RESUMO
BACKGROUND: For patients with peripheral T-cell lymphoma (PTCL), outcomes using frontline treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like therapy are typically poor. The ECHELON-2 study demonstrated that brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) exhibited statistically superior progression-free survival (PFS) per independent central review and improvements in overall survival versus CHOP for the frontline treatment of patients with systemic anaplastic large cell lymphoma or other CD30-positive PTCL. PATIENTS AND METHODS: ECHELON-2 is a double-blind, double-dummy, randomized, placebo-controlled, active-comparator phase III study. We present an exploratory update of the ECHELON-2 study, including an analysis of 5-year PFS per investigator in the intent-to-treat analysis group. RESULTS: A total of 452 patients were randomized (1 : 1) to six or eight cycles of A+CHP (N = 226) or CHOP (N = 226). At median follow-up of 47.6 months, 5-year PFS rates were 51.4% [95% confidence interval (CI): 42.8% to 59.4%] with A+CHP versus 43.0% (95% CI: 35.8% to 50.0%) with CHOP (hazard ratio = 0.70; 95% CI: 0.53-0.91), and 5-year overall survival (OS) rates were 70.1% (95% CI: 63.3% to 75.9%) with A+CHP versus 61.0% (95% CI: 54.0% to 67.3%) with CHOP (hazard ratio = 0.72; 95% CI: 0.53-0.99). Both PFS and OS were generally consistent across key subgroups. Peripheral neuropathy was resolved or improved in 72% (84/117) of patients in the A+CHP arm and 78% (97/124) in the CHOP arm. Among patients who relapsed and subsequently received brentuximab vedotin, the objective response rate was 59% with brentuximab vedotin retreatment after A+CHP and 50% with subsequent brentuximab vedotin after CHOP. CONCLUSIONS: In this 5-year update of ECHELON-2, frontline treatment of patients with PTCL with A+CHP continues to provide clinically meaningful improvement in PFS and OS versus CHOP, with a manageable safety profile, including continued resolution or improvement of peripheral neuropathy.
Assuntos
Antígeno Ki-1 , Linfoma de Células T Periférico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Brentuximab Vedotin , Humanos , Antígeno Ki-1/metabolismo , Antígeno Ki-1/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico , Vincristina/efeitos adversosRESUMO
There is a strong evidence-based rationale for community capacity building and community empowerment as part of a strategic response to reduce health inequalities. Within the current UK policy context, there are calls for increased public engagement in prevention and local decision-making in order to give people greater control over the conditions that determine health. With reference to the challenges and opportunities within the English public health system, this essay seeks to open debate about what is required to mainstream community-centred approaches and ensure that the public is central to public health. The essay sets out the case for a reorientation of public health practice in order to build impactful action with communities at scale leading to a reduction in the health gap. National frameworks that support local practice are described. Four areas of challenge that could potentially drive an implementation gap are discussed: (i) achieving integration and scale, (ii) effective community mobilization, (iii) evidencing impact and (iv) achieving a shift in power. The essay concludes with a call to action for developing a contemporary public health practice that is rooted in communities and offers local leadership to strengthen local assets, increase community control and reduce health inequalities.
Assuntos
Participação da Comunidade , Liderança , Prática de Saúde Pública , Disparidades nos Níveis de Saúde , Humanos , Saúde Pública , Reino UnidoRESUMO
Cell death and the release of chromatin have been demonstrated to activate the immune system producing autoantibodies against nuclear antigens in patients with systemic lupus erythematosus (SLE). Apoptosis, necrosis, necroptosis, secondary necrosis, autophagy and the clearance of dying cells by phagocytosis are processes believed to have a role in tolerance avoidance, activation of autoimmune lymphocytes and tissue damage by effector cells. The released chromatin not only activates the immune system; it also acts as antigen for the autoantibodies produced, including anti-dsDNA antibodies. The subsequent immune complex formed is deposited within the basement membranes and the mesangial matrix of glomeruli. This may be considered as an initiating event in lupus nephritis. The origin of the released chromatin is still debated, and the possible mechanisms and cell sources are discussed in this study.
