Fisetin inhibits IL-1β-induced inflammatory response in human osteoarthritis chondrocytes through activating SIRT1 and attenuates the progression of osteoarthritis in mice

Publication date: April 2017
Source:International Immunopharmacology, Volume 45
Author(s): Wenhao Zheng, Zhenhua Feng, Shengban You, Hui Zhang, Zhenyu Tao, Quan Wang, Hua Chen, Yaosen Wu
Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and inflammation. Fisetin, a polyphenol extracted from fruits and vegetables, has been reported to have anti-inflammatory effects. Our study aimed to investigate the effect of fisetin on OA both in vitro and in vivo. In vitro, chondrocytes were pretreated with fisetin alone or fisetin combined with sirtinol (an inhibitor of SIRT1) for 2h before IL-1β stimulation. Production of NO, PGE2, TNF-α and IL-6 were evaluated by the Griess reaction and ELISAs. The mRNA (COX-2, iNOS, MMP-3, MMP-13, ADAMTS-5, Sox-9, aggrecan and collagen-II) and protein expression (COX-2, iNOS, MMP-3, MMP-13, ADAMTS-5 and SIRT1) were measured by qRT-PCR and Western blot respectively. Immunofluorescence was used to assess the expression of collagen-II and SIRT1. SIRT1 activity was quantified with SIRT1 fluorometric assay kit. The in vivo effect of fisetin was evaluated by gavage in mice OA models induced by destabilization of the medial meniscus (DMM). We found that fisetin inhibited IL-1β-induced expression of NO, PGE2, TNF-α, IL-6, COX-2, iNOS, MMP-3, MMP-13, ADAMTS-5. Besides, fisetin remarkably decreased IL-1β-induced degradation of Sox-9, aggrecan and collagen-II. Furthermore, fisetin significantly inhibited IL-1β-induced SIRT1 decrease and inactivation. However, the inhibitory effect of fisetin was obvious abolished by sirtinol, suggesting that fisetin exerts anti-inflammatory effects through activating SIRT1. In vivo, fisetin-treated mice exhibited less cartilage destruction and lower OARSI scores. Moreover, fisetin reduced subchondral bone plate thickness and alleviated synovitis. Taken together, these findings indicate that fisetin may be a potential agent in the treatment of OA.

Graphical abstract

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Role of MRI in differentiating benign from malignant breast lesions using dynamic contrast enhanced MRI and diffusion weighted MRI

Publication date: Available online 15 February 2017
Source:Alexandria Journal of Medicine
Author(s): Mohamed Ahmed Youssef, Hanan Mohamed Saleh Elahwal, Mohamed Morsi Alwageeh, Sally Elbially Attya
ObjectiveTo evaluate the role of MRI in differentiation of benign from malignant breast lesions using dynamic contrast enhanced MRI (DCE-MRI) and diffusion weighted MRI (DW-MRI).Patients and methodsThe study included 33 female patients with clinically suspicious breast lesions detected by mammography and/or breast ultrasound. Cases were referred from general surgery departments in Tanta university hospital. The patients underwent full history taking and clinical examination, full field digital mammography and US, for those patients cases diagnosed on sonomammography as BI-RADS 3 & 4 were selected for MRI examination.ResultsQuantitative analysis of DWI was done for the 33 breast lesions and their ADC values are recorded at 3 different b-values (250, 600, and 1000). Seventeen lesions showed facilitated diffusion, proved to be benign and 10 lesions showed restricted diffusion, 9 lesions of them proved to be malignant and one proved to be benign. There are 6 lesions showed mixed restricted and facilitated diffusion proved to be malignant.ConclusionDWI improves the diagnostic ability of the DCE-MRI of the breast. It is a better method for detecting breast lesions than either T1- or T2-weighted imaging, but it is better to be performed in conjunction with contrast enhanced MRI.



http://ift.tt/2lTOVQD

In vivo instability of platensimycin and platencin: Synthesis and biological evaluation of urea- and carbamate-platensimycin

Publication date: Available online 16 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Liao-Bin Dong, Jeffrey D. Rudolf, Li Lin, Claudia Ruiz, Michael D. Cameron, Ben Shen
Platensimycin (PTM) and platencin (PTN), two natural products and promising drug leads that target bacterial and mammalian fatty acid synthases, are known to have unfavorable pharmacokinetic properties. It is not clear, however, what the metabolic fates of PTM and PTN are and no efforts have been reported to address this key roadblock in the development of these compounds as viable drug options. Here we describe the pharmacokinetics of PTM and PTN, and reveal rapid renal clearance as the primary metabolic liability with three additional sites of chemical liability: (i) amide hydrolysis, (ii) glucuronidation, and (iii) oxidation. We determined that hydrolysis is a viable clearance mechanism in vivo and synthesized two PTM analogues to address in vivo hydrolysis. Urea- and carbamate-PTM analogues showed no detectable hydrolysis in vivo, at the expense of antibacterial activity, with no further improvement in systemic exposure. The antibacterial sulfur-containing analogues PTM D1 and PTM ML14 showed significant decreases in renal clearance. These studies set the stage for continued generation of PTM and PTN analogues in an effort to improve their pharmacokinetics while retaining or improving their biological activities.

Graphical abstract

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Synthesis and anti-inflammatory activity of isoquebecol

Publication date: Available online 16 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Sébastien Cardinal, Pierre-Alexandre Paquet-Côté, Jabrane Azelmat, Corinne Bouchard, Daniel Grenier, Normand Voyer
We report here the synthesis of isoquebecol, an unprecedented constitutional isomer of quebecol, a polyphenolic compound discovered in maple syrup. The methodology used to prepare isoquebecol involves, as key steps, the formation of a dibromoalkene from an α-ketoester precursor, followed by a double Suzuki-Miyaura reaction. The anti-inflammatory activity of isoquebecol was studied on macrophage cells by monitoring its ability to inhibit LPS-induced IL-6 secretion. Results show that this new compound has an improved bioactivity over that of its natural isomer. Precursors and derivatives of quebecol, isoquebecol and model analog 2,3,3-triphenylpropanol were also prepared and tested in this study. Comparison between the three series of compounds led to establishing new SARs concerning the aryl ring substitution pattern on the triarylpropanol scaffold and substructure functionalization.

Graphical abstract

http://ift.tt/2lTIddj

Design and synthesis of novel, potent and selective hypoxanthine analogs as adenosine A1 receptor antagonists and their biological evaluation

Publication date: Available online 16 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Summon Koul, Vidya Ramdas, Dinesh A. Barawkar, Yogesh B. Waman, Neela Prasad, Santosh Kumar Madadi, Yogesh D. Shejul, Rajesh Bonagiri, Sujay Basu, Suraj Menon, Srinivasa B. Reddy, Sandhya Chaturvedi, Srinivas Rao Chennamaneni, Gaurav Bedse, Rhishikesh Thakare, Jayasagar Gundu, Sumit Chaudhary, Siddhartha De, Ashwinkumar V. Meru, Venkata Palle, Anita Chugh, Kasim A. Mookhtiar
Multipronged approach was used to synthesize a library of diverse C-8 cyclopentyl hypoxanthine analogs from a common intermediate III. Several potent and selective compounds were identified and evaluated for pharmacokinetic (PK) properties in Wistar rats. One of the compounds 14 with acceptable PK parameters was selected for testing in in-vivo primary acute diuresis model. The compound demonstrated significant diuretic activity in this model.

Graphical abstract

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Iminosugar-based ceramide mimicry for the design of new CERT START domain ligands

Publication date: Available online 14 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Cécile Santos, Fabien Stauffert, Stéphanie Ballereau, Cécile Dehoux, Frédéric Rodriguez, Anne Bodlenner, Philippe Compain, Yves Génisson
The enigmatical dichotomy between the two CERT/GPBP protein isoforms, their vast panel of biological implications and the scarcity of known antagonist series call for new ligand chemotypes identification. We report the design of iminosugar-based ceramide mimics for the development of new START domain ligands potentially targeting either protein isoforms. Strategic choice of i) an iminoxylitol core structure and ii) the positioning of two dodecyl residues led to an extent of protein binding comparable to that of the natural cargo lipid ceramide or the archetypical inhibitor HPA-12. Molecular docking study evidenced a possible mode of protein binding fully coherent with the one observed in crystalline co-structures of known ligands. The present study thus paves the way for cellular CERT inhibition activity studies en route to the development of pharmacological tools aiming at deciphering the respective function and therapeutic potential of the two CERT/GPBP protein isoforms.

Graphical abstract

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Multifunctional thioxanthone derivatives with acetylcholinesterase, monoamine oxidases and β-amyloid aggregation inhibitory activities as potential agents against Alzheimer’s disease

Publication date: Available online 14 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Li Luo, Yan Li, Xiaoming Qiang, Zhongcheng Cao, Rui Xu, Xia Yang, Ganyuan Xiao, Qing Song, Zhenghuai Tan, Yong Deng
A series of 1-hydroxyl-3-aminoalkoxy-thioxanthone derivatives were designed, synthesized and evaluated as potential multifunctional agents against Alzheimer's disease (AD). The results indicated that most of these compounds exhibited good AChE and MAOs inhibitory activities, significant inhibition of self- and Cu²⁺-induced Aβ1-42 aggregation, and moderate to good antioxidant activities. Specifically, compound 9e displayed high inhibitory potency toward AChE (IC50 = 0.59 ± 0.02 μM), MAO-A and MAO-B (IC50 = 1.01 ± 0.02 μM and 0.90 ± 0.01 μM respectively), excellent efficiency to block both self- and Cu²⁺-induced Aβ1-42 aggregation (74.8 ± 1.2% and 87.7 ± 1.9% at 25 μM, respectively), good metal-chelating property and a low toxicity in SH-SY5Y cells. Furthermore, kinetic and molecular modeling studies revealed that compound 9e binds simultaneously to the catalytic active site and peripheral anionic site of AChE, and could penetrate the BBB. Collectively, these results suggested that 9e might be a potential multifunctional agent for further development in the treatment of AD.

