The Toxicity and Therapeutic Efficacy of Mefenamic Acid and its Hydroxyethyl Ester in Mice: In Vivo Comparative Study: A promising Drug Derivative

الخلفية العلمية: يتميز هيدروكسي إيثيل إستر حمض الميفيناميك، وهو أحد المشتقات غير التجارية من حمض الميفيناميك، بخصائص مقاومة ضد التحلل الإنزيمي في المحاليل المنظمة المختلفة وكذلك في بلازما الدم. وبالرغم من ذلك، لا تتوفر دراسات توضح التأثيرات البيولوجية لهذا المركب داخل الجسم الحي. يقدم هذا البحث دراسة حول التأثيرات العلاجية لهذا المركب وسميته داخل جسم الكائن الحي مقارنة مع حمض الميفينامك الشبيه له في التركيب الكيميائي. منهجية البحث: تم تقييم السمية الحادة لمركب هيدروكسي إيثيل إستر حمض الميفيناميك ومقارنتها مع سمية حمض الميفينامك من خلال حقن جرعات مكافئة في مجموعات من فئران التجارب ورصد القياسات التالية: نسبة حدوث الإغماء التخشبي، درجة (شدة) نوبت الصرع، نسبة حدوث النوبة التوترية الرمعية، نسبة الوفيات، درجة (مقياس) التجهم والنشاط الحركي. إضافة إلى ذلك، تم تقيم التأثير المضاد للالتهابات لهذا المركب من خلال فحص وذمة القدم التي يسببها الكارجينان وتقييم التأثير المضاد للألم باستخدام فحص التلوي الذي يسببه حمض الخليك في الفئران. النتائج: أظهرت الفئران المعالجة بمركب هيدروكسي إيثيل إستر حمض الميفيناميك أن نسبة حدوث كل من الإغماء التخشبي والنوبة التوترية الرمعية والوفيات بالإضافة إلى درجة (مقياس) الصرع والتجهم كانت أقل منها في الفئران التي عولجت بجرعات مكافئة من حمض الميفينامك. كما أظهرت النتائج أن العلاج بمركب هيدروكسي إيثيل إستر حمض الميفيناميك سبب نشاط مضاد للالتهابات مكافئ لنشاط حمض الميفيناميك في فحص وذمة القدم التي يسببها الكارجينان. كذلك أظهر العلاج بمركب هيدروكسي إيثيل إستر حمض الميفيناميك نشاط مضاد للألم فاق نشاط حمض الميفيناميك في تجربة التلوي الذي يسببه حمض الخليك في الفئران. الاستنتاج: تدل نتائج البحث على مقدرة هيدروكسي ايثل استر حمض الميفينامك على احداث نشاط علاجي اعلى من نشاط حمض الميفيناميك وتأثيرات جانبية أقل على الوظائف العصبية والعضلية.Background: Hydroxyethyl Ester of Mefenamic acid (HEMA), which is an available derivative of mefenamic acid (MFA) in the literature, was shown to exert a strong resistance to enzymatic hydrolysis in various buffer solutions as well as in the plasma. However, there are no studies yet that investigate the biological effects of HEMA as a possible active drug in-vivo. This study provides an in-vivo investigation of the efficacy and toxicity of HEMA in comparison to those of a related drug, MFA, that has a similar chemical structure. Methods: Acute toxicity evaluations were conducted in various groups of mice following administration of high equimolar doses of HEMA and MFA and were measured at various parameters including the percentage of catalepsy, seizure score, percentage of clonic-tonic seizure and death, grimace scale score (GSS) and locomotor activity. In addition, the anti-inflammatory and anti-nociceptive effects of HEMA were evaluated in the carrageenan-induced paw edema test and acetic acid-induced writhing test, respectively. Results: The findings of this study revealed that the percentage of catalepsy, clonic-tonic seizure and death as well as seizure and grimace scale scores were lower in mice treated with HEMA than those treated with equimolar doses of MFA. In addition, treatment with HEMA caused a comparable anti-inflammatory activity in the carrageenan-induced paw edema test and a significantly (p<0.05) higher anti-nociceptive effect in the acetic acid-induced writhing test than that of MFA. Conclusion: Results obtained from this study may indicate that HEMA has superior therapeutic advantages for the management of acute and inflammatory events with a less potential risk of neuromuscular adverse effects

