Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 64
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Phys Rev Lett ; 129(6): 061104, 2022 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-36018635

RESUMEN

We report on a search for compact binary coalescences where at least one binary component has a mass between 0.2 M_{⊙} and 1.0 M_{⊙} in Advanced LIGO and Advanced Virgo data collected between 1 April 2019 1500 UTC and 1 October 2019 1500 UTC. We extend our previous analyses in two main ways: we include data from the Virgo detector and we allow for more unequal mass systems, with mass ratio q≥0.1. We do not report any gravitational-wave candidates. The most significant trigger has a false alarm rate of 0.14 yr^{-1}. This implies an upper limit on the merger rate of subsolar binaries in the range [220-24200] Gpc^{-3} yr^{-1}, depending on the chirp mass of the binary. We use this upper limit to derive astrophysical constraints on two phenomenological models that could produce subsolar-mass compact objects. One is an isotropic distribution of equal-mass primordial black holes. Using this model, we find that the fraction of dark matter in primordial black holes in the mass range 0.2 M_{⊙}

2.
Kathmandu Univ Med J (KUMJ) ; 20(78): 166-170, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-37017160

RESUMEN

Background Postpartum depression (PPD) is a disabling but treatable mental disorder that represents one of the most common complications of childbearing which can exert a wide range of effect on social, physical and mental health conditions of the mother and baby. Objective To identify the prevalence and factors associated with postpartum depression among mothers visiting immunization clinic at Birendranagar Municipality, Surkhet in year 2020. Method This study was a cross-sectional study. A total of 347 postpartum mothers were interviewed for data collection. Validated Nepali version of Edinburg Postnatal Depression Scale (EPDS) was used to identify postpartum depression. These mothers were permanent resident of Birendranagar who had delivered their babies in municipal hospital. Analysis was done using SPSS version 21.0. Chi square test was applied to identify association of postpartum depression with major interest of variables namely parity of mother, sex of a baby and recent planned or unplanned pregnancy. Odds ratio (OR) was calculated with 95% Confidence Interval (CI). Result The prevalence of postpartum depression was found to be 32.9% (27.9%, 37.8%). Several factors which were significantly associated with postpartum depression were; sex of the baby, history of abortion and recent pregnancy planned or unplanned. Conclusion Nearly one-third of postpartum mothers had depression. Hence screening of mothers for depression is of prime importance throughout the continuum of care. Likewise, the factors identified for postpartum depression needs to be taken care of well in advance for healthy mother and a baby.


Asunto(s)
Depresión Posparto , Femenino , Embarazo , Humanos , Depresión Posparto/epidemiología , Depresión Posparto/diagnóstico , Depresión Posparto/psicología , Madres/psicología , Prevalencia , Nepal/epidemiología , Estudios Transversales , Factores de Riesgo , Periodo Posparto/psicología , Inmunización
3.
Kathmandu Univ Med J (KUMJ) ; 19(74): 137-142, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34819443

RESUMEN

Background The spread of SARS-CoV-2 has become a global public health crisis. Nepal is facing the second wave of COVID-19 pandemic but, there is still a limited data on the genomic sequence of SARS-CoV-2 variants circulating in Nepal. Objective The objective of this study is to sequence the whole genome of SARS-CoV-2 in Nepal to detect possible mutation profiles and phylogenetic lineages of circulating SARSCoV-2 variants. Method In this study, swab samples tested positive for SARS-CoV-2 were investigated. After RNA extraction, the investigation was performed through real-time PCR followed by whole genome sequencing. The consensus genome sequences were, then, analyzed with appropriate bioinformatics tools. Result Sequence analysis of two SARS-CoV-2 genomes from patient without travel history (Patient A1 and A2) were found to be of lineage B.1.1. Similarly, among other four samples from subjects returning from the United Kingdom, genomes of two samples were of lineage B.1.36, and the other two were of lineage B.1.1.7 (Alpha Variant). The mutations in the consensus genomes contained the defining mutations of the respective lineages of SARS-CoV-2. Conclusion We confirmed two genomic sequences of variant of concern VOC-202012/01 in Nepal. Our study provides the concise genomic evidence for spread of different lineages of SARS-CoV-2 - B.1.1, B.1.36 and B.1.1.7 of SARS-CoV-2 in Nepal.


Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , Nepal , Pandemias , Filogenia , Secuenciación Completa del Genoma
4.
Kathmandu Univ Med J (KUMJ) ; 16(62): 151-155, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30636756

RESUMEN

Background Multidrug resistant in clinical bacterial isolates has increasingly been reported through out the world and is associated with high morbidity, mortality and increased health care costs. It is important to determine the status of multidrug resistance pattern to understand the current resistance trend so that appropriate antibiotics can be used in practice. Objective To determine the antibiotic resistant profile and prevalence of extended spectrum ß-lactamase producing multidrug resistant strains in pediatric patients of Kanti Children's Hospital, Kathmandu, Nepal. Method Urine sample was cultured by standard microbiological techniques and bacterial isolates were identified using different biochemical tests. Antibiotic susceptibility testing was performed by Kirby Bauer disc diffusion method and extended spectrum ß-lactamase detection was carried out using combined disc method as recommended by Clinical Laboratory Standard Institute guidelines. Result All together 65 different bacteria were isolated and subsequently identified. E. coli was the most common isolate with 46 (71%) isolates 63% of these isolates were multidrug resistant. Gram negative isolates were most resistant to nalidixic acid (81.97%) followed by ampicillin (69.35%) and co-trimoxazole (69.35%). The extended spectrum ß-lactamase producing isolates were 43% among total isolates. Conclusion Higher rate of Extended Spectrum ß-lactamase production among multidrug resistant isolates suggested routine extended spectrum ß-lactamase testing in clinical isolates.


Asunto(s)
Bacterias/aislamiento & purificación , Resistencia a Múltiples Medicamentos , Orina/microbiología , beta-Lactamasas/análisis , Antibacterianos/farmacología , Proteínas Bacterianas/análisis , Niño , Pruebas Antimicrobianas de Difusión por Disco , Hospitales Pediátricos , Humanos , Pruebas de Sensibilidad Microbiana , Nepal
5.
BMC Med Res Methodol ; 17(1): 106, 2017 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-28716047

RESUMEN

BACKGROUND: The standard definition for protocol adherence is the proportion of all scheduled doses that are delivered. In clinical research, this definition has several limitations when evaluating protocol adherence in trials that study interventions requiring continuous titration. DISCUSSION: Building upon a specific case study, we analyzed a recent trial of a continuously titrated intervention to assess the impact of different definitions of protocol deviations on the interpretation of protocol adherence. The OVATION pilot trial was an open-label randomized controlled trial of higher (75-80 mmHg) versus lower (60-65 mmHg) mean arterial pressure (MAP) targets for vasopressor therapy in shock. In this trial, potential protocol deviations were defined as MAP values outside the targeted range for >4 consecutive hours during vasopressor therapy without synchronous and consistent adjustments of vasopressor doses. An adjudication committee reviewed each potential deviation to determine if it was clinically-justified or not. There are four reasons for this contextual measurement and reporting of protocol adherence. First, between-arm separation is a robust measure of adherence to complex protocols. Second, adherence assessed by protocol deviations varies in function of the definition of deviations and the frequency of measurements. Third, distinguishing clinically-justified vs. not clinically-justified protocol deviations acknowledges clinically sensible bedside decision-making and offers a clear terminology before the trial begins. Finally, multiple metrics exist to report protocol deviations, which provides different information but complementary information on protocol adherence. CONCLUSIONS: In trials of interventions requiring continuous titration, metrics used for defining protocol deviations have a considerable impact on the interpretation of protocol adherence. Definitions for protocol deviations should be prespecified and correlated with between-arm separation, if it can be measured.


Asunto(s)
Protocolos Clínicos , Cooperación del Paciente , Ensayos Clínicos Controlados Aleatorios como Asunto/normas , Proyectos de Investigación/normas , Presión Arterial/efectos de los fármacos , Humanos , Hipotensión/tratamiento farmacológico , Hipotensión/etiología , Proyectos Piloto , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Choque/complicaciones , Vasoconstrictores/uso terapéutico
6.
SAR QSAR Environ Res ; 35(2): 157-179, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38346125

