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Cotton is an important cash crop for both the Indian economy and rural livelihoods. In the present study, metagenomic analysis is used to characterize microbial diversity in cotton rhizosphere soil from the Alwar district, located in the semiarid northeast region of the state of Rajasthan in India.
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OBJECTIVE: This study aimed to assess the feasibility of reusing nickel-titanium (NiTi) alloy wires after 6 weeks of intraoral use by evaluating the changes in the load-deflection properties and surface characterization of these alloy wires after cold sterilization by immersion in 2% of acidic glutaraldehyde for 10 h. MATERIAL AND METHODS: Twenty wires each in three groups of G1-as-received wires (ARW), G2-unsterilized used wires, and G3-sterilized used wires (SUW) were tested by the three-point bending test and scanning electron microscopy (SEM). The data were subjected to statistics, one-way analysis of variance, and Bonferroni posthoc test for comparison. RESULTS: Recycling of NiTi wires produced statistically insignificant changes in both the loading and unloading properties of the wires. The forces needed to twist the used wires, that is, G2-(UUW) and G3-(SUW) were lower than G1-(ARW), suggesting lowering of the stiffness of the wires. Superelasticity is well-maintained by G2-(UUW) and G3-(SUW) although there is an insignificant lowering of the forces exerted by them during loading and unloading. SEM demonstrated no increase in the pitting of surfaces in both G2-(UUW) and G3-(SUW); multiple areas were seen to be more smoothened over G2-(UUW) and G3-(SUW) NiTi wires surfaces. CONCLUSION: The findings of this study support the reuse of NiTi wires after 6 weeks of use in oral conditions followed by cold sterilization by immersion in 2% acidic glutaraldehyde for 10 h.
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INTRODUCTION: Lung cancer is the most common malignant disease and is the topmost cause of cancer deaths in the world across all age groups and in both sexes. It is the most common cause of cancer deaths in developed countries and is also rising at an alarming rate in the developing countries. OBJECTIVE: The present study was undertaken to explore the clinicopathological and molecular profile of bronchogenic carcinoma in northwestern population of India. MATERIALS AND METHODS: A total of 136 consecutive patients with histologically proven bronchogenic carcinoma, registered between May 2014 and April 2016 at a tertiary care hospital in New Delhi, India, were analyzed. RESULTS: Out of a total of 136 diagnosed cases, 6% were in the third to fourth decade of life, 49% in the fifth to sixth decade, and 45% in the seventh decade and above. Seventy-one percent of patients were male. Smoking was the major risk factor in 65.40% of patients. About 33% of female patients were smokers with a significant overlap in the use of smoking objects. Twenty-one percent of patients had been initially empirically treated with antitubercular therapy. Most common symptoms at presentation were cough, dyspnea, weight loss, and chest pain. Pleural effusion, paraneoplastic phenomenon, clubbing, peripheral lymphadenopathy, and Pancoast syndrome were the major signs at presentation. Twenty-one percent of nonsmokers and 40% of smoker patients presented with ECOG Performance Status 3 or 4. Ninety-three percent of patients presented in stage III or IV. Metastases to skeleton, brain, liver, pleura, adrenals, lung, and distant lymph nodes were present in 30.8%, 16.9%, 15.4%, 15.4%, 14.7%, 13.2%, and 11.8%, respectively. Fiberoptic bronchoscopy was found to be the most efficient diagnostic procedure as compared to transthoracic and thoracoscopic methods. Histologically, squamous cell carcinoma, adenocarcinoma, and small cell carcinoma and its variants were seen in 35.30%, 44.9%, and 15.40% cases, respectively. Nearly 4.4% of patients were diagnosed as poorly differentiated carcinoma. Driver mutations (epidermal growth factor receptor or anaplastic lymphoma kinase) were detected in 48% (25 of 52 tested) of adenocarcinomas and 55.55% (5 of 9 tested) of young, nonsmoker, female squamous cell carcinoma patients. CONCLUSION: This study highlights that the adenocarcinoma incidence is surpassing squamous cell carcinoma in Indian lung cancer patients also, as observed in Western population. Mean age at diagnosis is about one decade earlier than in the Western population. Driver mutations are more common in India than in the West as also reported in other Asian studies.
