Medicine and Otorhinolaryngology in Ancient Egypt

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Future challenges and paradigmatic changes in international arbitration: A peek behind the curtain

لا ينبغي للازدهار غير المسبوق الذي يشهده التحكيم الدولي والابتهاج الراهن به أن يحجب ع ّنا العديد من التحديات الماثلة أمامه. وبالرغم من أن بعض هذه التحديات ربما لا يخص سوى مسائل عملية، وإن كان بالوسع التعامل معها، إلا أن بعضها الآخر ربما يتحول إلى أزمة وجودية. فهل ينجو التحكيم من ردة الفعل المناوئة له؟ لقد تعرض التحكيم لاستقصاءات حادة من قبل المجتمع المدني، وظهرت العديد من الأصوات المنتقدة له والتي بدأت تتساءل عما إذا كان التحكيم الدولي وسيلًة مناسبة لتسوية المنازعات، ولا سيما تلك المنازعات التي قد تتولد عنها تداعيات خطيرة على السياسة العامة والسيادة الوطنية، مثل منازعات الاستثمار. وقد وصفت صحيفة الجارديان (ديسمبر 2013 (محاكم الاستثمار الدولية بأنها ”آلية سامة“ تسمح ”للشركات الكبرى بمقاضاة الحكومات أمام هيئات تحكيم سرية تشكل من محامين للشركات وتلتف على سلطة المحاكم الوطنية و تتجاوز إرادة البرلمانات“. هذا وقد حظي قانون جديد صدر في دولة قطر الشهر الماضي من أجل تحديث نظام التحكيم في هذا البلد العربي بالإشادة لكونه خطوة إيجابية على سبيل تشجيع الاستثمار الأجنبي في البلاد، وإن كان لا يزال بعض ممارسي التحكيم يتساءلون عما إذا كانت هذه الخطوة هي بالفعل فرصة ضائعة. وحتى يتم تغيير هذا التصور، يتعين على المحامين والمؤسسات التحكيمية أن يبرهنوا على المساهمة المرتقبة التي يمكن للتحكيم الدولي أن يحققها لسيادة القانون. ويتعين عليهم أيضاً أن يبرهنوا على أنه يمكن للتحكيم أن يعمل كنظام حر وشفاف يأخذ في الاعتبار المصلحة العامة، وأنه يمكنه أن يصبح قوة دفع نافعة لا لقطاع الأعمال فحسب بل للمجتمع المدني أيضا.The unprecedented growth of international arbitration and the current state of euphoria should not serve to obscure the several challenges that lie ahead. While some challenges may only concern practical, albeit manageable issues, others may well turn into existential crisis. Will arbitration survive the backlash against it? Arbitration has come under the intense scrutiny of civil society, with many critical voices questioning whether international arbitration is an appropriate mode of dispute resolution, particularly for disputes that have important implications on national public policy and sovereignty, such as investment disputes. The Guardian (December 2013) described international investment tribunals as a “toxic mechanism” that allows “big corporations to sue governments before secretive arbitration panels composed of corporate lawyers, which bypass domestic courts and override the will of parliaments”. Meanwhile, a new law enacted last month in Qatar modernizing the Arab nation’s arbitration regime is being praised as a welcome development to encourage foreign investment in the country, but some practitioners still question whether the measure is actually a missed opportunity. To change this perception, arbitration lawyers and institutions must demonstrate the potential contribution of international arbitration to the rule of law. They also need to demonstrate that arbitration can function as an open and transparent system that takes account of the public interest, and can be a force of good not only for business but for civil society too

The theory of a "staphylococcus superantigen" in chronic rhinosinusitis with nasal polyps: myth or reality?