Anxiolytic Effect of Ethanolic Extract of Medjool Dates of Phoenix Dactylifera in Mice

الخلفية: القلق هو أحد الاضطرابات النفسية الأكثر شيوعًا، حيث يصيب 33.7٪ من عامة السكان. ومع ذلك، فقد وجد أن استهلاك الأنظمة الغذائية الصحية يساعد، على الأقل جزئيًا، في الوقاية من الاضطرابات الشبيهة بالقلق وعلاجها. الطرق البحثية: في هذه الدراسة، تم تقييم سلوكيات القلق لدى الفئران التي تعرضت للتناول المزمن لجرعات منخفضة وعالية من المستخلص الكحولي لتمور المجهول (Phoenix Dactylifera) مقارنة بنظيراتها من الفئران الضابطة التي لم تتناول التمر. تم استخدام اختبار ارتفاع متاهة الصفر واختبار دفن كرات الرخام كنماذج مفضلة لتقييم سلوكيات القلق لدى هذه الفئران. بالإضافة إلى ذلك، تم إجراء تحليل كيميائي نباتي لمجموعات الأيض الثانوية الرئيسية لمستخلص تمر المجهول. النتائج: بينت نتائج هذه الدراسة أن مستخلص تمر المحهول غني بالفلافونويد والستيرويدات مع نشاط معروف باسم مزيلات القلق مثل الكايمفيرول. أظهرت الفئران التي تلقت جرعة منخفضة (300 مجم / كجم) من المستخلص قلقًا أقل من خلال استخدام اختبار ارتفاع متاهة الصفر من الفئران التي لم تتناول مستخلص التمر، والذي تم تحديده من خلال زيادة كبيرة في زمن الوصول إلى المنطقة المغلقة و انخفاض كبير في الوقت الذي يقضيه في المنطقة المغلقة و أيضا زيادة كبيرة في عدد الإدخالات إلى الأرباع المفتوحة. كان تأثير مزيل القلق لمستخلص التمر من الجرعة المنخفضة مشابهًا للتأثير الناتج في الفئران التي عولجت بالديازيبام (1.5 مجم / كجم) في جميع المتغيرات المختبرة  الدالة على مستوى القلق. باللإضافة إلى ما سبق، أظهرت نتائج اختبار دفن كرات الرخام فرقا احصائيا في إزالة القلق بجرعة منخفضة (300 مجم / كجم) من مستخلص التمر مقارنة بالفئران التي لم تتناول مستخلص التمر، والذي تبيين من خلال إنخفاض في العدد الإجمالي لكرات الرخام المدفون. إضافة إلى ذلك، كان التأثير المزيل للقلق لمستخلص التمر من الجرعة المنخفضة في اختبار دفن كرات الرخام مشابهًا للتأثير الناتج في الفئران التي عولجت بفلوكستين (5 مجم / كجم). من ناحية أخرى، فإن تناول جرعات عالية من مستخلص التمر (2583 مجم / كجم) لم يسبب أي تأثير مزيل للقلق في متاهة الصفر المرتفعة واختبارات دفن كرات الرخام.  الاستنتاجات: بشكل عام، تشيرالنتائج هذه الدراسة إلى أن تناول جرعة منخفضة بانتظام من المستخلص الكحولي من التمر المجهول قد يساعد في منع وإدارة اضطرابات القلق. ومع ذلك، يوصى بإجراء مزيد من الدراسات لتوضيح الآلية المفترضة الكامنة وراء التأثير المزيل للقلق لدى تمر المجهول.Background: Anxiety is one of the most frequent psychiatric disorders, affecting 33.7% of the general population. However, the consumption of healthy diets has been found to help, at least in part, in the prevention and treatment of anxiety-like disorders. Methods: In this study, the anxiety behaviors of mice subjected to chronic intake of low-and high doses of ethanolic extract of Medjool dates (Phoenix Dactylifera) were evaluated in comparison to the counterparts of control mice. The elevated zero maze (EZM) test and marbles burying test were used as models of choice for evaluating anxiety behaviors in these mice. In addition, aphytochemical analysis of major secondary metabolite groups was done. Results: The findings of this study revealed that the ethanolic extract of dates is rich in flavonoids and steroids with known activity as anxiolytics, such as kaempherol. Mice received a low dose (300 mg/kg) of the extract exhibited lower anxiety in the EZM than the untreated mice (negative control), which was determined by a significant increase in the latency to the closed area, a significant decrease in the time spent in the closed area and a significant increase in the number of the entries to the open quadrants. The anxiolytic effect of low dose extract was comparable to that produced in positive control mice treated with diazepam (1.5 mg/kg, i.p) in all tested parameters. Data obtained from the marble burying test also showed a significant anxiolytic effect by low dose (300 mg/kg) of the extract as compared to untreated mice, which was manifested by significant decrease in the total number of buried marbles. The anxiolytic effect of low dose extract in the marbles burying test was comparable to that produced in counterparts of positive control mice treated with fluoxetine (5mg/kg, i.p). On the other hand, chronic intake of high doses (2583 mg/kg) of the extract did not cause any significant anxiolytic effect in the EZM and marbles burying tests. Conclusions: Overall, these results indicate that regular intake of low dose of ethanolic extract of Medjool dates may help to prevent and manage anxiety disorders. However, further studies are recommended to elucidate the putative mechanism underlying the anxiolytic effect of these dates