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Quinasa de Linfoma Anaplásico/genética , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Pequeñas/epidemiología , Carcinoma de Células Pequeñas/genética , Carcinoma de Células Pequeñas/patología , Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/patología , Receptores ErbB/genética , Femenino , Humanos , Incidencia , India/epidemiología , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Factores de Riesgo , Fumadores/estadística & datos numéricos , Adulto JovenRESUMEN
In the current COVID-19 pandemic, tremendous pressure is been exerted on the existing health infrastructure of many developing nations. Limb salvage surgeries in bone and soft tissue sarcomas cannot be delayed beyond a certain time-period and constitute an orthopaedic emergency in certain situations. Evaluation of intra-operative surgical margins forms an important step especially in cases with planned close margins or intercalary resections. Techniques such as imprint cytology can be preferred over frozen sections for evaluation of the surgical margins especially in COVID-19 positive patients. The advantages it offers such as completion of the procedure within the operation room complex, no generation of aerosols, and almost equal sensitivity and specificity when compared with frozen section method do warrant a modification of current surgical practice in the current health crisis especially in resource-constrained nations. Awareness and better communication regarding the same from the pathologist to the surgical team will go a long way in conserving resources and avoid unnecessary exposure to potentially infected aerosols.
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AIM: The present study was conducted for the evaluation of Interleukin (IL)-1b levels in human gingival crevicular fluid (GCF), intensity of pain, and the amount of tooth movement measured during canine retraction using different magnitudes of continuous orthodontic force. MATERIALS AND METHOD: A statistically significant number of subjects were included for the study (n = 16, 6 male subjects and 10 female subjects). The age ranged from 18 to 24 years and all were diagnosed with Class I bimaxillary protrusion. They underwent first premolar extractions prior to participating in the study. The maxillary cuspids were then retracted using a continuous force of either 50 or 150 g. This was executed using nickel-titanium coil springs on segmented archwires. The opposite counterpart, that is, mandibular cuspid was used as control. GCF was then drawn from the distal aspect of each tooth at defined time intervals. This was followed by the assessment of IL-1b concentrations, pain intensity, using the visual analogue scale (VAS), and the amount of tooth movement. ANOVA test, Friedman test, and paired t-tests were used for comparisons of IL-1b in GCF, the plaque and gingival indices, and the efficiency of tooth movement on pain perception, respectively. RESULTS: The 150 g group showed the highest level of IL-1b concentration at 24 h from baseline and at 2 with significant differences compared with the control group (P < 0.05). The mean VAS score of pain intensity from the 150 g force was significantly greater than from the 50 g force at 24 h (P < 0.01). CONCLUSION: No significant difference in the amount of tooth movement was found between these two different magnitudes of continuous force at 2 months. A 50 g force could effectively induce tooth movement similar to 150 g with less pain and less inflammation.
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INTRODUCTION: Acute pancreatitis (AP) is the most common gastroenterology-related reason for hospital admission, and a major source of morbidity and mortality in the United States. This study examines the National Emergency Database Sample, a large national database, to analyze trends in emergency department (ED) utilization and costs, risk factors for hospital admission, and associated hospital costs and length of stay (LOS) in patients presenting with AP. METHODS: The National Emergency Database Sample (2006 to 2012) was evaluated for trends in ED visits, ED charges, hospitalization rates, hospital charges, and hospital LOS in patients with primary diagnosis of AP (further subcategorized by age and etiology). A survey logistic-regression model was used to determine factors predictive of hospitalization. RESULTS: A total of 2,193,830 ED visits were analyzed. There was a nonsignificant 5.5% (P=0.07) increase in incidence of ED visits for AP per 10,000 US adults from 2006 to 2012, largely driven by significant increases in ED visits for AP in the 18 to <45 age group (+9.2%; P=0.025), AP associated with alcohol (+15.9%; P=0.001), and AP associated with chronic pancreatitis (+59.5%; P=0.002). Visits for patients aged ≥65 decreased over the time period. Rates of admission and LOS decreased during the time period, while ED and inpatient costs increased (62.1%; P<0.001 and 7.9%; P=0.0011, respectively). Multiple factors were associated with increased risk of hospital admission from the ED, with the strongest predictors being morbid alcohol use [odds ratio (OR), 4.53; P<0.0001], advanced age (age>84 OR, 3.52; P<0.0001), and smoking (OR, 1.75; P<0.0001). CONCLUSIONS: Despite a relative stabilization in the overall incidence of ED visits for AP, continued increases in ED visits and associated costs appear to be driven by younger patients with alcohol-associated and acute on chronic pancreatitis. While rates of hospitalization and LOS are decreasing, associated inflation-adjusted costs are rising. In addition, identified risk factors for hospitalization, such as obesity, alcohol use, and increased age, should be explored in further study for potential use in predictive models and clinical improvement projects.
