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To overcome critical size bone defects, calcium phosphate (CaP)-based ceramics have been widely explored. The compositional similarity with bone matrix and degradability are the main reasons for their selection in orthopaedic biomaterials. However, the low solubility rate under in vivo conditions raises concerns about these CaP groups, particularly hydroxyapatite (HA) and tricalcium phosphate (TCP) ceramics. Therefore, reliable and suitable degradable ceramics for bone defect repair are always an important research direction for researchers. The magnesium phosphate (MgP) group of bioceramics has been studied for orthopaedic applications and is comparatively new compared to traditional CaP ceramics. The role of magnesium in different biochemical processes, such as DNA stabilization, bone density maintenance, regulating Ca and Na ion channels, and cell proliferation and differentiation enhancement, is a key parameter for the development of MgP bioceramics. This article aims to give a comprehensive review of MgP ceramics in bone tissue engineering. Here, we have highlighted several preparation techniques, the existence of porosity, and the impact of metal ion doping on MgP bioceramics. Finally, in vitro and in vivo responses of MgP bioceramics in bone formation are discussed.
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A trio of Ir(III) complexes that are held together by a picolinamidato moiety were created. In our earlier research, we demonstrated the catalytic activity of the complexes for producing alpha-alkylated ketones from a ketone or secondary alcohol with a primary alcohol in the presence of a catalytic amount of a Cp*Ir(III) catalyst and tBuOK in toluene at 110 °C using the hydrogen-borrowing technique. Earlier many research groups had synthesized quinoline, pyrrole, and pyridine derivatives using 2-amino alcohol and ketone or secondary alcohol derivatives as starting materials, but in all those cases the reaction conditions are not suitable in terms of green synthesis like more catalyst loading, base loading, long reaction time, and high temperature. In addition, most of the reactions contain phosphine a hazardous by-product, along with the catalyst. Keeping in mind these shortcomings, we tried to expand the use of our catalysts after achieving an excellent result in our previous work, and we were successful in producing quinoline, pyrrole, and pyridine derivatives through acceptor-less dehydrogenative coupling (ADC) procedures at 90-110 °C under neat/solvent-free conditions and achieved good to exceptional yields of those nitrogen-containing heterocycles. This methodology is attractive because it is environmentally benign and allows for the "green" synthesis of nitrogen-containing heterocycles. All that is required is a modest quantity of catalyst and base, and the by-products are merely H2O and H2.
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OBJECTIVES: Homelessness among families with children under 5 residing in temporary accommodation is a growing global concern, especially in high-income countries (HICs). Despite significant impacts on health and development, these 'invisible' children often fall through the gaps in policy and services. The study's primary objective is to map the content and delivery methods of culturally sensitive interventions for children under 5 experiencing homelessness in HICs. DESIGN: A scoping review guided by the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews checklist. DATA SOURCES: Databases include PubMed, Medline, SCOPUS, The Cochrane Library and Google Scholar were searched up to 24 March 2022. ELIGIBILITY CRITERIA: This scoping review includes studies that describe, measure or evaluate intervention strategies aimed at improving child health programmes, specifically those yielding positive outcomes in key areas like feeding, nutrition, care practices and parenting. DATA EXTRACTION AND SYNTHESIS: Articles were selected and evaluated by two independent reviewers, with a dispute resolution system involving a third reviewer for contested selections. The methodological quality of the studies was assessed using various tools including the Risk of Bias (RoB) tool, Cochrane RoB V.2.0, the Risk of Bias Assessment Tool for Non-randomized Studies (RoBANS) and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), each selected according to the type of article. RESULTS: The database search yielded 951 results. After deduplication, abstract screening and full review, 13 articles met the inclusion criteria. Two predominant categories of intervention delivery methods were identified in this research: group-based interventions (educational sessions) and individual-based interventions (home visits). CONCLUSION: This review highlights effective interventions for promoting the health and well-being of children under 5 experiencing homelessness, including educational sessions and home visits. Research has supported the importance of home visiting to be instrumental in breaking down language, cultural and health literacy barriers.
