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1.
S Afr Med J ; 109(6): 387-391, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31266556

RESUMO

South Africa (SA) is in the process of amending its patent laws. Since its 2011 inception, Fix the Patent Laws, a coalition of 40 patient groups, has advocated for reform of SA's patent laws to improve affordability of medicines in the country. Building on two draft policies (2013, 2017) and a consultative framework (2016) for reform of SA's patent laws, Cabinet approved phase 1 of the Intellectual Property Policy of the Republic of South Africa on 23 May 2018. Fix the Patent Laws welcomed the policy, but highlighted concerns regarding the absence of important technical details, as well as the urgent need for government to develop bills, regulations and guidelines to provide technical detail and to codify and implement patent law reform in the country. In this article, we explore how reforms proposed in SA's new intellectual property policy could improve access to medicine through four medicine case studies.


Assuntos
Custos de Medicamentos , Acessibilidade aos Serviços de Saúde , Patentes como Assunto/legislação & jurisprudência , Preparações Farmacêuticas/economia , Antineoplásicos/economia , Antivirais/economia , Custos e Análise de Custo , Indústria Farmacêutica , Cloridrato de Erlotinib/economia , Guanina/análogos & derivados , Guanina/economia , Humanos , Fatores Imunológicos/economia , Lenalidomida/economia , Sorafenibe/economia , África do Sul
2.
J Hosp Infect ; 95(2): 154-160, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27756489

RESUMO

BACKGROUND: The insertion of external ventricular drains (EVDs) is necessary in some neurosurgical patients, but increases the risk of meningitis/ventriculitis. While there are well-recognized risk factors, the proportion of patients who develop meningitis/ventriculitis varies partly due to differences in definitions. A multi-disciplinary working group was established to agree definitions for EVD-associated meningitis/ventriculitis, and a surveillance system was piloted in four centres in the UK and Ireland. METHODS: Definitions were agreed based on those published previously and on clinical and microbiological criteria. An agreed dataset was developed to monitor patients after the insertion of an EVD and until the EVD was removed and the microbial aetiology was recorded. FINDINGS: Four neurosurgical centres participated, with 61-564 patients surveyed in each unit. The vast majority of drains were cranial. Intracranial haemorrhage was the most common indication for the EVD insertion. Between 6% and 35% of EVDs were inserted by consultants rather than junior doctors. The proportion of patients who developed meningitis/ventriculitis varied from 3% to 18% and from 4.8 to 12.7/1000 EVD-days. Coagulase-negative staphylococci were the most common microbial causes. CONCLUSIONS: Routine and ongoing monitoring of patients with an EVD in situ to detect meningitis/ventriculitis presents logistical difficulties, and few units do so. This pilot study suggests that a national system of surveillance with agreed definitions and a methodology to enable unit-to-unit comparisons of EVD meningitis/ventriculitis is both necessary and feasible. This will, in turn, inform quality improvement processes leading to the minimization of infection.


Assuntos
Ventriculite Cerebral/epidemiologia , Drenagem/efeitos adversos , Meningite/epidemiologia , Procedimentos Neurocirúrgicos/efeitos adversos , Infecções Relacionadas à Prótese/epidemiologia , Monitoramento Epidemiológico , Feminino , Humanos , Irlanda/epidemiologia , Masculino , Projetos Piloto , Reino Unido/epidemiologia
3.
Sci Rep ; 6: 18910, 2016 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-26752378

RESUMO

Proteoglycan 4 (PRG4/lubricin) is secreted by cells that reside in articular cartilage and line the synovial joint. Lubricin may play a role in modulating inflammatory responses through interaction with CD44. This led us to examine if lubricin could be playing a larger role in the modulation of inflammation/immunity through interaction with Toll-like receptors (TLRs). Human Embryonic Kidney (HEK) cells overexpressing TLRs 2, 4 or 5 and surface plasmon resonance were employed to determine if full length recombinant human lubricin was able to bind to and activate TLRs. Primary human synovial fibroblasts were also examined using flow cytometry and Luminex multiplex ELISA. A rat destabilization model of osteoarthritis (OA) was used to determine if lubricin injections were able to regulate pain and/or inflammation in vivo. Lubricin can bind to and regulate the activity of TLRs, leading to downstream changes in inflammatory signalling independent of HA. We confirmed these findings in vivo through intra-articular injections of lubricin in a rat OA model where the inhibition of systemic inflammatory signaling and reduction in pain were observed. Lubricin plays an important role in regulating the inflammatory environment under both homeostatic and tissue injury states.