OBJECTIVE: The aim of our study was to search for evidence of a "staphylococcus superantigen" in chronic rhinosinusitis with nasal polyps. PATIENTS AND METHODS: Sixty-nine patients with chronic rhinosinusitis with nasal polyps and 45 healthy controls were included in the study. All patients in the study and control groups underwent bacteriological and immunological examination on nasal smear samples. Total IgE and the following cytokines were tested in all patients: tumor necrosis factor (TNF), interleukin-1 (IL1), interleukin-6 (IL6), interleukin-8 (IL8). RESULTS: The concentration of bacteria in the nasal cavity was much higher in patients in the study group compared to those in the control group, mainly due to staphylococci. In species identification of staphylococci, bacteria most represented were S. aureus and S. epidermidis. The greater the concentration of S. aureus, the lower the level of IgE. Proinflam-matory cytokines were uniformly increased in patients with nasal polyps. The level of IgE was maximal in patients with chronic rhinosinusitis with nasal polyps with a poor growth of culture and minimal in patients with abundant growth, suggesting that in the latter the effect of eosinophilic inflammation on the disease was reduced, and conversely, the activity of eosinophilic inflammation was maximal with a poor seeding of the nasal cavity. CONCLUSIONS: Although this study has some limits, our findings do not support the theory of a staphylococcus superantigen in which the IgE level and eosinophilic inflammation should increase with increasing activity of Staphylococcus aureus. Further research supported by a larger sample of patients is required to better delineate the role of a staphylococcus superantigen in the pathogenesis of patients with chronic rhinosinusitis with nasal polyps

A protein microarray assay for serological determination of antigen-specific antibody responses following Clostridium difficile infection

We provide a detailed overview of a novel high-throughput protein microarray assay for the determination of anti-C. difficile antibody levels in human sera and in separate preparations of polyclonal IVIg. The protocol describes the methodological steps involved in sample preparation, printing of arrays, assay procedure and data analysis. In addition, this protocol could be further developed to incorporate diverse clinical samples including plasma and cell culture supernatants. Herein, a combination of isotype (IgG, IgA IgM), subclass (IgG1, IgG2, IgG3, IgG4, IgA1, IgA2), and strain-specific antibodies to highly purified whole C. difficile toxins A and B (toxinotype 0, strain VPI 10463, ribotype 087), toxin B from a C. difficile toxin-B-only expressing strain (CCUG 20309), precursor form of B fragment of binary toxin, pCDTb, ribotype-specific whole surface layer proteins (SLPs; 001, 002, 027) and control proteins (Tetanus toxoid and Candida albicans) were determined by protein microarray. Microarrays were probed with sera from individuals with C. difficile infection (CDI), cystic fibrosis (CF) without diarrhea, healthy controls and individuals pre- and post-IVIg therapy for treatment of CDI, combined immunodeficiency disorder and chronic inflammatory demyelinating polyradiculopathy. Significant differences in toxin neutralization efficacies and multi-isotype specific antibody levels were seen between patient groups, commercial preparations of IVIg and sera before and following IVIg administration. A significant correlation was observed between microarray and enzyme-linked immunosorbent assay (ELISA) for antitoxin IgG levels in serum samples. These results suggest that microarray could become a promising tool for profiling antibody responses to C. difficile antigens in vaccinated or infected humans. With further refinement of antigen panels and a reduction in production costs, it is anticipated that microarray technology may help optimize and select the most clinically useful immunotherapies for C. difficile infection in a patient-specific manner

The role of indoleamine 2,3-dioxygenase-aryl hydrocarbon receptor pathway in the TLR4-induced tolerogenic phenotype in human DCs

A controlled inflammatory response is required for protection against infection, but persistent inflammation causes tissue damage. Dendritic cells (DCs) have a unique capacity to promote both inflammatory and anti-inflammatory processes. One key mechanism involved in DC-mediated immunosuppression is the expression of tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase (IDO). IDO has been implicated in diverse processes in health and disease but its role in endotoxin tolerance in human DCs is still controversial. Here we investigated the role of IDO in shaping DCs phenotype and function under endotoxin tolerance conditions. Our data show that TLR4 ligation in LPS-primed DCs, induced higher levels of both IDO isoforms together with the transcription factor aryl-hydrocarbon receptor (AhR), compared to unprimed controls. Additionally, LPS conditioning induced an anti-inflammatory phenotype in DCs - with an increase in IL-10 and higher expression of programmed death ligand (PD-L)1 and PD-L2 - which were partially dependent on IDO. Furthermore, we demonstrated that the AhR-IDO pathway was responsible for the preferential activation of noncanonical NF-κB pathway in LPS-conditioned DCs. These data provide new insight into the mechanisms of the TLR4-induced tolerogenic phenotype in human DCs, which can help the better understanding of processes involved in induction and resolution of chronic inflammation and tolerance