Graphical abstract

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Synthesis of 1,3,5-trisubstituted pyrazolines as potential antimalarial and antimicrobial agents

Publication date: Available online 14 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Vikash K Mishra, Mitali Mishra, Varsha Kashaw, Sushil K Kashaw
A series of novel 1,3,5-trisubstituted pyrazolines derivatives have been synthesized from chalcones and nicotinic acid hydrazide in two steps. In first step, chalcones were prepared by treatment of 4-hydroxy acetophenone with different substituted benzaldehyde by Claisen-Schimidt Condensation. In second step, various pyrazoline derivatives were prepared by reflux reaction of chalcones with nicotinic acid hydrazide in ethanolic solution. Compounds were confirmed by elemental analyses, IR, ¹H NMR and ¹³C NMR spectral data and were evaluated for antimalarial and antibacterial activity. Compounds 5n (IC50=0.022 μM for MRC-2 and IC50=0.192 μM for RKL-9) displayed better antiplasmodial activity than the chloroquine (CQ) against chloroquine-sensitive (MRC-2) and chloroquine-resistant (RKL-9) P. falciparum strains. The in vitro cytotoxicity study conducted on the human HepG2 cell line (>30μM) and selectivity index (100-220) indicate that this series presents an interesting selective antiplasmodial profile. Further, in vitro heme crystallization inhibition assay showed compound 5e inhibited formation of β-hematin more efficiently than CQ. In addition, antibacterial and antifungal evaluations were conducted, compounds 5c, 5i and 5j displayed better antibacterial activity against S. aureus, B. subtilis, E. coli and P. aeruginosa than ciproafloxacin. Antifungal activity of compound 5l against A. niger (MIC-3.25μg/ml) and C. albicans(MIC-6.5μg/ml) was found to be better than the standard drug fluconazole.

Graphical abstract

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Decellularized human colorectal cancer matrices polarize macrophages towards an anti-inflammatory phenotype promoting cancer cell invasion via CCL18

Publication date: April 2017
Source:Biomaterials, Volume 124
Author(s): M.L. Pinto, E. Rios, A.C. Silva, S.C. Neves, H.R. Caires, A.T. Pinto, C. Durães, F.A. Carvalho, A.P. Cardoso, N.C. Santos, C.C. Barrias, D.S. Nascimento, P. Pinto-do-Ó, M.A. Barbosa, F. Carneiro, M.J. Oliveira
Macrophages are frequently identified in solid tumors, playing important roles in cancer progression. Their remarkable plasticity makes them very sensitive to environmental factors, including the extracellular matrix (ECM). In the present work, we investigated the impact of human colorectal tumor matrices on macrophage polarization and on macrophage-mediated cancer cell invasion. Accordingly, we developed an innovative 3D-organotypic model, based on the decellularization of normal and tumor tissues derived from colorectal cancer patients' surgical resections. Extensive characterization of these scaffolds revealed that DNA and other cell constituents were efficiently removed, while native tissue characteristics, namely major ECM components, architecture and mechanical properties, were preserved. Notably, normal and tumor decellularized matrices distinctly promoted macrophage polarization, with macrophages in tumor matrices differentiating towards an anti-inflammatory M2-like phenotype (higher IL-10, TGF-β and CCL18 and lower CCR7 and TNF expression). Matrigel invasion assays revealed that tumor ECM-educated macrophages efficiently stimulated cancer cell invasion through a mechanism involving CCL18. Notably, the high expression of this chemokine at the invasive front of human colorectal tumors correlated with advanced tumor staging. Our approach evidences that normal and tumor decellularized matrices constitute excellent scaffolds when trying to recreate complex microenvironments to understand basic mechanisms of disease or therapeutic resistance.



http://ift.tt/2lKaPJY

Exploring deformable particles in vascular-targeted drug delivery: Softer is only sometimes better

Publication date: April 2017
Source:Biomaterials, Volume 124
Author(s): Margaret B. Fish, Catherine A. Fromen, Genesis Lopez-Cazares, Alexander W. Golinski, Timothy F. Scott, Reheman Adili, Michael Holinstat, Omolola Eniola-Adefeso
The ability of vascular-targeted drug carriers (VTCs) to localize and bind to a targeted, diseased endothelium determines their overall clinical utility. Here, we investigate how particle modulus and size determine adhesion of VTCs to the vascular wall under physiological blood flow conditions. In general, deformable microparticles (MPs) outperformed nanoparticles (NPs) in all experimental conditions tested. Our results indicate that MP modulus enhances particle adhesion in a shear-dependent manner. In low shear human blood flow profiles in vitro, low modulus particles showed favorable adhesion, while at high shear, rigid particles showed superior adhesion. This was confirmed in vivo by studying particle adhesion under venous shear profiles in a mouse model of mesenteric inflammation, where MP adhesion was 127% greater (p < 0.0001) for low modulus particles compared to more rigid ones. Mechanistically, we establish that particle collisions with leukocytes drive these trends, rather than differences in particle deformation, localization, or detachment. Overall, this work demonstrates the importance of VTC modulus as a design parameter for enhanced VTC interaction with vascular walls, and thus, contributes important knowledge for development of successful clinical theranostics with applications for many diseases.



http://ift.tt/2lPHjhI

Tracking Training-Related Plasticity by Combining fMRI and DTI: The Right Hemisphere Ventral Stream Mediates Musical Syntax Processing

<span class="paragraphSection"><div class="boxTitle">Abstract</div>As a functional homolog for left-hemispheric syntax processing in language, neuroimaging studies evidenced involvement of right prefrontal regions in musical syntax processing, of which underlying white matter connectivity remains unexplored so far. In the current experiment, we investigated the underlying pathway architecture in subjects with 3 levels of musical expertise. Employing diffusion tensor imaging tractography, departing from seeds from our previous functional magnetic resonance imaging study on music syntax processing in the same participants, we identified a pathway in the right ventral stream that connects the middle temporal lobe with the inferior frontal cortex via the extreme capsule, and corresponds to the left hemisphere ventral stream, classically attributed to syntax processing in language comprehension. Additional morphometric consistency analyses allowed dissociating tract core from more dispersed fiber portions. Musical expertise related to higher tract consistency of the right ventral stream pathway. Specifically, tract consistency in this pathway predicted the sensitivity for musical syntax violations. We conclude that enduring musical practice sculpts ventral stream architecture. Our results suggest that training-related pathway plasticity facilitates the right hemisphere ventral stream information transfer, supporting an improved sound-to-meaning mapping in music.</span>

http://ift.tt/2llUZ7m

Geometric Navigation of Axons in a Cerebral Pathway: Comparing dMRI with Tract Tracing and Immunohistochemistry

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Brain fiber pathways are presumed to follow smooth curves but recent high angular resolution diffusion MRI (dMRI) suggests that instead they follow 3 primary axes often nearly orthogonal. To investigate this, we analyzed axon pathways under monkey primary motor cortex with (1) dMRI tractography, (2) axon tract tracing, and (3) axon immunohistochemistry. dMRI tractography shows the predicted crossings of axons in mediolateral and dorsoventral orientations and does not show axon turns in this region. Axons labeled with tract tracer in the motor cortex dispersed in the centrum semiovale by microscopically sharp axonal turns and/or branches (radii ≤15 µm) into 2 sharply defined orientations, mediolateral and dorsoventral. Nearby sections processed with SMI-32 antibody to label projection axons and SMI-312 antibody to label all axons revealed axon distributions parallel to the tracer axons. All 3 histological methods confirmed preponderant axon distributions parallel with dMRI axes with few axons (<20%) following smooth curves or diagonal orientations. These findings indicate that axons navigate deep white matter via microscopic sharp turns and branches between primary axes. They support dMRI observations of primary fiber axes, as well as the prediction that fiber crossings include navigational events not yet directly resolved by dMRI. New methods will be needed to incorporate coherent microscopic navigation into dMRI of connectivity.</span>

http://ift.tt/2kAlUbm

Neuronal Activation After Prolonged Immobilization: Do the Same or Different Neurons Respond to a Novel Stressor?

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Despite extensive research on the impact of emotional stressors on brain function using immediate-early genes (e.g., c-<span style="font-style:italic;">fos</span>), there are still important questions that remain unanswered such as the reason for the progressive decline of c-<span style="font-style:italic;">fos</span> expression in response to prolonged stress and the neuronal populations activated by different stressors. This study tackles these 2 questions by evaluating c-<span style="font-style:italic;">fos</span> expression in response to 2 different emotional stressors applied sequentially, and performing a fluorescent double labeling of c-Fos protein and c-<span style="font-style:italic;">fos</span> mRNA on stress-related brain areas. Results were complemented with the assessment of the hypothalamic–pituitary–adrenal axis activation. We showed that the progressive decline of c-<span style="font-style:italic;">fos</span> expression could be related to 2 differing mechanisms involving either transcriptional repression or changes in stimulatory inputs. Moreover, the neuronal populations that respond to the different stressors appear to be predominantly separated in high-level processing areas (e.g., medial prefrontal cortex). However, in low-hierarchy areas (e.g., paraventricular nucleus of the hypothalamus) neuronal populations appear to respond unspecifically. The data suggest that the distinct physiological and behavioral consequences of emotional stressors, and their implication in the development of psychopathologies, are likely to be closely associated with neuronal populations specifically activated by each stressor.</span>

http://ift.tt/2llXlmw

Decellularized human colorectal cancer matrices polarize macrophages towards an anti-inflammatory phenotype promoting cancer cell invasion via CCL18

Publication date: April 2017
Source:Biomaterials, Volume 124
Author(s): M.L. Pinto, E. Rios, A.C. Silva, S.C. Neves, H.R. Caires, A.T. Pinto, C. Durães, F.A. Carvalho, A.P. Cardoso, N.C. Santos, C.C. Barrias, D.S. Nascimento, P. Pinto-do-Ó, M.A. Barbosa, F. Carneiro, M.J. Oliveira
Macrophages are frequently identified in solid tumors, playing important roles in cancer progression. Their remarkable plasticity makes them very sensitive to environmental factors, including the extracellular matrix (ECM). In the present work, we investigated the impact of human colorectal tumor matrices on macrophage polarization and on macrophage-mediated cancer cell invasion. Accordingly, we developed an innovative 3D-organotypic model, based on the decellularization of normal and tumor tissues derived from colorectal cancer patients' surgical resections. Extensive characterization of these scaffolds revealed that DNA and other cell constituents were efficiently removed, while native tissue characteristics, namely major ECM components, architecture and mechanical properties, were preserved. Notably, normal and tumor decellularized matrices distinctly promoted macrophage polarization, with macrophages in tumor matrices differentiating towards an anti-inflammatory M2-like phenotype (higher IL-10, TGF-β and CCL18 and lower CCR7 and TNF expression). Matrigel invasion assays revealed that tumor ECM-educated macrophages efficiently stimulated cancer cell invasion through a mechanism involving CCL18. Notably, the high expression of this chemokine at the invasive front of human colorectal tumors correlated with advanced tumor staging. Our approach evidences that normal and tumor decellularized matrices constitute excellent scaffolds when trying to recreate complex microenvironments to understand basic mechanisms of disease or therapeutic resistance.



http://ift.tt/2lKaPJY

Exploring deformable particles in vascular-targeted drug delivery: Softer is only sometimes better

