The Effects of a Novel Therapeutic Intervention in Diabetic Peripheral Neuropathy Patients

Diabetes mellitus (DM) is a common disorder affecting individuals in the United States and in the world. The prevalence of DM has increased noticeably over the last three decades with an estimated 380 million people currently diagnosed with this disease. DM is associated with numerous systemic complications that affect the retina, heart, brain, kidneys, and nerves. The most common complication of DM is diabetic peripheral neuropathy. Diabetic peripheral neuropathy causes reduced sensation, reflexes, proprioception, and strength in lower limbs that leads to balance problems. Various manual therapy techniques have not approached a pilot study for the efficacy of a manual therapy technique to evaluate symptom alleviation in patients with diabetic peripheral neuropathy in order to improve balance. The purpose of this study is to look at the impact of a novel intervention called Intraneual facilitation (INF) on objective static, objective dynamic, subjective balance measures, and a peripheral neuropathy scale in patients with Diabetic Peripheral Neuropathy (DPN). Balance will be assessed using VSR Computerized Dynamic Posturography Sensory Organization Test (SOT, objective static balance measure), VSR Computerized Dynamic Posturography Limits of Stability (LOS, objective dynamic balance measure), and Activities-Specific Confidence in Balance Scale (ABC, subjective balance measure) and neuropathy will be assessed using modified total neuropathy scale (mTNS). Evaluation will be conducted at baseline (pre intervention) and (post intervention). The results of this study showed hat subjects showed significant improvement in the SOT, one component in the LOS (movement velocity, MVL), and mTNS (P \u3c .05). In conclusion, intraneural facilitation improved objective balance measures and neuropathy symptoms in patients with diabetic peripheral neuropathy. Further study is needed to determine long-term benefits of this intervention

ASSESSMENT OF THE QUALITY OF OUTPATIENT PRESCRIPTIONS FROM VARIOUS CLINICAL SETTING IN A TERTIARY HOSPITAL, SAUDI ARABIA

Objective: The quality of prescribing influences, to a large extent, the health outcomes of patients as errors made could result in adverse drug reactions.The aim of this study is to assess determine the quality of outpatient prescriptions in various clinical settings in Aseer region, Kingdom of Saudi Arabia.Methods: An observational, cross-sectional descriptive study was carried out in various community pharmacies where the prescriptions receivedwere analyzed for their quality.Results: The prescriptions were checked for the completeness of the patients’ biodata (name, age, sex, and hospital number), categories of drugs,prescribing by generic name, legibility of prescriber’s writing, the name, and signature of the prescriber. Two hundred and fifty prescriptions werecollected and used for analysis. A significant number of the prescriptions were written in illegible (26%) handwriting. The name (15%), age (48%),and sex (46%) of the patient were not mentioned in the majority of the prescriptions. Most of the prescriptions (94%) failed to demonstrate thepresence of address, height, and weight of the patient. Brand name of the drugs was mentioned in all the prescriptions, with only 17% of them havingthe generic name. The doctor’s name, signature was present in 81% and 70% of the prescription, respectively.Conclusion: Study shows that there is a need for improvement in the quality of prescription written by doctors. The adoption of a computer-aidedprescribing system in an outpatient setting would go a long way in achieving this objective

In vivo neurological assessment of sedative hypnotic effect of Coriandrum sativum L. seeds in mice.

ABSTRACTEthnopharmacological relevance: seeds of Coriandrum sativum L. have been used in the traditional medicine to relieve stress and other neurological disease conditions.Aim of the study: The present study was under taken to evaluate the sedative hypnotic response of ethanolic extract of seeds of Coriandrum sativum L. (CSEE) in mice.Materials and methods: seeds of Coriandrum sativum L. Ethanolic extract was screened for sedative hypnotic response by using potentiation of Pentobarbital sleeping time at doses of 100mg/kg, 150mg/kg and 200 mg/kg. Saline and Pentobarbital sodium were employed as negative and positive control groups, respectively.Results: Ethanol extract increases Pentobarbital sodium induced sleeping time at dose of 100 mg/kg, 150 mg/kg and 200 mg/kg by 106 %, 111 % and 114% respectively as compared to negative control group and by 06 %, 11% & 14% respectively as compared to positive control group Conclusion: from present study finding it is found that seeds of Coriandrum sativum L. potentiate the sedative hypnotic efficacy in mice.

