Αρχειοθήκη ιστολογίου

Πέμπτη 7 Σεπτεμβρίου 2017

Contraintes de doses aux organes à risque en radiothérapie conformationnelle et stéréotaxique : intestin grêle et duodénum

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Publication date: Available online 6 September 2017
Source:Cancer/Radiothérapie
Author(s): F. Goupy, E. Chajon, J. Castelli, É. Le Prisé, L. Duvergé, N. Jaksic, G. Vogin, É. Monpetit, V. Klein, L. de Bosschère, P. Maingon
La radiothérapie des lésions primitives ou secondaires abdominopelviennes en techniques conformationnelle ou stéréotaxique est en plein développement. L'intestin grêle, possédant une radiosensibilité élevée, est le principal organe à risque limitant les doses de prescription. Cette revue de la littérature a pour objectif de définir les contraintes de doses à l'intestin grêle et au duodénum en radiothérapie conformationnelle ou stéréotaxique. L'intestin grêle comprenant le duodénum, le jéjunum et l'iléon est délinéé sur la tomodensitométrie de simulation. La toxicité intestinale radio-induite est précoce, liée à la dépopulation cellulaire de la muqueuse intestinale, et tardive, de physiopathologie plus complexe, associant déplétion de cellules souches, microangiopathie, inflammation chronique et fibrose. Le facteur prédictif principal de toxicité intestinale est le ratio dose–volume. En radiothérapie conformationnelle, les contraintes de dose au duodénum sont : V25Gy<45 % (VxGy : volume recevant x Gy) et V35Gy<20 %. Les contraintes de dose dans le jéjunum et l'iléon sont, pour une délinéation par anse intestinale ou pour la cavité péritonéale, respectivement : V15Gy<275mL ou V15Gy<830mL et V45Gy<150mL. En radiothérapie stéréotaxique, les contraintes de dose dans l'intestin grêle dépendent du fractionnement et sont définies sur un faible volume et sur une dose maximale en un point. La toxicité intestinale dépend également de facteurs intrinsèques au patient et de radiosensibilisants comme les thérapies ciblées ou chimiothérapies. Avec l'essor des nouvelles techniques permettant une escalade de dose sur la tumeur et le développement de la planification inverse, la définition des contraintes de doses à l'intestin grêle est primordiale pour la pratique courante.Radiotherapy of abdominopelvic primary or secondary lesions in conformational or stereotactic techniques is in full development. The small bowel is highly sensitive to irradiation and is the main organ at risk limiting prescription doses. This literature review aims to define the dose constraints to the small bowel and the duodenum in conformational and stereotactic body radiotherapy. The small bowel including the duodenum, jejunum and ileum is delineated on the simulation scanner. The radio-induced intestinal toxicities are acute related to the cellular depopulation of the intestinal mucosa, and late of more complex pathophysiology associating depletion in stem cells, microangiopathy, chronic inflammation and fibrosis. The main predictive factor of intestinal toxicity is the dose–volume ratio. In conformational radiotherapy, the dose constraints to the duodenum are: V25Gy<45% and V35Gy<20%. The jejunum and ileum dose constraints are for delineation by intestinal loop or peritoneal cavity respectively: V15Gy<275mL or V15Gy<830mL and V45Gy<150mL. In stereotactic body radiotherapy, small bowel dose constraints depend on fractionation and are defined on a small volume and on a maximum dose at one point. Intestinal toxicity is also dependent on factors intrinsic to the patient and radiosensitizers such as targeted therapies or chemotherapies. With the development of new techniques allowing dose escalation on the tumour and the development of inverse planning, the definition of dose constraints to the small bowel is essential for current practice.



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TNFAIP3 levels in lung dendritic cells instruct Th2 or Th17 cell differentiation in eosinophilic or neutrophilic asthma

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Publication date: Available online 6 September 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Heleen Vroman, Ingird M. Bergen, Jennifer .A.C. van Hulst, Memno van Nimwegen, Denise van Uden, Martin J. Schuijs, Saravanan Y. Pillai, Geert van Loo, Hamida Hammad, Bart N. Lambrecht, Rudi W. Hendriks, Mirjam Kool
BackgroundIt is currently unknown, why allergen exposure or environmental triggers in mild to moderate asthma patients results in Th2-mediated eosinophilic inflammation, whereas severe asthma patients often present with Th17-mediated neutrophilic inflammation. The activation state of dendritic cells (DCs) is crucial for both Th2 and Th17-cell differentiation, and is mediated through NF-κB activation. Ablation of TNFAIP3, one of the crucial negative regulators of NF-κB activation in myeloid cells and DCs was shown to control DC activation.ObjectiveIn this study we investigated the precise role of TNFAIP3 in myeloid cells for the development of Th2 and Th17-cell mediated asthma.MethodsWe exposed mice with conditional deletion of the Tnfaip3 gene in either myeloid cells (using the LysM promotor) or specifically in DCs (using the Cd11c promotor) to acute and chronic house dust mite (HDM)-driven asthma models.ResultsWe demonstrated that reduced Tnfaip3 gene expression in DCs in either Tnfaip3CD11c or Tnfaip3LysM mice dose-dependently controlled development of Th17-mediated neutrophilic severe asthma in both acute and chronic HDM-driven models, whereas wildtype mice developed a purely Th2-mediated eosinophilic inflammation. TNFAIP3-deficient DCs induced HDM-specific Th17-cell differentiation, through increased expression of Th17-instructing cytokines, IL-1ß, IL-6 and IL-23, whereas HDM-specific Th2-cell differentiation was hampered by the increased IL-12 and IL-6 production.ConclusionsThese data show that the extent of TNFAIP3 expression in DCs controls Th2/Th17-cell differentiation. This implies that reducing DC activation could be a new pharmacological intervention to treat severe asthma patients that present with a Th17-mediated neutrophilic inflammation.



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Siglec-8 is an activating receptor mediating β2 integrin-dependent function in human eosinophils

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Publication date: Available online 6 September 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Daniela J. Carroll, Jeremy A. O'Sullivan, David B. Nix, Yun Cao, Michael Tiemeyer, Bruce S. Bochner
BackgroundSiglec-8 is a CD33 subfamily cell surface receptor that is selectively expressed on human eosinophils. Following cytokine-priming, Siglec-8 mAb or glycan ligand binding causes eosinophil apoptosis associated with reactive oxygen species (ROS) production. Most CD33-related Siglecs function as inhibitory receptors, but the ability of Siglec-8 to stimulate eosinophil ROS production and apoptosis suggests that Siglec-8 may instead function as an activating receptor.ObjectiveTo determine the role of IL-5 priming and to identify the signaling molecules involved in Siglec-8 function for human eosinophils.MethodsWe used a mAb and/or a multimeric synthetic sulfated sialoglycan ligand recognizing Siglec-8, in combination with integrin blocking antibodies, pharmacological inhibitors, phosphoproteomics and western blot analysis, to define the necessity of various proteins involved in Siglec-8 function for human eosinophils.ResultsCytokine priming was required to elicit the unanticipated finding that Siglec-8 engagement promotes rapid β2-integrin dependent eosinophil adhesion. Also novel was the finding that this adhesion was necessary for subsequent ROS production and apoptosis. Siglec-8-mediated ROS was generated via NADPH oxidase activation, because pretreatment of eosinophils with catalase (an extracellular superoxide scavenger) or NSC23766 (a Rac GTPase inhibitor) completely inhibited Siglec-8 mediated eosinophil apoptosis. Finally, engagement of Siglec-8 on IL-5 primed eosinophils resulted in increased phosphorylation of Akt, p38 and JNK1 that was also β2-integrin dependent; pharmacologic inhibition of these kinases completely prevented Siglec-8-mediated eosinophil apoptosis.ConclusionsThese data demonstrate that Siglec-8 uniquely functions as an activating receptor on IL-5 primed eosinophils via a novel pathway involving regulation of β2-integrin-dependent adhesion, NADPH oxidase and a subset of protein kinases.

Teaser

Siglec-8 can unexpectedly function as an activating receptor, not an inhibitory receptor, because its engagement on IL-5-primed eosinophils promotes β2-integrin-mediated adhesion and activates NADPH oxidase and protein kinases, all of which are necessary for causing human eosinophil apoptosis.


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[Tumors of the inner ear and adjacent structures].

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[Tumors of the inner ear and adjacent structures].

Pathologe. 2017 Sep 05;:

Authors: Schittenhelm J

Abstract
Tumors of the inner ear and adjacent structures often present with hearing loss, tinnitus and vertigo due to compression of the traversing cranial nerves. More than 90% of the tumors of the inner ear with or without expansion into the cerebellopontine angle are histologically diagnosed as vestibular schwannomas. Less common tumorous lesions include ectopic meningiomas located in the petrous bone, glomus tympanicum paragangliomas or endolymphatic sac tumors (ELST) originating in the vestibular recess. Most tumors are sporadic, but hereditary disorders have to be considered. Bilateral vestibular schwannomas are indicative of neurofibromatosis type 2 and ELST in conjunction with other abdominal tumors indicates von Hippel-Lindau disease. The neuropathological diagnostics and grading guides the subsequent therapy of these mostly benign lesions.

PMID: 28875382 [PubMed - as supplied by publisher]



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Intraoperative imaging during minimally invasive transoral robotic surgery using near-infrared light

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Publication date: Available online 6 September 2017
Source:American Journal of Otolaryngology
Author(s): Nicholas Scott-Wittenborn, Ryan S. Jackson
PurposeThe purpose of this study was to determine if the use of the FIREFLY imaging system could be an asset in transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC). The system uses indocyanine green dye (ICG), which fluoresces when illuminated by near-infrared light from the Da Vinci robot. The system may improve visualization of tumor margins, highlight important vascular structures, and help identify the location of tumors and unknown primary head and neck cancers.MethodsSix patients with OPSCC were enrolled in the study. Two of these cases were unknown primaries, one was base of tongue, and three were palatine tonsils. Each patient was given two 3ml doses of ICG, one at the beginning of the surgical case and one during resection of the tumor. The oropharynx was then visualized using the near-infrared light of the Da Vinci robot for a minute after injection.ResultsThe FIREFLY system was unable to detect gross tumors, positive margins, unknown primaries, or vascular structures in any of the six subjects in the study. In addition, there were no adverse events or side effects in any of the subjects.ConclusionThe use of the FIREFLY system with indocyanine green fluorescence did not identify tumor boundaries, unknown primary head and neck cancers, or vascular structures in the oropharynx.



