In vitro and ex vivo models to study drug delivery barriers in the posterior segment of the eye

Publication date: Available online 19 September 2017
Source:Advanced Drug Delivery Reviews
Author(s): Karen Peynshaert, Joke Devoldere, Stefaan C. De Smedt, Katrien Remaut
Many ocular disorders leading to blindness could benefit from efficient delivery of therapeutics to the retina. However, despite extensive research into drug delivery vehicles and administration techniques, efficacy remains limited because of the many static and dynamic barriers present in the eye. Comprehension of the various barriers and especially how to overcome them can improve our ability to estimate the potential of existent drug delivery vectors and support the design of new ones. To this end, this review gives an overview of the most important ocular barriers for each administration route to the back of the eye. For each barrier, its biological composition and its role as an obstacle towards macromolecules, nanoparticles and viral vectors will be discussed; special attention will be paid to the influence of size, charge and lipophilicity of drug(s) (carrier) on their ability to overcome each barrier. Finally, the most significant available in vitro and ex vivo methods and models to test the potential of a therapeutic to cross each barrier are listed.

Graphical abstract

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Une nouvelle extension du devoir d’information appliquée au Service Public

Publication date: Available online 19 September 2017
Source:Médecine & Droit
Author(s): Gerard Memeteau
L'identité du praticien qui prend en charge un patient dans le cadre du service public est un des éléments constitutifs du devoir d'information.Every physician has a duty of information. He must tell the patient the risks and benefits of the treatments. Some authors write actually that it is a legal duty and not only a contractual one. But, there is not only the physician; there is also the private or public hospital. That institution ought to present to the patient a competent professional, and to inform the public about the specialties offered. The judgment tries to precise the parts of this information.



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Editorial Board

Publication date: October 2017
Source:Dental Materials, Volume 33, Issue 10





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Dimensional changes from the sintering process and fit of Y-TZP copings: Micro-CT analysis

Publication date: Available online 19 September 2017
Source:Dental Materials
Author(s): Carlos Eduardo Edwards Rezende, Ana Flávia Sanches Borges, Rander Moreira Macedo, José Henrique Rubo, Jason Alan Griggs
ObjectiveTo evaluate the dimensional changes from the sintering process of Y-TZP and relate them to the fit of zirconia copings.MethodsThe sintering shrinkage rate (SSR) was obtained from the measurement of geometric specimens (4×4×2mm). Thirty-six zirconia copings made using CAD/CAM were equally divided into three groups (n=12): ZMAX — IPS e.max ZirCAD (Ivoclar Vivadent, Liechtenstein); ZYZ — InCeram YZ (Vita Zahnfabrik, Germany); and ZK — Zirklein (Zirklein, Brazil). The copings were scanned in micro-CT before and after sintering so that SSR was obtained. The SSR of geometrical specimens and copings was compared to each other and those the manufacturers reported (ANOVA-2 and Tukey, p≤.05). The copings were settled on an abutment and taken to the micro-CT to evaluate their marginal and internal fit. The data enabled the statistical comparison (ANOVA-2 and Tukey, p≤.05) between groups and measurement sites and between the fit obtained with that stipulated by the CAD/CAM software (80μm) (Dunnett test, p≤.05).ResultsAll groups showed statistical differences between the SSR the manufacturer reported and those obtained experimentally and between the SSR of the geometric specimens and copings. In general, the SSR of the copings showed no uniformity. There was no statistical difference among the groups for marginal fit, with differences only for internal fit and between the different regions measured. The fit obtained experimentally differed from the internal space determined in the CAD/CAM software.SignificanceThe lack of uniformity of sintering shrinkage might lead to a non-uniform internal fit of Y-TZP copings.



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Does intensity-modulated radiation therapy (IMRT) alter prostate size? Magnetic resonance imaging evaluation of patients undergoing IMRT alone

Publication date: November–December 2017
Source:Reports of Practical Oncology & Radiotherapy, Volume 22, Issue 6
Author(s): Hidekazu Tanaka, Takahiro Yamaguchi, Kae Hachiya, Masahide Hayashi, Shinichi Ogawa, Hironori Nishibori, Shingo Kamei, Satoshi Ishihara, Masayuki Matsuo
AimTo assess the changes in prostate size in patients with prostate cancer undergoing intensity-modulated radiation therapy (IMRT).BackgroundThe effect of size change produced by IMRT is not well known.Materials and methodsWe enrolled 72 patients who received IMRT alone without androgen-deprivation therapy and underwent magnetic resonance imaging (MRI) examination before and after IMRT. The diameter of the entire prostate in the anterior–posterior (P-AP) and left–right (P-LR) directions was measured. The transitional zone diameter in the anterior–posterior (T-AP) and left–right (T-LR) directions was also measured.ResultsThe average relative P-AP values at 3, 6, 12, 24, and 36 months after IMRT compared to the pre-IMRT value were 0.94, 0.90, 0.89, 0.89, and 0.90, respectively; the average relative P-LR values were 0.93, 0.92, 0.91, 0.91, and 0.90, respectively. The average P-AP and P-LR decreased by approximately 10% during the 12 months post-IMRT, and remained unchanged thereafter. The average relative T-AP values at 3, 6, 12, 24, and 36 months after IMRT compared to the pre-IMRT value were 0.93, 0.88, 0.91, 0.87, and 0.89, respectively; the average relative T-LR values were 0.96, 0.90, 0.91, 0.87, and 0.88, respectively. The average T-AP and T-LR also decreased by approximately 10% during the 12 months post-IMRT, and remained unchanged thereafter. At 12 months after IMRT, the average relative T-AP was significantly lower in patients with recurrence than in those without recurrence.ConclusionsThe average prostate diameter decreased by approximately 10% during the 12 months after IMRT; thereafter remained unchanged.



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Adaptive radiotherapy in a case of adenoid cystic carcinoma of bronchus and its favourable impact on treatment outcome: A case report

Publication date: November–December 2017
Source:Reports of Practical Oncology & Radiotherapy, Volume 22, Issue 6
Author(s): Suman Das, Yogaraja Dorairaja, Anandakrishnan Kuppusamy
Adenoid cystic carcinoma is a very rare malignancy commonly originating from the salivary glands of the head and neck. It is again very scantily seen in sites like the bronchus. Surgical resection is the mainstay of treatment but many a times the tumour site and size preclude a favourable outcome of surgery and the patient is advised for other forms of local treatment like Radiotherapy. Here, we present a case report of a young female with primary adenoid cystic carcinoma of the bronchus. The tumour was located in the carina and the left bronchus which was obstructing the airway resulting in collapse of the left lung, this resulted in shifting the mediastinum and abdominal structures in to the thorax. The tumour was inoperable and was advised for radiotherapy. The adenoid cystic carcinoma of the bronchus with such presentation and mediastinal shift is a rare and special situation. During radiotherapy the collapsed lung was inflated which resulted in the shifting of the tumour and other normal structures. The use of adaptive radiotherapy in such situation helped us to achieve improved dose delivery to the tumour and this resulted in an improved survival for the patient as compared to the available literature.



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The stability and transformation of TiC with different stoichiometries in Cu–Si melts

Publication date: 5 December 2017
Source:Materials & Design, Volume 135
Author(s): Haimin Ding, Xianlong Wang, Qing Liu, Jinfeng Wang, Chunyan Li, Xinchun Zhang
In this work, the stability and transformation of two kinds of TiC with different stoichiometries in Cu–Si melts are studied, respectively. It is found that the near-stoichiometirc TiC with fewer carbon vacancies (designated as TiCx), such as TiC0.9, is relatively stable in Cu–Si melts, while the non-stoichiometric TiC with more carbon vacancies (designated as TiCy), such as TiC0.6, is unstable. And TiCy tends to transform into TiCx. Meanwhile, some Ti element from TiCy will be dissolved into the melts. It is considered that the addition of Si influences the equilibrium between TiC with different stoichiometries and soluble Ti in Cu melts, which results in the transformation of TiC. According to the results, the stoichiometry of TiC must be controlled when it is used as the reinforced phase in Cu–Si alloys.

Graphical abstract

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Low temperature formation of Mg2FeH6 by hydrogenation of ball-milled nano-crystalline powder mixture of Mg and Fe

Publication date: 5 December 2017
Source:Materials & Design, Volume 135
Author(s): Julien O. Fadonougbo, Jee-Yun Jung, Jin-Yoo Suh, Young-Su Lee, Jae-Hyeok Shim, Young Whan Cho
Low temperature formation of Mg2FeH6 is demonstrated by hydrogenation of Mg-Fe elemental powder mixture at a temperature as low as 350°C which is lower than the conventional process temperature, 500°C. To enable the low temperature synthesis, the powder mixture of Mg and Fe has been prepared by high energy ball milling using different process control agents (PCAs). A systematic study on the ball milling and hydrogenation conditions has been carried out to maximize the yield of the ternary line compound. The hydrogenation conditions together with the particle size of the starting materials turn out to play a significant role in the hydrogenation kinetics of the system. An optimized condition has demonstrated a significant hydrogenation as well as a robust cycling ability at low temperature which suggests the strong potential of the process for practical applications.

