RESUMO
BACKGROUND: To date, the efficacy of the androgen receptor inhibitors enzalutamide and apalutamide for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC) has not been compared directly in a clinical trial setting. Indirect comparisons can be used to assess relative efficacy and provide important information to guide treatment decisions. PROSPER and SPARTAN were double-blind, randomized, placebo-controlled, phase III trials in patients with nmCRPC with overall similar study designs and inclusion and exclusion criteria. Using an anchored matching-adjusted indirect comparison, based on the final data from the PROSPER and SPARTAN studies, we assessed the comparative efficacy of enzalutamide and apalutamide, both plus androgen deprivation therapy. METHODS: Using placebo as the common comparator, individual patient data from PROSPER were matched to the aggregate patient data from SPARTAN and efficacy endpoints from PROSPER were re-weighted accordingly. Patient baseline characteristics and endpoints were clinically and statistically tested to identify potential effect modifiers, according to National Institute for Health and Care Excellence guidelines. Hazard ratios for overall survival (OS), metastasis-free survival (MFS), and time to chemotherapy (TTCx) were re-estimated for PROSPER using weighted Cox proportional hazards models and indirectly compared with those of SPARTAN using a Bayesian network meta-analysis. RESULTS: Estimated hazard ratios [95% credible interval (CrI)] for enzalutamide versus apalutamide were 0.80 (95% CrI 0.58-1.10) for OS, 0.94 (95% CrI 0.69-1.29) for MFS2, and 0.90 (95% CrI 0.63-1.29) for TTCx. Similar results were seen for sensitivity analyses conducted for OS and MFS. Bayesian probability analyses showed a 91.7% favoring enzalutamide for OS, 65.1% for MFS, and 71.4% for TTCx. CONCLUSIONS: The results of this matching-adjusted indirect comparison of final data from PROSPER and SPARTAN indicate comparable efficacy of enzalutamide and apalutamide with potentially a greater probability of longer MFS, OS, and TTCx in patients with nmCRPC treated with enzalutamide versus apalutamide.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Antagonistas de Androgênios/uso terapêutico , Teorema de Bayes , Benzamidas , Ensaios Clínicos Fase III como Assunto , Humanos , Masculino , Nitrilas , Feniltioidantoína , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Tioidantoínas , Resultado do TratamentoRESUMO
The main source of potable water in high water-stress areas is commonly produced in brackish and seawater desalination plants. Owing to the presence of high concentration of suspended solids, organic matter and colloidal particles in raw water, pretreatment processes are needed for a stable operation of desalination plants. A submerged membrane ultrafiltration pilot plant has been operated as pretreatment of complex brackish surface water to study the filtration performance. The results show the membrane performance, chemical reagent requirements, water quality and cleaning procedures efficiency of an ultrafiltration pilot plant used as pretreatment for a reverse osmosis system. Alternative chemical cleaning procedures have been satisfactorily implemented, which maximize permeability recovery and allow a stable operation.
Assuntos
Água Potável , Purificação da Água/instrumentação , Purificação da Água/métodos , Qualidade da Água , Membranas Artificiais , Osmose , Projetos Piloto , Rios , Água do Mar , Espanha , Ultrafiltração/instrumentação , Ultrafiltração/métodosRESUMO
IgM molecules circulate in serum as large polymers, mainly pentamers, which can be transported by the poly-Ig receptor (pIgR) across epithelial cells to mucosal surfaces and released as secretory IgM (SIgM). The mucosal SIgM molecules have non-covalently attached secretory component (SC), which is the extracellular part of pIgR which is cleaved from the epithelial cell membrane. Serum IgM antibodies do not contain SC and have previously been shown to make a conformational change from 'a star' to a 'staple' conformation upon reaction with antigens on a cell surface, enabling them to activate complement. However, it is not clear whether SIgM similarly can induce complement activation. To clarify this issue, we constructed recombinant chimeric (mouse/human) IgM antibodies against hapten 5-iodo-4-hydroxy-3-nitro-phenacetyl (NIP) and in addition studied polyclonal IgM formed after immunization with a meningococcal group B vaccine. The monoclonal and polyclonal IgM molecules were purified by affinity chromatography on a column containing human SC in order to isolate joining-chain (J-chain) containing IgM, followed by addition of excess amounts of soluble SC to create SIgM (IgM J+ SC+). These SIgM preparations were tested for complement activation ability and shown to be nearly as active as the parental IgM J+ molecules. Thus, SIgM may offer protection against pathogens at mucosal surface by complement-mediated cell lysis or by phagocytosis mediated by complement receptors present on effector cells on mucosa.