Assuntos
Morte Celular/imunologia , Nefrite Lúpica/imunologia , Animais , Apoptose/imunologia , Autoimunidade , Cromatina/imunologia , Cromatina/metabolismo , Humanos , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Nucleossomos/imunologia , Nucleossomos/metabolismoRESUMO
BACKGROUND: Two human herpesviruses, human herpesvirus 6 (HHV-6), and Epstein-Barr virus (EBV), have been repeatedly linked to multiple sclerosis (MS). OBJECTIVE: The aim of this study was to investigate HHV-6 and EBV reactive oligoclonal bands (OCBs), and viral DNA in the intrathecal compartment in MS. METHODS: The reactivity of OCBs in cerebrospinal fluid (CSF) for EBV and HHV-6 antigens and stability of virus reactive OCBs over time were studied in a well-characterized MS patient cohort. Associations between virus reactive OCBs and viral DNA in CSF (and any clinical and/or radiological findings) were investigated. RESULTS: Of patients with MS, 38% had OCBs reactive to either one of the viruses studied, compared to none in the patients with other inflammatory neurological diseases (p=0.005). The banding pattern of virus reactive OCBs remained the same over time. Furthermore, MS patients with viral DNA in CSF had more contrast enhancing lesions (CELs). CONCLUSION: The stable presence of herpesvirus reactive OCBs in CSF further strengthens the association of MS with these viruses. The finding that herpesviruses might be linked to the appearance of active lesions warrants investigation of new therapeutic strategies to treat these viruses in MS.
Assuntos
Infecções por Vírus Epstein-Barr/complicações , Esclerose Múltipla/virologia , Infecções por Roseolovirus/complicações , Adulto , DNA Viral/líquido cefalorraquidiano , Infecções por Vírus Epstein-Barr/líquido cefalorraquidiano , Feminino , Herpesvirus Humano 4 , Herpesvirus Humano 6 , Humanos , Immunoblotting , Focalização Isoelétrica , Medições Luminescentes , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/patologia , Bandas Oligoclonais/líquido cefalorraquidiano , Reação em Cadeia da Polimerase , Infecções por Roseolovirus/líquido cefalorraquidiano , Adulto JovemRESUMO
The burden of disease due to chronic viral hepatitis constitutes a global threat. In many Balkan and Mediterranean countries, the disease burden due to viral hepatitis remains largely unrecognized, including in high-risk groups and migrants, because of a lack of reliable epidemiological data, suggesting the need for better and targeted surveillance for public health gains. In many countries, the burden of chronic liver disease due to hepatitis B and C is increasing due to ageing of unvaccinated populations and migration, and a probable increase in drug injecting. Targeted vaccination strategies for hepatitis B virus (HBV) among risk groups and harm reduction interventions at adequate scale and coverage for injecting drug users are needed. Transmission of HBV and hepatitis C virus (HCV) in healthcare settings and a higher prevalence of HBV and HCV among recipients of blood and blood products in the Balkan and North African countries highlight the need to implement and monitor universal precautions in these settings and use voluntary, nonremunerated, repeat donors. Progress in drug discovery has improved outcomes of treatment for both HBV and HCV, although access is limited by the high costs of these drugs and resources available for health care. Egypt, with the highest burden of hepatitis C in the world, provides treatment through its National Control Strategy. Addressing the burden of viral hepatitis in the Balkan and Mediterranean regions will require national commitments in the form of strategic plans, financial and human resources, normative guidance and technical support from regional agencies and research.