Graphical abstract

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Quantitative vascular neuroimaging of the rat brain using superparamagnetic nanoparticles: New insights on vascular organization and brain function

Publication date: December 2017
Source:NeuroImage, Volume 163
Author(s): Codi A. Gharagouzloo, Liam Timms, Ju Qiao, Zihang Fang, Joseph Nneji, Aniket Pandya, Praveen Kulkarni, Anne L. van de Ven, Craig Ferris, Srinivas Sridhar
A method called Quantitative Ultra-Short Time-to-Echo Contrast Enhanced (QUTE-CE) Magnetic Resonance Imaging (MRI) which utilizes superparamagnetic iron oxide nanoparticles (SPIONs) as a contrast agent to yield positive contrast angiograms with high clarity and definition is applied to the whole live rat brain. QUTE-CE MRI intensity data are particularly well suited for measuring quantitative cerebral blood volume (qCBV). A global map of qCBV in the awake resting-state with unprecedented detail was created via application of a 3D MRI rat brain atlas with 173 segmented and annotated brain areas. From this map we identified two distributed, integrated neural circuits showing the highest capillary densities in the brain. One is the neural circuitry involved with the primary senses of smell, hearing and vision and the other is the neural circuitry of memory. Under isoflurane anesthesia, these same circuits showed significant decreases in qCBV suggesting a role in consciousness. Neural circuits in the brainstem associated with the reticular activating system and the maintenance of respiration, body temperature and cardiovascular function showed an increase in qCBV with anesthesia. During awake CO2 challenge, 84 regions showed significant increases relative to an awake baseline state. This CO2 response provides a measure of cerebral vascular reactivity and regional perfusion reserve with the highest response measured in the somatosensory cortex. These results demonstrate the utility of QUTE-CE MRI for qCBV analysis and offer a new perspective on brain function and vascular organization.

Graphical abstract

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cTBS disruption of the supplementary motor area perturbs cortical sequence representation but not behavioural performance

Publication date: December 2017
Source:NeuroImage, Volume 163
Author(s): Oleg Solopchuk, Andrea Alamia, Laurence Dricot, Julie Duque, Alexandre Zénon
Neuroimaging studies have repeatedly emphasized the role of the supplementary motor area (SMA) in motor sequence learning, but interferential approaches have led to inconsistent findings. Here, we aimed to test the role of the SMA in motor skill learning by combining interferential and neuroimaging techniques. Sixteen subjects were trained on simple finger movement sequences for 4 days. Afterwards, they underwent two neuroimaging sessions, in which they executed both trained and novel sequences. Prior to entering the scanner, the subjects received inhibitory transcranial magnetic stimulation (TMS) over the SMA or a control site. Using multivariate fMRI analysis, we confirmed that motor training enhances the neural representation of motor sequences in the SMA, in accordance with previous findings. However, although SMA inhibition altered sequence representation (i.e. between-sequence decoding accuracy) in this area, behavioural performance remained unimpaired. Our findings question the causal link between the neuroimaging correlate of elementary motor sequence representation in the SMA and sequence generation, calling for a more thorough investigation of the role of this region in performance of learned motor sequences.



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The impact of GABAergic drugs on TMS-induced brain oscillations in human motor cortex

Publication date: December 2017
Source:NeuroImage, Volume 163
Author(s): Isabella Premoli, Til O. Bergmann, Matteo Fecchio, Mario Rosanova, Andrea Biondi, Paolo Belardinelli, Ulf Ziemann
Brain responses to transcranial magnetic stimulation (TMS) as measured with electroencephalography (EEG) have so far been assessed either by TMS-evoked EEG potentials (TEPs), mostly reflecting phase-locked neuronal activity, or time-frequency-representations (TFRs), reflecting oscillatory power arising from a mixture of both evoked (i.e., phase-locked) and induced (i.e., non-phase-locked) responses. Single-pulse TMS of the human primary motor cortex induces a specific pattern of oscillatory changes, characterized by an early (30–200 ms after TMS) synchronization in the α- and β-bands over the stimulated sensorimotor cortex and adjacent lateral frontal cortex, followed by a late (200–400 ms) α- and β-desynchronization over the stimulated and contralateral sensorimotor cortex. As GABAergic inhibition plays an important role in shaping oscillatory brain activity, we sought here to understand if GABAergic inhibition contributes to these TMS-induced oscillations. We tested single oral doses of alprazolam, diazepam, zolpidem (positive modulators of the GABAA receptor), and baclofen (specific GABAB receptor agonist). Diazepam and zolpidem enhanced, and alprazolam tended to enhance while baclofen decreased the early α-synchronization. Alprazolam and baclofen enhanced the early β-synchronization. Baclofen enhanced the late α-desynchronization, and alprazolam, diazepam and baclofen enhanced the late β-desynchronization. The observed GABAergic drug effects on TMS-induced α- and β-band oscillations were not explained by drug-induced changes on corticospinal excitability, muscle response size, or resting-state EEG power. Our results provide first insights into the pharmacological profile of TMS-induced oscillatory responses of motor cortex.



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Towards understanding rTMS mechanism of action: Stimulation of the DLPFC causes network-specific increase in functional connectivity

Publication date: 15 November 2017
Source:NeuroImage, Volume 162
Author(s): Martin Tik, André Hoffmann, Ronald Sladky, Livia Tomova, Allan Hummer, Lucia Navarro de Lara, Henryk Bukowski, Jürgen Pripfl, Bharat Biswal, Claus Lamm, Christian Windischberger
Transcranial magnetic stimulation (TMS) is a powerful non-invasive technique for the modulation of brain activity. While the precise mechanism of action is still unknown, TMS is applied in cognitive neuroscience to establish causal relationships between stimulation and subsequent changes in cerebral function and behavioral outcome. In addition, TMS is an FDA-approved therapeutic agent in psychiatric disorders, especially major depression. Successful repetitive TMS in such disorders is usually applied over the left dorso-lateral prefrontal cortex (DLPFC) and treatment response mechanism was therefore supposed to be based on modulations in functional networks, particularly the meso-cortico-limbic reward circuit. However, mechanistic evidence for the direct effects of rTMS over DLPFC is sparse. Here we show the specificity and temporal evolution of rTMS effects by comparing connectivity changes within 20 common independent components in a sham-controlled study. Using an unbiased whole-brain resting-state network (RSN) approach, we successfully demonstrate that stimulation of left DLPFC modulates anterior cingulate cortex (ACC) connectivity in one specific meso-cortico-limbic network, while all other networks are neither influenced by rTMS nor by sham treatment. The results of this study show that the neural correlates of TMS treatment response are also traceable in DLPFC stimulation of healthy brains and therefore represent direct effects of the stimulation procedure.



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Histone H3 Methylated at Arginine 17 Is Essential for Reprogramming the Paternal Genome in Zygotes

Publication date: 19 September 2017
Source:Cell Reports, Volume 20, Issue 12
Author(s): Yuki Hatanaka, Takeshi Tsusaka, Natsumi Shimizu, Kohtaro Morita, Takehiro Suzuki, Shinichi Machida, Manabu Satoh, Arata Honda, Michiko Hirose, Satoshi Kamimura, Narumi Ogonuki, Toshinobu Nakamura, Kimiko Inoue, Yoshihiko Hosoi, Naoshi Dohmae, Toru Nakano, Hitoshi Kurumizaka, Kazuya Matsumoto, Yoichi Shinkai, Atsuo Ogura
At fertilization, the paternal genome undergoes extensive reprogramming through protamine-histone exchange and active DNA demethylation, but only a few maternal factors have been defined in these processes. We identified maternal Mettl23 as a protein arginine methyltransferase (PRMT), which most likely catalyzes the asymmetric dimethylation of histone H3R17 (H3R17me2a), as indicated by in vitro assays and treatment with TBBD, an H3R17 PRMT inhibitor. Maternal histone H3.3, which is essential for paternal nucleosomal assembly, is unable to be incorporated into the male pronucleus when it lacks R17me2a. Mettl23 interacts with Tet3, a 5mC-oxidizing enzyme responsible for active DNA demethylation, by binding to another maternal factor, GSE (gonad-specific expression). Depletion of Mettl23 from oocytes resulted in impaired accumulation of GSE, Tet3, and 5hmC in the male pronucleus, suggesting that Mettl23 may recruit GSE-Tet3 to chromatin. Our findings establish H3R17me2a and its catalyzing enzyme Mettl23 as key regulators of paternal genome reprogramming.

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Teaser

Maternal factors mediate nucleosome assembly and active DNA demethylation of the paternal genome during reprogramming in mouse oocytes; however, the underlying mechanisms are poorly described. Hatanaka et al. show that maternally provided H3R17me2a is responsible not only for H3.3 incorporation but also for active DNA demethylation in the paternal genome.