The Influence of Body Mass Index on the Outcomes of Video-assisted Thoracoscopic Sympathectomy for Primary Hyperhidrosis Patients

Background: Primary hyperhidrosis (PH) is an autonomic disorder described as having excessive sweating in greater amounts than physiologically needed for thermoregulation. The aim of this retrospective study is to investigate the effect of body mass index (BMI) on surgical outcomes of bilateral video-assisted thoracoscopic sympathectomy (VATS) for PH patients from Arabian ethnic group. Methods: Between January 2009 and December 2018, a total of 79 patients underwent VATS as a treatment for PH at Jordan University Hospital. Postoperative assessment was done via patients’ subjective reporting of their satisfaction with the outcome of performed procedure. Results: The mean age of the studied population was 23.2 ± 4.5 years, of which 34 (43%) were males and 45 (57%) were females. Satisfaction with the outcome of VATS was significantly associated with having dry palms as a desirable outcome (p < 0.001), and with older age (p = 0.002). BMI was neither significantly associated with their satisfaction (p = 0.128), nor with compensatory hyperhidrosis (CH) (p= 0.859).Conclusion: VATS is considered an effective treatment for PH, with high rates of patient’s satisfaction. Neither the level of satisfaction nor the occurrence of CH was associated with patients’ BMI

Reconstruction of primary vertices at the ATLAS experiment in Run 1 proton–proton collisions at the LHC

This paper presents the method and performance of primary vertex reconstruction in proton–proton collision data recorded by the ATLAS experiment during Run 1 of the LHC. The studies presented focus on data taken during 2012 at a centre-of-mass energy of √s=8 TeV. The performance has been measured as a function of the number of interactions per bunch crossing over a wide range, from one to seventy. The measurement of the position and size of the luminous region and its use as a constraint to improve the primary vertex resolution are discussed. A longitudinal vertex position resolution of about 30μm is achieved for events with high multiplicity of reconstructed tracks. The transverse position resolution is better than 20μm and is dominated by the precision on the size of the luminous region. An analytical model is proposed to describe the primary vertex reconstruction efficiency as a function of the number of interactions per bunch crossing and of the longitudinal size of the luminous region. Agreement between the data and the predictions of this model is better than 3% up to seventy interactions per bunch crossing

RBM6 splicing factor promotes homologous recombination repair of double-strand breaks and modulates sensitivity to chemotherapeutic drugs

RNA-binding proteins regulate mRNA processing and translation and are often aberrantly expressed in cancer. The RNA-binding motif protein 6, RBM6, is a known alternative splicing factor that harbors tumor suppressor activity and is frequently mutated in human cancer. Here, we identify RBM6 as a novel regulator of homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Mechanistically, we show that RBM6 regulates alternative splicing-coupled nonstop-decay of a positive HR regulator, Fe65/APBB1. RBM6 knockdown leads to a severe reduction in Fe65 protein levels and consequently impairs HR of DSBs. Accordingly, RBM6-deficient cancer cells are vulnerable to ATM and PARP inhibition and show remarkable sensitivity to cisplatin. Concordantly, cisplatin administration inhibits the growth of breast tumor devoid of RBM6 in mouse xenograft model. Furthermore, we observe that RBM6 protein is significantly lost in metastatic breast tumors compared with primary tumors, thus suggesting RBM6 as a potential therapeutic target of advanced breast cancer. Collectively, our results elucidate the link between the multifaceted roles of RBM6 in regulating alternative splicing and HR of DSBs that may contribute to tumorigenesis, and pave the way for new avenues of therapy for RBM6-deficient tumors