Assuntos
Carcinoma Hepatocelular/epidemiologia , Hepatite B Crônica/epidemiologia , Hepatite C Crônica/epidemiologia , Neoplasias Hepáticas/epidemiologia , Antivirais/economia , Antivirais/uso terapêutico , Península Balcânica/epidemiologia , Carcinoma Hepatocelular/etiologia , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/prevenção & controle , Infecção Hospitalar/transmissão , Transmissão de Doença Infecciosa/prevenção & controle , Monitoramento Epidemiológico , Vacinas contra Hepatite B/administração & dosagem , Hepatite B Crônica/complicações , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/prevenção & controle , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/prevenção & controle , Humanos , Neoplasias Hepáticas/etiologia , Região do Mediterrâneo/epidemiologia , Resultado do Tratamento , Vacinação/estatística & dados numéricosRESUMO
We compare attitudes, experiences of learning about sex and first intercourse among Indians (n = 393) and Pakistanis (n = 365) using a probability survey of Britain's general population aged 16-44 years conducted during 1999-2001 (n = 12,110). Higher proportions of Pakistanis (64.6%) and Indians (28.1%) reported religion as 'very important' versus 6.2% of other ethnicities. Pakistanis were more conservative in their attitudes, e.g. reporting premarital sex as wrong (adjusted odds ratios [AORs] for sociodemographic differences, 4.71 [men] and 6.59 [women]). Pakistanis were more likely to be married at first sex (AORs 6.2 [men] and 9.53 [women]), yet men were more likely than women to be in non-marital relationships at this time (69.4% versus 25.2%). Pakistani men and women and Indian women were more likely to report not using reliable contraception at first sex relative to others (AORs 2.33, 3.16 and 1.90, respectively). Pakistani and Indian women were more likely than others to report school lessons as their main source of sex education (AORs 2.23 and 1.77) and not discussing sex with their parents during adolescence (AORs 2.04 and 2.62). These unique data have implications for ensuring that sex and relationship education and health promotion messages are appropriately planned, targeted and delivered to benefit Pakistanis and Indians.
Assuntos
Comportamento Sexual/etnologia , Comportamento Sexual/estatística & dados numéricos , Adolescente , Adulto , Atitude , Coito , Feminino , Inquéritos Epidemiológicos , Humanos , Índia/etnologia , Modelos Logísticos , Masculino , Casamento , Paquistão/etnologia , Comportamento Sexual/psicologia , Reino Unido/epidemiologiaRESUMO
We compared sociodemographic characteristics, sexual risk behaviours and sexual health experiences of 266 heterosexual black Caribbeans recruited at a London sexual health clinic between September 2005 and January 2006 with 402 heterosexual black Caribbeans interviewed for a British probability survey between May 1999 and August 2001. Male clinic attendees were more likely than men in the national survey to report: ≥10 sexual partners (lifetime; adjusted odds ratio [AOR]: 3.27, 95% confidence interval [CI]: 1.66-6.42), ≥2 partners (last year; AOR: 5.40, 95% CI: 2.64-11.0), concurrent partnerships (AOR: 3.26, 95% CI: 1.61-6.60), sex with partner(s) from the Caribbean (last 5 years; AOR: 7.97, 95% CI: 2.42-26.2) and previous sexually transmitted infection (STI) diagnosis/diagnoses (last 5 years; AOR: 16.2, 95% CI: 8.04-32.6). Similar patterns were observed for women clinic attendees, who also had increased odds of termination of pregnancy (AOR: 3.25, 95% CI: 1.87-5.66). These results highlight the substantially higher levels of several high-risk sexual behaviours among UK black Caribbeans attending a sexual health clinic compared with those in the general population. High-risk individuals are under-represented in probability samples, and it is therefore important that convenience samples of high-risk individuals are performed in conjunction with nationally representative surveys to fully understand the risk behaviours and sexual health-care needs of ethnic minority communities.