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PexRAP Inhibits PRDM16-Mediated Thermogenic Gene Expression

Publication date: 19 September 2017
Source:Cell Reports, Volume 20, Issue 12
Author(s): Irfan J. Lodhi, John M. Dean, Anyuan He, Hongsuk Park, Min Tan, Chu Feng, Haowei Song, Fong-Fu Hsu, Clay F. Semenkovich
How the nuclear receptor PPARγ regulates the development of two functionally distinct types of adipose tissue, brown and white fat, as well as the browning of white fat, remains unclear. Our previous studies suggest that PexRAP, a peroxisomal lipid synthetic enzyme, regulates PPARγ signaling and white adipogenesis. Here, we show that PexRAP is an inhibitor of brown adipocyte gene expression. PexRAP inactivation promoted adipocyte browning, increased energy expenditure, and decreased adiposity. Identification of PexRAP-interacting proteins suggests that PexRAP function extends beyond its role as a lipid synthetic enzyme. Notably, PexRAP interacts with importin-β1, a nuclear import factor, and knockdown of PexRAP in adipocytes reduced the levels of nuclear phospholipids. PexRAP also interacts with PPARγ, as well as PRDM16, a critical transcriptional regulator of thermogenesis, and disrupts the PRDM16-PPARγ complex, providing a potential mechanism for PexRAP-mediated inhibition of adipocyte browning. These results identify PexRAP as an important regulator of adipose tissue remodeling.

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Teaser

Lodhi et al. find that the peroxisomal lipid synthetic enzyme PexRAP is also a nuclear protein that suppresses adipose tissue browning. PexRAP interacts with PPARγ and PRDM16 and inhibits PRDM16-mediated thermogenic gene expression.


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Dynamic Rearrangement of Cell States Detected by Systematic Screening of Sequential Anticancer Treatments

Publication date: 19 September 2017
Source:Cell Reports, Volume 20, Issue 12
Author(s): Simon Koplev, James Longden, Jesper Ferkinghoff-Borg, Mathias Blicher Bjerregård, Thomas R. Cox, Janine T. Erler, Jesper T. Pedersen, Franziska Voellmy, Morten O.A. Sommer, Rune Linding
Signaling networks are nonlinear and complex, involving a large ensemble of dynamic interaction states that fluctuate in space and time. However, therapeutic strategies, such as combination chemotherapy, rarely consider the timing of drug perturbations. If we are to advance drug discovery for complex diseases, it will be essential to develop methods capable of identifying dynamic cellular responses to clinically relevant perturbations. Here, we present a Bayesian dose-response framework and the screening of an oncological drug matrix, comprising 10,000 drug combinations in melanoma and pancreatic cancer cell lines, from which we predict sequentially effective drug combinations. Approximately 23% of the tested combinations showed high-confidence sequential effects (either synergistic or antagonistic), demonstrating that cellular perturbations of many drug combinations have temporal aspects, which are currently both underutilized and poorly understood.

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Teaser

Therapeutic strategies, such as combination chemotherapy, rarely consider the timing of drug perturbations. Koplev et al. present a Bayesian dose-response framework for the prediction of sequentially effective drug combinations. They find widespread time dependency that is partially conserved between cancer cells of the same tissue origin.


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Cohesin Can Remain Associated with Chromosomes during DNA Replication

Publication date: 19 September 2017
Source:Cell Reports, Volume 20, Issue 12
Author(s): James D.P. Rhodes, Judith H.I. Haarhuis, Jonathan B. Grimm, Benjamin D. Rowland, Luke D. Lavis, Kim A. Nasmyth
To ensure disjunction to opposite poles during anaphase, sister chromatids must be held together following DNA replication. This is mediated by cohesin, which is thought to entrap sister DNAs inside a tripartite ring composed of its Smc and kleisin (Scc1) subunits. How such structures are created during S phase is poorly understood, in particular whether they are derived from complexes that had entrapped DNAs prior to replication. To address this, we used selective photobleaching to determine whether cohesin associated with chromatin in G1 persists in situ after replication. We developed a non-fluorescent HaloTag ligand to discriminate the fluorescence recovery signal from labeling of newly synthesized Halo-tagged Scc1 protein (pulse-chase or pcFRAP). In cells where cohesin turnover is inactivated by deletion of WAPL, Scc1 can remain associated with chromatin throughout S phase. These findings suggest that cohesion might be generated by cohesin that is already bound to un-replicated DNA.

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Teaser

How sister chromatids become entrapped within cohesin rings is not known. Rhodes et al. show that cohesin that is loaded onto DNA before S phase can remain associated with chromatin throughout DNA replication. This is consistent with the conversion of G1-loaded cohesin into its cohesive form.


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Structural and Functional Analysis of GRP94 in the Closed State Reveals an Essential Role for the Pre-N Domain and a Potential Client-Binding Site

Publication date: 19 September 2017
Source:Cell Reports, Volume 20, Issue 12
Author(s): John D. Huck, Nanette L. Que, Feng Hong, Zihai Li, Daniel T. Gewirth
Hsp90 chaperones undergo ATP-driven conformational changes during the maturation of client proteins, populating a closed state upon ATP binding in which the N-terminal domains of the homodimer form a second inter-protomer dimer interface. A structure of GRP94, the endoplasmic reticulum hsp90, in a closed conformation has not been described, and the determinants that regulate closure are not well understood. Here, we determined the 2.6-Å structure of AMPPNP-bound GRP94 in the closed dimer conformation. The structure includes the pre-N domain, a region preceding the N-terminal domain that is highly conserved in GRP94, but not in other hsp90s. We show that the GRP94 pre-N domain is essential for client maturation, and we identify the pre-N domain as an important regulator of ATPase rates and dimer closure. The structure also reveals a GRP94:polypeptide interaction that partially mimics a client-bound state. The results provide structural insight into the ATP-dependent client maturation process of GRP94.

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Teaser

Huck et al. determined the structure of the ER hsp90 chaperone GRP94, and they show that it adopts a closed dimer conformation. The non-conserved pre-N-terminal domain is shown to be essential for GRP94 client maturation, but it is structurally distinct. A captured polypeptide fragment in the structure mimics a bound client.


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DNA Ligase IV Guides End-Processing Choice during Nonhomologous End Joining

Publication date: 19 September 2017
Source:Cell Reports, Volume 20, Issue 12
Author(s): Michael P. Conlin, Dylan A. Reid, George W. Small, Howard H. Chang, Go Watanabe, Michael R. Lieber, Dale A. Ramsden, Eli Rothenberg
Nonhomologous end joining (NHEJ) must adapt to diverse end structures during repair of chromosome breaks. Here, we investigate the mechanistic basis for this flexibility. DNA ends are aligned in a paired-end complex (PEC) by Ku, XLF, XRCC4, and DNA ligase IV (LIG4); we show by single-molecule analysis how terminal mispairs lead to mobilization of ends within PECs and consequent sampling of more end-alignment configurations. This remodeling is essential for direct ligation of damaged and mispaired ends during cellular NHEJ, since remodeling and ligation of such ends both require a LIG4-specific structural motif, insert1. Insert1 is also required for PEC remodeling that enables nucleolytic processing when end structures block direct ligation. Accordingly, cells expressing LIG4 lacking insert1 are sensitive to ionizing radiation. Cellular NHEJ of diverse ends thus identifies the steps necessary for repair through LIG4-mediated sensing of differences in end structure and consequent dynamic remodeling of aligned ends.

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Teaser

Conlin et al. show that, when DNA double-strand breaks have terminal mispairs or damage, an unstructured loop unique to DNA ligase IV allows for dynamic remodeling of the alignment and end repair; the loop is also required for cellular resistance to ionizing radiation.


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Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma

Publication date: 19 September 2017
Source:Cell Reports, Volume 20, Issue 12
Author(s): Johannes Brägelmann, Marcel A. Dammert, Felix Dietlein, Johannes M. Heuckmann, Axel Choidas, Stefanie Böhm, André Richters, Debjit Basu, Verena Tischler, Carina Lorenz, Peter Habenberger, Zhizhou Fang, Sandra Ortiz-Cuaran, Frauke Leenders, Jan Eickhoff, Uwe Koch, Matthäus Getlik, Martin Termathe, Muhammad Sallouh, Zoltán Greff, Zoltán Varga, Hyatt Balke-Want, Christopher A. French, Martin Peifer, H. Christian Reinhardt, László Örfi, György Kéri, Sascha Ansén, Lukas C. Heukamp, Reinhard Büttner, Daniel Rauh, Bert M. Klebl, Roman K. Thomas, Martin L. Sos
Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number of oncogenic drivers are directly druggable. By interrogating the activity of 1,505 kinase inhibitors, we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells are specifically killed by CDK9 inhibition (CDK9i) and depend on CDK9 and Cyclin-T1 expression. We show that CDK9i leads to robust induction of apoptosis and of markers of DNA damage response in NMC cells. While both CDK9i and bromodomain inhibition over time result in reduced Myc protein expression, only bromodomain inhibition induces cell differentiation and a p21-induced cell-cycle arrest in these cells. Finally, RNA-seq and ChIP-based analyses reveal a BRD4-NUT-specific CDK9i-induced perturbation of transcriptional elongation. Thus, our data provide a mechanistic basis for the genotype-dependent vulnerability of NMC cells to CDK9i that may be of relevance for the development of targeted therapies for NMC patients.

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Teaser

By screening 1,505 compounds against 78 cancer cell lines, Brägelmann et al. identify a specific sensitivity of BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells to CDK9 inhibition. CDK9 inhibition affects transcriptional elongation, de-regulates MYC signaling, and induces apoptosis by suppressing anti-apoptotic MCL1. CDK9 may thus be a promising target in NMC.


