RESUMO
BACKGROUND: Implant survival after conventional total hip replacement (THR) is often poor in younger patients, so alternatives such as hip resurfacing, with various sizes to fit over the femoral head, have been explored. We assessed the survival of different sizes of metal-on-metal resurfacing in men and women, and compared this survival with those for conventional stemmed THRs. METHODS: We analysed the National Joint Registry for England and Wales (NJR) for primary THRs undertaken between 2003 and 2011. Our analysis involved multivariable flexible parametric survival models to estimate the covariate-adjusted cumulative incidence of revision adjusting for the competing risk of death. FINDINGS: The registry included 434,560 primary THRs, of which 31,932 were resurfacings. In women, resurfacing resulted in worse implant survival than did conventional THR irrespective of head size. Predicted 5-year revision rates in 55-year-old women were 8·3% (95% CI 7·2-9·7) with a 42 mm resurfacing head, 6·1% (5·3-7·0) with a 46 mm resurfacing head, and 1·5% (0·8-2·6) with a 28 mm cemented metal-on-polyethylene stemmed THR. In men with smaller femoral heads, resurfacing resulted in poor implant survival. Predicted 5-year revision rates in 55-year-old men were 4·1% (3·3-4·9) with a 46 mm resurfacing head, 2·6% (2·2-3·1) with a 54 mm resurfacing head, and 1·9% (1·5-2·4) with a 28 mm cemented metal-on-polyethylene stemmed THR. Of male resurfacing patients, only 23% (5085 of 22076) had head sizes of 54 mm or above. INTERPRETATION: Hip resurfacing only resulted in similar implant survivorship to other surgical options in men with large femoral heads, and inferior implant survivorship in other patients, particularly women. We recommend that resurfacing is not undertaken in women and that preoperative measurement is used to assess suitability in men. Before further new implant technology is introduced we need to learn the lessons from resurfacing and metal-on-metal bearings. FUNDING: National Joint Registry for England and Wales.
Assuntos
Artroplastia de Quadril/métodos , Cabeça do Fêmur/anatomia & histologia , Prótese de Quadril/efeitos adversos , Osteoartrite do Quadril/cirurgia , Desenho de Prótese/efeitos adversos , Falha de Prótese/tendências , Adulto , Idoso , Inglaterra/epidemiologia , Feminino , Humanos , Masculino , Metais/efeitos adversos , Pessoa de Meia-Idade , Sistema de Registros , Fatores de Risco , Fatores Sexuais , Resultado do Tratamento , País de Gales/epidemiologiaRESUMO
BACKGROUND: Total hip replacement (THR) is extremely common. Some prostheses fail, particularly in younger patients, and need to be revised, most commonly for loosening secondary to wear or dislocation. Surgeons have tried to address these problems by implanting large diameter metal-on-metal bearing surfaces. Our aim was to assess if metal-on-metal bearing surfaces lead to increased implant survival compared with other bearing surfaces in stemmed THR and, additionally, if larger head sizes result in improved implant survival. METHODS: We analysed the National Joint Registry of England and Wales for primary hip replacements (402,051, of which 31,171 were stemmed metal-on-metal) undertaken between 2003 and 2011. Our analysis was with a multivariable flexible parametric survival model to estimate the covariate-adjusted cumulative incidence of revision adjusting for the competing risk of death. FINDINGS: Metal-on-metal THR failed at high rates. Failure was related to head size, with larger heads failing earlier (3·2% cumulative incidence of revision [95% CI 2·5-4·1] for 28 mm and 5·1% [4·2-6·2] for 52 mm head at 5 years in men aged 60 years). 5 year revision rates in younger women were 6·1% (5·2-7·2) for 46 mm metal-on-metal compared with 1·6% (1·3-2·1) for 28 mm metal-on-polyethylene. By contrast, for ceramic-on-ceramic articulations larger head sizes were associated with improved survival (5 year revision rate of 3·3% [2·6-4·1] with 28 mm and 2·0% [1·5-2·7] with 40 mm for men aged 60 years). INTERPRETATION: Metal-on-metal stemmed articulations give poor implant survival compared with other options and should not be implanted. All patients with these bearings should be carefully monitored, particularly young women implanted with large diameter heads. Since large diameter ceramic-on-ceramic bearings seem to do well we support their continued use. FUNDING: National Joint Registry of England and Wales.
