Putative biomarkers for cervical cancer: SNVs, methylation and expression profiles

Publication date: Available online 30 June 2017
Source:Mutation Research/Reviews in Mutation Research
Author(s): Maria de Fátima Senra Cardoso, Carlos Henrique Madeiros Castelletti, José Luiz de Lima-Filho, Danyelly Bruneska Gondim Martins, José António Couto Teixeira
Cervical cancer is primarily caused by Human papillomavirus (HPV) infection, but other factors such as smoking habits, co-infections and genetic background, can also contribute to its development. Although this cancer is avoidable, it is the fourth most frequent type of cancer in females worldwide and can only be treated with chemotherapy and radical surgery. There is a need for biomarkers that will enable early diagnosis and targeted therapy for this type of cancer. Therefore, a systems biology pipeline was applied in order to identify potential biomarkers for cervical cancer, which show significant reports in three molecular aspects: DNA sequence variants, DNA methylation pattern and alterations in mRNA/protein expression levels. CDH1, CDKN2A, RB1 and TP53 genes were selected as putative biomarkers, being involved in metastasis, cell cycle regulation and tumour suppression. The other ten genes (CDH13, FHIT, PTEN, MLH1, TP73, CDKN1A, CACNA2D2, TERT, WIF1, APC) seemed to play a role in cervical cancer, but the lack of studies prevented their inclusion as possible biomarkers. Our results highlight the importance of these genes. However, further studies should be performed to elucidate the impact of DNA sequence variants and/or epigenetic deregulation and altered expression of these genes in cervical carcinogenesis and their potential as biomarkers for cervical cancer diagnosis and prognosis.



http://ift.tt/2taMBcv

Perioperative Retinal Artery Occlusion: Incidence and Risk Factors in Spinal Fusion Surgery From the US National Inpatient Sample 1998-2013.

Background: Retinal artery occlusion (RAO) is a rare but devastating complication of spinal fusion surgery. We aimed to determine its incidence and associated risk factors. Methods: Hospitalizations involving spinal fusion surgery were identified by searching the National Inpatient Sample, a database of hospital discharges, from 1998 to 2013. RAO cases were identified using ICD-9-CM codes. Using the STROBE guidelines, postulated risk factors were chosen based on literature review and identified using ICD-9-CM codes. Multivariate logistic models with RAO as outcome, and risk factors, race, age, admission, and surgery type evaluated associations. Results: Of an estimated 4,784,275 spine fusions in the United States from 1998 to 2013, there were 363 (CI: 291-460) instances of RAO (0.76/10,000 spine fusions, CI: 0.61-0.96). Incidence ranged from 0.35/10,000 (CI: 0.11-1.73) in 2001-2002 to 1.29 (CI: 0.85-2.08) in 2012-2013, with no significant trend over time (P = 0.39). Most strongly associated with RAO were stroke, unidentified type (odds ratio, OR: 14.33, CI: 4.54-45.28, P

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Intracranial Aneurysms of Neuro-Ophthalmologic Relevance.

Background: Intracranial saccular aneurysms are acquired lesions that often present with neuro-ophthalmologic symptoms and signs. Recent advances in neurosurgical techniques, endovascular treatments, and neurocritical care have improved the optimal management of symptomatic unruptured aneurysms, but whether the chosen treatment has an impact on neuro-ophthalmologic outcomes remains debated. Evidence Acquisition: A review of the literature focused on neuro-ophthalmic manifestations and treatment of intracranial aneurysms with specific relevance to neuro-ophthalmologic outcomes was conducted using Ovid MEDLINE and EMBASE databases. Cavernous sinus aneurysms were not included in this review. Results: Surgical clipping vs endovascular coiling for aneurysms causing third nerve palsies was compared in 13 retrospective studies representing 447 patients. Complete recovery was achieved in 78% of surgical patients compared with 44% of patients treated with endovascular coiling. However, the complication rate, hospital costs, and days spent in intensive care were reported as higher in surgically treated patients. Retrospective reviews of surgical clipping and endovascular coiling for all ocular motor nerve palsies (third, fourth, or sixth cranial nerves) revealed similar results of complete resolution in 76% and 49%, respectively. Improvement in visual deficits related to aneurysmal compression of the anterior visual pathways was also better among patients treated with clipping than with coiling. The time to treatment from onset of visual symptoms was a predictive factor of visual recovery in several studies. Few reports have specifically assessed the improvement of visual deficits after treatment with flow diverters. Conclusions: Decisions regarding the choice of therapy for intracranial aneurysms causing neuro-ophthalmologic signs ideally should be made at high-volume centers with access to both surgical and endovascular treatments. The status of the patient, location of the aneurysm, and experience of the treating physicians are important factors to consider. Although a higher rate of visual recovery was reported with neurosurgical clipping, this must be weighed against the potentially longer intensive care stays and increased early morbidity. (C) 2017 by North American Neuro-Ophthalmology Society

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History of Neuro-Ophthalmology in Argentina.

No abstract available

http://ift.tt/2u87bdC

Linear dimensions of normal upper airway structure by magnetic resonance imaging in Chinese Han infants and preschool children

To establish normative data of upper airway structure in Chinese Han infants and preschool children.

http://ift.tt/2tAgx4S

Restless Legs Syndrome after High Risk TIA and Minor Stroke: Association with Reduced Quality of Life

Restless Legs Syndrome (RLS) is a movement disorder associated with poor quality of life and depressive symptoms in the general population. Emerging evidence suggests that RLS is closely linked with cerebrovascular disease. We assessed the impact of RLS on quality of life after stroke and transient ischemic attack (TIA).

http://ift.tt/2u918FM

Letter to Editors: Detection of endolymphatic hydrops using traditional MR imaging sequences

We would like to comment on the manuscript entitled "Detection of endolymphatic hydrops using traditional MR imaging sequences." by Keller et al. [1]. It is of great clinical value if non-contrast MR imaging can be used to differentiate the endo- and perilymph space as the authors have stated. We read this article with great interest and thank the authors for citing our six papers. However, there are some critical points that need to be clarified in this paper.

http://ift.tt/2swYyaJ

Criterion-Referenced Fitness Standards Associated with Maintaining Functional Capacity in Chilean Older Adults

Rejuvenation Research , Vol. 0, No. 0.


http://ift.tt/2turvZl

Letter to Editors: Detection of endolymphatic hydrops using traditional MR imaging sequences

We would like to comment on the manuscript entitled "Detection of endolymphatic hydrops using traditional MR imaging sequences." by Keller et al. [1]. It is of great clinical value if non-contrast MR imaging can be used to differentiate the endo- and perilymph space as the authors have stated. We read this article with great interest and thank the authors for citing our six papers. However, there are some critical points that need to be clarified in this paper.

http://ift.tt/2swYyaJ

Solitary fibrous tumour of the pleura presenting as a giant intrathoracic mass

Solitary fibrous tumours (SFTs) are relatively rare neoplasms thought to originate from the submesothelial connective tissue. SFTs have been described in a variety of sites, including the pleura, orbit, lower respiratory tract, peritoneal cavity and heart. These neoplasms are usually benign, though locally aggressive, and metastatic behaviour has been observed in some cases. We describe a case of a 61-year-old man presenting with weight loss, poor appetite, malaise, worsening dyspnoea on exertion and lower extremity oedema, who was found to have a gigantic—21x21 cm—tumour occupying the entire right hemithorax causing compression and displacement of the mediastinum and liver. Transthoracic CT-guided biopsy revealed SFT of the pleura. The patient underwent preoperative angiography and embolisation of the tumour followed by successful surgical resection via thoracotomy.

http://ift.tt/2sbubr1

Central Focused Convolutional Neural Networks: Developing a Data-driven Model for Lung Nodule Segmentation

Publication date: Available online 30 June 2017
Source:Medical Image Analysis
Author(s): Shuo Wang, Mu Zhou, Zaiyi Liu, Zhenyu Liu, Dongsheng Gu, Yali Zang, Di Dong, Olivier Gevaert, Jie Tian
Accurate lung nodule segmentation from computed tomography (CT) images is of great importance for image-driven lung cancer analysis. However, the heterogeneity of lung nodules and the presence of similar visual characteristics between nodules and their surroundings make it difficult for robust nodule segmentation. In this study, we propose a data-driven model, termed the Central Focused Convolutional Neural Networks (CF-CNN), to segment lung nodules from heterogeneous CT images. Our approach combines two key insights: 1) the proposed model captures a diverse set of nodule-sensitive features from both 3-D and 2-D CT images simultaneously; 2) when classifying an image voxel, the effects of its neighbor voxels can vary according to their spatial locations. We describe this phenomenon by proposing a novel central pooling layer retaining much information on voxel patch center, followed by a multi-scale patch learning strategy. Moreover, we design a weighted sampling to facilitate the model training, where training samples are selected according to their degree of segmentation difficulty. The proposed method has been extensively evaluated on the public LIDC dataset including 893 nodules and an independent dataset with 74 nodules from Guangdong General Hospital (GDGH). We showed that CF-CNN achieved superior segmentation performance with average dice scores of 82.15% and 80.02% for the two datasets respectively. Moreover, we compared our results with the inter-radiologists consistency on LIDC dataset, showing a difference in average dice score of only 1.98%.

Graphical abstract

http://ift.tt/2sbdUT2

Three-dimensional printed haptic model from a prenatal surface-rendered oropalatal sonographic view: a new tool in the surgical planning of cleft lip/palate

Three-dimensional (3D) ultrasound has significantly improved prenatal screening and perinatal care in the area of cleft lip/palate and other deformities, providing essential preoperative information to the surgical team. However, current 3D reconstruction modalities are limited primarily to display on a two-dimensional surface. In contrast, a 3D printed haptic model allows both the surgeon and the parents to develop a better understanding of the anatomy and the surgical procedure through the ability to interact directly with the printed model.

http://ift.tt/2tuByh7

Traction suture modification to tongue-in-groove caudal septoplasty

Caudal septal deviation leads to unfavorable esthetic as well as functional effects on the nasal airway. A modification to the tongue-in-groove (TIG) technique to correct these caudal septal deformities is described. With placement of a temporary suspension suture to the caudal septum, manual traction is applied, assuring that the caudal septum remains in the midline position while it is being secured with multiple through-and-through, trans-columellar and trans-septal sutures. From 2003 to 2016, 148 patients underwent endonasal septoplasty using this modified technique, with excellent functional and cosmetic outcomes and a revision rate of 1.4%.

