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Chitosan based microgels have gained great attention because of their chemical stability, biocompatibility, easy functionalization and potential uses in numerous fields. Production, properties, characterization and applications of chitosan based microgels have been systematically reviewed in this article. Some of these systems exhibit responsive behavior towards external stimuli like pH, light, temperature, glucose, etc. in terms of swelling/deswelling in an aqueous medium depending upon the functionalities present in the network which makes them a potential candidate for various applications in the fields of biomedicine, agriculture, catalysis, sensing and nanotechnology. Current research development and critical overview in this field accompanying by future possibilities is presented. The discussion is concluded with recommended possible future works for further progress in this field.
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Quitosano , Microgeles , Microgeles/química , Quitosano/química , Geles/química , Catálisis , NanotecnologíaRESUMEN
Spiradenoma is a rare benign adnexal tumor arising from eccrine sweat glands. It presents as a painful bluish nodular lesion which occurs rarely over the arms. This case report adds to a case where a recurrent spiradenoma occurred over the arm. The majority of reported cases involve young adults, making our pediatric case particularly unusual. Early diagnosis through excisional biopsy is crucial for optimal management and prevention of recurrence or malignant transformation. Eccrine spiradenoma is an uncommon tumor that should be kept in mind in case of a patient with a painful nodule. More genetic studies are needed for the best understanding of this rare tumor entity.
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Chitosan based monodisperse poly[chitosan-N-isopropylmethacrylamide-acrylic acid] [P(CNA)] microgels were produced via precipitation polymerization. Resulting crosslinked P(CNA) micro particles were used as micro-reactors to prepare silver nanoparticles within the polymeric network by chemical reduction of Ag+ ions with sodium borohydride. Various techniques including transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy and ultraviolet-visible (UV-vis) spectroscopy were used to analyze P(CNA) microgels and Ag-P(CNA) hybrid microgels. Catalytic potential of Ag-P(CNA) hybrid system towards individual and simultaneous reduction of various nitroarenes like p-nitrophenol (pNP), o-nitrophenol (oNP), p-nitroaniline (pNA) and o-nitroaniline (oNA) into corresponding aminoarenes using sodium borohydride as a reductant in aqueous medium was evaluated. The catalytic activity of Ag-P(CNA) system towards both the individual and simultaneous reduction of nitroarenes was examined at various concentrations of catalyst. The values of pseudo first order rate constant (k1) for reduction of individual nitroarene and multiple nitroarenes were determined for comparison. The Ag-P(CNA) hybrid microgel system was found to be stable, economical and efficient catalyst for rapid individual and simultaneous reduction of nitroarenes.
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Quitosano , Nanopartículas del Metal , Microgeles , Nanopartículas del Metal/química , Quitosano/química , Plata/química , CatálisisRESUMEN
The study focused on the fabrication of nickel, cobalt, and their bimetallic oxide via a facile electrodeposition approach over the surface of conducting glass has been reported here. Fabricated electrodes have been employed as binder-free and effective anode materials toward oxygen evolution reactions (OER) in electrochemical water splitting at high pH. Nickel and cobalt oxides showed overpotential values of 520 mV and 536 mV at the current density of 10 mAcm-2 with charge transfer resistances of 170 and 195 Ω. For bimetallic oxides (NiCoO@FTO), the overpotential depressed up to 460 mV and lower charge transfer value of 80 Ω. Additionally, double-layer capacitance also boosted for the bimetallic oxide with a value of 199 µF as compared to monometallic nickel oxide (106 µF) and cobalt oxide (120 µF). Multimetal oxides of Ni-Co showed the best performance, which was further supported with larger electrochemical surface area. This facile approach toward the electrode fabrication could be a charming alternate to replace the Ru- and Ir-based expensive materials for OER in electrochemical water splitting.