Balancing Functional Tradeoffs between Protein Stability and ACE2 Binding in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB Lineages: Dynamics-Based Network Models Reveal Epistatic Effects Modulating Compensatory Dynamic and Energetic Changes

Evolutionary and functional studies suggested that the emergence of the Omicron variants can be determined by multiple fitness trade-offs including the immune escape, binding affinity for ACE2, conformational plasticity, protein stability and allosteric modulation. In this study, we systematically characterize conformational dynamics, structural stability and binding affinities of the SARS-CoV-2 Spike Omicron complexes with the host receptor ACE2 for BA.2, BA.2.75, XBB.1 and XBB.1.5 variants. We combined multiscale molecular simulations and dynamic analysis of allosteric interactions together with the ensemble-based mutational scanning of the protein residues and network modeling of epistatic interactions. This multifaceted computational study characterized molecular mechanisms and identified energetic hotspots that can mediate the predicted increased stability and the enhanced binding affinity of the BA.2.75 and XBB.1.5 complexes. The results suggested a mechanism driven by the stability hotspots and a spatially localized group of the Omicron binding affinity centers, while allowing for functionally beneficial neutral Omicron mutations in other binding interface positions. A network-based community model for the analysis of epistatic contributions in the Omicron complexes is proposed revealing the key role of the binding hotspots R498 and Y501 in mediating community-based epistatic couplings with other Omicron sites and allowing for compensatory dynamics and binding energetic changes. The results also showed that mutations in the convergent evolutionary hotspot F486 can modulate not only local interactions but also rewire the global network of local communities in this region allowing the F486P mutation to restore both the stability and binding affinity of the XBB.1.5 variant which may explain the growth advantages over the XBB.1 variant. The results of this study are consistent with a broad range of functional studies rationalizing functional roles of the Omicron mutation sites that form a coordinated network of hotspots enabling a balance of multiple fitness tradeoffs and shaping up a complex functional landscape of virus transmissibility

Subspace Identification of a Glucose-Insulin model Using Meal Tracer Protocol Measurements

In this study, the problem of identifying a low complexity state space model describing glucose and insulin dynamics from low sample meal tracer experiments is investigated. Triple tracer meal protocol measurements (sampled as low as 15 samples per meal) together with continuous glucose monitoring measurements, measured concurrently at a rate of 5 minutes per sample, are used. A new formulation to estimate the missing input and output measurements at such low sample rates is developed. Nuclear norm minimization is used to exploit low rankness of the stacked input and output matrix, while the {ell1} norm is used to exploit an available sparse basis for the glucose flux profiles. Simulation results, using the UVa Padova simulator, show that the technique outperforms previous methods and also demonstrate the possibility of identifying state space models from triple tracer measurements with good prediction performance under non-ideal conditions

Exploring Conformational Landscapes and Cryptic Binding Pockets in Distinct Functional States of the SARS-CoV-2 Omicron BA.1 and BA.2 Trimers: Mutation-Induced Modulation of Protein Dynamics and Network-Guided Prediction of Variant-Specific Allosteric Binding Sites

A significant body of experimental structures of SARS-CoV-2 spike trimers for the BA.1 and BA.2 variants revealed a considerable plasticity of the spike protein and the emergence of druggable binding pockets. Understanding the interplay of conformational dynamics changes induced by the Omicron variants and the identification of cryptic dynamic binding pockets in the S protein is of paramount importance as exploring broad-spectrum antiviral agents to combat the emerging variants is imperative. In the current study, we explore conformational landscapes and characterize the universe of binding pockets in multiple open and closed functional spike states of the BA.1 and BA.2 Omicron variants. By using a combination of atomistic simulations, a dynamics network analysis, and an allostery-guided network screening of binding pockets in the conformational ensembles of the BA.1 and BA.2 spike conformations, we identified all experimentally known allosteric sites and discovered significant variant-specific differences in the distribution of binding sites in the BA.1 and BA.2 trimers. This study provided a structural characterization of the predicted cryptic pockets and captured the experimentally known allosteric sites, revealing the critical role of conformational plasticity in modulating the distribution and cross-talk between functional binding sites. We found that mutational and dynamic changes in the BA.1 variant can induce the remodeling and stabilization of a known druggable pocket in the N-terminal domain, while this pocket is drastically altered and may no longer be available for ligand binding in the BA.2 variant. Our results predicted the experimentally known allosteric site in the receptor-binding domain that remains stable and ranks as the most favorable site in the conformational ensembles of the BA.2 variant but could become fragmented and less probable in BA.1 conformations. We also uncovered several cryptic pockets formed at the inter-domain and inter-protomer interface, including functional regions of the S2 subunit and stem helix region, which are consistent with the known role of pocket residues in modulating conformational transitions and antibody recognition. The results of this study are particularly significant for understanding the dynamic and network features of the universe of available binding pockets in spike proteins, as well as the effects of the Omicron-variant-specific modulation of preferential druggable pockets. The exploration of predicted druggable sites can present a new and previously underappreciated opportunity for therapeutic interventions for Omicron variants through the conformation-selective and variant-specific targeting of functional sites involved in allosteric changes