Publication date: April 2017
Source:Biomaterials, Volume 124
Author(s): Margaret B. Fish, Catherine A. Fromen, Genesis Lopez-Cazares, Alexander W. Golinski, Timothy F. Scott, Reheman Adili, Michael Holinstat, Omolola Eniola-Adefeso
The ability of vascular-targeted drug carriers (VTCs) to localize and bind to a targeted, diseased endothelium determines their overall clinical utility. Here, we investigate how particle modulus and size determine adhesion of VTCs to the vascular wall under physiological blood flow conditions. In general, deformable microparticles (MPs) outperformed nanoparticles (NPs) in all experimental conditions tested. Our results indicate that MP modulus enhances particle adhesion in a shear-dependent manner. In low shear human blood flow profiles in vitro, low modulus particles showed favorable adhesion, while at high shear, rigid particles showed superior adhesion. This was confirmed in vivo by studying particle adhesion under venous shear profiles in a mouse model of mesenteric inflammation, where MP adhesion was 127% greater (p < 0.0001) for low modulus particles compared to more rigid ones. Mechanistically, we establish that particle collisions with leukocytes drive these trends, rather than differences in particle deformation, localization, or detachment. Overall, this work demonstrates the importance of VTC modulus as a design parameter for enhanced VTC interaction with vascular walls, and thus, contributes important knowledge for development of successful clinical theranostics with applications for many diseases.



http://ift.tt/2lPHjhI

Precocious glucocorticoid exposure reduces skeletal muscle satellite cells in the fetal rat

Perinatal skeletal muscle growth rates are a function of protein and myonuclear accretion. Precocious exposure of the fetus to glucocorticoids (GLC) in utero impairs muscle growth. Reduced muscle protein synthesis rates contribute to this response, but the consequences for myonuclear hyperplasia are unknown. To test the hypothesis that blunting of Pax7+ muscle progenitor cell proliferative activity by GLC in vivo also contributes to reduced fetal muscle growth, pregnant rats were administered dexamethasone (DEX: 1 mg/L drinking water) from embryonic day (ED) 13 to ED21. Their responses were compared to pair-fed (PF) and ad libitum-fed controls (CON). Bromodeoxyuridine (BrdU) was administered before delivery to measure myonuclear accretion. Fetal hind limb and diaphragm muscles were collected at term and analyzed for myofiber cross-sectional area (CSA), total and BrdU+ myonuclei, Pax7+ nuclei, MyoD and myogenin protein and mRNA abundance and myosin heavy chain (MyHC) isoform composition. Mean fiber CSA, myonuclei/myofiber and Pax7+ nuclei/myofiber ratios were reduced in DEX compared to those in CON and PF muscles; CSA/myonucleus, BrdU+/total myonuclei and BrdU+ myonuclei/Pax7+ nuclei were similar among groups. Myogenin abundance was reduced and MyHC-slow was increased in DEX fetuses. The data are consistent with GLC inhibition of muscle progenitor cell proliferation limiting satellite cell and myonuclear accretion. The response of PF-fed compared to CON muscles indicated that decreased food consumption by DEX dams contributed to the smaller myofiber CSA but did not affect Pax7+ nuclear accretion. Thus, the effect on satellite cell reserve and myonuclear number also contributes to the blunting of fetal muscle growth by GLC.

http://ift.tt/2ljRnmG

Effects of impacted maxillary canines on root resorption of lateral incisors

Abstract

Objectives

The aim of this study was to analyze the amount of root resorption of maxillary lateral incisors by relating the position, location, and angulation of the impacted canine using cone-beam computed tomography (CBCT).

Materials and methods

The study sample consisted of panoramic and CBCT radiographs of 46 patients with a unilateral impacted canine (16 males and 30 females; mean age: 19.53 ± 6.66 and 19.44 ± 5.77 years, respectively). Sector location and canine angulation were measured in panoramics. All tomographs were obtained using CBCT (NewTom 5G, QR, Verona, Italy) and three-dimensional (3D) reconstructions of the maxillary laterals assessed by Mimics 14.01 image analysis software.

Results

Upper lateral incisor volume was smaller on the impacted side (401.95 ± 83.69 mm³) than on the nonimpacted side (433.54 ± 92.6 mm³, P < 0.05). There were no significant differences of lateral root resorption volume when comparing the impacted canines being on the labial or palatal sides (P > 0.05), but impacted canine angulation was significantly steeper on the labial side (70.85°) than on the palatal side (46.09°, P < 0.05). The volume of root resorption of laterals when comparing the various positions of the canine in different sectors or canine angulation in 30^o intervals was not statistically significantly different (P > 0.05).

Conclusions

The impacted canines caused root resorption of lateral incisors. The angulation of the canine was steeper on the labial side than on the palatal side but root resorption of adjacent laterals was not different. There were no statistically significant differences in the amount of root resorption of the laterals when the canine was evaluated according to localization and angulation.

http://ift.tt/2lkDhks

Retrospective 25-year follow-up of treatment outcomes in Angle Class III patients

Abstract

Objectives

Despite recommendations for early treatment of hereditary Angle Class III syndrome, late pubertal growth may cause a relapse requiring surgical intervention. This study was performed to identify predictors of successful Class III treatment.

Materials and methods

Thirty-eight Class III patients treated with a chincup were retrospectively analyzed. Data were collected from the data archive, cephalograms, and casts, including pretreatment (T0) and posttreatment (T1) data, as well as long-term follow-up data collected approximately 25 years after treatment (T2). Each patient was assigned to a success or a failure group. Data were analyzed based on time (T0, T1, T2), deviations from normal (Class I), and prognathism types (true mandibular prognathism, maxillary retrognathism, combined pro- and retrognathism).

Results

Compared to Class I normal values, the data obtained in both groups yielded 11 significant parameters. The success group showed values closer to normal at all times (T0, T1, T2) and vertical parameters decreased from T0 to T2. The failure group showed higher values for vertical and horizontal mandibular growth, as well as dentally more protrusion of the lower anterior teeth and more negative overjet at all times. In adittion, total gonial and upper gonial angle were higher at T0 and T1. A prognostic score—yet to be evaluated in clinical practice—was developed from the results. The failure group showed greater amounts of horizontal development during the years between T1 and T2. Treatment of true mandibular prognathism achieved better outcomes in female patients. Cases of maxillary retrognathism were treated very successfully without gender difference. Failure was clearly more prevalent, again without gender difference, among the patients with combined mandibular prognathism and maxillary retrognathism. Crossbite situations were observed in 44% of cases at T0. Even though this finding had been resolved by T1, it relapsed in 16% of the cases by T2.

Conclusion

The failure rate increased in cases of combined mandibular prognathism and maxillary retrognathism. Precisely in these combined Class III situations, it should be useful to apply the diagnostic and prognostic parameters identified in the present study and to provide the patients with specific information about the increased risk of failure.

http://ift.tt/2kyNyWs

Nonsyndromic oligodontia

Abstract

Objectives

The literature suggests an association between phenotype and causative mutation in nonsyndromic oligodontia. Thus, the present study was designed to verify this hypothesis in a consecutive cohort of patients.

Methods

All patients with nonsyndromic oligodontia who had been treated at the study center (Department of Orthodontics, University of Giessen, Germany) over the period 1986–2013 were contacted. Candidates were included only if at least one more family member had hypo- or oligodontia (i.e., without regard to the number of congenitally missing teeth). A total of 20 patients were included. After evaluating the dental status of each participant, the Tooth Agenesis Code (TAC) was applied. On this basis, a tentative diagnosis was made to predict which gene (MSX1, AXIN2, EDA, or PAX9) was likely to show mutation. Afterwards this hypothesis was confirmed or rejected by analyzing a saliva sample for mutation of the predicted gene. If confirmed, any available family members were also genetically analyzed.

Results

Based on their TAC scores and sums, gene mutations were predicted for MXS1 in 11, AXIN2 in 3, EDA in 6, and PAX9 in none of the patients. The evaluation of MSX1 yielded variants in 4 of 11 cases, all of which were classified as nonpathogenic since they were not considered as functional mutations. The evaluation of EDA yielded a pathogenic exon-7 mutation in 2 of 6 patients, both being brothers with different TAC scores; the same mutation, which represents a novel missense mutation, was also found in other members of the same family. The evaluation of AXIN2 yielded variants in 3 of 3 cases, all of which were classified as nonpathogenic.

Conclusions

Our findings obtained in consecutive patients with nonsyndromic oligodontia did not reveal any clinically relevant associations between oligodontia phenotype (based on TAC) and causative mutations for nonsyndromic oligodontia.

http://ift.tt/2lkyQ9l

Novel germline mutation (Leu512Met) in the thyrotropin receptor gene (TSHR) leading to sporadic non-autoimmune hyperthyroidism

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


http://ift.tt/2kAhYYb

Adiposity Indexes as Phenotype-Specific Markers of Preclinical Metabolic Alterations and Cardiovascular Risk in Polycystic Ovary Syndrome: A Cross-Sectional Study

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0042-119524

Polycystic ovary syndrome (PCOS) is a common condition in women of reproductive age. 2 PCOS phenotypes (classic and ovulatory) are currently recognized as the most prevalent, with important differences in terms of cardiometabolic features. We studied the performance of different adiposity indexes to predict preclinical metabolic alterations and cardiovascular risk in 234 women with PCOS (173 with classic and 61 with ovulatory PCOS) and 129 controls. Performance of waist circumference, waist-to-height ratio, conicity index, lipid accumulation product, and visceral adiposity index was assessed based on HOMA-IR ≥ 3.8 as reference standard for screening preclinical metabolic alterations and cardiovascular risk factors in each group. Lipid accumulation product had the best accuracy for classic PCOS, and visceral adiposity index had the best accuracy for ovulatory PCOS. By applying the cutoff point of lipid accumulation product<34, we identified a subgroup of patients without cardiometabolic alterations (P<0.05) in the group with classic PCOS, a population at higher risk for hypertension, dyslipidemia, and impaired glucose tolerance. In ovulatory PCOS, visceral adiposity index ≥ 1.32 was capable of detecting women with significantly higher blood pressure and less favorable glycemic and lipid variables as compared to ovulatory PCOS with lower visceral adiposity index (P<0.05). These results suggest LAP ≥ 34 as the best marker for classic PCOS, and VAI ≥ 1.32 for ovulatory PCOS women. Both indexes can be easily calculated with measures obtained in routine clinical practice and may be useful to detect cardiometabolic risk and secure early interventions.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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

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Heart Rate and Oxygen Uptake Kinetics in Type 2 Diabetes Patients – A Pilot Study on the Influence of Cardiovascular Medication on Regulatory Processes

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0042-119526

The aim of this pilot study was to investigate whether there are differences in heart rate and oxygen uptake kinetics in type 2 diabetes patients, considering their cardiovascular medication. It was hypothesized that cardiovascular medication would affect heart rate and oxygen uptake kinetics and that this could be detected using a standardized exercise test. 18 subjects were tested for maximal oxygen uptake. Kinetics were measured in a single test session with standardized, randomized moderate-intensity work rate changes. Time series analysis was used to estimate kinetics. Greater maxima in cross-correlation functions indicate faster kinetics. 6 patients did not take any cardiovascular medication, 6 subjects took peripherally acting medication and 6 patients were treated with centrally acting medication. Maximum oxygen uptake was not significantly different between groups. Significant main effects were identified regarding differences in muscular oxygen uptake kinetics and heart rate kinetics. Muscular oxygen uptake kinetics were significantly faster than heart rate kinetics in the group with no cardiovascular medication (maximum in cross-correlation function of muscular oxygen uptake vs. heart rate; 0.32±0.08 vs. 0.25±0.06; p=0.001) and in the group taking peripherally acting medication (0.34±0.05 vs. 0.28±0.05; p=0.009) but not in the patients taking centrally acting medication (0.28±0.05 vs. 0.30±0.07; n.s.). It can be concluded that regulatory processes for the achievement of a similar maximal oxygen uptake are different between the groups. The used standardized test provided plausible results for heart rate and oxygen uptake kinetics in a single measurement session in this patient group.
[...]