Assuntos
Análise de Falha de Equipamento/estatística & dados numéricos , Prótese de Quadril/estatística & dados numéricos , Metais , Osteoartrite do Quadril/cirurgia , Desenho de Prótese/estatística & dados numéricos , Sistema de Registros/estatística & dados numéricos , Fatores Etários , Idoso , Cerâmica , Interpretação Estatística de Dados , Inglaterra , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polietileno , Ajuste de Prótese , Fatores Sexuais , País de GalesRESUMO
BACKGROUND: Prosthetic joint infection is an uncommon but serious complication of hip replacement. There are two main surgical treatment options, with the choice largely based on the preference of the surgeon. Evidence is required regarding the comparative effectiveness of one-stage and two-stage revision to prevent reinfection after prosthetic joint infection. METHODS: We conducted a systematic review to identify randomised controlled trials, systematic reviews and longitudinal studies in unselected patients with infection treated exclusively by one- or two-stage methods or by any method. The Embase, MEDLINE and Cochrane databases were searched up to March 2011. Reference lists were checked, and citations of key articles were identified by using the ISI Web of Science portal. Classification of studies and data extraction were performed independently by two reviewers. The outcome measure studied was reinfection within 2 years. Data were combined to produce pooled random-effects estimates using the Freeman-Tukey arc-sine transformation. RESULTS: We identified 62 relevant studies comprising 4,197 patients. Regardless of treatment, the overall rate of reinfection after any treatment was 10.1% (95% CI = 8.2 to 12.0). In 11 studies comprising 1,225 patients with infected hip prostheses who underwent exclusively one-stage revision, the rate of reinfection was 8.6% (95% CI = 4.5 to 13.9). After two-stage revision exclusively in 28 studies comprising 1,188 patients, the rate of reinfection was 10.2% (95% CI = 7.7 to 12.9). CONCLUSION: Evidence of the relative effectiveness of one- and two-stage revision in preventing reinfection of hip prostheses is largely based on interpretation of longitudinal studies. There is no suggestion in the published studies that one- or two stage methods have different reinfection outcomes. Randomised trials are needed to establish optimum management strategies.
Assuntos
Prótese de Quadril/efeitos adversos , Infecções Relacionadas à Prótese/cirurgia , Humanos , Estudos Longitudinais , Prevenção Secundária , Resultado do TratamentoRESUMO
BACKGROUND: For the majority of patients with osteoarthritis (OA), joint replacement is a successful intervention for relieving chronic joint pain. However, between 10-30% of patients continue to experience chronic pain after joint replacement. Evidence suggests that a risk factor for chronic pain after joint replacement is the severity of acute post-operative pain. The aim of this randomised controlled trial (RCT) is to determine if intra-operative local anaesthetic wound infiltration additional to a standard anaesthesia regimen can reduce the severity of joint pain at 12-months after total knee replacement (TKR) and total hip replacement (THR) for OA. METHODS: 300 TKR patients and 300 THR patients are being recruited into this single-centre double-blind RCT. Participants are recruited before surgery and randomised to either the standard care group or the intervention group. Participants and outcome assessors are blind to treatment allocation throughout the study. The intervention consists of an intra-operative local anaesthetic wound infiltration, consisting of 60 mls of 0.25% bupivacaine with 1 in 200,000 adrenaline. Participants are assessed on the first 5 days post-operative, and then at 3-months, 6-months and 12-months. The primary outcome is the WOMAC Pain Scale, a validated measure of joint pain at 12-months. Secondary outcomes include pain severity during the in-patient stay, post-operative nausea and vomiting, satisfaction with pain relief, length of hospital stay, joint pain and disability, pain sensitivity, complications and cost-effectiveness. A nested qualitative study within the RCT will examine the acceptability and feasibility of the intervention for both patients and healthcare professionals. DISCUSSION: Large-scale RCTs assessing the effectiveness of a surgical intervention are uncommon, particularly in orthopaedics. The results from this trial will inform evidence-based recommendations for both short-term and long-term pain management after lower limb joint replacement. If a local anaesthetic wound infiltration is found to be an effective and cost-effective intervention, implementation into clinical practice could improve long-term pain outcomes for patients undergoing lower limb joint replacement. TRIAL REGISTRATION: Current Controlled Trials ISRCTN96095682.