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Pessoas Mal Alojadas , Humanos , Países Desenvolvidos , Idioma , Poder Familiar , Problemas Sociais , Pré-EscolarRESUMO
Diabesity is a major global health concern, and ghrelin O-acyltransferase (GOAT) acts as an important target for the development of new inhibitors of this disease. The present work highlights a detailed QSAR study using QSARINS software, which provides an excellent model equation using descriptors. Here, the best model equation developed has two variables, namely MLFER_E and XlogP, with statistical parameters R2 = 0.8433, LOF = 0.0793, CCCtr = 0.915, Q2LOO = 0.8303, Q2LMO = 0.8275, CCCcv = 0.9081, R2ext = 0.7712, and CCCext = 0.8668. A higher correlation of the key structural fragments with activity is validated by the developed QSAR model. Furthermore, molecular docking helped us identify the binding interactions. Thirty four new molecules with better predicted biological activity (pIC50) were designed. The binding energy of four compounds have shown higher binding activity into the membrane protein (PDB Id: 6BUG). Molecular dynamics simulation has established the stability of the protein-ligand complex over 100 ns. DFT and ADME-toxicity analyses also confirmed their drug-like properties. Based on our findings, we report that these new oxadiazolo pyridine derivatives lead to the development of potent candidates for further development. Graphical abstract: METTL3-mediated HOTAIRM1 promotes vasculogenic mimicry in glioma via regulating IGFBP2 expression. METTL3 expression is high in glioma cells and tissues that stabilize and enhance HOTAIRM1 expression. This HOTAIRM1 then interacts with IGFBP2 which in turn promotes glioma cell malignancy and vasculogenic mimicry (VM) formation, thus providing a new direction for glioma therapy. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-023-00167-z.
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This paper scrutinises the development of low-cost hypersensitive fluorescent probes manipulated chemically with Schiff base complexes and their prospective applicability for the detection of nitro explosives in light of the rapidly expanding demand for anti-trafficking measures. In this study, a new Zn(II) metal complex has been synthesized in one pot using the Schiff base ligand L= 2-methoxy-5-methyl-N-(2-pyridin-2-ylmethylene) aniline. The complex was also thoroughly characterised using various spectroscopic tools and subjected to single crystal XRD analysis. In the asymmetric unit, square pyramidal zinc (II) centre exist in the inner N2O compartment of the ligand L. The intermolecular Cg···Cg interactions exist between two different asymmetric residual units lead to supramolecular assembly along b axis. By turning off the fluorescence response, the complex serves as a sensor for the detection of nitro aromatics in CH3CN solution. A significant quenching efficiency has been reported with a quenching constant (KSV) 1.8 × 104 M-1 for 4-nitrobenzoic acid during investigation of sensing phenomenon in solution phase. In addition, determining the binding stoichiometry of the chemosensor with NO2 and the binding constant, the mechanism of fluorescence quenching has also been postulated. The detection limit of NO2 is 7.6×10 -7 M, with the binding constant k = 1.1021× 108 M-1. Additionally, the DFT calculation makes it easier to comprehend the appropriate binding process in light of the findings of experiments. We also designed a paper sensor strip for the visual detection of Nitro Explosive Residues in light of the sensor's potential used in forensic investigations.
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Human adenovirus (HADV) infection can pose a serious threat to children, leading to a variety of respiratory illnesses and other complications. Particularly, children with weak immune systems are vulnerable to severe adenovirus infections with high mortality. The main focus of this study is to propose new antiviral agents as lead HADV inhibitors for children. So, several antiviral agents used in children were subjected to finding new HADV inhibitors using important computational methods of molecular docking, molecular dynamics (MD) simulation, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) binding free energy calculations, density functional theory (DFT), and pharmacokinetic analysis. Molecular docking of standard cidofovir along with other ligands, suggested that sofosbuvir has the highest binding energy (-10.8 kcal/mol), followed by baloxavir marboxil (-10.36 kcal/mol). Further, the analysis of molecular interactions using MD simulation (100 ns) and MM-PBSA indicated that baloxavir marboxil has formed the most stable protein-ligand complex with HADV, followed by sofosbuvir. The binding free energies of baloxavir marboxil and sofosbuvir were found to be -61.724 kJ/mol and -48.123 kJ/mol, respectively. The DFT and drug-likeness properties of these compounds were also investigated. Overall, two antiviral agents, such as baloxavir marboxil, and sofosbuvir are suggested as lead repurposed candidates against HADV.Communicated by Ramaswamy H. Sarma.