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Hypogonadotropic Hypogonadism in Non-Functioning Pituitary Adenomas: Impact of Intervention

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0042-124355

To determine the prevalence of hypogonadotropic hypogonadism (HH) among patients with non-functioning pituitary adenomas (NFPA) and the post-surgery outcome on pituitary gonadotropins secretion (PGS); to determine the prevalence of erectile dysfunction (ED) on male patients with NFPA, to evaluate the impact of testosterone replacement therapy (TRT) in those with HH. Retrospective evaluation of gonadal function in 109 NFPA patients (45 males), with a mean age of 51.8 years, diagnosed on the last 10 years. ED questionnaire applied to 34 male patients. Male patients with NFPA were significantly older (males 58.1±15.8 vs. females 47.4±16.94; p=0.001). Most patients had macroadenomas (67%; p=0.001) and only a minority were incidentalomas (19%; p<0.001). Prevalence of HH was 40% (60% on males, 25% on females; p<0.001). Surgery was performed in 54% of all patients (71% of males, 42% of females; p<0.003). After intervention, 14% became HH, 69% maintained previous function and 17% improved. On the questionnaire, 76% reported having ED, 54% of which had HH and 21% were under TRT. Of the patients under TRT, 79% still had ED. Median age of patients with ED was significantly higher [with ED 65 vs. without 49 years; p=0.012). There was no BMI difference between patients with or without TRT (28.0 vs. 27.4 Kg/m2). NFPA was more frequent in older rather than younger patients. Males were older, had more HH and surgery. There was no significant improvement of pituitary function with surgery (17%) and 13% became iatrogenic HH. TRT had a low efficacy to improve ED in these patients.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Add on Exenatide Treatment is Beneficial in Poorly Controlled Obese Type 2 Diabetics under Intensive Insulin Regimens

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0042-120708

Background: Intensive insulin treatment is bothersome in obese patients with type 2 diabetes mellitus. High insulin dosages further increase weight gain and the risk of hypoglycemia. Glucagon like peptide-1 receptor agonists decrease the insulin need, cause weight loss and reduce the risk of hypoglycemia. There is limited data about the effect of exenatide on obese diabetics under intensive insulin regimens. Methods: This retrospective case series report the clinical outcomes of 23 obese (13 morbidly obese) patients with uncontrolled type 2 diabetes mellitus (Age=59±10.44 years, body mass index 41.1±6.8 kg/m2, HbA1c 9.9±1.5%), under high dose (94.1±39.6 unit) intensive insulin. Exenatide twice daily was added for a mean follow-up period of 11.22±7.01 (3–30) months. Intensive insulin regimens were continued in 7 patients while the others were switched to basal insulin during the follow-up. Results: During the follow-up, mean HbA1c levels of the patients significantly improved (p=0.019), along with the significant decrease in body mass index and the total insulin need (p<0.001 for both). Baseline insulin dosages were significantly higher in the intensive regimen group (p=0.013) while other demographical and clinical characteristics were similar. No significant difference was present between the groups regarding the alterations of HbA1c, body mass index and the reduction in total insulin dosages. Conclusion: Add on exenatide appears to be a rational treatment modality in uncontrolled obese patients with type 2 diabetes mellitus despite intensive insulin regimens. Further prospective randomized studies with longer follow-up periods are recommended.
[...]

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Editorial Board

Publication date: 23 February 2017
Source:Journal of Proteomics, Volume 155





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Quantitative proteomic analysis of human testis reveals system-wide molecular and cellular pathways associated with non-obstructive azoospermia

Publication date: Available online 15 February 2017
Source:Journal of Proteomics
Author(s): Mehdi Alikhani, Mehdi Mirzaei, Marjan Sabbaghian, Pouria Parsamatin, Razieh Karamzadeh, Samane Adib, Niloofar Sodeifi, Mohammad Ali Sadighi Gilani, Masoud Zabet-Moghaddam, Lindsay Parker, Yunqi Wo, Vivek Gupta, Paul A. Haynes, Hamid Gourabi, Hossein Baharvand, Ghasem Hosseini Salekdeh
Male infertility accounts for half of the infertility problems experienced by couples. Azoospermia, having no measurable level of sperm in seminal fluid, is one of the known conditions resulting in male infertility. In order to elucidate the complex molecular mechanisms causing male azoospermia, label-free quantitative shotgun proteomics was carried out on testicular tissue specimens from patients with obstructive azoospermia and non-obstructive azoospermia, including maturation arrest (MA) and Sertoli cell only syndrome (SCOS). The abundance of 520 proteins was significantly changed across three groups of samples. We were able to identify several functional biological pathways enriched in azoospermia samples and confirm selected differentially abundant proteins, using multiple histological methods. The results revealed that cell cycle and proteolysis, and RNA splicing were the most significant biological processes impaired by the substantial suppression of proteins related to the aforementioned categories in SCOS tissues. In the MA patient testes, generation of precursor metabolites and energy as well as oxidation-reduction were the most significantly altered processes. Novel candidate proteins identified in this study include key transcription factors, many of which have not previously been shown to be associated with azoospermia. Our findings, can provide substantial insights into the molecular regulation of spermatogenesis and human reproduction.SignificanceThe obtained data showed a drastic suppression of proteins involved in spliceosome, cell cycle and proteasome proteins, as well as energy and metabolic production in Sertoli cell only syndrome testis tissue and to a lesser extent in maturation arrest samples. Moreover, we identified new transcription factors that are highly down-regulated in SCOS and MA patients, thus helping to understand the molecular complexity of spermatogenesis in male infertility. Our findings provide novel candidate protein targets associated with SCOS or MA azoospermia.



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Impact of Continuous Two-Team Approach in Autologous Breast Reconstruction

J reconstr Microsurg
DOI: 10.1055/s-0037-1598199

Background Autologous breast reconstruction has been noted in the literature to provide superior aesthetic outcomes and patient satisfaction. Additionally, free perforator flap tissue transfer has the potential for lower abdominal donor site morbidity. However, it has been noted that the percentage of women who are undergoing autologous breast reconstruction in the United States is decreasing. Factors related to the technical difficulty, prolonged operative times, and decreasing reimbursement have been implicated as the causes. Methods A retrospective review of electronic medical records over a 5-year period was performed with evaluation of 77 autologous breast reconstructions at a single institution. Patient demographics, comorbidities, number of surgeons involved, operative times, length of stay, and postoperative complications were measured. Wilcoxon rank-sum, Pearson's chi-squared, and proportional odds likelihood ratio tests were performed to compare continuous, categorical, and ordinal outcomes, respectively. Propensity score weighting was used to adjust for presurgical covariates and laterality. Results Operative time and length of stay were both significantly lower in the two- versus the single-microsurgeon groups in the unadjusted setting. When covariates and laterality were adjusted for, operative times still remained significantly shorter in the two-microsurgeon group; there were no differences in complications. Conclusion Based on our findings, we propose that the two-microsurgeon approach can be utilized in more time-consuming microsurgical cases, such as autologous breast reconstruction, to safely decrease operative times and potentially alleviate surgeon fatigue, reduce operative costs, and thus increase overall surgeon productivity.
[...]

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Ventricular Geometry From Non-contrast Non-ECG-gated CT Scans

Publication date: Available online 15 February 2017
Source:Academic Radiology
Author(s): Farbod N. Rahaghi, Gonzalo Vegas-Sanchez-Ferrero, Jasleen K. Minhas, Carolyn E. Come, Isaac De La Bruere, James M. Wells, Germán González, Surya P. Bhatt, Brett E. Fenster, Alejandro A. Diaz, Puja Kohli, James C. Ross, David A. Lynch, Mark T. Dransfield, Russel P. Bowler, Maria J. Ledesma-Carbayo, Raúl San José Estépar, George R. Washko
Rationale and ObjectivesImaging-based assessment of cardiovascular structure and function provides clinically relevant information in smokers. Non-cardiac-gated thoracic computed tomographic (CT) scanning is increasingly leveraged for clinical care and lung cancer screening. We sought to determine if more comprehensive measures of ventricular geometry could be obtained from CT using an atlas-based surface model of the heart.Materials and MethodsSubcohorts of 24 subjects with cardiac magnetic resonance imaging (MRI) and 262 subjects with echocardiography were identified from COPDGene, a longitudinal observational study of smokers. A surface model of the heart was manually initialized, and then automatically optimized to fit the epicardium for each CT. Estimates of right and left ventricular (RV and LV) volume and free-wall curvature were then calculated and compared to structural and functional metrics obtained from MRI and echocardiograms.ResultsCT measures of RV dimension and curvature correlated with similar measures obtained using MRI. RV and LV volume obtained from CT inversely correlated with echocardiogram-based estimates of RV systolic pressure using tricuspid regurgitation jet velocity and LV ejection fraction respectively. Patients with evidence of RV or LV dysfunction on echocardiogram had larger RV and LV dimensions on CT. Logistic regression models based on demographics and ventricular measures from CT had an area under the curve of >0.7 for the prediction of elevated right ventricular systolic pressure and ventricular failure.ConclusionsThese data suggest that non-cardiac-gated, non-contrast-enhanced thoracic CT scanning may provide insight into cardiac structure and function in smokers.