Assuntos
População Negra , Heterossexualidade/estatística & dados numéricos , Assunção de Riscos , Infecções Sexualmente Transmissíveis/epidemiologia , Adolescente , Adulto , Região do Caribe/epidemiologia , Feminino , Humanos , Londres/epidemiologia , Masculino , Inquéritos e Questionários , Adulto JovemRESUMO
Murine and human lupus nephritis are characterized by glomerular deposits of electron-dense structures (EDS). Dominant components of EDS are chromatin fragments and IgG antibodies. Whether glomerular EDS predispose for similar deposits in skin is unknown. We analysed (i) whether dermo-epidermal immune complex deposits have similar molecular composition as glomerular deposits, (ii) whether chromatin fragments bind dermo-epidermal structures, and (iii) whether deposits in nephritic glomeruli predispose for accumulation of similar deposits in skin. Paired skin and kidney biopsies from nephritic (NZBxNZW)F1 and MRL-lpr/lpr mice and from five patients with lupus nephritis were analysed by immunofluorescence, immune electron microscopy (IEM) and co-localization TUNEL IEM. Affinity of chromatin fragments for membrane structures was determined by surface plasmon resonance. Results demonstrated (i) presence of EDS containing chromatin fragments and IgG in both organs in nephritic patients, (ii) chromatin fragments possessed high affinity for dermo-epidermal laminins and collagens, (iii) glomerular immune complex deposits did not predict similar interstitial deposits in skin, although such complexes were present in capillary lumina in glomeruli and skin of all nephritic individuals. Thus, chromatin-IgG complexes accounting for lupus nephritis seem to reach skin through circulation, but other undetermined factors are required for these complexes to deposit within skin membranes.
Assuntos
Anticorpos Anti-Idiotípicos/sangue , Complexo Antígeno-Anticorpo/sangue , Cromatina/imunologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Pele/imunologia , Pele/patologia , Animais , Biópsia , Capilares/imunologia , Capilares/metabolismo , Capilares/patologia , Moléculas de Adesão Celular/metabolismo , Cromatina/metabolismo , Colágeno Tipo I/metabolismo , Colágeno Tipo IV/metabolismo , Modelos Animais de Doenças , Feminino , Histonas/metabolismo , Humanos , Imunoglobulina G/metabolismo , Glomérulos Renais/imunologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Nefrite Lúpica/sangue , Camundongos , Camundongos Endogâmicos MRL lpr , Camundongos Endogâmicos NZB , Pele/metabolismo , Fatores de Transcrição/metabolismo , CalininaRESUMO
OBJECTIVES: The INSIGHT case-control study confirmed that HIV serodiscordant unprotected anal intercourse (SdUAI) remains the primary risk factor for HIV infection in gay men in England. This paper uses qualitative follow-up data to examine the contexts of SdUAI and other risk factors among the case-control study participants. METHODS: In-depth interviews were conducted with 26 recent HIV seroconverters and 22 non-converters. Purposive selection was used to provide diversity in demographics and sexual behaviour and to facilitate exploration of risk factors identified in the case-control study. RESULTS: Condoms were perceived as barriers to intimacy, trust and spontaneity. The potential consequences of the loss of these were traded off against the consequences of HIV infection. Previous negative HIV tests and the adoption of risk reduction strategies diminished the perceived threat of HIV infection, supporting beliefs that HIV was something that happened to others. Depression and low self-esteem, often combined with use of alcohol or other drugs, led to further risk taking and loss of control over risk reduction strategies. CONCLUSIONS: A range of psychosocial reasons led some men to engage in UAI with serodiscordant or unknown partners, despite high levels of risk awareness. Men in their mid-life, those in serodiscordant relationships and men that had experienced bereavement or other significant, negative, life events revealed factors related to these circumstances that contributed to increases in risky UAI. A diverse portfolio of interventions is required to build confidence and control over safer sex practices that are responsive to gay men's wider emotional needs.