A Lightweight and Efficient Digital Image Encryption Using Hybrid Chaotic Systems for Wireless Network Applications

Due to limited processing capabilities and other constraints of most wireless networks, many existing security algorithms do not consider the network efficiency. This is because most of these security solutions exhibit intolerable overhead and consider only securing scalar data, which are not suitable for other data types such as digital images, hence affecting the provided security level and network performance. Thus, in this paper, we propose a lightweight and efficient security scheme based on chaotic algorithms to efficiently encrypt digital images. Our proposed algorithm handles digital images in two phases: Firstly, digital images are split into blocks and compressed by processing them in frequency domain instead of Red-Green-Blue (RGB) domain. The ultimate goal is to reduce their sizes to speed up the encryption process and to break the correlation among image pixel values. Secondly, 2D Logistic chaotic map is deployed in key generation, permutation, and substitution stages for image pixel shuffling and transposition. In addition, 2D Henon chaotic map is deployed to change the pixel values in the diffusion stage in order to enhance the required level of security and resist various security attacks. Security performance analysis based on standard test images shows that our proposed scheme overcomes the performance of other existing techniques

Head and pelvis are the key segments recruited by adult spinal deformity patients during daily life activities

Functional assessment is a key element in evaluating adult spinal deformity (ASD) patients. The multitude of 3D kinematic parameters provided by movement analysis can be confusing for spine surgeons. The aim was to investigate movement patterns of ASD based on key kinematic parameters. 115 primary ASD and 36 controls underwent biplanar radiographs and 3D movement analysis during walking, sit-to-stand and stair ascent to calculate joint and segment kinematics. Principal component analysis was applied to identify the most relevant kinematic parameters that define movement strategies adopted by ASD. Pelvis and head relative to pelvis kinematics were the most relevant parameters. ASD patients adopted four different movement strategies. Class 1: normative head and pelvis kinematics. Class 2: persistent pelvic backward tilt. Class 3: persistent forward shift of the head. Class 4: both pelvic backward tilt and forward shift of the head. Patients in class 3 and 4 presented sagittal malalignment on static radiographs with increased pelvic tilt, pelvic incidence-lumbar lordosis mismatch and sagittal vertical axis. Surprisingly, patients in class 3 had normal pelvic kinematics during movement, showing the importance of functional evaluation. In addition to being key segments in maintaining static global posture, head and pelvis were found to define movement patterns

Kinematic adaptations from self-selected to fast speed walking in patients with adult spinal deformity

Purpose To investigate kinematic adaptations from self-selected to fast speed walking in ASD patients. Methods 115 primary ASD and 66 controls underwent biplanar radiographic X-rays and 3D gait analysis to calculate trunk, segmental spine and lower limb kinematics during self-selected and fast speed walking. Kinematic adaptation was calculated as the difference (Δ) between fast and self-selected speed walking. ASD with 7 or more limited kinematic adaptation parameters were classified as ASD-limited-KA, while those with less than 7 limited kinematic adaptation parameters were classified as ASD-mild-KA. Results 25 patients were classified as ASD-limited-KA and 90 as ASD-mild-KA. ASD-limited-KA patients walked with a lesser increase of pelvic rotation (Δ = 1.7 vs 5.5°), sagittal hip movement (Δ = 3.1 vs 7.4°) and shoulder–pelvis axial rotation (Δ = 3.4 vs 6.4°) compared to controls (all p < 0.05). ASD-limited-KA had an increased SVA (60.6 vs − 5.7 mm), PT (23.7 vs 11.9°), PI–LL (9.7 vs − 11.7°), knee flexion (9.2 vs − 0.4°) and a decreased LL (44.0 vs 61.4°) compared to controls (all p < 0.05). Kinematic and radiographic alterations were less pronounced in ASD-mild-KA. The limited increase of walking speed was correlated to the deteriorated physical component summary score of SF-36 (r = 0.37). Discussion Kinematic limitations during adaptation from self-selected to fast speed walking highlight an alteration of a daily life activity in ASD patients. ASD with limited kinematic adaptations showed more severe sagittal malalignment with an increased SVA, PT, PI–LL, and knee flexion, a decreased LL and the most deteriorated quality of life. This highlights the importance of 3D movement analysis in the evaluation of ASD