Assuntos
Anestésicos Locais/uso terapêutico , Artroplastia de Quadril/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Cuidados Intraoperatórios , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/prevenção & controle , Anestésicos Locais/economia , Bupivacaína/economia , Bupivacaína/uso terapêutico , Doença Crônica , Análise Custo-Benefício , Método Duplo-Cego , Seguimentos , Humanos , Estudos Longitudinais , Dor Pós-Operatória/epidemiologia , Satisfação do Paciente , Prevalência , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: Deep vein thrombosis is common after total joint replacement. It is frequently asymptomatic, and it is unclear whether this leads to longer-term problems such as post-thrombotic syndrome and leg ulceration. We investigated whether the postoperative prevalence of ulceration in patients who had undergone primary total hip replacement (THR) or total knee replacement (TKR) was higher than that found in a control group who had not undergone total joint replacement. METHODS: The study group consisted of patients who had undergone THR or TKR at one orthopedic center 12-16 years previously without routine chemothromboprophylaxis, and who had not undergone revision surgery. The control group was recruited via primary care. All participants were recruited by post and asked to complete a questionnaire. Age- and sex-adjusted prevalence of self-reported leg ulceration was calculated, and logistic regression was used to determine whether there were any associations between THR or TKR and leg ulceration. RESULTS: Completed questionnaires were received from 441 THR patients (54% response rate), 196 TKR patients (48%) and 967 control participants (36%). No statistically significant differences in age- and sex-adjusted prevalence of ulceration were found between the groups, for either lifetime prevalence or prevalence over the previous 15 years. INTERPRETATION: Patients who undergo THR and TKR without chemothromboprophylaxis are unlikely to be at a higher risk of long-term venous ulceration than the normal population.
Assuntos
Artroplastia de Quadril/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Complicações Pós-Operatórias/etiologia , Úlcera Varicosa/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome Pós-Trombótica/etiologia , Fatores de Risco , Inquéritos e Questionários , Fatores de TempoRESUMO
The authors of this study noticed that the elastic garters of below knee anti-embolism stockings (AES) were indenting the proximal calves of patients after application and feared this might be interrupting venous return. This was lower on one ward which had a rigorous standardized protocol for sizing and checking stockings. Hypotheses were that proximal indentation caused higher proximal than distal pressures (reverse gradients) and that by adopting the standardized protocol throughout the unit, proximal indentation could be reduced. Fifty-seven patients were recruited after total hip replacement (THR) or total knee replacement (TKR) in a regional orthopaedic centre. The authors implemented the standardized protocol for sizing stockings and measured the pressures under them. After implementation of the standardized protocol, proximal indentation fell from 53% to 19% (p<0.05), incorrectly sized stockings from 74% to 34% (p<0.05) and removal of stockings by patients from 32% to 0% (p<0.05). In total, 21% of patients had reverse gradients which occurred in 41% of legs with proximal indentation and 8% without. When reverse gradients or proximal indentation exist, AES may not be as effective and may be counterproductive. A standardized protocol of nursing practice is critical to optimizing AES after THR and TKR. More in-vivo research is needed on AES after hip and knee replacement.