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Editorial Board

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Publication date: September–October 2017
Source:American Journal of Otolaryngology, Volume 38, Issue 5





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Guidelines for Contributing Authors

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Publication date: September–October 2017
Source:American Journal of Otolaryngology, Volume 38, Issue 5





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Commentary on: Treatment of laryngopharyngeal reflux using a sleep positioning device: A prospective cohort study

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Publication date: Available online 6 September 2017
Source:American Journal of Otolaryngology
Author(s): Zhengcai Lou




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Relationship between intracranial aneurysms and the severity of autosomal dominant polycystic kidney disease

Abstract

Background

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary kidney disease characterized by the progressive enlargement of innumerable renal cysts. Although the association of intracranial aneurysms (ICANs) with ADPKD is well known, the relationship between the ICAN and the disease severity including total kidney volume (TKV) and estimated glomerular filtration rate (eGFR) is poorly understood.

Methods

We screened 265 patients with ADPKD (mean age, 48.8 years; range, 14.9–88.3 years) with MR angiography. The patients with a past history related to ICANs were excluded from the study. The incidence and characteristics of ICAN in patients with ADPKD were evaluated. TKV was measured by volumetric analyses of MR imaging.

Results

We detected 65 ICANs in 49 patients (37 women and 12 men, mean age, 52.7 years; range, 20.4–86 years). The incidence of ICANs was 18.5% and female patients had was higher incidence (23.1%) than male patients (11.4%) (p = 0.02). An age of those with ICANs was significantly higher than those without (p = 0.006), and the cumulative risk of diagnosis of ICANs increased with age. TKV was significantly larger in those with ICANs than those without (p = 0.001), but eGFR was not different between two groups (p = 0.07). By multivariate analyses, only TKV was significantly related to the development of ICANs (p = 0.02).

Conclusions

The incidence of ICANs increased with age, was higher in females, and correlated with kidney enlargement in patients with ADPKD. Necessity of screening ICANs would be particularly high in elderly women with large kidneys.



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Regional differences of Turkey in risk factors of newborn hearing loss

Publication date: November 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 102
Author(s): Ozlem Konukseven, Sule Kaya, Aydan Genc, Nuray Bayar Muluk, Figen Suren Basar, Gunay Kirkim, Ulku Tuncer, Erkan Karatas, Cigdem Topcu, Hilal Bolat, Ilknur Dincol
ObjectiveThe aim of this study was to discover Turkish regional differences in the risk factors of newborn hearing loss.MethodA multi-centered retrospective design was used. A total of 443 children, registered to the national newborn hearing screening programme, with bilateral hearing loss, from five different regions of Turkey, were evaluated in terms of the types of hearing loss, the degree of hearing loss, the types of risk factors, parental consanguinity, age at diagnosis and age of auditory intervention, respectively.ResultsThere was no significant difference in the prevalence of hearing loss between regions (χ2 = 3.210, P = 0.523). Symmetric Sensorineural Hearing Loss (SSHL) was the most common type of HL in all regions (91.8%). Profound HL was the most common degree of HL in all regions (46.2%). There were statistically significant differences between regions in terms of types of HL (χ2 = 14.151, P = 0.000). As a total, 323 (72.9%) of subjects did not have any risk factors. There were statistically significant differences between regions in terms of the types of risk factors (pre, peri and post-natal) for SSNHL (χ2 = 16.095, P = 0.000). For all regions, the age of diagnosis was convenient with the JCIH criteria. However the age of hearing aid application was prolonged in some regions. There were statistically significant differences between regions in terms of the age of diagnosis (χ2 = 93.570, P = 0.000) and the age of auditory intervention (χ2 = 47.323, P = 0.000). The confounding effects of gender, age of diagnosis, age of hearing aids applications, HL in the family, types of risk factors for HL on SSNHL were detected.ConclusionTo reach the goal of a high quality newborn hearing screening, there is a need to develop an evidence-based standard for follow up guideline. In addition, risk factors should be re-evaluated according to regional differences and all regions should take their own precautions according to their evidence based data.



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Conservative treatment of vestibular schwannoma: growth and Penn Acoustic Neuroma Quality of Life scale in French language.

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Conservative treatment of vestibular schwannoma: growth and Penn Acoustic Neuroma Quality of Life scale in French language.

Acta Otorhinolaryngol Ital. 2017 Aug;37(4):320-327

Authors: Oddon PA, Montava M, Salburgo F, Collin M, Vercasson C, Lavieille JP

Abstract
The aim of this study was to determine the natural history of growth and quality of life (QoL) outcomes for vestibular schwannoma (VS) managed conservatively, and to validate the disease-specific Penn Acoustic Neuroma Quality-of-Life (PANQOL) scale in French language. We retrospectively studied 26 patients with VS managed conservatively. Patient characteristics and radiological findings were collected. Two scales were used to measure QoL: the Short Form-36 Health Survey (SF-36) and the PANQOL scale translated into French. Internal consistency and scores were compared with previous studies. The mean follow-up was 25 months (range 6-72). We observed tumour growth in 14 patients (53.8%), no growth in 12 patients (46.2%) and no case of tumour shrinkage. The mean tumour growth was 2.22 mm/year. No predictive factor of growth was found. Patients with vertigo or dizziness experienced a poorer QoL according to the SF-36 (Social Functioning and Emotional Role Limitation dimensions) and to the PANQOL scale (Balance and Energy dimensions). Our results were comparable with the literature using the SF-36. With the PANQOL scale, our scores were not statistically different with those from Dutch and North American studies except in the field of hearing (p = 0.019). Quality of life becomes essential in the management of VS. According to these results, we support a non-conservative strategy associated with vestibular rehabilitation for patients with dizziness or vertigo. The PANQOL is a validated specific scale for VS, which can be useful in French.

PMID: 28872162 [PubMed - in process]



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Temporal changes in impedance of implanted adults for various cochlear segments.

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Temporal changes in impedance of implanted adults for various cochlear segments.

Acta Otorhinolaryngol Ital. 2017 Aug;37(4):312-319

Authors: Leone CA, Mosca F, Grassia R

Abstract
Electrode impedance (EI) is the first objective assessment carried out during the surgical procedure and follow-up of cochlear implanted patients. This measure provides information on the integrity of electrodes and on the surrounding environment. It is one of the main factors responsible for energy consumption of the cochlear implant (CI). The aim of our study is to investigate changes over time in EI in adult recipients implanted with the perimodiolar array by comparing differences in various cochlear segments. In addition, we explore the relationship between these objective measures and subjective measures such as T-level and C-level. We studied 28 adult patients. Impedance values (IVs) were calculated in "common-ground" (CG) and in monopolar (M1+2) mode for electrode groups in basal middle and apical segments. We found significant decreases in IVs between activation and 1 month. We obtained higher values for basal impedance, whereas lower IVs were found for apical electrodes at all observation times. Statistical pairing over time between impedance and T/C values showed significant correlation for both global impedance (GI) and T-C levels at CG and M1+2 mode up to 6 months. Segregated statistical analysis also showed a significant and prolonged correlation of basal IVs and fitting parameters. The higher basal impedance over time can be explained by the higher proportion of newly formed tissue in this region. The linear correlation of impedances with the fitting parameters become not significant after 3/6 months for the apical and middle segments and remained significant only for the basal region over time. This behaviour underlines the importance of persistence in intra-cochlear factors in influencing fitting parameters in the basal segment.

PMID: 28872161 [PubMed - in process]



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A mild phenotype of sensorineural hearing loss and palmoplantar keratoderma caused by a novel GJB2 dominant mutation.

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A mild phenotype of sensorineural hearing loss and palmoplantar keratoderma caused by a novel GJB2 dominant mutation.

Acta Otorhinolaryngol Ital. 2017 Aug;37(4):308-311

Authors: Stanghellini I, Genovese E, Palma S, Falcinelli C, Presutti L, Percesepe A

Abstract
Dominant GJB2 mutations are known to cause a syndromic form of sensorineural hearing loss associated with palmo-plantar skin manifestations. We present the genotype/phenotype correlations of a new GJB2 mutation identified in three generations of an Italian family (proband, mother and grandfather) whose members are affected by sensorineural hearing impairment associated with adult-onset palmoplantar keratoderma. In all affected members we identified a new heterozygous GJB2 mutation (c.66G > T, p.Lys22Asn) whose segregation, population frequency and in silico prediction analysis have suggested a pathogenic role. The p.Lys22Asn GJB2 mutation causes a dominant form of hearing loss associated with variable expression of palmoplantar keratoderma, representing a model of full penetrance, with an age-dependent effect on the phenotype.

PMID: 28872160 [PubMed - in process]



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Stabilometric findings in patients affected by organic dysphonia before and after phonomicrosurgery.

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Stabilometric findings in patients affected by organic dysphonia before and after phonomicrosurgery.

Acta Otorhinolaryngol Ital. 2017 Aug;37(4):286-294

Authors: Nacci A, Romeo SO, Berrettini S, Matteucci J, Cavaliere MD, Mancini V, Panicucci E, Ursino F, Fattori B

Abstract
The purpose of this study is to understand if there is any alteration in the posture of patients affected by organic dysphonia and describe possible postural modifications after phonomicrosurgery on the vocal folds. Forty subjects (22 males, 18 females; mean age 32.6 ± 7.5 years) suffering from organic dysphonia (15 cases of polyps, 11 submucosal retention cysts, 10 bilateral fibrous vocal fold nodules and 4 bilateral Reinke's oedema) were examined by open-eye and closed-eye posturography while breathing spontaneously before surgery, 24 hours after surgery and after 6 months. The variables taken into account were: the coordinates of the centre of pressure on both frontal and sagittal planes, length and surface of the track, mean velocity of the oscillations and relative standard deviations, spectral analysis of oscillation frequency, statokinesigram and stabilogram values. No characteristic pathological pattern was seen in basal stabilometry in any of the subgroups (polyps, cysts, Reinke's oedema). Only the subgroup of patients with fibrous vocal fold nodules (8/10; 80%) showed a slight forward shift from the centre of gravity when analysed in both open-eye and closed-eye posturography. A comparison performed within the same subgroup using open-eye and closed-eye posturography before and after surgery revealed no significant difference in any of the parameters being studied. The use of static stabilometry in this study demonstrates the absence of characteristic postural alterations in patients affected by organic dysphonia and also excludes that simple removal of the vocal fold lesion can change posture.