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Electrochemical sensors are gaining significant demand for real-time monitoring of health-related parameters such as temperature, heart rate, and blood glucose level. A fiber-like microelectrode composed of copper oxide-modified carbon nanotubes (CuO@CNTFs) has been developed as a flexible and wearable glucose sensor with remarkable catalytic activity. The unidimensional structure of CNT fibers displayed efficient conductivity with enhanced mechanical strength, which makes these fibers far superior as compared to other fibrous-like materials. Copper oxide (CuO) nanoparticles were deposited over the surface of CNT fibers by a binder-free facile electrodeposition approach followed by thermal treatment that enhanced the performance of non-enzymatic glucose sensors. Scanning electron microscopy and energy-dispersive X-ray analysis confirmed the successful deposition of CuO nanoparticles over the fiber surface. Amperometric and voltammetric studies of fiber-based microelectrodes (CuO@CNTFs) toward glucose sensing showed an excellent sensitivity of â¼3000 µA/mM cm2, a low detection limit of 1.4 µM, and a wide linear range of up to 13 mM. The superior performance of the microelectrode is attributed to the synergistic effect of the electrocatalytic activity of CuO nanoparticles and the excellent conductivity of CNT fibers. A lower charge transfer resistance value obtained via electrochemical impedance spectroscopy (EIS) also demonstrated the superior electrode performance. This work demonstrates a facile approach for developing CNT fiber-based microelectrodes as a promising solution for flexible and disposable non-enzymatic glucose sensors.
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The rising environmental challenges are capturing the attention of stakeholders of corporations due to increasing competition. The sustainable performance of firms does not merely gauge their economic performance but also their sustainable development. Since the environmental supply chain management of firms has an important part in maneuvering their sustainable performance, the present study focuses on assessing the impact of green supply chain management practices on the sustainable performance of the textile, automobile, and tobacco industries. The data were collected from 384 organizations and analyzed through SPSS and AMOS. The results reveal that the impact of green manufacturing, green purchases, eco-design, and green information system are significant and positive on the sustainable performance of the organizations, whereas the impact of cooperation with customers is insignificant. Similarly, the moderation of institutional pressures between green manufacturing, green purchases, eco-design, and sustainability performance is insignificant, whereas it significantly moderates between cooperation with customers, green information systems, and sustainable performance. The study is significant and novel for considering five different factors of green supply chain management (GSCM): green manufacturing, green purchasing, cooperation with customers, eco-design, and green information systems. Furthermore, adding institutional pressures as a moderator between GSCM and sustainable performance adds to the novelty and uniqueness of the research. The managerial implications have also been discussed.
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OBJECTIVE: Modern treatment of peptic ulcers includes antibacterial and gastroprotective medications. However, current anti-ulcer drugs possess severe side effects. Therefore, all attempts to find new effective medications free from side effects are justified. Though Berberis vulgaris is a medicinal plant commonly used for the treatment of numerous disorders, gastroprotective effect of its leaf extract was not investigated before. MATERIALS AND METHODS: Gastric ulcer was modelled in Sprague-Dawley rats after treatment with B. vulgaris leaf extract containing 0.07% of alkaloids, 0.48% of flavonoids and 8.05% of tanning substances, 10 or 50 mg of dry extract/kg, changes in the stomach mucosa were assessed semi-quantitatively, and the gastric wall was evaluated for prostaglandin E2 level using ELISA and assessed histologically by calculation of the lesion index. RESULTS: B. vulgaris leaf extract at the dose of 50 mg/kg reduced the macroscopic ulcer score and the microscopic lesion index, increased prostaglandin E2 concentration in the gastric wall significantly higher than atropine and B. vulgaris leaf extract 10 mg/kg. CONCLUSION: The gastroprotective effect of the high dose of B. vulgaris leaf extract may be due to stimulation of prostaglandin E2 secretion in the stomach, and anti-oxidative and anti-inflammatory properties of polyphenolic complex of flavonoids and tannins present in the leaves of this plant.