Assuntos
Embolia/prevenção & controle , Meias de Compressão , Artroplastia de Quadril/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Humanos , Reino UnidoRESUMO
Neurons are a diverse cell type exhibiting hugely different morphologies and neurotransmitter specifications. Their distinctive phenotypes are established during differentiation from pluripotent precursor cells. The signalling pathways that specify the lineage down which neuronal precursor cells differentiate remain to be fully elucidated. Among the many signals that impinge on the differentiation of neuronal cells, cytosolic calcium (Ca2+) has an important role. However, little is known about the nature of the Ca2+ signals involved in fate choice in neuronal precursor cells, or their sources. In this study, we show that activation of either muscarinic or platelet-derived growth factor (PDGF) receptors induces a biphasic increase in cytosolic Ca2+ that consists of release from intracellular stores followed by sustained entry across the plasma membrane. For both agonists, the prolonged Ca2+ entry occurred via a store-operated pathway that was pharmacologically indistinguishable from Ca2+ entry initiated by thapsigargin. However, muscarinic receptor-activated Ca2+ entry was inhibited by siRNA-mediated knockdown of TRPC6, whereas Ca2+ entry evoked by PDGF was not. These data provide evidence for agonist-specific activation of molecularly distinct store-operated Ca2+ entry pathways, and raise the possibility of privileged communication between these Ca2+ entry pathways and downstream processes.
Assuntos
Canais de Cálcio/efeitos dos fármacos , Cloreto de Metacolina/farmacologia , Agonistas Muscarínicos/farmacologia , Neurônios/efeitos dos fármacos , Fator de Crescimento Derivado de Plaquetas/farmacologia , Canais de Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Células Cultivadas , Humanos , Immunoblotting , Neurônios/citologia , Neurônios/metabolismo , Fatores de TempoRESUMO
A series of high-affinity GABA(A) agonists with good oral bioavailability in rat and dog and functional selectivity for the GABA(A)alpha2 and -alpha3 subtypes is reported. The 7-trifluoromethylimidazopyrimidine 14g and the 7-propan-2-olimidazopyrimidine 14k are anxiolytic in both conditioned and unconditioned animal models of anxiety with minimal sedation observed at full BZ binding site occupancy.
Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Agonistas de Receptores de GABA-A , Pirimidinas/farmacologia , Administração Oral , Animais , Sítios de Ligação , Disponibilidade Biológica , Linhagem Celular , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Técnicas de Patch-Clamp , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos , Receptores de GABA-A , Relação Estrutura-AtividadeRESUMO
The identification of a series of imidazo[1,2-b][1,2,4]triazines with high affinity and functional selectivity for the GABA(A) alpha3-containing receptor subtype is described, leading to the identification of a clinical candidate, 11. Compound 11 shows good bioavailability and half-life in preclinical species, and it is a nonsedating anxiolytic in both rat and squirrel monkey behavioral models.
Assuntos
Ansiolíticos/síntese química , Agonistas de Receptores de GABA-A , Imidazóis/síntese química , Triazinas/síntese química , Animais , Ansiolíticos/química , Ansiolíticos/farmacologia , Disponibilidade Biológica , Meia-Vida , Humanos , Imidazóis/química , Imidazóis/farmacologia , Técnicas de Patch-Clamp , Ensaio Radioligante , Ratos , Receptores de GABA-A/fisiologia , Saimiri , Relação Estrutura-Atividade , Triazinas/química , Triazinas/farmacologiaRESUMO
The development of a series of GABA(A) alpha2/alpha3 subtype selective pyridazine based benzodiazepine site agonists as anxiolytic agents with reduced sedative/ataxic potential is described, including the discovery of 16, a remarkably alpha3-selective compound ideal for in vivo study. These ligands are antagonists at the alpha1 subtype, with good CNS penetration and receptor occupancy, and excellent oral bioavailability.
Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Agonistas GABAérgicos/farmacologia , Agonistas de Receptores de GABA-A , Piridazinas/farmacologia , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/síntese química , Sítios de Ligação , Agonistas GABAérgicos/administração & dosagem , Agonistas GABAérgicos/síntese química , Humanos , Ligantes , Estrutura Molecular , Piridazinas/administração & dosagem , Piridazinas/síntese química , Ratos , Proteínas Recombinantes/agonistas , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The prospect of manipulating endogenous neural stem cells to replace damaged tissue and correct functional deficits represents a novel mechanism for treating a variety of central nervous system disorders. Using human neural precursor cultures and a variety of assays for studying stem cell behavior we have screened two libraries of commercially available compounds using an endpoint high content screening assay. We then performed detailed follow-up mechanistic studies on confirmed hits using endpoint and kinetics assays to characterize and differentiate the mechanisms of action of these compounds. The screening cascade employed successfully identified a number of active compounds with differing mechanisms of action. This approach shows how hits from a phenotypic screen can be prioritized and characterized by high content screening to identify potentially novel mechanisms and druggable targets to take forward into more conventional high-throughput screening approaches.