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NLRP6: A Multifaceted Innate Immune Sensor

Publication date: Available online 15 February 2017
Source:Trends in Immunology
Author(s): Maayan Levy, Hagit Shapiro, Christoph A. Thaiss, Eran Elinav
NLRP6, a member of the nucleotide-binding domain, leucine-rich repeat-containing (NLR) innate immune receptor family, regulates inflammation and host defense against microorganisms. Similar to other NLRs, NLRP6 not only participates in inflammasome formation, but is also involved in nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling regulation and facilitation of gastrointestinal antiviral effector functions. Additionally, NLRP6 contributes to the regulation of mucus secretion and antimicrobial peptide production, thereby impacting intestinal microbial colonization and associated microbiome-related infectious, autoinflammatory, metabolic, and neoplastic diseases. However, several of the mechanisms attributed to the functions of NLRP6 remain debatable, leaving open questions as to the relevant molecular mechanisms and interacting partners, and putative human relevance. We herein discuss recent findings related to NLRP6 activity, while highlighting outstanding questions and future perspectives in elucidating its roles in health and disease.



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Clinical Features and Current Optimal Management of Natural Killer/T-Cell Lymphoma

Publication date: Available online 30 January 2017
Source:Hematology/Oncology Clinics of North America
Author(s): Shinichi Makita, Kensei Tobinai

Teaser

Extranodal natural killer/T-cell lymphoma, nasal type (ENKL) is a rare subtype of non-Hodgkin lymphoma, and its treatment outcome was previously poor. Novel treatment strategies have improved the outcomes of ENKL remarkably in the last decade. Nowadays, patients with localized nasal ENKL are recommended treatment with concurrent chemoradiotherapy, and their 5-year overall survival rate is approximately 70%. In patients with advanced or relapsed/refractory disease, the efficacy of l-asparaginase-containing therapy has been confirmed. However, there still remain unmet needs in the treatment of ENKL. Continued efforts should be made to further improvements in the treatment of ENKL.


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Effect of food on the bioavailability of palbociclib

Abstract

Purpose

This phase I study estimated the effect of food on bioavailability of palbociclib (IBRANCE^®), and a selective inhibitor of cyclin-dependent kinase 4/6 approved for oncology indications has pH-dependent solubility and high permeability.

Methods

In this randomized, four-sequence, four-period crossover study, 28 healthy volunteers received a single 125-mg dose of palbociclib (free-base capsule) following an overnight fast or (1) after a high-fat/-calorie meal, (2) after a low-fat/-calorie meal, and (3) between two moderate-fat/standard-calorie meals. Pharmacokinetic samples were collected predose and serially ≤144 h postdose; palbociclib concentrations were measured using validated high-performance liquid chromatography tandem mass spectrometry. Pharmacokinetic data were analyzed using a noncompartmental approach based on a mixed-effects model.

Results

Median time to maximum concentration was 8 h for all conditions. Exposure (AUC_inf and C _max) increased slightly in the fed versus fasted conditions; ratios (90% CIs) of the adjusted geometric mean relative to the fasted condition ranged from 111.8 (104.3–119.9%) to 120.6% (112.6–129.1%) for AUC_inf and from 124.0 (108.4–141.9%) to 137.8% (120.6–157.5%) for C _max due mainly to three subjects with significantly lower exposure (low liers) in the fasted condition. Pharmacokinetic variability was reduced in the fed (AUC_inf, 23–27%; C _max, 21–24%) versus fasted (AUC_inf, 39%; C _max, 73%) conditions. In a supplemental analysis excluding the three low liers, food intake did not affect palbociclib exposure.

Conclusions

Food intake modestly increased palbociclib exposure while greatly reducing pharmacokinetic variability. For subjects with normal absorption, food intake did not affect palbociclib exposure. Thus, palbociclib should be administered with food.

Trial registration

ClinicalTrials.gov: NCT01904747.

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Accumulation of alpha-fluoro-beta-alanine and fluoro mono acetate in a patient with 5-fluorouracil-associated hyperammonemia

Abstract

Purpose

High-dose 5-fluorouracil (5-FU) containing chemotherapy occasionally causes hyperammonemia and can be lethal. However, the mechanism of 5FU-associated hyperammonemia has not been known. The aim of this study was to reveal the pharmacokinetics of 5-FU-associated hyperammonemia in a recurrent colorectal cancer patient with end-stage renal disease (ESRD).

Methods

We experienced a case of hyperammonemia during mFOLFOX6 plus bevacizumab therapy for recurrent colorectal cancer. He was a dialyzed patient due to diabetic nephropathy and was registered to prospective blood sampling for pharmacokinetics analysis during chemotherapy. Blood concentrations of 5-FU and its catabolites were determined by inductively coupled plasma-mass spectrometry.

Results

The patient developed hyperammonemia encephalopathy 41 h after the initiation of continuous 5-FU infusion (on the third day). Before onset of hyperammonemia encephalopathy, serum alpha-fluoro-beta-alanine (FBAL, 59.2 µg/ml) and fluoro mono acetate (FMA, 905.8 ng/ml) were gradually increased. After hemodialysis for hyperammonemia, FBAL and FMA were collaterally decreased and his symptom was improved. Other intermediate catabolites of 5-FU, dihydrofluorouracil, and alpha-fluoro-beta-ureidopropionic acid were not changed.

Conclusion

We found increases of serum FBAL and FMA under the condition of hyperammonemia in the patient with ESRD during mFOLFOX6 plus bevacizumab therapy. This research supported the hypothesis that impairment of tricarboxylic acid (TCA) cycle by FMA would cause 5-FU-associated hyperammonemia.

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Application of magnetic susceptibility in assessment of heavy metal contamination of Saxonian soil (Germany) caused by industrial dust deposition

Publication date: 1 June 2017
Source:Geoderma, Volume 295
Author(s): Marzena Rachwał, Kati Kardel, Tadeusz Magiera, Oliver Bens
Magnetic susceptibility is used worldwide as a measure of concentration of (ferri)magnetic minerals in soil, sediment and dust. In soils, these minerals are of various origins: air-derived particulate pollution, parent rocks or pedogenesis. Human activity causes different changes in the content of magnetic minerals as well as their spatial and vertical distribution in soil profiles. Magnetic minerals are characterised by an affinity to other elements occurring in the soil, e.g. heavy metals. Therefore magnetic susceptibility has been widely applied as approximation of soil contamination by heavy metals.The archival soil samples collected from different soil horizons in the territory of the Free State of Saxony (Germany) were subjected to magnetic susceptibility measurements using Bartington MS2B. Additionally, samples were chemically analysed in order to determine the content of Fe, Mn, Ni, Cu, Zn, Cd, Pb and As using a method of atomic absorption spectroscopy (AAS). The contamination factor (CF) and geoaccumulation index (Igeo) were applied for assessment of soil contamination with particular potentially toxic elements (PTE), while the more general pollution load index (PLI) was used for comparison between different geographic sites.Values of magnetic susceptibility varied from 16.6 to 1382×10⁻⁸m³kg⁻¹ in organic soil horizons and from 0.1 to 1580×10⁻⁸m³kg⁻¹ in deeper layers. Significant and relatively high correlation coefficients between soil magnetic susceptibility and the content of some heavy metals indicated that they were of the similar origin as (ferri)magnetic minerals occurring in soil (viz. industrial pollution, parent rocks or pedogenic processes). PLI distribution over the entire area of Saxony corresponds well with the magnetic susceptibility distribution, especially in the organic soil horizon. The indices qualify the northeastern part of Saxony as extremely or heavily polluted in the organic soil horizon (under forests) with decreasing contamination in deeper layers, being classified as non-polluted to moderately polluted. However, the prevailing Saxony area is characterised by low and moderate contamination by potentially toxic elements, such as heavy metals.



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Impact of Hormonal Contraception and Weight Loss on HDL-C efflux and Lipoprotein Particles in Women with Polycystic Ovary Syndrome

Abstract

Objective

To study the effects of oral contraceptive pills (OCP), the first line treatment for PCOS, on HDL-C function (reverse cholesterol efflux capacity) and lipoprotein particles measured by NMR spectroscopy.

Design

Secondary analysis of a randomized controlled trial (OWL-PCOS) of OCP or Lifestyle (intensive lifestyle modification) or Combined (OCP+Lifestyle) treatment for 16 weeks.

Patients

87 overweight/obese women with PCOS at two academic centers.

Measurements

Change in HDL-C efflux capacity and lipoprotein particles.

Results

HDL-C efflux capacity increased significantly at 16 weeks in the OCP group (0.11; 95% CI 0.03, 0.18, p=0.008) but not in the Lifestyle (p=0.39) or Combined group (p=0.18). After adjusting for HDL-C and TG levels, there was significant mean change in efflux in the Combined group (0.09; 95% CI 0.01, 0.15; p=0.01). Change in HDL-C efflux correlated inversely with change in serum testosterone (r_s = -0.21; p=0.05). In contrast, OCP use induced an atherogenic LDL-C profile with increase in small (p=0.006) and large LDL-particles (p=0.002). Change in small LDL-particles correlated with change in serum testosterone (r_s = -0.31, p=0.009) and insulin sensitivity index (r_s = -0.31, p=0.02). Both Lifestyle and Combined groups did not show significant changes in the atherogenic LDL-particles.

Conclusions

OCP use is associated with improved HDL-C function and a concomitant atherogenic LDL-C profile. Combination of a Lifestyle program with OCP use improved HDL-C function and mitigated adverse effects of OCP on lipoproteins. Our study provides evidence for use of OCP in overweight/obese women with PCOS when combined with Lifestyle changes.

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Spectrum of Disease Associated with Partial Lipodystrophy (PL): Lessons from a Trial Cohort

Abstract

Context

Partial lipodystrophy (PL) is associated with metabolic co-morbidities but may go undiagnosed as the disease spectrum is not fully described.

Objective

Define disease spectrum in PL using genetic, clinical (historical, morphometric) and laboratory characteristics.

Design

Cross-sectional evaluation.

Participants

23 patients (22 with familial, one acquired, 78.3% female, aged 12-64 years) with PL and non-alcoholic fatty liver disease (NAFLD).

Measurements

Genetic, clinical and laboratory characteristics, body composition indices, liver fat content by MRI, histopathological and immunofluorescence examinations of liver biopsies.

Results

7 patients displayed heterozygous pathogenic variants in LMNA. Two related patients had a heterozygous, likely pathogenic novel variant of POLD1 (NM002691.3: c.3199 G>A; p.E1067K). Most patients had high ratios (>1.5) of %fat trunk to %fat legs (FMR) when compared to reference normals. Liver fat quantified using MR Dixon method was high (11.3+6.3%) and correlated positively with hemoglobin A1c and triglycerides while leg fat by dual-energy X-ray absorptiometry (DEXA) correlated negatively with triglycerides. In addition to known metabolic comorbidities; chronic pain (78.3%), hypertension (56.5%) and mood disorders (52.2%) were highly prevalent. Mean NAFLD Activity Score (NAS) score was 5±1 and 78.3% had fibrosis. LMNA-immunofluorescence staining from select patients (including one with the novel POLD1 variant) showed a high degree of nuclear atypia and disorganization.

