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1.
Mymensingh Med J ; 30(4): 1079-1085, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34605480

RESUMO

Complete assessment of obstructive jaundice requires the use of various imaging modalities that are required to detect the cause and level of obstruction thus helping in treatment planning. Magnetic Resonance Cholangio Pancreatography (MRCP) is a current available technology which is a non-invasive technique that visualizes the gallbladder, biliary tree and pancreatic duct and also provides information about surrounding structures. This study was done to correlate the MRCP findings with post-operative result and thereby demonstrate the specificity, sensitivity and efficacy of MRCP as an accurate investigatory tool for biliary obstruction. Total of fifty (50) patients of clinically diagnosed obstructive jaundice were studied from March 2017 to August 2017 in the Department of Radiology and Imaging, Combined Military Hospital, Dhaka, Bangladesh. In all these cases, USG was the initial screening investigation followed by MRCP. Cause and level of obstruction were evaluated using MRCP findings. MRCP results were correlated with surgical findings and few cases also with direct ERCP findings. Statistical analysis was done to see the sensitivity, specificity, accuracy, positive and negative predictive values of MRCP in diagnosis of biliary obstruction. In this study, USG detected level of obstruction in 56% (28 out of 50) cases. USG could detect causes of obstruction in 100% (02 out of 02) cases of choledocal cyst and 66.67% (02 out of 03) benign stricture, 60% (03 out of 05) cases of periampullary carcinoma, 57.70% (06 out of 14) cases of choledocholithiasis, and 42.86% (15 out of 26) cases of cholangiocarcinoma. On the other hand, MRCP detected level of obstruction in 98% (49 out of 50) cases. MRCP could detect causes of obstruction in 100% cases of cholangiocarcinoma, choledocholithiasis, benign stricture and choledocal cyst and 80% (04 out of 05) cases of periampullary carcinoma. In this study, ERCP could detect causes of obstruction in 32 cases of choledocholithiasis and benign stricture, but in case of cholangiocarcinoma ERCP was failed in 3 cases. In this study, for detection of cause of obstruction, ERCP had the highest sensitivity (97.79%); followed by MRCP (96.65%) and USG (60.25%). The overall diagnostic accuracy for detection of cause of obstruction was the highest for ERCP (95.50%); followed by MRCP (94.50%) and USG (64.50%). MRCP can be done in a short duration and is a noninvasive diagnostic modality compared to ERCP. MRCP needs to be advocated as a viable and non-invasive alternative with compararable sensitivity and specificity to ERCP.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Colestase , Bangladesh , Ductos Biliares Intra-Hepáticos , Colangiopancreatografia por Ressonância Magnética , Colestase/diagnóstico por imagem , Colestase/etiologia , Humanos
2.
Nat Commun ; 12(1): 6107, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34671016

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) play an important role in interstellar chemistry and are subject to high energy photons that can induce excitation, ionization, and fragmentation. Previous studies have demonstrated electronic relaxation of parent PAH monocations over 10-100 femtoseconds as a result of beyond-Born-Oppenheimer coupling between the electronic and nuclear dynamics. Here, we investigate three PAH molecules: fluorene, phenanthrene, and pyrene, using ultrafast XUV and IR laser pulses. Simultaneous measurements of the ion yields, ion momenta, and electron momenta as a function of laser pulse delay allow a detailed insight into the various molecular processes. We report relaxation times for the electronically excited PAH*, PAH+* and PAH2+* states, and show the time-dependent conversion between fragmentation pathways. Additionally, using recoil-frame covariance analysis between ion images, we demonstrate that the dissociation of the PAH2+ ions favors reaction pathways involving two-body breakup and/or loss of neutral fragments totaling an even number of carbon atoms.