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Pancreatitis/epidemiología , Admisión del Paciente/estadística & datos numéricos , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Bases de Datos Factuales , Servicio de Urgencia en Hospital , Femenino , Costos de la Atención en Salud , Humanos , Incidencia , Tiempo de Internación , Masculino , Persona de Mediana Edad , Pancreatitis/economía , Pancreatitis/etiología , Estados Unidos/epidemiología , Adulto JovenRESUMEN
OBJECTIVES: Chronic pancreatitis (CP) hospitalizations along with associated morbidity and costs are increasing. The goal of this study was to use the National Readmission Database to identify the incidence and risk factors for 30-day readmissions among patients with CP. METHODS: We performed a retrospective analysis of National Readmission Database from January 2013 to December 2013 to determine patient demographic and clinical characteristics predictive of 30-day hospital readmission for adult patients (aged >18 years) discharged with a principle diagnosis of CP. A survey logistic regression model was used to determine the predictive value of selected variables for 30-day readmission. RESULTS: In 2013, 12,545 admissions with primary diagnosis of CP were noted, and 30.4% were readmitted within 30 days. Cholecystectomy (odds ratio [OR], 0.53; P = 0.0024) or endoscopic retrograde cholangiopancreatography (OR, 0.70; P = 0.01) during index admission was associated with decreased all-cause readmissions. Pancreatectomy during index admission was associated with reduced (OR, 0.2; P = 0.0005) pancreatitis-related readmissions. CONCLUSIONS: Hospital readmissions for CP are frequent and pose a significant healthcare burden. Performing cholecystectomy, endoscopic retrograde cholangiopancreatography, or pancreatectomy during index admission was associated with reduced odds of readmission.
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Hospitalización/estadística & datos numéricos , Pancreatitis Crónica/cirugía , Admisión del Paciente/estadística & datos numéricos , Readmisión del Paciente/estadística & datos numéricos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Colangiopancreatografia Retrógrada Endoscópica/métodos , Colangiopancreatografia Retrógrada Endoscópica/estadística & datos numéricos , Colecistectomía/métodos , Colecistectomía/estadística & datos numéricos , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Pancreatectomía/métodos , Pancreatectomía/estadística & datos numéricos , Pancreatitis Crónica/epidemiología , Estudios Retrospectivos , Factores de Tiempo , Estados Unidos/epidemiología , Adulto JovenRESUMEN
BACKGROUND: We evaluated the clinical presentation and risk factors of pulmonary embolism (PE) in soldiers posted at high altitude areas (HAA). METHODS: We conducted a retrospective analysis of all cases of PE presented to us between March 2011 and Aug 2014. The patients were serving at an altitude between 10,000 and 22,000ft above sea level and PE was diagnosed using the pulmonary CT angiography. Screening for the deep vein thrombosis (DVT) and procoagulant conditions was done at presentation and after six months of treatment. The patients were managed as per the American College of Cardiology (ACC) guidelines and descriptive statistics were used to present the data. RESULTS: The patients (53 males) had a mean age of 33±4.2 year and were serving at a mean altitude of 12,176±448 feet (ranged between 10,000 and 20,500) at the onset of symptoms. Dyspnea (79%) and tachycardia (68%) were the commonest symptom and sign, respectively. D dimer was positive in 96.2% of the cases while nonspecific T inversion in the ECG was seen in 54.7% of the patients. Procoagulant work up revealed a hereditary thrombophilic condition in 9 out of 53 patients. A total of 44 cases were idiopathic and DVT of lower limb veins was seen in 2 patients. There was no mortality in our case series. CONCLUSION: PE is a common complication of HAA and hereditary thrombophilia contributes in a minority of the patients. Further studies are needed to ascertain the risk factors of PE at HAA.