PMID: 28872158 [PubMed - in process]



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Indications of cone beam CT in head and neck imaging in children.

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Indications of cone beam CT in head and neck imaging in children.

Acta Otorhinolaryngol Ital. 2017 Aug;37(4):270-275

Authors: Walliczek-Dworschak U, Diogo I, Strack L, Mandapathil M, Teymoortash A, Werner JA, Güldner C

Abstract
For imaging of bony structures, especially for the anterior and lateral skull base in ORL medicine, cone beam computed tomography (CBCT) is an increasingly used alternative to CT, with a lower exposition to plain radiography that makes its use for imaging, particularly in children, very interesting. The aim of this study was to analyse possible indications and settings for CBCT in children and compare them to those of adults. A total of 554 patients (age range 0-18 years, mean age 10.36 years), who underwent CBCT between 01/2004-06/2013 in the ENT department at the university clinic of Marburg were enrolled in this retrospective analysis to evaluate technical parameters and indications. Data on CBCT of all children were compared with previously published data collected from 1730 adults who were diagnosed with the help of CBCT in the ENT department at the university clinic of Marburg, during the years 2012-2013. The most frequent indications of CBCT in children vs. adults were in the anterior skull base region: mid-facial trauma (60.4%) vs. chronic rhinosinusitis (54.8%), disturbed nasal breathing (13.9% vs. 13.0%) and chronic rhinosinusitis (12%) vs. mid-facial trauma (10.8%). For the lateral skull base the main indications were cholesteatoma (20.3%) vs. position control of cochlear implant (CI) electrode (31.2%), chronic otorrhoea (17.5%) vs. cholesteatoma (20.9%), and position control of CI electrode (11.8%) vs. chronic otitis media mesotympanalis (6.8%). CBCT is a suitable imaging modality for bony structures in adults and children. Settings mainly depend on the region of interest. One aim should also be to reduce exposure to radiation in both adults and children.

PMID: 28872156 [PubMed - in process]



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The rising incidence of parotid metastases: our experience from four decades of parotid gland surgery.

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The rising incidence of parotid metastases: our experience from four decades of parotid gland surgery.

Acta Otorhinolaryngol Ital. 2017 Aug;37(4):264-269

Authors: Franzen A, Buchali A, Lieder A

Abstract
Secondary neoplasia in the parotid gland is increasingly frequent. We examined outcomes from 40 years of parotid surgery to analyse patterns for metastasis, review the staging procedure and discuss management. We retrospectively examined 772 consecutive cases of parotid surgery in a university hospital between 1975 and 2015 and assessed changes in incidence and management over four decades. In all, 71% percent of patients were male and 29% were female, with a mean age of 68 years, aged between 23 and 93 years. We diagnosed 683 parotid tumours of which 15.8% (n = 108) were malignant; 44% (n = 48) of all malignant lesions were metastases. The incidence of malignant tumours rose from 8% in the first decade, 14% in the second, 17% in the third to 21% in the fourth. The incidence increased even further from 10% in the first to 57% in the final decade. Most frequent tumours were metastases of squamous cell carcinoma (79%), and the majority of these lesions (87%) arose from above the clavicle, with 30 primary tumours in the skin. In most cases, the skin tumour had been excised between 6 and 24 months prior to parotid metastasis. Management consisted of surgery with neck dissection. 48 patients (67%) received adjuvant therapy, but despite aggressive multimodal treatment, disease progressed in the majority of cases, in 57% squamous cell carcinoma of the skin primaries, 67% of mucosal primaries above the clavicle and 83% of infraclavicular primaries. Parotid malignant tumours are increasing in incidence, mostly due to a rise in metastatic malignant tumours within the parotid gland, most of which are metastases of skin tumours, commonly squamous cell carcinoma. Despite multimodal therapy, their recurrence and progression rate remains high. We propose inclusion in head and neck follow-up in all cases of head and neck skin cancers.

PMID: 28872155 [PubMed - in process]



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Periodic population codes: From a single circular variable to higher dimensions, multiple nested scales, and conceptual spaces

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Publication date: October 2017
Source:Current Opinion in Neurobiology, Volume 46
Author(s): Andreas VM Herz, Alexander Mathis, Martin Stemmler
Across the nervous system, neurons often encode circular stimuli using tuning curves that are not sine or cosine functions, but that belong to the richer class of von Mises functions, which are periodic variants of Gaussians. For a population of neurons encoding a single circular variable with such canonical tuning curves, computing a simple population vector is the optimal read-out of the most likely stimulus. We argue that the advantages of population vector read-outs are so compelling that even the neural representation of the outside world's flat Euclidean geometry is curled up into a torus (a circle times a circle), creating the hexagonal activity patterns of mammalian grid cells. Here, the circular scale is not set a priori, so the nervous system can use multiple scales and gain fields to overcome the ambiguity inherent in periodic representations of linear variables. We review the experimental evidence for this framework and discuss its testable predictions and generalizations to more abstract grid-like neural representations.



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Sleep correlates of substance use in community-dwelling Ethiopian adults

Abstract

Purpose

The relationship between sleep disturbances and substance use can have harmful effects. Evidence shows widespread use of substances, including khat, in the Ethiopian population. However, to the best of our knowledge, no study has investigated the sleep correlates of substance use in community-dwelling Ethiopian adults.

Materials and methods

A cross-sectional study using simple random sampling was performed on community-dwelling adults (n = 371, age = 25.5 ± 5.7 years, body mass index = 22.0 ± 2.2 kg/m2) in Mizan-Aman, Ethiopia. Dichotomized sleep measures (sleep quality and sleep latency) assessed by the Pittsburgh Sleep Quality Index (PSQI) were used in association analysis using binary logistic regression with substance use (khat, smoking, and alcohol).

Result

Sleep latency was associated with khat chewing (adjusted odds ratio (AOR) = 2.8, 95% confidence interval (CI) 1.7–4.4) and tobacco smoking (AOR = 2.1, 95% CI 1.4–3.0). Sleep quality was associated with khat chewing (AOR = 3.1, 95% CI 1.8–5.2), tobacco smoking (AOR = 1.7, 95% CI 1.2–2.5), and alcohol intake (AOR = 1.9, 95% CI 1.1–3.1).

Conclusion

Sleep correlates of substance use were found in community-dwelling Ethiopians. These findings may aid in the development of targeted strategies to manage substance use-related sleep disturbances.



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Classical gonadoblastoma: its relationship to the “dissecting” variant and undifferentiated gonadal tissue

Abstract

Classical gonadoblastoma occurs almost entirely in the dysgenetic gonads of an individual who has a disorder of sex development. Approximately 40% of such neoplasms are bilateral. Almost all gonadoblastomas occur in patients who have a Y chromosome or part thereof; testis specific protein Y-encoded 1 (TSPY1) is the putative gene. If a gonad in a patient who has a disorder of sex development contains germ cells with delayed maturation and also harbors the TSPY1 gene, the cells can undergo transformation to classical gonadoblastoma. The latter consists of rounded islands composed of germ cells, sex cord elements, and hyaline basement membrane material surrounded by a variably cellular gonadal stroma that sometimes contains steroid cells. Classical gonadoblastoma can be interpreted as a noninvasive neoplasm that is the precursor of germinoma, and, indirectly, other more aggressive germ cell neoplasms. Undifferentiated gonadal tissue is the precursor of classical gonadoblastoma and contains germ cells with delayed maturation that express octamer-binding transcription factor 4 (OCT4); however, other germ cells show normal maturation and express TSPY1. If all germ cells in a patient with undifferentiated gonadal tissue involute, the result is a secondary streak. Undifferentiated gonadal tissue is a non-neoplastic condition that should be clearly distinguished from "dissecting gonadoblastoma," a neoplasm derived from classical gonadoblastoma that is the precursor of some germinomas. "Dissecting gonadoblastoma" is a variant of classical gonadoblastoma that has unusual growth patterns and contains both sex cord and germ cell elements. Clonal expansion of germ cells is a characteristic of the late stage of "dissecting gonadoblastoma".

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From large to small: The immunohistochemical panel in the diagnosis of early hepatocellular carcinoma

Abstract

Aims

(i) to validate the immunohistochemical (IHC) markers Glutamine Synthetase (GS), Glypican-3 (GPC3), Heat Shock Protein-70 (HSP70) and Enhancer of Zeste homologue 2 (EZH2) on liver biopsy for the differential diagnosis between small HCC and non-neoplastic liver nodules, with special attention on <1 cm nodules; (ii) to assess the actual sensitivity and specificity of the single markers, and their combination, on needle biopsies.

Methods and Results

One-hundred (100) liver nodules, 66 HCC and 34 non-neoplastic nodules, were prospectively collected from 43 consecutive OLT patients, and subjected to "backtable" needle biopsies directly on surgical specimen. IHC was semi-automatically performed with Benchmark® ultra immunostainer. The morphological and IHC diagnosis on surgical specimen was considered "gold standard".

GS, GPC3, HSP70 and EZH2 showed 16.6%, 10.7%, 28.8%, and 62.1% decrease in sensitivity respectively from surgical specimen to needle biopsy. Higher decreases were observed in <1 cm nodules. In 18 HCC with no morphological diagnostic features of malignancy on biopsy, GPC3 or GS were positive in 16; in 7 HCC neither morphology nor IHC ruled out the differential diagnosis on needle biopsy.

Conclusions

We present for the first time a direct confrontation between surgical specimens and needle biopsies to confirm the usefulness and reproducibility of the most widely used antibodies for the diagnosis of small liver nodules. Our results recommend the use of IHC on biopsy for the diagnosis of small liver lesions, albeit the IHC panel could result negative also in front of obvious HCC and false positive should always be considered.

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Podoplanin expression in cancer-associated fibroblasts predicts unfavourable prognosis in patients with pathological stage IA lung adenocarcinoma

Abstract

Aims

Podoplanin expression in cancer-associated fibroblasts (CAFs) has been proposed as an unfavourable indicator in squamous cell carcinoma of the lung, but little is known about its clinical significance in early-stage lung adenocarcinoma. We evaluated the prognostic impact of podoplanin expression in patients with pathological stage (p-stage) IA lung adenocarcinoma as categorized by the 8th edition of the tumour-node-metastasis classification for lung cancer.