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INTRODUCTION: We performed a single-center study of real-world health data to investigate the direct clinical consequence of targeted next-generation sequencing (NGS) results integrated in the clinicopathological evaluation of patients with cytopenia suspected of myelodysplastic syndrome (MDS). METHODS: The study included 87 newly referred patients, who had a bone marrow examination, which included targeted NGS analysis. NGS was requested at the discretion of either examining pathologist or hematologist. Data were collected retrospectively from patient files including pathology reports with integrated NGS results. RESULTS: The NGS results had a diagnostic impact in 67 cases (77%) when combining both histopathological and final clinical evaluation and provided prognostic value in 19 cases (22%). NGS supported a confident or tentative histopathological diagnosis in 52 cases (60%). Twenty cases (23%) had a final diagnosis of either Clonal Cytopenia of Undetermined Significance (CCUS) or Idiopathic Cytopenia of Undetermined Significance (ICUS). In 4 cases, NGS results affected the choice of principal treatment strategy, including considerations of allotransplantation. Twenty-one patients (24%) could be discharged to primary care physician. CONCLUSION: In a multidisciplinary clinicopathological real-world setting, NGS analysis of bone marrow samples from selected patients contributed substantially to the diagnostic evaluation and management of patients with cytopenia suspected of MDS. Consequently, we have now included NGS analysis in most routine bone marrow examinations from patients with MDS or unexplained cytopenia.
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Anemia , Síndromes Mielodisplásicos , Trombocitopenia , Hematopoyesis Clonal , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , Estudios RetrospectivosRESUMEN
@#Introduction: School students are young adolescents who are in a period of acquiring good oral hygiene habits that are practised as they grow up. This study aimed to determine the association between oral health knowledge, attitude and practices (KAP) of the adolescents and their dental plaque maturity status. Methods: A cross-sectional study was conducted among 174 school students aged 13 to 14 years in Kota Bharu, Kelantan. The oral health knowledge, attitude and practices were assessed by self-administered questionnaires, while the dental plaque maturity status was assessed using GC Tri Plaque ID gel TM (TPID). The data were analysed using IBM SPSS version 24.0. Results: The mean (SD) for knowledge and attitude score of the students were 4.69 (1.44) and 3.63 (0.63), respectively. The mean (SD) dental plaque maturity score (DPMS) of the students was 1.02 (0.55). Students who had answered correctly on sugar and practised tooth brushing twice daily had significantly lower mean DPMS as compared to those who had answered incorrectly and practised tooth brushing less than twice daily (p<0.05). Conclusion: Adolescents participated in this study had moderate oral health knowledge and good oral health attitude. Correct knowledge regarding sugar and toothbrushing routines of at least twice a day significantly associated with the dental plaque maturity status.
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The parasite Entamoeba histolytica is the etiological agent of amoebiasis, a major cause of morbidity and mortality due to parasitic diseases in developing countries. Phagocytosis is an essential mode of obtaining nutrition and has been associated with the virulence behaviour of E. histolytica. Signalling pathways involved in activation of cytoskeletal dynamics required for phagocytosis remains to be elucidated in this parasite. Our group has been studying initiation of phagocytosis and formation of phagosomes in E. histolytica and have described some of the molecules that play key roles in the process. Here we showed the involvement of non-Dbl Rho Guanine Nucleotide Exchange Factor, EhGEF in regulation of amoebic phagocytosis by regulating activation of EhRho1. EhGEF was found in the phagocytic cups during the progression of cups, until closure of phagosomes, but not in the phagosomes themselves. Our observation from imaging, pull down experiments and down regulating expression of different molecules suggest that EhGEF interacts with EhRho1 and it is required during initiation of phagocytosis and phagosome formation. Also, biophysical, and computational analysis reveals that EhGEF mediates GTP exchange on EhRho1 via an unconventional pathway. In conclusion, we describe a non-Dbl EhGEF of EhRho1 which is involved in endocytic processes of E. histolytica.