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Altitud , Personal Militar , Enfermedades Profesionales/epidemiología , Exposición Profesional/efectos adversos , Embolia Pulmonar/epidemiología , Medición de Riesgo/métodos , Adulto , Angiografía , Femenino , Estudios de Seguimiento , Humanos , Incidencia , India/epidemiología , Masculino , Enfermedades Profesionales/etiología , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/etiología , Estudios Retrospectivos , Factores de Riesgo , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVES: Acute pancreatitis (AP) is a common cause for hospitalization, and readmission is common, with variable associated risk factors for readmission. Here, we assessed the incidence and risk factors for readmission in AP in a large national database. METHODS: We analyzed data from the National Readmission Database during the year 2013. Index admissions with a primary discharge diagnosis of AP using the International Classification of Diseases, Ninth Revision, Clinical Modification were identified from January to November to identify 30-day readmission rates. Demographic, hospital, and clinical diagnoses were included in multivariate regression analysis to identify readmission risk factors. RESULTS: We identified 243,816 index AP discharges with 39,623 (16.2%) readmitted within 30 days. The most common reason for readmission was recurrent AP (41.5%). Increased odds of all-cause readmission were associated with younger age, nonhome discharge, increasing Charlson Comorbidity Index, and increased length of stay. Cholecystectomy during index admission was associated with reduced all-cause and recurrent AP readmissions (odds ratios of 0.5, and 0.35, respectively). CONCLUSIONS: Readmission for AP is common, most often due to recurrent AP. Multiple factors, including cholecystectomy, during index admission, are associated with significantly reduced odds of all-cause and recurrent AP readmissions.
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Pancreatitis/diagnóstico , Pancreatitis/terapia , Alta del Paciente/estadística & datos numéricos , Readmisión del Paciente/estadística & datos numéricos , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Incidencia , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pancreatitis/epidemiología , Pronóstico , Análisis de Regresión , Estudios Retrospectivos , Factores de Riesgo , Estados Unidos/epidemiología , Adulto JovenRESUMEN
INTRODUCTION: Increase in life expectancy across the globe has led to rise in geriatric population. Geriatric population is now living longer and healthier. This rise in geriatric population has also led to increase in the geriatric ailments leading to increased number of geriatric patients requiring intensive care including mechanical ventilation. Data on outcomes of geriatric patients requiring mechanical ventilation from India is scarce. AIM: To study the profile and outcome of geriatric patients more than equal to 60 years requiring mechanical ventilation in Intensive Care Unit (ICU). MATERIALS AND METHODS: The data of all the geriatric patients, more than 60 years of age, admitted to ICU between January 2008 to August 2014 requiring mechanical ventilation for various reasons were extracted from the hospital records. Various reasons for ventilation, duration of ventilation/hospital stay, mortality and associated comorbidities were recorded and analysed. RESULTS: Total 140 geriatric patients were mechanically ventilated in the study period, out of which 43.5% (61/140) were above 70 years of age and 67.8% (95/140) were above 65 years of age. Chronic Obstructive Pulmonary Disease (COPD) was the most common cause for mechanical ventilation constituting 20% of patients followed by severe sepsis (17.8%), cerebro-vascular accident (12.8%), post-surgical patients (12.8%) and Coronary Artery Disease (CAD) in 10%. In our study, 44.28% of the geriatric patients requiring mechanical ventilation in the ICU were successfully weaned off the ventilator. Early tracheostomy helped in weaning off from ventilator as 83.33% (5/6) of patients requiring tracheostomy could be weaned off the ventilator suggesting that tracheostomy may help in improving the outcome. Reintubation carried a very poor prognosis and increased mortality, as 80% (4/5) of the patients who were reintubated in our study could not survive. CONCLUSION: Our study revealed that in appropriate intensive care setting and with standard protocol based therapy for primary ailments, outcomes with mechanical ventilation in geriatric population can be comparable to outcomes in younger population.