Assuntos
Soropositividade para HIV/psicologia , Homossexualidade Masculina/psicologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Sexo sem Proteção/psicologia , Adulto , Idoso , Atitude Frente a Saúde , Preservativos/estatística & dados numéricos , Inglaterra , Humanos , Masculino , Pessoa de Meia-Idade , Percepção , Adulto JovemRESUMO
OBJECTIVES: To detect and quantify current risk factors for HIV seroconversion among gay men seeking repeat tests at sexual health clinics. DESIGN: Unmatched case control study conducted in London, Brighton and Manchester, UK. METHODS: 75 cases (recent HIV positive test following a negative test within the past 2 years) and 157 controls (recent HIV negative test following a previous negative test within the past 2 years) completed a computer-assisted self interview focused on sexual behaviour and lifestyle between HIV tests. RESULTS: Cases and controls were similar in socio-demographics, years since commencing sex with men, lifetime number of HIV tests, reasons for seeking their previous HIV tests and the interval between last HIV tests (mean = 10.5 months). Risk factors between tests included unprotected receptive anal intercourse (URAI) with partners not believed to be HIV negative (adjusted odds ratio (AOR) and 95% confidence interval 4.1, 1.8 to 9.3), where increased risk was associated with concomitant use of nitrite inhalants, receiving ejaculate and increasing numbers of partners. Independent risk was also detected for unprotected insertive anal intercourse (UIAI) with more than one man (AOR 2.7, 1.3 to 5.5) and use of nitrite inhalants (AOR 2.4, 1.1 to 5.2). CONCLUSIONS: HIV serodiscordant unprotected anal intercourse remains the primary context for HIV transmission among gay men, with increased risk associated with being the receptive partner, receiving ejaculate and use of nitrite inhalants. Although the HIV transmission risk of URAI is widely acknowledged, this study highlights the risk of UIAI and that nitrite inhalants may be an important facilitator of transmission when HIV exposure occurs.
Assuntos
Soropositividade para HIV/epidemiologia , Homossexualidade Masculina/estatística & dados numéricos , Adulto , Idoso , Estudos de Casos e Controles , Inglaterra/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Fatores de Risco , Sexo sem Proteção/estatística & dados numéricosRESUMO
It is more than 25 years since the first case of AIDS was reported in the United Kingdom. In December 1981 a gay man was referred to a London hospital with opportunistic infections indicative of immunosuppression. National surveillance began the following year, in September 1982, with the notification of deaths and clinical reports of AIDS and Kaposi's sarcoma plus laboratory reports of opportunistic infections. Since then epidemiological surveillance systems have evolved, adapting to, and taking advantage of advances in treatments and laboratory techniques. The introduction of the HIV antibody test in 1984 led to the reporting of HIV-positive tests by laboratories and the establishment of an unlinked anonymous survey in 1990 measuring undiagnosed HIV infection among gay men attending sexual health clinics. The widespread use of highly active antiretroviral therapies (HAART) since 1996 has averted many deaths among HIV-positive gay men and has also resulted in a large reduction in AIDS cases. This led to a need for an enumeration of gay men with HIV accessing NHS treatment and care services (1995 onwards), more clinical information on HIV diagnoses for epidemiological surveillance (2000 onwards) and the routine monitoring of drug resistance (2001 onwards). Twenty-five years after the first case of AIDS was reported, gay and bisexual men remain the group at greatest risk of acquiring HIV in the United Kingdom. Latest estimates suggest that in 2004, 26 500 gay and bisexual men were living with HIV in the United Kingdom, a quarter of whom were undiagnosed. In this review, we examine how national surveillance systems have evolved over the past 25 years in response to the changing epidemiology of HIV/AIDS among gay and bisexual men in the United Kingdom as well as advances in laboratory techniques and medical treatments. We also reflect on how they will need to continue evolving to effectively inform health policy in the future.