Conclusions

PL is a complex multi-system disorder. Metabolic parameters correlate negatively with extremity fat and positively with liver fat. DEXA-based FMR may prove useful as a diagnostic tool. Nuclear disorganization and atypia may be a common biomarker even in the absence of pathogenic variants in LMNA.

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Thyroid dysfunction in children with autism spectrum disorder is associated with folate receptor alpha autoimmune disorder

Abstract

Folate receptor α (FRα) autoantibodies (FRAAs) are prevalent in Autism Spectrum Disorder (ASD). FRAAs disrupt folate transport across the blood-brain barrier by binding to the FRα. Thyroid dysfunction is frequently found in children with ASD. We measured blocking and binding FRAAs and thyroid stimulating hormone (TSH), free T4 (FT4), total T3 (TT3), reverse T3 (rT3), thyroid releasing hormone (TRH) and other metabolites in 87 children with ASD, 84 of whom also underwent behavior and cognition testing and in 42 of whom FRAAs, TSH and FT4 were measured at two time points. To better understand the significance of the FRα in relation to thyroid development, we examined FRα expression on prenatal and postnatal thyroid. TSH, TT3 and rT3 were above the normal range in 7%, 33% and 51% of the participants and TRH was below the normal range in 13% of the participants. FT4 was rarely outside the normal range. TSH concentration was positively and the FT4/TSH, TT3/TSH and rT3/TSH ratios were inversely related to blocking FRAA titers. On repeated measurements, change in TSH and FT4/TSH ratio were found to correspond to change in blocking FRAA titers. TSH and the FT4/TSH, TT3/TSH and rT3/TSH ratios were related to irritability on the Aberrant Behavior Checklist and several scales of the Social Responsiveness Scale (SRS), while TT3 was associated with SRS subscales and TRH were related to Vineland Adaptive Behavior Scale subscales. The thyroid showed significant FRα expression during the early prenatal period but expression decreased significantly in later gestation and postnatal thyroid tissue. This study suggests that thyroid dysfunction in ASD may be related to the blocking FRAA. The high expression of FRα in the early fetal thyroid suggests that fetal and neonatal exposure to maternal FRAAs could affect the development of the thyroid and may contribute to the pathology in ASD.

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Skull 5 from Dmanisi: Descriptive anatomy, comparative studies, and evolutionary significance

Publication date: March 2017
Source:Journal of Human Evolution, Volume 104
Author(s): G. Philip Rightmire, Marcia S. Ponce de León, David Lordkipanidze, Ann Margvelashvili, Christoph P.E. Zollikofer
A fifth hominin skull (cranium D4500 and mandible D2600) from Dmanisi is massively constructed, with a large face and a very small brain. Traits documented for the first time in a basal member of the Homo clade include the uniquely low ratio of endocranial volume to basicranial width, reduced vertex height, angular vault profile, smooth nasal sill coupled with a long and sloping maxillary clivus, elongated palate, and tall mandibular corpus. The convex clivus and receding symphysis of skull 5 produce a muzzle-like form similar to that of Australopithecus afarensis. While the Dmanisi cranium is very robust, differing from OH 13, OH 24, and KNM-ER 1813, it resembles Homo habilis specimens in the "squared off" outline of its maxilla in facial view, maxillary sulcus, rounded and receding zygomatic arch, and flexed zygomaticoalveolar pillar. These characters distinguish early Homo from species of Australopithecus and Paranthropus. Skull 5 is unlike Homo rudolfensis cranium KNM-ER 1470. Although it appears generally primitive, skull 5 possesses a bar-like supraorbital torus, elongated temporal squama, occipital transverse torus, and petrotympanic traits considered to be derived for Homo erectus. As a group, the Dmanisi crania and mandibles display substantial anatomical and metric variation. A key question is whether the fossils document age-related growth and sex dimorphism within a single population, or whether two (or more) distinct taxa may be present at the site. We use the coefficient of variation to compare Dmanisi with Paranthropus boisei, H. erectus, and recent Homo sapiens, finding few signals that the Dmanisi sample is excessively variable in comparison to these reference taxa. Using cranial measurements and principal components analysis, we explore the proposal that the Dmanisi skulls can be grouped within a regionally diverse hypodigm for H. erectus. Our results provide only weak support for this hypothesis. Finally, we consider all available morphological and paleobiological evidence in an attempt to clarify the phyletic relationship of Dmanisi to Homo species evolving >2.0 to 1.0 Ma.



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Identification of candidate miRNA biomarkers for pancreatic ductal adenocarcinoma by weighted gene co-expression network analysis

Abstract

Purpose

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal prognosis which is, among others, due to a lack of suitable biomarkers and therapeutic targets. Previously, basic gene expression analysis methods have been used for their identification, but recently new algorithms have been developed allowing more comprehensive data analyses. Among them, weighted gene co-expression network analysis (WGCNA) has already been applied to several cancer types with promising results.

Methods

We applied WGCNA to miRNA expression data from PDAC patients. Specifically, we processed microarray-based expression data of 2555 miRNAs in serum from 100 PDAC patients and 150 healthy subjects. We identified network modules of co-expressed miRNAs in the healthy subject dataset and verified their preservation in the PDAC dataset. In the non-preserved modules, we selected key miRNAs and carried out functional enrichment analyses of their experimentally known target genes. Finally, we tested their prognostic significance using overall survival analyses.

Results

Through WGCNA we identified several miRNAs that discriminate healthy subjects from PDAC patients and that, therefore, may play critical roles in PDAC development. At a functional level, we found that they regulate p53, FoxO and ErbB associated cellular signalling pathways, as well as cell cycle progression and various genes known to be involved in PDAC development. Some miRNAs were also found to serve as novel prognostic biomarkers, whereas others have previously already been proposed as such, thereby validating the WGCNA approach. In addition, we found that these novel data may explain at least some of our previous PDAC gene expression analysis results.

Conclusions

We identified several miRNAs critical for PDAC development using WGCNA. These miRNAs may serve as biomarkers for PDAC diagnosis/prognosis and patient stratification, and as putative novel therapeutic targets.

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Effects of impacted maxillary canines on root resorption of lateral incisors

Abstract

Objectives

The aim of this study was to analyze the amount of root resorption of maxillary lateral incisors by relating the position, location, and angulation of the impacted canine using cone-beam computed tomography (CBCT).

Materials and methods

The study sample consisted of panoramic and CBCT radiographs of 46 patients with a unilateral impacted canine (16 males and 30 females; mean age: 19.53 ± 6.66 and 19.44 ± 5.77 years, respectively). Sector location and canine angulation were measured in panoramics. All tomographs were obtained using CBCT (NewTom 5G, QR, Verona, Italy) and three-dimensional (3D) reconstructions of the maxillary laterals assessed by Mimics 14.01 image analysis software.

Results

Upper lateral incisor volume was smaller on the impacted side (401.95 ± 83.69 mm³) than on the nonimpacted side (433.54 ± 92.6 mm³, P < 0.05). There were no significant differences of lateral root resorption volume when comparing the impacted canines being on the labial or palatal sides (P > 0.05), but impacted canine angulation was significantly steeper on the labial side (70.85°) than on the palatal side (46.09°, P < 0.05). The volume of root resorption of laterals when comparing the various positions of the canine in different sectors or canine angulation in 30^o intervals was not statistically significantly different (P > 0.05).

Conclusions

The impacted canines caused root resorption of lateral incisors. The angulation of the canine was steeper on the labial side than on the palatal side but root resorption of adjacent laterals was not different. There were no statistically significant differences in the amount of root resorption of the laterals when the canine was evaluated according to localization and angulation.

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Retrospective 25-year follow-up of treatment outcomes in Angle Class III patients

Abstract

Objectives

Despite recommendations for early treatment of hereditary Angle Class III syndrome, late pubertal growth may cause a relapse requiring surgical intervention. This study was performed to identify predictors of successful Class III treatment.

Materials and methods

Thirty-eight Class III patients treated with a chincup were retrospectively analyzed. Data were collected from the data archive, cephalograms, and casts, including pretreatment (T0) and posttreatment (T1) data, as well as long-term follow-up data collected approximately 25 years after treatment (T2). Each patient was assigned to a success or a failure group. Data were analyzed based on time (T0, T1, T2), deviations from normal (Class I), and prognathism types (true mandibular prognathism, maxillary retrognathism, combined pro- and retrognathism).

Results

Compared to Class I normal values, the data obtained in both groups yielded 11 significant parameters. The success group showed values closer to normal at all times (T0, T1, T2) and vertical parameters decreased from T0 to T2. The failure group showed higher values for vertical and horizontal mandibular growth, as well as dentally more protrusion of the lower anterior teeth and more negative overjet at all times. In adittion, total gonial and upper gonial angle were higher at T0 and T1. A prognostic score—yet to be evaluated in clinical practice—was developed from the results. The failure group showed greater amounts of horizontal development during the years between T1 and T2. Treatment of true mandibular prognathism achieved better outcomes in female patients. Cases of maxillary retrognathism were treated very successfully without gender difference. Failure was clearly more prevalent, again without gender difference, among the patients with combined mandibular prognathism and maxillary retrognathism. Crossbite situations were observed in 44% of cases at T0. Even though this finding had been resolved by T1, it relapsed in 16% of the cases by T2.

Conclusion

The failure rate increased in cases of combined mandibular prognathism and maxillary retrognathism. Precisely in these combined Class III situations, it should be useful to apply the diagnostic and prognostic parameters identified in the present study and to provide the patients with specific information about the increased risk of failure.

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Nonsyndromic oligodontia

Abstract

Objectives

The literature suggests an association between phenotype and causative mutation in nonsyndromic oligodontia. Thus, the present study was designed to verify this hypothesis in a consecutive cohort of patients.

Methods

All patients with nonsyndromic oligodontia who had been treated at the study center (Department of Orthodontics, University of Giessen, Germany) over the period 1986–2013 were contacted. Candidates were included only if at least one more family member had hypo- or oligodontia (i.e., without regard to the number of congenitally missing teeth). A total of 20 patients were included. After evaluating the dental status of each participant, the Tooth Agenesis Code (TAC) was applied. On this basis, a tentative diagnosis was made to predict which gene (MSX1, AXIN2, EDA, or PAX9) was likely to show mutation. Afterwards this hypothesis was confirmed or rejected by analyzing a saliva sample for mutation of the predicted gene. If confirmed, any available family members were also genetically analyzed.