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INTRODUCTION: In the event of any mass fatality incident, DNA analysis plays a vital role in disaster victim identification. Teeth are one of the most resistant structures in the human body that resist decomposition hence making them prime choice for extracting DNA for identification of individuals. Polymerase Chain Reaction (PCR) analysis that target regions of Amelogenin gene have become the method of choice for sex determination of biological samples. AIM: Determining the sex of a given DNA sample from either dental pulp or dentin of tooth and help in identification of missing persons and disaster victims. MATERIALS AND METHODS: In our study 50 teeth samples were studied and they were subjected to various environmental conditions along with freshly extracted teeth taken as control for duration of one month and three months. Pulpal tissue was retrieved from the teeth specimens by access opening of root canals and for incinerated samples, the specimens were crushed. From the DNA that was extracted from the dental pulp sample Amelogenin gene locus was used for sex determination by amplifying a segment of X-Y homologous gene locus through PCR analysis. RESULTS: ANOVA test and t-test proved to be statistically significant and 100% retrieval rate was observed in samples. CONCLUSION: Pulpal tissue along with degenerating odontoblastic processes yield sufficient amount of DNA for gender determination when subjected to various forensic conditions with maximum accuracy.
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BACKGROUND: Debonding of brackets commonly occurs during orthodontic treatment. Due to increase in costs replacement of a damaged bracket is not liked by the dentist. This study is done to assess the shear bond strength of recycled brackets using different methods. MATERIALS AND METHODS: This study was conducted using five groups of orthodontic brackets (0.022" × 0.028", MBT prescription) bonded on the premolars mounted in cubes. Other materials required were cubical trays, bonding material, light cure unit, universal testing machine, digital camera and sandblasting unit. RESULTS: From the result of ANOVA test we observed the test is significant (F = 20.79, P < 0.01) and the test is rejected. When the Tukey's t-test result was applied it was seen that the mean shear bond strength of all groups of brackets is as follows: Group I (5.31 Megapascals [Mpa]) < Group II (7.37 Mpa) < Group III (8.96 Mpa) < Group IV (5.56 Mpa) < Control group (9.24 Mpa). Alternatively we can say that shear bond strength of following bracket groups can be arranged as Group I < Group IV < Group II < Group III. CONCLUSION: From this study we conclude that Group III, which was recycled with an ultrasonic cleaner with electropolisher and silane coupling agent in place of primer, showed the highest shear bond strength.
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BACKGROUND: Musculoskeletal disorders have serious impact on the profession of dentistry. There is common occurrence of pain due to incorrect posture in dental professionals. Complementary and alternative medicine (CAM) therapies may cast a new light on preventing and intercepting musculoskeletal disorders (MSD). An epidemiological study was conducted in an effort to contribute to the prevention of musculoskeletal disorders in dentistry. The purpose of this study was to determine the prevalence of MSD at dentists using CAM as a treatment and preventive modality for MSD and to compare job/career satisfaction between dentists who use CAM and conventional therapy (CT). MATERIAL AND METHODS: Dentists registered in Uttrakhand state, India, under the Dental Council of India and registered members of the Indian Dental Association, Uttrakhand branch (N = 1496) were surveyed. Statistical analysis was conducted using SPSS 17. RESULTS: A response rate of 84% (N = 1257) was obtained, revealing that 90% (N = 1131) had the problem of MSD. Seventy three percentage (N = 826) of dentists with MSD reported the use of CAM and CT. Complementary and alternative medicine users reported greater overall health (72.7% vs. 51%, p < 0.001), job satisfaction (61.2% vs. 35%, p < 0.001) and work efficiency compared to CT users. CONCLUSION: Complementary and alternative medicine therapies may improve quality of life, reduce work interruption and enhance job satisfaction for dentists who suffers from MSD. Through the course of their studies, dentists should be equipped with knowledge on ergonomics and CAM therapies, such as yoga and others, to help them prevent musculoskeletal disorders more effectively.