Assuntos
Bissexualidade , Infecções por HIV/epidemiologia , Infecções por HIV/história , Homossexualidade Masculina , Vigilância da População/métodos , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , História do Século XX , História do Século XXI , Humanos , Masculino , Reino Unido/epidemiologiaRESUMO
BACKGROUND: Over the past 20 years, there has been a huge increase in the number of overseas trips made by UK residents. Although a number of studies have examined the frequency of overseas partner acquisition, they have used convenience samples and thus are not generalisable to the British general population. METHODS: A national probability sample survey was carried out in 1999-2001 of 12,110 men and women aged 16-44 years resident in Britain. Sociodemographic, health-related, travel, sexual behaviour and attitudinal data were collected by computer-assisted interviewing. The main outcomes were the proportion of British residents who reported new sexual partners overseas in the past 5 years, the country of origin of these new sex partners, and the association between reporting a new partner while overseas with a range of demographic, behavioural and attitudinal variables. RESULTS: 13.9% of men and 7.1% of women reported having new sexual partner(s) while overseas in the past 5 years. Among respondents who were aged 16-24 and never married, the proportions were significantly higher (23.0% of men and 17.0% of women). Half of those with new sex partners overseas reported their partner's origin as the UK, and over a third as another European country. In addition to age and marital status, reporting new partners overseas was associated with a higher number of partners, paying for sex (among men), reporting a diagnosis of sexually transmitted infection, and HIV testing. Adjustment for sociodemographic factors attenuated the magnitude of, but did not remove, these associations. CONCLUSIONS: A substantial minority of young, unmarried people form new sexual partnerships abroad, but these are typically with residents from the UK or other European countries. Those who have new partners abroad are likely to have higher-risk sexual lifestyles more generally, and to be at higher risk of sexually transmitted infections. Greater attention should be paid to sexual health promotion for travellers abroad, especially young travellers, emphasising the risks of new sexual relationships with compatriots as well as those from other countries in terms of STI/HIV acquisition and onwards transmission.
Assuntos
Parceiros Sexuais , Viagem , Sexo sem Proteção/estatística & dados numéricos , Adolescente , Adulto , Atitude Frente a Saúde , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Percepção , Medição de Risco , Reino Unido , Sexo sem Proteção/psicologiaRESUMO
OBJECTIVES: To estimate HIV prevalence and the distribution of high risk sexual behaviours, sexual health service use, and HIV testing among black Africans aged 16 years or over in England. To determine demographic, behavioural and service use factors associated with HIV prevalence. METHODS: A cross-sectional community-based survey (Mayisha II) in London, Luton and the West Midlands. A short (24-item) anonymous self-completion questionnaire with linked voluntary anonymous oral fluid sampling, using an Orasure device for HIV testing. RESULTS: A total of 1359 eligible black African men (51.9%) and women (48.1%) were recruited, of whom 74% (1006) provided a sufficient oral fluid sample for HIV testing. 42.9% of men and 50.9% of women reported ever having had an HIV test. Overall, 14.0% (141, 95% CI 11.9 to 16.3) of respondents tested HIV positive (13.1% of men and 15.0% of women); 9.2% (93) had undiagnosed HIV infection, while 4.8% (48) had a diagnosed HIV infection. HIV prevalence was significantly higher in men: born in East Africa; who had had a previous STI diagnosis; or who were recruited in bars and clubs; and in women: born in East or Southern Africa; aged 25 years and over; who had had two new sexual partners in the past 12 months; or who had had a previous STI diagnosis. CONCLUSIONS: Despite about half the sample having had an HIV test at some time in the past, 9.2% of respondents had an undiagnosed HIV infection. This study supports current policy efforts to further promote HIV testing and serostatus awareness.
Assuntos
Atitude Frente a Saúde , População Negra/estatística & dados numéricos , Infecções por HIV/etnologia , Estilo de Vida , Sexo sem Proteção/estatística & dados numéricos , Adulto , Idoso , População Negra/psicologia , Inglaterra/epidemiologia , Feminino , Infecções por HIV/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Sexo sem Proteção/psicologiaRESUMO
National guidance on sexual health in England recommends service development to meet the specific needs of ethnic minority populations. Our aim was to evaluate mode of referral, number of sexually transmitted infections (STIs) diagnosed, and the offering and uptake of HIV testing in patients of South Asian ethnicity. A retrospective case-control study was undertaken in two London genito-urinary (GU) medicine clinics. There were 250 case-control pairs with approximately equal numbers of men and women. South Asians were less likely to have an STI (Odds ratio [OR] 0.66, 95% confidence interval [CI] 0.45, 0.97) or to report risk factors for HIV (OR 0.45, 95% CI 0.28, 0.71). Offering and uptake of HIV antibody testing were high in both South Asian and non-South Asian groups (OR 0.62, 95% CI 0.27, 1.51). South Asians were significantly more likely than controls to have been referred by other medical services rather than self-referred (OR 2.00, 95% CI 1.32, 3.01), which is in keeping with poorer access to GU medicine services in London.
