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3.
Int J Parasitol Drugs Drug Resist ; 11: 118-128, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31208892

RESUMO

Leishmaniasis is a Neglected Tropical Disease caused by the insect-vector borne protozoan parasite, Leishmania species. Infection affects millions of the World's poorest, however vaccines are absent and drug therapy limited. Recently, public-private partnerships have developed to identify new modes of controlling leishmaniasis. Most of these collaborative efforts have relied upon the small molecule synthetic compound libraries held by industry, but the number of New Chemical Entities (NCE) identified and entering development as antileishmanials has been very low. In light of this, here we describe a public-private effort to identify natural products with activity against Leishmania mexicana, a causative agent of cutaneous leishmanaisis (CL). Utilising Hypha Discovery's fungal extract library which is rich in small molecule (<500 molecular weight) secondary metabolites, we undertook an iterative phenotypic screening and fractionation approach to identify potent and selective antileishmanial hits. This led to the identification of a novel oxidised bisabolane sesquiterpene which demonstrated activity in an infected cell model and was shown to disrupt multiple processes using a metabolomic approach. In addition, and importantly, this study also sets a precedent for new approaches for CL drug discovery.

6.
Clin Pharmacol Ther ; 100(5): 454-463, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27351344

RESUMO

Solute carrier (SLC) transporters represent 52 families of membrane transport proteins that function in endogenous compound homeostasis and xenobiotic disposition, and have been exploited in drug delivery and therapeutic targeting strategies. In particular, the SLC16 family that encodes for the 14 isoforms of the monocarboxylate transporter (MCT) family plays a significant role in the absorption, tissue distribution, and clearance of both endogenous and exogenous compounds. MCTs are required for the transport of essential cell nutrients and for cellular metabolic and pH regulation. Recent publications have indicated their novel roles in disease, and thus their potential as biomarkers and new therapeutic targets in disease are under investigation. More research into MCT isoform function, specificity, expression, and regulation will allow researchers to exploit the potential utility of MCTs in the clinic as therapeutic targets and prognostic factors of disease.


Assuntos
Terapia de Alvo Molecular/métodos , Transportadores de Ácidos Monocarboxílicos/efeitos dos fármacos , Transportadores de Ácidos Monocarboxílicos/metabolismo , Prognóstico , Isoformas de Proteínas/efeitos dos fármacos , Isoformas de Proteínas/metabolismo , Humanos , Modelos Biológicos
7.
Lett Appl Microbiol ; 62(1): 30-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26518358

RESUMO

UNLABELLED: Future therapies for the treatment of dental decay have to consider the importance of preserving bacterial ecology while reducing biofilm adherence to teeth. A multi-species plaque-derived (MSPD) biofilm model was used to assess how concentrations of N-acetyl-l-cysteine (NAC) (0, 0·1, 1, 10%) affected the growth of complex oral biofilms. Biofilms were grown (n = 96) for 24 h on hydroxyapatite discs in BMM media with 0·5% sucrose. Bacterial viability and biomass formation was examined on each disc using a microtitre plate reader. In addition, fluorescence microscopy and Scanning Electron Microscopy was used to qualitatively examine the effect of NAC on bacterial biofilm aggregation, extracellular components and bacterial morphology. The total biomass was significantly decreased after exposure of both 1% (from 0·48, with a 95% confidence interval of (0·44, 0·57) to 0·35, with confidence interval (0·31, 0·38)) and 10% NAC (0·14 with confidence interval (0·11, 0·17)). 16S rRNA amplicon sequencing analysis indicated that 1% NAC reduced biofilm adherence while preserving biofilm ecology. SIGNIFICANCE AND IMPACT OF THE STUDY: As a compound with a wide safety margin, N-acetyl-l-cysteine (NAC) has the potential to be used as a long term anti-plaque bacteriostatic agent for managing chronic dental decay without substantially altering biofilm's bacterial ecology. The potential anti-caries benefit of NAC is directly related to reducing the biofilm coverage which reduces the degree of acid generation and the amount of time that the surface is exposed to a lower pH.