Methods and results

Immunohistochemical analyses using anti-podoplanin antibody were performed on resected specimens from 158 patients with p-stage IA lung adenocarcinoma. When more than 10% of cancer cells or CAFs showed immunoreactivity with podoplanin, the specimens were classified as podoplanin-positive. Podoplanin-positive status in cancer cells (n = 8) was not correlated with clinicopathological factors or with patient prognosis. Podoplanin-positive status in CAFs (n = 41) was significantly correlated with more poorly tumour differentiation (P < 0.001), the presence of lymphatic invasion (P < 0.001) and high-grade (solid and/or micropapillary) components constituting ≥1% of the entire tumour (P < 0.001). The log-rank test showed that podoplanin-positive status in CAFs was significantly associated with shorter disease-free survival (DFS) (P < 0.001) and disease-specific survival (P = 0.015). In Cox's multivariate analysis, podoplanin-positive status in CAFs had the most significant effect on shorter DFS (hazard ratio [HR] = 4.411, P = 0.004) followed by the presence of high-grade components (HR = 3.581, P = 0.013).

Conclusions

Podoplanin expression in CAFs could be an independent predictor of increased risk of recurrence in patients with p-stage IA lung adenocarcinoma.

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Pulmonary Sclerosing Pneumocytoma Remains a Diagnostic Challenge using Frozen Sections: A Clinicopathological Analysis of 59 Cases

Abstract

Aims

Using intraoperative frozen sections to diagnose pulmonary sclerosing pneumocytoma is always challenging. However, an accurate diagnosis is needed to guide surgical management and prevent unnecessary treatment. The aim of this study was to investigate the most frequently misdiagnosed histological patterns and evaluate the potential diagnostic pitfalls of using frozen sections.

Methods and results

We retrospectively reviewed 59 cases of sclerosing pneumocytoma that underwent an intraoperative frozen section examination. All original frozen section slides and permanent section slides were reviewed. The rate of accurate diagnosis using frozen sections was 44.1%, the deferral rate was 15.3%, and 10 cases (16.9%) were misdiagnosed as malignancy. A solid-predominant pattern is more frequently misdiagnosed than other growth patterns. We also summarized the five major diagnostic pitfalls, including hypercellularity, glandular spaces, desmoplasia-like sclerosis, cellular atypia and coagulative necrosis.

Conclusions

In addition to evaluating the tumour circumscription and identifying the various growth patterns, we propose that the key to avoiding a misdiagnosis is to recognize the dual-cell populations in a tumour, i.e., cuboidal surface cells and stromal round cells.

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Comprehensive Histopathologic Comparison of Epidermotropic/Dermal Metastatic Melanoma and Primary Nodular Melanoma

Abstract

Aims

Metastatic melanoma involving the epidermis and/or upper dermis may show significant histologic overlap with primary cutaneous melanoma, especially the nodular subtype. Proper histopathologic classification is crucial to appropriate staging and management, yet often challenging. This study aims to identify helpful histopathologic features in differentiating epidermotropic/dermal metastatic melanoma (EDMM) and primary nodular melanoma (PNM).

Methods and Results

A cohort of EDMM (n=74) and PNM (n=75) was retrospectively reviewed for various histopathologic features, and the data were compared between groups by univariate analysis. Features significantly associated with EDMM included tumor size of <0.2 cm, absence of tumor-infiltrating lymphocytes and plasma cells, monomorphism, and involvement of adnexal epithelium. Features associated with PNM included polypoid (exophytic) configuration, prominent tumor-infiltrating plasma cells (TIPs), tumor size of >1 cm, ulceration, epidermal collarette, higher mitotic rate, necrosis, multiple phenotypes, significant pleomorphism, and lichenoid inflammation. By multivariate analysis, a logistic regression model including large tumor size, ulceration, prominent TIPs, lichenoid inflammation, and epidermal collarette was highly predictive of PNM. Six (8%) EDMM cases from three patients demonstrated an "epidermal-only" or "epidermal-predominant" pattern closely simulating in-situ or microinvasive melanoma. Two of these cases were tested by fluorescence in situ hybridization which confirmed clonal relationship with their corresponding primary melanomas.

Conclusions

This is the first comprehensive histopathologic comparison of EDMM and PNM. Recognition of the above histopathologic associations should aid in correct classification and staging of cutaneous melanoma. Epidermotropic metastatic melanomas may occasionally display an epidermal-only/predominant pattern; accurate diagnosis requires prudent clinical correlation and, when necessary, ancillary molecular tests.

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Diagnostic accuracy of immunofluorescence versus immunoperoxidase staining to distinguish immune complex-mediated glomerulonephritis and C3 dominant glomerulopathy

Abstract

Aims

Membranoproliferative glomerulonephritis (MPGN) has been reclassified from an electron microscopy to an immunofluorescence (IF) based semi quantitative classification with immunoperoxidase (IP) technique as a backup option when IF is not possible. However, no data are available on the interobserver variability, the correlation and the reclassification of MPGN based on these two techniques.

Methods & Results

We retrospectively analyzed cases of type 1 MPGN. We repeated IF and performed IP for IgG, kappa, lambda, C3c, and C4d in 35 renal biopsies among which 19 biopsies having a matched IP and IF. We observed a substantial to near perfect agreement among the 7 observers for both IF and IP (W coefficients from 0.66 for IF lambda to 0.89 for IF C4d). Of the 19 cases with matching IP and IF, 5 (26%) turned out to have a different diagnosis on IF as compared to IP. Also, C4d ability to discriminate immune complex-mediated GN (ICGN) from C3 glomerulopathy (C3G) was poor with an area under the curve of 0.44 (95% CI = 0.24 - 0.63) and 0.66 (95% CI = 0.50 - 0.81) for the receiver operating characteristic curves of IF and IP respectively. Limitations include that no clinical data regarding complement activation were available.

Conclusion

The diagnosis of ICGN versus C3GN depends on the immunochemical technique used. Also, the use of C4d failed to discriminate ICGN from C3G in our study. Further validation studies are required to avoid misdiagnosis based on kidney biopsy.

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Nutrition and Aging: a Practicing Oncologist’s Perspective

Abstract

Malnutrition is common in patients with cancer and is associated with a variety of negative outcomes. These can include reduced treatment tolerance and worsened cancer prognosis. Various aspects of aging, including sensory, physical, or psychosocial changes, place older patients at a particularly high risk for malnutrition, and these geriatric factors must be identified early and addressed. Despite the lack of available evidence on the optimal nutritional interventions for older adults with cancer, the oncologist must be prepared to address the common nutritional concerns that arise in both advanced cancer and survivorship settings. While BMI, weight loss, and serum albumin are commonly used as surrogates of malnutrition, the use of a comprehensive screening tool may promote early identification of disrupted eating patterns and allow for prompt intervention. New digital technologies have also demonstrated promise to improve nutritional assessment capabilities. Use of conventional nutritional support in conjunction with novel nutraceutical and anti-cachexia approaches may enhance the effectiveness of interventions and improve our ability to reverse malnutrition-associated alterations in body composition. Future geriatric-focused nutrition research will be crucial in helping guide our patients and effectively addressing their dietary and lifestyle concerns.



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Thyroid autoimmune antibodies in patients with papillary thyroid carcinoma: a double-edged sword?

Abstract

Purpose

The relationship between thyroid autoimmunity and thyroid cancer remains controversial. The objective of this study is to comprehensively analyze the association between thyroid autoimmune antibodies and disease statuses of papillary thyroid carcinoma (PTC).

Methods

Patients were divided into different groups according to their final diagnoses after radioiodine therapy as well as their serum anti-thyroglobulin antibody (TgAb) and anti-thyroidperoxidase antibody (TPOAb) titers. Clinicopathologic characteristics were then compared between groups.

Results

In all, 1126 PTC patients met the inclusion criteria. When compared with thyroid autoimmune antibody negative group, patients in positive group were young female predominant. After age and gender adjusted, patients in thyroid autoimmune antibody positive group had much more cervical metastatic node count and this effect was limited to the central compartment but not to the lateral compartment. Antibody positivity rate was much lower in patients with distant metastasis and multivariable logistic regression analysis showed positive status of antibody was a protective factor of distant metastasis of PTC with an OR value of 0.403 (95% CI 0.216–0.622, p < 0.001). Additionally, subgroup analysis demonstrated single TgAb positivity and combined positivity of TgAb and TPOAb were shown to be related to less distant metastatic disease.

Conclusions

Positive thyroid auto-antibody status could be a risk factor of more metastatic cervical lymph nodes while a protective factor of distant metastatic disease in PTC patients. The association between thyroid autoimmunity and thyroid cancer can be patient and antibody specific. A systemic immunosupression status may exist in PTC patients with distant metastasis.



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Thyroid autoimmune antibodies in patients with papillary thyroid carcinoma: a double-edged sword?

Abstract

Purpose

The relationship between thyroid autoimmunity and thyroid cancer remains controversial. The objective of this study is to comprehensively analyze the association between thyroid autoimmune antibodies and disease statuses of papillary thyroid carcinoma (PTC).

Methods

Patients were divided into different groups according to their final diagnoses after radioiodine therapy as well as their serum anti-thyroglobulin antibody (TgAb) and anti-thyroidperoxidase antibody (TPOAb) titers. Clinicopathologic characteristics were then compared between groups.

Results

In all, 1126 PTC patients met the inclusion criteria. When compared with thyroid autoimmune antibody negative group, patients in positive group were young female predominant. After age and gender adjusted, patients in thyroid autoimmune antibody positive group had much more cervical metastatic node count and this effect was limited to the central compartment but not to the lateral compartment. Antibody positivity rate was much lower in patients with distant metastasis and multivariable logistic regression analysis showed positive status of antibody was a protective factor of distant metastasis of PTC with an OR value of 0.403 (95% CI 0.216–0.622, p < 0.001). Additionally, subgroup analysis demonstrated single TgAb positivity and combined positivity of TgAb and TPOAb were shown to be related to less distant metastatic disease.

Conclusions

Positive thyroid auto-antibody status could be a risk factor of more metastatic cervical lymph nodes while a protective factor of distant metastatic disease in PTC patients. The association between thyroid autoimmunity and thyroid cancer can be patient and antibody specific. A systemic immunosupression status may exist in PTC patients with distant metastasis.