http://ift.tt/2sbwY3p

Inflammation and myeloproliferative neoplasms

Publication date: Available online 30 June 2017
Source:Journal of Autoimmunity
Author(s): Federico Lussana, Alessandro Rambaldi
Myeloproliferative neoplasms (MPN) include three main entities: Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Myelofibrosis (MF). MPN represent a unique model of the relationship between the clonal development of a hematologic malignancy and chronic inflammation. The neoplastic clone is the main driver of this inflammatory reaction as demonstrated by the curative effect of allogeneic stem cell transplantation which leads not only to a complete restore of the hematopoiesis, but also to regression of bone marrow fibrosis. The neoplastic clone and its differentiated progeny are also the main source of an indirect paracrine secretion of inflammatory cytokines released by different normal cells present within the tumor microenvironment. In the end, the cytokine storm within the bone marrow niche leads to fibrosis. In addition, chronic inflammation is responsible of the constitutional symptoms which negatively affect the quality of life of MPN patients and represents a major driver for the development of premature atherosclerosis and disease progression. Here we describe the available data about the link between MPN and chronic inflammation in animal models as well as in clinical studies. We also review the practical value of including acute phase inflammatory proteins such as high sensitivity C-reactive protein (hs-CRP) and pentraxin 3 (PTX-3) in prognostic stratification of MPN patients. Interestingly, the plasma levels of these proteins is often increase in MPN patients and this may be important when considering the well-established link between these two inflammatory proteins and the risk of both arterial and venous thrombosis. Although the available drugs are unable to eradicate the malignant clone, the ability to identify patient with a high inflammatory burden and an adverse molecular profile is important to advise therapy with ruxolitinib or even allogeneic stem cell transplantation that currently represents the only potentially curative option for these diseases.



http://ift.tt/2uu1hD4

Phonological awareness in German-speaking preschool children with cochlear implants – 3 case examples

The aim was to explore PA skills German-speaking preschool children with cochlea implants (CIs) and how these skills may be related to their speech and language skills.

http://ift.tt/2tvEYzK

Cold atmospheric plasma restores tamoxifen sensitivity in resistant MCF-7 breast cancer cell

Publication date: September 2017
Source:Free Radical Biology and Medicine, Volume 110
Author(s): Seungyeon Lee, Hyunkyung Lee, Dawoon Jeong, Juyeon Ham, Sungbin Park, Eun Ha Choi, Sun Jung Kim
Cancer recurrence, which is frequently accompanied by chemotherapy, has been a challenge in cancer treatment. This study was carried out to examine the potential applications of the reactive oxygen species (ROS)-producing cold atmospheric plasma (CAP) to overcome the cancer cells' drug resistance, which has been emerging as an alternative therapeutic tool for cancer. For this, we developed a tamoxifen (Tam)-resistant MCF-7 (MCF-7/TamR) breast cancer cell model and examined the effect of CAP on the recovery of Tam sensitivity at the cellular and molecular level. The ROS level was increased 1.9-fold in CAP-treated MCF-7/TamR cells compared to the non-treated cell. CAP was proven to restore sensitivity by up to 50% for MCF-7/TamR cells against Tam after CAP treatment. The comparison of genome-wide expression between the acquisition of Tam resistance and CAP treatment identified 20 genes that commonly showed significant expression changes. Notably, all the genes except two have been oppositely dysregulated in the two cellular statuses, and the majority of them are known to contribute to the acquisition of Tam resistance. The protein expression of selected genes, MX1 and HOXC6, was recovered to that of their parental cell by CAP. Furthermore, the dysregulation of MX1 and HOXC6 in MCF-7/TamR alleviated the drug sensitivity recovery effect of CAP. Taken together, CAP inhibited the growth of Tam-resistant MCF-7 cancer cells and reset it to the Tam-sensitive status by restoring the expression of drug resistance–related genes. These findings may lend credence to CAP as an alternative or complementary tool in the treatment or prevention of Tam-resistant cancer.

Graphical abstract

http://ift.tt/2ttEJWs

Oxidative stress contributes to hepatocyte growth factor-dependent pro-senescence activity of ovarian cancer cells

Publication date: September 2017
Source:Free Radical Biology and Medicine, Volume 110
Author(s): Justyna Mikuła-Pietrasik, Paweł Uruski, Martyna Pakuła, Konstantin Maksin, Sebastian Szubert, Aldona Woźniak, Eryk Naumowicz, Dariusz Szpurek, Andrzej Tykarski, Krzysztof Książek
The cancer-promoting activity of senescent peritoneal mesothelial cells (HPMCs) has already been well evidenced both in vitro and in vivo. Here we sought to determine if ovarian cancer cells may activate senescence in HPMCs. The study showed that conditioned medium (CM) from ovarian cancer cells (OVCAR-3, SKOV-3, A2780) inhibited growth and promoted the development of senescence phenotype (increased SA-β-Gal, γ-H2A.X, 53BP1, and decreased Cx43) in HPMCs. An analysis of tumors isolated from the peritoneum of patients with ovarian cancer revealed an abundance of senescent HPMCs in proximity to cancerous tissue. The presence of senescent HPMCs was incidental when fragments of peritoneum free from cancer were evaluated. An analysis of the cells' secretome followed by intervention studies with exogenous proteins and neutralizing antibodies revealed hepatocyte growth factor (HGF) as the mediator of the pro-senescence impact of the cancer cells. The activity of cancerous CM and HGF was associated with an induction of mitochondrial oxidative stress. Signaling pathways involved in the senescence of HPMCs elicited by the cancer-derived CM and HGF included p38 MAPK, AKT and NF-κB. HPMCs that senesced prematurely in response to the cancer-derived CM promoted adhesion of ovarian cancer cells, however this effect was effectively prevented by the cell protection against oxidative stress. Collectively, our findings indicate that ovarian cancer cells can elicit HGF-dependent senescence in HPMCs, which may contribute to the formation of a metastatic niche for these cells within the peritoneal cavity.

Graphical abstract

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Neuronal nitric oxide synthase mediates insulin- and oxidative stress-induced glucose uptake in skeletal muscle myotubes

Publication date: September 2017
Source:Free Radical Biology and Medicine, Volume 110
Author(s): Dean L. Kellogg, Karen M. McCammon, Kathryn S. Hinchee-Rodriguez, Martin L. Adamo, Linda J. Roman
Previously published studies strongly suggested that insulin- and exercise-induced skeletal muscle glucose uptake require nitric oxide (NO) production. However, the signal transduction mechanisms by which insulin and contraction regulated NO production and subsequent glucose transport are not known. In the present study, we utilized the myotube cell lines treated with insulin or hydrogen peroxide, the latter to mimic contraction-induced oxidative stress, to characterize these mechanisms. We found that insulin stimulation of neuronal nitric oxide synthase (nNOS) phosphorylation, NO production, and GLUT4 translocation were all significantly reduced by inhibition of either nNOS or Akt2. Hydrogen peroxide (H2O2) induced phosphorylation of nNOS at the same residue as did insulin, and also stimulated NO production and GLUT4 translocation. nNOS inhibition prevented H2O2-induced GLUT4 translocation. AMP activated protein kinase (AMPK) inhibition prevented H2O2 activation and phosphorylation of nNOS, leading to reduced NO production and significantly attenuated GLUT4 translocation. We conclude that nNOS phosphorylation and subsequently increased NO production are required for both insulin- and H2O2-stimulated glucose transport. Although the two stimuli result in phosphorylation of the same residue on nNOS, they do so through distinct protein kinases. Thus, insulin and H2O2-activated signaling pathways converge on nNOS, which is a common mediator of glucose uptake in both pathways. However, the fact that different kinases are utilized provides a basis for the use of exercise to activate glucose transport in the face of insulin resistance.

Graphical abstract

http://ift.tt/2tuJcYG

Onabotulinumtoxin A for the management of chronic migraine in current clinical practice: results of a survey of sixty-three Italian headache centers

Chronic migraine is a complex clinical condition often undertreated. Onabotulinumtoxin A (OBT-A) was approved in Italy in 2013 for symptom relief in patients with chronic migraine who have failed, or do not to...

http://ift.tt/2tzGAcA

Laser irradiation promotes the proliferation of mouse pre-osteoblast cell line MC3T3-E1 through hedgehog signaling pathway

Abstract

Low-level laser could promote osteoblast proliferation, and it has been applied in clinical practice to promote wound healing and tissue regeneration. However, the mechanism related to laser irradiation remains unclear. This study aimed to investigate the effects of low-level laser irradiation on the cell proliferation and the expressions of hedgehog signaling molecules Indian hedgehog (Ihh), Ptch, and Gli in vitro. In our present study, the MTT method was used to evaluate the effect on cell proliferation of laser irradiation on MC3T3-E1 cells. And cell cycle was examined by flow cytometry. Gene and protein expressions of hedgehog signaling molecules, including Ihh, Ptch, Smoothened (Smo), and Gli, were examined by qRT-PCR and western blot analysis. The results showed that laser irradiation at dosage of 3.75 J/cm² enhances the proliferation of MC3T3-E1 cells compared with control groups (p = 0.00). Moreover, laser irradiation (3.75 J/cm²) increased the cell amount at S phase (p = 0.00). In addition, the expressions of Ihh, Ptch, Smo, and Gli were significantly increased compared to the control during laser irradiation (3.75 J/cm²)-induced MC3T3-E1 osteoblast proliferation. After adding the hedgehog signaling inhibitor CY (cyclopamine), cell proliferation and Ihh, Ptch, Smo, and Gli expressions were inhibited (p = 0.00), and the cell amount at S phase was reduced compared with combination groups (p = 0.00). These results indicated that laser irradiation promotes proliferation of MC3T3-E1 cells through hedgehog signaling pathway. Our findings provide insights into the mechanistic link between laser irradiation-induced osteogenesis and hedgehog signaling pathway.

http://ift.tt/2sbnTHR

Effects of biotic and abiotic factors on the temporal dynamic of bat-fruit interactions

Publication date: August 2017
Source:Acta Oecologica, Volume 83
Author(s): Rafael de Souza Laurindo, Renato Gregorin, Davi Castro Tavares
Mutualistic interactions between animals and plants vary over time and space based on the abundance of fruits or animals and seasonality. Little is known about this temporal dynamic and the influence of biotic and abiotic factors on the structure of interaction networks. We evaluated changes in the structure of network interactions between bats and fruits in relation to variations in rainfall. Our results suggest that fruit abundance is the main variable responsible for temporal changes in network attributes, such as network size, connectance, and number of interactions. In the same way, temperature positively affected the abundance of fruits and bats. An increase in temperature and alterations in rainfall patterns, due to human induced climate change, can cause changes in phenological patterns and fruit production, with negative consequences to biodiversity maintenance, ecological interactions, and ecosystem functioning.



http://ift.tt/2sbhFYC

Evaluating the performance and intellectual structure of construction and demolition waste research during 2000–2016

Abstract

Construction and demolition (C&D) waste diminishes scarce land resources and endangers human health and the surrounding environment. Quantitative and visualized analysis was conducted to evaluate worldwide scientific research output on C&D waste from 2000 to 2016. The related information of 857 publications was collected from SCI-Expanded database and statistically analyzed. The number of documents about C&D waste presented a general growth during the last 17 years. Construction and Building Materials publication ranked first in the most productive journals. China and Spain acted as dominated roles comparing to other countries, and Hong Kong Polytechnic University was the institution with the largest amount of C&D waste research. Recycled aggregates, sustainable C&D waste management, and the rewarding program and commerce system were the hottest topics during 2000–2016 and in the near future according to the intellectual structure analysis.

http://ift.tt/2t1atkA

Effects of low doses of glyphosate on DNA damage, cell proliferation and oxidative stress in the HepG2 cell line