Assuntos
Acetilcisteína/farmacologia , Antibacterianos/farmacologia , Aderência Bacteriana/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Cárie Dentária/prevenção & controle , Placa Dentária/prevenção & controle , Biofilmes/efeitos dos fármacos , Cárie Dentária/microbiologia , Placa Dentária/microbiologia , Viabilidade Microbiana/efeitos dos fármacos , RNA Ribossômico 16S
8.
Oral Dis ; 22(2): 155-61, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26662044

RESUMO

OBJECTIVES: The objective of this study is to evaluate the effect of short-term changes in the oral microbial ecology of dental plaque and plaque levels after topical treatment of a combination of 10% povidone iodine (PI) and 5% sodium fluoride varnish (FV). MATERIALS AND METHODS: A single group design intervention study on 12 pediatric patients, who underwent two baseline plaques samplings before the intervention, were enrolled in the study. A modified mixed dentition Silness-Löe plaque index score was used to assess plaque accumulation and microbial composition was assessed by amplicon sequencing analysis of the 16S rRNA V4 region. RESULTS: Dental plaque accumulation (P = 0.0424) was reduced after 1 week using PI/FV application. This reduction was not observed between the two double-baseline visits. 16S rRNA analysis showed that the single PI/FV therapy did not have dramatic shifts in the plaque microbiome community depicted by hierarchical cluster and principle component analysis. More subtle changes were found when analyzing the Shannon diversity index after the application of PI/FV vs two baselines prior to combination therapy. CONCLUSIONS: The bacteria within the dental biofilms showed resilience in maintaining the overall community diversity but reduced biofilm accumulation following PI/FV therapy. Repeated uses of PI/FV may augment plaque control during dental rehabilitation in children.


Assuntos
Anti-Infecciosos Locais/uso terapêutico , Biofilmes/efeitos dos fármacos , Placa Dentária/microbiologia , Microbiota/efeitos dos fármacos , Povidona-Iodo/uso terapêutico , Fluoreto de Sódio/uso terapêutico , Cariostáticos , Criança , Placa Dentária/prevenção & controle , Índice de Placa Dentária , Combinação de Medicamentos , Humanos
9.
Nat Commun ; 6: 8910, 2015 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-26608558

RESUMO

Outlet glaciers grounded on a bed that deepens inland and extends below sea level are potentially vulnerable to 'marine ice sheet instability'. This instability, which may lead to runaway ice loss, has been simulated in models, but its consequences have not been directly observed in geological records. Here we provide new surface-exposure ages from an outlet of the East Antarctic Ice Sheet that reveal rapid glacier thinning occurred approximately 7,000 years ago, in the absence of large environmental changes. Glacier thinning persisted for more than two and a half centuries, resulting in hundreds of metres of ice loss. Numerical simulations indicate that ice surface drawdown accelerated when the otherwise steadily retreating glacier encountered a bedrock trough. Together, the geological reconstruction and numerical simulations suggest that centennial-scale glacier thinning arose from unstable grounding line retreat. Capturing these instability processes in ice sheet models is important for predicting Antarctica's future contribution to sea level change.

10.
J Appl Microbiol ; 117(6): 1798-809, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25263195

RESUMO

AIMS: To test the effect of 0·4% stannous fluoride (SnF2 ) glycerine-based gels on specific portions of the bacterial community in both a clinical observational study and in vitro multispecies plaque-derived (MSPD) biofilm model. METHODS AND RESULTS: Potential changes to specific portions of the bacterial community were determined through the Human Oral Microbial Identification Microarray (HOMIM). Both the observational clinical study and the biofilm model showed that short-term use of 0·4% SnF2 gel has little effect on the bacterial community depicted by hierarchical cluster analysis. The amount of plaque accumulation on a subject's teeth, which was measured by plaque index scores, failed to show statistical significant changes over the two baselines or after treatment (P = 0·9928). The in vitro results were similar when examining the effect of 0·4% SnF2 gels on biofilm adherence through a crystal violet assay (P = 0·1157). CONCLUSIONS: The bacteria within the dental biofilms showed resilience in maintaining the overall community diversity after exposure to 0·4% SnF2 topical gels. SIGNIFICANCE AND IMPACT OF THE STUDY: The study supports that the immediate benefits of using 0·4% SnF2 gels in children may be strictly from fluoride ions inhibiting tooth demineralization rather than delivering substantial antimicrobial effects.