3.
Mol Genet Metab Rep ; 21: 100540, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31844629

RESUMO

Gaucher disease (GD) is a genetic disorder characterized by an accumulation of glucosylceramide in cells in the monocyte-macrophage system. We describe a case of a 33-year-old man with a previous diagnosis of type 3 GD who displayed a progressive weakening of the limbs followed by upper motor neuron involvement. A diagnosis of definite Amyotrophic Lateral Sclerosis was made. This is the first reported case of concurrent Gaucher disease and the ALS phenotype in the same patient.

4.
Artigo em Inglês | MEDLINE | ID: mdl-30834363

RESUMO

We report here the draft genome sequences of Staphylococcus bacteriophages JBug18, Pike, Pontiff, and Pabna, which infect and lyse S. epidermidis and S. aureus strains. All bacteriophages belong to the morphological family Podoviridae and constitute attractive candidates for use as whole-phage therapeutics due to their compact genomes and lytic lifestyles.

5.
United European Gastroenterol J ; 7(1): 146-154, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30788127

RESUMO

Background: Endoscopic mucosal resection of large non-pedunculated colon polyps is challenging. Objective: To determine if the time of day or daily endoscopic workload play a role in outcomes of endoscopic mucosal resection for large non-pedunculated colon polyps greater than 20 mm. Methods: This is a retrospective study of patients who underwent endoscopic mucosal resection of large non-pedunculated colon polyps. The time of day and endoscopic workload were compared across the following outcomes: the rate of complete resection of the polyp, the rate of referral for surgery, and the rate of residual neoplasia on follow-up. Results: One hundred and three endoscopic mucosal resection procedures were performed. There were no differences in the rates of complete resection (80.8% vs. 70.0%; P = 0.25), the need for surgery (27.4% vs. 33.3%; P = 0.55), and rate of residual neoplasia (24.5% vs. 50.0%; P = 0.07) when comparing the time of day. Colon polyps greater than 40 mm were less likely to be completely resected versus polyps sized 20-39 mm (56.8% vs. 91.9%; P < 0.001). In cases with no residual neoplasia on follow-up, the mean duration for the index procedure was 45.6 minutes versus 60.7 minutes when there was residual neoplasia (P < 0.01). Conclusion: The time of day and endoscopic workload does not affect outcomes for endoscopic mucosal resection of large non-pedunculated colon polyps, but the size of large non-pedunculated colon polyps and resection times do.


Assuntos
Pólipos do Colo/diagnóstico por imagem , Pólipos do Colo/cirurgia , Colonoscopia , Ressecção Endoscópica de Mucosa , Carga de Trabalho , Pólipos do Colo/patologia , Colonoscopia/métodos , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Ressecção Endoscópica de Mucosa/métodos , Feminino , Humanos , Masculino , Avaliação de Resultados da Assistência ao Paciente , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Fluxo de Trabalho
6.
Mymensingh Med J ; 28(1): 8-14, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30755544

RESUMO

The standard treatment of high variety anorectal malformation (ARM) is the staged approach. A growing interest in one stage correction of high variety ARM was noted recently. The aim of this study was to examine the feasibility, safety and outcome of single stage correction of High variety ARM. This prospective study was carried out in the Department of Paediatric Surgery, Mymensingh Medical College Hospital (MMCH), Mymensingh, Bangladesh from July 2012 to September 2013. It was conducted among 30 patients, all having high ARM. The type of ARM was diagnosed by clinical examinations and imaging studies like Invertogram and Transperineal USG. Other associated congenital anomalies were excluded. Out of 30 patients 11(36.67%) were male and 19(63.33%) were female. The age incidence ranges from 2 days to 5 months with the mean±SD age 1.70±1.63 months. The type of fistula present along with ARM in male varies from rectobulber urethral fistula, recto prostatic urethral fistula, recto vesical fistula and in one case without any fistula. Type of fistula was rectovestibular, rectovaginal and one cloacal malformation among the female patients. The treatment modalities in male patients vary in transabdominal pull through anorectoplasty and PSARP, in which the former was done more (72.73%). In case of female patients, treatment modalities vary in transabdominal pull through and anorectoplasty and transfistulous anorectoplasty, with the later done more (52.63%). Regarding post operative complications, there was 1(14.29%) wound infection in male and 1(33.33%) in female, partial wound disruption in 1(14.29%) male patient, mucosal prolapse 2(28.57%) in male and 1(33.33%) in female, anal stenosis 1(14.29%) in male and 1(33.33%) in female, perianal soiling in 1(14.29%) male patient. All the complications were treated by adopting various measures. One stage correction of High variety ARM in both male and female patients is technically feasible. The safeties of this approach depend on the adherence to strict inclusion criteria. The early post operative complications are acceptable and can be managed successfully.