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Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6

Publication date: 19 September 2017
Source:Cell Reports, Volume 20, Issue 12
Author(s): Nina Kerres, Steffen Steurer, Stefanie Schlager, Gerd Bader, Helmut Berger, Maureen Caligiuri, Christian Dank, John R. Engen, Peter Ettmayer, Bernhard Fischerauer, Gerlinde Flotzinger, Daniel Gerlach, Thomas Gerstberger, Teresa Gmaschitz, Peter Greb, Bingsong Han, Elizabeth Heyes, Roxana E. Iacob, Dirk Kessler, Heike Kölle, Lyne Lamarre, David R. Lancia, Simon Lucas, Moriz Mayer, Katharina Mayr, Nikolai Mischerikow, Katja Mück, Christoph Peinsipp, Oliver Petermann, Ulrich Reiser, Dorothea Rudolph, Klaus Rumpel, Carina Salomon, Dirk Scharn, Renate Schnitzer, Andreas Schrenk, Norbert Schweifer, Diane Thompson, Elisabeth Traxler, Roland Varecka, Tilman Voss, Alexander Weiss-Puxbaum, Sandra Winkler, Xiaozhang Zheng, Andreas Zoephel, Norbert Kraut, Darryl McConnell, Mark Pearson, Manfred Koegl
The transcription factor BCL6 is a known driver of oncogenesis in lymphoid malignancies, including diffuse large B cell lymphoma (DLBCL). Disruption of its interaction with transcriptional repressors interferes with the oncogenic effects of BCL6. We used a structure-based drug design to develop highly potent compounds that block this interaction. A subset of these inhibitors also causes rapid ubiquitylation and degradation of BCL6 in cells. These compounds display significantly stronger induction of expression of BCL6-repressed genes and anti-proliferative effects than compounds that merely inhibit co-repressor interactions. This work establishes the BTB domain as a highly druggable structure, paving the way for the use of other members of this protein family as drug targets. The magnitude of effects elicited by this class of BCL6-degrading compounds exceeds that of our equipotent non-degrading inhibitors, suggesting opportunities for the development of BCL6-based lymphoma therapeutics.

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Kerres et al. show that the BTB domain of BCL6 is highly druggable and that potent binders can be derived that cause rapid degradation of BCL6. Inhibitors that induce degradation cause stronger anti-proliferative effects than other BCL6 inhibitors and offer new routes to the development of lymphoma treatments.


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Differential Mechanisms for SHP2 Binding and Activation Are Exploited by Geographically Distinct Helicobacter pylori CagA Oncoproteins

Publication date: 19 September 2017
Source:Cell Reports, Volume 20, Issue 12
Author(s): Takeru Hayashi, Miki Senda, Nobuhiro Suzuki, Hiroko Nishikawa, Chi Ben, Chao Tang, Lisa Nagase, Kaori Inoue, Toshiya Senda, Masanori Hatakeyama
Helicobacter pylori East Asian CagA is more closely associated with gastric cancer than Western CagA. Here we show that, upon tyrosine phosphorylation, the East Asian CagA-specific EPIYA-D segment binds to the N-SH2 domain of pro-oncogenic SHP2 phosphatase two orders of magnitude greater than Western CagA-specific EPIYA-C. This high-affinity binding is achieved via cryptic interaction between Phe at the +5 position from phosphotyrosine in EPIYA-D and a hollow on the N-SH2 phosphopeptide-binding floor. Also, duplication of EPIYA-C in Western CagA, which increases gastric cancer risk, enables divalent high-affinity binding with SHP2 via N-SH2 and C-SH2. These strong CagA bindings enforce enzymatic activation of SHP2, which endows cells with neoplastic traits. Mechanistically, N-SH2 in SHP2 is in an equilibrium between stimulatory "relaxed" and inhibitory "squeezed" states, which is fixed upon high-affinity CagA binding to the "relaxed" state that stimulates SHP2. Accordingly, East Asian CagA and Western CagA exploit distinct mechanisms for SHP2 deregulation.

Graphical abstract

Teaser

Helicobacter pylori CagA binds and deregulates SHP2 to promote gastric carcinogenesis. Hayashi et al. examine the structural and molecular determinants underpinning the CagA-SHP2 interaction and find that totally distinct mechanisms of SHP2 binding are differentially exploited by two major oncogenic CagA isoforms, revealing highly plastic evolution in bacterial virulence acquisition.


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Tumor-Derived Mesenchymal Stem Cells Use Distinct Mechanisms to Block the Activity of Natural Killer Cell Subsets

Publication date: 19 September 2017
Source:Cell Reports, Volume 20, Issue 12
Author(s): Sabine Galland, Joanna Vuille, Patricia Martin, Igor Letovanec, Anne Caignard, Giulia Fregni, Ivan Stamenkovic
Mesenchymal stem cells (MSCs) display pleiotropic functions, which include secretion of soluble factors with immunosuppressive activity implicated in cancer progression. We compared the immunomodulatory effects on natural killer (NK) cells of paired intratumor (T)- and adjacent non-tumor tissue (N)-derived MSCs from patients with squamous cell lung carcinoma (SCC). We observed that T-MSCs were more strongly immunosuppressive than N-MSCs and affected both NK function and phenotype, as defined by CD56 expression. T-MSCs shifted NK cells toward the CD56^dim phenotype and differentially modulated CD56^bright/dim subset functions. Whereas MSCs affected both degranulation and activating receptor expression in the CD56^dim subset, they primarily inhibited interferon-γ production in the CD56^bright subset. Pharmacological inhibition of prostaglandin E2 (PGE2) synthesis and, in some MSCs, interleukin-6 (IL-6) activity restored NK function, whereas NK cell stimulation by PGE2 alone mimicked T-MSC-mediated immunosuppression. Our observations provide insight into how stromal responses to cancer dampen NK cell activity in human lung SCC.

Graphical abstract

Teaser

Galland et al. compare natural killer (NK) cell immunosuppression by mesenchymal stem cells (MSCs) from primary human squamous cell carcinomas and adjacent normal lung tissue. Tumor-associated MSCs exert stronger immunosuppression than normal-tissue-derived MSCs and modulate different NK functions by distinct mechanisms.


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Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites

Publication date: 19 September 2017
Source:Cell Reports, Volume 20, Issue 12
Author(s): Brahma V. Kumar, Wenji Ma, Michelle Miron, Tomer Granot, Rebecca S. Guyer, Dustin J. Carpenter, Takashi Senda, Xiaoyun Sun, Siu-Hong Ho, Harvey Lerner, Amy L. Friedman, Yufeng Shen, Donna L. Farber
Tissue-resident memory T cells (TRMs) in mice mediate optimal protective immunity to infection and vaccination, while in humans, the existence and properties of TRMs remain unclear. Here, we use a unique human tissue resource to determine whether human tissue memory T cells constitute a distinct subset in diverse mucosal and lymphoid tissues. We identify a core transcriptional profile within the CD69⁺ subset of memory CD4⁺ and CD8⁺ T cells in lung and spleen that is distinct from that of CD69⁻ TEM cells in tissues and circulation and defines human TRMs based on homology to the transcriptional profile of mouse CD8⁺ TRMs. Human TRMs in diverse sites exhibit increased expression of adhesion and inhibitory molecules, produce both pro-inflammatory and regulatory cytokines, and have reduced turnover compared with circulating TEM, suggesting unique adaptations for in situ immunity. Together, our results provide a unifying signature for human TRM and a blueprint for designing tissue-targeted immunotherapies.

Graphical abstract

Teaser

Kumar et al. identify a core transcriptional and phenotypic signature that defines human TRMs for both CD4⁺ and CD8⁺ T cells that is preserved across diverse individuals and in mucosal and lymphoid sites.


http://ift.tt/2xvUopM

Role of the intestinal microbiota in the immunomodulation of influenza virus infection

Publication date: Available online 19 September 2017
Source:Microbes and Infection
Author(s): Chi-Jene Chen, Guan-Hong Wu, Rei-Lin Kuo, Shin-Ru Shih
Prevention and treatment measures against influenza virus infection remain limited, and alternative host protection strategies are badly needed. In this review, we discuss the regulatory role of intestinal microbiota in influenza infections, and present the latest evidence for strategies seeking to harness gut microbiota for the management of influenza infections.



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Incidence and all-cause mortality for hip fracture in comparison to stroke, and myocardial infarction: a fifteen years population-based longitudinal study

Abstract

Purpose

This population-based study investigated the incidence, in-hospital and long-term all-cause mortality, for hip fracture (HipFx), stroke (STR), and myocardial infarction (MI) in residents hospitalized between 2000 and 2014.

Methods

Data about hospitalization were drawn from the administrative discharge database, whereas information about residents and all-cause mortality from the municipality of our town. Patients were followed-up from the first hospital admission until death or study end. For each cause, crude and age-adjusted all-cause mortality of men and women were compared by Mann–Whitney's test and Poisson models. Separate age-sex adjusted Cox models were estimated and the corresponding adjusted survival curves were drawn.