Assuntos
Biofilmes/efeitos dos fármacos , Cariostáticos/farmacologia , Placa Dentária/microbiologia , Fluoretos de Estanho/farmacologia , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Cariostáticos/administração & dosagem , Criança , Índice de Placa Dentária , Géis , Humanos , Fluoretos de Estanho/administração & dosagem
11.
Acta Biomater ; 10(1): 375-83, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24008178

RESUMO

Oral biofilms can degrade the components in dental resin-based composite restorations, thus compromising marginal integrity and leading to secondary caries. This study investigates the mechanical integrity of the dentin-composite interface challenged with multi-species oral biofilms. While most studies used single-species biofilms, the present study used a more realistic, diverse biofilm model produced directly from plaques collected from donors with a history of early childhood caries. Dentin-composite disks were made using bovine incisor roots filled with Z100(TM) or Filtek(TM) LS (3M ESPE). The disks were incubated for 72 h in paired CDC biofilm reactors, using a previously published protocol. One reactor was pulsed with sucrose, and the other was not. A sterile saliva-only control group was run with sucrose pulsing. The disks were fractured under diametral compression to evaluate their interfacial bond strength. The surface deformation of the disks was mapped using digital image correlation to ascertain the fracture origin. Fracture surfaces were examined using scanning electron microscopy/energy-dispersive X-ray spectroscopy to assess demineralization and interfacial degradation. Dentin demineralization was greater under sucrose-pulsed biofilms, as the pH dropped <5.5 during pulsing, with LS and Z100 specimens suffering similar degrees of surface mineral loss. Biofilm growth with sucrose pulsing also caused preferential degradation of the composite-dentin interface, depending on the composite/adhesive system used. Specifically, Z100 specimens showed greater bond strength reduction and more frequent cohesive failure in the adhesive layer. This was attributed to the inferior dentin coverage by Z100 adhesive, which possibly led to a higher level of chemical and enzymatic degradation. The results suggested that factors other than dentin demineralization were also responsible for interfacial degradation. A clinically relevant in vitro biofilm model was therefore developed, which would effectively allow assessment of the degradation of the dentin-composite interface subjected to multi-species biofilm challenge.


Assuntos
Resinas Acrílicas/química , Biofilmes , Resinas Compostas/química , Dentina/microbiologia , Poliuretanos/química , Animais , Biofilmes/efeitos dos fármacos , Reatores Biológicos , Bovinos , Pré-Escolar , Colagem Dentária , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Teste de Materiais , Microscopia Eletrônica de Varredura , Especificidade da Espécie , Espectrometria por Raios X , Sacarose/farmacologia
12.
J Intellect Disabil Res ; 57(2): 191-7, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22292862

RESUMO

BACKGROUND: Although children with intellectual disability (ID) seemed to be at increased risk for Attention deficit hyperactivity disorder (ADHD)/hyperactivity problems when assessed with parent report questionnaires and clinical interviews, there has been little attention to the associations between parent reports and observed child behaviours. The purpose of the present study was to compare clinical symptoms and observed impulsivity in children with ID whose parents reported them as being relatively high and low in ADHD symptoms, and to examine whether any differences were associated with developmental level. METHODS: Parents of 28 children with ID completed a behaviour rating scale of hyperactivity symptoms. Parents were also interviewed using a robust clinical interview tool focused on hyperactivity symptoms. The children were all tested by an experimenter to measure their impulsive behaviour. RESULTS: Those children with clinical range scores on parent questionnaire ratings were also reported by parents to have more ADHD symptoms using a parent report clinical interview. Although these children were also more impulsive on an experimental task, when children's developmental ages were statistically controlled impulsivity differences disappeared. CONCLUSIONS: Parent reports of ADHD symptoms in children with ID may be positively associated with data derived using clinical interview methods, but they may be less sensitive to developmental expectations when compared with observed child behaviour. Practical implications include the need for multiple sources of information and normative data for children with ID on simple experimental tasks that can be used to aid diagnosis of ADHD in clinical settings.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Comportamento Infantil/psicologia , Comportamento Impulsivo/epidemiologia , Deficiência Intelectual/epidemiologia , Pais , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Criança , Feminino , Humanos , Comportamento Impulsivo/psicologia , Deficiência Intelectual/psicologia , Inquéritos e Questionários , Análise e Desempenho de Tarefas
13.
J Appl Microbiol ; 113(6): 1540-53, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22925110