Assuntos
Glicoproteínas/metabolismo , Receptores Toll-Like/metabolismo , Adulto , Animais , Células CHO , Cricetinae , Cricetulus , Citocinas/metabolismo , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Ácido Hialurônico/metabolismo , Inflamação/patologia , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , Osteoartrite/patologia , Ligação Proteica/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Ratos
4.
Pediatr Transplant ; 15(8): E174-6, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20731785

RESUMO

A woman who had undergone liver transplantation for genetically documented ATP8B1 disease/progressive familial intrahepatic cholestasis, type 1, successfully conceived, carried, and was delivered of a healthy child. The pregnancy and its management are described; implications are discussed.


Assuntos
Colestase Intra-Hepática/cirurgia , Transplante de Fígado , Complicações na Gravidez/terapia , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez
6.
Leukemia ; 18(11): 1798-803, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15385923

RESUMO

The purpose of our study was (i) to evaluate the impact of all-trans retinoic acid (ATRA) given as adjunct to chemotherapy and (ii) to compare second consolidation vs maintenance therapy in elderly patients with acute myeloid leukemia (AML). A total of 242 patients aged >or=61 years (median, 66.6 years) with AML were randomly assigned to ATRA beginning on day +3 after the initiation of chemotherapy (ATRA-arm, n=122) or no ATRA (standard-arm, n=120) in combination with induction and first consolidation therapy. A total of 61 patients in complete remission (CR) were randomly assigned to second intense consolidation (n=31) or 1-year oral maintenance therapy (n=30). After induction therapy the intention-to-treat analysis revealed a significant difference in CR rates between the ATRA- and the standard-arm (52 vs 39%; P=0.05). Event-free (EFS) and overall survival (OS) were significantly better in the ATRA-compared to the standard-arm (P=0.03 and 0.01, respectively). OS after second randomization was significantly better for patients assigned to intensive consolidation therapy (P<0.001). The multivariate model for survival revealed lactate dehydrogenase, cytogenetic risk group, age, and first and second randomization as prognostic variables. In conclusion, the addition of ATRA to induction and consolidation therapy may improve CR rate, EFS and OS in elderly patients with AML.


Assuntos
Anemia Refratária com Excesso de Blastos/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide/terapia , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Citarabina/administração & dosagem , Etoposídeo/administração & dosagem , Humanos , Idarubicina/administração & dosagem , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Taxa de Sobrevida , Transplante Homólogo , Tretinoína/administração & dosagem
7.
Leukemia ; 16(10): 2062-71, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12357358

RESUMO

NF-kappaB/Rel transcription factors are modulators of immune and inflammatory processes and are also involved in malignancy. Phosphorylation of the IkappaB inhibitors by the IkappaB kinase (IKK) complex leads to their proteasomal degradation, resulting in activated NF-kappaB. Here, we investigated the activation status of NF-kappaB and the IKK complex in acute myeloid leukemia (AML). Gelshift assays revealed an increased level of activated nuclear NF-kappaB in myeloid blasts. Both bone marrow and peripheral blood blasts from AML patients showed enhanced IKK activity relative to controls, whereas the IKK protein concentrations were comparable. In addition, an increased level of IkappaB-alpha was detected in AML blast cells, although this appeared to be insufficient to block nuclear translocation of NF-kappaB, also confirmed by immunofluorescence. In subtype M4 and M5 AML cells a more extensive NF-kappaB activation and higher IKK activity was found than in M1/M2 specimens. Isolated AML blasts cultured ex vivo responded to external stimulation (TNF, LPS) by further IKK activation, IkappaB degradation and NF-kappaB activation. Preincubation with the proteasome inhibitor PSI inhibited the NF-kappaB system in isolated AML blasts. This study established for the first time a dysregulation of IKK signaling in AML leading to increased NF-kappaB activity suggesting potential therapeutic avenues.