Assuntos
Malformações Anorretais/cirurgia , Fístula Retal/cirurgia , Fístula Retovaginal/cirurgia , Reto/cirurgia , Canal Anal/cirurgia , Bangladesh , Criança , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Estudos de Viabilidade , Feminino , Humanos , Masculino , Estudos Prospectivos , Fístula Retal/congênito , Fístula Retovaginal/congênito , Resultado do Tratamento
7.
Methods Enzymol ; 616: 385-409, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30691652

RESUMO

Phages are the most abundant entities in the biosphere and profoundly impact the bacterial populations within and around us. They attach to a specific host, inject their DNA, hijack the host's cellular processes, and replicate exponentially while destroying the host. Historically, phages have been exploited as powerful antimicrobials, and phage-derived proteins have constituted the basis for numerous biotechnological applications. Only in recent years have metagenomic studies revealed that phage genomes harbor a rich reservoir of genetic diversity, which might afford further therapeutic and/or biotechnological value. Nevertheless, functions for the majority of phage genes remain unknown, and due to their swift and destructive replication cycle, many phages are intractable by current genetic engineering techniques. Whether to advance the basic understanding of phage biology or to tap into their potential applications, efficient methods for phage genetic engineering are needed. Recent reports have shown that CRISPR-Cas systems, a class of prokaryotic immune systems that protect against phage infection, can be harnessed to engineer diverse phages. In this chapter, we describe methods to genetically manipulate virulent phages using CRISPR-Cas10, a Type III-A CRISPR-Cas system native to Staphylococcus epidermidis. A method for engineering phages that infect a CRISPR-less Staphylococcus aureus host is also described. Both approaches have proved successful in isolating desired phage mutants with 100% efficiency, demonstrating that CRISPR-Cas10 constitutes a powerful tool for phage genetic engineering. The relatively widespread presence of Type III CRISPR-Cas systems in bacteria and archaea imply that similar strategies may be used to manipulate the genomes of diverse prokaryotic viruses.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/métodos , Fagos de Staphylococcus/genética , Staphylococcus aureus/virologia , Staphylococcus epidermidis/virologia , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Engenharia Genética/métodos , Staphylococcus aureus/genética , Staphylococcus epidermidis/genética
8.
Artigo em Inglês | MEDLINE | ID: mdl-34113778

RESUMO

Following a 1983 chromic acid (hexavalent chromium [CrVI]) spill from a Garfield, NJ electroplating plant, CrVI-contaminated water was found in a local firehouse basement in 1993. An ATSDR public health advisory was issued for the plant site in 2010, and from 2008-2015, fourteen residential properties have required remediation to address CrVI-contaminated dust in the basements. As part of the Community Outreach and Engagement Core of the NYU NIEHS Center, seventytwo Garfield residents aged 18-65 years, participated in a community survey with the goal of identifying concerns related to environmental and community health. Thirty-two percent responded that they 'didn't know' if they were exposed to chemicals or pollutants where they live. This finding suggests a limited awareness of environmental chemical exposures, chromium contamination and/or potential exposure to CrVI. Furthermore, toenail clippings were collected from forty-seven Garfield residents and analyzed for total chromium levels to assess potential long-term exposure. On average, residents living on/inside the contaminated plume area had higher total chromium levels in their toenail clippings than residents living outside the plume area. However, chromium levels for all participants were within the range of historical normal. This study highlights the value of partnerships between environmentally-impacted community's and academic scientists working together to identify potential contaminant exposures and address public health concerns through research and environmental health education.