RESUMEN

A Disintegrin and Metalloproteinase 17 (ADAM17), a Zn2+-dependent metalloenzyme of the adamalysin family of the metzincin superfamily, is associated with various pathophysiological conditions including rheumatoid arthritis and cancer. However, no specific inhibitors have been marketed yet for ADAM17-related disorders. In this study, 94 quinolinyl methoxyphenyl sulphonyl-based hydroxamates as ADAM17 inhibitors were subjected to classification-based molecular modelling and binding pattern analysis to identify the significant structural attributes contributing to ADAM17 inhibition. The statistically validated classification-based models identified the importance of the P1' substituents such as the quinolinyl methoxyphenyl sulphonyl group of these compounds for occupying the S1' - S3' pocket of the enzyme. The quinolinyl function of these compounds was found to explore stable binding of the P1' substituents at the S1' - S3' pocket whereas the importance of the sulphonyl and the orientation of the P1' moiety also revealed stable binding. Based on the outcomes of the current study, four novel compounds of different classes were designed as promising ADAM17 inhibitors. These findings regarding the crucial structural aspects and binding patterns of ADAM17 inhibitors will aid the design and discovery of novel and effective ADAM17 inhibitors for therapeutic advancements of related diseases.


Asunto(s)
Ácidos Hidroxámicos , Relación Estructura-Actividad Cuantitativa , Proteína ADAM17 , Modelos Moleculares , Ácidos Hidroxámicos/química
7.
SAR QSAR Environ Res ; 35(8): 665-692, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39193767

RESUMEN

MMP-2 overexpression is strongly related to several diseases including cancer. However, none of the MMP-2 inhibitors have been marketed as drug candidates due to various adverse effects. Here, a set of sulphonyl pyrrolidines was subjected to validation of molecular modelling followed by binding mode analysis to explore the crucial structural features required for the discovery of promising MMP-2 inhibitors. This study revealed the importance of hydroxamate as a potential zinc-binding group compared to the esters. Importantly, hydrophobic and sterical substituents were found favourable at the terminal aryl moiety attached to the sulphonyl group. The binding interaction study revealed that the S1' pocket of MMP-2 similar to 'a basketball passing through a hoop' allows the aryl moiety for proper fitting and interaction at the active site to execute potential MMP-2 inhibition. Again, the sulphonyl pyrrolidine moiety can be a good fragment necessary for MMP-2 inhibition. Moreover, some novel MMP-2 inhibitors were also reported. They showed the significance of the 3rd position substitution of the pyrrolidine ring to produce interaction inside S2' pocket. The current study can assist in the design and development of potential MMP-2 inhibitors as effective drug candidates for the management of several diseases including cancers in the future.


Asunto(s)
Inhibidores de la Metaloproteinasa de la Matriz , Simulación de Dinámica Molecular , Pirrolidinas , Relación Estructura-Actividad Cuantitativa , Pirrolidinas/química , Pirrolidinas/farmacología , Inhibidores de la Metaloproteinasa de la Matriz/química , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Ligandos , Metaloproteinasa 2 de la Matriz/química , Metaloproteinasa 2 de la Matriz/metabolismo , Diseño de Fármacos
8.
SAR QSAR Environ Res ; 35(5): 367-389, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38757181

RESUMEN

Histone deacetylase 3 (HDAC3), a Zn2+-dependent class I HDACs, contributes to numerous disorders such as neurodegenerative disorders, diabetes, cardiovascular disease, kidney disease and several types of cancers. Therefore, the development of novel and selective HDAC3 inhibitors might be promising to combat such diseases. Here, different classification-based molecular modelling studies such as Bayesian classification, recursive partitioning (RP), SARpy and linear discriminant analysis (LDA) were conducted on a set of HDAC3 inhibitors to pinpoint essential structural requirements contributing to HDAC3 inhibition followed by molecular docking study and molecular dynamics (MD) simulation analyses. The current study revealed the importance of hydroxamate function for Zn2+ chelation as well as hydrogen bonding interaction with Tyr298 residue. The importance of hydroxamate function for higher HDAC3 inhibition was noticed in the case of Bayesian classification, recursive partitioning and SARpy models. Also, the importance of substituted thiazole ring was revealed, whereas the presence of linear alkyl groups with carboxylic acid function, any type of ester function, benzodiazepine moiety and methoxy group in the molecular structure can be detrimental to HDAC3 inhibition. Therefore, this study can aid in the design and discovery of effective novel HDAC3 inhibitors in the future.