RESUMO

AIMS: Most studies of biofilm effects on dental materials use single-species biofilms, or consortia. Microcosm biofilms grown directly from saliva or plaque are much more diverse, but difficult to characterize. We used the Human Oral Microbial Identification Microarray (HOMIM) to validate a reproducible oral microcosm model. METHODS AND RESULTS: Saliva and dental plaque were collected from adults and children. Hydroxyapatite and dental composite discs were inoculated with either saliva or plaque, and microcosm biofilms were grown in a CDC biofilm reactor. In later experiments, the reactor was pulsed with sucrose. DNA from inoculums and microcosms was analysed by HOMIM for 272 species. Microcosms included about 60% of species from the original inoculum. Biofilms grown on hydroxyapatite and composites were extremely similar. Sucrose pulsing decreased diversity and pH, but increased the abundance of Streptococcus and Veillonella. Biofilms from the same donor, grown at different times, clustered together. CONCLUSIONS: This model produced reproducible microcosm biofilms that were representative of the oral microbiota. Sucrose induced changes associated with dental caries. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first use of HOMIM to validate an oral microcosm model that can be used to study the effects of complex biofilms on dental materials.


Assuntos
Biofilmes/crescimento & desenvolvimento , Materiais Dentários/análise , Placa Dentária/microbiologia , Saliva/microbiologia , Adulto , Reatores Biológicos , Criança , Contagem de Colônia Microbiana , Meios de Cultura/química , DNA Bacteriano/análise , Durapatita/análise , Humanos , Teste de Materiais , Análise de Sequência com Séries de Oligonucleotídeos , Streptococcus/crescimento & desenvolvimento , Sacarose/química , Veillonella/crescimento & desenvolvimento
14.
Lett Appl Microbiol ; 54(6): 537-42, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22435929

RESUMO

AIMS: Quantifying the ex vivo growth of complex multispecies dental biofilms using cross-polarization 1310-nm optical coherence tomography (CP-OCT) system was investigated. METHODS AND RESULTS: Bacterial microcosms, which were derived from plaque samples of paediatric subjects, were incubated in a biofilm reactor system containing discs of different dental materials for 72 h with daily sucrose pulsing (5×). CP-OCT analysis of biofilm mass was validated with crystal violet (CV) assays at various growth stages of these complex biofilms. CP-OCT was able to filter out the back-reflected signals of water layers in the hydrated biofilm and allowed for direct biofilm quantification. The overall depth-resolved scattering intensity of the biofilm showed very strong positive correlation with CV assay quantification (Spearman's ρ = 0.92) during the growth phase of the biofilm. CONCLUSION: CP-OCT was able to quantify the mass of the biofilm by measuring the overall depth-resolved scattering of the biofilm. SIGNIFICANCE AND IMPACT OF THE STUDY: CP-OCT has the ability to nondestructively monitor biofilm growth and elucidate the growth characteristics of these microcosms on different dental material compositions.


Assuntos
Bactérias/crescimento & desenvolvimento , Biofilmes/crescimento & desenvolvimento , Placa Dentária/microbiologia , Tomografia de Coerência Óptica/métodos , Técnicas Bacteriológicas , Reatores Biológicos , Criança , Meios de Cultura , Humanos
15.
Vet J ; 192(3): 467-71, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22030475