10.
J Postgrad Med ; 64(4): 206-211, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29943747

RESUMO

Introduction: The role of physicians often extends beyond provision of direct patient care and includes appearance in courts as professional or expert witnesses to give their testimony in various legal cases. This often consumes precious time and resources of the doctors and the hospitals. This study was taken up to evaluate the present system of the physical appearance of the doctors to various courts and compare it with the videoconferencing mode of giving testimony (tele-evidence). Materials and Methods: Available records of summons and vehicles used were analyzed to calculate the cost involved and man-hours consumed in honoring the court summons. Telemedicine facility, available in our institute, was used for conducting tele-evidence with selected courts of the two states as a pilot, which was later expanded. A survey was also done to assess the experience of the physicians with physical appearance and videoconferencing using structured questionnaire after approval from the Institute's Ethics Committee. Likert scale of 0-10 points was used to measure satisfaction. Results: There was 43% drop in the monthly mileage of vehicles, 49% reduction in the fuel cost per month, and 28% savings in terms of time consumed for court duties. Satisfaction score for parameters of time consumed, physical strain, mental strain, communication with Honorable Judges, and overall experience was 87% through tele-evidence as compared to 31% with physical appearance. Conclusion: Tele-evidence is an acceptable and implementable mode of testifying and has led to tremendous resource savings in our tertiary care setting. The model needs to be replicated for deliverance of justice and is in consonance with Government's push toward Digital India.


Assuntos
Prova Pericial/métodos , Médicos/estatística & dados numéricos , Comunicação por Videoconferência/estatística & dados numéricos , Humanos , Índia , Estudos Retrospectivos
11.
Phys Rev Lett ; 120(13): 133202, 2018 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-29694177

RESUMO

Double and triple detachment of the F^{-}(1s^{2}2s^{2}2p^{6}) negative ion by a single photon have been investigated in the photon energy range 660 to 1000 eV. The experimental data provide unambiguous evidence for the dominant role of direct photodouble detachment with a subsequent single-Auger process in the reaction channel leading to F^{2+} product ions. Absolute cross sections were determined for the direct removal of a (1s+2p) pair of electrons from F^{-} by the absorption of a single photon.

12.
ACS Synth Biol ; 6(12): 2316-2325, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-28885820

RESUMO

Staphylococci are prevalent skin-dwelling bacteria that are also leading causes of antibiotic-resistant infections. Viruses that infect and lyse these organisms (virulent staphylococcal phages) can be used as alternatives to conventional antibiotics and represent promising tools to eliminate or manipulate specific species in the microbiome. However, since over half their genes have unknown functions, virulent staphylococcal phages carry inherent risk to cause unknown downstream side effects. Further, their swift and destructive reproductive cycle make them intractable by current genetic engineering techniques. CRISPR-Cas10 is an elaborate prokaryotic immune system that employs small RNAs and a multisubunit protein complex to detect and destroy phages and other foreign nucleic acids. Some staphylococci naturally possess CRISPR-Cas10 systems, thus providing an attractive tool already installed in the host chromosome to harness for phage genome engineering. However, the efficiency of CRISPR-Cas10 immunity against virulent staphylococcal phages and corresponding utility as a tool to facilitate their genome editing has not been explored. Here, we show that the CRISPR-Cas10 system native to Staphylococcus epidermidis exhibits robust immunity against diverse virulent staphylococcal phages. On the basis of this activity, a general two-step approach was developed to edit these phages that relies upon homologous recombination machinery encoded in the host. Variations of this approach to edit toxic phage genes and access phages that infect CRISPR-less staphylococci are also presented. This versatile set of genetic tools enables the systematic study of phage genes of unknown functions and the design of genetically defined phage-based antimicrobials that can eliminate or manipulate specific Staphylococcus species.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Fagos de Staphylococcus/genética , Staphylococcus aureus/virologia , Staphylococcus epidermidis/virologia , Fagos de Staphylococcus/patogenicidade , Staphylococcus aureus/genética , Staphylococcus epidermidis/genética
13.
PLoS One ; 12(7): e0180838, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28700707