A point process framework for modeling electrical stimulation of the auditory nerve

Model-based studies of auditory nerve responses to electrical stimulation can provide insight into the functioning of cochlear implants. Ideally, these studies can identify limitations in sound processing strategies and lead to improved methods for providing sound information to cochlear implant users. To accomplish this, models must accurately describe auditory nerve spiking while avoiding excessive complexity that would preclude large-scale simulations of populations of auditory nerve fibers and obscure insight into the mechanisms that influence neural encoding of sound information. In this spirit, we develop a point process model of the auditory nerve that provides a compact and accurate description of neural responses to electric stimulation. Inspired by the framework of generalized linear models, the proposed model consists of a cascade of linear and nonlinear stages. We show how each of these stages can be associated with biophysical mechanisms and related to models of neuronal dynamics. Moreover, we derive a semi-analytical procedure that uniquely determines each parameter in the model on the basis of fundamental statistics from recordings of single fiber responses to electric stimulation, including threshold, relative spread, jitter, and chronaxie. The model also accounts for refractory and summation effects that influence the responses of auditory nerve fibers to high pulse rate stimulation. Throughout, we compare model predictions to published physiological data and explain differences in auditory nerve responses to high and low pulse rate stimulation. We close by performing an ideal observer analysis of simulated spike trains in response to sinusoidally amplitude modulated stimuli and find that carrier pulse rate does not affect modulation detection thresholds.Comment: 1 title page, 27 manuscript pages, 14 figures, 1 table, 1 appendi

SMAD4 loss enables EGF, TGF\u3b21 and S100A8/A9 induced activation of critical pathways to invasion in human pancreatic adenocarcinoma cells

Epidermal Growth Factor (EGF) receptor overexpression, KRAS, TP53, CDKN2A and SMAD4 mutations characterize pancreatic ductal adenocarcinoma. This mutational landscape might influence cancer cells response to EGF, Transforming Growth Factor \u3b21 (TGF\u3b21) and stromal inflammatory calcium binding proteins S100A8/A9. We investigated whether chronic exposure to EGF modifies in a SMAD4-dependent manner pancreatic cancer cell signalling, proliferation and invasion in response to EGF, TGF\u3b21 and S100A8/A9. BxPC3, homozigously deleted (HD) for SMAD4, and BxPC3-SMAD4+ cells were or not stimulated with EGF (100 ng/mL) for three days. EGF pre-treated and non pretreated cells were stimulated with a single dose of EGF (100 ng/mL), TGF\u3b21 (0,02 ng/mL), S100A8/A9 (10 nM). Signalling pathways (Reverse Phase Protein Array and western blot), cell migration (Matrigel) and cell proliferation (XTT) were evaluated. SMAD4 HD constitutively activated ERK and Wnt/\u3b2-catenin, while inhibiting PI3K/AKT pathways. These effects were antagonized by chronic EGF, which increased p-BAD (anti-apoptotic) in response to combined TGF\u3b21 and S100A8/A9 stimulation. SMAD4 HD underlied the inhibition of NF-\u3baB and PI3K/AKT in response to TGF\u3b21 and S100A8/A9, which also induced cell migration. Chronic EGF exposure enhanced cell migration of both BxPC3 and BxPC3-SMAD4+, rendering the cells less sensitive to the other inflammatory stimuli. In conclusion, SMAD4 HD is associated with the constitutive activation of the ERK and Wnt/\u3b2-catenin signalling pathways, and favors the EGF-induced activation of multiple signalling pathways critical to cancer proliferation and invasion. TGF\u3b21 and S100A8/A9 mainly inhibit NF-\u3baB and PI3K/AKT pathways and, when combined, sinergize with EGF in enhancing anti-apoptotic p-BAD in a SMAD4-dependent manner

Ubiquitous distribution and different subcellular localization of sorbitol dehydrogenase in fruit and leaf of apple