Kinematic limitations during stair ascent and descent in patients with adult spinal deformity

Background: Adults with spinal deformity (ASD) are known to have spinal malalignment, which can impact their quality of life and their autonomy in daily life activities. Among these tasks, ascending and descending stairs is a common activity of daily life that might be affected. Research question: What are the main kinematic alterations in ASD during stair ascent and descent? Methods: 112 primary ASD patients and 34 controls filled HRQoL questionnaires and underwent biplanar X-from which spino-pelvic radiographic parameters were calculated. Patients were divided into 3 groups: 44 with sagittal malalignment (ASD-Sag: PT > 25°, SVA>5 cm or PI-LL>10°), 42 with isolated thoracic hyperkyphosis (ASD-HyperTK: TK > 60°), 26 with isolated frontal spine deformity (ASD-Front: Cobb>20°). All participants underwent 3D motion analysis of the whole body while ascending and descending a stair step from which kinematic waveforms were extracted. Results: During stair ascent, ASD-Sag exhibited an increased thorax flexion (20 vs 5°), a decreased lumbar lordosis L1L3-L3L5 (7 vs 14°), and an increased ROM of lumbo-pelvic joint (15 vs 10°, all p < 0.05), compared to controls. Similar compensations were shown while descending the stairstep. ASD-HyperTK had similar kinematic limitations as ASD-Sag but to a lesser extent. ASD-Front had normal kinematic patterns. PCS-SF36 correlated to thorax flexion (r = -0.45) and ODI was correlated to pelvic tilt ROM (r = 0.46). Discussion and conclusion: ASD subjects with sagittal malalignment tend to ascend and descend stairs with increased thorax flexion, making them more prone to falls. Compensation mechanisms occur at the head and lumbo-pelvic levels to maintain balance and avoid falling forward

Functional assessment using 3D movement analysis can better predict health-related quality of life outcomes in patients with adult spinal deformity: a machine learning approach

IntroductionAdult spinal deformity (ASD) is classically evaluated by health-related quality of life (HRQoL) questionnaires and static radiographic spino-pelvic and global alignment parameters. Recently, 3D movement analysis (3DMA) was used for functional assessment of ASD to objectively quantify patient's independence during daily life activities. The aim of this study was to determine the role of both static and functional assessments in the prediction of HRQoL outcomes using machine learning methods.MethodsASD patients and controls underwent full-body biplanar low-dose x-rays with 3D reconstruction of skeletal segment as well as 3DMA of gait and filled HRQoL questionnaires: SF-36 physical and mental components (PCS&amp;MCS), Oswestry Disability Index (ODI), Beck's Depression Inventory (BDI), and visual analog scale (VAS) for pain. A random forest machine learning (ML) model was used to predict HRQoL outcomes based on three simulations: (1) radiographic, (2) kinematic, (3) both radiographic and kinematic parameters. Accuracy of prediction and RMSE of the model were evaluated using 10-fold cross validation in each simulation and compared between simulations. The model was also used to investigate the possibility of predicting HRQoL outcomes in ASD after treatment.ResultsIn total, 173 primary ASD and 57 controls were enrolled; 30 ASD were followed-up after surgical or medical treatment. The first ML simulation had a median accuracy of 83.4%. The second simulation had a median accuracy of 84.7%. The third simulation had a median accuracy of 87%. Simulations 2 and 3 had comparable accuracies of prediction for all HRQoL outcomes and higher predictions compared to Simulation 1 (i.e., accuracy for PCS = 85 ± 5 vs. 88.4 ± 4 and 89.7% ± 4%, for MCS = 83.7 ± 8.3 vs. 86.3 ± 5.6 and 87.7% ± 6.8% for simulations 1, 2 and 3 resp., p &lt; 0.05). Similar results were reported when the 3 simulations were tested on ASD after treatment.DiscussionThis study showed that kinematic parameters can better predict HRQoL outcomes than stand-alone classical radiographic parameters, not only for physical but also for mental scores. Moreover, 3DMA was shown to be a good predictive of HRQoL outcomes for ASD follow-up after medical or surgical treatment. Thus, the assessment of ASD patients should no longer rely on radiographs alone but on movement analysis as well