Results

Among 1292 hospitalizations (of 1109 patients), 434 were for HipFx, 526 for STR, 332 for MI (183 with and 149 without coronary revascularization –MIwCR and MIwoCR, respectively). The incidence of HipFx and STR did not vary over time, MI slightly increasing in men. Age-adjusted in-hospital mortality for HipFx was lower than for STR and MIwoCR in the whole sample and in women (p < 0.001), but not in men. After discharge, men with HipFx had shorter survival and higher crude and age-adjusted mortality rate than women. The estimated HRs(95%CI) in respect to patients with MIwCR (having the lowest mortality) were: 6.11(3.12–11.97), p < 0.001 for HipFx; 5.78(2.93–11.32), p < 0.001 for STR; 2.68(1.27–5.66), p = 0.010 for MIwoCR in the whole sample [HR: 16.58(6.70–40.98) p < 0.001 for HipFx; 7.35(3.01–17.93) p < 0.001 for STR, in men].

Conclusions

HipFx markedly impacts hospital care, and causes high in-hospital and long-term all-cause mortality, comparable to the two commonest non-tumor causes of death.

http://ift.tt/2xwcec1

ISOLATION AND CHARACTERISATION OF THEOBROMINE-DEGRADING FILAMENTOUS FUNGI

Publication date: Available online 19 September 2017
Source:Microbiological Research
Author(s): Daniel Oduro-Mensah, Augustine Ocloo, Sammy T. Lowor, Evelyn Y. Bonney, Laud K.N.A. Okine, Naa Ayikailey Adamafio
Strategies for achieving global food security include identification of alternative feedstock for use as animal feed, to contribute towards efforts at increasing livestock farming. The presence of theobromine in cocoa pod husks, a major agro-waste in cocoa-producing countries, hinders its utilisation for this purpose. Cheap treatment of cocoa pod husks to remove theobromine would allow largescale beneficial use of the millions of metric tonnes generated annually. The aim of this study was to isolate theobromine-degrading filamentous fungi that could serve as bioremediation agents for detheobromination of cocoa pod husks. Filamentous fungi were screened for ability to degrade theobromine. The most promising isolates were characterized with respect to optimal environmental conditions for theobromine degradation. Secretion of theobromine-degrading enzymes by the isolates was investigated. Theobromine degradation was monitored by HPLC. Of fourteen theobromine-degrading isolates collected and identified by rDNA 5.8S and ITS sequences, seven belonged to Aspergillus spp. and six were Talaromyces spp. Based on the extent of theobromine utilization, four isolates; Aspergillus niger, Talaromyces verruculosus and two Talaromyces marneffei, showed the best potential for use as bioagents for detheobromination. First-time evidence was found of the use of xanthine oxidase and theobromine oxidase in degradation of a methylxanthine by fungal isolates. Metabolism of theobromine involved initial demethylation at position 7 to form 3-methylxanthine, or initial oxidation at position 8 to form 3,7-dimethyuric acid. All four isolates degraded theobromine beyond uric acid. The data suggest that the four isolates can be applied to substrates, such as cocoa pod husks, for elimination of theobromine.



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Comparison of Fixed-Dose Combinations of Amlodipine/Losartan Potassium/Chlorthalidone and Amlodipine/Losartan Potassium in Patients With Stage 2 Hypertension Inadequately Controlled With Amlodipine/Losartan Potassium: A Randomized, Double-blind, Multicenter, Phase III Study

Publication date: Available online 19 September 2017
Source:Clinical Therapeutics
Author(s): Soon Jun Hong, Han Saem Jeong, Seung Hwan Han, Ki Yuk Chang, Bum Kee Hong, Bong Ki Lee, Shung Chull Chae, Woo Shik Kim, Chang Gyu Park, Jung Ho Heo, Seung Uk Lee, Young Dae Kim, Kee Sik Kim, Jung Hyun Choi, Hyun Jae Kang, Jae Joong Kim, Seok Min Kang, Young Jin Choi, Joon Han Shin, Kook Jin Chun, Dong Gu Shin, Seong Hoon Park, Jun Kwan, Yu Jeong Choi, Myung Ho Jeong, Jei Keon Chae, Dong Woon Kim, Jung Rae Cho, Kyoo Rok Han, Kyung Heon Won, Sang Ho Park, Sang Kon Lee, Sang Hoon Kim, Jina Jung, Cheol Ho Kim
PurposeThe goal of this study was to compare the efficacy and safety of fixed-dose combinations of amlodipine/losartan potassium/chlorthalidone (A/L/C) and A/L in Korean patients with stage 2 hypertension inadequately controlled by A/L.MethodsThis study was an 8-week, randomized double-blind, multicenter, phase III clinical trial. Three hundred forty volunteer patients with stage 2 hypertension were randomized to receive A/L/C or A/L. The primary end point was a change in sitting systolic blood pressure (SitSBP) after 8 weeks of treatment. As secondary end points, the change in SitSBP after 2 weeks of treatment and the change in sitting diastolic blood pressure (SitDBP) were compared between treatment groups. All patients were assessed for adverse events, clinical laboratory data, and vital signs.FindingsOf 330 patients from 33 medical centers, 328 patients who had available efficacy data were analyzed. After 8 weeks of double-blind treatment, the mean (SD) changes in SitSBP at 8 weeks were −16.4 (0.9) mm Hg and −6.9 (1.0) mm Hg in the A/L/C and A/L groups, respectively. A/L/C had a statistically superior blood pressure–lowering effect compared with that of A/L (mean [SD] difference, 9.5 [1.3] mm Hg; P < 0.001). The mean (SD) change in SitDBP at 8 weeks was significantly greater with A/L/C (−8.0 [0.6] mm Hg) than with A/L (−3.6 [0.6] mm Hg) (P < .001). In terms of the mean (SD) change in SitDBP at 2 weeks compared with baseline, A/L/C (−5.9 [0.5] mm Hg) was statistically different from A/L (−2.9 [0.5] mm Hg) (P < .001). Mean (SD) SitSBP change from baseline to week 2 was −13.2 (0.9) and −5.5 (0.9) in the A/L/C and A/L groups, respectively, with a statistically significant blood pressure–lowering effect (P < 0.001). The number of participants who achieved target blood pressure at week 8 was significantly higher in the A/L/C group (93 patients [55.7%]) than in the A/L group (48 [29.8%]) (P < 0.001). Adverse drug reactions were observed in 23 patients (7.0%), and the incidence of dizziness was significantly higher in the A/L/C group than in the A/L group (4.8% vs 0.6%, P = 0.037) There were no serious adverse events associated with the study drugs.ImplicationsThe results of this study suggest that A/L/C had a significantly increased blood pressure–lowering efficacy compared with that of A/L and had a good safety profile. ClinicalTrials.gov identifier: NCT02916602.



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Current Standards of Chemotherapy for Pancreatic Cancer

Publication date: Available online 19 September 2017
Source:Clinical Therapeutics
Author(s): May Tun Saung, Lei Zheng
PurposePancreatic cancer has a dismal prognosis due to the early development of systemic metastatic disease. Chemotherapeutic agents are the only systemic therapy that offers patients meaningful benefit.MethodsThis study reviewed the literature for recently published Phase III clinical trials whose results have guided the current standards of chemotherapy for pancreatic cancer.FindingsAlthough combination chemotherapy regimens are shown to be superior to gemcitabine monotherapy for both metastatic pancreatic cancer and adjuvant chemotherapy after surgical resection, it should be recognized that all combination chemotherapy regimens offer only limited benefits. In addition, there is a paucity of clinical trials that directly compare the various combination chemotherapy regimens.ImplicationsWith the advancement of systemic cancer treatment beyond chemotherapy, it is important to devote more investigation into better understanding the biology of these chemotherapy regimens, such that we combine them with targeted therapeutics and immunotherapeutics in a rational and scientific manner. For the current treatment of pancreatic cancer, the available chemotherapy regimens have shown modest but statistically significant improvements in survival. However, it is important to avoid cross-comparisons of trials and choose regimens based on patient characteristics and the side-effect profiles of the regimen.



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Efficacy and Safety of Hyperbaric Oxygen Therapy Used in Patients With Diabetic Foot: A Meta-Analysis of Randomized Clinical Trials

Publication date: Available online 19 September 2017
Source:Clinical Therapeutics
Author(s): Di Zhao, Shaowei Luo, Wencan Xu, Jun Hu, Shaoda Lin, Nasui Wang
PurposeThe efficacy and safety profile of hyperbaric oxygen therapy (HBOT) in patients with diabetic foot ulcer have been controversial in recent years. Our meta-analysis was undertaken to evaluate the efficacy and safety profile of HBOT in patients with diabetic foot ulcer.MethodsWe searched the PubMed, Cochrane Library, EMBASE, and Clinical Trials.gov databases for controlled trials. The efficacy end points included the incidence of healed ulcers, major amputations, minor amputations, and reduction in the ulcer wound area. The tolerability end point was the incidence of adverse events.FindingsNine randomized clinical trials involving 526 patients met the inclusion criteria. No difference was found in the incidence of healed ulcers (risk ratio [RR] = 2.22; 95% CI, 0.87–5.62; P = 0.32; I² = 81%), minor amputations (RR = 0.95; 95% CI, 0.39–2.29; P = 0.91; I² = 74%), major amputations (RR = 0.47; 95% CI, 0.17–1.28; P = 0.14; I² = 61%), and adverse events (RR = 1.00; 95% CI, 0.64–1.56; P = 0.99; I² = 26%) between the HBOT and standard therapy (ST) groups. HBOT was associated with a greater reduction in the ulcer wound area versus ST (standard mean difference = 1.12; 95% CI, 0.20–2.04; P = 0.04; I² = 70%).ImplicationsNo differences existed between HBOT and ST with respect to the incidence of healed ulcers, risk of minor or major amputations, and adverse events. HBOT was associated with a greater reduction in the ulcer wound area than ST. HBOT is a clinically meaningful adjuvant therapy for patients with diabetic foot ulcer.