Abstract

We studied the toxic effects of glyphosate in vitro on HepG2 cells exposed for 4 and 24 h to low glyphosate concentrations likely to be encountered in occupational and residential exposures [the acceptable daily intake (ADI; 0.5 μg/mL), residential exposure level (REL; 2.91 μg/mL) and occupational exposure level (OEL; 3.5 μg/mL)]. The assessments were performed using biomarkers of oxidative stress, CCK-8 colorimetric assay for cell proliferation, alkaline comet assay and cytokinesis-block micronucleus (CBMN) cytome assay. The results obtained indicated effects on cell proliferation, both at 4 and 24 h. The levels of primary DNA damage after 4-h exposure were lower in treated vs. control samples, but were not significantly changed after 24 h. Using the CBMN assay, we found a significantly higher number of MN and nuclear buds at ADI and REL after 4 h and a lower number of MN after 24 h. The obtained results revealed significant oxidative damage. Four-hour exposure resulted in significant decrease at ADI [lipid peroxidation and glutathione peroxidase (GSH-Px)] and OEL [lipid peroxidation and level of total antioxidant capacity (TAC)], and 24-h exposure in significant decrease at OEL (TAC and GSH-Px). No significant effects were observed for the level of reactive oxygen species (ROS) and glutathione (GSH) for both treatment, and for 24 h for lipid peroxidation. Taken together, the elevated levels of cytogenetic damage found by the CBMN assay and the mechanisms of primary DNA damage should be further clarified, considering that the comet assay results indicate possible cross-linking or DNA adduct formation.

http://ift.tt/2sw5EfG

Occurrence, distribution, and risk assessment of antibiotics in the Songhua River in China

Abstract

The occurrence, distribution, and risk assessment of antibiotics in freshwater systems are receiving global attention, because of their impact on the environment and human health. However, few studies have focused on this topic in Northeast China and its Songhua River, the third-largest river in China. This study investigated the occurrence and distribution of 12 antibiotics, including three cephalosporins (cefazolin, cefmetazole, cefotaxime), three macrolides (azithromycin, clarithromycin, roxithromycin), three fluoroquinolones (ofloxacin, norfloxacin, flumequine), and three sulfonamides (sulfadiazine, sulfapyridine, sulfamethoxazole) in the mainstream and tributaries of the Songhua River. A total of 152 surface water samples were collected in January, May, July, and October 2016. These samples were analyzed using solid-phase extraction (SPE) and ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). The results indicated the wide use of all 12 antibiotics in the mainstream of the Songhua River. Sulfamethoxazole and cefazolin were the dominant antibiotics, with maximum concentrations of 73.1 and 65.4 ng L⁻¹, respectively. Other antibiotics were present at mean concentrations below 15 ng L⁻¹, except cefmetazole, present at a mean concentration of 35.6 ng L⁻¹. The spatial distribution of antibiotics showed that unbalanced regional development may lead to the distribution pattern of the antibiotics in the tributaries and the mainstream. Thus study also assessed the seasonal variation of antibiotics in urban surface water; cephalosporin, sulfonamide, fluoroquinolone, and macrolide concentrations were significantly higher during the icebound season than during non-icebound season. This may be due to the low temperature and water flow of the river in winter. Risk assessment showed that azithromycin, clarithromycin, roxithromycin, flumequine, and sulfamethoxazole posed a low or median risk to the aquatic organisms in the mainstream. The potential risks created by antibiotics to the aquatic environment should not be neglected in the Songhua River. The potential risks created by antibiotics to the aquatic environment should not be neglected in the Songhua River.

http://ift.tt/2swbiym

Phytoremediation of cadmium-polluted soil by Chlorophytum laxum combined with chitosan-immobilized cadmium-resistant bacteria

Abstract

This study examined the performance of the chitosan-immobilized cadmium-resistant bacteria Arthrobacter sp. and Micrococcus sp. on cadmium phytoremediation by Chlorophytum laxum in cadmium-polluted soil. These immobilized cadmium-resistant bacteria can survive in cadmium-contaminated soil and significantly increased soil cadmium solubility, but the ability of chitosan-immobilized cells to increase cadmium solubility was lower than that of free cells. A pot experiment demonstrated that chitosan-immobilized Micrococcus sp. promoted the growth of C. laxum planted in cadmium-contaminated soil. A significant increase in the cadmium concentration in the roots and aboveground parts of C. laxum was found in plants inoculated with free and chitosan-immobilized cells of these bacteria. The performance of Arthrobacter sp. free cells to augment cadmium accumulation in C. laxum was a little bit better than that of chitosan-immobilized Arthrobacter sp., except at 9 weeks after planting. The phytoextraction coefficient, bioaccumulation factor, and translocation factor of C. laxum inoculated with free and chitosan-immobilized cells of cadmium-resistant bacteria were higher than those of the uninoculated control and increased with time. Our findings suggest that chitosan-immobilized cells can be exploited to enhance the efficiency of cadmium phytoremediation by C. laxum.

http://ift.tt/2t0Kp94

What Are the Costs of Degraded Parafoveal Previews During Silent Reading?.

Author: Vasilev, Martin R.; Slattery, Timothy J.; Kirkby, Julie A.; Angele, Bernhard

DOI: 10.1037/xlm0000433

Publication Date: POST AUTHOR CORRECTIONS, 29 June 2017

http://ift.tt/2sbwSsH

Retrieval Practice Makes Procedure From Remembering: An Automatization Account of the Testing Effect.

Author: Racsmany, Mihaly; Szollosi, Agnes; Bencze, Dorottya

DOI: 10.1037/xlm0000423

Publication Date: POST AUTHOR CORRECTIONS, 29 June 2017

http://ift.tt/2sbyjXK

Can the First Letter Advantage Be Shaped by Script-Specific Characteristics?.

Author: Winskel, Heather; Ratitamkul, Theeraporn; Perea, Manuel

DOI: 10.1037/xlm0000434

Publication Date: POST AUTHOR CORRECTIONS, 29 June 2017

http://ift.tt/2tu8WEE

Attending Globally or Locally: Incidental Learning of Optimal Visual Attention Allocation.

Author: Beck, Melissa R.; Goldstein, Rebecca R.; van Lamsweerde, Amanda E.; Ericson, Justin M.

DOI: 10.1037/xlm0000428

Publication Date: POST AUTHOR CORRECTIONS, 29 June 2017

http://ift.tt/2tu8q9w

Primacy and Recency Effects for Taste.

Author: Daniel, Thomas A.; Katz, Jeffrey S.

DOI: 10.1037/xlm0000437

Publication Date: POST AUTHOR CORRECTIONS, 29 June 2017

http://ift.tt/2sbaEXJ

Das endoskopische Browlift mittels Endotine Forehead Device bei Fazialisparese

Laryngo-Rhino-Otol
DOI: 10.1055/s-0043-113040

Hintergrund: Die Augenpartie ist sowohl in funktioneller Hinsicht als auch für die Expression von Emotionen von zentraler Bedeutung. Eine chronische Fazialisparese mit Lähmung des Stirnastes kann zu einer Brauenptosis mit Einschränkungen des Gesichtsfeldes und einer deutlichen Asymmetrie des Gesichts führen. Das endoskopische Browlift mit resorbierbarem Endotine Forehead Device stellt ein attraktives Konzept zur Korrektur der Brauenptosis und Symmetrisierung der Stirn-/Brauenregion dar. Material und Methoden Das endoskopische Augenbrauen- und Stirnlift unter Anwendung des Endotine Forehead Devices wurde in unserer Klinik bisher an 9 Patienten mit Fazialisparese durchgeführt. Das intraoperative Handling, Komplikationen und das postoperative Ergebnis wurden analysiert. Die Symmetrisierung der Augenbrauen wurde durch die FACEgram-Software erfasst. Zur postoperativen Abfrage der Patientenzufriedenheit wurde nach durchschnittlich 10 Monaten der Glasgow Benefit Inventory Fragebogen eingesetzt. Ergebnisse Mit Hilfe des endoskopischen Stirnlifts mit dem Endotine Forehead Device gelang eine minimal-invasive, komplikationsarme Symmetrisierung der Stirn- und Augenbrauenregion. Operationsbedingte Morbiditäten wurden nicht kaum beobachtet. Folgende Komplikationen wurden beobachtet: Eine Patientin erlitt eine Rezidivptosis bei postoperativem Hämatom. Eine weitere empfand die Palpabilität des Device als störend. Die Patienten berichteten über eine postoperative Steigerung der Lebensqualität, d.er durchschnittliche Punktwert im Glasgow Benefit Inventory nach der Operation lag bei + 29,2 (SD 13,6). Schlussfolgerungen Das endoskopische Brow- und Stirnlift mit dem Endotine Forehead Device stellt eine erfolgreiche, komplikationsarme Therapieoption bei Brauenptosis in Folge einer Fazialisparese dar.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Hereditäre Innenohrdysplasie mit Betroffenheit von aufeinanderfolgenden Generationen einer Familie

Laryngo-Rhino-Otol
DOI: 10.1055/s-0043-113039

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

http://ift.tt/2u90NmK

Musikalische Fähigkeiten bei Kindern mit auditiver Verarbeitungs- und Wahrnehmungsstörung

Laryngo-Rhino-Otol
DOI: 10.1055/s-0043-113038

Hintergrund In der klinischen Praxis wurden bei Kindern mit auditiven Verarbeitungs- und Wahrnehmungsstörungen (AVWS) Schwierigkeiten bei der Lösung musikalischer Aufgaben beobachtet. Musikalität bei AVWS ist bisher wenig erforscht. Material und Methoden 15 AVWS-Patienten im Alter zwischen 6 und 11 Jahren wurden mit der Messung musikalischer Fähigkeiten (MMF) untersucht und mit 15 Kontrollprobanden verglichen. Ergebnisse AVWS-Patienten zeigen statistisch signifikante Defizite in den Aufgaben zur Tonhöhendifferenzierung, Reproduktion von Rhythmen und Melodien. Zusammenhänge zwischen sprachlichen und musikalischen Leistungen bei AVWS-Patienten wurden nachgewiesen. Schlussfolgerungen Musikalische Fähigkeiten sollten in der AVWS-Diagnostik mehr Beachtung finden. Positive Transfereffekte musikalischen Trainings auf die Sprachentwicklung und allgemeine kognitive Fähigkeiten wurden in zahlreichen Studien nachgewiesen. Bei Vorliegen musikalischer Defizite sollte musikalische Förderung als Therapiemethode bei AVWS diskutiert werden.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Progrediente Verschlechterung des Sprachverstehens nach Cochlea-Implantation

Laryngo-Rhino-Otol
DOI: 10.1055/s-0043-113041

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

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Double Vision After Minimally Invasive Orbital Decompression.

Introduction: New onset Diplopia following orbital decompression in thyroid eye disease patients is estimated to occur in up to 30% to 40% of decompression patients, mostly related to deep lateral and medial wall decompressions. Methods: A retrospective chart review of all minimally invasive (fat and minimal bone orbital decompression performed at the UCLA Stein Eye Institute between 2005 and 2015. Inclusion criteria were thyroid eye disease patients older than 18 years undergoing fat only orbital decompression with no previous muscle surgery. Results: The chart review revealed only 5 patients with new onset diplopia after this surgery. The cases are discussed and a possible mechanism for the diplopia is proposed. Discussion: Double vision following minimally invasive orbital decompression is rare and the mechanisms are poorly understood. (C) 2017 by Mutaz B. Habal, MD.