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Transcriptomic analysis of the tumor microenvironment to guide prognosis and immunotherapies

Abstract

Tumors are highly heterogeneous tissues where malignant cells are surrounded by and interact with a complex tumor microenvironment (TME), notably composed of a wide variety of immune cells, as well as vessels and fibroblasts. As the dialectical influence between tumor cells and their TME is known to be clinically crucial, we need tools that allow us to study the cellular composition of the microenvironment. In this focused research review, we report MCP-counter, a methodology based on transcriptomic markers that assesses the proportion of several immune and stromal cell populations in the TME from transcriptomic data, and we highlight how it can provide a way to decipher the complex mechanisms at play in tumors. In several malignancies, MCP-counter scores have been used to show various prognostic impacts of the TME, which we also show to be linked with the mutational burden of tumors. We also compared established molecular classifications of colorectal cancer and clear-cell renal cell carcinoma with the output of MCP-counter, and show that molecular subgroups have different TME profiles, and that these profiles are consistent within a given subgroup. Finally, we provide insights as to how knowing the TME composition may shape patient care in the near future.



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Transcriptomic analysis of the tumor microenvironment to guide prognosis and immunotherapies

Abstract

Tumors are highly heterogeneous tissues where malignant cells are surrounded by and interact with a complex tumor microenvironment (TME), notably composed of a wide variety of immune cells, as well as vessels and fibroblasts. As the dialectical influence between tumor cells and their TME is known to be clinically crucial, we need tools that allow us to study the cellular composition of the microenvironment. In this focused research review, we report MCP-counter, a methodology based on transcriptomic markers that assesses the proportion of several immune and stromal cell populations in the TME from transcriptomic data, and we highlight how it can provide a way to decipher the complex mechanisms at play in tumors. In several malignancies, MCP-counter scores have been used to show various prognostic impacts of the TME, which we also show to be linked with the mutational burden of tumors. We also compared established molecular classifications of colorectal cancer and clear-cell renal cell carcinoma with the output of MCP-counter, and show that molecular subgroups have different TME profiles, and that these profiles are consistent within a given subgroup. Finally, we provide insights as to how knowing the TME composition may shape patient care in the near future.



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Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly

Abstract
Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype–phenotype correlations. We sought to further delineate this spectrum, study levels of mosaicism and identify genotype–phenotype correlations of AKT3-related disorders. We performed targeted sequencing of AKT3 on individuals with these phenotypes by molecular inversion probes and/or Sanger sequencing to determine the type and level of mosaicism of mutations. We analysed all clinical and brain imaging data of mutation-positive individuals including neuropathological analysis in one instance. We performed ex vivo kinase assays on AKT3 engineered with the patient mutations and examined the phospholipid binding profile of pleckstrin homology domain localizing mutations. We identified 14 new individuals with AKT3 mutations with several phenotypes dependent on the type of mutation and level of mosaicism. Our comprehensive clinical characterization, and review of all previously published patients, broadly segregates individuals with AKT3 mutations into two groups: patients with highly asymmetric cortical dysplasia caused by the common p.E17K mutation, and patients with constitutional AKT3 mutations exhibiting more variable phenotypes including bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia and diffuse megalencephaly without cortical dysplasia. All mutations increased kinase activity, and pleckstrin homology domain mutants exhibited enhanced phospholipid binding. Overall, our study shows that activating mutations of the critical AKT3 gene are associated with a wide spectrum of brain involvement ranging from focal or segmental brain malformations (such as hemimegalencephaly and polymicrogyria) predominantly due to mosaic AKT3 mutations, to diffuse bilateral cortical malformations, megalencephaly and heterotopia due to constitutional AKT3 mutations. We also provide the first detailed neuropathological examination of a child with extreme megalencephaly due to a constitutional AKT3 mutation. This child has one of the largest documented paediatric brain sizes, to our knowledge. Finally, our data show that constitutional AKT3 mutations are associated with megalencephaly, with or without autism, similar to PTEN-related disorders. Recognition of this broad clinical and molecular spectrum of AKT3 mutations is important for providing early diagnosis and appropriate management of affected individuals, and will facilitate targeted design of future human clinical trials using PI3K-AKT pathway inhibitors.

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The L444P Gba1 mutation enhances alpha-synuclein induced loss of nigral dopaminergic neurons in mice

Abstract
Mutations in glucocerebrosidase 1 (GBA1) represent the most prevalent risk factor for Parkinson's disease. The molecular mechanisms underlying the link between GBA1 mutations and Parkinson's disease are incompletely understood. We analysed two aged (24-month-old) Gba1 mouse models, one carrying a knock-out mutation and the other a L444P knock-in mutation. A significant reduction of glucocerebrosidase activity was associated with increased total alpha-synuclein accumulation in both these models. Gba1 mutations alone did not alter the number of nigral dopaminergic neurons nor striatal dopamine levels. We then investigated the effect of overexpression of human alpha-synuclein in the substantia nigra of aged (18 to 21-month-old) L444P Gba1 mice. Following intraparenchymal injections of human alpha-synuclein carrying viral vectors, pathological accumulation of phosphorylated alpha-synuclein occurred within the transduced neurons. Stereological counts of nigral dopaminergic neurons revealed a significantly greater cell loss in Gba1-mutant than wild-type mice. These results indicate that Gba1 deficiency enhances neuronal vulnerability to neurodegenerative processes triggered by increased alpha-synuclein expression.

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Drug Repurposing to treat Asthma and Allergic Disorders: Progress and Prospects

Abstract

Allergy and atopic asthma have continued to become more prevalent in modern society despite the advent of new treatments, representing a major global health problem. Common medications such as antihistamines and steroids may have undesirable long-term side effects and lack efficacy in some resistant patients. Biologic medications are increasingly given to treat resistant patients, but they can represent high costs, complex dosing and management, and are not widely available around the world. The field needs new, cheap and convenient treatment options in order to bring better symptom relief to patients. Beyond continued research and development of new drugs, a focus on drug repurposing could alleviate this problem by repositioning effective and safe small molecule drugs from other fields of medicine and applying them toward the treatment of asthma and allergy. Herein, preclinical models, case reports, and clinical trials of drug repurposing efficacy in allergic disease are reviewed. Novel drugs are also proposed for repositioning based on their mechanism of action to treat asthma and allergy. Overall, drug repurposing could become increasingly important as a way of advancing allergy and atopic asthma treatment, filling a need in treatment for patients today.

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Sleep correlates of substance use in community-dwelling Ethiopian adults

Abstract

Purpose

The relationship between sleep disturbances and substance use can have harmful effects. Evidence shows widespread use of substances, including khat, in the Ethiopian population. However, to the best of our knowledge, no study has investigated the sleep correlates of substance use in community-dwelling Ethiopian adults.

Materials and methods

A cross-sectional study using simple random sampling was performed on community-dwelling adults (n = 371, age = 25.5 ± 5.7 years, body mass index = 22.0 ± 2.2 kg/m2) in Mizan-Aman, Ethiopia. Dichotomized sleep measures (sleep quality and sleep latency) assessed by the Pittsburgh Sleep Quality Index (PSQI) were used in association analysis using binary logistic regression with substance use (khat, smoking, and alcohol).

Result

Sleep latency was associated with khat chewing (adjusted odds ratio (AOR) = 2.8, 95% confidence interval (CI) 1.7–4.4) and tobacco smoking (AOR = 2.1, 95% CI 1.4–3.0). Sleep quality was associated with khat chewing (AOR = 3.1, 95% CI 1.8–5.2), tobacco smoking (AOR = 1.7, 95% CI 1.2–2.5), and alcohol intake (AOR = 1.9, 95% CI 1.1–3.1).

Conclusion

Sleep correlates of substance use were found in community-dwelling Ethiopians. These findings may aid in the development of targeted strategies to manage substance use-related sleep disturbances.



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Ambulatory screening tool for sleep apnea: analyzing a single-lead electrocardiogram signal (ECG)

Abstract

Study objective

The goal was to determine the utility and accuracy of automated analysis of single-lead electrocardiogram (ECG) data using two algorithms, cardiopulmonary coupling (CPC), and cyclic variation of heart rate (CVHR) to identify sleep apnea (SA).

Methods

The CPC-CVHR algorithms were applied to identify SA by analyzing ECG from diagnostic polysomnography (PSG) from 47 subjects. The studies were rescored according to updated AASM scoring rules, both manually by a certified technologist and using an FDA-approved automated scoring software, Somnolyzer (Philips Inc., Monroeville, PA). The CPC+CVHR output of Sleep Quality Index (SQI), Sleep Apnea Indicator (SAI), elevated low frequency coupling broadband (eLFCBB) and elevated low frequency coupling narrow-band (eLFCNB) were compared to the manual and automated scoring of apnea hypopnea index (AHI).

Results

A high degree of agreement was noted between the CPC-CVHR against both the manually rescored AHI and the computerized scored AHI to identify patients with moderate and severe sleep apnea (AHI > 15). The combined CPC+CVHR algorithms, when compared to the manually scored PSG output presents sensitivity 89%, specificity 79%, agreement 85%, PPV (positive predictive value) 0.86 and NPV (negative predictive value) 0.83, and substantial Kappa 0.70. Comparing the output of the automated scoring software to the manual scoring demonstrated sensitivity 93%, specificity 79%, agreement 87%, PPV 0.87, NPV 0.88, and substantial Kappa 0.74.

Conclusion

The CPC+CVHR technology performed as accurately as the automated scoring software to identify patients with moderate to severe SA, demonstrating a clinically powerful tool that can be implemented in various clinical settings to identify patients at risk for SA.

Trial registration

NCT01234077.



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Insulin Resistance and Hunger in Childhood Obesity: A Patient and Physician’s Perspective

Abstract

This article is co-authored by the mother of a child with obesity and insulin resistance, who gives her perspective. It is also co-authored by the treating Obesity Medicine clinician and an investigator in obesity clinical research (both certified in Obesity Medicine), who give their perspectives. The discussion focuses upon the potential clinical use of metformin in managing young patients with obesity and insulin resistance. The article integrates what is scientifically known about the mechanisms of actions of metformin and how these mechanisms are reflected in the clinical response of young patients.



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Risk Factors for Knee Injury in Golf: A Systematic Review

Abstract

Background

Golf is commonly considered a low-impact sport that carries little risk of injury to the knee and is generally allowed following total knee arthroplasty (TKA). Kinematic and kinetic studies of the golf swing have reported results relevant to the knee, but consensus as to the loads experienced during a swing and how the biomechanics of an individual's technique may expose the knee to risk of injury is lacking.