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The Utility of Collaterals as a Biomarker in Pediatric Unilateral Intracranial Arteriopathy

Publication date: Available online 20 September 2017
Source:Pediatric Neurology
Author(s): Jorina Elbers, Derek Armstrong, Susanne Benseler, Nomazulu Dlamini, Gary Steinberg, Kristen W. Yeom
ObjectiveIntracranial arteriopathies are frequent causes of pediatric stroke and important risk factors for stroke recurrence. Without tissue diagnosis, vascular imaging is relied upon to identify the underlying etiology and prognosis. We hypothesized that children with unilateral intracranial arteriopathy with lenticulostriate collaterals would demonstrate distinct vascular outcomes compared to children without collaterals.MethodsWe retrospectively identified children with unilateral intracranial arteriopathy from two institutions. Two blinded raters from each institution reviewed magnetic resonance or digital subtraction angiography at baseline and ≥12-months. Patients were grouped according to presence or absence of lenticulostriate collaterals. Clinical features and vascular imaging outcomes were compared using univariate analysis and multivariate logistic regression.ResultsForty-four children were included: 22 males, median age 8.2 years (range 2-16.9 years), and further stratified into the collateral group (n=20) and non-collateral group (n=24), with median follow-up of 25.5-months and 23-months, respectively. Both groups demonstrated similar rates of progression on vascular imaging at >12-months, 50% in the collateral group versus 38% in the non-collateral group (p>0.05). The collateral group was associated with asymptomatic clinical presentation, normal brain MRI, border zone infarcts, and either vascular stabilization or new contralateral disease. The non-collateral group demonstrated either vascular improvement or discordant progression (combination of improved and progressive lesions). Using a multivariate model, collaterals continued to be an independent predictor of vascular outcome.ConclusionsThis study suggests lenticulostriate collaterals in pediatric unilateral intracranial arteriopathy may serve as a useful neuroimaging biomarker that helps to stratify patients with distinct clinical features and patterns of vascular evolution.



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Magnetoencephalographic Characteristics of Cortical Dysplasia in Children

Publication date: Available online 19 September 2017
Source:Pediatric Neurology
Author(s): Nitin Agarwal, Balu Krishnan, Richard C. Burgess, Richard A.Prayson, Andreas V. Alexopoulos, Ajay Gupta
Background & RationaleMagnetoencephalography (MEG) has emerged as a tool for pre-surgical evaluation in children. We aimed to study MEG characteristics in sub-types of Focal Cortical Dysplasia (FCD) and correlate with post surgical seizure outcome.MethodsInclusion criteria were children ≤18 years who had MEG during pre-surgical workup followed by epilepsy surgery and a histopathological diagnosis of FCD between February 2008- February 2013. Patient demographics, MRI, video EEG and MEG data were reviewed. Postsurgical seizure outcome data was categorized per ILAE definitions.ResultsOf 178 MEG performed in children during the study period, 33 patients met inclusion criteria. FCD Type I, II and III were found on histopathology in 52%, 39% and 9% patients respectively. Thirty patients had positive MEG dipoles including all patients with FCD Type II and III and 82% patients with FCD Type I. Three patients had MEG unique spikes. Brain MRI lesions were noted pre-operatively in 21 (64%) patients. Twenty-three (77%) patients had surgical resection of MEG dipoles and 11 (48%) of these achieved favorable outcome.ConclusionsMEG supplements scalp EEG data in spike source localization and showed unique spikes in 10% of the FCD patients. MEG spikes and tight MEG clusters were found more frequently in patients with FCD Type II and III as compared to FCD Type I. Presence of a MRI lesion and complete vs incomplete resection of MEG cluster did not result in significant difference in postsurgical seizure outcome likely reflecting selection bias of doing MEG in only difficult to localize epilepsies.



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Scholar : These new articles for Journal of Architectural Conservation are available online

The online platform for Taylor & Francis Online content New for Journal of Architectural Conservation and online now on Taylor & Francis Online: Original Articles A construction technique using closed hollow ceramic elements, typical of historical buildings in Calabria Caterina Gattuso Pages: 1-25 | DOI: 10.1080/13556207.2017.1368248 Read selected content from the Journal of Structural Integrity and Maintenance for free! http://ift.tt/2coiFom To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Scholar : These new articles for Norwegian Archaeological Review are available online

The online platform for Taylor & Francis Online content New for Norwegian Archaeological Review and online now on Taylor & Francis Online: Discussion The Nature of Archaeological Knowledge and Its Ontological Turns Kristian Kristiansen Pages: 1-4 | DOI: 10.1080/00293652.2017.1372802 To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Scholar : These new articles for Journal of the Institute of Conservation are available online

The online platform for Taylor & Francis Online content New for Journal of the Institute of Conservation and online now on Taylor & Francis Online: Original Articles A less invasive treatment solution for a bound seventeenth century parchment volume Solange FitzGerald Pages: 1-10 | DOI: 10.1080/19455224.2017.1365742 To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Effects of municipal solid waste- and sewage sludge-compost-based growing media on the yield and heavy metal content of four lettuce cultivars

Abstract

Compost has been recently suggested as an alternative to peat for the preparation of growing substrates in soilless cultivation systems. However, some physico-chemical properties of compost may reduce plant performance and endanger the quality of productions, in particular for possible heavy metal accumulation in edible parts. This study aims at evaluating the suitability of a municipal solid waste compost (MSWC) and a sewage sludge compost (SSC) as components of growing media for the soilless cultivation of lettuce (Lactuca sativa L.). Heavy metal content of SSC complied with legislation limits but, in MSWC, it exceeded (Cu, Pb) or was very close (Cd, Zn) to safe limits. A greenhouse experiment was carried out by cultivating four lettuce cultivars ("Maximus," "Murai," "Patagonia," and "Aleppo") in pots containing a mixture of MSWC and perlite (MSWC + P), SSC and perlite (SSC + P), or peat and perlite (peat + P), the latter used as control. Plant biometric parameters measured after 72 days of growth revealed that the yield of plants cultivated on SSC + P was similar to control plants, independently of the cultivar. Conversely, MSWC + P suppressed in general the biomass production, especially for Murai and Patagonia cultivars. Compared to peat + P, both compost-based substrates reduced the leaf accumulation of heavy metals, with a major effect in Maximus plants. The levels of Cd and Pb in the edible part were always below the safe limits imposed by European regulation. Therefore, risks of heavy metal intake in food chain associated with the replacement of peat with compost in the growing media are negligible, even when a compost with a significant amount of heavy metals is used. Besides compost quality monitoring, also an appropriate varietal choice is crucial to obtain good yields and safe products.

http://ift.tt/2xgAn47

Scholar : These new articles for Contemporary Music Review are available online

The online platform for Taylor & Francis Online content New for Contemporary Music Review and online now on Taylor & Francis Online: Original Articles Percussionist-Centred Design for Touchscreen Digital Musical Instruments Charles P. Martin Pages: 1-22 | DOI: 10.1080/07494467.2017.1370794 To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Successful treatment of trichoepithelioma with a novel insulated, monopolar, radiofrequency microneedle device

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Folliculocentric hyperkeratotic lichen sclerosus in a 7-year-old child successfully treated with narrowband ultraviolet B phototherapy

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Fever, lipodystrophy and cutaneous lesions

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Serum IL-17 in patients with erythema multiforme or Stevens–Johnson syndrome/toxic epidermal necrolysis drug reaction, and correlation with disease severity

Summary

Background

There is strong evidence that drug-induced cutaneous eruptions have an immunological component. Interleukin (IL)-17, a proinflammatory cytokine that is predominantly produced by T helper 17 cells, has been linked to various autoimmune and inflammatory diseases.

Aim

To measure serum IL-17 levels in patients with cutaneous drug reactions [erythema multiforme (EM) and Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN)] in order to study the associations between IL-17 and disease severity.

Methods

In total, 32 patients (13 with EM and 19 with SJS/TEN) and 15 age- and sex-matched healthy controls (HCs) were enrolled. Patients with SJS/TEN were assessed clinically using the SCORe of Toxic Epidermal Necrosis (SCORTEN) scale. Serum IL-17 levels were determined by ELISA.

Results

Serum IL-17 levels were significantly higher compared with HCs (16.46 ± 5.21 pg/mL) in the EM (35.1 ± 23.89 pg/mL, P < 0.02) and SJS/TEN (68.19 ± 35.42 pg/mL, P = 0.001) groups. IL-17 levels were also significantly higher in the SJS/TEN group than in the EM group (P = 0.004). Mean affected body surface area percentage was 0.9 ± 0.21 in the EM group and 22.8 ± 10.67 in the SJS/TEN group. The SJS/TEN SCORTEN ranged from 1 to 5, with a mean of 2.5 ± 1. Serum IL-17 level correlated positively with both percentage surface area of detached skin and SCORTEN.