Asunto(s)
Teorema de Bayes , Inhibidores de Histona Desacetilasas , Histona Desacetilasas , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Relación Estructura-Actividad Cuantitativa , Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Análisis Discriminante , Estructura Molecular
9.
J Dairy Sci ; 96(12): 7739-42, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24119794

RESUMEN

Protothecae are algal pathogens, capable of causing bovine mastitis, that are unresponsive to treatment; they are believed to have an environmental reservoir. The role of bedding management in control of protothecal mastitis has not been studied. The purpose of this study was to evaluate the growth of either environmental or mastitis-associated Prototheca genotypes in dairy bedding materials that are commonly used in Maine. Prototheca zopfii genotypes 1 and 2 (gt1 and gt2) were inoculated into sterile broth only (control ), kiln-dried spruce shavings, "green" hemlock sawdust, sand, or processed manure-pack beddings with broth, and incubated for 2 d. Fifty microliters of each isolate was then cultured onto plates and the resulting colonies counted at 24 and 48 h postinoculation. Shavings were associated with significantly less total Prototheca growth than other bedding types. Growth of P. zopfii gt1 was significantly higher than that of gt2 in the manure-pack bedding material. Spruce shavings, compared with manure, sand, or sawdust, may be a good bedding type to prevent growth of Prototheca. Based on these in vitro findings, bedding type may affect Prototheca infection of cattle in vivo.


Asunto(s)
Industria Lechera/métodos , Mastitis Bovina/etiología , Prototheca/fisiología , Animales , Ropa de Cama y Ropa Blanca/veterinaria , Bovinos , Industria Lechera/instrumentación , Femenino , Genotipo , Técnicas In Vitro , Maine , Estiércol , Mastitis Bovina/genética , Mastitis Bovina/prevención & control , Prototheca/genética , Prototheca/crecimiento & desarrollo
10.
Kathmandu Univ Med J (KUMJ) ; 11(42): 144-6, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24096222

RESUMEN

BACKGROUND: Cesarean section has been identified as one of the commonest indication for blood transfusion in obstetric practice because it involves risk of major intra-operative blood loss. Different figures varying from less than 500 ml to more than 1000 ml have been quoted as estimated blood loss associated with caesarean section. There is also a wide variation in blood ordering practices for this surgery. OBJECTIVE: The objective of this study is to evaluate the blood ordering practice and transfusion for cesarean sections at our institute, to see post-operative drop in hemoglobin and hematocrit and to correlate those parameters with the duration between uterine incision and repair. METHODS: In this prospective observational study, non-randomised purposive sample was taken from 121 ladies who underwent elective and emergency cesarean section at the department of obstetrics of Dhulikhel Hospital-Kathmandu University Hospital. Post-cesarean drop in hemoglobin and hematocrit and their relation with duration of uterine manipulation was calculated. Cross-match to transfusion (C/T ratio) ratio, transfusion probability (%T) and transfusion index (Ti) were also calculated. RESULTS: Most frequent blood group was found to be O positive (38%) among those ladies. Average post-cesarean drop in hemoglobin was 1.52±1.27 gm/dl and drop in haematocrit was 5.49±4.1%. Post-operative drop in hemoglobin and haematocrit had weak and positive linear relation with duration between uterine incision and repair. Cross-match to transfusion ratio was 1, transfusion probability 100% and transfusion index was 2. CONCLUSION: There is no need of routine cross-matching of blood for cesarean section. Only grouping with confirmation of availability should be done for emergency situation.


Asunto(s)
Transfusión Sanguínea/métodos , Cesárea/efectos adversos , Hemoglobinas/análisis , Hemorragia Posoperatoria/terapia , Adolescente , Adulto , Femenino , Hematócrito , Humanos , Nepal , Hemorragia Posoperatoria/sangre , Estudios Prospectivos , Factores de Tiempo , Adulto Joven
11.
SAR QSAR Environ Res ; 34(10): 805-830, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37850742