Assuntos
Serviços de Saúde Comunitária/estatística & dados numéricos , Acessibilidade aos Serviços de Saúde , Grupos Minoritários , Encaminhamento e Consulta/estatística & dados numéricos , Infecções Sexualmente Transmissíveis/epidemiologia , Adolescente , Adulto , Idoso , Ásia Ocidental/etnologia , Estudos de Casos e Controles , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Infecções por HIV/etnologia , Necessidades e Demandas de Serviços de Saúde , Humanos , Londres , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Estudos Retrospectivos , Infecções Sexualmente Transmissíveis/diagnóstico , Infecções Sexualmente Transmissíveis/etnologiaRESUMO
AIM: Lupus nephritis is closely associated with in vivo autoantibody-binding to glomerular membrane-associated electron-dense structures (EDS). The biochemical nature and cellular origin of EDS are controversial, and definitive characterisation needs to be performed. METHODS: By using the terminal transferase biotin-dUTP nick end-labelling (TUNEL) assay at the electron microscopic level, we have traced extracellular chromatin within the glomerular basement membranes of nephritic (NZBxNZW)F1 mice. The TUNEL assay was subsequently used in combination with standard immune electron microscopy (IEM). To analyse why chromatin particles associate with membranes, we determined the affinity of nucleosomes and DNA for glomerular laminin, collagen IV and the mesangial matrix proteoglycan perlecan by surface plasmon resonance. RESULTS: This intra-assay colocalisation TUNEL IEM demonstrated that autoantibodies fully colocalised with extracellular TUNEL-positive chromatin observed as EDS in glomerular membranes, similar to results obtained by the same technique applied to human lupus nephritis. Most importantly, these data validate the murine variant of lupus nephritis as a model to study origin of extracellular chromatin as a key element in human lupus nephritis. Kinetic analyses demonstrated that nucleosomes had a high affinity for collagen IV and laminin, but not for perlecan. CONCLUSION: Collectively, these results provide firm evidence that dominant target structures for nephritogenic autoantibodies are constituted by TUNEL-positive chromatin associated with glomerular capillary and mesangial matrix membranes at high affinity.
Assuntos
Autoanticorpos/análise , Colágeno Tipo IV/metabolismo , Glomérulos Renais/ultraestrutura , Laminina/metabolismo , Nefrite Lúpica/metabolismo , Nucleossomos/ultraestrutura , Animais , Membrana Basal/metabolismo , Membrana Basal/ultraestrutura , Cromatina , Colágeno Tipo IV/análise , Proteoglicanas de Heparan Sulfato/análise , Proteoglicanas de Heparan Sulfato/metabolismo , Marcação In Situ das Extremidades Cortadas , Laminina/análise , Nefrite Lúpica/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Mutantes , Microscopia Imunoeletrônica , Modelos Animais , Nucleossomos/metabolismo , Ligação Proteica , Ressonância de Plasmônio de SuperfícieRESUMO
Antibodies to double-stranded (dsDNA) are associated with systemic lupus erythematosus (SLE) and directly involved in human lupus nephritis. Information about their glomerular target antigens is inconsistent, and whether availability of target antigens, antibody specificity or avidity are nephritogenic parameters, is not determined. In this study, we analyzed renal tissue from anti-dsDNA antibody-positive lupus patients with nephritis by morphological and immunological assays, including immune electron microscopy (IEM) and colocalization IEM, an EM-based confocal microscopy assay. IEM demonstrated that antibody deposits were confined to electron dense structures (EDS) in glomerular membranes. These autoantibodies colocalized with nucleosome-binding anti-dsDNA/-histone/-transcription factor antibodies. To confirm the colocalization IEM-data, we developed a colocalization terminal deoxynucleotidyl-transferase (TdT) biotin-dUTP nicked end-labeled (TUNEL) IEM assay where extracellular DNA was traced by TdT-mediated introduction of biotinylated nucleotides and autoantibodies by IEM. Results consistently demonstrated that DNA colocalized with autoantibodies in glomerular membrane-associated EDS. The colocalization IEM and colocalization TUNEL IEM assays thus demonstrate that intra-glomerular membrane-associated nucleosomes are targeted by anti-dsDNA autoantibodies in human lupus nephritis. The data provide a new approach to understand basic molecular and immunological processes accounting for antibody-mediated nephritis in human SLE.