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Terapias Complementarias , Odontólogos , Satisfacción en el Trabajo , Enfermedades Musculoesqueléticas/terapia , Enfermedades Profesionales/terapia , Adulto , Anciano , Estudios Transversales , Ergonomía , Femenino , Humanos , India/epidemiología , Masculino , Persona de Mediana Edad , Enfermedades Musculoesqueléticas/epidemiología , Enfermedades Musculoesqueléticas/psicología , Enfermedades Profesionales/epidemiología , Enfermedades Profesionales/psicología , Prevalencia , Calidad de Vida , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Periodontal diseases are ubiquitous, affecting all dentate animals. Regular methods for controlling it have been found to be ineffective, which have paved the way for the use of herbal products as an adjunctive to mechanical therapy as they are free to untoward effects and hence can be used for a long period of time. Ocimum sanctum is a plant which has the greater medicinal value and enormous properties for curing and preventing disease. OBJECTIVE: In the present study we assessed the effectiveness of Ocimum sanctum on dental plaque, gingival inflammation and comparison with gold standard chlorhexidine and normal saline (placebo). MATERIALS AND METHODS: A triple blind randomized control trial was conducted among volunteered medical students. They were randomly allocated into three study groups: (1) Ocimum sanctum mouthwash (n = 36); (2) Chlorhexidine (active control) (n = 36); (3) normal saline (negative control) (n = 36). Assessment was carried out according to plaque score and gingival score. Statistical analysis was carried out later to compare the effect of both mouthwash. ANOVA (Analysis of variance) and post-hoc LSD tests were performed using software package used for statistical analysis (SPSS) version 17. P ≤0.05 was considered as statistically significant. RESULTS: Our result showed that Ocimum sanctum mouthrinse is equally effective in reducing plaque and gingivitis as Chlorhexidine. The results demonstrated a significant reduction in gingival bleeding and plaque indices in both groups over a period of 15 and 30 days as compared to control group. CONCLUSION: The results of the present study indicate that Ocimum sanctum mouthrinse may prove to be an effective mouthwash owing to its ability in decreasing periodontal indices by reducing plaque accumulation, gingival inflammation and bleeding. It has no side effect as compared to chlorhexidine.
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A series of novel 6-(aminomethylphenoxy)benzoxaborole analogs was synthesized for the investigation of the structure-activity relationship of the inhibition of TNF-alpha, IL-1beta, and IL-6, from lipopolysaccharide stimulated peripheral blood mononuclear cells. Compounds 9d and 9e showed potent activity against all three cytokines with IC50 values between 33 and 83nM. Chloro substituted analog 9e (AN3485) is considered to be a promising lead for novel anti-inflammatory agent with a favorable pharmacokinetic profile.
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Antiinflamatorios/química , Benzoxazoles/química , Compuestos de Boro/química , Compuestos Bicíclicos Heterocíclicos con Puentes/metabolismo , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacocinética , Compuestos de Boro/metabolismo , Compuestos de Boro/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Semivida , Humanos , Interleucina-1beta/antagonistas & inhibidores , Interleucina-1beta/metabolismo , Interleucina-6/antagonistas & inhibidores , Interleucina-6/metabolismo , Cinética , Leucocitos Mononucleares/efectos de los fármacos , Lipopolisacáridos/toxicidad , Ratones , Unión Proteica , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Gram-negative bacteria cause approximately 70% of the infections in intensive care units. A growing number of bacterial isolates responsible for these infections are resistant to currently available antibiotics and to many in development. Most agents under development are modifications of existing drug classes, which only partially overcome existing resistance mechanisms. Therefore, new classes of Gram-negative antibacterials with truly novel modes of action are needed to circumvent these existing resistance mechanisms. We have previously identified a new a way to inhibit an aminoacyl-tRNA synthetase, leucyl-tRNA synthetase (LeuRS), in fungi via the oxaborole tRNA trapping (OBORT) mechanism. Herein, we show how we have modified the OBORT mechanism using a structure-guided approach to develop a new boron-based antibiotic class, the aminomethylbenzoxaboroles, which inhibit bacterial leucyl-tRNA synthetase and have activity against Gram-negative bacteria by largely evading the main efflux mechanisms in Escherichia coli and Pseudomonas aeruginosa. The lead analogue, AN3365, is active against Gram-negative bacteria, including Enterobacteriaceae bearing NDM-1 and KPC carbapenemases, as well as P. aeruginosa. This novel boron-based antibacterial, AN3365, has good mouse pharmacokinetics and was efficacious against E. coli and P. aeruginosa in murine thigh infection models, which suggest that this novel class of antibacterials has the potential to address this unmet medical need.