RESUMO

This study evaluated the use of sugammadex for reversal of profound neuromuscular blockade induced with rocuronium or vecuronium in dogs. Anaesthesia was induced and maintained with isoflurane in oxygen in eight dogs on two occasions. Neuromuscular blockade was monitored using peroneal nerve stimulation and acceleromyography. Rocuronium 0.6 mg/kg or vecuronium 0.1mg/kg was administered intravenously (IV), followed 5 min later by sugammadex 8 mg/kg IV. Lag and onset time of rocuronium and vecuronium, lag time from sugammadex injection to recovery of first twitch response, recovery of T1/T0 to 25% and 75%, recovery index, and time to recovery of the train-of-four ratio (T4/T1) to 0.9 were recorded. Cardiovascular and respiratory parameters were also noted. Statistical analysis was performed using one-way ANOVA. Onset time for rocuronium (37 ± 18s; [mean ± SD]) was significantly shorter than for vecuronium (62 ± 15s) (P<0.04). No other significant differences were found between the two groups. After both rocuronium and vecuronium blockade, T4/T1 recovered to 0.9 in under 2 min after sugammadex (58.1 ± 67.8s and 98.1 ± 70.3s, respectively; P<0.32). Sugammadex can reverse profound neuromuscular blockade induced by vecuronium or rocuronium safely and rapidly in isoflurane-anaesthetised dogs.


Assuntos
Androstanóis/antagonistas & inibidores , Isoflurano/farmacologia , Fármacos Neuromusculares não Despolarizantes/antagonistas & inibidores , Brometo de Vecurônio/antagonistas & inibidores , gama-Ciclodextrinas/uso terapêutico , Androstanóis/farmacologia , Anestesia por Inalação , Anestésicos Inalatórios , Animais , Cães , Relação Dose-Resposta a Droga , Estimulação Elétrica , Feminino , Masculino , Bloqueio Neuromuscular , Fármacos Neuromusculares não Despolarizantes/farmacologia , Rocurônio , Sugammadex , Brometo de Vecurônio/farmacologia
16.
Br J Anaesth ; 105(4): 480-6, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20650917

RESUMO

BACKGROUND: This clinical study evaluated the speed of reversal of profound rocuronium block in ponies using sugammadex and investigated the differences in onset and recovery from block in three different muscle groups. METHODS: Anaesthesia was induced and maintained with isoflurane in oxygen 100% in eight ponies. Neuromuscular monitoring was performed at each site using acceleromyography: in the extensor muscles of the pelvic limb (peroneal nerve) and thoracic limb (radial nerve), and in the orbicularis oris muscle (OOM; facial nerve). Rocuronium 0.6 mg kg(-1) i.v. was administered, followed 5 min later by sugammadex 4 mg kg(-1) i.v. Onset time (onsetROC), maximum block, and time to recovery of the train-of-four ratio to 0.9 (TOFR=0.9) were recorded. The differences between monitored sites were compared using one-way anova followed by a post hoc Dunn's test. RESULTS: Onset of ROC was significantly delayed in OOM compared with both limbs [pelvic limb, thoracic limb, and OOM: 43.1 (sd 16.9), 50.6 (15.9), and 204.4 (35.8) s, respectively; P<0.001]. Complete block was achieved in the pelvic and thoracic limbs, but in none of the eight ponies in the OOM [mean T1=15.3 (9.4)%; range: 7-36%]. No differences were observed between muscle sites in recovery to TOFR=0.9 [pelvic limb, thoracic limb, and OOM: 2.3 (0.9), 3.4 (1.7), and 2.8 (2.1) min, respectively]. No adverse effects of sugammadex were detected throughout the study period. CONCLUSIONS: Sugammadex can be used to reverse profound rocuronium-induced block in ponies during isoflurane anaesthesia. Thoracic limb muscles represent a suitable alternative for monitoring neuromuscular block compared with pelvic limb muscles.