RESUMO

METHODS: Phages isolated from environmental waters in Bangladesh were tested for their host specificity towards V. cholerae O1 and O139, and the ability to disperse V. cholerae biofilms formed in the laboratory. Representative phages were further characterized by electron microscopy and whole genome sequencing. Selected phages were then introduced in various combinations to biofilms of toxigenic V. cholerae added to samples of river water, and the dispersion of biofilms as well as the growth kinetics of V. cholerae and the phages were monitored. RESULTS: A phage cocktail composed of three different phages isolated from surface waters in Bangladesh and designated as JSF7, JSF4, and JSF3 could significantly influence the distribution and concentration of the active planktonic form and biofilm associated form of toxigenic V. cholerae in water. While JSF7 showed a biofilm degrading activity and dispersed cells from both V. cholerae O1 and O139 derived biofilms thus increasing the concentration of planktonic V. cholerae in water, JSF4 and JSF3 showed strong bactericidal activity against V. cholerae O1 and O139 respectively. A mixture of all three phages could effectively reduce both biofilm-associated and planktonic V. cholerae in river water microcosms. SIGNIFICANCE: Besides potential applicability in phage-mediated control of cholera, our results have relevance in appreciating possible intricate role of diverse environmental phages in the epidemiology of the disease, since both biofilms and phages influence the prevalence and infectivity of V. cholerae in a variety of ways.


Assuntos
Bacteriófagos/fisiologia , Biofilmes/crescimento & desenvolvimento , Plâncton/virologia , Vibrio cholerae/virologia , Cólera/epidemiologia , Vibrio cholerae O1/virologia , Vibrio cholerae O139/virologia , Microbiologia da Água
14.
mSphere ; 2(2)2017.
Artigo em Inglês | MEDLINE | ID: mdl-28357414

RESUMO

Drug-resistant staphylococci, particularly Staphylococcus aureus and Staphylococcus epidermidis, are leading causes of hospital-acquired infections. Bacteriophages and their peptidoglycan hydrolytic enzymes (lysins) are currently being explored as alternatives to conventional antibiotics; however, only a limited diversity of staphylococcal phages and their lysins has yet been characterized. Here, we describe a novel staphylococcal phage and its lysins. Bacteriophage Andhra is the first reported S. epidermidis phage belonging to the family Podoviridae. Andhra possesses an 18,546-nucleotide genome with 20 open reading frames. BLASTp searches revealed that gene product 10 (gp10) and gp14 harbor putative catalytic domains with predicted peptidase and amidase activities, characteristic functions of phage lysins. We purified these proteins and show that both Andhra_gp10 and Andhra_gp14 inhibit growth and degrade cell walls of diverse staphylococci, with Andhra_gp10 exhibiting more robust activity against the panel of cell wall substrates tested. Site-directed mutagenesis of its predicted catalytic residues abrogated the activity of Andhra_gp10, consistent with the presence of a catalytic CHAP domain on its C terminus. The active site location combined with the absence of an SH3b cell wall binding domain distinguishes Andhra_gp10 from the majority of staphylococcal lysins characterized to date. Importantly, close homologs of Andhra_gp10 are present in related staphylococcal podophages, and we propose that these constitute a new class of phage-encoded lysins. Altogether, our results reveal insights into the biology of a rare family of staphylococcal phages while adding to the arsenal of antimicrobials with potential for therapeutic use. IMPORTANCE The spread of antibiotic resistance among bacterial pathogens is inciting a global public health crisis. Drug-resistant Staphylococcus species, especially S. aureus and S. epidermidis, have emerged in both hospital and community settings, underscoring the urgent need for new strategies to combat staphylococcal infections. Bacterial viruses (phages) and the enzymes that they use to degrade bacterial cell walls (lysins) show promise as alternative antimicrobials; however, only a limited variety of staphylococcal phages and their lysins have yet been identified. Here, we report the discovery and characterization of a novel staphylococcal phage, Andhra. We show that Andhra encodes two lysins (Andhra_gp10 and Andhra_gp14) that inhibit growth and degrade the cell walls of diverse staphylococci, including S. aureus and S. epidermidis strains. Andhra and its unique lysins add to the arsenal of antimicrobials with potential for therapeutic use.