Results

Based on their TAC scores and sums, gene mutations were predicted for MXS1 in 11, AXIN2 in 3, EDA in 6, and PAX9 in none of the patients. The evaluation of MSX1 yielded variants in 4 of 11 cases, all of which were classified as nonpathogenic since they were not considered as functional mutations. The evaluation of EDA yielded a pathogenic exon-7 mutation in 2 of 6 patients, both being brothers with different TAC scores; the same mutation, which represents a novel missense mutation, was also found in other members of the same family. The evaluation of AXIN2 yielded variants in 3 of 3 cases, all of which were classified as nonpathogenic.

Conclusions

Our findings obtained in consecutive patients with nonsyndromic oligodontia did not reveal any clinically relevant associations between oligodontia phenotype (based on TAC) and causative mutations for nonsyndromic oligodontia.

http://ift.tt/2lkyQ9l

Wet nitrogen and phosphorus deposition in the eutrophication of the Lagos Lagoon, Nigeria

Abstract

Air pollution is influenced by wind-aided particulate suspension, open-air waste burning, and fossil fuel combustion. The pollutants from these sources eventually deposit on ambient surfaces. Atmospheric wet deposition into Lagos Lagoon may be significant additions to the nutrient levels of the eutrophic lagoon. Precipitation was monitored at three stations in the Lagos Lagoon basin from May to November, 2012, in order to estimate the contribution of wet deposition to the nutrient cycles of the lagoon. Water samples were digested with potassium persulfate, and the species of phosphorus (P) and nitrogen (N) were analyzed by colorimetric methods. The mean [NO₃⁻+NO₂⁻]-N level was 0.39 ± 0.51 kg ha⁻¹ month⁻¹. The average total N was 3.16 ± 6.39 kg ha⁻¹ month⁻¹. The mean soluble reactive P was lower than the [NO₃⁻+NO₂⁻]-N averaging 0.06 ± 0.09 (at control site S2) to 0.24 ± 0.10 kg ha⁻¹ month⁻¹ (at site S1). Average total P was 1.25 ± 0.82 kg ha⁻¹ month⁻¹. The annual total N (May–September) was 4.55 (at S2) to 32.4 kg ha⁻¹ year⁻¹ (at S3). The annual total P (May–November) over Lagos Lagoon basin was 5.06 kg ha⁻¹ year⁻¹ (at S2). This study demonstrated that wet deposition of anthropogenically derived nutrients to the Lagos Lagoon is ongoing and may represent a considerable proportion of the total nutrient loading to it. The increased P availability in the wet deposition is likely responsible for the water hyacinths, which usually blossom on Lagos Lagoon during the late rainy season, and the reported harmattan-season bottom water hypoxia.

http://ift.tt/2lRyQe6

A preliminary report of indigenous fungal isolates from contaminated municipal solid waste site in India

Abstract

Municipal solid waste (MSW) containing harmful substances is a major concern in waste management and can cause adverse effects on diversity of fungi in soil. The main objective was to evaluate the fungal diversity inhabiting in the soil nearby MSW disposal site. The fungal strains were isolated in potato dextrose agar (PDA), media at temperatures 28 ± 1 °C by using standard serial dilution pour plate method, and appeared fungal colonies identified based on morphological characteristics. The overall most fungal diversity was found in soil sample collected from S5, followed by S4, S3, S1, and least in S2 site. A total of 24 fungal isolates recovered from the different MSW sites and Aspergillus sp., Fusarium sp., and Curvularia sp. genus has isolated from all the samples. In addition, the metal tolerance index performed because it needs to classify the fungus for their best use as potential agent for environmental protection. The metal tolerance outcomes revealed that both metals (cadmium and chromium) has appeared as the highest growth inhibitor for most strains and even fungal colonies did not propagate very well on the surface of media. Therefore, these findings suggest that the pre-adapted indigenous fungal isolates have proven remarkable tolerance ability to both metals. Furthermore, these highly metal-tolerant fungal strains are recommended for detail research or can use in pilot-scale bioremediation application to treat contaminated site.

http://ift.tt/2lLUR22

Alterations in the skin of Labeo rohita exposed to an azo dye, Eriochrome black T: a histopathological and enzyme biochemical investigation

Abstract

Histopathological changes and alterations in the activity of certain metabolic and antioxidant enzymes were analyzed in the head skin of Labeo rohita, exposed to sublethal test concentrations of the azo dye, Eriochrome black T for 4 days, using 24 h renewal bioassay method. Hypertrophied epithelial cells, increased density of mucous goblet cells, and profuse mucous secretion at the surface were considered to protect the skin from toxic impact of the azo dye. Degenerative changes including vacuolization, shrinkage, decrease in dimension, and density of club cells with simultaneous release of their contents in the intercellular spaces were associated to plug them, preventing indiscriminate entry of foreign matter. On exposure of fish to the dye, significant decline in the activity of enzymes—alkaline phosphatase, acid phosphatase, carboxylesterase, succinate dehydrogenase, catalase, and peroxidase—was associated with the binding of dye to the enzymes. Gradual increase in the activity of lactate dehydrogenase was considered to reflect a shift from aerobic to anaerobic metabolism. On transfer of azo dye exposed fish to freshwater, skin gradually recovers and, by 8 days, density and area of mucous goblet cells, club cells, and activity of the enzymes appear similar to that of controls. Alteration in histopathology and enzyme activity could be considered beneficial tool in monitoring environmental toxicity, valuable in the sustenance of fish populations.

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Possible role of zinc in diminishing lead-related occupational stress—a zinc nutrition concern

Abstract

Lead and zinc are mostly present at the same occupational source and usually found as co-contaminants. Lead is known to associate with detrimental effects to humans. Zinc however is an essential nutrient and its deficiency causes debilitating effects on growth and development. Besides, it acts as core ion of important enzymes and proteins. The purpose of this study was to examine if zinc concentrations are associated with blood lead levels and if zinc may prevent lead-induced DNA damage. Blood samples were collected from 92 workers as participants occupationally exposed to lead or lead and zinc and 38 comparison participants having no history of such exposure. Lead and zinc levels were determined from blood by atomic absorption spectrophotometry and genetic damage was assessed by comet assay. Correlation was calculated by Spearman's rho. Lead concentrations were observed to increase among workers with increase in years of exposure. There was a significant difference (p < 0.001) in blood lead levels between workers and controls. In addition, significant difference (p < 0.001) in the genetic damage was observed among workers and controls. A clear effect of increased occupational exposure was visible among workers. Multiple regression analysis further reveals the positive effect of lead, while as the inverse effect of zinc on DNA damage. The results suggest that zinc may influence body lead absorption and may have a role in preventing the genetic damage caused by lead.

http://ift.tt/2lM1fq3

Effect of pH on the adsorption and photocatalytic degradation of sulfadimidine in Vis/g-C 3 N 4 progress

Abstract

In this study, g-C₃N₄ was synthesized by thermal polycondensation of melamine and was characterized by X-ray powder diffraction, X-ray photoelectron spectroscopy, UV–visible diffuse reflection spectroscopy, and scanning electron microscopy. Results showed that g-C₃N₄ degraded sulfadimidine (SMD) under visible light, in which the adsorption and photocatalytic degradation was influenced by pH. The maximum adsorption capacity was achieved at approximately pH 5. The highest degradation rate constant was obtained at strong acid and alkali. In addition, the degradation mechanism of g-C₃N₄ was evaluated with the help of quencher agents. The intermediates, degradation pathways, and mineralization of SMD were also determined to evaluate the degradation and oxidation ability of g-C₃N₄.

http://ift.tt/2lRr0Ru

Incidence of Abnormal Liver Biochemical Tests in Hyperthyroidism

Abstract

Objective

Abnormal serum liver function tests are common in patients with untreated thyrotoxicosis, even prior to the initiation of antithyroidal medications that may worsen their severity. There is a wide range of the incidence of these abnormalities in the published literature. The aim of this study was to assess the risks factors and threshold of thyrotoxicosis severity for developing an abnormal liver biochemical test upon the diagnosis of new thyrotoxicosis.

Design

Single-institution retrospective cohort study.

Patients

Patients ≥18 years old receiving medical care at a large, academic, urban U.S. medical center between 2002-2016.

Measurements

Inclusion criteria were a serum thyroid stimulating hormone [TSH] concentration < 0.3 mIU/L or ICD-9 code for thyrotoxicosis, with thyrotoxicosis confirmed by either a concurrent elevated serum triiodothyronine (T3) and/or thyroxine (T4) concentration [total or free] within 3 months), and an available liver biochemical test(s) within 6 months of thyrotoxicosis. The biochemical liver tests assessed were serum aspartate transaminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AP), gamma-glutamyltransferase (GGT), total bilirubin, and conjugated bilirubin concentrations.

Results

In this cohort of 1,514 subjects, the overall incidence of any biochemical liver test abnormality within 6 months of thyrotoxicosis was 39%. An initial serum TSH concentration <0.02 mIU/L, male gender, and African-American race were significant predictors of an abnormal serum liver biochemical test within 6 months of the diagnosis of new-onset untreated thyrotoxicosis.

Conclusions

This study identifies risk factors for patients who develop an abnormal serum liver biochemical test result within 6 months of a diagnosis of untreated thyrotoxicosis.

This article is protected by copyright. All rights reserved.

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Obesity in Children with Congenital Adrenal Hyperplasia in the Minnesota Cohort: Importance of Adjusting Body Mass Index for Height-Age

Abstract

Objectives

To evaluate obesity and overweight in children with congenital adrenal hyperplasia (CAH), and associations with glucocorticoids, fludrocortisone and disease control. Adjusting body mass index for-height-age (BMI_HA) percentile is proposed to correct misclassification of obese/overweight status in CAH children with advanced bone age and tall-for-age stature.

Design

Longitudinal.

Patients

194 children with CAH seen from 1970-2013: 124 salt-wasting (SW); 70 simple-virilizing (SV); 102 females.

Measurements

BMI endpoints were overweight (85-94%tile) and obese (≥95%tile).

Results

Approximately 50% of the children had at least one BMI measurement ≥95%tile and about 70% had at least one ≥85%tile. Using BMI_HA percentiles, obesity incidence decreased slightly in SW children (47% to 43%) and markedly in SV children (50% to 33%); however, overweight status was not reduced. Only 6% of SW and 1% of SV children were persistently obese (>3 clinic visits) when BMI_HA was applied whereas overweight status persisted in 35% of SW and 33% of SV children. Most obesity or overweight when using BMI_HA occurred before age 10 and there was no association with hydrocortisone or fludrocortisone dosing. Adiposity rebound for SW children occurred by 3.3 years and in SV females by age 3.8 years, over a year earlier than the adiposity rebound for healthy children.