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Entamoeba histolytica/fisiología , Entamebiasis/parasitología , Fagocitosis , Proteínas Protozoarias/metabolismo , Factores de Intercambio de Guanina Nucleótido Rho/metabolismo , Proteínas de Unión al GTP rho/metabolismo , Membrana Celular/parasitología , Entamebiasis/genética , Entamebiasis/metabolismo , Eritrocitos/parasitología , Fagosomas , Proteínas Protozoarias/genética , Factores de Intercambio de Guanina Nucleótido Rho/genética , Proteínas de Unión al GTP rho/genéticaRESUMEN
Conservation translocation and reintroduction for the purpose of repopulating and reinforcing extirpated or depleted populations has been recognised as an important conservation tool, particularly for gibbon conservation in the immediate future. Feasibility assessments involving multiple factors, including taxonomic and genetic assessment of rescued and captive gibbons, are imperative prior to translocation and reintroduction programmes. In this study, we attempt to determine the subspecies and origin of captive Hylobateslar, White-handed gibbons, from Peninsular Malaysia to assist in future translocation and reintroduction programmes. A total of 12 captive and rescued H.lar samples were analysed using the control region segment of mitochondrial DNA. Sequence analyses and phylogenetic trees constructed using neighbour-joining, maximum likelihood, Bayesian inference, and network methods congruently differentiate all 12 captive individuals used in this study from other H.lar subspecies suggesting that these individuals belong to the H.larlar subspecies. In addition, two populations of H.l.lar were observed: (1) a southern population consisting of all 12 individuals from Peninsular Malaysia, and (2) a possible northern population represented by three individuals (from previous studies), which might have originated from the region between the Isthmus of Kra, Surat Thani-Krabi depression, and Kangar-Pattani. Our findings suggest that the complete control region segment can be used to determine the subspecies and origin of captive H.lar.
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Protein kinases are known to regulate several cellular processes like metabolism, motility and endocytosis through phosphorylation of specific target proteins which forms a communication system relaying extracellular signals to intracellular milieu for an adaptive response. One of the protozoan parasite Entamoeba histolytica, which causes amoebiasis and is one of the prominent reason for causing diarrhoea in infants of developing countries, where it remains the third leading cause of deaths in infants(1). The genome of this parasite codes for 331 putative protein kinases which accounts for 3.7% of the proteome. The kinome of the parasite is composed of several conserved and as well as kinase with unusual domain architecture. About one-third of kinome codes for transmembrane kinases (TMK) which is proposed to help the parasite to sense and adapt to the gut environment which is constantly changing. Many kinases are known to be involved in virulence but, the kinome of this important parasite is unexplored. In this review, we present an overview of E. histolytica kinases and their role in amoebic biology understood till now.
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Entamoeba histolytica/enzimología , Entamebiasis/prevención & control , Proteínas Quinasas/metabolismo , Proteínas Protozoarias/metabolismo , Animales , Entamoeba histolytica/genética , Entamoeba histolytica/patogenicidad , Entamebiasis/diagnóstico , Entamebiasis/parasitología , Humanos , Lactante , Proteínas Quinasas/genética , Proteoma/genética , Proteoma/metabolismo , Proteómica/métodos , Proteínas Protozoarias/genética , Virulencia/genéticaRESUMEN
INTRODUCTION: Bacteraemia in adult patients undergoing treatment for leukaemia is common and associated with profound morbidity and mortality. Infections related to the use of a central venous catheter (CVC) are difficult to eliminate with systemic antibiotics. Premature catheter removal is often due to retained biofilm infection. This study investigated if the additional use of hydrochloric acid (HCl) as an intraluminal lock solution may prolong the lifetime of the CVC. METHODS: The study was performed retrospectively based on a database including patients with a tunnelled Leonard 10 F dual or triple lumen CVC implanted who received HCl instillation due to bacteraemia during a five-year period. RESULTS: In a total of 71 cases of bacteraemia, HCl instil-lation was performed. Following HCI instillation, the CVC was not removed due to infection in 49 out of 71 patients (69%). Furthermore, 22 patients (31%) retained their CVC until the end of treatment. Non-infectious mortality (19/71), accidental pull (2/71) or mechanical CVC dysfunction (6/71) were other reasons for premature removal. Twenty-two catheters (31%) had to be removed due to ongoing infection. The median time from CVC placement until HCl instillation was 39 days. The median time from HCl instillation until removal of CVC was 58 days. The most common bacteriological findings were coagulase-negative staphylococci 34%, Enterococcus spp 14% and Escherichia coli 14%. CONCLUSIONS: The study's findings indicate that a prolonged use of CVC is possible following HCl instillation in adult haematologic patients with bacteraemia. FUNDING: none. TRIAL REGISTRATION: not relevant.