RESUMEN

MMP-2 is potentially contributing to several cancer progressions including leukaemias. Therefore, considering MMP-2 as a promising target, novel anticancer compounds may be designed. Here, 32 in-house arylsulfonyl L-(+) glutamines were subjected to various structure-based computational modelling approaches to recognize crucial structural attributes along with the spatial orientation for higher MMP-2 inhibition. Again, the docking-based 2D-QSAR study revealed that the Coulomb energy conferred by Tyr142 and total interaction energy conferred by Ala84 was crucial for MMP-2 inhibition. Importantly, the docking-dependent CoMFA and CoMSIA study revealed the importance of favourable steric, electrostatic, and hydrophobic substituents at the terminal phenyl ring. The MD simulation study revealed a lower fluctuation in the RMSD, RMSF, and Rg values indicating stable binding interactions of MMP-2 and these molecules. Moreover, the residual hydrogen bond and their interaction analysis disclosed crucial amino acid residues responsible for forming potential hydrogen bonding for higher MMP-2 inhibition. The results can effectively aid in the design and discovery of promising small-molecule drug-like MMP-2 inhibitors with greater anticancer potential in the future.


Asunto(s)
Antineoplásicos , Glutamina , Metaloproteinasa 2 de la Matriz , Inhibidores de la Metaloproteinasa de la Matriz , Antineoplásicos/química , Antineoplásicos/farmacología , Simulación por Computador , Glutamina/química , Glutamina/farmacología , Inhibidores de la Metaloproteinasa de la Matriz/química , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Relación Estructura-Actividad Cuantitativa
12.
SAR QSAR Environ Res ; 34(4): 299-319, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37170840

RESUMEN

Among various matrix metalloproteinases (MMPs), overexpression of MMP9 has been established as a key player in a variety of cancers. Therefore, MMP9 has emerged as a promising biomolecule that may be targeted to design potent inhibitors as novel anticancer therapeutics. In this study, a large database containing 1,123 drug-like MMP-9 inhibitors was considered for robust classification-dependent fragment-based QSAR study through SARpy, Bayesian classification, and recursive partitioning analyses and were validated by both internal and external validation techniques. In a nutshell, all these classification-dependent techniques revealed some common structural alerts and sub-structural fingerprints responsible for modulating MMP-9 inhibition. These observations are in agreement with the interactions obtained from the ligand-bound co-crystal structures of MMP-9 justifying the robustness of the current study. Finally, based on these crucial structural fragments, some new lead compounds were designed and further validated by the binding mode of interaction analysis. Therefore, these findings may be beneficial in designing novel and potential MMP-9 inhibitors in the future as a weapon to combat several cancers.


Asunto(s)
Metaloproteinasa 9 de la Matriz , Inhibidores de la Metaloproteinasa de la Matriz , Teorema de Bayes , Metaloproteinasa 9 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/química , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Relación Estructura-Actividad Cuantitativa
13.
Kathmandu Univ Med J (KUMJ) ; 10(38): 51-4, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23132476

RESUMEN

BACKGROUND: Anesthesiologists and anesthesia has been considered behind the scene. The image and status of anesthesiologist in the eyes of the medical and lay communities has always been a problem. OBJECTIVES: This study was designed to assess the knowledge about the role of anesthesiologist among the paramedical staffs at Kathmandu University Hospital. METHODS: This prospective questionnaire based study was done at Kathmandu University School of Medical Science, Dhulikhel Hospital for 2nd January 2011 to 30th Jan 2011 among the paramedical staffs working in different department of the hospital. RESULTS: There were 150 questionnaire distributed out of which 120 responded. Mean Age was 23.33 and most of the respondents were female with majority having education qualification equivalent to intermediate level. Only 49.20 said it to be a different specialty and 72.5% said anaesthesiologist work differently in the theatre where as 70% knew anaesthesiologist did something in the post-operative period too. CONCLUSION: Anesthesiologists have duty to visit patients pre operatively and post operatively. The role inside the theatre and expanding role outside the theatre is poorly known. The awareness about the role of anesthesiologist in operation theatre, in intensive care unit, acute and chronic pain management and emergency care areas should be highlighted to all the staffs.