Assuntos
Ativação do Complemento , Proteínas do Sistema Complemento/imunologia , Imunoglobulina M/imunologia , Vacinas Meningocócicas/imunologia , Animais , Citotoxicidade Celular Dependente de Anticorpos , Cápsulas Bacterianas/imunologia , Humanos , Imunidade Humoral , Camundongos , Mucosa/imunologia , Nitro-Hidroxi-Iodofenilacetato/imunologia , Conformação Proteica , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Componente Secretório/imunologiaRESUMO
BACKGROUND: To determine suitability of progression-free survival (PFS) as a surrogate end-point for overall survival (OS), we evaluated the relationship between PFS and OS in 750 treatment-naïve metastatic renal cell carcinoma (mRCC) patients who received sunitinib or interferon-alpha (IFN-α) in a phase III study. METHODS: The relationship between PFS and post-progression survival (PPS; the difference between PFS and OS) was studied, which correctly removes inherent dependencies between PFS and OS, to properly estimate whether and to what extent PFS can serve as a surrogate for OS. A Weibull parametric model to failure time data was fit to determine whether longer PFS was significantly and meaningfully predictive of longer PPS. In a sensitivity analysis by Kaplan-Meier non-parametric method, PPS curves for three approximately equal numbered groups of patients categorised by PFS were compared by log-rank test. RESULTS: In the Weibull parametric model, longer PFS was significantly predictive of longer PPS (P<0.001). The model also allowed prediction of estimated median PPS duration from actual PFS times. In the Kaplan-Meier (non-parametric) analysis, incrementally longer PFS was also associated with longer PPS, and the PPS curves for the three PFS groups were significantly different (P<0.0001). CONCLUSIONS: A positive relationship was found between PFS and PPS duration in individual mRCC patients randomised to first-line treatment with sunitinib or IFN-α. These results indicate that PFS can act as a surrogate end-point for OS in the first-line mRCC setting and provide clinical researchers with a potentially useful approach to estimate median PPS based on PFS.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Indóis/uso terapêutico , Interferon-alfa/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Pirróis/uso terapêutico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Intervalo Livre de Doença , Determinação de Ponto Final , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Sunitinibe , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: This retrospective register study assessed overall survival (OS) and influential factors on OS in Swedish renal cell carcinoma (RCC) patients. METHODS: Using three merged national health registers, Cox proportional-hazards analysis was conducted and, in three models, it was used to assess the impact of cytokine (interferon-α and tyrosine kinase inhibitor (TKI; sunitinib or sorafenib) treatment on OS in metastatic (m)RCC. RESULTS: From 2000 to 2008, 8009 patients were diagnosed with RCC and 2753 with mRCC (2002-2008). Median OS in RCC patients diagnosed from 2006 to 2008 compared with 2000-2005 was not reached vs 47.9 months (P<0.001), and in mRCC patients diagnosed from 2006 to 2008 compared with 2002-2005, was 12.4 vs 9.6 months, respectively (P=0.004). Factors associated with significantly improved OS in RCC were female gender, lower age, and previous nephrectomy, and, in mRCC female gender, previous nephrectomy, and any TKI prescription (Model 1: median-adjusted OS, 19.4 months (TKI patients) vs 9.7 months (non-TKI patients); hazard ratio, 0.621; P<0.001). CONCLUSION: OS was improved in Swedish patients diagnosed with RCC and mRCC in the period 2006-2008 compared with 2000-2005 (RCC) and 2002-2005 (mRCC). Although multifactorial in origin, results suggest that increased nephrectomy rates and the use of TKIs contributed to the improvement seen in mRCC patients.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/mortalidade , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/mortalidade , Idoso , Feminino , Humanos , Interferon-alfa/uso terapêutico , Masculino , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/uso terapêutico , Sistema de Registros , Estudos Retrospectivos , Análise de Sobrevida , Suécia/epidemiologia , Resultado do TratamentoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/economia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapia , Indóis/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Pirróis/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab , Carcinoma de Células Renais/economia , Custos de Cuidados de Saúde , Humanos , Indóis/uso terapêutico , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Neoplasias Renais/economia , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/economia , Metástase Neoplásica , Pirróis/uso terapêutico , Proteínas Recombinantes , Sunitinibe , Reino UnidoRESUMO