Medication errors in a health care facility in southern Saudi Arabia

Purpose: To identify medication errors at Aseer Central Hospital (ACH, Abha) in the southern province of Saudi Arabia. Methods: A cross-sectional retrospective study was conducted by reviewing adult patients’ records (> 15 years old) at ACH’s inpatient and outpatients settings over an 8-week period in October and November 2015. Results: We identified 113 medication errors, including 112 prescribing errors and 1 dispensing error. Most medication errors (91.2 %) in this study were for inpatient prescriptions. The most common prescribing error was medication duplication (31.2 %) followed by missing patient identifying information (25 %). Conclusion: Medication errors, mainly in inpatient prescriptions, have been fully identified at ACH. Educational interventions such as workshops could help minimize and prevent medication errors

Investigating novel platelet immunoreceptor ‘CEACAM2’ in contact-dependent events that modulate platelet thrombus formation

CVD is the general term for a class of heart diseases involving heart and blood vessels. Whilst the term commonly refers to any form of disorder affecting the cardiovascular system, it is most typically linked to atherosclerosis. The mortality rates for CVD have increased in the past few years within high-income countries and it is now the leading cause of death in the Western world [5]. Thrombi are formed in response to damage to the endothelial lining of the blood vessels, which causes platelets to clump together and activate at the site of damage. In the pathological sequelae of atherosclerosis, rupture of collagen-rich plaques leads to in vivo platelet activation, adhesion and thrombus formation. In a physiological context, Ig-ITIM superfamily members negatively regulate the initial phase of contact-dependent events involving platelet-collagen GPVI interactions, thereby limiting the in vivo growth of thrombi. Few examples of naturally occurring inhibitors of platelet-collagen interactions have been described [6]. Prostacyclin and nitrous oxide (NO) are natural inhibitors released from the endothelium [7], while Ig-ITIM members appear to be the first identified natural inhibitors that serve an autoregulatory role when platelets come into contact with each other following exposure to collagen [8]. Carcinoembryonic antigen-related cell adhesion molecule-2 (CEACAM2) is a cell surface glycoprotein expressed on blood, epithelial and vascular cells. CEACAM2 possesses adhesive and signalling properties mediated by immunoreceptor tyrosine-based inhibitory motifs. In this study, we demonstrate that CEACAM2 is expressed on the surface and in intracellular pools of platelets. Functional studies of platelets from Ceacam2–/– deficient mice (Cc2–/–) revealed that CEACAM2 serves to negatively regulate collagen GPVI-FcRγ–chain and the C-type lectin-like receptor 2 (CLEC-2) signalling. Cc2–/– platelets displayed enhanced GPVI and CLEC-2-selective ligands, collagen related peptide (CRP), collagen and rhodocytin (Rhod)-mediated platelet aggregation. They also exhibited increased adhesion on type I collagen, and hyper-responsive CRP and CLEC-2-induced alpha and dense granule release compared to wild-type platelets. Furthermore, using intravital microscopy to ferric chloride (FeCl3) injured mesenteric arterioles and laser induced injury of cremaster muscle arterioles, we herein show that thrombi formed in Cc2–/– mice were larger and more stable than wild-type controls in vivo. Thus, CEACAM2 is a novel platelet immunoreceptor that acts as a negative regulator of platelet GPVI-collagen interactions and of ITAM receptor CLEC-2 pathways. Previous studies have implicated that the Ig-ITIM superfamily member, CEACAM1 may regulate integrin function. As CEACAM2 is the twin of CEACAM1, it is possible that CEACAM2 may also have a physiologic role in integrin aIIbb3-mediated platelet function. In this project, we investigated the functional importance of CEACAM2 in murine platelets. Using Ceacam2-deficient mice, we showed that they have prolonged tail bleeding times and volume of blood lost. Cc2–/– platelets have moderate integrin aIIbb3 mediated functional defects with impaired kinetics of platelet spreading on fibrinogen and type I collagen and delayed kinetics in retraction of fibrin clots in vitro. This functional integrin aIIbb3 defect could not be attributed to altered integrin aIIbb3 expression. Cc2–/– platelets displayed normal ‘inside-out’ signalling properties as demonstrated by normal agonist-induced binding of soluble FITC-fibrinogen and JON/A antibody binding. This project provides direct evidence that CEACAM2 is essential for normal integrin aIIbb3-mediated platelet function and that disruption of mouse CEACAM2 induced a moderate integrin aIIbb3-mediated platelet functional defects