgF344-AD rats showed significant age-dependent decline in brainstem-elicited hippocampal theta oscillation and decreased theta-phase gamma-amplitude coupling comparing to their age-matched wild-type counterparts. In freely-behaving condition, the power of hippocampal theta oscillation and gamma power during sharp-wave ripples were significantly lower in TgF344-AD rats. Additionally, these rats showed impaired coherence in both intercortical and hippocampal–cortical network dynamics, and increased incidence of paroxysmal high-voltage spindles, which occur during awake, behaviorally quiescent state. TgF344-AD rats demonstrated impairments in sensory processing, having diminished auditory gating and 40-Hz auditory evoked steady-state response. The observed differences in neurophysiological activities in TgF344-AD rats, which mirror several abnormalities described in AD patients, may be used as promising markers to monitor disease-modifying therapies.https://ift.tt/2leWhjf
Versatile graphene biosensors for enhancing human cell therapy
Publication date: 15 October 2018
Source:Biosensors and Bioelectronics, Volume 117
Author(s): George M. Vlăsceanu, Roxana-Maria Amărandi, Mariana Ioniță, Teddy Tite, Horia Iovu, Luisa Pilan, Jorge S. Burns
Technological advances in engineering and cell biology stimulate novel approaches for medical treatment, in particular cell-based therapy. The first cell-based gene therapy against cancer was recently approved by the US Food and Drug Administration. Progress in cancer diagnosis includes a blood test detecting five cancer types. Numerous stem cell phase I/II clinical trials showing safety and efficacy will soon pursue qualifying criteria for advanced therapy medicinal products (ATMP), aspiring to join the first stem-cell therapy approved by the European Medicines Agency. Cell based therapy requires extensive preclinical characterisation of biomarkers indicating mechanisms of action crucial to the desired therapeutic effect. Quantitative analyses monitoring critical functions for the manufacture of optimal cell and tissue-based clinical products include successful potency assays for implementation. The challenge to achieve high quality measurement is increasingly met by progress in biosensor design. We adopt a cell therapy perspective to highlight recent examples of graphene-enhanced biointerfaces for measurement of biomarkers relevant to cancer treatment, diagnosis and tissue regeneration. Graphene based biosensor design problems can thwart their use for health care transformative point of care testing and real-time applications. We discuss concerns to be addressed and emerging solutions for establishing clinical grade biosensors to accelerate human cell therapy.
https://ift.tt/2yiRPJA
Photodynamic therapy of balloon-injured rat carotid arteries using indocyanine green
Abstract
Photodynamic therapy (PDT) has been used to inhibit intimal hyperplasia in injured arteries. Because of the limited tissue penetration of visible light, an endovascular light source with a guided wire is often required for effective treatment. Indocyanine green (ICG), a near-infrared (NIR) photosensitizer, has been used in PDT for cancers. An extracorporeal light source may be used for shallow tissue because of the better tissue penetration of NIR light. The aim of this study was to evaluate the effect of ICG-PDT using extracorporeal NIR light on the inhibition of intimal hyperplasia in balloon-injured carotid arteries. A balloon injury (BI) model was used to induce intimal hyperplasia of carotid artery. Sprague–Dawley rats were divided into control, BI, BI + 1 × PDT, and BI + 2 × PDT groups. The control group underwent a sham procedure. PDT was performed 7 days after BI. In the BI + 1 × PDT group, ICG was administered 1 h before light irradiation. External illumination with 780-nm light-emitting diode light at a fluence of 4 J/cm2 was applied. For the BI + 2 × PDT group, PDT was performed again at day 7, following the first PDT. Hematoxylin and eosin (H & E) staining was performed to assess vessel morphology. Arterial wall thickness was significantly larger in the BI group compared with the control group. ICG-PDT significantly reduced arterial wall thickness compared with the BI group. Repeated PDT further decreased arterial wall thickness to the level of the control group. These findings indicate a promising approach for the treatment of restenosis of carotid arteries.
https://ift.tt/2Myxpz8
Correction to: Electroretinogram evaluation for the treatment of proliferative diabetic retinopathy by short-pulse pattern scanning laser panretinal photocoagulation
The published online version contains incorrect data in Table 2 caption. Argon should not be mentioned in the caption as this is not used in this paper.
https://ift.tt/2JQskAD
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