The C1q binding epicentre on IgG molecules involves residues Asp(270), Lys(322), Pro(329) and Pro(331) in the C(H)2 domain. IgG1 and IgG3 are usually the most efficient of the four human IgG subclasses in activating complement and they both share all these residues. To reveal possible differences in the structural requirement for complement activation, we created a number of NIP (5-iodo-4-hydroxy-3-nitro-phenacetyl) specific IgG1 and IgG3 antibodies with parallel mutations in or near the putative C1q binding site. The mutants were tested simultaneously for antibody induced, antibody-dependent complement-mediated lysis (ADCML) at high and low antigen concentration on the target cells using sera of human, rabbit and guinea pig as complement source. In addition, we tested the antibodies against target cells decorated with the NP hapten, which has 10-fold lower affinity for the antibodies compared to the NIP hapten. We also used ELISA methods to measure complement activation. We observed a clear difference between IgG1 and IgG3 localized to residues Asp(270), Leu(334), Leu(335). For all these residues, and especially for Asp(270), IgG1 was heavily reduced in complement activation, while IgG3 was only moderated reduced, by alanine substitution. This difference was independent of the long hinge region of IgG3, demonstrated by hinge region truncation of this isotype such that it resembles that of IgG1. This report indicates the presence of structural differences between human IgG1 and IgG3 in the C1q binding site, and points to a specialization of the two isotypes with respect to complement activation.
Assuntos
Sítios de Ligação de Anticorpos/imunologia , Ativação do Complemento/imunologia , Complemento C1q/imunologia , Imunoglobulina G/imunologia , Animais , Afinidade de Anticorpos/genética , Afinidade de Anticorpos/imunologia , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Sítios de Ligação de Anticorpos/genética , Complemento C1q/metabolismo , Cobaias , Humanos , Imunoglobulina G/química , Imunoglobulina G/genética , Mutação , Nitro-Hidroxi-Iodofenilacetato/imunologia , CoelhosRESUMO
BACKGROUND: Dreams are more frequently reported than awareness after surgery. We define awareness as explicit recall of real intraoperative events during anaesthesia. The importance of intraoperative dreaming is poorly understood. This study was performed to evaluate whether intraoperative dreams can be associated with, or precede, awareness. We also studied whether dreams can be related to case-specific parameters. METHODS: A cohort of 6991 prospectively included patients given inhalational anaesthesia were interviewed for dreams and awareness at three occasions; before they left the post-anaesthesia care unit, days 1-3 and days 7-14 after the operation. Uni- and multivariate statistical relations between dreams, awareness and case-specific parameters were assessed. RESULTS: Two hundred and thirty-two of 6991 patients (3.3%) reported a dream. Four of those also reported awareness and remembered real events that were distinguishable from their dream. Awareness was 19 times more common among patients who after surgery reported a dream [1.7% vs. 0.09%; odds ratio (OR) 18.7; P=0.000007], but memories of dreams did not precede memories of awareness in any of the 232 patients reporting a dream. Unpleasant dreams were significantly more common when thiopentone was used compared with propofol (OR 2.22; P=0.005). Neutral or pleasant dreams were related to lower body mass index, female gender and shorter duration of anaesthesia. CONCLUSIONS: We found a statistically significant association between dreams reported after general anaesthesia and awareness, although intraoperative dreams were not an early interpretation of delayed awareness in any case. A typical dreamer in this study is a lean female having a short procedure.