Assuntos
Bioensaio/métodos , Neurônios/citologia , Células-Tronco/citologia , Animais , Cálcio/metabolismo , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Cinética , Neuritos/fisiologia , Neuritos/ultraestrutura , Neurônios/fisiologia , Ratos , Transdução de Sinais/fisiologia , Células-Tronco/fisiologiaRESUMO
L-655,708 is an imidazobenzodiazepine possessing 30-70-fold selectivity for the benzodiazepine binding site of GABA(A) receptors containing an alpha5 rather than alpha1, alpha2 or alpha3 subunit. In the present study, [(3)H]L-655,708 was used to label mouse brain benzodiazepine binding sites in vivo. When compared to inhibition of in vivo binding of the non-selective ligand [(3)H]Ro 15-1788, the pharmacology of mouse in vivo [(3)H]L-655,708 binding was consistent with selective in vivo labelling of alpha5 subunit-containing GABA(A) receptors. Thus, diazepam was equipotent at inhibiting in vivo [(3)H]L-655,708 and [(3)H]Ro 15-1788 binding; zolpidem, which has very low affinity for alpha5-containing GABA(A) receptors, gave no inhibition of in vivo [(3)H]L-655,708 binding despite inhibiting in vivo [(3)H]Ro 15-1788 binding; and L-655,708 was more potent at inhibiting the in vivo binding of [(3)H]L-655,708 compared to [(3)H]Ro 15-1788. This pharmacological specificity of in vivo [(3)H]L-655,708 binding was confirmed autoradiographically. Hence, the anatomical distribution of in vivo [(3)H]L-655,708 binding was comparable to the distribution of alpha5-containing GABA(A) receptors identified in vitro. Moreover, this distribution was distinct from that identified using [(3)H]Ro 15-1788. These data therefore suggest that [(3)H]L-655,708 can be used to identify alpha5-containing GABA(A) receptors in vivo and that this ligand can be used to measure receptor occupancy of alpha5-selective ligands.
Assuntos
Imidazóis/farmacologia , Receptores de GABA-A/metabolismo , Animais , Benzodiazepinas/metabolismo , Sítios de Ligação , Ligação Competitiva , Encéfalo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Flumazenil/farmacologia , Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/farmacologia , Moduladores GABAérgicos/farmacologia , Substâncias Macromoleculares , Masculino , Camundongos , Subunidades Proteicas/efeitos dos fármacos , Ensaio Radioligante/métodos , Receptores de GABA-A/química , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/metabolismo , Medula Espinal/efeitos dos fármacos , Fatores de Tempo , TrítioRESUMO
Antibody drugs have become an increasingly significant component of the therapeutic landscape. Their success has been driven by some of their unique properties, in particular their very high specificity and selectivity, in contrast to the off-target liabilities of small molecules (SMs). Antibodies can bring additional functionality to the table with their ability to interact with the immune system, and this can be further manipulated with advances in antibody engineering. This review summarizes what antibody therapeutics have achieved to date and what opportunities and challenges lie ahead. The target landscape for large molecules (LMs) versus SMs and some of the challenges for antibody drug development are discussed. Effective penetration of membrane barriers and intracellular targeting is one challenge, particularly across the highly resistant blood-brain barrier. The expanding pipeline of antibody-drug conjugates offers the potential to combine SM and LM modalities in a variety of creative ways, and antibodies also offer exciting potential to build bi- and multispecific molecules. The ability to pursue more challenging targets can also be further exploited but highlights the need for earlier screening in functional cell-based assays. I discuss how this might be addressed given the practical constraints imposed by high-throughput screening sample type and process differences in antibody primary screening.