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Here we demonstrated a solvent free, mechanochemical I2 catalyzed C(sp2)-H sulfenylation of enaminones under grinding condition. Only catalytic amount of I2 is required on silica surface without any external heating. The reaction time has reduced to a great extent in comparison to their solution based counterpart. The frictional energy created by ball-mill on mesoporous silica materials has attracted much attention towards this mechanochemical approach for molecular heterogeneous catalysis. Their large surface area and well defined porous architecture certainly increase the catalytic ability of iodine in this developed protocol. Anti-microbial activities of our synthesized compounds were investigated against two gram positive (Staphylococcus aureus and Bacillus cereus) and two gram negative (Escherichia coli and Klebsiella pneumonia) bacteria. To understand the potency of these compounds (3a-3m) as antimalarial agents, molecular docking studies were also performed. Density functional theory was also used to investigate the chemical reactivity and kinetic stability of the compound 3a-3m.
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Low-income countries are struggling with the health impacts of both surface and groundwater chemical contamination. Although the impact of biological contaminants on children's health is acknowledged, the long-term effects of these and emerging contaminants on young children may be underestimated. To map the existing evidence on health impacts of water contaminated with chemicals on young children (<5 years), we conducted a scoping review to select and organize relevant literature. Of the 98 studies in the review, 24 revealed that the hazard ratio of arsenic, nitrates, cadmium, and fluoride (all of which are on the World Health Organisation's list of 10 chemicals of public health concern) was higher in very young children than in older age groups. Anthropogenic activities (textile manufacturing, waste disposal, and intensified agriculture) are leading contributors to the release of chemicals to groundwater used for drinking. Three major pathways for chemical contamination exposure in young children were confirmed: maternal transmission during pregnancy and breastfeeding, and early school years. Children exhibited acute and chronic disruptions to their neurological, skeletal, reproductive, and endocrine systems, as well as cumulative carcinogenic risks, amongst other life-altering consequences. The lack of research on emerging contaminants' effects on young children in low-income countries is worrisome, as their increased use may compound the issues caused by the existing problem of "legacy chemicals." Precautionary principle should regulate the operation of industries producing these chemicals in a robust manner. Evidence from major producers and exporters in high-income countries is sufficient to warrant action, even without waiting for direct harm to be observed in low-income countries. Literature recommends prioritising prevention of contamination over demand side treatment or finding alternative water sources, especially in water-scarce areas affected by climate change. Local and transnational efforts are required to enforce safer industry practices and prevent further water quality deterioration in low-income countries.
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Arsênio , Água Potável , Água Subterrânea , Poluentes Químicos da Água , Criança , Humanos , Idoso , Pré-Escolar , Monitoramento Ambiental , Poluentes Químicos da Água/análise , Água Subterrânea/química , Saúde PúblicaRESUMO
Introduction: Patients suffering from stricture urethra and deranged renal function have poor quality of life. The incidence of urethral stricture co-existing with renal failure is comparatively small and cause may be multifactorial. There is paucity of literature on management of urethral stricture associated with deranged renal function. We present our experience of managing stricture urethra associated with chronic renal failure. Materials and Methods: This was a retrospective study conducted from 2010 to 2019. Patients with stricture urethra and deranged renal function (serum creatinine >1.5 mg/dl) who underwent urethroplasty or perineal urethrostomy were included in our study. A total of 47 patients met the inclusion criteria and were included in this study. Patients were followed every 3 months in their 1st year of surgery and 6 monthly thereafter. Statistical analysis was done using SPSS version 16. Results: There was a significant increase in the mean postopérative maximum and average urinary flow rates when compared to the preoperative values. The overall success rate was 76.59%. Out of 47 patients, 10 had wound infection and delayed wound healing, 2 patients developed ventricular arrhythmias, 6 patients developed fluid and electrolyte imbalance, 2 patients developed seizures, and 1 patient developed septicemia in the postoperative period. Conclusion: Prevalence of patients with chronic renal failure associated with stricture urethra was 4.58% and features suggestive of deranged renal function at presentation were present in 1.81% patients. In the present study, complications related with chronic renal failure occurred in 17 (36.17%) patients. Multidisciplinary care of the patient along with appropriate surgical management is a viable option in this sub-group of patients.