Conclusion

Children with CAH are at higher risk for early onset obesity and overweight with or without using BMI_HA but rates of persistent obesity were lower than previously reported. Careful hydrocortisone dosing during early childhood is needed to prevent increased weight gain and an early adiposity rebound.

This article is protected by copyright. All rights reserved.

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Impact of US Immigration Ban on Oncologists and Patients

This Viewpoint describes the disproportionate domestic impact on rural and inner-city citizens of the United States caused by the recent immigration and travel ban, and seeks to affirm physicians' commitment to more and not less diversity and inclusion.

http://ift.tt/2lhMKJY

Factors Affecting Gastrointestinal Absorption of Levothyroxine: A Review

Publication date: Available online 30 January 2017
Source:Clinical Therapeutics
Author(s): Marko Skelin, Tomo Lucijanić, Daniela Amidžić Klarić, Arnes Rešić, Miro Bakula, Ana-Marija Liberati-Čizmek, Hossein Gharib, Dario Rahelić
PurposeLevothyroxine (LT4) is a drug with a narrow therapeutic index, applied in small amounts (micrograms), which makes interactions in the absorption phase clinically significant. The main aim of this article was to review and present the latest information on factors that affect the gastrointestinal absorption of this drug.MethodsRelevant data were collected by using the MEDLINE, PubMed, EMBASE, Web of Science, Science Direct, and Scopus databases with the key words levothyroxine and absorption. Searches were not limited to specific publication types, study designs, dates, or languages. The reports were highly variable in the amount of information provided regarding study design and methods. Because of the heterogeneity of studies, no statistical analysis was performed.FindingsMany gastrointestinal disorders, such as celiac disease, atrophic gastritis, lactose intolerance, and Helicobacter pylori infection, may impede the absorption of levothyroxine. During treatment of these disorders, it is necessary to monitor serum thyroid-stimulating hormone and free T4 values to reduce the risk of developing iatrogenic hyperthyroidism. Soybeans and coffee have the greatest impact on the reduction of absorption, whereas vitamin C has the ability to increase it. Conversely, the effect of dietary fiber on the absorption of LT4 is not yet fully understood; further research is needed on this topic. A decrease in the absorption of LT4 is established and clinically significant when administered concomitantly with cholestyramine, colesevelam, lanthanum, calcium carbonate, calcium citrate, calcium acetate, iron sulfate, ciprofloxacin, aluminum hydroxide, sevelamer, or proton pump inhibitors. This effect should be taken into consideration when prescribing these drugs concomitantly with LT4. The effects of Giardia lamblia infection and the influence of orlistat, polystyrene sulfonate, raloxifene, and simethicone on absorption of LT4 have been poorly documented. For bariatric surgery, sucralfate and H2-antagonist interactions are not well founded or contradictory evidence is available regarding their existence; additional research should be conducted.ImplicationsThe majority of the interactions are clinically significant. They are based on the LT4 adsorption on interfering substances in the digestive tract, as well as a consequently reduced amount of the drug available for absorption. These interactions can be avoided by separating the administration of LT4 and the interfering substance.



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Developing New Medicines for Pediatric Oncology: Assessing Needs and Overcoming Challenges

Publication date: Available online 30 January 2017
Source:Clinical Therapeutics
Author(s): Kenneth I. Kaitin




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Organ-specific biomarkers in lupus

Publication date: Available online 14 February 2017
Source:Autoimmunity Reviews
Author(s): Haijing Wu, Jinrong Zeng, Ming Zhao, Qianjin Lu
Systemic lupus erythematosus (SLE) is a complex and highly heterogeneous disease, which affects multiple organs, including joints, skin, kidneys, heart, hematopoietic system, and nerve system. While the etiopathogenesis of SLE still remains unclear, genetic susceptibilities and aberrant epigenetic modifications are believed to be involved. For precision therapy, it is necessary to assess accurately and objectively organ involvements and disease activity, which is difficult by current clinical laboratory tests. Biomarkers, which are a biologic, genetic, epigenetic or a chemical characteristic and conveniently detectable, serve as measures of disease diagnosis, activity, prognosis, and manifestation prediction, thereby providing instruction for individualized therapy. In addition, biomarkers differ according to different manifestations, since the disease activity index and treatments vary significantly. For example, unlike other non-renal SLE, lupus nephritis requires significant immunosuppressive drugs. Over the past decades, the research on biomarkers in lupus has been strengthened and numerous promising biomarkers have been identified at levels of genomics, transcriptomics and proteomics. In this review, we summarize the conventional and novel biomarkers in the tissue-specific manner, and discuss their roles in specific organ diagnosis, future manifestation prediction, disease activity assessment and their correlation with histology results. By doing so, it aims to shed a light on individualized treatment.



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Neonatal Lupus: Follow-up in infants with anti-SSA/Ro antibodies and review of the literature

Publication date: Available online 14 February 2017
Source:Autoimmunity Reviews
Author(s): Antonio Alberto Zuppa, Riccardo Riccardi, Simonetta Frezza, Francesca Gallini, Rita Maria Paola Luciano, Giovanni Alighieri, Costantino Romagnoli, Sara De Carolis
Neonatal Lupus Syndrome (NLS) is a distinct clinical entity caused by transplacental passage of maternal anti-SSA/Ro antibodies (Ab). Mothers may have systemic lupus erythematosus, Sjögren syndrome, or other connective tissue disease, or may be completely healthy at the time of giving birth. NLS includes several clinical manifestations: complete congenital heart block (CCHB) and cutaneous lupus are the most common, while hepatobiliary disease, hematological manifestations and central nervous system involvement may occur.Data from literature on the incidence of the different clinical manifestations of NLS are difficult to compare because they come mostly from retrospective studies or prospective studies, but up to date no systematic follow-up was carried out. We performed a large prospective single-center study with a systematic clinical and instrumental follow-up until 9months of life, in order to evaluate the incidence and the clinical impact of NLS features.From 2004 to 2014 all infants born in our center to mothers with anti-SSA/Ro Ab were enrolled in a specific diagnostic and follow-up (FU) program.At birth, 50 infants born to mothers with anti-SSA/Ro Ab were found positive for anti-SSA/Ro Ab. Infants were tested for anti SSA/Ro Ab at 3months of life, if positive they were re-tested at 6 and 9months. At 9months anti-SSA/Ro Ab were positive in 10% of children. In two cases (4%) a CCHB was identified during pregnancy and required pacemaker implantation at birth. In 10% of cases a transient ECG alterations was found during follow-up. Hematological NLS features (anemia, neutropenia, thrombocytopenia) were found at birth and during FU in several patients, in all cases without clinical manifestations and in most cases with complete normalization at 9months. Mild and transient elevation of aminotransferases between 3 and 6months of life were found in 56% and 40% of patient, respectively; non-specific ultrasound cerebral anomalies in absence of clinical neurological signs were found at birth in 9 patients (18%), subsequently normalized.Prenatal maternal screening is of primary importance in order to early detect CCHB, which requires maternal treatment and pacemaker implantation at birth. Infants born to mothers with anti-SSA/Ro Ab should be monitored for all NLS features at birth. However, during the first months of life, these infants seem to develop only mild, transient and self-limited clinical manifestations, which in most cases are completely solved at 9months of life. This consideration, together with the evidence that only 10% of infants had anti-SSA/Ro Ab persistent in blood at 9months, suggests that follow-up of these children can be performed until 6–9months of life with good clinical safety. Moreover, a clinical and laboratory monitoring at 3months of life, when the highest incidence of hematological features and liver tests alterations are observed, is strongly recommended. In the future, it would be clarified if a follow-up until adulthood would be indicated in cases with persistent anti SSA/Ro or in all infants born to mother with anti SSA/Ro.



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IBD immunopathogenesis: A comprehensive review of inflammatory molecules

Publication date: Available online 14 February 2017
Source:Autoimmunity Reviews
Author(s): Jae Hyon Park, Laurent Peyrin-Biroulet, Michael Eisenhut, Jae Il Shin
Inflammatory molecules play a crucial role in the pathogenesis of inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn's disease, both of which are chronic inflammatory conditions of the gastrointestinal tract. Abnormal expressions of pro-and anti-inflammatory molecules have been described to cause an imbalance to the gut innate and adaptive immunity, and recently a large portion of research in IBD has been geared towards identifying novel molecules that may be used as potential therapeutic targets. Understanding of these inflammatory molecules has suggested that although ulcerative colitis and Crohn's disease share many common clinical symptoms and signs, they are in fact two separate clinical entities characterized by different immunopathogenesis. In this review, we comprehensively discuss the roles of numerous inflammatory molecules including but not limited to cytokines, chemokines, inflammasomes, microRNAs and neuropeptides and their expression status in ulcerative colitis and Crohn's disease in relation to their effects on the overall intestinal inflammatory process.



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Multiple sclerosis in the real world: A systematic review of fingolimod as a case study

Publication date: Available online 15 February 2017
Source:Autoimmunity Reviews
Author(s): Tjalf Ziemssen, Jennie Medin, C. Anne-Marie Couto, Catherine R. Mitchell
IntroductionThe aim of our study was to systematically review the growing body of published literature reporting on one specific multiple sclerosis (MS) treatment, fingolimod, in the real world to assess its effectiveness in patients with MS, evaluate methodologies used to investigate MS in clinical practice, and describe the evidence gaps for MS as exemplified by fingolimod.MethodsWe conducted a PRISMA-compliant systematic review of the literature (cut-off date: 4 March 2016). Published papers reporting real-world data for fingolimod with regard to clinical outcomes, persistence, adherence, healthcare costs, healthcare resource use, treatment patterns, and patient-reported outcomes that met all the eligibility criteria were included for data extraction and quality assessment.Results and discussionBased on 34 included studies, this analysis found that fingolimod treatment improved outcomes compared to the period before treatment initiation and was more effective than interferons or glatiramer acetate. However, among studies comparing fingolimod with natalizumab, overall trends were inconsistent: some reported natalizumab to be more effective than fingolimod and others reported similar effectiveness for natalizumab and fingolimod. These studies illustrate the challenges of investigating MS in the real world, including the subjectivity in evaluating some clinical outcomes and the heterogeneity of methodologies used and patient populations investigated, which limit comparisons across studies. Gaps in available real-world evidence for MS are also highlighted, including those relating to patient-reported outcomes, combined clinical outcomes (to measure overall treatment effectiveness), and healthcare costs/resource use.ConclusionsThe included studies provide good evidence of the real-world effectiveness of fingolimod and highlight the diversity of methodologies used to assess treatment benefit in clinical practice. Future studies could address the evidence gaps found in the literature and the challenges associated with researching MS when designing real-world studies, assessing data, and comparing evidence across studies.



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