Assuntos
Androstanóis/antagonistas & inibidores , Cavalos , Bloqueio Neuromuscular/veterinária , Fármacos Neuromusculares não Despolarizantes/antagonistas & inibidores , gama-Ciclodextrinas/farmacologia , Androstanóis/administração & dosagem , Anestesia por Inalação/métodos , Anestesia por Inalação/veterinária , Animais , Pressão Sanguínea/efeitos dos fármacos , Esquema de Medicação , Estimulação Elétrica/métodos , Frequência Cardíaca/efeitos dos fármacos , Masculino , Monitorização Intraoperatória/métodos , Monitorização Intraoperatória/veterinária , Bloqueio Neuromuscular/métodos , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/fisiologia , Fármacos Neuromusculares não Despolarizantes/administração & dosagem , Nervo Radial/fisiologia , Rocurônio , Sugammadex , gama-Ciclodextrinas/administração & dosagem
17.
Neuroscience ; 167(2): 456-74, 2010 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-20167261

RESUMO

Although most anti-epileptic drugs are considered to have a primary molecular target, it is clear that their actions are unlikely to be limited to effects on a single aspect of inhibitory synaptic transmission, excitatory transmission or voltage-gated ion channels. Systemically administered drugs can obviously simultaneously access all possible targets, so we have attempted to determine the overall effect of diverse agents on the balance between GABAergic inhibition, glutamatergic excitation and cellular excitability in neurones of the rat entorhinal cortex in vitro. We used an approach developed for estimating global background synaptic excitation and inhibition from fluctuations in membrane potential obtained by intracellular recordings. We have previously validated this approach in entorhinal cortical neurones [Greenhill and Jones (2007a) Neuroscience 147:884-892]. Using this approach, we found that, despite their differing pharmacology, the drugs tested (phenytoin, lamotrigine, valproate, gabapentin, felbamate, tiagabine) were unified in their ability to increase the ratio of background GABAergic inhibition to glutamatergic excitation. This could occur as a result of decreased excitation concurrent with increased inhibition (phenytoin, lamotrigine, valproate), a decrease in excitation alone (gabapentin, felbamate), or even with a differential increase in both (tiagabine). Additionally, we found that the effects on global synaptic conductances agreed well with whole cell patch recordings of spontaneous glutamate and GABA release (our previous studies and further data presented here). The consistency with which the synaptic inhibition:excitation ratio was increased by the antiepileptic drugs tested was matched by an ability of all drugs to concurrently reduce intrinsic neuronal excitability. Thus, it seems possible that specific molecular targets among antiepileptic drugs are less important than the ability to increase the inhibition:excitation ratio and reduce overall neuronal and network excitability.


Assuntos
Anticonvulsivantes/farmacologia , Córtex Entorrinal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Córtex Entorrinal/fisiologia , Técnicas In Vitro , Masculino , Inibição Neural , Neurônios/fisiologia , Técnicas de Patch-Clamp , Ratos , Ratos Wistar
18.
J Bone Joint Surg Br ; 91(1): 44-51, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19092003

RESUMO

When using a staged approach to eradicate chronic infection after total hip replacement, systemic delivery of antibiotics after the first stage is often employed for an extended period of typically six weeks together with the use of an in situ antibiotic-eluting polymethylmethacrylate interval spacer. We report our multi-surgeon experience of 43 consecutive patients (44 hips) who received systemic vancomycin for two weeks in combination with a vancomycin- and gentamicin-eluting spacer system in the course of a two-stage revision procedure for deep infection with a median follow-up of 49 months (25 to 83). The antibiotic-eluting articulating spacers fractured in six hips (13.9%) and dislocated in five patients (11.6%). Successful elimination of the infecting organisms occurred in 38 (92.7%) of 41 hips with three patients developing superinfection with a new organism. We conclude that prolonged systemic antibiotic therapy may not be essential in the two-stage treatment of a total hip replacement for Gram-positive infection, provided that a high concentration of antibiotics is delivered locally using an antibiotic-eluting system.