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Aesthetic Lateral Canthoplasty: a Gray Line Split Approach.

Background: Many women in Asian countries chase larger and brighter eyes, but to most Asian people only double eye plasty and epicanthoplasty is not enough. As a result, aesthetic lateral canthoplasty, another procedure to lengthen the palpebral fissure, is becoming more and more popular. However, the current procedure of aesthetic lateral canthoplasty has many potential complications, restricting the wide application of this procedure. Methods: Here, the authors developed a minimally invasive method through gray line split and canthopexy to achieve lateral canthoplasty. Eighty-seven patients from February 2013 to January 2016 were included and had the procedure. The lengthen of the palpebral fissure was measured and photographs were also taken before the surgery and in the follow-up periods. Besides, the complications related to this procedure were also investigated. Results: The authors have performed aesthetic lateral canthoplasty in 87 patients, almost all of the follow-up patients have satisfactory results with a lengthen of palpebral fissure ranging from 2.3 to 4.2 mm. Through the long-term follow-up the authors found the lengthen of the palpebral fissure is stable. No serious complications like lacrimal system fistula or hypertrophic scars emerged except 1 patient with conjunctival exposure. Conclusions: Through this gray line split method, the authors can acquire larger and brighter eyes without serious complications. The authors think that this is a good method and worthy of promotion. (C) 2017 by Mutaz B. Habal, MD.

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Variations in Current Procedural Terminology Coding for Craniofacial Surgery: a Need for Review and Change.

Background: A survey was utilized to study the coding practices of surgeons performing craniofacial procedures, in order to determine whether coding for these procedures might be standardized or expanded. Methods: An online survey was designed with 6 sample cases to cover a variety of procedures encountered in the field of craniofacial surgery which was sent to members of 3 professional organizations centered around the practice of craniofacial/maxillofacial surgery. Surgeons were asked to read the vignettes and choose from a series of multiple-choice responses to code the cases, or write in their own response. Codes were based on the American Medical Association current procedural terminology listings. Responses were compiled and tabulated. Results: One hundred twenty-eight people initiated the survey. The largest common coding responses for each vignette were selected by 45.2% of respondents for the case describing placement of an internal mandibular distractor; 45.3% for the case of scaphocephaly remodeling; 67.1% for a case of cranioplasty for trigonocephaly; 47.2% for hypertelorism repair with periorbital osteotomies; 60% for LeFort III advancement with external distractors; and 53.6% for the case describing the removal of an internal mandibular distractor. Between 4 and 12 codes were identified for possible use in each clinical scenario. Conclusion: There appears to be wide variability among those who routinely perform craniofacial surgery as to the appropriate ways to code these procedures. We hope to bring this to the attention of coding committees for further discussion to hopefully bring about more accurate and descriptive codes for craniofacial surgical procedures. (C) 2017 by Mutaz B. Habal, MD.

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Speech Perceptions and Health-Related Quality of Life Among Children With Cleft Lip and Palate.

Background: The association between perception of speech and health-related quality of life (HRQOL) among patients with cleft palate is not well understood. The purpose of this study was to determine: the agreement between patient and parent perception of speech, the correlation between patient/parent speech perception and objective analysis by a speech-language pathologist (SLP), and the relationship between objective speech analysis and HRQOL among children with cleft lip with or without palate (CLCP). Methods: The authors surveyed 108 CLCP patients who received treatment at a large tertiary medical center from 2013 to 2014. Patients and parents were queried regarding their difficulty with speech, and an SLP performed perceptual speech analysis with each patient. Patient-reported survey instruments were used to assess anxiety, depression, anger, peer relationships, stigma, and overall psychosocial health. The authors assessed the agreement between patients and SLP analysis as well as association between speech and HRQOL. Results: Patient and parent-reported speech quality demonstrated moderate agreement regarding the quality of the child's speech (r = 0.46-0.64). Parent and patient speech perception was not well associated with SLP analysis (V = 0.06-0.30). Patient speech perception was correlated with depression (P = 0.03), while SLP analysis was correlated with anger (P = 0.03, P = 0.004), depression (P = 0.007), and difficulty with peer relationships (P = 0.02). Conclusions: Patients and parents have different perceptions of the quality of the child's speech, and their ratings differ from SLP perceptual speech analysis. Both patient speech perception and SLP analysis are correlated with important aspects of quality of life, and should be considered when evaluating children with CLCP. (C) 2017 by Mutaz B. Habal, MD.

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Review of "Mastery of Care-Toward Communitarian Regulation" by Pronovost P and Higgins RS in Ann Surg 265: 271-272, 2017.

No abstract available

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The Effect of Anterior Palatoplasty Plus Modified Expansion Sphincter Pharyngoplasty on Voice Performance in Obstructive Sleep Apnea Syndrome.

Objective: We aimed to investigate the effect of anterior palatoplasty (AP) plus modified expansion sphincter pharyngoplasty (MESP) on voice performance in patients with obstructive sleep apnea syndrome (OSAS). Methods: Fourteen OSAS patients who had AP + MESP procedure were included in the study. Voice performances of the patients were analyzed with acoustic voice analysis before surgery, and 6 months after surgery. Results: Preoperative and postoperative F0, jitter percentage, and shimmer percentage were compared. Mean preoperative F0 was 129.85 Hz, and mean postoperative F0 was 138.07 Hz, with a significant difference in between (P = 0.017). Mean preoperative jitter percentage was 0.65, and mean shimmer percentage was 0.88, while those values were 0.67 and 0.84, respectively, in the postoperative period. The differences were not statistically significant (P = 0.801 and 0.652). Conclusion: The AP + MESP procedure performed for OSAS results in improvement of F0 in the long term; however, there were no differences in jitter percentage and shimmer percentage. (C) 2017 by Mutaz B. Habal, MD.

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Three-Dimensional Anthropometric Evaluation of Facial Morphology.

Objectives: The objectives of this study were to evaluate sexual dimorphism for facial features within Colombian and Mexican-American populations and to compare the facial morphology by sex between these 2 populations. Materials and Methods: Three-dimensional facial images were acquired by using the portable 3dMDface system, which captured 223 subjects from 2 population groups of Colombians (n = 131) and Mexican-Americans (n = 92). Each population was categorized into male and female groups for evaluation. All subjects in the groups were aged between 18 and 30 years and had no apparent facial anomalies. A total of 21 anthropometric landmarks were identified on the 3-dimensional faces of each subject. The independent t test was used to analyze each data set obtained within each subgroup. Results: The Colombian males showed significantly greater width of the outercanthal width, eye fissure length, and orbitale than the Colombian females. The Colombian females had significantly smaller lip and mouth measurements for all distances except upper vermillion height than Colombian males. The Mexican-American females had significantly smaller measurements with regard to the nose than Mexican-American males. Meanwhile, the heights of the face, the upper face, the lower face, and the mandible were all significantly less in the Mexican-American females. The intercanthal and outercanthal widths were significantly greater in the Mexican-American males and females. Meanwhile, the orbitale distance of Mexican-American sexes was significantly smaller than those of the Colombian males and females. The Mexican-American group had significantly larger nose width and length of alare than the Colombian group regarding both sexes. With respect to the nasal tip protrusion and nose height, they were significantly smaller in the Colombian females than in the Mexican-American females. The face width was significantly greater in the Colombian males and females. Conclusions: Sexual dimorphism for facial features was presented in both the Colombian and Mexican-American populations. In addition, there were significant differences in facial morphology between these 2 populations. (C) 2017 by Mutaz B. Habal, MD.

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Change in Posterior Pharyngeal Space After Counterclockwise Rotational Orthognathic Surgery for Class II Dentofacial Deformity Diagnosed With Obstructive Sleep Apnea Based on Cephalometric Analysis.

Although maxillomandibular advancement (MMA) is an orthognathic surgical procedure used to manage obstructive sleep apnea (OSA) in individuals who are noncompliant with continuous positive airway pressure therapy, simple MMA encounters problems in terms of aesthetic outcomes in Asian populations with preexisting dentoalveolar protrusion. Our current prospective investigation describes changes in posterior pharyngeal space and aesthetic outcomes after counterclockwise rotational orthognathic surgery, which is known to be quite difficult in terms of the maintenance of the skeletal stability in skeletal class II patients with OSA. This prospective study investigated the surgical outcome of patients who suffered from OSA following counterclockwise rotational orthognathic surgery. The patients were skeletal class II patients who underwent orthognathic surgery between March 2013 and December 2014. Cephalometric posterior airway analysis and a questionnaire for facial perception were used to assess pharyngeal airway and patient perception of facial appearance. A total of 14 patients were included. Satisfactory results were achieved without complications in all OSA patients. The airway parameters for anteroposterior length significantly increased. Thirteen patients answered a questionnaire on their facial appearance, and the visual analog scale averaged 7.31 points, indicating a favorable facial appearance. Counterclockwise rotational orthognathic surgery without maxilla advancement for the correction of OSA can effectively increase the posterior pharyngeal space, with favorable aesthetic results. With thoughtful application, this novel approach may be an alternative to standard approaches for the correction of OSA using orthognathic surgery. (C) 2017 by Mutaz B. Habal, MD.

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Displacement of a Broken Dental Injection Needle Into the Perivertebral Space.

Dental injection needle breakage is an uncommon problem in dental practice. Displacement of the broken fragment into anatomical spaces is, on the other hand, a serious complication that occurs most commonly during inferior alveolar nerve blocks as a result of material wear, incorrect application of the anesthesia technique, or sudden movement of the patient during injection. Further complications such as infection, trismus, and nerve paralysis may exacerbate the condition and, if not treated adequately, life-threatening conditions may develop over time as the fragment dislodges deeper in soft tissues. Clinical symptoms of the patient, as well as the findings gathered from detailed physical examination and radiographic evaluation, are important factors to consider before performing an exploratory surgery. Removal of a broken needle may be troublesome due to its proximity to vital anatomic structures. Multislice computed tomography is a reliable imaging modality that provides accurate information to pinpoint the exact location of the needle fragment. This report describes a case of needle breakage occurred during inferior alveolar nerve block which was performed to extract a third molar tooth and the migration of the broken fragment from the right mandibular ramus area into the perivertebral space, with special emphasis on the surgical retrieval technique with multiplanar computed tomography imaging guidance. (C) 2017 by Mutaz B. Habal, MD.

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Demarcative Necrosis Along Previous Laceration Line After Filler Injection.

In recent years, fillers have been widely used for soft tissue augmentation. Although they are generally considered to be safe, many complications have been reported to date. Nose and nasolabial fold augmentations with fillers can lead to an implementation of nasal skin necrosis, possibly caused by intravascular embolism and/or extravascular compression. Herein, we present a case of a successfully treated patient who experienced skin necrosis after an injection of dermal fillers into the nasolabial fold. Interestingly, we discovered that the patient had experienced a laceration 8 years ago around the area in which the filler was injected. (C) 2017 by Mutaz B. Habal, MD.

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Mozart Ear Deformity: a Rare Diagnosis in the Ear Reconstruction Clinic.