Assuntos
Apoptose/imunologia , Glomérulos Renais/imunologia , Nefrite Lúpica/imunologia , Nucleossomos/imunologia , Humanos , Nefrite Lúpica/patologiaRESUMO
The majority of new HIV diagnoses in the UK occur in people with heterosexually acquired HIV infection, the majority of whom are migrant Africans. In the UK HIV positive Africans access HIV services at a later stage of disease than non-Africans (Burns et al., 2001; Sinka et al., 2003). Employing purposive sampling techniques, semi-structured interviews were conducted with key informants to identify the key issues affecting utilization of HIV services for Africans in Britain. Considerable agreement about the major issues influencing uptake of HIV services existed amongst the key informants. Respondents felt there was high HIV awareness but this did not translate into perception of individual risk. Home country experience and community mobilization was highly influential on HIV awareness, appreciation of risk, and attitudes to health services. Institutional barriers to care exist; these include lack of cultural understanding, lack of open access or community clinics, failure to integrate care with support organizations, and the inability of many General Practitioners to address HIV effectively. Community involvement should include input to ensure there is: better cultural understanding within the health care system; normalization of the HIV testing process; and a clear message on the effectiveness of therapy.
Assuntos
Serviços de Saúde Comunitária/estatística & dados numéricos , Emigração e Imigração , Infecções por HIV/etnologia , Conhecimentos, Atitudes e Prática em Saúde , Aceitação pelo Paciente de Cuidados de Saúde/etnologia , População Negra/etnologia , Confidencialidade/psicologia , Feminino , Infecções por HIV/psicologia , Infecções por HIV/terapia , Humanos , Masculino , Estereotipagem , Fatores de Tempo , Reino Unido/epidemiologiaRESUMO
The performance of a time-resolved fluorescence immunoassay (TRFIA) for detection of treponemal IgG from oral fluid specimens has been assessed in a predominantly HIV-infected population. Serological investigation is the method of choice for confirming clinical suspicion of syphilis; however, in the primary stage of disease, direct detection of treponemes in lesion fluid or Treponema pallidum DNA is recommended because of the reduced sensitivity of serological tests. There may be occasions when blood for serological investigation is difficult to obtain due to individual patient preference or logistical necessity to improve participation in screening initiatives, particularly in outreach situations. Collection of oral fluid for detection of treponemal antibody may prove an attractive alternative and, with this in mind, an oral fluid assay for detection of treponemal IgG was developed. Time-resolved fluorescence was used to detect treponemal IgG extracted from commercially available oral fluid collection devices. Paired serum and saliva samples were obtained from 210 individuals, 101 of whom were diagnosed with syphilis on the grounds of medical examination confirmed by serological testing. Oral fluid specimens from 14 subjects were rejected because they contained insufficient control antibody or were inhibitory. The population tested was predominantly men who have sex with men, many of whom were HIV infected. The overall sensitivity and specificity of the oral fluid assay was 95.8 and 86.1%, respectively, based on the 5th percentile of the positive results, and 93.7 and 91.1%, respectively, based on a cutoff derived by mixture model analysis. For individuals with primary syphilis, the optimum sensitivity of the oral fluid assay was 87.5%, whereas in those with disease classified as secondary syphilis and early latent syphilis, the sensitivity of the oral fluid assay was 100 and 94.7%, respectively. The oral fluid assay is a useful alternative to serological testing in certain situations, and further development of this technology to enable detection of treponemal IgM should increase its sensitivity for detecting cases of primary syphilis.