Assuntos
Leucemia Mieloide/enzimologia , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Núcleo Celular/metabolismo , Eletroforese em Gel de Poliacrilamida , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Citometria de Fluxo , Imunofluorescência , Humanos , Quinase I-kappa B , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patologia , Lipopolissacarídeos/farmacologia , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/farmacologia
8.
Exp Cell Res ; 269(1): 109-16, 2001 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-11525644

RESUMO

We previously reported that IL-1beta and the decoy receptor for IL-1 (IL-1RII) are expressed by intestinal epithelial cells (IEC) during detachment-induced cell death, or "anoikis." We now investigated whether IL-1 regulates anoikis. Skewing the balance in favor of IL-1, by blocking IL-1RII or by adding IL-1beta to detached rat IEC-18 cells, reduced cell death. The protective effect of anti-IL-1RII was reversed by blocking IL-1beta, confirming the anti-apoptotic effect was due to endogenous IL-1beta. Added IL-1beta also rescued cells from anoikis and was associated with considerable aggregation of the detached cells. Aggregate formation and the anti-apoptotic effect of added IL-1beta were prevented by blocking E-cadherin, indicating that IL-1 promoted aggregation and indirectly, survival. On the other hand, treating detached cells with IL-1beta and an anti-beta(1) integrin antibody abolished the protective effect of IL-1beta but not the aggregates. We conclude that the anti-apoptotic effect of IL-1 is mediated through a beta(1) integrin-dependent event secondary to cell-cell adhesion. This illustrates a previously uncharacterized role for IL-1 in the intestine wherein this cytokine may facilitate the preservation of the epithelial monolayer integrity.


Assuntos
Anoikis/fisiologia , Adesão Celular/fisiologia , Comunicação Celular/fisiologia , Células Cultivadas/metabolismo , Interleucina-1/metabolismo , Mucosa Intestinal/metabolismo , Receptores de Interleucina-1/metabolismo , Animais , Anoikis/efeitos dos fármacos , Caderinas/efeitos dos fármacos , Caderinas/metabolismo , Caspases/efeitos dos fármacos , Caspases/metabolismo , Adesão Celular/efeitos dos fármacos , Agregação Celular/efeitos dos fármacos , Agregação Celular/fisiologia , Comunicação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas/citologia , Células Cultivadas/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/fisiopatologia , Integrina beta1/efeitos dos fármacos , Integrina beta1/metabolismo , Interleucina-1/farmacologia , Mucosa Intestinal/citologia , Mucosa Intestinal/efeitos dos fármacos , Receptores de Interleucina-1/agonistas , Receptores de Interleucina-1/antagonistas & inibidores , Receptores Tipo II de Interleucina-1
9.
J Interferon Cytokine Res ; 21(4): 223-30, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11359653

RESUMO

The intestinal epithelial cell (IEC) represents the first cellular barrier to infection. Consistent with this sentinel role, IEC are known to produce a variety of chemokines in response to bacterial infection or proinflammatory cytokines. These chemokines act as potent leukocyte activators and chemoattractants in vivo. In this report, we begin to characterize the regulation of expression of the chemokine monocyte chemoattractant protein-1 (MCP-1) in the rat small intestinal IEC-18 line. Following stimulation with either interleukin-1beta (IL-1beta) or lipopolysaccharide (LPS), IEC-18 cells produced MCP-1, with IL-1 proving a more effective stimulus than LPS at both the mRNA and protein levels. Expression of MCP-1 due to either stimulus was inhibited by tyrosine kinase inhibitors, prompting us to investigate potential phosphotyrosine-dependent targets responsible for MCP-1 expression. We detected activation of p38, a member of the mitogen-activated protein kinase family, following either IL-1 or LPS treatment. Specific inhibition of this kinase using the compound SB203580 caused a destabilization of MCP-1 mRNA. These data point to a role for p38 in the regulation of MCP-1 mRNA expression by the IEC.