Mozart ear is a rare auricular deformity; clinically the auricle is characterized by the bulging appearance of the anterosuperior portion of the auricle due to fusion of the crura of the antihelix, an inversion in the normal form of the cavum conchae resulting in its convexity and a slit-like narrowing of the orifice of the external auditory meatus. A retrospective review of clinical and photographic records of patients attended at the ear reconstruction clinic of our hospital between June of 2010 and May 2016 was performed; out of 576 consecutive patients only 3 fulfilled the inclusion criteria, with a prevalence of 0.5%. The authors present these patients. Surgical interventions mainly focus on the correction of the convex concha; however, the procedure should be tailored to the severity of the deformity and the wishes of the patient. (C) 2017 by Mutaz B. Habal, MD.

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Review of "Surgical Education and Health Care Reform, Defining the Role and Value of Trainees in an Evolving Medical Landscape" by Fayanju OM, Aggarwal R, Baucom RB, Ferrone CR, Massaro D, Terhune KP in Ann Surg 265: 459-460, 2017.

No abstract available

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Morphometric Analysis of the Posterior Cranial Fossa in Syndromic and Nonsyndromic Craniosynostosis.

Posterior cranial fossa (PCF) anatomy can be abnormal in craniosynostosis, and hindbrain herniation may occur. This study analyzed PCF anatomy in single suture and complex craniosynostosis. Children with craniosynostosis and age-matched controls were identified. Cephalic index (CI) for cranial vault and PCF as well as tentorial (TA) and occipital angles (OA) were measured on preoperative imaging. Children with syndromic (N = 6), bicoronal (N = 4), sagittal (N = 12), and metopic synostosis (N = 4) as well as controls (N = 10) were enrolled. Mean CI for cranial vault was 0.89, 0.93, 0.65, 0.74, and 0.78, respectively. Corresponding CI for PCF was 0.81, 0.93, 0.62, 0.74, and 0.78. Mean TA and OA were 45.4[degrees] and 96.6[degrees] in syndromic, 39.7[degrees] and 87.0[degrees] in bicoronal, 34.0 and 75.0[degrees] in sagittal, 39.7[degrees] and 87.0[degrees] in metopic synostosis, and 42.9[degrees] and 88.3[degrees] in controls. While CI, TA, and OA in metopic synostosis were similar to controls, abnormalities were found in syndromic, bicoronal, and sagittal synostosis. Syndromic and bicoronal craniosynostosis patients had a higher CI for both cranial vault and PFC as well as larger TA and OA, indicating a brachycephalic skull with steep tentorium and narrow PCF. In sagittal synostosis, CI for cranial vault and PCF were lower and TA and OA smaller, reflecting scaphocephalic deformity also at PCF, with a flat tentorium. This study provides basic PCF morphometry in craniofacial conditions. (C) 2017 by Mutaz B. Habal, MD.

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Lower Eyelid Reconstruction After Ablation of Skin Malignancies: How Far Can We Get in a Single-Stage Procedure?.

: Reconstruction of full-thickness lower eyelid defects tends to be a devastating procedure, especially when big amount of tissue has to be removed because of oncological reasons. The applied techniques are mostly difficult to execute and multistaged, often require extensive dissection, and result in scarring and facial disfigurement. The aim of the present study is to demonstrate the authors' experience in single-staged reconstructions of full-thickness defects of the lower eyelid with local tissue only. Material and Methods: A retrospective analysis was conducted identifying patients with postexcisional defects after skin cancer occurring in the lower eyelid, reconstructed in 1 stage. Appropriate demographic, pathological, preoperative, and postoperative clinical data and photo documentation were collected and analyzed. Results: After excluding patients with partial thickness defects (n=5), a total of 13 patients with lower eyelid full-thickness defects were studied, including 9 women and 4 men with mean age 66.5 years (age range 53-79 years). The most common malignancy was basal cell carcinoma (n = 11). In one of the patients 2 synchronous neoplasms were excised simultaneously from the same lower eyelid. The reconstruction was successfully performed in 1 stage in all the patients by recruiting the same eyelid tissue and/or temporal tissue. No additional surgery was needed at a minimal follow-up of 9 months. Conclusion: Local tissue flaps have proven to be a reliable option for a single-stage reconstruction of large full-thickness defects. Tenzel flap technique seems to be a reliable option for repair of defects as large as 60% of the total eyelid length. (C) 2017 by Mutaz B. Habal, MD.

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Nasal Septal Deformity in Relation to the Mode of Delivery.

Objective: The aim of this study was to find the relation between mode of delivery and the types of septal deviation. Materials and Methods: Records of patients treated for a deviated nasal septum from March 2003 to October 2015 were reviewed. Those with previous facial trauma were excluded. Information retrieved included basic demographic data, mode of delivery, sibling birthing order, type and date of surgery, and postoperational outcomes. Results: A total of 130 records were recovered. According to Guyuron's classification of nasal septal deviation, we found that type 5 was the most common type for patients delivered normally, whereas type 2 was the most common type for those who were delivered by cesarean section. Conclusion: Mode of delivery may be related to a certain type of deviation. However, studies with larger samples are required to support the finding in our study. (C) 2017 by Mutaz B. Habal, MD.

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Open Craniosynostosis Surgery: Effect of Early Intraoperative Blood Transfusion on Postoperative Course.

Correction of craniosynostosis can result in blood loss when the patient already has physiologic anemia. The aim of this study was to determine whether patients benefit from early blood transfusion and whether the timing of blood transfusion affects metabolic disturbances and the postoperative course. In this retrospective review, 71 patients who underwent open calvarial vault remodeling for correction of craniosynostosis were separated into 2 groups according to whether they received blood transfusions early (within the first 30 minutes of surgery) or later (after the first 30 minutes of surgery). Patients were further separated into nonsyndromic and syndromic cohorts. Tracked variables included hemoglobin, hematocrit, arterial blood gas values, lactate level, length of stay, estimated blood loss, and amount of blood transfused in the operating room, amount transfused postoperatively, and total amount transfused. Among all patients, the early transfusion group had a higher hemoglobin nadir overall and received less postoperative blood. Within the nonsyndromic cohort, the early transfusion group had a higher estimated blood loss and received more transfused blood. In the syndromic cohort, the early transfusion group had a hemoglobin nadir that was significantly higher than in the late transfusion group and a lower estimated blood loss, shorter pediatric intensive care unit stay, and less postoperative blood transfused. Syndromic patients also received significantly more blood overall. For syndromic patients undergoing open calvarial vault remodeling, transfusion within the first 30 minutes of surgery should be considered. (C) 2017 by Mutaz B. Habal, MD.

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Post-Surgical Relapse in Metopic Synostosis and Limitations of the Interfrontal Angle as an Outcome Measure.

Background: The interfrontal angle (IFA) has been utilized as a surrogate for morphologic assessment of the anterior cranial region in metopic synostosis with success in characterizing presenting severity. Its utility as an outcome measure has not been assessed similarly. In this study, we aimed to determine whether meaningful information relative to shape, and relapse in particular, could be assessed using the IFA. Methods: Patients with operatively treated isolated metopic synostosis were identified and included based on the availability of "previously obtained" low-dose computerized tomography (CT) scans at (1) preoperative and 2 postoperative (2) postoperative day-3 and (3) 1 year time points. Relapse was calculated as the percentage of the operatively induced change in IFA that was retained after the first postoperative year. Results: After exclusionary criteria, 19 patients were identified. The mean IFA values at the 3 time points were 119.3[degrees] (+/-9.8), 139.6[degrees] (+/-6.3), and 135.3[degrees] (+/-7.1), chronologically. Of the 19 patients, 14 (73.7%) experienced relapse, with this subgroup averaging 62.4% retention of their surgical change after 1 year. Increased preoperative severity and delayed age at surgical intervention were concurrently associated with an increased occurrence of relapse (P = 0.011). Another model utilizes preoperative IFA to predict the change in IFA that would accompany surgery on a case-by-case basis (P

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Surgical Outcomes of Endonasal Conjunctivodacryocystorhinostomy According to Jones Tube Location.

Purpose: The aim of this study was to compare surgical outcomes and complications of endonasal conjunctivodacryocystorhinostomy (CDCR) according to Jones tube location. Methods: Patients who underwent endonasal CDCR owing to proximal obstruction of the lacrimal drainage system between 2009 and 2016 were retrospectively reviewed. Patients were divided into 2 groups according to the location of the proximal end of the Jones tube. The canthal-based group included patients in which the proximal end of the Jones tube was located in the medial canthal angle, and the fornix-based group included patients in which the proximal end of the Jones tube was located in the inferomedial conjunctival fornix. Success rates were evaluated at 3 months and 6 months after surgery. Causes of failure, incidence of tube migration, and incidence of canthal deformity were also evaluated. Results: The success rate at 3 months postoperative was 95% in the canthal-based group and 78.6% in the fornix-based group (P = 0.283). Success rates at 6 months postoperative were 85% in the canthal-based group and 71.4% in the fornix-based group, respectively (P = 0.410). The main cause of failure was granuloma in the canthal-based group (2/20) and medial migration in the fornix-based group (3/14). Medial canthal deformity occurred in 12 of 20 cases in the canthal-based group, but none occurred in the fornix-based group. Conclusion: The canthal-based group had a lower migration rate and slightly better surgical success rate than the fornix based group, but canthal deformity was more prevalent. (C) 2017 by Mutaz B. Habal, MD.

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Our Surgical Past: An Aid to Understanding the Present and a Guide to the Future.

No abstract available

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Reconstruction of a Marjolin Ulcer Defect of the Scalp Invading Brain and Causing Brain Abscess Formation Using Free Latissimus Dorsi Flap.

Marjolin ulcers are known as aggressive malignant tumors that mostly arise over chronic wounds and cutaneous scars. Brain abscess is a serious medical condition that requires surgical drainage along with antibiotic treatment. Here, we report a case with a Marjolin ulcer located over the right parietal bone with intracranial abscess formation along with tumor invasion into brain parenchyma. This patient was a 64-year-old man and had a 4 x 4 cm open wound on his scalp from which a purulent discharge was coming. This wound required surgical excision with security margins, resection of bone, evacuation of the cystic cavity, and excision of the walls of the cystic cavity, which were invaded by the tumor. Duraplasty and reconstruction of the defect with a free lattisimus dorsi flap are performed. To the best of our knowledge, the case reported here is unique because of the formation of brain abscess in the background of a long-lasting Marjolin ulcer invading brain parenchyma. It must be remembered that on the background of cutaneous scars located over the scalp, a Marjolin ulcer may develop, and if left untreated, tumor cells may invade even the brain parenchyma. Long-term asymptomatic brain infections may also accompany the given scenario, and complicate differential diagnosis. (C) 2017 by Mutaz B. Habal, MD.