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Aminoacil-ARNt Sintetasas/antagonistas & inhibidores , Antibacterianos/farmacología , Compuestos de Boro/farmacología , Escherichia coli/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Pseudomonas aeruginosa/efectos de los fármacos , Aminoacil-ARNt Sintetasas/metabolismo , Animales , Antibacterianos/síntesis química , Antibacterianos/farmacocinética , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Compuestos de Boro/síntesis química , Compuestos de Boro/farmacocinética , Cristalografía por Rayos X , Descubrimiento de Drogas , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Escherichia coli/enzimología , Femenino , Infecciones por Bacterias Gramnegativas/microbiología , Humanos , Leucina/metabolismo , Ratones , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Pseudomonas aeruginosa/enzimología , Relación Estructura-Actividad , Muslo/microbiología , Inhibidores de beta-Lactamasas , beta-Lactamasas/metabolismoRESUMEN
We have used boron-based molecules to create novel, competitive, reversible inhibitors of phosphodiesterase 4 (PDE4). The co-crystal structure reveals a binding configuration which is unique compared to classical catechol PDE4 inhibitors, with boron binding to the activated water in the bimetal center. These phenoxybenzoxaboroles can be optimized to generate submicromolar potency enzyme inhibitors, which inhibit TNF-α, IL-2, IFN-γ, IL-5 and IL-10 activities in vitro and show safety and efficacy for topical treatment of human psoriasis. They provide a valuable new route for creating novel potent anti-PDE4 inhibitors.
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Compuestos de Boro/química , Compuestos de Boro/farmacología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Unión Competitiva , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Dominio Catalítico , Cristalografía por Rayos X , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Citocinas/biosíntesis , Humanos , Técnicas In Vitro , Isoenzimas/antagonistas & inhibidores , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Cinética , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Metales/química , Modelos Moleculares , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
γ-Secretase-mediated cleavage of amyloid precursor protein (APP) results in the production of Alzheimer disease-related amyloid-ß (Aß) peptides. The Aß42 peptide in particular plays a pivotal role in Alzheimer disease pathogenesis and represents a major drug target. Several γ-secretase modulators (GSMs), such as the nonsteroidal anti-inflammatory drugs (R)-flurbiprofen and sulindac sulfide, have been suggested to modulate the Alzheimer-related Aß production by targeting the APP. Here, we describe novel GSMs that are selective for Aß modulation and do not impair processing of Notch, EphB2, or EphA4. The GSMs modulate Aß both in cell and cell-free systems as well as lower amyloidogenic Aß42 levels in the mouse brain. Both radioligand binding and cellular cross-competition experiments reveal a competitive relationship between the AstraZeneca (AZ) GSMs and the established second generation GSM, E2012, but a noncompetitive interaction between AZ GSMs and the first generation GSMs (R)-flurbiprofen and sulindac sulfide. The binding of a (3)H-labeled AZ GSM analog does not co-localize with APP but overlaps anatomically with a γ-secretase targeting inhibitor in rodent brains. Combined, these data provide compelling evidence of a growing class of in vivo active GSMs, which are selective for Aß modulation and have a different mechanism of action compared with the original class of GSMs described.