15.
Sci Rep ; 6: 37956, 2016 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-27892495

RESUMO

Predation by bacteriophages can significantly influence the population structure of bacterial communities. Vibrio cholerae the causative agent of cholera epidemics interacts with numerous phages in the aquatic ecosystem, and in the intestine of cholera patients. Seasonal epidemics of cholera reportedly collapse due to predation of the pathogen by phages. However, it is not clear how sufficient number of the bacteria survive to seed the environment in the subsequent epidemic season. We found that bacterial cell density-dependent gene expression termed "quorum sensing" which is regulated by signal molecules called autoinducers (AIs) can protect V. cholerae against predatory phages. V. cholerae mutant strains carrying inactivated AI synthase genes were significantly more susceptible to multiple phages compared to the parent bacteria. Likewise when mixed cultures of phage and bacteria were supplemented with exogenous autoinducers CAI-1 or AI-2 produced by recombinant strains carrying cloned AI synthase genes, increased survival of V. cholerae and a decrease in phage titer was observed. Mutational analyses suggested that the observed effects of autoinducers are mediated in part through the quorum sensing-dependent production of haemaglutinin protease, and partly through downregulation of phage receptors. These results have implication in developing strategies for phage mediated control of cholera.


Assuntos
Bacteriófagos/patogenicidade , Percepção de Quorum/fisiologia , Vibrio cholerae/virologia , Aglutinação , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Regulação para Baixo , Regulação Bacteriana da Expressão Gênica , Homosserina/análogos & derivados , Homosserina/metabolismo , Soros Imunes , Cetonas/metabolismo , Lactonas/metabolismo , Mutação , Antígenos O/genética , Antígenos O/imunologia , Antígenos O/metabolismo , Peptídeo Hidrolases/genética , Peptídeo Hidrolases/metabolismo , Percepção de Quorum/genética , Coelhos , Vibrio cholerae/genética , Vibrio cholerae/crescimento & desenvolvimento
16.
Mymensingh Med J ; 25(3): 567-70, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27612909

RESUMO

Ilizarov method is the best weapon for the treatment of the limb length discrepancy, especially in traumatic or congenital shortening of long bones. Post burn bony defect can be corrected by osteosynthesis. Here we treated a 7 years old boy, suffering from 33% electric burn affecting face, trunk, left upper limb & both lower limbs with loss of soft tissue of medial side of right leg along with dead and exposed of some segment (about 14cm) of Left tibia . Initially the patient was managed by plastic surgeons in the form of surgical toileting, wound debridement and wound coverage by split thickness skin graft. After about 6 weeks, we applied Ilizarov fixator on the affected limb and maintained it for 7 days to increase vascularity. As there was minimum bone in the proximal part, we did corticotomy at the distal end. After 7 days further, we started distal to proximal bone transport at a rate of 1mm per day. Staged excision of about 2.5 to 3cm dead bone was done, after transporting the same length of bone each time. In 5 such sittings, a total of 14cm bone was excised. Thus the burned portion was replaced by new bone; bony union was achieved after applying compression. Now the patient is able to walk individually, without any difficulty. So, we found that, Ilizarov method is a good option for the management of post burn bone loss. To our knowledge, such an application of the Ilizarov external fixation device in post burn bone loss has yet to be reported.