Conclusions

Serum IL-17 levels may have prognostic and diagnostic value in patients with EM or SJS/TEN reactions, and can provide a valuable approach in managment.

http://ift.tt/2xwhWuI

Inducible T-cell costimulator (ICOS) and CD28 polymorphisms possibly play a role in the pathogenesis of chronic autoreactive urticaria

Summary

Background

Clinical experience emphasizes the coexistence of chronic spontaneous urticaria (CSU) and autoimmune disturbances. In chromosome 2q33-34, there is a cluster of homologous genes that are considered promising candidate genes for susceptibility to autoimmune diseases.

Aim

To examine the possible role of polymorphisms in the genes for CD28 and inducible T-cell costimulator (ICOS) in the background of CSU.

Methods

In total, 149 patients with CSU with positive autologous serum skin test were enrolled in the study. The healthy control (HC) group consisted of 100 healthy volunteers. In all subjects, the CD28 rs2140148 and rs3116496 and the ICOS rs6726035 polymorphisms were analysed. Disease severity was assessed by means of Urticaria Activity Score.

Results

We found a statistically significantly lower prevalence of the ICOS rs6726035 TT genotype among patients with CSU compared with HCs. Furthermore, the haplotype rs2140148A, rs3116496T and rs6726035C presented a possible association with CSU. We did not find any association between the examined polymorphisms and either urticaria severity or age of disease onset.

Conclusions

Our results underline the role of autoimmune components in the pathogenesis of chronic autoreactive urticaria, and indicate it as a potentially genetically related disorder.

http://ift.tt/2wxKN2d

Measuring atmospheric ammonia with remote sensing campaign: Part 1 – Characterisation of vertical ammonia concentration profile in the centre of The Netherlands

Publication date: November 2017
Source:Atmospheric Environment, Volume 169
Author(s): E. Dammers, M. Schaap, M. Haaima, M. Palm, R.J. Wichink Kruit, H. Volten, A. Hensen, D. Swart, J.W. Erisman
Ammonia (NH3) is difficult to monitor at atmospheric concentrations due its high solubility and reactivity and the strong spatial and temporal variations of its concentrations. Monitoring is mostly performed using passive samplers or filter packs with daily coverage at best. Only at a few sites ammonia is measured with more expensive wet chemical or spectroscopic measurement techniques. Instruments using an open path show the most potential as these avoid the use of inlets and thus the interactions of NH3 with tubing, filters, and inlets. Measurements on the vertical distribution of NH3 are even scarcer, with only a few available airborne and tower measurements. Satellite observations of NH3 show potential to be used for real-time monitoring as these have global coverage often with daily overpasses. Unfortunately, validation of satellite NH3 products representing the total atmospheric column with ground based instruments measuring in situ NH3 has been troublesome due to a lack of knowledge about the vertical distribution. Validation with FTIR instruments has shown potential but has been performed for only a limited number of stations. In this study we report on measurements performed during the Measuring atmospheric Ammonia with Remote Sensing (MARS) field campaign at Cabauw, the Netherlands. The aim of the campaign was to improve the general understanding of the vertical distribution of NH3. An approach was taken using four mini-DOAS instruments installed in the meteorological tower at Cabauw, supplemented by measurements with a MARGA and a mobile FTIR instrument. The measurements between May and October 2014 showed large variations in the concentrations and maximum concentrations reached up to 240 μg m⁻³. The lower three mini-DOAS and MARGA measurements showed large differences on an hourly basis, which were shown to originate from multiple measurement artefacts of the MARGA. The mini-DOAS concentrations varied sharply between the different levels with the lower three instruments showing maxima at night while the mini-DOAS at 160 m in the tower showed maxima during the day. The study shows that the daytime boundary layer is well-mixed with only small gradients between concentrations measured at various heights. Differences were found in the origin of the NH3 with the instrument at 20 m showing higher concentrations with transport from the north, where the largest nearby sources are located, while the instrument at 160 m showed the highest concentrations coming from the east which shows a more regional influence. The measurement campaign data is freely available for model and satellite validation studies.



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Comparisons of traffic-related ultrafine particle number concentrations measured in two urban areas by central, residential, and mobile monitoring

Publication date: November 2017
Source:Atmospheric Environment, Volume 169
Author(s): Matthew C. Simon, Neelakshi Hudda, Elena N. Naumova, Jonathan I. Levy, Doug Brugge, John L. Durant
Traffic-related ultrafine particles (UFP; <100 nm diameter) are ubiquitous in urban air. While studies have shown that UFP are toxic, epidemiological evidence of health effects, which is needed to inform risk assessment at the population scale, is limited due to challenges of accurately estimating UFP exposures. Epidemiologic studies often use empirical models to estimate UFP exposures; however, the monitoring strategies upon which the models are based have varied between studies. Our study compares particle number concentrations (PNC; a proxy for UFP) measured by three different monitoring approaches (central-site, short-term residential-site, and mobile on-road monitoring) in two study areas in metropolitan Boston (MA, USA). Our objectives were to quantify ambient PNC differences between the three monitoring platforms, compare the temporal patterns and the spatial heterogeneity of PNC between the monitoring platforms, and identify factors that affect correlations across the platforms. We collected >12,000 h of measurements at the central sites, 1000 h of measurements at each of 20 residential sites in the two study areas, and >120 h of mobile measurements over the course of ∼1 year in each study area. Our results show differences between the monitoring strategies: mean 1 min PNC on-roads were higher (64,000 and 32,000 particles/cm³ in Boston and Chelsea, respectively) compared to central-site measurements (23,000 and 19,000 particles/cm³) and both were higher than at residences (14,000 and 15,000 particles/cm³). Temporal correlations and spatial heterogeneity also differed between the platforms. Temporal correlations were generally highest between central and residential sites, and lowest between central-site and on-road measurements. We observed the greatest spatial heterogeneity across monitoring platforms during the morning rush hours (06:00-09:00) and the lowest during the overnight hours (18:00-06:00). Longer averaging times (days and hours vs. minutes) increased temporal correlations (Pearson correlations were 0.69 and 0.60 vs. 0.39 in Boston; 0.71 and 0.61 vs. 0.45 in Chelsea) and reduced spatial heterogeneity (coefficients of divergence were 0.24 and 0.29 vs. 0.33 in Boston; 0.20 and 0.27 vs. 0.31 in Chelsea). Our results suggest that combining stationary and mobile monitoring may lead to improved characterization of UFP in urban areas.

Graphical abstract

http://ift.tt/2fbsGUW

Scholar : New articles have been published for Baltic Journal of Economics, Volume 17, Issue 2

The online platform for Taylor & Francis Online content The following articles have been newly published in the issue Baltic Journal of Economics, Volume 17, Issue 2 on Taylor & Francis Online: Original Articles Influence of internet and social media presence on small, local banks' market power | Dariusz Filip, Krzysztof Jackowicz, Łukasz Kozłowski Pages: 190-214 | DOI: 10.1080/1406099X.2017.1376856 The issue is in progress. To view all articles already published in this issue, please visit: http://ift.tt/2pOJKWA Find out more about the issues and challenges in Governing Asia. This collection includes free access papers on security challenges, the Abe and Modi administration, reflections on the Chinese Governance and more. Browse today! To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Visual artificial grammar learning in dyslexia: A meta-analysis

Publication date: November 2017
Source:Research in Developmental Disabilities, Volume 70
Author(s): Merel van Witteloostuijn, Paul Boersma, Frank Wijnen, Judith Rispens
BackgroundLiteracy impairments in dyslexia have been hypothesized to be (partly) due to an implicit learning deficit. However, studies of implicit visual artificial grammar learning (AGL) have often yielded null results.AimsThe aim of this study is to weigh the evidence collected thus far by performing a meta-analysis of studies on implicit visual AGL in dyslexia.Methods and proceduresThirteen studies were selected through a systematic literature search, representing data from 255 participants with dyslexia and 292 control participants (mean age range: 8.5–36.8 years old).ResultsIf the 13 selected studies constitute a random sample, individuals with dyslexia perform worse on average than non-dyslexic individuals (average weighted effect size=0.46, 95% CI [0.14 … 0.77], p=0.008), with a larger effect in children than in adults (p=0.041; average weighted effect sizes 0.71 [sig.] versus 0.16 [non-sig.]). However, the presence of a publication bias indicates the existence of missing studies that may well null the effect.Conclusions and implicationsWhile the studies under investigation demonstrate that implicit visual AGL is impaired in dyslexia (more so in children than in adults, if in adults at all), the detected publication bias suggests that the effect might in fact be zero.