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A new parameter for quantifying the variability of surface electromyographic signals during gait: the occurrence frequency

Publication date: Available online 30 June 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Francesco Di Nardo, Alessandro Mengarelli, Annachiara Strazza, Valentina Agostini, Marco Knaflitz, Laura Burattini, Sandro Fioretti
Natural variability of myoelectric activity during walking was recently analyzed considering hundreds of strides. This allowed assessing a parameter seldom considered in classic surface EMG (sEMG) studies: the occurrence frequency, defined as the frequency each muscle activation occurs with, quantified by the number of strides when a muscle is recruited with that specific activation modality. Aim of present study was to propose the occurrence frequency as a new parameter for assessing sEMG-signal variability during walking. Aim was addressed by processing sEMG signals acquired from Gastrocnemius Lateralis, Tibialis Anterior, Rectus Femoris and Biceps femoris in 40 healthy subjects in order to: 1) show that occurrence frequency is not correlated with ON/OFF instants (Rmean=0.11±0.07; P>0.05) and total time of activation (Rmean=0.15±0.08; P>0.05); 2) confirm the above results by two handy examples of application (analysis of gender and age) which highlighted that significant (P<0.05) gender-related and age-related differences within population were detected in occurrence frequency, but not in temporal sEMG parameters. In conclusion, present study demonstrated that occurrence frequency is able to provide further information, besides those supplied by classical temporal sEMG parameters and thus it is suitable to complement them in the evaluation of variability of myoelectric activity during walking.



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Craniofacial features affecting mandibular asymmetries in skeletal Class II patients

Abstract

Objectives

The aim of this study was to evaluate the characteristics affecting different intensities of mandibular asymmetry in skeletal Class II adults using three-dimensional images. This study is clinically relevant since it allows professionals to evaluate the morphological components related to these deformities and more carefully obtain correct diagnosis and treatment plan for such patients.

Methods

Cone-beam computed tomography data of 120 Class II patients (40 with relative symmetry, 40 with moderate asymmetry, and 40 with severe asymmetry) were imported to SimPlant Ortho Pro^® 2.0 software (Dental Materialise, Leuven, Belgium). Three reference planes were established and linear measurements were performed from specific landmarks to these planes, comparing the deviated side and the contralateral side in each group, as well as the differences between groups. The correlation between midline mandibular asymmetry and other variables was also evaluated. Statistical analyses considered a significance level of 5%.

Results

Comparing the values obtained on the deviated side and on the contralateral side, there were significant differences for patients with moderate asymmetry and severe asymmetry. However, differences were seen more often in severe mandibular asymmetries. In those patients, there was a significant correlation of the gnathion deviation with lower dental midline deviation, difference in the lateral gonion positions, difference in the mandibular rami heights, and difference in the jugale vertical displacements.

Conclusions

For skeletal Class II patients with mandibular asymmetry, some craniofacial features are related to chin deviation and require proper evaluation, including the bilateral differences in the ramus height, mandibular body length, transverse and vertical positioning of the gonion and jugale points.

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Incidence of Hepatitis B Viral Reactivation After Kidney Transplantation With Low-dose Rituximab Administration.

Background: In hematological malignancy patients intended to receive rituximab, hepatitis B virus (HBV) serology screening, viral reactivation monitoring, are recommended. However, the effect of single-dose rituximab (RIT) on HBV reactivation in kidney transplant patients with previous HBV infection is still unclear. Methods: In this retrospective cohort study consisting of 1294 kidney transplant patients, we identified 76 patients showing preoperative hepatitis B surface antigen-negative, hepatitis B core antibody-positive, and HBV-DNA negative results. A rituximab dose of 200mg/body was administered to 48 patients, 46 of whom did not receive prophylaxis (RIT+ group). Twenty-eight patients received neither rituximab nor prophylaxis (RIT- group). We monitored HBV-DNA by polymerase chain reaction every 1-3 months, and HBV reactivation was defined as detectable HBV-DNA. Results: HBV reactivation was found in 1 patient in the RIT+ group (2.2%) and 1 patient in the RIT- group (3.6%) at 6 weeks and 5.5 years posttransplant, respectively, but spontaneously cleared. Both patients showed positive hepatitis B surface antibody (anti-HBs) preoperatively. HBV reactivation was not found in 6 patients lacking anti-HBs preoperatively. Conclusions: Low-dose RIT administration in kidney transplant patients without prophylaxis is associated with low incidence of HBV reactivation. However, the comparisons amongst standard-dose RIT, low-dose RIT, and controls with high quality study design is necessary. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Aggregating Marginal Gains in Posttransplant CMV Risk Stratification.

No abstract available

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The use of Ex Vivo Generated Regulatory T Cell Preparations in a Canine Lung Allograft Model.

No abstract available

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Non-HLA Antibodies Impact on C4d staining, Stellate Cell Activation and Fibrosis in Liver Allografts.

Background: Recent data has shown an increased risk for rejection, fibrosis progression, and death in liver transplant (LT) recipients with preformed or de novo HLA donor-specific alloantibodies (DSA). However, the role of non-HLA autoantibodies and the interaction between HLA DSA and non-HLA autoantibodies remains uncharacterized. Methods: We analyzed 1269 primary LT recipients from 1/2000-4/2009 with known HLA DSA status for Angiotensin II Type-1 Receptor and Endothelin-1 Type A receptor autoantibodies(anti-AT1R-Abs and anti-ETAR-Abs respectively) pre-LT and year-1 post-LT. Results: Preformed non-HLA autoantibodies alone did not impact outcomes. In multivariable modeling, the combination of preformed non-HLA autoantibodies and HLA-DSA were associated with an increased risk for death [Hazard Ratio (HR)=1.66; p=0.02] especially if the HLA DSA was of the IgG3 subclass (HR=2.28; p=0.01). A single de novo non-HLA autoantibody was associated with an increased risk for TCMR or AMR rejection(68% vs. 41%, p=0.01) and fibrosis progression (HR=1.84; p=0.02). Biopsies with de novo non-HLA autoantibodies revealed a new sinusoidal C4d staining pattern when compared to HLA DSA(71% vs. 3%; p

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Relevance of chromosomal band 11q13 in oral carcinogenesis: An update of current knowledge

Publication date: September 2017
Source:Oral Oncology, Volume 72
Author(s): Pablo Ramos-García, Isabel Ruiz-Ávila, José Antonio Gil-Montoya, Ángela Ayén, Lucía González-Ruiz, Francisco José Navarro-Triviño, Miguel Ángel González-Moles
An important event in oral carcinogenesis is the amplification of chromosomal band 11q13, in which numerous oncogenes and some tumor-suppressor genes are localized and frequently co-amplified during the malignant transformation of oral epithelium. The objectives of this study were to review published data on the involvement of 11q13 amplification in oral cancer, to provide an update on novel concepts and terminology related to gene amplification, and to explore the composition of the 11q13 amplicon in OSCC, including its most relevant amplicon cores and potential drivers. We report on the critical oncogenes and tumor-suppressor genes in 11q13 that may play a major role in oral cancer, focusing on their functions, on the characteristics acquired by their amplification, and on their clinicopathological implications. Finally, we discuss the possible usefulness of the 11q13 region as a therapeutic target in oral cancer.



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Craniofacial features affecting mandibular asymmetries in skeletal Class II patients

Abstract

Objectives

The aim of this study was to evaluate the characteristics affecting different intensities of mandibular asymmetry in skeletal Class II adults using three-dimensional images. This study is clinically relevant since it allows professionals to evaluate the morphological components related to these deformities and more carefully obtain correct diagnosis and treatment plan for such patients.

Methods

Cone-beam computed tomography data of 120 Class II patients (40 with relative symmetry, 40 with moderate asymmetry, and 40 with severe asymmetry) were imported to SimPlant Ortho Pro^® 2.0 software (Dental Materialise, Leuven, Belgium). Three reference planes were established and linear measurements were performed from specific landmarks to these planes, comparing the deviated side and the contralateral side in each group, as well as the differences between groups. The correlation between midline mandibular asymmetry and other variables was also evaluated. Statistical analyses considered a significance level of 5%.

Results

Comparing the values obtained on the deviated side and on the contralateral side, there were significant differences for patients with moderate asymmetry and severe asymmetry. However, differences were seen more often in severe mandibular asymmetries. In those patients, there was a significant correlation of the gnathion deviation with lower dental midline deviation, difference in the lateral gonion positions, difference in the mandibular rami heights, and difference in the jugale vertical displacements.

Conclusions

For skeletal Class II patients with mandibular asymmetry, some craniofacial features are related to chin deviation and require proper evaluation, including the bilateral differences in the ramus height, mandibular body length, transverse and vertical positioning of the gonion and jugale points.

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Letter to the editor

Publication date: Available online 30 June 2017
Source:American Journal of Otolaryngology
Author(s): Satvinder Singh Bakshi




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Letter to Editors: Detection of endolymphatic hydrops using traditional MR imaging sequences

Publication date: Available online 30 June 2017
Source:American Journal of Otolaryngology
Author(s): Shinji Naganawa, Michihiko Sone




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Ultrasound-dependent cytoplasmic internalization of a peptide-sonosensitizer conjugate

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Yuki Inaba, Kazunori Watanabe, Mizuki Kitamatsu, Eiji Nakata, Atsushi Harada, Takashi Ohtsuki
A method to induce cytoplasmic peptide delivery, using ultrasound, was demonstrated using a molecular conjugate of a cell-penetrating peptide (CPP), a functional peptide, and a sonosensitizer. As a model of such molecular conjugates, TatBim-RB, consisting of the Tat CPP, the Bim apoptosis inducing peptide, and the sonosensitizer rose bengal was synthesized. CPPs have been widely used for intracellular delivery of various cargos; however, CPP-fused molecules tend to become entrapped in endosomes, as was observed for TatBim-RB molecules applied to cells. To promote escape of the entrapped TatBim-RB molecules, cells were irradiated with ultrasound, which successfully induced endosomal escape and cytoplasmic dispersion of TatBim-RB, and subsequently apoptosis. Our results suggest that this peptide-sonosensitizer conjugate strategy may facilitate numerous kinds of medicinal chemistry studies, and furthermore, this specific conjugate may exhibit potential as a novel therapeutic agent for the promotion of apoptosis.

Graphical abstract

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Synthesis and biological evaluation of JL-A7 derivatives as potent ABCB1 inhibitors

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Miaobo Pan, Jian Cui, Lei Jiao, Hesham Ghaleb, Chen Liao, Jiaqi Zhou, Mutta Kairuki, Haiyan Lin, Wenlong Huang, Hai Qian
Cancer chemotherapy failure is often due to the overexpression of ATP-binding cassette (ABC) transporters (particularly ABCB1), resulting in a variety of structurally and pharmacologically unrelated drugs efflux. The multidrug resistance (MDR) phenomenon could be reversed by ABCB1 inhibitors. Now, JL-A7 as the lead compound based on a triazol-N-ethyl-tetrahydroisoquinoline scaffold, 18 compounds were designed and synthesized. Substitution in para positions yielded high activities toward ABCB1. Moreover, compound 5 could effectively block the drug efflux function of ABCB1 and increase the accumulation of anti-cancer drugs to achieve effective treatment concentration in MDR cells.