Assuntos
Técnica de Ilizarov , Salvamento de Membro , Fraturas da Tíbia , Criança , Fixadores Externos , Humanos , Masculino , Tíbia , Fraturas da Tíbia/cirurgia
17.
SAR QSAR Environ Res ; 27(2): 125-45, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26911562

RESUMO

The Gly/NMDA receptor has become known as potential target for the management of neurodegenerative diseases. Discovery of Gly/NMDA antagonists has thus attracted much attention in recent years. In the present research, a cheminformatics approach has been used to determine structural requirements for Gly/NMDA antagonism and to identify potential antagonists. Here, 37 quinoxaline derivatives were selected to develop a significant pharmacophore model with good certainty. The selected model was validated by leave-one-out cross-validation, an external test set, decoy set and Y-randomization test. Applicability domain was verified by the standardization approach. The validated 3D-QSAR model was used to screen virtual hits from the ZINC database by pharmacophore mapping. Molecular docking was used for assessment of receptor-ligand binding modes and binding affinities. The GlideScore and molecular interactions with critical amino acids were considered as crucial features to identify final hits. Furthermore, hits were analysed for in silico pharmacokinetic parameters and Lipinski's rule of five, demonstrating their potential as drug-like candidates. The PubChem and SciFinder search tools were used to authenticate the novelty of leads retrieved. Finally, five different leads have been suggested as putative novel candidates for the exploration of potent Gly/NMDA receptor antagonists.


Assuntos
Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Quinoxalinas/química , Quinoxalinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Sítios de Ligação , Simulação por Computador , Descoberta de Drogas/métodos , Glicina/metabolismo , Modelos Moleculares , Quinoxalinas/farmacocinética , Reprodutibilidade dos Testes
18.
Infect Immun ; 82(9): 3636-43, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24935981

RESUMO

In El Tor biotype strains of toxigenic Vibrio cholerae, the CTXϕ prophage often resides adjacent to a chromosomally integrated satellite phage genome, RS1, which produces RS1ϕ particles by using CTX prophage-encoded morphogenesis proteins. RS1 encodes RstC, an antirepressor against the CTXϕ repressor RstR, which cooperates with the host-encoded LexA protein to maintain CTXϕ lysogeny. We found that superinfection of toxigenic El Tor strains with RS1ϕ, followed by inoculation of the transductants into the adult rabbit intestine, caused elimination of the resident CTX prophage-producing nontoxigenic derivatives at a high frequency. Further studies using recA deletion mutants and a cloned rstC gene showed that the excision event was recA dependent and that introduction of additional copies of the cloned rstC gene instead of infection with RS1ϕ was sufficient to enhance CTXϕ elimination. Our data suggest that once it is excised from the chromosome, the elimination of CTX prophage from host cells is driven by the inability to reestablish CTXϕ lysogeny while RstC is overexpressed. However, with eventual loss of the additional copies of rstC, the nontoxigenic derivatives can act as precursors of new toxigenic strains by acquiring the CTX prophage either through reinfection with CTXϕ or by chitin-induced transformation. These results provide new insights into the role of RS1ϕ in V. cholerae evolution and the emergence of highly pathogenic clones, such as the variant strains associated with recent devastating epidemics of cholera in Asia, sub-Saharan Africa, and Haiti.