Graphical abstract

http://ift.tt/2xwhj4k

Use of ribosomal proteins as biomarkers for identification of Flavobacterium psychrophilum by MALDI-TOF mass spectrometry

Publication date: Available online 19 September 2017
Source:Journal of Proteomics
Author(s): Clara Fernández-Álvarez, Yolanda Torres-Corral, Ysabel Santos
Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS) is a rapid methodology for identification of bacteria that is increasingly used in diagnostic laboratories. This work aimed at evaluating the potential of MALDI-TOF-MS for identification of the main serotypes of Flavobacterium psychrophilum isolated from salmonids, and its discrimination from closely related Flavobacterium spp. A mass spectra library was constructed by analysing 70 F. psychrophilum strains representing the serotypes O1, O2a, O2b and O3, including reference and clinical isolates. Peak mass lists were examined using the Mass-Up software for the detection of potential biomarkers, similarity and cluster analysis. Sixteen species-identifying biomarkers were detected in all the F. psychrophilum isolates tested, moreover, sets of serotype-identifying biomarkers ions were selected. F. psychrophilum-specific biomarkers were identified as ribosomal proteins by matching with protein databases. Furthermore, sequence variation corresponding to amino acid exchanges in several biomarker proteins were tentatively assigned. Closely related Flavobacterium species (F. flevense, F. succinicans, F. columnare, F. branchiophilum and F. johnsoniae) could be differentiated from F. psychrophilum by defining species identifying biomarkers and hierarchical cluster analysis. These results demonstrated that MALDI-TOF spectrometry represents a powerful tool for an accurate identification of the fish pathogen F. psychrophilum as well as for epidemiological studies.Biological significanceThe results obtained in this study demonstrated that MALDI-TOF mass spectrometry represents a powerful tool that can be used by diagnostic laboratories for rapid identification of the fish pathogen Flavobacterium psychrophilum and its differentiation from other Flavobacterium-related species. Analysis of mass peak lists revealed the potential of the MALDI-TOF technique to identify epidemiologically important serotypes affecting salmonid fish. Furthermore, this study revealed the importance of the technique in the early and fast detection of bacterial pathogens, with the subsequent improvement in the health status and animal welfare and food safety in farmed fish.

Graphical abstract

http://ift.tt/2xPh991

Clinical Features and Prognosis of Thymic Neuroendocrine Tumors Associated with Multiple Endocrine Neoplasia Type 1: A Single Center Study, Systematic Review, and Meta-analysis

Summary

Objective

Thymic neuroendocrine tumor (TH-NET) accounts for almost 20% of multiple endocrine neoplasia type 1 (MEN1)-associated mortality. Identifying risk factors for the development of these rare tumors and prognostic factors for clinical outcomes will be helpful in clinical practice.

Design and Patients

We performed a retrospective analysis of patients treated for TH-NET associated with MEN1 in a single institution and meta-analysis of literature reports. We used a fixed effect model to pool results across studies to evaluate the prevalence, clinical features, and prognosis.

Results

TH-NET were detected in nine (7.4%) of 121 MEN1 patients seen in our institution and five (55.6%) were women. Seven additional studies were identified through a systematic review of the literature. The pool estimate of TH-NET prevalence was 3.7% (n=99) in MEN1 (n=2710), sex ratio was 79:20 (male vs female) and the median age at diagnosis was 43.0 years (range, 16.0-72.0 years). Forty-three patients died with a median survival time of 8.4 years. Older age at diagnosis (HR=1.4, 95% CI=1.0-1.8, P=0.03), maximum tumor diameter (HR=1.5, 95%CI=1.0-2.3, P=0.04), and presence of metastasis (HR=1.6, 95%CI=1.0-2.5, P=0.04) were associated with worse outcome. A male predominance (91.9% vs 59.5%, P<0.001) and history of smoking (59.0% vs 23.5%, P=0.015) were more common in American/European series compared to Asian reports.

Conclusion

TH-NET is a rare but fatal component of MEN1. Earlier detection of TH-NET in patients with MEN1 may be recommended which should theoretically result in better outcomes. Different genetic backgrounds (race) appear to result in clinical difference.

This article is protected by copyright. All rights reserved.

http://ift.tt/2wG5eWc

The risk of metabolic syndrome in polycystic ovary syndrome: A systematic review and meta-analysis

Abstract

Background and Objective

Polycystic ovary syndrome (PCOS) is a common heterogeneous endocrine disorder associated with metabolic syndrome (MetS). The aim of this systematic review and meta-analysis was to provide the most reliable estimate risk of MetS in women with PCOS, compared to healthy controls.

Methods

A comprehensive literature search was performed in PubMed [including Medline], Web of Science and Scopus databases for retrieving articles in English language on the prevalence/incidence and odds of MetS in women with PCOS compared to healthy controls. Mantel–Haenszel methods of meta-analysis were used to present results in terms of the pooled odds ratio (OR) [95% confidence interval (CI)] using fixed/random-effects models with/without the publication bias correction, based on the various subgroups of age and study methods. Newcastle–Ottawa Scaling and The Cochrane Collaboration's risk of bias assessment tool were used to evaluate the quality of studies included.

Results

The search strategy yielded 2759 potentially relevant articles of which 44 articles were included for meta-analysis. Results of the meta-analysis demonstrated that the PCOS patients regardless of age, BMI and recruitment sources of samples, had higher odds of MetS compared to healthy controls (OR 2.5, 95% CI 2.0-3.2). However, adolescents with PCOS had an increased odds of MetS compared to healthy adolescent controls in population- and non-population-based studies (OR 4.7, 95% CI 1.8-11.9; OR 6.1, 95% CI 6.0- 6.1, respectively). However, the odds of MetS had no differences between adults with PCOS compared to healthy controls in population-based studies. These results were confirmed by the subgroup meta-analysis of some studies using age and BMI adjustment/matching. In addition, subgroup analysis based on diagnostic criteria of PCOS showed that the OR of MetS in PCOS using NIH criteria was higher than AES and Rotterdam criteria (Pooled Overall OR based on NIH criteria = 6.05, 95% CIL: 6.0-6.04).

Conclusion

These findings provide some information on the real features and a broader view of this syndrome that also help clarify conflicting results documented in literature. Accordingly, in prevention strategies, routine screening for metabolic syndrome are suggested for adolescents with PCOS.

This article is protected by copyright. All rights reserved.

http://ift.tt/2xlVOCA

Factitious ACTH- dependent, apparent hypercortisolism: the problem with late night salivary cortisol measurements collected at home

Abstract

Cushing's Syndrome (CS) is critical to identify because of the numerous and sometimes irreversible sequelae. Surreptitious glucocorticoid use is usually a straightforward consideration in the Cushingoid patient having suppressed ACTH levels, in the absence of adrenal mass or hyperplasia, and in whom screening tests for CS have unexpectedly low or high results depending on the specific steroid used and vulnerability of the assay employed to analytical cross-reactivity. We present a case of a patient with factitious hypercortisolism without suppressed ACTH.

This article is protected by copyright. All rights reserved.

http://ift.tt/2wG0Kil

Analysis of the performance, emission and combustion characteristics of a turbocharged diesel engine fuelled with Jatropha curcas biodiesel-diesel blends using kernel-based extreme learning machine

Abstract

The purpose of this study is to investigate the performance, emission and combustion characteristics of a four-cylinder common-rail turbocharged diesel engine fuelled with Jatropha curcas biodiesel-diesel blends. A kernel-based extreme learning machine (KELM) model is developed in this study using MATLAB software in order to predict the performance, combustion and emission characteristics of the engine. To acquire the data for training and testing the KELM model, the engine speed was selected as the input parameter, whereas the performance, exhaust emissions and combustion characteristics were chosen as the output parameters of the KELM model. The performance, emissions and combustion characteristics predicted by the KELM model were validated by comparing the predicted data with the experimental data. The results show that the coefficient of determination of the parameters is within a range of 0.9805–0.9991 for both the KELM model and the experimental data. The mean absolute percentage error is within a range of 0.1259–2.3838. This study shows that KELM modelling is a useful technique in biodiesel production since it facilitates scientists and researchers to predict the performance, exhaust emissions and combustion characteristics of internal combustion engines with high accuracy.

http://ift.tt/2xmQuit

Integration of digital dental casts in cone beam computed tomography scans—a clinical validation study

Abstract

Objectives

Images derived from cone beam computed tomography (CBCT) scans lack detailed information on the dentition and interocclusal relationships needed for proper surgical planning and production of surgical splints. To get a proper representation of the dentition, integration of a digital dental model into the CBCT scan is necessary. The aim of this study was to validate a simplified protocol to integrate digital dental models into CBCT scans using only one scan.

Materials and methods

Conventional protocol A used one combined upper and lower impression and two CBCT scans. The new protocol B included placement of ten markers on the gingiva, one CBCT scan, and two separate impressions of the upper and lower dentition. Twenty consecutive patients, scheduled for mandibular advancement surgery, were included. To validate protocol B, 3-dimensional reconstructions were made, which were compared by calculating the mean intersurface distances obtained with both protocols.

Results

The mean distance for all patients for the upper jaw is 0.39 mm and for the lower jaw is 0.30 mm. For ten out of 20 patients, all distances were less than 1 mm. For the other ten patients, all distances were less than 2 mm.

Conclusions

Mean distances of 0.39 and 0.30 mm are clinically acceptable and comparable to other studies; therefore, this new protocol is clinically accurate.

Clinical relevance

This new protocol seems to be clinically accurate. It is less time consuming, gives less radiation exposure for the patient, and has a lower risk for positional errors of the impressions compared to other integration protocols.

http://ift.tt/2ypzXZl