Graphical abstract

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Editorial board

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15





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The selective cytotoxicity of new triazene compounds to human melanoma cells

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Ana Sousa, Fábio Santos, Maria Manuela Gaspar, Susana Calado, João D. Pereira, Eduarda Mendes, Ana Paula Francisco, Maria Jesus Perry
Metastatic melanoma still remains one the most difficult cancers to overcome. The aim of our research was the design of anti-tumour triazene compounds 3 for application to a melanoma-specific therapy. The strategy exploits the unique enzyme pathway of melanin biosynthesis for conversion of non-toxic prodrugs into toxic drugs in the melanoma cell. The compounds 3 were designed by coupling two active moieties, the alkylating triazenes and different tyrosinase substrates. All compounds 3 revealed to be chemically stable in isotonic phosphate buffer (PBS) at physiologic pH (t½≥48h), and most of them showed to be slowly hydrolysed in human plasma (1.5≤t½ (h)≤161). Compounds 3c–n revealed to be excellent tyrosinase substrates (0.74≤t½ (min)≤6) with the best tyrosinase substrate 3l releasing MMT 45s after tyrosinase activation. Structure-activity relationship studies allowed the identification of the better structural features for enzyme affinity. Furthermore, the derivatives 3l and 3m showed cell selectivity with significant cytotoxic effects (IC50 values of 46–65μM) against melanoma cell lines with tyrosinase overexpression MNT-1 and B16F10.

Graphical abstract

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Synthesis and pharmacological evaluation of glycine amide derivatives as novel vascular adhesion protein-1 inhibitors without CYP3A4 and CYP2C19 inhibition

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Susumu Yamaki, Yuji Koga, Akira Nagashima, Mitsuhiro Kondo, Yoshiaki Shimada, Keitaro Kadono, Ayako Moritomo, Kosei Yoshihara
Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted optimization studies of our lead compound 1, which we previously reported as a novel VAP-1 inhibitor, to enhance the inhibition of human VAP-1 and to reduce CYP3A4 and CYP2C19 inhibition. As a result, we identified 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid (17h) as a novel orally active VAP-1 inhibitor, with 14-fold increased human VAP-1 inhibitory activity compared to 1, without CYP3A4 and CYP2C19 inhibition. Oral administration of 17h significantly inhibited the progression of proteinuria in streptozotocin (STZ) induced diabetic rats at 0.3 and 1mg/kg, suggesting that this compound has potential to be a therapeutic agent for the treatment of diabetic nephropathy.

Graphical abstract

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Design, synthesis, and evaluation of DNA topoisomerase II-targeted nucleosides

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Hironobu Matsumoto, Mitsuaki Yamashita, Teruyuki Tahara, Shinya Hayakawa, Shun-ichi Wada, Kiyoshi Tomioka, Akira Iida
We developed novel nucleoside-based topoisomerase II selective inhibitors and showed that small structural units, such as catechols, are essential for DNA topoisomerase II inhibitory activity. Moreover, nucleoside analogues containing TBS and 1,3-dithian moieties had potent and selective DNA topoisomerase II inhibitory activities. In further experiments, compound 25b having a beta configuration of the thymine moiety showed relatively strong growth inhibitory activity against cancer cell lines, and was more potent against all cancer cell lines than compound 26b, which carries a thymine moiety in the alpha configuration.

Graphical abstract

http://ift.tt/2sqwjiT

Discovery of novel 5-oxa-2,6-diazaspiro[3.4]oct-6-ene derivatives as potent, selective, and orally available somatostatin receptor subtype 5 (SSTR5) antagonists for treatment of type 2 diabetes mellitus

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Hideki Hirose, Takeshi Yamasaki, Masaki Ogino, Ryo Mizojiri, Yumiko Tamura-Okano, Hiroaki Yashiro, Yo Muraki, Yoshihide Nakano, Jun Sugama, Akito Hata, Shinji Iwasaki, Masanori Watanabe, Tsuyoshi Maekawa, Shizuo Kasai
Somatostatin receptor subtype 5 (SSTR5) has emerged as a novel attractive drug target for type 2 diabetes mellitus. Starting from N-benzyl azetidine derivatives 1 and 2 as in-house hit compounds, we explored the introduction of a carboxyl group into the terminal benzene of 1 to enhance SSTR5 antagonistic activity by the combination of the substituents at the 3-position of the isoxazoline. Incorporation of a carboxyl group at the 4-position of the benzene ring resulted in a significant enhancement in potency, however, the 4-benzoic acid derivative 10c exhibited moderate human ether-a-go-go related gene (hERG) inhibitory activity. A subsequent optimization study revealed that replacement of the 4-benzoic acid with an isonipecotic acid dramatically reduced hERG inhibition (5.6% inhibition at 30μM) by eliminating π-related interaction with hERG K⁺ channel, which resulted in the identification of 1-(2-((2,6-diethoxy-4′-fluorobiphenyl-4-yl)methyl)-5-oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl)piperidin-4-carboxylic acid 25a (hSSTR5/mSSTR5 IC50=9.6/57nM). Oral administration of 25a in high-fat diet fed C57BL/6J mice augmented insulin secretion in a glucose-dependent manner and lowered blood glucose concentration.

Graphical abstract

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Synthesis and biological activity of peptide proline-boronic acids as proteasome inhibitors

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Liqiang Han, Yanzhao Wen, Ridong Li, Bo Xu, Zemei Ge, Xin Wang, Tieming Cheng, Jingrong Cui, Runtao Li
On the basis of the application of proline-boronic acid as pharmacophore in the kinase inhibitors and our previous research results, using proline-boronic acid as warhead, two series of peptide proline-boronic acids, dipeptide proline-boronic acids (I) and tripeptide proline-boronic acids (II), were designed and synthesized. All the synthesized compounds were first evaluated for their biological activity against MGC803 cell, and then, the best compound II-7 was selected to test its anti-tumor spectrum on six human tumor cell lines and proteasome inhibition against three subunits. The results indicated that series II have much better biological activities than series I. The compound II-7 exhibited not only excellent biological activities with IC50 values of nM level in both cell and proteasome models, but also much better subunit selectivity. Thus, proline-boronic acid as warhead is reasonable in the design of proteasome inhibitors.

Graphical abstract

http://ift.tt/2sr0wy3

Design, synthesis and tumor cell growth inhibitory activity of 3-nitro-2H-cheromene derivatives as histone deacetylaes inhibitors

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Shuai Tan, Feng He, Tingting Kong, Jingde Wu, Zhaopeng Liu
As a continuous research for the discovery of coumarin-based targeted anticancer agents, we designed and synthesized a series of novel histone deacetylases (HDAC) inhibitors using the 8-ethoxy-3-nitro-2H-chromene as the surface binding or cap group, linear dicarboxylic acid or ω-amino acid moiety with different length as the linking motif, ortho-aminoanilides, amides or α-aminoamides as the zinc binding group and the internal cavity motifs. Most of these 3-nitro-2H-chromene derivatives exhibited good growth inhibitory activity against K562, A549, MCF-7, PC3 and Hela cells and were more potent than the reference drug SAHA and MS-275. At the concentration of 10µM, the ortho-aminoanilide series and the d-Phe derived α-aminoamide derivatives 16a and 16b displayed more potent activity toward HADC1 over HADC2, and only moderate to weak activity over HADC6. In contrast, the amide ZBG analogues, 12a and 12b, 14 and 15, were only moderate HDAC6 inhibitors, but more selective over HDAC1 and HDAC2. The ortho-aminoanilides 9b, 9c, 10b, 10c, 11b, and the α-aminoamides 16a and 16b were potent HADC1 inhibitors with the IC50 values in the nanomolar ranges. The ortho-aminoanilides 10b and10c with a phenyl internal cavity motif were more potent than MS-275 as HADC1 inhibitors and more selective over HADC2.

Graphical abstract

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Olaparib hydroxamic acid derivatives as dual PARP and HDAC inhibitors for cancer therapy

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Zigao Yuan, Shaopeng Chen, Qinsheng Sun, Ning Wang, Dan Li, Shuangshuang Miao, Chunmei Gao, Yuzong Chen, Chunyan Tan, Yuyang Jiang
Olaparib was the first PARP inhibitor approved by the FDA for patients with BRCA-mutated ovarian cancer. Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of olaparib and HDAC inhibitors. Herein, based on rational drug design strategy, hydroxamic acid derivatives of olaparib were constructed as dual PARP and HDAC inhibitors. These hybrid compounds showed potent inhibitory activities against PARP1/2 and HDAC1/6 with IC50 values in the nanomolar range. Furthermore, compound P1 exhibited broad-spectrum antiproliferative activities in selected human cancer cell lines. Specially, P1 showed more potent activity than olaparib and SAHA in cancer cells MDA-MB-231, HCC1937 and Raji, and 4.1-fold less cytotoxicity compared with SAHA to normal cells MCF-10A. Further mechanism study indicated that P1 could induce the cleavage of PARP and the hyperacetylation of histones, increase the expression of DNA damage biomarker γ-H2AX, decrease the level of BRCA1 and RAD51, and regulate tumor cell growth and apoptosis through modulating both mitochondrial- and death receptor-mediated pathways. Therefore, our study suggested that compounds targeting PARP and HDAC concurrently might be a practical approach for cancer therapy.

Graphical abstract

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Discovery of novel somatostatin receptor subtype 5 (SSTR5) antagonists: Pharmacological studies and design to improve pharmacokinetic profiles and human Ether-a-go-go-related gene (hERG) inhibition

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Takeshi Yamasaki, Hideki Hirose, Tohru Yamashita, Nobuyuki Takakura, Sachie Morimoto, Takashi Nakahata, Asato Kina, Yoshihide Nakano, Yumiko Okano Tamura, Jun Sugama, Tomoyuki Odani, Yuji Shimizu, Shinji Iwasaki, Masanori Watanabe, Tsuyoshi Maekawa, Shizuo Kasai
Somatostatin (SST) is a peptide hormone comprising 14 or 28 amino acids that inhibits endocrine and exocrine secretion via five distinct G-protein-coupled receptors (SSTR1–5). SSTR5 has an important role in inhibiting the secretion of pancreatic and gastrointestinal hormones (e.g., insulin, GLP-1, PYY) through the binding of SSTs; hence, SSTR5 antagonists are expected to be novel anti-diabetic drugs. In the course of our lead generation program of SSTR5 antagonists, we have discovered a novel spiroazetidine derivative 3a. However, pharmacological evaluation of 3a revealed that it had to be administered at a high dose (100mg/kg) to show a persistent glucose-lowering effect in an oral glucose tolerance test (OGTT). We therefore initiated an optimization study based on 3a aimed at improving the antagonistic activity and mean residence time (MRT), resulting in the identification of 2-cyclopropyl-5-methoxybiphenyl derivative 3k. However, 3k did not show a sufficient persistent glucose-lowering effect in an OGTT; moreover, hERG inhibition was observed. Hence, further optimization study of the biphenyl moiety of compound 3k, focused on improving the pharmacokinetic (PK) profile and hERG inhibition, was conducted. Consequently, the introduction of a chlorine atom at the 6-position on the biphenyl moiety addressed a putative metabolic soft spot and increased the dihedral angle of the biphenyl moiety, leading to the discovery of 3p with an improved PK profile and hERG inhibition. Furthermore, 3p successfully exhibited a persistent glucose-lowering effect in an OGTT at a dose of 3mg/kg.