Assuntos
Anticorpos/uso terapêutico , Anticorpos/química , Descoberta de DrogasRESUMO
Neurosteroids have been shown to mediate some of their physiological effects via a modulatory site on type A inhibitory gamma-aminobutyric acid (GABAA) receptors. In particular, recent evidence has implicated selective potentiation of the delta subunit of GABAA receptors as an important mediator of in vitro and in vivo neurosteroid activity. However, this has been demonstrated for only a very small number of steroids, so both the generality of this finding, and the structural features of steroids which mediate functional delta-selectivity, are unclear. We have used a potentiometric assay based on fluorescence resonance energy transfer to measure GABA-activated responses in L(tk-) cells stably transfected with human GABAA receptor alpha4beta3delta and alpha4beta3gamma2 receptor subtypes. A set of 28 steroids were evaluated on these subtypes to characterise their functional potency and efficacy in modulating GABA responses. For most compounds there was a clear separation of their efficacy profiles between the receptor subtypes, with a substantially larger maximal response at the alpha4beta3delta receptor. 5beta-Pregnan-3beta-ol-20-one, 5beta-pregnane-3alpha,20beta-diol and 5beta-pregnane-3alpha,17alpha-diol-11,20-dione showed particularly high efficacy for alpha4beta3delta. No compounds were identified that simply inhibited responses at delta-containing receptors. However, 5beta-pregnane-3alpha,17alpha,20beta-triol, prednisolone 21-acetate, 4-pregnene-17alpha,20alpha-diol-3-one-20-acetate, 4-pregnen-20alpha-ol-3-one, and 5beta-pregnane-3alpha,17alpha,21-triol-20-one inhibited, though did not abolish, GABA responses at the alpha4beta3gamma2 subtype, while evoking modest-amplitude potentiation of alpha4beta3delta responses. Molecular modelling on this compound series using principal components analysis indicates that several structural features of steroids underlie their relative functional selectivity for potentiation of delta-containing GABAA receptors.
Assuntos
Subunidades Proteicas/metabolismo , Receptores de GABA-A/metabolismo , Esteroides/farmacologia , Animais , Células Cultivadas , Humanos , Cinética , Camundongos , Conformação Molecular , Subunidades Proteicas/efeitos dos fármacos , Receptores de GABA-A/efeitos dos fármacos , Esteroides/química , Relação Estrutura-Atividade , TransfecçãoRESUMO
OBJECTIVE: This paper reports the effects of naturally occurring levels of distress on the development of delayed-type hypersensitivity (DTH) skin test responses. These in vivo measures provide a biologically relevant assessment of cellular immune competence. METHODS: Subjects (N = 166) were immunized (baseline) with the novel antigen, keyhole limpet hemocyanin (KLH), and DTH skin test responses against KLH were assessed 3 weeks later (follow-up). The CMI Multitest (Merieux, France), which evaluates DTH responses to a panel of seven antigens, was also administered at follow-up. Emotional distress was assessed at baseline and follow-up by the Profile of Mood States. RESULTS: Distress levels at baseline were associated with a reduced likelihood of developing DTH responses against KLH at follow-up (r = -0.22, p =.01). There was no relationship between distress at follow-up and cutaneous DTH in response to KLH (r = 0.09, p =.24) or in the Multitest (r = -0.03, p =.70). In addition, higher levels of alcohol consumption at baseline (r = -0.19, p =.02) and at follow-up (r = -0.20, p =.01) were associated with a decreased likelihood of developing cutaneous DTH against KLH. CONCLUSIONS: Everyday levels of distress predicted the capacity of the cellular arm of the immune system to exhibit recall responses to an antigen, when the experimental paradigm allowed the assessment of distress at the time of antigen sensitization. Moderate alcohol consumption independently affected cutaneous DTH.