Objectives

Our objective was to establish (1) the prevalence of knee injury resulting from participation in golf and (2) the risk factors for knee injury from a biomechanical perspective, based on an improved understanding of the internal loading conditions and kinematics that occur in the knee from the time of addressing the ball to the end of the follow-through.

Methods

A systematic literature search was conducted to determine the injury rate, kinematic patterns, loading, and muscle activity of the knee during golf.

Results

A knee injury prevalence of 3–18% was established among both professional and amateur players, with no clear dependence on skill level or sex; however, older players appear at greater risk of injury. Studies reporting kinematics indicate that the lead knee is exposed to a complex series of motions involving rapid extension and large magnitudes of tibial internal rotation, conditions that may pose risks to the structures of a natural knee or TKA. To date, the loads experienced by the lead knee during a golf swing have been reported inconsistently in the literature. Compressive loads ranging from 100 to 440% bodyweight have been calculated and measured using methods including inverse dynamics analysis and instrumented knee implants. Additionally, the magnitude of loading appears to be independent of the club used.

Conclusions

This review is the first to highlight the lack of consensus regarding knee loading during the golf swing and the associated risks of injury. Results from the literature suggest the lead knee is subject to a higher magnitude of stress and more demanding motions than the trail knee. Therefore, recommendations regarding return to golf following knee injury or surgical intervention should carefully consider the laterality of the injury.



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Saddle nose deformity and septal perforation in granulomatosis with polyangiitis

Abstract

Background

Patients who have granulomatosis with polyangiitis (GPA, syn. M. Wegener) often develop an external nose deformity which may have devastating psychological effects. Therefore, reconstruction of nasal deformities by rhinoplasty may become necessary to achieve a normal appearance.

Objective of review

The aim of this systematic review was to investigate the efficacy and safety of surgical reconstruction in external nasal deformities and septal perforation in GPA patients.

Search strategy

A systematic literature search with defined search terms was performed for scientific articles archived in the MEDLINE-Database up to June 10th, 2016 (PubMed Advanced MEDLINE Search), describing management of cases or case series in GPA patients with saddle nose deformity and/or septal perforation.

Results

Eleven of 614 publications met the criteria for this analysis including 41 GPA patients undergoing external nasal reconstruction and/ or septal reconstruction with a median follow-up of 2.6 years. Overall, saddle nose reconstruction in GPA patients is safe even if an increased rate of revision surgery has to be expected compared with individuals without GPA undergoing septorhinoplasty. Most implanted grafts were autografts of calvarial bone or costal cartilage. For septal perforation reconstruction, few studies were available. Therefore, based upon the available data for surgical outcomes, it is impossible to make evidence-based recommendations. All included GPA patients had minimal or no local disease at the time of reconstructive surgery. Therefore, the relationship between disease activity and its impact on surgical outcomes remains unanswered. The potential impact of immune-modulating medications on increased complication rates and the impact of prophylactic antibiotics are unknown.

Conclusions

This study systematically reviews the efficacy and safety of surgical reconstruction of external nasal deformities in GPA patients for the first time. Saddle nose reconstruction in GPA patients with minimal or no local disease is a safe procedure despite an increased rate of revision surgery. Further research is required regarding the impact of antibiotic prophylaxis, immune-modulating therapy, long-term outcomes, and functional outcomes measured with subjective and objective parameters.

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Neonatal congenital lung tumors — the importance of mid-second-trimester ultrasound as a diagnostic clue

Abstract

Background

The differential diagnosis for primary lung masses in neonates includes a variety of developmental abnormalities; it also consists of the much rarer congenital primary lung tumors: cystic pleuropulmonary blastoma (cystic PPB), fetal lung interstitial tumor (FLIT), congenital peribronchial myofibroblastic tumor (CPMT), and congenital fibrosarcoma. Radiologic differentiation between malformations and tumors is often very challenging.

Objective

The objective was to establish distinctive features between developmental pulmonary abnormalities and primary lung tumors.

Materials and methods

We conducted a retrospective study of 135 congenital lung lesions at a university mother and child center over a period of 10 years (2005–2015). During this time, we noted four tumors (two cystic PPBs and two FLITs) and 131 malformations. We recorded the following parameters: timing of conspicuity in utero (mid-second trimester, third trimester, or not seen prenatally), presence of symptoms at birth, prenatal and perinatal radiologic findings, and either histological diagnoses by pathology or follow-up imaging in non-operated cases.

Results

All lesions except the four tumors were detected during mid-second-trimester ultrasound. In none of the tumors was any pulmonary abnormality found on the mid-second-trimester sonogram, contrary to the developmental pulmonary abnormalities.

Conclusion

The timing of conspicuity in utero appears to be a key feature for the differentiation between malformations and tumors. Lesions that were not visible at the mid-second-trimester ultrasound should be considered as tumor. A cystic lung lesion in the context of a normal mid-second-trimester ultrasound is highly suggestive of a cystic PPB. Differentiating the types of solid congenital lung tumors based upon imaging features is not yet feasible.



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Characterization of the Capsule Surrounding Smooth and Textured Tissue Expanders and Correlation with Contracture

imageBackground: Capsular contracture is a common complication after breast augmentation surgery. This study pathologically evaluated the soft-tissue response to surface modifications in both smooth and textured tissue expander prostheses. Methods: Smooth tissue expanders and textured tissue expanders in 5 cases each were used for breast reconstruction after mastectomy. Histological samples were harvested from the capsules when the tissue expanders were replaced by silicone implants. Collagen orientation and cellular responses were assessed histologically. Capsular contracture was evaluated using the Baker classification 6 months and 2 years after the removal of the tissue expander. Results: The capsules surrounding the smooth tissue expanders tended to produce more contracture than those surrounding the textured tissue expanders. The collagen architecture of the capsules of the smooth tissue expanders showed random orientation with fragmentation. Conversely, the capsules of the textured tissue expanders showed parallel orientation with collagen bundles of almost normal structure. Significantly more fibrils of elastin and myofibroblasts were found in the capsules surrounding the smooth tissue than in those surrounding the textured ones. Conclusions: The collagen fibers surrounding the smooth tissue expanders could be cracked during expansion, which may lead to scarring and contracture. Conversely, the collagen orientation surrounding the textured tissue expanders was excellent. Moreover, the increase in elastic fibers and myofibroblasts in the capsules surrounding the smooth tissue expanders may be associated with in vivo contraction patterns. Therefore, the surface type of tissue expanders affects capsular contraction after replacement with definitive implants.

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Periauricular Keloids on Face-Lift Scars in a Patient with Facial Nerve Paralysis

imageSummary: Keloids are caused by excessive scar formation that leads to scar growth beyond the initial scar boundaries. Keloid formation and progression is promoted by mechanical stress such as skin stretch force. Consequently, keloids rarely occur in paralyzed areas and areas with little skin tension, such as the periauricular region. Therefore, periauricular incision is commonly performed for face lifts. We report a rare case of keloids that arose from face-lift scars in a patient with bilateral facial nerve paralysis. A 51-year-old Japanese man presented with abnormal proliferative skin masses in bilateral periauricular scars. Seventeen years before, he had a cerebral infarction that resulted in permanent bilateral facial nerve paralysis. Three years before presentation, the patient underwent face-lift surgery with periauricular incisions. We diagnosed multiple keloids. We removed the masses surgically, closed the wounds with sutures in the superficial musculoaponeurotic system layer to reduce tension on the wound edges, reconstructed the earlobes with local skin flaps, and provided 2 consecutive days of radiotherapy. The wounds/scars were managed with steroid plasters and injections. Histology confirmed that the lesions were keloids. Ten months after surgery, the lesions did not exhibit marked regrowth. The keloids appeared to be caused by the patient's helmet, worn during his 3-hour daily motorcycle rides, which placed repeated tension on the periauricular area. This rare case illustrates how physical force contributes to auricular and periauricular keloid development and progression. It also shows that when performing surgery with periauricular incisions, care should be taken to eliminate wound/scar stretching.

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The Versatile Modiolus Perforator Flap

imageBackground: Perforator flaps are well established, and their usefulness as freestyle island flaps is recognized. The whereabouts of vascular perforators and classification of perforator flaps in the face are a debated subject, despite several anatomical studies showing similar consistency. In our experience using freestyle facial perforator flaps, we have located areas where perforators are consistently found. This study is focused on a particular perforator lateral to the angle of the mouth; the modiolus and the versatile modiolus perforator flap. Methods: A cohort case series of 14 modiolus perforator flap reconstructions in 14 patients and a color Doppler ultrasonography localization of the modiolus perforator in 10 volunteers. Results: All 14 flaps were successfully used to reconstruct the defects involved, and the location of the perforator was at the level of the modiolus as predicted. The color Doppler ultrasonography study detected a sizeable perforator at the level of the modiolus lateral to the angle of the mouth within a radius of 1 cm. This confirms the anatomical findings of previous authors and indicates that the modiolus perforator is a consistent anatomical finding, and flaps based on it can be recommended for several indications from the reconstruction of defects in the perioral area, cheek and nose. Conclusions: The modiolus is a well-described anatomical area containing a sizeable perforator that is consistently present and readily visualized using color Doppler ultrasonography. We have used the modiolus perforator flap successfully for several indications, and it is our first choice for perioral reconstruction.

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Levels of Antioxidant Activity and Fluoride Content in Coffee Infusions of Arabica, Robusta and Green Coffee Beans in According to their Brewing Methods

Abstract

Coffee is a rich source of dietary antioxidants, and this property links with the fact that coffee is one of the world's most popular beverages. Moreover, it is a source of macro- and microelements, including fluoride. The aim of this work was to determine antioxidant activity of coffee beverages and fluoride content depending on different coffee species and conditions of brewing. Three species of coffee, arabica, robusta and green coffee beans obtained from retail stores in Szczecin (Poland) were analyzed. Five different techniques of preparing drink were used: simple infusion, french press, espresso maker, overflow espresso and Turkish coffee. Antioxidant potential of coffee beverages was investigated spectrophotometrically by DPPH method. Fluoride concentrations were measured by potentiometric method with a fluoride ion-selective electrode. Statistical analysis was performed using Stat Soft Statistica 12.5. Antioxidant activity of infusions was high (71.97–83.21% inhibition of DPPH) depending on coffee species and beverage preparing method. It has been shown that the method of brewing arabica coffee and green coffee significantly affects the antioxidant potential of infusions. The fluoride concentration in the coffee infusions changed depending, both, on the species and conditions of brewing, too (0.013–0.502 mg/L). Methods of brewing didn't make a difference to the antioxidant potential of robusta coffee, which had also the lowest level of fluoride among studied species. Except overflow espresso, the fluoride content was the highest in beverages from green coffee. The highest fluoride content was found in Turkish coffee from green coffee beans.