Graphical abstract

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Discovery of novel quinazoline-2,4(1H,3H)-dione derivatives as potent PARP-2 selective inhibitors

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Hailong Zhao, Ming Ji, Guonan Cui, Jie Zhou, Fangfang Lai, Xiaoguang Chen, Bailing Xu
The PARP-2 selective inhibitor is important for clarifying specific roles of PARP-2 in the pathophysiological process and developing desired drugs with reduced off-target side effects. In this work, a series of novel quinazoline-2,4(1H,3H)-dione derivatives was designed and synthesized to explore isoform selective PARP inhibitors. As a result, compound 11a (PARP-1 IC50=467nM, PARP-2 IC50=11.5nM, selectivity PARP-1/PARP-2=40.6) was disclosed as the most selective PARP-2 inhibitor with high potency to date. The binding features of compound 11a within PARP-1 and PARP-2 were investigated respectively to provide useful insights for the further construction of new isoform selective inhibitors of PARP-1 and PARP-2 by using CDOCKER program.

Graphical abstract

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Isolation, structure elucidation, and synthesis of antiplasmodial quinolones from Crinum firmifolium

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Christopher C. Presley, Yongle Du, Seema Dalal, Emilio F. Merino, Joshua H. Butler, Stéphan Rakotonandrasana, Vincent E. Rasamison, Maria B. Cassera, David G.I. Kingston
Antiplasmodial bioassay guided fractionation of a Madagascar collection of Crinum firmifolium led to the isolation of seven compounds. Five of the seven compounds were determined to be 2-alkylquinolin-4(1H)-ones with varying side chains. Compounds 1 and 4 were determined to be known compounds with reported antiplasmodial activities, while 5 was believed to be a new branched 2-alkylquinolin-4(1H)-one, however, it was isolated in limited quantities and in admixture and therefore was synthesized to confirm its structure as a new antiplasmodial compound. Along with 5, two other new and branched compounds 6 and 7 were synthesized as well. Accompanying the five quinolones were two known compounds 2 and 3 which are inactive against Plasmodium falciparum. The isolation, structure elucidation, total synthesis, and biological evaluation of these compounds are discussed in this article.

Graphical abstract

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Synthesis, antiviral evaluation and molecular docking studies of N4-aryl substituted/unsubstituted thiosemicarbazones derived from 1-indanones as potent anti-bovine viral diarrhea virus agents

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): María C. Soraires Santacruz, Matías Fabiani, Eliana F. Castro, Lucía V. Cavallaro, Liliana M. Finkielsztein
A series of N⁴-arylsubstituted thiosemicarbazones derived from 1-indanones and a set of compounds lacking such substitution in the N⁴ position of the thiosemicarbazone moiety were synthesized and evaluated for their anti-bovine viral diarrhea virus (BVDV) activity. Among these, derivatives 2 and 15 displayed high activity (EC50=2.7±0.4 and 0.7±0.1µM, respectively) as inhibitors of BVDV replication. Novel key structural features related to the anti-BVDV activity were identified by structure-activity relationship (SAR) analysis. In a previous study, the thiosemicarbazone of 5,6-dimethoxy-1-indanone (5,6-TSC) was characterized as a non-nucleoside inhibitor (NNI) of the BVDV RNA-dependent RNA polymerase. In the present work, cross-resistance assays were performed with the most active compounds. Such studies were carried out on 5,6-TSC resistant BVDV (BVDV-TSC^r T1) carrying mutations in the viral polymerase. This BVDV mutant was also resistant to compound 15. Molecular docking studies and MM/PBSA calculations were performed to assess the most active derivatives at the 5,6-TSC viral polymerase binding site. The differences in the interaction pattern and the binding affinity of derivative 15 either to the wild type or BVDV-TSC^r T1 polymerase were key factors to define the mode of action of this compound.

Graphical abstract

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1,2,4-Triazole and 1,3,4-oxadiazole analogues: Synthesis, MO studies, in silico molecular docking studies, antimalarial as DHFR inhibitor and antimicrobial activities

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Sampark S. Thakkar, Parth Thakor, Hiren Doshi, Arabinda Ray
1,2,4-Triazole and 1,3,4-oxadiazole analogues are of interest due to their potential activity against microbial and malarial infections. In search of suitable antimicrobial and antimalarial compounds, we report here the synthesis, characterization and biological activities of 1,2,4-triazole and 1,3,4-oxadiazole analogues (SS 1-SS 10). The molecules were characterized by IR, mass, ¹H NMR, ¹³C NMR and elemental analysis. The in vitro antimicrobial activity was investigated against pathogenic strains, the results were explained with the help of DFT and PM6 molecular orbital calculations. In vitro cytotoxicity and genotoxicity of the molecules were studied against S. pombe cells. In vitro antimalarial activity was studied. The active compounds were further evaluated for enzyme inhibition efficacy against the receptor Pf-DHFR computationally as well as in vitro to prove their candidature as lead dihydrofolate reductase inhibitors.

Graphical abstract

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Synthesis, molecular modelling and CYP24A1 inhibitory activity of novel of (E)-N-(2-(1H-imidazol-1-yl)-2-(phenylethyl)-3/4-styrylbenzamides

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Ismail M. Taban, Jinge Zhu, Hector F. DeLuca, Claire Simons
CYP24A1 (25-hydroxyvitamin D-24-hydroxylase) is a useful enzyme target for a range of medical conditions including cancer, cardiovascular and autoimmune disease, which show elevated CYP24A1 levels and corresponding reduction of calcitriol (the biologically active form of vitamin D). A series of (E)-N-(2-(1H-imidazol-1-yl)-2-(phenylethyl)-3/4-styrylbenzamides have been synthesised using an efficient synthetic route and shown to be potent inhibitors of CYP24A1 (IC50 0.11–0.35μM) compared with the standard ketoconazole. Molecular modelling using our CYP24A1 homology model showed the inhibitors to fill the hydrophobic binding site, forming key transition metal interaction between the imidazole nitrogen and the haem Fe³⁺ and multiple interactions with the active site amino acid residues.

Graphical abstract

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Synthesis, biological evaluation and molecular modeling of imidazo[1,2-a]pyridine derivatives as potent antitubulin agents

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Jin Liu, Daiying Zuo, Tongfei Jing, Ming Guo, Lingyun Xing, Wenyu Zhang, Jianwen Zhao, Jiwei Shen, Ping Gong, Dajun Zhang, Xin Zhai
Two series of novel 5,7-diarylimidazo[1,2-a]pyridine-8-carbonitrile derivatives (3a–3q and 7a–7n) were designed by modification of CA-4 pharmacophore to develop colchicine targeted antitubulin agents. All compounds were efficiently synthesized and evaluated for their cytotoxicity against five selected cancer cell lines (HT-29, H460, A549, MKN-45 and SMMC-7721) which got an insight in structure and activity relationships (SARs). Several molecules (7e, 7f, 7h–7j and 7m) were disclosed to exhibit promising antiproliferative activity with IC50 values in double-digit nanomolar degree. Optimization toward these compounds led to the discovery of a promising lead 7e, which showed noteworthy potency with IC50 value ranging from 0.01 to 3.2µM superior to CA-4 and Crolibulin. Importantly, immunofluorescence staining and colchcine competitive binding assay revealed that microtubule dynamics was disrupted by 7e by binding at the colchicine site of tubulin. Moreover, molecular docking studies suggested the binding of this mimic at colchcine-binding site is similar to Crolibulin, as was in conformity with the observed SARs for these compounds.

Graphical abstract

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Discovery of simplified leucyladenylate sulfamates as novel leucyl-tRNA synthetase (LRS)-targeted mammalian target of rapamycin complex 1 (mTORC1) inhibitors

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Suyoung Yoon, Jong Hyun Kim, Yura Koh, Phuong-Thao Tran, Jihyae Ann, Ina Yoon, Jayun Jang, Won Kyung Kim, Sangkook Lee, Jiyoun Lee, Sunghoon Kim, Jeewoo Lee
Leucyl-tRNA synthetase (LRS) has been reported to be a possible mediator of intracellular amino acids signaling to mTORC1. Given that mTORC1 is associated with cell proliferation and tumorigenesis, the LRS-mediated mTORC1 pathway may offer an alternative strategy in anticancer therapy. In this study, we developed a series of simplified analogues of leucyladenylate sulfamate (1) as LRS-targeted mTORC1 inhibitors. We replaced the adenylate group with a N-(3,4-dimethoxybenzyl)benzenesulfonamide (2a) or a N-(2-phenoxyethyl)benzenesulfonamide groups (2b) that can maintain specific binding, but has more favorable physicochemical properties such as reduced polarity and asymmetric centers. Among these simplified analogues, compound 16 and its constrained analogue 22 effectively inhibited S6K phosphorylation in a dose-dependent manner and exhibited cancer cell specific cytotoxicity against six different types of cancer cells. This result supports that LRS is a viable target for novel anticancer therapy.

Graphical abstract

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Cyclic MOG35–55 ameliorates clinical and neuropathological features of experimental autoimmune encephalomyelitis

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Athanasios Lourbopoulos, George Deraos, Minos-Timotheos Matsoukas, Olga Touloumi, Aggeliki Giannakopoulou, Hubert Kalbacher, Nikolaos Grigoriadis, Vasso Apostolopoulos, John Matsoukas
EAE is induced to susceptible mice using linear peptides of myelin proteins of the central nervous system. Specific peptide motifs within the peptide-binding groove of the MHC peptide-complex determines the affinity of the peptide in each animal and the consequent T-cell receptor recognition and activation of the cell. Altered peptide ligand (APL) vaccination is a novel approach based on an effort to induce T-cell tolerance or alter cytokine profile from pro-inflammatory to anti-inflammatory. In the present study we synthesized the MOG35–55 peptide and altered its 3-dimensional conformation to make it a cyclic one (c-MOG35–55). EAE was induced in C57BL/6 mice and pathology was studied on acute and chronic phase of the disease. Our data indicates that c-MOG35–55 peptide alone induces a mild transient acute phase without chronic axonopathy. Administration of the c-MOG35–55 peptide at a 1:1 ratio during disease induction significantly ameliorates clinical disease and underlying pathology, such as demyelination and axonopathy in the acute and chronic phases. Binding and structural studies revealed milder interactions between the c-MOG35–55 and mouse or human MHC class II alleles (H2-IA^b and HLA-DR2). Collectively, we provide data supporting for the first time the concept that the cyclic modification of an established encephalitogenic peptide ameliorates the clinical outcomes and underlying pathological processes of EAE. Such a cyclic modification of linear peptides could provide a novel treatment approach for future, patient-selective, immunomodulative treatments of multiple sclerosis.

Graphical abstract

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Evidence-Based Medicine: Mandible Fractures

Learning Objectives: After reading this article, the participant should be able to: 1. Explain the epidemiology of mandible fractures. 2. Discuss preoperative evaluation of the patient with a mandible fracture. 3. Compare the various modalities of fracture fixation. 4. Identify common complications after fracture repair. Summary: In this Maintenance of Certification/Continuing Medical Education article, the reader is provided with a review of the epidemiology, preoperative evaluation, perioperative management, and surgical outcomes of mandible fractures. The objective of this series is to present a review of the literature so that the practicing physician can remain up-to-date on key evidence-based guidelines to enhance management and improve outcomes. The physician can also seek further in-depth study of the topic through the references provided.

http://ift.tt/2utrOQZ