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Epitaxial titanium nitride (TiN) and titanium oxynitride (TiON) thin films have been grown on sapphire substrates using a pulsed laser deposition (PLD) method in high-vacuum conditions (base pressure <3 × 10-6 T). This vacuum contains enough residual oxygen to allow a time-independent gas phase oxidation of the ablated species as well as a time-dependent regulated surface oxidation of TiN to TiON films. The time-dependent surface oxidation is controlled by means of film deposition time that, in turn, is controlled by changing the number of laser pulses impinging on the polycrystalline TiN target at a constant repetition rate. By changing the number of laser pulses from 150 to 5000, unoxidized (or negligibly oxidized) and oxidized TiN films have been obtained with the thickness in the range of four unit cells to 70 unit cells of TiN/TiON. X-ray photoelectron spectroscopy (XPS) investigations reveal higher oxygen content in TiON films prepared with a larger number of laser pulses. The oxidation of TiN films is achieved by precisely controlling the time of deposition, which affects the surface diffusion of oxygen to the TiN film lattice. The lattice constants of the TiON films obtained by x-ray diffraction (XRD) increase with the oxygen content in the film, as predicted by molecular dynamics (MD) simulations. The lattice constant increase is explained based on a larger electrostatic repulsive force due to unbalanced local charges in the vicinity of Ti vacancies and substitutional O. The bandgap of TiN and TiON films, measured using UV-visible spectroscopy, has an asymmetric V-shaped variation as a function of the number of pulses. The bandgap variation following the lower number of laser pulses (150-750) of the V-shaped curve is explained using the quantum confinement effect, while the bandgap variation following the higher number of laser pulses (1000-5000) is associated with the modification in the band structure due to hybridization of O2p and N2p energy levels.
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The present work reports the effect of decellularized platelet-rich fibrin (dPRF) loaded strontium (Sr) doped porous magnesium phosphate (MgP) bioceramics on biocompatibility, biodegradability, and bone regeneration. Sustained release of growth factors from dPRF is a major objective here, which conformed to the availability of dPRF on the scaffold surface even after 7 days of in vitro degradation. dPRF-incorporated MgP scaffolds were implanted in the rabbit femoral bone defect and bone rejuvenation was confirmed by radiological examination, histological examination, fluorochrome labeling study, and micro-CT. µ-CT examination of the regained bone samples exhibited that invasion of mature bone in the pores of the MgP2Sr-dPRF sample was higher than the MgP2Sr which indicated better bone maturation capability of this composition. Quantifiable assessment using oxytetracycline labeling showed 73.55 ± 1.12% new osseous tissue regeneration for MgP2Sr-dPRF samples in contrast to 65.47 ± 1.16% for pure MgP2Sr samples, after 3 months of implantation. Histological analysis depicted the presence of abundant osteoblastic and osteoclastic cells in dPRF-loaded Sr-doped MgP samples as compared to other samples. Radiological studies also mimicked similar results in the MgP2Sr-dPRF group with intact periosteal lining and significant bridging callus formation. The present results indicated that dPRF-loaded Sr-doped magnesium phosphate bioceramics have good biocompatibility, bone-forming ability, and suitable biodegradability in bone regeneration.
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Fibrina Rica em Plaquetas , Alicerces Teciduais , Animais , Coelhos , Porosidade , Regeneração Óssea , Magnésio/farmacologia , Estrôncio/farmacologia , OsteogêneseRESUMO
Pain, a physiological protective mechanism, turns into a complex dynamic neural response when it becomes chronic. The role of neuroplastic brain changes is more evident than the peripheral factors in the maintenance, modulation and amplification of chronic low back pain (cLBP). In this background, we summarise the brain changes in cLBP in a coordinate-based activation likelihood estimation (ALE) meta-analysis of previous functional magnetic resonance imaging (fMRI) studies. Databases ('PubMed', 'Scopus' and 'Sleuth') were searched till May 2022 and the activity pattern was noted under the 'without stimulation' and 'with stimulation' groups. A total of 312 studies were selected after removing duplicates. Seventeen (553 cLBP patients, 192 activation foci) studies were fulfilled the eligibility criteria and included in the 'without stimulation' group. Twelve statistically significant clusters are localized in the prefrontal cortex, primary somatosensory cortex, primary motor cortex, parietal cortex, anterior cingulate cortex, caudate, putamen, globus pallidus amygdala, occipital lobe, temporal lobe and associated white matter in this group. Ten studies (353 cLBP patients, 125 activation foci) were selected in the' with stimulation' groups. In this group, seven statistically significant clusters were found in the frontal cortex, orbitofrontal cortex, premotor cortex, parietal cortex, claustrum and insula. These statistically significant clusters indicate a probable imbalance in GABAergic modulation of brain circuits and dysfunction in the descending pain modulation system. This disparity in the pain neuro-matrix is the source of spontaneous and persisting pain in cLBP.