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Cadmium Concentration in Human Autopsy Tissues

Abstract

The concentration of cadmium in human tissues obtained on the basis of autopsies of non-poisoned Polish people (n = 150), aged from 1 to 80 years, examined between 1990 and 2010, is presented. The following values were found in wet digested samples by flame atomic absorption spectrometry (FAAS) (mean ± SD, median, and range, μg/g of wet weight): brain 0.020 ± 0.031, 0.084, 0–0.120 (n = 41); stomach 0.148 ± 0.195, 0.084, 0–1.25 (n = 89); small intestine 0.227 ± 0.231, 0.130, 0–0.830 (n = 39); liver 1.54 ± 1.55, 1.01, 0.015–9.65 (n = 99); kidney 16.0 ± 13.2, 14.0, 0.62–61.3 (n = 91); lung 0.304 ± 0.414, 0.130, 0–1.90 (n = 25); and heart 0.137 ± 0.107, 0.140, 0.017–0.250 (n = 4). Additionally, results (n = 13 people, aged from 2 to 83 years, 63 samples) obtained by inductively coupled plasma optical emission spectrometry (ICP OES) between 2010 and 2015 are given. The obtained data on Cd concentration in the human body can be used to estimate the amounts occurring in "healthy" people and those occurring in cases of chronic or acute poisonings with Cd compounds, which are examined for forensic purposes or to assess environmental exposure levels.



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Zinc: the Other Suspected Environmental Factor in Kashin-Beck Disease in Addition to Selenium

Abstract

Kashin-Beck disease (KBD) is an endemic chronic osteochondral disease characterized by high prevalence, disability, and morbidity and is distributed from the northeast to the southwest in China, in some regions of Eastern Siberia in Russia, and in North Korea. Although the selenium deficiency etiological hypothesis for KBD has been proposed by scientists for decades, the idea that selenium deficiency is one of the most important environmental factors but not the primary and sole pathogenic factor for KBD has been widely accepted. Zn2+, which is closely involved in the synthesis of enzymes, nucleic acids, and proteins, is an essential microelement in vivo. A conundrum still exists in research on the relationship between Zn2+ and KBD due to inconsistent results, but it has been confirmed that Zn2+ can help repair metaphyseal lesions in patients with KBD, indicating that Zn2+ might play a key role in the pathogenesis of KBD, although the mechanism is unknown. The zinc-ZIP8-MTF1 axis in chondrocytes forms a catabolic cascade that promotes upregulation of the crucial effector matrix-degrading enzymes MMP3, MMP13, and ADAMTS5, thereby leading to osteoarthritis (OA) cartilage destruction. Zinc finger protein-related genes, the ZNT family, and the ZIP family of Zn2+ transporter genes have been found to be differentially expressed in KBD by high-throughput screening. Therefore, Zn2+ could play a key role in the pathogenesis of KBD.



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The Effects of Cerium Valence States at Cerium Oxide Coatings on the Responses of Bone Mesenchymal Stem Cells and Macrophages

Abstract

Ideal orthopedic coatings should trigger good osteogenic response and limited inflammatory response. The cerium valence states in ceria are associated with their anti-oxidative activity and anti-inflammatory property. In the study, we prepared two kinds of plasma sprayed CeO2 coatings with different Ce4+ concentrations to investigate the effects of Ce valence states on the response of bone mesenchymal stem cells (BMSCs) and macrophage RAW264.7. Both the coatings (CeO2-A and CeO2-B) were characterized via XRD, SEM, and X-ray photoelectron spectroscopy. The CeO2 coatings enhanced osteogenic behaviors of BMSCs in terms of cellular proliferation, alkaline phosphatase (ALP) activity and calcium deposition activity in comparison with the Ti substrate. In particular, the CeO2-B coating (higher Ce4+ concentration) elicited greater effects than the CeO2-A coating (higher Ce3+ concentration). RT-PCR and western blot results suggested that the CeO2-B coating promoted BMSCs osteogenic differentiation through the SMAD-dependent BMP signaling pathway, which activated Runx2 expression and subsequently enhanced the expression of ALP and OCN. With respect to either CeO2-A coating or Ti substrate, the CeO2-B coating exerted greater effects on the macrophages, increasing the anti-inflammatory cytokines (IL-10 and IL-1ra) expression and suppressing the expression of the pro-inflammatory cytokines (TNF-α and IL-6) and ROS production. Furthermore, it also upregulated the expression of osteoinductive molecules (TGF-β1 and BMP2) in the macrophages. The regulation of cerium valence states at plasma sprayed ceria coatings can be a valuable strategy to improve osteogenic properties and alleviate inflammatory response.



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Effects of Boron Supplementation on Peripartum Dairy Cows’ Health

Abstract

Although many different dietary studies on the prevention of negative energy balance related diseases are often encountered, this is the first study investigating the effects of boron supplementation on peripartum dairy cows' health in the light of an omics approach. Twenty-eight healthy cows (1 control and 3 experimental groups) were enrolled from 2 months before predicted calving until 2 months after calving. Experimental groups were assigned to receive boron at increasing doses as an oral bolus. Production parameters, biochemical profile, Nuclear Magnetic Resonance based metabolomics profile, and mRNA abundance of gluconeogenic enzymes and lipid oxidation genes were determined. Pivotal knowledge was obtained on boron distribution in the body. Production parameters and mRNA abundance of the genes were not affected by the treatments. Postpartum nonesterified fatty acids, β-hydroxybutyrate, and triglyceride concentrations were significantly decreased in experimentals. The primary differences among groups were in lipid-soluble metabolites. There were significant differences in metabolites including postpartum valine, β-hydroxybutyrate, polyunsaturated fatty acid and citrate, propionate, isobutyrate, choline metabolites (betaine, phosphatidylcholine, and sphingomyelin), and some types of fatty acids and cholesterol in experimentals. Boron appears to be effective in minimizing negative energy balance and improving health of postpartum dairy cows.



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Erratum to: Screening of Blood Levels of Mercury, Cadmium, and Copper in Pregnant Women in Dakahlia, Egypt: New Attention to an Old Problem



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Magnesium Ions Promote the Biological Behaviour of Rat Calvarial Osteoblasts by Activating the PI3K/Akt Signalling Pathway

Abstract

Magnesium has been investigated as a biodegradable metallic material. Increased concentrations of Mg2+ around magnesium implants due to biodegradation contribute to its satisfactory osteogenic capacity. However, the mechanisms underlying this process remain elusive. We propose that activation of the PI3K/Akt signalling pathway plays a role in the Mg2+-enhanced biological behaviours of osteoblasts. To test this hypothesis, 6, 10 and 18 mM Mg2+ was used to evaluate the stimulatory effect of Mg2+ on osteogenesis, which was assessed by evaluating cell adhesion, cell viability, ALP activity, extracellular matrix mineralisation and RT-PCR. The expression of p-Akt was also determined by western blotting. The results showed that 6 and 10 mM Mg2+ elicited the highest stimulatory effect on cell adhesion, cell viability and osteogenic differentiation as evidenced by cytoskeletal staining, MTT assay results, ALP activity, extracellular matrix mineralisation and expression of osteogenic differentiation-related genes. In contrast, 18 mM Mg2+ had an inhibitory effect on the behaviour of osteoblasts. Furthermore, 10 mM Mg2+ significantly increased the phosphorylation of Akt in osteoblasts. Notably, the aforementioned beneficial effects produced by 10 mM Mg2+ were abolished by blocking the PI3K/Akt signalling pathway through the addition of wortmannin. In conclusion, these results demonstrate that 6 mM and 10 mM Mg2+ can enhance the behaviour of osteoblasts, which is at least partially attributed to activation of the PI3K/Akt signalling pathway. Furthermore, a high concentration (18 mM Mg2+) showed an inhibitory effect on the biological behaviour of osteoblasts. These findings advance the understanding of cellular responses to biodegradable metallic materials and may attract greater clinical interest in magnesium.



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Highly Simple Deep Eutectic Solvent Extraction of Manganese in Vegetable Samples Prior to Its ICP-OES Analysis

Abstract

In the present work, simple and sensitive extraction methods for selective determination of manganese have been successfully developed. The methods were based on solubilization of manganese in deep eutectic solvent medium. Three deep eutectic solvents with choline chloride (vitamin B4) and tartaric/oxalic/citric acids have been prepared. Extraction parameters were optimized with using standard reference material (1573a tomato leaves). The quantitative recovery values were obtained with 1.25 g/L sample to deep eutectic solvent (DES) volume, at 95 °C for 2 h. The limit of detection was found as 0.50, 0.34, and 1.23 μg/L for DES/tartaric, DES/oxalic, and DES/citric acid, respectively. At optimum conditions, the analytical signal was linear for the range of 10–3000 μg/L for all studied DESs with the correlation coefficient >0.99. The extraction methods were applied to different real samples such as basil herb, spinach, dill, and cucumber barks. The known amount of manganese was spiked to samples, and good recovery results were obtained.



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Assessment of Cu-Zn EDTA Parenteral Toxicity in Calves

Abstract

Copper (Cu) parenteral administration is used in a beef cow-calf operations to prevent or correct Cu deficiency in bovines. At present, Zinc (Zn) salts have been incorporated to complement Cu antioxidant effect. A risk of hepatotoxicity generated by overdose is a negative consequence of injectable Cu application. Cu-Zn EDTA appears as an alternative; however, data about its toxicity is unknown. The aim of this study was to assess toxicity risk of different doses of Cu-Zn EDTA in calves. Thirty two Aberdeen Angus calves of 162 (±20) kg BW were assigned to 4 groups (n = 8), homogeneous in weight, sex, and age. Cu-Zn EDTA was administrated in doses of 0.3 mg/kg BW (group 1X); 0.6 mg/kg BW (group 2X); 0.9 mg/kg BW (group 3X) and sterile saline solution (control group-with no treatment). Clinical and blood parameters in animals were monitored during 28 days. In groups' control, 1X and 2X there were no alterations in the assessed parameters. In group 3X, one of the animals showed depression, permanent decubitus, and muscular twitching; that animal had to be killed in extremis for humanitarian reasons. Necropsy and Cu tissue concentration findings confirmed intoxication in the clinically affected animal. The rest of the animals in group 3X showed only a temporary increase in liver enzymes. The results indicate that a dose of 0.9 mg/kg BW of Cu as Cu-Zn EDTA is potentially hepatotoxic, this dose is similar to other soluble salts of parenteral administration.