Asunto(s)
Técnicos Medios en Salud/psicología , Anestesia , Anestesiología , Adulto , Femenino , Hospitales Universitarios , Humanos , Conocimiento , Masculino , Nepal , Rol del Médico , Estudios Prospectivos , Encuestas y Cuestionarios
14.
Kathmandu Univ Med J (KUMJ) ; 10(37): 24-9, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22971857

RESUMEN

BACKGROUND: Disc diffusion technique is the routine susceptibility testing procedure for isolates of enteric fever, the most common clinical diagnosis among febrile patients in Nepal. OBJECTIVE: To evaluated the current fluoroquinolones (FQs) susceptibility criteria and nalidixic acid screening test in Salmonella enterica serovar Typhi and Paratyphi A. METHODS: S. Typhi and Paratyphi A strains isolated from 443 suspected enteric fever patients visiting National Public Health Laboratory (NPHL) during April through October 2008 were analyzed. All isolates were confirmed by standard microbiological procedures including serotyping. Antibiotic susceptibility testing was performed by using Kirby Bauer disc diffusion method and Clinical and Laboratory Standards Institute (CLSI) approved interpretive criteria. Agar dilution method was used to determine Minimum Inhibitory Concentration (MIC) of ciprofloxacin, ofloxacin and nalidixic acid. RESULT: Out of 41 Salmonella isolates, 80.49% were nalidixic acid resistant, with S. Paratyphi A showing higher resistance rate (88.23%) compared to S. Typhi (75%). The difference in both MIC and zone diameter in nalidixic acid susceptible and nalidixic acid resistant isolates was found to be significant (P < 0.001) and decreased susceptibility to FQs was strongly correlated (sensitivity and specificity of 100%) with resistance to nalidixic acid. Regression analysis of MIC against zone diameter based on the current CLSI recommended guidelines suggests that accommodation of current susceptible and resistant MIC requires increase in the zone diameter of ciprofloxacin and ofloxacin. CONCLUSION: Before using these drugs for management of enteric fever, appropriate identification of Salmonella isolates with reduced susceptibility to FQs is essential to limit the possible treatment failure and development of highly resistant strains. The current FQs susceptibility break point criteria for Salmonella need re-evaluation.


Asunto(s)
Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple , Fluoroquinolonas/farmacología , Salmonella enterica/efectos de los fármacos , Ciprofloxacina/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , Ácido Nalidíxico/farmacología , Ofloxacino/farmacología
15.
SAR QSAR Environ Res ; 33(12): 987-1011, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36533308

RESUMEN

Histone deacetylase 8 (HDAC8) is a verified biomolecular target associated with diverse diseases including cancer. Though several HDAC inhibitors emerged effective against such diseases, no selective HDAC8 inhibitor is approved to date. Therefore, the development of potent HDAC8-selective inhibitors is inevitable to combat such diseases. Here, some benzothiazine-derived HDAC8 inhibitors were considered for a comparative QSAR analysis which may elucidate the prime structural components responsible for modulating their efficacy. Several outcomes from these diverse modelling techniques justified one another and thus validated each other. The ligand-based pharmacophore modelling study identified ring aromatic, positive ionizable, and hydrophobic features as essential structural attributes for HDAC8 inhibition. Besides, MLR, HQSAR and field-based 3D-QSAR studies signified the utility of the positive ionizable and hydrophobic features for potent HDAC8 inhibition. Again, the field-based 3D-QSAR study provided useful insight regarding the substitution in the fused phenyl ring. Moreover, the current observations also validated the previously reported molecular docking observations. Based on the outcomes, some new molecules were designed and predicted. Therefore, this comparative structural analysis of these HDAC8 inhibitors will surely assist in the development of potent HDAC8 inhibitors as promising anticancer therapeutics in the future.


Asunto(s)
Diseño de Fármacos , Relación Estructura-Actividad Cuantitativa , Simulación del Acoplamiento Molecular , Ligandos , Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química
16.
SAR QSAR Environ Res ; 33(11): 861-883, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36412121

RESUMEN

Alteration and abnormal epigenetic mechanisms can lead to the aberration of normal biological functions and the occurrence of several diseases. The histone deacetylase (HDAC) family of enzymes is one of the prime regulators of epigenetic functions modifying the histone proteins, and thus, regulating epigenetics directly. HDAC1 is one of those HDACs which have important contributions to cellular epigenetics. The abnormality of HDAC is correlated to the occurrence, progression, and poor prognosis in several disease conditions namely neurodegenerative disorders, cancer cell proliferation, metastasis, chemotherapy resistance, and survival in various cancers. Therefore, the progress of potent and effective HDAC1 inhibitors is one of the prime approaches to combat such diseases. In this study, both regression and classification-based molecular modelling studies were conducted on some AR-42 derivatives as HDAC1 inhibitors to elucidate the crucial structural aspects that are responsible for regulating their biological responses. This study revealed that the molecular polarizability, van der Waals volume, the presence of aromatic rings as well as the higher number of hydrogen bond acceptors might affect prominently their inhibitory activity and might be responsible for proper fitting and interactions at the HDAC1 active site to pertain effective inhibition.