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Dor Lombar , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico/métodos , Humanos , Dor Lombar/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Medição da Dor/métodosRESUMO
Parathyroid hormone receptor 1 (PTH1R) is a class B G-protein coupled receptor with key roles in bone development. The receptor signals through both the Gs and Gq G-proteins as well as through ß-arrestin in a G-protein independent manner. Current treatments for bone disorders, such as osteoporosis, target the PTH1R but are suboptimal in their efficacy. Monoclonal antibodies represent a major growth area in therapeutics as a result of their superior specificity and long serum half-life. Here, we discovered antibodies against the extracellular domain (ECD) of PTH1R from a phage display library. One of these antibodies, ECD-ScFvhFc, binds PTH1R with high affinity and although it has little or no effect on G-protein dependent receptor signaling, it does reduce PTH1R mediated ß-arrestin signaling. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) demonstrated that the ECD-ScFvhFc binding site overlapped partially with that of the cognate ligand, PTH. The results of this study demonstrate the suitability of PTH1R as a target for therapeutic antibody development.
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Hormônio Paratireóideo , Receptor Tipo 1 de Hormônio Paratireóideo , Proteínas de Ligação ao GTP/metabolismo , Humanos , Hormônio Paratireóideo/metabolismo , Receptor Tipo 1 de Hormônio Paratireóideo/química , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Transdução de Sinais , beta-Arrestinas/metabolismoRESUMO
Stunting is a major unresolved and growing health issue for India. There is a need for a broader interdisciplinary cross-sectoral approach in which disciplines such as the environment and health have to work together to co-develop integrated socio-culturally tailored interventions. However, there remains scant evidence for the development and application of such integrated, multifactorial child health interventions across India's most rural communities. In this paper we explore and demonstrate the linkages between environmental factors and stunting thereby highlighting the scope for interdisciplinary research. We examine the associations between household environmental characteristics and stunting in children under 5 years of age across rural Rajasthan, India. We used Demographic and Health Survey (DHS)-3 India (2005-2006) data from 1194 children living across 109,041 interviewed households. Multiple logistic regression analyses independently examined the association between (i) the primary source of drinking water, (ii) primary type of sanitation facilities, (iii) primary cooking fuel type, and (iv) agricultural land ownership and stunting adjusting for child age. The results suggest, after adjusting for child age, household access to (i) improved drinking water source was associated with 23% decreased odds [odds ratio (OR) = 0.77, 95% confidence interval (CI) 0.5-1.00], (ii) improved sanitation facility was associated with 41% decreased odds (OR = 0.51, 95% CI 0.3-0.82), and (iii) agricultural land ownership was associated with 30% decreased odds of childhood stunting (OR 0.70, 95% CI 0.51-0.94]. The cooking fuel source was not associated with stunting. Our findings indicate that a shift is needed from nutrition-specific to contextually appropriate interdisciplinary solutions, which incorporate environmental improvements. This will not only improve living conditions in deprived communities but also help to tackle the challenge of childhood malnutrition across India's most vulnerable communities.