Assuntos
Consumo de Bebidas Alcoólicas/imunologia , Hipersensibilidade Tardia/imunologia , Estresse Psicológico/imunologia , Adolescente , Adulto , Etanol/farmacologia , Feminino , Nível de Saúde , Hemocianinas/administração & dosagem , Hemocianinas/imunologia , Humanos , Hipersensibilidade Tardia/psicologia , Imunização/métodos , Imunização/psicologia , Modelos Logísticos , Masculino , Modelos Imunológicos , Inventário de Personalidade , Psiconeuroimunologia , Testes Cutâneos , Estresse Psicológico/psicologiaRESUMO
OBJECTIVE: To determine whether use of metal-on-metal bearing surfaces is associated with an increased risk of a diagnosis of cancer in the early years after total hip replacement and specifically with an increase in malignant melanoma and haematological, prostate, and renal tract cancers. DESIGN: Linkage study with multivariable competing risks flexible parametric survival model to examine the incidence of new diagnoses of cancer in patients with metal-on-metal hip replacement compared with those with alternative bearings and to compare the observed incidence of diagnoses in patients undergoing hip replacement with that predicted by national incidence rates in the general population. SETTING: National Joint Registry of England and Wales (NJR) linked to NHS hospital episode statistics data. PARTICIPANTS: 40,576 patients with hip replacement with metal-on-metal bearing surfaces and 248,995 with alternative bearings. MAIN OUTCOME MEASURES: Incidence of all cancers and incidence of malignant melanoma and prostate, renal tract, and haematological cancers. RESULTS: The incidence of new diagnoses of cancer was low after hip replacement (1.25% at one year, 95% confidence interval 1.21% to 1.30%) and lower than that predicted from the age and sex matched normal population (1.65%, 1.60% to 1.70%). Compared with alternative bearings, there was no evidence that metal-on-metal bearing surfaces were associated with an increased risk of any cancer diagnosis in the seven years after surgery (mean follow-up of three years, 23% (n=67,361) of patients observed for five years or more). Similarly, there was no increase in the risk of malignant melanoma or haematological, prostate, and renal tract cancers. The adjusted five year incidence of all cancers for men aged 60 was 4.8% (4.4% to 5.3%) with resurfacing, 6.2% (5.7% to 6.7%) with stemmed metal-on-metal, and 6.7% (6.5% to 7.0%) for other bearing surfaces. Equivalent rates for women aged 60 were lower: 3.1% (2.8% to 3.4%) with resurfacing, 4.0% (3.7% to 4.3%) with stemmed metal-on-metal, and 4.4% (4.2% to 4.5%) with other bearings. CONCLUSIONS: These data are reassuring, but the findings are observational with short follow-up. The use of hospital episode statistics data might underestimate cancer diagnoses, and there is the possibility of confounding by indication. Furthermore, as some cancers have a long latency period it is important that we study the longer term outcomes and continue to investigate the effects of exposure to orthopaedic metals.
Assuntos
Artroplastia de Quadril/efeitos adversos , Neoplasias Hematológicas/epidemiologia , Prótese de Quadril/efeitos adversos , Melanoma/epidemiologia , Neoplasias da Próstata/epidemiologia , Neoplasias Urológicas/epidemiologia , Artroplastia de Quadril/instrumentação , Coleta de Dados , Inglaterra/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Metais/efeitos adversos , Desenho de Prótese , Sistema de Registros/estatística & dados numéricos , Fatores de Risco , País de Gales/epidemiologiaRESUMO
BACKGROUND: Previous research has mainly focused on how factors such as surgical approach might affect implant survivorship and the incidence of complications. Given the increasing interest in patient-reported outcomes, the purpose of this study is to explore whether surgical approach is associated with patient-reported pain, function, and satisfaction at 1-3 years after primary total hip replacement (THR). METHODS: Details of surgical factors were collated from operation notes for all consecutive patients at our centre from 2004-2006. All patients were mailed a questionnaire 1-3 years following surgery that collected WOMAC pain and function scores and the Self-Administered Patient Satisfaction Scale for Primary Hip and Knee Arthroplasty. Of the eligible 1,315 patients, 911 patients returned a completed questionnaire (69% response rate). Multivariable fractional logit models were used to identify whether surgical approach was associated with outcome scores. RESULTS: Surgical approach was found to be a significant predictor of patient-reported outcomes at 1-3 years after surgery, even after controlling for patient-specific factors. A posterior approach was associated with better scores on all three outcome measures. On average, predicted outcome scores for a typical patient with a posterior approach were between 3.5 and 7.2 percentage points higher than an equivalent patient with an anterolateral approach. INTERPRETATION: These findings suggest that clinical decisions concerning surgical approach may have an observable impact on patient-reported levels of pain, function, and satisfaction following THR.
Assuntos
Artroplastia de Quadril/métodos , Osteoartrite do Quadril/cirurgia , Satisfação do Paciente , Autorrelato , Idoso , Artroplastia de Quadril/psicologia , Feminino , Articulação do Quadril/fisiopatologia , Articulação do Quadril/cirurgia , Humanos , Masculino , Osteoartrite do Quadril/fisiopatologia , Osteoartrite do Quadril/psicologia , Dor , Medição da Dor , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Implementing functional cell-based screens in early antibody discovery has become increasingly important to select antibodies with the desired profile. However, this is limited by assay tolerance to crude antibody preparations and assay sensitivity. The current study aims to address this challenge and identify routes forward. Two common types of high-throughput screening (HTS) antibody sample, derived from either phage display or hybridoma techniques, have been screened across a wide range of CellSensor beta-lactamase reporter assays in a variety of cell backgrounds to more extensively characterize assay tolerance. Pathway-, sample-, and cell background-specific effects were observed. Reporter assays for agonism were less affected by crude antibody preparations, with 8 of 21 sample tolerant, and the potential to implement an additional 8 assays by choosing the best-tolerated sample type. Antagonist mode assays exhibited more complexity, with potentiating as well as inhibitory effects. However, 5 of 24 antagonist assays were fully tolerant, with the potential to implement an additional 11 assays. Different subsets of assays were affected in agonist versus antagonist mode, and hybridoma sample sets were better tolerated overall. The study clearly demonstrates the potential to use cell-based reporter assays in biologics HTS, particularly if the method of antibody production is considered in the context of the required assay mode (agonist/antagonist).
Assuntos
Anticorpos Monoclonais/isolamento & purificação , Bioensaio , Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala , Animais , Anticorpos Monoclonais/farmacologia , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Genes Reporter , Células HEK293 , Humanos , Hibridomas , Células Jurkat , Transdução de Sinais/efeitos dos fármacos , beta-Lactamases/metabolismoRESUMO
BACKGROUND: Fully asexually reproducing taxa lack outcrossing. Hence, the classic Biological Species Concept cannot be applied. METHODOLOGY/PRINCIPAL FINDINGS: We used DNA sequences from the mitochondrial COI gene and the nuclear ITS2 region to check species boundaries according to the evolutionary genetic (EG) species concept in five morphospecies in the putative ancient asexual ostracod genera, Penthesilenula and Darwinula, from different continents. We applied two methods for detecting cryptic species, namely the K/θ method and the General Mixed Yule Coalescent model (GMYC). We could confirm the existence of species in all five darwinulid morphospecies and additional cryptic diversity in three morphospecies, namely in Penthesilenula brasiliensis, Darwinula stevensoni and in P. aotearoa. The number of cryptic species within one morphospecies varied between seven (P. brasiliensis), five to six (D. stevensoni) and two (P. aotearoa), respectively, depending on the method used. Cryptic species mainly followed continental distributions. We also found evidence for coexistence at the local scale for Brazilian cryptic species of P. brasiliensis and P. aotearoa. Our ITS2 data confirmed that species exist in darwinulids but detected far less EG species, namely two to three cryptic species in P. brasiliensis and no cryptic species at all in the other darwinulid morphospecies. CONCLUSIONS/SIGNIFICANCE: Our results clearly demonstrate that both species and cryptic diversity can be recognized in putative ancient asexual ostracods using the EG species concept, and that COI data are more suitable than ITS2 for this purpose. The discovery of up to eight cryptic species within a single morphospecies will significantly increase estimates of biodiversity in this asexual ostracod group. Which factors, other than long-term geographic isolation, are important for speciation processes in these ancient asexuals remains to be investigated.