Asunto(s)
Histona Desacetilasas , Relación Estructura-Actividad Cuantitativa , Histona Desacetilasas/metabolismo , Fenilbutiratos , Proliferación Celular
17.
SAR QSAR Environ Res ; 33(1): 1-22, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34979835

RESUMEN

Histone deacetylase 2 (HDAC2) has been implicated in a variety of cardiovascular and neurodegenerative disorders as well as in cancers. Thus, HDAC2 has become an exclusive target for anticancer drug development. Therefore, the development of newer HDAC2 inhibitors in disease conditions is a prime goal to restrain such a scenario. Although a handful of HDAC inhibitors was accepted for the treatment of HDAC-related disease conditions, the non-selective nature of these entities is one of the major setbacks in the treatment of specific HDAC isoform-related pathophysiology. In this framework, the analyses of pre-existing molecules are essential to identify the important structural features that can fulfil the requirements for the cap and linker moieties to obtain potent and effective HDAC2 inhibition. Thus, in this study, the implementation of a combined comparative 2D and 3D molecular modelling techniques was done on a group of 92 diverse hydroxamate derivatives having a wide range of HDAC2 inhibitory potency. Besides other crucial features, this study upheld the importance of groups like triazole and benzyl moieties along with the molecular fields that are crucial for regulating HDAC2 inhibition. The outcomes of this study may be employed for the designing of HDAC2 inhibitors in future.


Asunto(s)
Histona Desacetilasa 2 , Relación Estructura-Actividad Cuantitativa , Histona Desacetilasa 2/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos , Modelos Moleculares
18.
J Clin Microbiol ; 49(4): 1323-30, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21270225

RESUMEN

Haemophilus influenzae type b (Hib) is a major cause of invasive bacterial infection in children that can be prevented by a vaccine, but there is still uncertainty about its relative importance in Asia. This study investigated the age-specific prevalence of Hib carriage and its molecular epidemiology in carriage and disease in Nepal. Oropharyngeal swabs were collected from children in Kathmandu, Nepal, from 3 different settings: a hospital outpatient department (OPD), schools, and children's homes. Hib was isolated using Hib antiserum agar plates, and serotyping was performed with latex agglutination. Hib isolates from children with invasive disease were obtained during active microbiological surveillance at Patan Hospital, Kathmandu, Nepal. Genotyping of disease and carriage isolates was undertaken using multilocus sequence typing (MLST). Swabs were taken from 2,195 children, including 1,311 children at an OPD, 647 children attending schools, and 237 children in homes. Overall, Hib was identified in 5.0% (110/2,195; 95% confidence interval [95% CI], 3.9% to 6.4%). MLST was performed on 108 Hib isolates from children carrying Hib isolates and 15 isolates from children with invasive disease. Thirty-one sequence types (STs) were identified, and 20 of these were novel STs. The most common ST isolates were sequence type 6 (ST6) and the novel ST722. There was marked heterogeneity among the STs from children with disease and children carrying Hib. STs identified from invasive infections were those commonly identified in carriage. This study provides evidence of Hib carriage among children in urban Nepal with genetically diverse strains prior to introduction of universal vaccination. The Hib carriage rate in Nepal was similar to the rates observed in other populations with documented high disease rates prior to vaccination, supporting implementation of Hib vaccine in Nepal in 2009.


Asunto(s)
Portador Sano/epidemiología , Infecciones por Haemophilus/epidemiología , Haemophilus influenzae tipo b/aislamiento & purificación , Técnicas de Tipificación Bacteriana , Portador Sano/microbiología , Niño , Preescolar , Composición Familiar , Femenino , Genotipo , Infecciones por Haemophilus/microbiología , Hospitales , Humanos , Lactante , Masculino , Tipificación de Secuencias Multilocus , Nepal/epidemiología , Orofaringe/microbiología , Prevalencia , Instituciones Académicas , Serotipificación , Población Urbana
19.
Kathmandu Univ Med J (KUMJ) ; 9(36): 229-32, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22710528