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BACKGROUND: Aurora kinases (AKs) belong to the serine/threonine kinase family and play a crucial role in regulating the cell cycle. Therefore, AKs are the hopeful target for anticancer therapies and these findings have encouraged researchers to rigorously hunt small molecule aurora kinase inhibitors, not only for research articles but also for use as therapeutic agents. OBJECTIVE: The present study helps us to identify and screen the best phytochemicals as potent inhibitors against AKs. These potent inhibitors come from the various substitution of rosmarinic acid (RA). METHODS: In this paper, we choose different tested derivative compounds for designing anticancer drugs by substituting various functional groups of standard drug RA. In silico studies were carried out to appreciate better drug candidature of some of these derivative compounds. This study was performed on 56 derived compounds of the standard RA. DFT study was conducted using the UB3LYP/6-311++G(d,p) basis set to study HOMO-LUMO energies, dipole moments, using the Gaussian16 suite. Some of the derived parameters, like ionization potential, electron affinity, softness- hardness, chemical potential, and electrophilicity index were noted. A docking study was performed with AKs inhibiting receptor using AutoDock 4.2. ADME prediction was made with the preADMET web tool. Molecular descriptor properties were predicted with molinspiration and OSIRIS property explorer. RESULTS: Out of the 56 derivatives, 11 have passed all the rules of drug candidature, to serve as best AKs inhibitor, in a theoretical manner. CONCLUSION: This study should be supported by a new proposal to explore future studies with these 11 compounds against cancer.
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Antineoplásicos , Preparações Farmacêuticas , Antineoplásicos/farmacologia , Aurora Quinases , Cinamatos , Depsídeos , Desenho de Fármacos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Ácido RosmarínicoRESUMO
Fibromyalgia is a multi-symptomatic disorder characterized by generalized pain. The pathophysiology of fibromyalgia is supposedly an interplay between central nervous system hyper-responsiveness, autonomic dysfunction, and peripheral pain. In this cross-sectional study, the objective was to assess central sensitization and autonomic activity in patients with fibromyalgia compared with control. Fifty adults diagnosed with fibromyalgia by the modified American College of Rheumatology 2010 criteria and an equal number of age- and sex-matched controls participated in the study in an urban tertiary care hospital. Central sensitization was assessed by history and by evidence of increased prefrontal cortical activity as measured by cortical oxygenation using functional near-infrared spectroscopy. Autonomic activity was assessed by heart rate variability, electrodermal activity, and deep breathing test in three physiological states: rest, sympathetic stress (cold pressor test), and deep breathing. Mann-Whitney U-test, paired t-test, Wilcoxon test, and Friedman test with Bonferroni a priori were used to analyze the data. Cortical activity was significantly higher in the fibromyalgia group than control. There was no significant difference in autonomic activity between the fibromyalgia and control groups. In the fibromyalgia group, variable degrees of sympathetic hyperactivity and normal parasympathetic activity were observed. Central sensitization may be playing a primary role in the pathophysiology of generalized pain in fibromyalgia.
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Hypospadias is a rare birth deformity characterised by shortening of urethra with dorsal ectopia of the urethral meatus. The occurrence of hypospadias in female patients is extremely rare. We present a young female complaining of recurrent urinary tract infection and voiding difficulty caused by hypospadias.
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Oral Cholera Vaccine (OCV) has been recognized as an adjunct tool for prevention and control of cholera. However, policy directions are currently unavailable in India to guide the vaccine delivery. We conducted a scoping review to inform the policy about the scopes and challenges of different strategic choices of OCV delivery in India in light of current evidences, highlighting the scope of new research. METHODS: Adopting the Arksey and O'Malley Framework for review, we searched for literatures on "efficacy", "effectiveness", and "cost" of oral cholera vaccine delivery through different strategies in Pubmed and Scopus. RESULTS: We found that the protective efficacy of OCV depends on its coverage. Evidence on effectiveness of OCV are available for both reactive and pre-vaccination campaigns. Reactive high-risk vaccination is more effective than reactive ring and mass vaccination. Pre-vaccination campaigns are more effective than reactive vaccination when vaccine availability is adequate. Pre-vaccination through school campaigns in 1-14â¯years age group have been cost effective in India. Vaccination campaigns in under-5 children are also cost effective in spite of low efficacy due to the scope of averting a higher number of cases. However, no evidence is available regarding efficacy and effectiveness of OCV in children <1â¯year as well as the effectiveness of delivering OCV through routine immunization. CONCLUSION: Little evidence exist to depict mass-campaign as more economic and effective than routine expanded programme on immunization (EPI) session for delivery of OCV. Considering operational feasibility, it needs to be explored whether OCV delivery strategy is compatible with India's current EPI, if it can be introduced in routine immunization at measles containing vaccine age-schedule, optionally preceded by a campaign in targeted hot-spots in the 1-14â¯year age-group. Safety and efficacy data of OCV during infancy as well as hot-spot surveillance are pre-requisites for formulation of such EPI policy.