Assuntos
Bacteriófagos/imunologia , Lisogenia/imunologia , Prófagos/imunologia , Vibrio cholerae/imunologia , Animais , Proteínas de Bactérias/imunologia , Cólera/genética , Cólera/microbiologia , Toxina da Cólera/genética , Genes Bacterianos/genética , Intestinos/imunologia , Intestinos/microbiologia , Coelhos , Serina Endopeptidases/imunologia
19.
Proc Natl Acad Sci U S A ; 110(24): 9926-31, 2013 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-23716683

RESUMO

Cholera epidemics have long been known to spread through water contaminated with human fecal material containing the toxigenic bacterium Vibrio cholerae. However, detection of V. cholerae in water is complicated by the existence of a dormant state in which the organism remains viable, but resists cultivation on routine bacteriological media. Growth in the mammalian intestine has been reported to trigger "resuscitation" of such dormant cells, and these studies have prompted the search for resuscitation factors. Although some positive reports have emerged from these investigations, the precise molecular signals that activate dormant V. cholerae have remained elusive. Quorum-sensing autoinducers are small molecules that ordinarily regulate bacterial gene expression in response to cell density or interspecies bacterial interactions. We have found that isolation of pathogenic clones of V. cholerae from surface waters in Bangladesh is dramatically improved by using enrichment media containing autoinducers either expressed from cloned synthase genes or prepared by chemical synthesis. These results may contribute to averting future disasters by providing a strategy for early detection of V. cholerae in surface waters that have been contaminated with the stools of cholera patients or asymptomatic infected human carriers.


Assuntos
Homosserina/análogos & derivados , Cetonas/farmacologia , Lactonas/farmacologia , Percepção de Quorum/efeitos dos fármacos , Vibrio cholerae/efeitos dos fármacos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Bangladesh , Liases de Carbono-Enxofre/genética , Liases de Carbono-Enxofre/metabolismo , Cólera/microbiologia , Meios de Cultura/farmacologia , Fezes/microbiologia , Homosserina/farmacologia , Humanos , Cinética , Mutação , Percepção de Quorum/genética , Percepção de Quorum/fisiologia , Vibrio cholerae/genética , Vibrio cholerae/crescimento & desenvolvimento , Microbiologia da Água
20.
Asian Pac J Trop Med ; 6(5): 352-9, 2013 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-23608373

RESUMO

OBJECTIVE: To investigate in vitro and in vivo antibacterial potentials of Vitex negundo (V. negundo) leaf extracts against diverse enteric pathogens. METHODS: Water and methanol extracts of V. negundo leaves were evaluated against enteric bacterial pathogens by using standard disc diffusion, viable bacterial cell count methods, determination of minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC). RESULTS: Methanol extract of V. negundo leaves showed potent antibacterial activity (inhibition zone: 9.9-22.6 mm, MIC: 200-3200 µg/mL, MBC: 200-6400 µg/mL) against all the pathogenic enteric bacteria (Vibrio cholerae, Vibrio parahaemolyticus, Vibrio mimicus, Echerichia coli, Shigella spps., and Aeromonas spps) tested. Methanol extract of V. negundo leaves showed potent bactericidal activity both in vitro laboratory conditions (MBC, 200-400 µg/mL) and in the intestinal environment (Dose, 1-2 mg/mL) of infant mice against pathogenic Vibrio cholerae, the major causative agent of cholera. Furthermore, assays using the mice cholera model showed that V. negundo methanol extract can protect mice from Vibrio cholerae infection and significantly decrease the mortality rate (P<0.0001). CONCLUSIONS: For the first time we showed that methanol extract of V. negundo leaves exhibited strong vibriocidal activity both in vitro and in vivo conditions. Therefore, it will be useful to identify and isolate the active compounds of this extract that could be a good alternative of antibiotics to treat cholera.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Extratos Vegetais/farmacologia , Vitex/química , Administração Oral , Animais , Antibacterianos/química , Farmacorresistência Bacteriana Múltipla , Feminino , Intestinos/microbiologia , Masculino , Metanol/química , Camundongos , Testes de Sensibilidade Microbiana , Extratos Vegetais/química , Folhas de Planta/química , Análise de Sobrevida , Vibrioses/tratamento farmacológico , Vibrioses/microbiologia
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