Assuntos
Quimiocina CCL2/biossíntese , Quimiocinas/biossíntese , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Animais , Linhagem Celular , Quimiocina CCL2/antagonistas & inibidores , Quimiocina CCL2/genética , Regulação para Baixo/imunologia , Ativação Enzimática/imunologia , Inibidores Enzimáticos/farmacologia , Interleucina-1/farmacologia , Lipopolissacarídeos/farmacologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/farmacologia , Estabilidade de RNA/imunologia , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/metabolismo , Ratos , Proteínas Quinases p38 Ativadas por Mitógeno
10.
Paediatr Child Health ; 6(8): 517-21, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20084120

RESUMO

The establishment of the Canadian Institutes of Health Research (CIHR) generated considerable excitement about the capacity for health research in Canada. The long term success of the CIHR will be determined, in part, by its ability to recruit, train and retain a cadre of talented researchers. During a workshop to develop the research agenda for one of the proposed institutes within the CIHR, a national, multidisciplinary group of clinical and basic science research trainees were invited to present their views about the challenges that face Canadian researchers of tomorrow. The objective of this paper is to present the challenges associated with recruiting, training and retaining health researchers, and to identify new opportunities provided by the creation of the CIHR. The present paper concludes with suggestions that may improve the success of researchers and, ultimately, the success of the CIHR.

11.
Inflammation ; 24(5): 447-61, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10921508

RESUMO

TNF-alpha and IL-1beta promote leukocyte recruitment to arthritic joints and may contribute to cartilage degradation while regulatory cytokines such as IL-4 and IL-1RA may in part determine the course of arthritis. Here we report the pattern of TNF-alpha, IL-1beta, IL-6, IFN-gamma, IL-1RA, and IL-4 mRNA expression, detected by RT/PCR, in the talar joint and draining popliteal lymph node (PLN) of rats with adjuvant arthritis (AA). Levels of TNF-alpha and IFN-gamma mRNA were increased in the PLN before clinical signs of arthritis. This was followed by increases in IL-1beta and IL-1RA mRNA at d9 and IL-6 mRNA at d12. PLN IL-1RA mRNA levels were positively correlated with those of IL-1beta and TNF-alpha throughout d5-d20. IL-4 mRNA levels were highest on days 7 and 20. In the synovium, a small increase in TNF-alpha, IL-1beta, and IL-6 mRNA was detected on d5 then again on d12. Maximal synovial TNF-alpha levels were reached on d20, while IL-1beta peak expression was on d16 and IL-6 on d14. IL-4, IL-1RA, and IFN-gamma mRNA was undetectable in the synovium. Cyclosporin treatment for 4 days, initiated at the height of arthritis, rapidly decreased clinical disease, and decreased migration of neutrophils and T lymphocytes into the joints. Yet no significant effect of CyA was observed on inflammatory cytokine expression, although the correlation between PLN IL-1RA and IL-1beta or TNF-alpha was lost in treated animals. Thus there is a variable pattern of cytokine gene expression in rat AA, the undetectable IL-4 and IFN-gamma mRNA in synovium being analogous to human rheumatoid arthritis.


Assuntos
Artrite Experimental/metabolismo , Ciclosporina/farmacologia , Citocinas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Imunossupressores/farmacologia , Linfonodos/metabolismo , RNA Mensageiro/biossíntese , Membrana Sinovial/metabolismo , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/genética , Artrite Reumatoide/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Ciclosporina/uso terapêutico , Citocinas/biossíntese , Modelos Animais de Doenças , Humanos , Hipersensibilidade Tardia/imunologia , Imunossupressores/uso terapêutico , Interferon gama/biossíntese , Interferon gama/genética , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-1/biossíntese , Interleucina-1/genética , Interleucina-4/biossíntese , Interleucina-4/genética , Interleucina-6/biossíntese , Interleucina-6/genética , Masculino , Modelos Animais , Ratos , Ratos Endogâmicos Lew , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sialoglicoproteínas/biossíntese , Sialoglicoproteínas/genética , Tarso Animal/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética
12.
J Interferon Cytokine Res ; 20(3): 299-308, 2000 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10762077