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Hair Zinc and Severity of Symptoms Are Increased in Children with Attention Deficit and Hyperactivity Disorder: a Hair Multi-Element Profile Study

Abstract

Determination of bioelement levels in hair is an emerging non-invasive approach for screening bioelement deposition. However, the role of essential bioelement levels in hair and attention deficit/hyperactivity disorder (ADHD) risk or severity is largely unknown. In this study, we have compared multi-element hair profiles between healthy and ADHD Thai children. In addition, the correlations between bioelements and ADHD symptoms according to Diagnostic and Statistical Manual of Mental Disorders, 5th edition, diagnostic criteria were identified. A case-control study was conducted in 111 Thai children (45 newly diagnosed ADHD and 66 matched healthy), aged 3–7 years, living in Bangkok and suburban areas. Levels of 39 bioelements in hair were measured by ICP-MS. Among the analyzed bioelements, Cu/Zn and P/Zn ratios in ADHD children were significantly lower than those in healthy children. Indeed, increased hair Zn level was correlated with more symptoms of inattention, hyperactivity, and total ADHD symptoms. Higher Zn content was also associated with being female and older age. Furthermore, Zn in hair was positively correlated with levels of Ca, Mg, and P; however, it showed a negative correlation with Al, As, Fe, and Mo. These findings warrant further confirmation in a large-scale study. Thai Clinical Trials Registry (TCTR) study ID: 20151113001



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Ternary cocktail nanoparticles for sequential chemo-photodynamic therapy

Previous clinical trials have already demonstrated that combinations of two or more drugs were more effective in the cancer treatment, especially sequential photodynamic design combing with sequential chemothe...

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Alzheimer’s disease pathological lesions activate the spleen tyrosine kinase

The pathology of Alzheimer's disease (AD) is characterized by dystrophic neurites (DNs) surrounding extracellular Aβ-plaques, microgliosis, astrogliosis, intraneuronal tau hyperphosphorylation and aggregation....

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IGF1R activation and the in vitro antiproliferative efficacy of IGF1R inhibitor are inversely correlated with IGFBP5 expression in bladder cancer

Abstract

Background

The insulin growth factor (IGF) pathway has been proposed as a potential therapeutic target in bladder cancer. We characterized the expression of components of the IGF pathway — insulin growth factor receptors (INSR, IGF1R, IGF2R), ligands (INS, IGF1, IGF2), and binding proteins (IGFBP1–7, IGF2BP1–3) — in bladder cancer and its correlation with IGF1R activation, and the anti-proliferative efficacy of an IGF1R kinase inhibitor in this setting.

Methods

We analyzed transcriptomic data from two independent bladder cancer datasets, corresponding to 200 tumoral and five normal urothelium samples. We evaluated the activation status of the IGF pathway in bladder tumors, by assessing IGF1R phosphorylation and evaluating its correlation with mRNA levels for IGF pathway components. We finally evaluated the correlation between inhibition of proliferation by a selective inhibitor of the IGF1R kinase (AEW541), reported in 13 bladder cancer derived cell lines by the Cancer Cell Line Encyclopedia Consortium and mRNA levels for IGF pathway components.

Results

IGF1R expression and activation were stronger in non-muscle-invasive than in muscle-invasive bladder tumors. There was a significant inverse correlation between IGF1R phosphorylation and IGFBP5 expression in tumors. Consistent with this finding, the inhibition of bladder cell line viability by IGF1R inhibitor was also inversely correlated with IGFBP5 expression.

Conclusion

The IGF pathway is activated and therefore a potential therapeutic target for non muscle-invasive bladder tumors and IGFBP5 could be used as a surrogate marker for predicting tumor sensitivity to anti-IGF therapy.



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Τετάρτη 6 Σεπτεμβρίου 2017

Table of Contents



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Editorial Board



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Guidelines for Contributing Authors



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Expression of transcription factors in MEN1-associated pancreatic neuroendocrine tumors

EDM17-0088fig1.tif?width=755

Summary

MEN1-associated pancreatic neuroendocrine tumors (pNETs) may potentially express distinct hormones, but the mechanism has not been elucidated. Transcription factors such as MafA and Pdx1 have been identified to lead to beta cell differentiation, while Arx and Brn4 to alpha cell differentiation in developing pancreas. We hypothesized those transcription factors are important to produce specific hormones in pNETs, similarly to developing pancreas, and examined the expression of transcription factors in a case of MEN1 who showed immunohistological coexistence of several hormone-producing pNETs including insulinoma. A 70-year-old woman was found to manifest hypoglycemia with non-suppressed insulinemia and hypercalcemia with elevated PTH level. She was diagnosed as MEN1 based on the manifestation of primary hyperparathyroidism, pituitary adenoma and insulinoma, with genetic variation of MEN1 gene. She had pylorus-preserving pancreaticoduodenectomy because CT scan and SACI test indicated that insulinoma was localized in the head of the pancreas. Histopathological finding was MEN1-associated NET, G1. Interestingly, immunohistological examination of the resected pancreas revealed that two insulinomas, a glucagon-positive NET and a multiple hormone-positive NET coexisted. Hence, we examined the expression of transcription factors immunohistochemically to elucidate the role of the transcription factors in MEN1-associated hormone-producing pNETs. We observed homogeneous expressions of MafA and Pdx1 in insulinomas and Arx in glucagon-positive NET, respectively. Moreover, multiple hormone-positive NETs expressed several transcription factors heterogeneously. Collectively, our results suggested that transcription factors could play important roles in the production of specific hormones in MEN1-associated pNETs, similar to islet differentiation.

Learning points:

To date, it has been shown that different hormone-producing tumors coexist in MEN1-associated pNETs; however, the underlying mechanism of the hormone production in MEN1-associated pNETs has not been well elucidated.

Although this case presented symptomatic hypoglycemia, several hormone-producing pNETs other than insulinoma also coexisted in the pancreas.

Immunohistochemical analysis showed MafA and Pdx1 expressions distinctly in insulinoma, and Arx expression particularly in a glucagon-positive NET, while a multiple hormone-positive NET expressed MafA, Pdx1 and Arx.

Collectively, clinicians should consider that several hormone-producing pNETs may coexist in a MEN1 case and examine both endocrinological and histopathological analysis of pNETs, regardless of whether symptoms related to the excess of hormones are observed or not.



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Indeterminate dendritic cell neoplasm of the skin: A 2-case report and review of the literature

Indeterminate dendritic cell neoplasm (IDCN) is an exceedingly rare and mostly cutaneous histiocytosis, frequently associated with other hematopoietic malignancies. We report 2 cases of multilesional cutaneous IDCN. A 55-year-old male with no associated malignancy and complete response to ultraviolet light therapy; and a 72-year-old male with chronic myelomonocytic leukemia (CMML). Both cases showed histiocytoid cytology, positivity for CD1a and no expression of Langerin or BRAFV600E. With our patients, the literature describes 79 cases of IDCNs, including 65 (82%) with only skin involvement, 7 cases (9%) with involvement of skin and a second site, 5 cases (6%) involving lymph nodes only, 1 splenic lesion and 1 systemic disease. Seventeen cases (22%) were associated with other hematopoietic malignancies, most commonly CMML (6 cases), follicular lymphoma (4 cases) and acute myeloid leukemia (3 cases). All IDCNs associated with myeloid malignancies were limited to the skin, while most cases associated with lymphoma were limited to lymph nodes. Reported responses of cutaneous lesions to ultraviolet light therapy are encouraging, while systemic chemotherapy is appropriate for clinically aggressive cases and treatment of associated malignancies. Recognition of the clinico-morphologic spectrum of IDCNs should prevent misdiagnoses and prompt investigation of possible associated neoplasms.



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TIMP-3 mRNA expression levels positively correlates with levels of miR-21 in in situ BC and negatively in PR positive invasive BC

Publication date: Available online 6 September 2017
Source:Pathology - Research and Practice
Author(s): Nina Petrovic, Ahmad Sami, Jelena Martinovic, Marina Zaric, Irina Nakashidze, Silvana Lukic, Snezana Jovanovic-Cupic
BackgroundBreast carcinomas (BC) belong to a heterogeneous group of malignant diseases. Correct categorization of BC based on molecular biomarkers has a very important role in deciding the proper course of therapy for each patient. It has been already shown that the decrease of TIMP metalloproteinase inhibitor 3 (TIMP-3) together with overexpression of microRNA-21 (miR-21) might be involved in the process of BC invasion. This is the first study that examined relationship among miR-21, TIMP-3 mRNA and TIPM-3 protein levels in BC groups formed according to invasiveness.MethodsIn this study, we used 46 breast cancer samples. Estrogen and progesterone receptor (ER, PR) protein levels were evaluated by immunohistochemistry (IHC) method. TIMP-3 mRNA expression was examined by two-step real-time quantitative PCR (qRT-PCR). Western blot analysis was performed for 16 samples.ResultsStatistically significant differences in TIMP-3 expression levels between invasive groups were discovered in ER positive (ER+) (p=0.015), Her-2 negative (p=0.026) subgroups, and patients without lymph-node metastasis (p=0.039). Interestingly, significant positive correlation was detected between miR-21 and TIMP-3 mRNA levels (P<0.001, ρ=0.949) in the group of in situ tumors. TIMP-3 mRNA expression levels highly negatively correlated with levels of miR-21 in PR+ invasive BCs (p=0.007, ρ=−0.641). TIMP-3 protein levels negatively correlated with miR-21 levels in pure invasive BCs.ConclusionThese data suggest that signaling pathways involved in formation and progression of BCs in groups formed according to invasiveness might be different. Our findings propose that TIMP-3 mRNA expression levels could be significant prognostic parameter, but within specific BC subtypes.



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