NAD+-dependent sorbitol dehydrogenase (NAD-SDH, EC 1.1.1.14), a key enzyme in sorbitol metabolism, plays an important role in regulating sink strength and determining the quality of apple fruit. Understanding the tissue and subcellular localization of NAD-SDH is helpful for understanding sorbitol metabolism in the apple. In this study, two NAD-SDH cDNA sequences were isolated from apple fruits (Malus domestica Borkh cv. Starkrimson) and named MdSDH5 and MdSDH6. Immunohistochemical analysis revealed that NAD-SDH is distributed in both the flesh and the vascular tissue of the fruit, and the vascular tissue and mesophyll tissue in the young and old leaves, indicating that it is a ubiquitous protein expressed in both sink and source organs. Immunogold electron microscopy analysis demonstrated that NAD-SDH is localized mainly in the cytoplasm and chloroplast of the fruit and leaves. The chloroplast localization of NAD-SDH was confirmed by the transient expression of MdSDH5-GFP and MdSDH6-GFP in the mesophyll protoplast of Arabidopsis. NAD-SDH was also found in electron opaque deposits of vacuoles in young and mature leaves. These data show that NAD-SDH has different subcellular localizations in fruit and leaves, indicating that it might play a different role in sorbitol metabolism in different tissues of apple

High prevalence of subclass-specific binding and neutralizing antibodies against Clostridium difficile toxins in adult cystic fibrosis sera: possible mode of immunoprotection against symptomatic C. difficile infection

Objectives: Despite multiple risk factors and a high rate of colonization for Clostridium difficile, the occurrence of C. difficile infection in patients with cystic fibrosis is rare. The aim of this study was to compare the prevalence of binding C. difficile toxin-specific immunoglobulin (Ig)A, IgG and anti-toxin neutralizing antibodies in the sera of adults with cystic fibrosis, symptomatic C. difficile infection (without cystic fibrosis) and healthy controls. Methods: Subclass-specific IgA and IgG responses to highly purified whole C. difficile toxins A and B (toxinotype 0, strain VPI 10463, ribotype 087), toxin B from a C. difficile toxin-B only expressing strain (CCUG 20309) and precursor form of B fragment of binary toxin, pCDTb, were determined by protein microarray. Neutralizing antibodies to C. difficile toxins A and B were evaluated using a Caco-2 cell-based neutralization assay. Results: Serum IgA anti-toxin A and B levels and neutralizing antibodies against toxin A were significantly higher in adult cystic fibrosis patients (n=16) compared with healthy controls (n=17) and patients with symptomatic C. difficile infection (n=16); p≤0.05. The same pattern of response prevailed for IgG, except that there was no difference in anti-toxin A IgG levels between the groups. Compared with healthy controls (toxins A and B) and patients with C. difficile infection (toxin A), sera from cystic fibrosis patients exhibited significantly stronger protective anti-toxin neutralizing antibody responses. Conclusion: A superior ability to generate robust humoral immunity to C. difficile toxins in the cystic fibrosis population is likely to confer protection against symptomatic C. difficile infection. This protection may be lost in the post-transplantation setting, where sera-monitoring of anti-C. difficile toxin antibody titers may be of clinical value

"Speed Control of a 3-Phase Induction Motor Based on Robust Optimal Preview Control Theory"

A synthesized method for speed control of a threephase induction motor (IM) based on optimal preview control systemtheory is implemented in this article. An IM model comprisesthree-input variables and three-output variables that coincidewith the synchronous reference frame that is implemented usingthe vector method. The input variables of this model are the stator angular frequency and the two components of the stator spacevoltage vector, whereas the output variables are the rotor angular speed and the two components of the stator space flux linkage. The objective of the synthesized control system is to achieve motor speed control, field orientation control, and constant flux control. A novel error system is derived and introduced into the control law to increase the robustness of the system. The preview feed-forward controller, which includes the desired and disturbance signals, is used to improve the transient response of the system. A space vector pulse-width modulation (PWM) control technique for voltage source-fed IM is prepared for microprocessor-based control. Spectral analysis of the output voltage is evaluated to predict the effect of the proposed space vector modulation technique on the dynamic performance of the IM. The optimal preview controlled system is implemented, and its applicability and robustness are demonstrated by computer simulation and experimental results