RESUMEN

BACKGROUND: High sex ratios at birth (SRB) are seen in China, Taiwan, South Korea, parts of India and Vietnam. The imbalance is the result of son preference, accentuated by declining fertility. Prenatal sex determination and female feticides are common in many countries. It is reflected in sex ratio OBJECTIVE: To determine reasons for the preferences for different sex; to find out whether there is altered sex ratio at birth and to find out whether female feticide are common among women who had abortion. METHOD: It is a prospective study. Women who had previous history of abortion and had delivered at Patan Hospital in the year 2066 were interviewed as per questionnaires. RESULTS: Among 560 women with total live births of 965, (462 male and 503 female) during their life time the overall sex ratio was 92 male per 100 female birth; total abortions were 663. Preferences for male were 10%, female 15.4% and either was for 74%. The reason for male preference was to continue family lineage, to bring honor, old age security, and performing funeral rites while the reasons for daughter preferences were that they understand mothers pain, help in household work. The sex ratio of the babies born during the study period was 113 male per 100 female births. The Sex ratio at birth from 1st to 6th deliveries was 61, 79, 101, 210, 286 and 1100 male per 100 female birth respectively. Prenatal sex selection was 8% (by USG) but none had sex selected abortion. CONCLUSION: Sex ratio of those delivered during the study period was skewed (136 boys per 100 girls) towards male. There was shift in SRB in 4th and subsequent pregnancies in favor of boys. As the male sex ratio increased the number of induced abortion decreased in subsequent pregnancies.


Asunto(s)
Aborto Inducido/estadística & datos numéricos , Prioridad del Paciente/estadística & datos numéricos , Razón de Masculinidad , Adolescente , Adulto , Tasa de Natalidad , Cultura , Femenino , Humanos , Masculino , Nepal , Estudios Prospectivos , Análisis para Determinación del Sexo , Preselección del Sexo/estadística & datos numéricos , Factores Socioeconómicos , Encuestas y Cuestionarios , Adulto Joven
20.
Kathmandu Univ Med J (KUMJ) ; 9(33): 45-9, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22610809

RESUMEN

BACKGROUND: Pneumococcal infection is one of the leading causes of pneumonia, meningitis and septicemia in developing countries. It accounts for one million deaths each year in children. OBJECTIVES: The objective of this study is to see the clinical profile of invasive pneumococcal disease, antibiotics sensitivity pattern and prevalent serotypes in children admitted at Patan Hospital. METHODS: This is a retrospective analytical study conducted in the department of Paediatrics, Patan hospital. The lab data of those children who grew pneumococci in their blood, cerebrospinal fluid or body fluids over a period of 3 years (January 2007 to Dec 2009) were collected and the case files were then studied. RESULTS: Out of 42 cases of invasive pneumococcal diseases studied admitted diagnoses included pneumonia, febrile seizure, bacteremia or septicemia, meningitis, acute gastroenteritis and glomerulonephritis. Twenty seven of them were children under five. The male to female ratio was 1.7:1. On investigation 64%, 52% and 5% of the patients had leucocytosis, anaemia, and leucopenia respectively. Twenty six of them had radiological changes suggestive of pneumonia. Streptococcus pneumoniae grew in 38 blood samples, 5 cerebrospinal fluid and 3 pleural fluids. Almost all of these isolates were sensitive to penicillin, cefotaxime, amoxycillin, choloramphenicol, erythromycin and ofloxacin and resistant to cotrimoxazole and gentamicin. Pneumococcal serotypes found in our study were 1, 14, 5, 23B, 6B, 8, 9A, 9V, 10A, 15 and 23F (11 serotypes). CONCLUSIONS: Penicillin is still the most effective antibiotic for streptococcal infection in our study. Of the pneumococcal serotypes identified; 36% were covered by the 7-valent pneumococcal conjugate vaccine, 54% each by PCV-10 and PCV-13, and 72% by the e 23 valent vaccines.


Asunto(s)
Antibacterianos/uso terapéutico , Infecciones Neumocócicas/epidemiología , Adolescente , Antibacterianos/farmacología , Niño , Preescolar , Farmacorresistencia Bacteriana Múltiple , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Pruebas de Sensibilidad Microbiana , Nepal/epidemiología , Infecciones Neumocócicas/tratamiento farmacológico , Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas/administración & dosificación , Serotipificación
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA