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1.
Eur Radiol ; 28(1): 3-10, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28710582

RESUMO

OBJECTIVES: To compare interobserver variability (IOV), reader confidence, and sensitivity/specificity in detecting architectural distortion (AD) on digital mammography (DM) versus digital breast tomosynthesis (DBT). METHODS: This IRB-approved, HIPAA-compliant reader study used a counterbalanced experimental design. We searched radiology reports for AD on screening mammograms from 5 March 2012-27 November 2013. Cases were consensus-reviewed. Controls were selected from demographically matched non-AD examinations. Two radiologists and two fellows blinded to outcomes independently reviewed images from two patient groups in two sessions. Readers recorded presence/absence of AD and confidence level. Agreement and differences in confidence and sensitivity/specificity between DBT versus DM and attendings versus fellows were examined using weighted Kappa and generalised mixed modeling, respectively. RESULTS: There were 59 AD patients and 59 controls for 1,888 observations (59 × 2 (cases and controls) × 2 breasts × 2 imaging techniques × 4 readers). For all readers, agreement improved with DBT versus DM (0.61 vs. 0.37). Confidence was higher with DBT, p = .001. DBT achieved higher sensitivity (.59 vs. .32), p < .001; specificity remained high (>.90). DBT achieved higher positive likelihood ratio values, smaller negative likelihood ratio values, and larger ROC values. CONCLUSIONS: DBT decreases IOV, increases confidence, and improves sensitivity while maintaining high specificity in detecting AD. KEY POINTS: • Digital breast tomosynthesis decreases interobserver variability in the detection of architectural distortion. • Digital breast tomosynthesis increases reader confidence in the detection of architectural distortion. • Digital breast tomosynthesis improves sensitivity in the detection of architectural distortion.


Assuntos
Neoplasias da Mama/diagnóstico , Mama/diagnóstico por imagem , Detecção Precoce de Câncer/métodos , Mamografia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Curva ROC , Intensificação de Imagem Radiográfica/métodos
2.
West Indian Med J ; 61(7): 743-5, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23620974

RESUMO

Herein, we present three cases of Pityriasis lichenoides chronica (PLC) in patients who developed the rash after use of 3-hydroxy-3-methyl-glutaryl-Coenzyme A (HMG-CoA) reductase inhibitors. The patients had complete resolution after standard treatment by dermatologists and withdrawal of the offending agents. In one case, the patient had a previous episode of a similar rash that occurred with HMG-CoA reductase inhibitors use many years previously. Pityriasis lichenoides chronica is a condition of unknown aetiology. Several agents have been associated with its presentation. We postulate HMG-CoA reductase inhibition in skin presents a final common pathway for the presentation of PLC in select patients.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Pitiríase Liquenoide/induzido quimicamente , Idoso , Toxidermias/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
3.
Drugs Future ; 36(9): 691-711, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23378700

RESUMO

Hepatitis C virus (HCV) infects more than 3% of the world's population, leading to an increased risk of cirrhosis and hepatocellular carcinoma. The current standard of care, a combination of pegylated interferon alfa and ribavirin, is poorly tolerated and often ineffective against the most prevalent genotype of the virus, genotype 1. The very recent approval of boceprevir and telaprevir, two HCV protease inhibitors, promises to significantly improve treatment options and outcomes. In addition to the viral protease NS3 and the viral polymerase NS5B, direct-acting antivirals are now in development against NS5A. A multifunctional phosphoprotein, NS5A is essential to HCV genome replication, but has no known enzymatic function. Here we report how the design of small-molecule inhibitors against NS5A has evolved from promising monomers to highly potent dimeric compounds effective against many HCV genotypes. We also highlight recent clinical data and how the inhibitors may bind to NS5A, itself capable of forming dimers.

4.
ESMO Open ; 6(1): 100005, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33399072

RESUMO

BACKGROUND: Cancer patients are at increased risk of death from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cancer and its treatment affect many haematological and biochemical parameters, therefore we analysed these prior to and during coronavirus disease 2019 (COVID-19) and correlated them with outcome. PATIENTS AND METHODS: Consecutive patients with cancer testing positive for SARS-CoV-2 in centres throughout the United Kingdom were identified and entered into a database following local governance approval. Clinical and longitudinal laboratory data were extracted from patient records. Data were analysed using Mann-Whitney U test, Fisher's exact test, Wilcoxon signed rank test, logistic regression, or linear regression for outcomes. Hierarchical clustering of heatmaps was performed using Ward's method. RESULTS: In total, 302 patients were included in three cohorts: Manchester (n = 67), Liverpool (n = 62), and UK (n = 173). In the entire cohort (N = 302), median age was 69 (range 19-93 years), including 163 males and 139 females; of these, 216 were diagnosed with a solid tumour and 86 with a haematological cancer. Preinfection lymphopaenia, neutropaenia and lactate dehydrogenase (LDH) were not associated with oxygen requirement (O2) or death. Lymphocyte count (P < 0.001), platelet count (P = 0.03), LDH (P < 0.0001) and albumin (P < 0.0001) significantly changed from preinfection to during infection. High rather than low neutrophils at day 0 (P = 0.007), higher maximal neutrophils during COVID-19 (P = 0.026) and higher neutrophil-to-lymphocyte ratio (NLR; P = 0.01) were associated with death. In multivariable analysis, age (P = 0.002), haematological cancer (P = 0.034), C-reactive protein (P = 0.004), NLR (P = 0.036) and albumin (P = 0.02) at day 0 were significant predictors of death. In the Manchester/Liverpool cohort 30 patients have restarted therapy following COVID-19, with no additional complications requiring readmission. CONCLUSION: Preinfection biochemical/haematological parameters were not associated with worse outcome in cancer patients. Restarting treatment following COVID-19 was not associated with additional complications. Neutropaenia due to cancer/treatment is not associated with COVID-19 mortality. Cancer therapy, particularly in patients with solid tumours, need not be delayed or omitted due to concerns that treatment itself increases COVID-19 severity.


Assuntos
COVID-19/prevenção & controle , Neoplasias/terapia , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , SARS-CoV-2/isolamento & purificação , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/análise , COVID-19/virologia , Feminino , Humanos , L-Lactato Desidrogenase/metabolismo , Modelos Logísticos , Estudos Longitudinais , Contagem de Linfócitos , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/metabolismo , Neutrófilos/metabolismo , Avaliação de Resultados em Cuidados de Saúde/métodos , Contagem de Plaquetas , SARS-CoV-2/fisiologia , Reino Unido , Adulto Jovem
5.
J Exp Med ; 150(3): 465-70, 1979 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-383875

RESUMO

Long surviving, passively enhanced (AS X AUG)F1 kidneys carried by AS recipients were retransplanted into (AS X WF)F1 second hosts. Acute graft rejection did not occur. Only one of six secondary recipients mounted a significant T-dependent IgG lymphocytotoxic antibody response. In all six, generation of cytotoxic T cells was markedly slower and depressed. These results are compatible with the hypothesis that kidney parenchyma, although carrying major histocompatibility complex specificity is able to induce T-independent but not T-dependent alloimmunity. A corollary is that passenger cells are responsible for exciting the T-dependent allimmune response normally observed after grafing. The practical difficulty of eliminating all T-dependent immunogenicity from (AS X AUG)F1 kidneys was emphasized by the observation that a 3-d residence in an intermediate AS recipient was insufficient time to prevent acute graft rejection after retransplantation.


Assuntos
Sobrevivência de Enxerto , Isoanticorpos/biossíntese , Transplante de Rim , Linfócitos T/imunologia , Animais , Imunidade Celular , Imunização Passiva , Imunoglobulina M/biossíntese , Masculino , Ratos , Ratos Endogâmicos , Transplante Homólogo
6.
J Exp Med ; 150(3): 455-64, 1979 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-383874

RESUMO

Long survival of (AS X AUG)F1 rat kidney allografts in AS recipients was induced by passive enhancement with AS anti-AUG antiserum at the time of grafting. After 1-3 mo, the kidney allografts were transferred to second AS recipients, either naive or sensitized against AUG tissue. Naive second recipients did not reject the grafts acutely and failed to mount T-dependent immunity against AUG targets. When later challenged with spleen cells carrying the AUG haplotype, the naive second AS recipients showed strong IgM, IgG, and cytotoxic T-cell responses after grafting, and the kidneys were rapidly destroyed by immune rejection in all but one rat. It is concluded that long-surviving kidney allografts fail to activate helper T cells and induce in naive second recipients the same state of unresponsiveness observed in the first recipient.


Assuntos
Sobrevivência de Enxerto , Isoanticorpos/biossíntese , Transplante de Rim , Linfócitos T/imunologia , Animais , Antígenos de Histocompatibilidade , Tolerância Imunológica , Imunidade Celular , Imunização Passiva , Masculino , Ratos , Ratos Endogâmicos , Transplante Homólogo
7.
Int J Hyg Environ Health ; 225: 113472, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32035287

RESUMO

Carbon nanotubes (CNT) trigger fascination as well as anxiety, given their unique physical and chemical properties, and continuing concerns around their possible health effects. CNT exposure assessment is an integral component of occupational and environmental epidemiology, risk assessment, and management. We conducted a systematic review to analyze the quality of CNT occupational exposure assessments in field studies and to assess the relevance of available quantitative data from occupational hygiene and epidemiological perspectives. PubMed and Scopus databases were searched for the period 2000-2018. To grade the quality of each study, we used a standardized grid of seven criteria. The first criterion addressed 12 items deemed most relevant CNT physical-chemical properties with respect to their in vitro and in vivo toxicity. We included 27 studies from 11 countries in the review and graded them high (n = 2), moderate (n = 15) and low quality (n = 10). Half of the studies measured elemental carbon mass concentration (EC) using different methods and aerosol fractions. In 85% of studies, the observed values exceed the US National Institute for Occupational Safety and Health Recommended Exposure Limit. The quantification of CNT agglomerates and/or CNT contained fibers becomes increasingly common although lacking methodological standardization. Work activities with the greatest mean CNT mass concentrations were non-enclosed and included sieving, harvesting, packaging, reactor cleaning, extrusion and pelletizing. Some of the large studies defined standardized job titles according to exposure estimates at corresponding workstations and classified them by decreasing CNT exposure level: technicians > engineers > chemists. The already initiated harmonization of CNT exposure assessment and result reporting need to continue to favor not only studies in the field, but also to identify companies and workers using CNTs to characterize their exposures as well as monitor their health. This will enable an objective and realistic evaluation of risks associated with CNT applications and an appropriate risk management.


Assuntos
Poluentes Ocupacionais do Ar , Nanotubos de Carbono , Exposição Ocupacional , Animais , Humanos , Medição de Risco
9.
J Mol Biol ; 292(5): 1051-69, 1999 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-10512702

RESUMO

NMR studies of the folding and conformational properties of a beta-hairpin peptide, several peptide fragments of the hairpin, and sequence-modified analogues, have enabled the various contributions to beta-hairpin stability in water to be dissected. Temperature and pH-induced unfolding studies indicate that the folding-unfolding equilibrium approximates to a two-state model. The hairpin is highly resistant to denaturation and is still significantly folded in 7 M urea at 298 K. Thermodynamic analysis shows the hairpin to fold in water with a significant change in heat capacity, however, DeltaCp degrees in 7 M urea is reduced. V/Y-->A mutations on one strand of the hairpin reduce folding to <10 %, consistent with a hydrophobic stabilisation model. We show that in a truncated peptide (residues 6-16) lacking the hydrophobic residues on one beta-strand, the type I' Asn-Gly turn in the sequence SINGKK is significantly populated in water in the absence of interstrand hydrophobic contacts. Unrestrained molecular dynamics simulations of unfolding, using an explicit solvation model, show that the conformation of the NG turn persists for longer than the AG analogue, which has a much lower propensity for type I' turn formation from a data base analysis of preferred turns. The origin of the high stability of the Asn-Gly turn is not entirely clear; data base analysis of 66 NG turns, together with molecular dynamics simulations, reveals no participation of the Asn side-chain in turn-stabilising interactions with the peptide backbone. However, hydration analysis of the molecular dynamics simulations reveals a pocket of "high density" water bridging between the Asn side-chain and peptide main-chain that suggests solvent-mediated interactions may play an important role in modulating phi,psi propensities in the NG turn region.


Assuntos
Modelos Moleculares , Ressonância Magnética Nuclear Biomolecular , Peptídeos/química , Peptídeos/metabolismo , Dobramento de Proteína , Sequência de Aminoácidos , Dicroísmo Circular , Simulação por Computador , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Modelos Químicos , Dados de Sequência Molecular , Mutação , Peptídeos/genética , Desnaturação Proteica , Estrutura Secundária de Proteína , Solventes , Temperatura , Termodinâmica , Fatores de Tempo , Ureia , Água/metabolismo
10.
J Mol Biol ; 284(5): 1597-609, 1998 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-9878373

RESUMO

Analysis of residues in coil regions of protein structures presents a novel approach to deconvoluting the various competing factors which determine the intrinsic phi,psi propensities of amino acids free from the regular interactions associated with beta-strands and alpha-helices. We have considered the role of context on phi,psi preferences by examining the effects of neighbouring residues in modulating coil propensities within a data base of 512 high-resolution, low-homology structures. In the general case, when flanking residues are beta-branched or aromatic (Val, Ile, Tyr and Phe) the beta-propensity (Pbeta) increases significantly, largely due to steric effects between flanking residues. More subtle residue-specific effects are apparant when Pbeta values are examined in detail, showing "random coil" conformations to be highly sequence-dependent. The effects of flanking residues on phi distributions have been used to calculate context-dependent average 3JNH-Halpha coupling constants. We have examined these findings in the context of the folding of a model 16-residue beta-hairpin peptide, "mutant" hairpin (VSI-->KSK sequence change) and the isolated C-terminal beta-strand fragments of both hairpins. We find a better correlation between 3JNH-Halpha values derived from the data base model and those determined experimentally when context-dependent phi distributions are considered. The individual C-terminal beta-strand sequences (GKKITVSI versus GKKITKSK) of the two hairpins are predisposed to different extents to formation of an extended beta-like conformation. Conformational "predisposition" in this context may contribute significantly to beta-hairpin stability.


Assuntos
Aminoácidos/química , Modelos Moleculares , Proteínas/química , Sequência de Aminoácidos , Espectroscopia de Ressonância Magnética , Dados de Sequência Molecular , Peptídeos/química , Conformação Proteica , Dobramento de Proteína , Estrutura Secundária de Proteína , Água
11.
Sci Total Environ ; 347(1-3): 131-47, 2005 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-16084974

RESUMO

Fine particle number concentration (D(p)>10 nm, cm(-3)), mass concentrations (approximation of PM(2.5), microg m(-3)) and indoor/outdoor number concentration ratio (I/O) measurements have been conducted for the first time in 11 urban households in India, 2002. The results indicate remarkable high indoor number and mass concentrations and I/O number concentration ratios caused by cooking. Besides cooking stoves that used liquefied petroleum gas (LPG) or kerosene as the main fuel, high indoor concentrations can be explained by poor ventilation systems. Particle number concentrations of more than 300,000 cm(-3) and mass concentrations of more than 1000 microg m(-3) were detected in some cases. When the number and mass concentrations during cooking times were statistically compared, a correlation coefficient r>0.50 was observed in 63% of the households. Some households used other fuels like wood and dung cakes along with the main fuel, but also other living activities influenced the concentrations. In some areas, outdoor combustion processes had a negative impact on indoor air quality. The maximum concentrations observed in most cases were due to indoor combustion sources. Reduction of exposure risk and health effects caused by poor indoor air in urban Indian households is possible by improving indoor ventilation and reducing penetration of outdoor particles.


Assuntos
Aerossóis/análise , Poluição do Ar em Ambientes Fechados , Culinária , Poeira/análise , Monóxido de Carbono/análise , Cidades , Monitoramento Ambiental , Habitação , Índia , Querosene , Tamanho da Partícula , Petróleo , Estações do Ano , Fatores de Tempo
12.
AIDS ; 9(7): 787-93, 1995 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-7546425

RESUMO

OBJECTIVE: To calculate the costs of treating HIV-infected haemophilic patients. DESIGN: Two-year retrospective study of hospital-based resource use and costs, from April 1991 to March 1993. SETTING: Haemophilia Centre and Haemostasis Unit, Royal Free Hospital and School of Medicine, London, UK. PATIENTS: Sixty patients infected with HIV between October 1979 and July 1985. RESULTS: During the 2-year period a total of 1668 hospital visits were made by patients. The mean number of episodes per patient-year (PY) was 0.6 inpatient admissions, 11.5 outpatient visits and 1.8 day cases. The mean cost per PY was 32,528 pounds, with the majority of this spent on clotting factor concentrate products and haemophilia inpatient admissions (81%). A mean cost for HIV-related treatment of 6050 pounds was estimated. The additional cost incurred in switching this group of haemophilic patients from intermediate-purity factor concentrate to high-purity products was 8614 pounds per PY. When clotting factor concentrate and expenditure on haemophilia-related inpatient admissions were excluded, the mean cost of treating HIV infection per PY was 6065 pounds, varying with CD4+ count (< or = 50 x 10(6)/l, 13,093 pounds; 51-200 x 10(6)/l, 6521 pounds; 201-500 x 10(6)/l, 2848 pounds; > 501 x 10(6)/l, 1497 pounds). CONCLUSIONS: CD4+ count may be used as a marker of costs of HIV infection. The HIV-related cost estimates can be used for the planning of current and future hospital-based care in the National Health Service in the United Kingdom. The switch from intermediate-purity factor concentrate to high-purity products has increased the mean HIV-related cost per PY of treating haemophilic patients infected with HIV.


Assuntos
Síndrome da Imunodeficiência Adquirida/economia , Hemofilia A/economia , Custos Hospitalares , Síndrome da Imunodeficiência Adquirida/complicações , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Adulto , Idoso , Contagem de Linfócito CD4 , Hemofilia A/complicações , Hemofilia A/terapia , Humanos , Londres , Masculino , Pessoa de Meia-Idade
13.
Eur J Cancer ; 29A Suppl 7: S6-9, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8312062

RESUMO

The use of techniques of economic analysis in improving the efficiency of cancer services is both complex and poorly understood. Like many other areas of health care, there are large variations in treatment patterns, a reluctance to invest in prevention, inadequate data about effectiveness, and a reluctance to invest in cost-effectiveness analysis to inform purchasers' choices. Without the deployment of such techniques and the basing of treatment choices on a balancing of costs and effects, resources will continue to be used inefficiently and to the detriment of patients' welfare.


Assuntos
Efeitos Psicossociais da Doença , Oncologia/economia , Neoplasias/economia , Custos e Análise de Custo , Feminino , Política de Saúde , Humanos , Longevidade , Masculino , Neoplasias/terapia , Padrões de Prática Médica , Projetos de Pesquisa , Reino Unido
14.
Eur J Cancer ; 30A(4): 463-8, 1994.
Artigo em Inglês | MEDLINE | ID: mdl-8018403

RESUMO

The economic evaluation of any new or existing therapy should include a comprehensive appraisal of costs. When evaluating pharmaceutical interventions, it is inappropriate to identify the purchase price alone. Other relevant costs include the costs of time of doctors, nurses and other personnel in administering and monitoring the effects of the therapy, and the costs of treating any side-effects. This study estimates direct National Health Service (NHS) costs in the U.K. of current medical practice in managing severe cancer pain, using a review of the published literature and constructing a cost analysis for four 'typical' patients. Costs are estimated for patients with severe cancer pain in a hospital and an ambulatory setting, with oral and subcutaneous routes of drug administration. The study includes costs of drugs, supplies, equipment and personnel time. The results demonstrate the importance of personnel time costs, and potential cost savings which could result from the use of transdermally administered opioid analgesics.


Assuntos
Custos de Cuidados de Saúde , Dor/economia , Dor/prevenção & controle , Administração Cutânea , Administração Oral , Assistência Ambulatorial/economia , Analgésicos/administração & dosagem , Redução de Custos , Custos de Medicamentos , Custos Hospitalares , Humanos , Entorpecentes/administração & dosagem , Neoplasias/complicações , Neoplasias/economia , Dor/etiologia , Reino Unido
15.
J Med Chem ; 41(9): 1371-81, 1998 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-9554870

RESUMO

Agents that target the two highly conserved Zn fingers of the human immunodeficiency virus (HIV) nucleocapsid p7 (NCp7) protein are under development as antivirals. These agents covalently modify Zn-coordinating cysteine thiolates of the fingers, causing Zn ejection, loss of native protein structure and nucleic acid binding capacity, and disruption of virus replication. Concentrations of three antiviral agents that promoted in vitro Zn ejection from NCp7 and inhibited HIV replication did not impact the functions of cellular Zn finger proteins, including poly(ADP-ribose) polymerase and the Sp1 and GATA-1 transcription factors, nor did the compounds inhibit HeLa nuclear extract mediated transcription. Selectivity of interactions of these agents with NCp7 was supported by molecular modeling analysis which (1) identified a common saddle-shaped nucleophilic region on the surfaces of both NCp7 Zn fingers, (2) indicated a strong correspondence between computationally docked positions for the agents tested and overlap of frontier orbitals within the nucleophilic loci of the NCp7 Zn fingers, and (3) revealed selective steric exclusion of the agents from the core of the GATA-1 Zn finger. Further modeling analysis suggests that the thiolate of Cys49 in the carboxy-terminal finger is the site most susceptible to electrophilic attack. These data provide the first experimental evidence and rationale for antiviral agents that selectively target retroviral nucleocapsid protein Zn fingers.


Assuntos
Fármacos Anti-HIV/farmacologia , Proteínas do Capsídeo , Capsídeo/metabolismo , Produtos do Gene gag/metabolismo , HIV-1/efeitos dos fármacos , Proteínas Virais , Dedos de Zinco , Animais , Fármacos Anti-HIV/metabolismo , Compostos Azo/metabolismo , Compostos Azo/farmacologia , Benzamidas/metabolismo , Benzamidas/farmacologia , Sítios de Ligação , Capsídeo/antagonistas & inibidores , Capsídeo/química , Linhagem Celular , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Fatores de Ligação de DNA Eritroide Específicos , Fator de Transcrição GATA1 , Produtos do Gene gag/antagonistas & inibidores , Produtos do Gene gag/química , HIV-1/metabolismo , HIV-1/fisiologia , Fator C1 de Célula Hospedeira , Humanos , Ligantes , Camundongos , Modelos Moleculares , Compostos Nitrosos/metabolismo , Compostos Nitrosos/farmacologia , Fator 1 de Transcrição de Octâmero , Poli(ADP-Ribose) Polimerases/química , Poli(ADP-Ribose) Polimerases/metabolismo , Fator de Transcrição Sp1/química , Fator de Transcrição Sp1/metabolismo , Sulfonas/metabolismo , Sulfonas/farmacologia , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Transcrição Gênica/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Produtos do Gene gag do Vírus da Imunodeficiência Humana
16.
J Med Chem ; 42(1): 67-86, 1999 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-9888834

RESUMO

Nucleocapsid p7 protein (NCp7) zinc finger domains of the human immunodeficiency virus type 1 (HIV-1) are being developed as antiviral targets due to their key roles in viral replication and their mutationally nonpermissive nature. On the basis of our experience with symmetrical disulfide benzamides (DIBAs; Rice et al. Science 1995, 270, 1194-1197), we synthesized and evaluated variants of these dimers, including sets of 4,4'- and 3,3'-disubstituted diphenyl sulfones and their monomeric benzisothiazolone derivatives (BITA). BITAs generally exhibited diminished antiviral potency when compared to their disulfide precursors. Novel, monomeric structures were created by linking haloalkanoyl groups to the benzamide ring through -NH-C(=O)- (amide) or -S-C(=O)- (thiolester) bridges. Amide-linked compounds generally lacked antiviral activity, while haloalkanoyl thiolesters and non-halogen-bearing analogues frequently exhibited acceptable antiviral potency, thus establishing thiolester benzamides per se as a new anti-HIV chemotype. Pyridinioalkanoyl thiolesters (PATEs) exhibited superior anti-HIV-1 activity with minimal cellular toxicity and appreciable water solubility. PATEs were shown to preferentially target the NCp7 Zn finger when tested against other molecular targets, thus identifying thiolester benzamides, and PATEs in particular, as novel NCp7 Zn finger inhibitors for in vivo studies.


Assuntos
Fármacos Anti-HIV/síntese química , Proteínas do Capsídeo , Capsídeo/antagonistas & inibidores , Produtos do Gene gag/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Compostos de Piridínio/síntese química , Sulfonamidas/síntese química , Sulfonas/síntese química , Proteínas Virais , Dedos de Zinco , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , HIV-1/metabolismo , Ligantes , Camundongos , Modelos Moleculares , Compostos de Piridínio/química , Compostos de Piridínio/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonas/química , Sulfonas/farmacologia , Replicação Viral/efeitos dos fármacos , Produtos do Gene gag do Vírus da Imunodeficiência Humana
17.
Aliment Pharmacol Ther ; 14(2): 187-91, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10651659

RESUMO

OBJECTIVE: To investigate whether ibuprofen was as well-regarded by patients as other non-steroidal anti-inflammatory drugs (NSAIDs). DESIGN: Questionnaire sent to 1137 consecutive recipients of an NSAID prescription from 21 doctors in six general practices with computerized records. Patient responses were subsequently linked to data held on the practice records. SETTING: General practices in and around Nottingham, selected to reflect local variations in number of partners, list size, geographical location, deprivation, prescribing burden and prescribing rate. SUBJECTS: Unselected patients receiving NSAIDs prescribed for all indications for use. MAIN OUTCOME MEASURES: Effectiveness of ibuprofen and other NSAIDs, possible drug related adverse events, patients' overall satisfaction with ibuprofen and other NSAIDs, factors associated with choice of ibuprofen, drug costs of ibuprofen and other NSAIDs. RESULTS: The main NSAIDs used were ibuprofen, diclofenac and naproxen. Ibuprofen use ranged from 1.0% of prescriptions in one practice to 69.1% in another. Although ibuprofen was generally prescribed in low doses, it was perceived by patients as being as effective as the other NSAIDs used, even after allowing for severity of the pre-treatment condition. Overall, 50.5% of patients rated their NSAID the best treatment they had received for their condition with no differences between individual drugs. CONCLUSIONS: Ibuprofen is as highly regarded as other NSAIDs when used in similar circumstances. Switching patients to ibuprofen may be a realistic way of reducing financial and medical costs associated with NSAIDs.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Prescrições de Medicamentos/estatística & dados numéricos , Ibuprofeno/uso terapêutico , Satisfação do Paciente/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/economia , Diclofenaco/efeitos adversos , Diclofenaco/economia , Diclofenaco/uso terapêutico , Prescrições de Medicamentos/economia , Humanos , Ibuprofeno/efeitos adversos , Ibuprofeno/economia , Sistemas Computadorizados de Registros Médicos , Pessoa de Meia-Idade , Naproxeno/efeitos adversos , Naproxeno/economia , Naproxeno/uso terapêutico , Satisfação do Paciente/economia , Inquéritos e Questionários , Reino Unido
18.
Aliment Pharmacol Ther ; 14(2): 177-85, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10651658

RESUMO

AIM: To investigate the pharmacoepidemiology of NSAID usage in Nottingham general practices. DESIGN: Questionnaire sent to 1137 consecutive recipients of an NSAID prescription from 21 doctors in six general practices with computerized records. Patient responses were subsequently linked to data held on the practice records. SETTING: General practices in and around Nottingham, selected to reflect local variations in number of partners, list size, geographical location, deprivation, prescribing burden and prescribing rate. SUBJECTS: Unselected patients receiving NSAIDs prescribed for all indications. MAIN OUTCOME MEASURES: Indication for treatment, differences in prescribing to different age groups, compliance and overall scheme drug exposure, drug effectiveness and tolerability, possible drug-related adverse events, patients' overall satisfaction with treatment and estimated costs of care. RESULTS: NSAIDs were used for a wide range of conditions and only a small number of patients had rheumatoid arthritis. The main drugs used were ibuprofen, diclofenac and naproxen. Patients making short-term use of NSAIDs had low compliance if they experienced adverse drug effects, whilst conversely in long-term users, those with high compliance reported more adverse drug effects. Calculated compliance did not vary with age although older patients (over 65 years) claimed in their questionnaires to be more compliant than younger patients. Half the patients reported good or complete symptom relief. Half of those questions (and two thirds of those with good or complete symptom relief) rated their NSAID as the best treatment they had received for their current condition. The frequency of gastrointestinal adverse events was higher in the young and the old, which correlated with the use of anti-ulcer drugs, and increased with the total number of medications used. CONCLUSIONS: NSAIDs are used for a wide-range of conditions. They give symptom relief to, and are perceived as effective by, most patients taking them.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Prescrições de Medicamentos/estatística & dados numéricos , Inflamação/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/economia , Diclofenaco/efeitos adversos , Diclofenaco/economia , Diclofenaco/uso terapêutico , Medicina de Família e Comunidade , Humanos , Ibuprofeno/efeitos adversos , Ibuprofeno/economia , Ibuprofeno/uso terapêutico , Inflamação/economia , Sistemas Computadorizados de Registros Médicos , Pessoa de Meia-Idade , Naproxeno/efeitos adversos , Naproxeno/economia , Naproxeno/uso terapêutico , Cooperação do Paciente , Farmacoepidemiologia , Reino Unido
19.
Theor Appl Genet ; 105(1): 106-112, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12582568

RESUMO

Willow is being developed as a crop for biomass plantations in the Northeast and North-central United States, but has only recently been the subject of controlled breeding to generate improved genotypes. Maximizing variability among progeny within full-sib families produced by controlled pollination may increase the probability of producing willow clones exhibiting desirable extreme phenotypes. Yet, predicting combinations of parents yielding highly variable progeny is not currently possible. Controlled pollinations were completed among 15 Salix eriocephala clones and the resulting progeny were vegetatively propagated and planted in a greenhouse progeny test. Heights of rooted cuttings were measured after 4 months of growth. Genetic similarity among parents was estimated based on 77 polymorphic AFLP bands. Strong negative correlation ( r = -0.88) was detected between mean female-parent similarity indices and the standard deviation of height among half-sib progeny from those females. Parent combinations that had relatively low similarity indices tended to produce progeny that had greater variability in height. This negative relationship suggests that AFLP fingerprints of S. eriocephala parents may be useful for predicting parent combinations that will yield families with large variability.

20.
AJNR Am J Neuroradiol ; 21(10): 1807-12, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-11110531

RESUMO

BACKGROUND AND PURPOSE: Patient selection for percutaneous vertebroplasty is often complicated by the presence of multiple fractures or non-localizing pain. Our purpose was to determine whether increased activity revealed by bone scan imaging is predictive of a positive clinical response to percutaneous vertebroplasty. METHODS: A retrospective chart review conducted at our institution yielded 28 vertebroplasty treatment sessions that had been performed after obtaining bone scan imaging for painful, osteoporotic compression fractures in 27 patients. Thirty-five compression fractures were treated during these 28 treatment sessions. In all cases, increased activity was revealed by bone scan imaging before treatment with vertebroplasty. Positive outcome was defined as subjective decrease in pain severity and/or increased level of patient mobility. RESULTS: Subjective pain relief was noted in 26 (93%) of 28 treatment sessions. In 14 (100%) of 14 cases with quantifiable pain levels, pain improved at least 3 points on a 10-point scale (range of improvement, 3-10 points; mean improvement, 7.4 points). Among the remaining 14 treatment sessions in which patients were unable or unwilling to quantify pain severity, the pain relief was described as complete or excellent pain relief in 11 (78%) of 14 cases. In 14 (100%) of 14 cases for which semiquantitative assessment of mobility was available, mobility improved at least one level (5-point graded scale; range of improvement, 1-4 points; mean improvement, 1.7 points). CONCLUSIONS: Increased activity revealed by bone scan imaging is highly predictive of positive clinical response to percutaneous vertebroplasty.


Assuntos
Fraturas da Coluna Vertebral/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/complicações , Medição da Dor , Seleção de Pacientes , Valor Preditivo dos Testes , Cintilografia , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Fraturas da Coluna Vertebral/etiologia , Fraturas da Coluna Vertebral/terapia , Medronato de Tecnécio Tc 99m , Resultado do Tratamento
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