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Bacteriemia/prevención & control , Infecciones Relacionadas con Catéteres/prevención & control , Catéteres Venosos Centrales/efectos adversos , Ácido Clorhídrico/farmacología , Leucemia/complicaciones , Adulto , Anciano , Antibacterianos/uso terapéutico , Bacteriemia/etiología , Cateterismo Venoso Central/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto , Estudios RetrospectivosAsunto(s)
Anticoagulantes/administración & dosificación , Fibrilación Atrial/complicaciones , Accidente Cerebrovascular/prevención & control , Administración Oral , Anticoagulantes/efectos adversos , Aspirina/administración & dosificación , Fibrilación Atrial/diagnóstico , Dabigatrán/administración & dosificación , Mal Uso de los Servicios de Salud/estadística & datos numéricos , Hemorragia/inducido químicamente , Humanos , Relación Normalizada Internacional/estadística & datos numéricos , Pirazoles/administración & dosificación , Piridinas/administración & dosificación , Piridonas/administración & dosificación , Rivaroxabán/administración & dosificación , Dispositivo Oclusor Septal , Accidente Cerebrovascular/etiología , Tiazoles/administración & dosificación , Warfarina/administración & dosificación , Warfarina/efectos adversosRESUMEN
AIMS: We used the US Department of Defense Military Health System database to compare the safety and effectiveness of direct oral anticoagulants (DOACs) in patients with non-valvular atrial fibrillation (NVAF) initiating dabigatran vs. rivaroxaban or apixaban. METHODS AND RESULTS: Two cohorts of adults with NVAF, newly initiated on standard-dose DOAC, were identified based on clinical approval dates: July 2011-June 2016 for dabigatran (150 mg b.i.d.) or rivaroxaban (20 mg QD) and January 2013-June 2016 for dabigatran (150 mg b.i.d.) or apixaban (5 mg b.i.d.). Propensity score matching (1:1) identified two well-balanced cohorts (dabigatran vs. rivaroxaban n = 12 763 per treatment group; dabigatran vs. apixaban n = 4802 per treatment group). In both cohorts, baseline characteristics and follow-up duration were similar between treatment groups. Patients newly initiating dabigatran had significantly lower risk of major bleeding vs. rivaroxaban [2.08% vs. 2.53%; hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.70-0.97; P = 0.018], while stroke risk was similar (0.60% vs. 0.78%; HR 0.77, 95% CI 0.57-1.04; P = 0.084). The dabigatran vs. apixaban cohort analysis found no differences in risk of major bleeding (1.60% vs. 1.21%; HR 1.37, 95% CI 0.97-1.94; P = 0.070) or stroke (0.44% vs. 0.35%; HR 1.26, 95% CI 0.66-2.39; P = 0.489). CONCLUSION: Among NVAF patients newly initiated on standard-dose DOAC therapy in this study, dabigatran was associated with significantly lower major bleeding risk vs. rivaroxaban, and no significant difference in stroke risk. For dabigatran vs. apixaban, the reduced sample size limited the ability to draw definitive conclusions.