RESUMO

When the intestine becomes infected by pathogenic organisms, intestinal epithelial cells (IEC) respond with the production of chemokines, which then attract and activate specific subsets of leukocytes. During chronic inflammation, the panel of IEC chemokines produced likely represents the net effect of a plethora of mediators present in the milieu, including cytokines from activated T lymphocytes. To explore the influence of T lymphocyte cytokines, we treated IEC-18 cells with interferon-y (IFN-gamma) and interleukin-4 (IL-4) and measured the effect on production of the CC chemokines, monocyte chemoattractant protein-1 (MCP-1) and eotaxin, and the CXC chemokine, macrophage inflammatory protein-2 (MIP-2). Both IFN-gamma and IL-4 enhanced MCP-1 mRNA levels but with different kinetics. IFN-gamma stimulated a transient increase in MCP-1 mRNA levels, which peaked at 2 h, whereas IL-4-stimulated MCP-1 mRNA levels were markedly increased at 1 h and remained elevated at all time points studied. With each stimulus, the increase in MCP-1 mRNA levels was accompanied by a steady time-dependent increase in MCP-1 secretion. In addition, treatment with IFN-gamma or IL-4 enhanced IL-1beta-stimulated MCP-1 mRNA production and protein secretion. Eotaxin mRNA was detectable in unstimulated IEC-18 cells, and IL-4 but not IFN-gamma caused a rapid enhancement in levels, which remained elevated for 24 h after treatment. Finally, IL-1beta but not IFN-gamma or IL-4 enhanced MIP-2 mRNA levels. Knowledge gained from studying the outcome of T lymphocyte-derived stimuli will help understand the complex sequence of events during chronic intestinal inflammation.


Assuntos
Quimiocina CCL2/biossíntese , Quimiocinas CC , Citocinas/biossíntese , Interferon gama/fisiologia , Interleucina-4/fisiologia , Mucosa Intestinal/metabolismo , Animais , Linhagem Celular , Quimiocina CCL11 , Fatores Quimiotáticos de Eosinófilos/biossíntese , Fatores Quimiotáticos de Eosinófilos/metabolismo , Citocinas/metabolismo , Interleucina-1/metabolismo , Mucosa Intestinal/citologia , RNA Mensageiro/biossíntese , Ratos , Fatores de Tempo
13.
Cell Immunol ; 193(1): 1-8, 1999 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-10202107

RESUMO

Intestinal epithelial cells have been shown to produce IL-1beta in vivo. This gene expression is rapid and precedes most determinants of inflammation, suggesting a pivotal role for IL-1beta in the early events leading to inflammation. To better understand the mechanisms leading to this IL-1beta production, we have developed an in vitro model system employing a nontransformed intestinal epithelial cell line that does not constitutively express IL-1beta. Following detachment, these cells rapidly expressed IL-1beta mRNA. This expression was enhanced, but not induced, by LPS. IL-1beta protein was detected by immunoprecipitation in the culture medium from passaged IEC-18 but not intracellularly, suggesting an efficient secretion of the molecule following induction. Interestingly, culture supernatants from passaged cells were without IL-1 bioactivity, suggesting the presence of an inhibitor as well. RT-PCR and Western blot analysis showed expression of IL-1RII by IEC-18 following detachment, possibly explaining the observed lack of bioactivity. These results indicate a novel pathway for IL-1beta production and suggest that proinflammatory effects of IEC-derived IL-1 may be modulated by the simultaneous production of IL-1 antagonists.


Assuntos
Interleucina-1/biossíntese , Mucosa Intestinal/metabolismo , Animais , Células Cultivadas , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-1/genética , Mucosa Intestinal/citologia , Lipopolissacarídeos/farmacologia , Biossíntese de Proteínas , RNA Mensageiro/análise , Ratos , Ratos Endogâmicos Lew , Receptores de Interleucina-1/biossíntese , Sialoglicoproteínas/fisiologia
17.
Pract Midwife ; 1(11): 46, 1998 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10214281
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