Assuntos
Antibacterianos/administração & dosagem , Artroplastia de Quadril/efeitos adversos , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Prótese de Quadril/efeitos adversos , Infecções Relacionadas à Prótese/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Desbridamento/métodos , Vias de Administração de Medicamentos , Quimioterapia Combinada , Feminino , Gentamicinas/administração & dosagem , Infecções por Bactérias Gram-Positivas/microbiologia , Prótese de Quadril/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Desenho de Prótese , Infecções Relacionadas à Prótese/microbiologia , Resultado do Tratamento , Vancomicina/administração & dosagem
19.
J Wound Care ; 17(8): 353-8, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18754197

RESUMO

OBJECTIVE: To investigate microbiology laboratory reporting policies, whether practitioners working in primary care adhered to the relevant guidelines when submitting swabs from venous leg ulcers (VLUs), and the impact of laboratory reports on antibiotic usage forVLUs. METHOD: Questionnaires were sent to all microbiology laboratories in England and Wales, and to clinicians who had submitted VLU swabs to one laboratory. RESULTS: Ninety-five (47%) laboratories responded. Laboratories processed a mean of 7.3 leg ulcer swabs/100,000 population/week but were often unable to identify the leg ulcer aetiology from the clinical details provided. All laboratories stated that they routinely reported group A haemolytic streptococci and meticillin-sensitive and resistant Staphylococcus aureus; 75% always reported antibiotic susceptibility for these isolates. The majority reported other beta-haemolytic streptococci. A total of 126 clinicians (64%) returned their questionnaires; 100 had confirmed in their swab submission that the ulcer was of venous aetiology and so were included in the analysis. Eighty per cent of the swabs were submitted in accordance with guidelines, with increased pain (61%) being the most common reason. Discharge/exudate (52%) and malodour (41%) were common reasons for swab submissions, even though the guidelines do not cite them as clinical signs of infection. Reporting of antibiotic susceptibilities was associated with increased antibiotic usage. CONCLUSION: Clinicians in primary care generally adhere to guidelines when submittingVLU specimens for microbiological investigation. Clinicians need to include clinical information with the swab so that laboratories can interpret the microbiology results. To reduce the use of antibiotics in the management ofVLUs, laboratories need to be selective in their organism and antibiotic-susceptibility reporting.


Assuntos
Fidelidade a Diretrizes , Técnicas Microbiológicas/normas , Padrões de Prática Médica , Úlcera Varicosa/microbiologia , Infecção dos Ferimentos/prevenção & controle , Antibacterianos/uso terapêutico , Notificação de Doenças , Inglaterra , Humanos , Controle de Infecções/normas , Laboratórios , Atenção Primária à Saúde , Manejo de Espécimes , País de Gales , Infecção dos Ferimentos/diagnóstico , Infecção dos Ferimentos/tratamento farmacológico
20.
Neuroscience ; 148(1): 7-21, 2007 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-17630217

RESUMO

Neurotransmitter release at CNS synapses occurs via both action potential-dependent and independent mechanisms, and it has generally been accepted that these two forms of release are regulated in parallel. We examined the effects of activation of group III metabotropic glutamate receptors (mGluRs) on stimulus-evoked and spontaneous glutamate release onto entorhinal cortical neurones in rats, and found a differential regulation of action potential-dependent and independent forms of release. Activation of presynaptic mGluRs depressed the amplitude of stimulus-evoked excitatory postsynaptic currents, but concurrently enhanced the frequency of spontaneous excitatory currents. Moreover, these differential effects on glutamate release were mediated by pharmacologically separable mechanisms. Application of the specific activator of adenylyl cyclase, forskolin, mimicked the effect of mGluR activation on spontaneous, but not evoked release, and inhibition of adenylyl cyclase with 9-tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22536) blocked mGluR-mediated enhancement of spontaneous release, but not depression of evoked release. Occlusion studies with calcium channel blockers suggested that the group III mGluRs might depress evoked release through inhibition of both N and P/Q, but not R-type calcium channels. We suggest that the concurrent depression of action potential-evoked, and enhancement of action potential-independent glutamate release operate through discrete second messenger/effector systems at excitatory entorhinal terminals in rat brain.


Assuntos
Córtex Entorrinal/metabolismo , Ácido Glutâmico/metabolismo , Vias Neurais/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Sinapses/metabolismo , Transmissão Sináptica/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Inibidores de Adenilil Ciclases , Adenilil Ciclases/metabolismo , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/efeitos dos fármacos , Canais de Cálcio/metabolismo , Estimulação Elétrica , Córtex Entorrinal/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Masculino , Vias Neurais/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Sistemas do Segundo Mensageiro/fisiologia , Sinapses/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos
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