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Antitrombinas/administración & dosificación , Fibrilación Atrial/tratamiento farmacológico , Dabigatrán/administración & dosificación , Inhibidores del Factor Xa/administración & dosificación , Pirazoles/administración & dosificación , Piridonas/administración & dosificación , Rivaroxabán/administración & dosificación , Accidente Cerebrovascular/prevención & control , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antitrombinas/efectos adversos , Fibrilación Atrial/complicaciones , Fibrilación Atrial/diagnóstico , Investigación sobre la Eficacia Comparativa , Dabigatrán/efectos adversos , Bases de Datos Factuales , Inhibidores del Factor Xa/efectos adversos , Femenino , Hemorragia/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Medicina Militar , Pirazoles/efectos adversos , Piridonas/efectos adversos , Estudios Retrospectivos , Factores de Riesgo , Rivaroxabán/efectos adversos , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/etiología , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos , United States Department of Defense , Adulto JovenRESUMEN
BACKGROUND: Apolipoprotein B (ApoB) is a superior predictor of low-density-lipoprotein (LDL) particle number and cardiovascular disease (CVD) risk compared with LDL-cholesterol (LDL-C) levels. Current evidence has shown a degree of discordance between LDL-C with ApoB levels among patients not receiving lipid-lowering therapy. The extent of this discordance among patients receiving LDL-lowering therapies however is less clear. METHODS: We performed a post hoc analysis of the InPractice data looking at the concordance between LDL-C, non-high density lipoprotein-cholesterol (nonHDL-C) and total cholesterol with ApoB values. The study involved 786 high-risk CVD patients from 34 primary care centers initially treated with simvastatin (S) 40 mg at baseline subsequently randomized to adding ezetimibe 10 mg to S 40 mg (E/S40) or changed to atorvastatin (A) 40 mg or to rosuvastatin (R) 5-10 mg for 6 weeks. RESULTS: At 6 weeks after treatment, the association between LDL-C and ApoB values for the different treatment regimes were similar; Pearson's correlation coefficients between LDL-C and ApoB were 0.84 (E/S40), 0.82 (A), and 0.83 (R). Overall, ApoB appeared to have a slightly greater correlation with nonHDL-C than with LDL-C across all treatment groups, for baseline and posttreatment values. The analysis of quintile frequencies showed a similar pattern; the proportion of patients who had values that fell in the same quintile post treatment for ApoB and LDL-C levels were 52.2% (E/S40), 44.5% (A), and 49.4% (R). Concordance between ApoB and nonHDL-C was 60.6% (E/S40), 62.4% (A), and 61.8% (R). Kappa analysis confirmed fair agreement between LDL-C and ApoB levels for all treatment groups; 0.59 (E/S40), 0.54 (A), and 0.56(R). CONCLUSION: We showed that the association between ApoB and LDL-C is similar across different lipid-lowering treatment regimes, which suggests that the use of different lipid-lowering agent confers similar ability to predict ApoB levels. When determining CVD risk at an individual patient level, limitation exists when using LDL-C or nonHDL-C per se as risk markers. In the absence of ApoB measurement, we believe that information from both LDL-C and nonHDL-C should be used together to improve the estimation of residual CVD risk among patients who are already receiving lipid lowering therapy.
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Apolipoproteínas B/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Anciano , Atorvastatina , Azetidinas/uso terapéutico , Biomarcadores/sangre , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/etiología , Ezetimiba , Femenino , Fluorobencenos/uso terapéutico , Ácidos Heptanoicos/uso terapéutico , Humanos , Hiperlipidemias/complicaciones , Hiperlipidemias/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Rosuvastatina Cálcica , Simvastatina/uso terapéutico , Sulfonamidas/uso terapéuticoRESUMEN
The potential of ketamine, an N-methyl D-aspartate (NMDA) receptor antagonist, in preventing central sensitization has led to numerous studies. Ketamine is increasingly used in the clinical setting to provide analgesia and prevent the development of central sensitization at subanaesthetic doses. However, few studies have looked into the potential of ketamine in combination with stress-induced analgesia. This study looks at the effects of swim stress, which is mediated by opioid receptor, on ketamine analgesia using formalin test. Morphine is used as the standard analgesic for comparison. Adult male Sprague-Dawley rats were assigned to 6 groups: 3 groups (stressed groups) were given saline 1ml/kg intraperitoneally (ip), morphine 10mg/kg ip or ketamine 5mg/kg ip and subjected to swim stress; 3 more groups (non-stressed groups) were given the same drugs without swim stress. Formalin test, which involved formalin injection as the pain stimulus and the pain score recorded over time, was performed on all rats ten minutes after cessation of swimming or 30 minutes after injection of drugs. Combination of swim stress and ketamine resulted in complete analgesia in the formalin test which was significantly different from ketamine alone (p<0.05) and saline with stress (p<0.01). There is no significant difference between ketamine stressed and morphine stressed. These results indicate that ketamine and swim stress act synergistically to produce profound analgesia in the formalin test. This suggests that in the clinical setting, under stressful situations such as operative stress, ketamine is capable of producing profound analgesia at a subanaesthetic dose.