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Vacinas contra Cólera/administração & dosagem , Cólera , Programas de Imunização/organização & administração , Administração Oral , Pré-Escolar , Cólera/prevenção & controle , Análise Custo-Benefício , Humanos , Índia , Vacinação em MassaRESUMO
Parathyroid hormone receptor 1 (PTH1R) belongs to the secretin class of G protein coupled receptors (GPCRs) and natively binds parathyroid hormone (PTH) and parathyroid hormone related peptide (PTHrP). Ligand binding to PTH1R involves binding to the large extracellular domain (ECD) and the orthosteric pocket, inducing conformational changes in the transmembrane domain and receptor activation. PTH1R regulates bone metabolism, signaling mainly through Gs and Gq/11 G-proteins. Here, we used phage display to generate PTH1R ECD-specific antibodies with the aim of modulating receptor functionality. We identified ECD-scFvhFc, which exhibited high affinity binding to both the isolated ECD and to the full-length receptor in styrene-maleic acid (SMA) lipid particles. Epitope mapping using hydrogen-deuterium exchange mass spectrometry (HDX-MS) indicates that the α1 helix of the ECD is ECD-scFvhFc's epitope which may partially overlap with the known PTH (1-34) binding site. However, PTH (1-34)-mediated Gs activation is Undisturbed by ECD-scFvhFc binding. In contrast, ECD-scFvhFc potently inhibits ß-arrestin-2 recruitment after PTH (1-34)-driven receptor activation and thus represents the first monoclonal antibody to selectively inhibit distinct PTH1R signaling pathways. Given the complexity of PTH1R signaling and the emerging importance of biased GPCR activation in drug development, ECD-scFvhFc could be a valuable tool to study PTH1R signaling bias.
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Anticorpos Monoclonais/farmacologia , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Transdução de Sinais , beta-Arrestina 2/antagonistas & inibidores , Anticorpos Monoclonais/imunologia , Técnicas de Visualização da Superfície Celular , Espaço Extracelular , Proteínas de Ligação ao GTP/metabolismo , Humanos , Modelos Moleculares , Ligação Proteica , Domínios Proteicos , Receptor Tipo 1 de Hormônio Paratireóideo/química , Transdução de Sinais/efeitos dos fármacos , beta-Arrestina 2/metabolismoRESUMO
In vitro and in vivo degradation behavior and biocompatibility of magnesium phosphate (MgP) bioceramics and the potential role of zinc (Zn) on degradation were compared. Samples were prepared by conventional solid-state sintering at 1200 °C for 2h. Zn-doped MgP (0.5 wt %) showed 50% less degradation than that of pure MgP after immersion into simulated body fluid (SBF) for 8 weeks. Osteoblast-like cell (MG-63) proliferation was evident in MgP ceramics, which was significantly enhanced upon Zn addition. Both Alamar Blue assay and Live/Dead imaging showed the highest cell attachment and proliferation for 0.5 wt % Zn-doped MgP. In vivo biocompatibility of these MgP ceramics were studied after implantation in the rabbit femur. The micro computed tomography (µ-CT) analysis showed that in vivo degradability increased with the increase in the Zn content which is in contradiction to in vitro degradability. Histological evaluation showed large influx of osteoclast cells to the implantation site for Zn-doped MgP samples compared to that of undoped MgP, which is the primary reason of increased degradability of these samples. After 90 days of implantation, large sections of 0.5 wt % Zn-doped MgP samples were replaced by newly formed bones. Fluorochrome labeling showed 78 ± 3% new bone formation for 0.5 wt % Zn-doped MgP ceramics compared to 56 ± 3% for pure MgP samples. Our findings suggest that the addition of Zn in MgP ceramics alters their sintering and degradation kinetics that leads to decreased in vitro degradation, however, when Zn-doped MgP ceramics were implanted in rabbits, higher degradability was observed due to lower Mg2+ ion concentration in the degradation media.