Assuntos
Anestesia Geral/efeitos adversos , Anestésicos Gerais , Conscientização/efeitos dos fármacos , Sonhos/efeitos dos fármacos , Índice de Massa Corporal , Estudos de Coortes , Sonhos/psicologia , Humanos , Período Intraoperatório , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Regressão , Fatores Sexuais , Fatores de TempoRESUMO
BACKGROUND: In earlier studies, between 1% and 57% of patients have been reported to dream during anaesthesia. Thus, dreaming is much more common than definite memories of real events. We wanted to examine whether dreaming during anaesthesia is related to insufficient hypnotic action, as indicated by BIS levels and, thus, may constitute a risk for awareness. METHODS: After IRB approval, 2653 consecutive surgical patients were included. BIS registrations were recorded continuously during the anaesthetic procedure. The patients were interviewed on three occasions after anaesthesia. Standard questions, according to Brice, to evaluate awareness and dreaming during anaesthesia were asked. The dreams were categorized as either pleasant/neutral or unpleasant without any further evaluation of the dream content. Episodes with a mean BIS below 40, above 60 and above 70 were identified and subdivided according to duration (1, 2, 4 and 6 min, respectively). The total time as well as number and duration of episodes for the three BIS-levels were used to analyze any relation to reported dreaming. The mean BIS was also analyzed. RESULTS: Dreaming during anaesthesia was reported by 211 of patients (8.0%) on at least one of the post-operative interviews. BIS data did not show any significant correlation with dreaming, and neither did any of the tested case-specific parameters (gender, age, ASA group, BMI, use of relaxants, induction agent, maintenance agent, length of procedure, omitting N(2)O and concomitant regional anaesthesia). CONCLUSION: Dreaming during anaesthesia seems to be a separate phenomenon, not in general related to insufficient anaesthesia as indicated by high BIS levels.
Assuntos
Anestesia Geral , Anestésicos Gerais , Sonhos/efeitos dos fármacos , Eletroencefalografia , Conscientização/efeitos dos fármacos , Sonhos/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória/métodos , Estatísticas não Paramétricas , Fatores de TempoRESUMO
BACKGROUND: Bispectral index (BIS) has been associated with benefits from less-deep anesthesia as well as preventing awareness, albeit not at the same time. We investigated how increasing experience from BIS in clinical practice affect the hypnotic level, drug consumption, as well as subjective opinions on this monitoring. METHODS: Eight certified registered nurse anesthetists (CRNAs) with previous experience from 88 (46-121) BIS monitored cases anesthetized 80 cases with concealed BIS, followed by 80 cases with available BIS. Additional education and training was followed by yet another 160 patients randomized to open or blindly recorded BIS. BIS levels, anesthetic gas consumption, fentanyl use, and subjective opinions on utility and reliability were investigated. RESULTS: After gaining initial experience from BIS monitoring, the fraction of time with BIS levels of 40-60 did not deteriorate in cases with concealed monitoring and no further improvement was found in subsequent cases with available data from the BIS monitoring, not even after additional training and encouragement to adhere to the 40-60 interval. Compared with the first experience from BIS monitoring the subjective opinions on utility had increased from 33 to 78 mm (100 mm visual analog scales) (P<0.0001). CONCLUSION: Although BIS became considerably appreciated, growing experience and repeated education had no impact on drug dosing and BIS levels.
Assuntos
Anestesia por Inalação/estatística & dados numéricos , Anestésicos Inalatórios/administração & dosagem , Eletroencefalografia , Fentanila/administração & dosagem , Éteres Metílicos/administração & dosagem , Monitorização Intraoperatória/métodos , Óxido Nitroso/administração & dosagem , Enfermeiros Anestesistas/psicologia , Adulto , Anestesia Intravenosa/estatística & dados numéricos , Atitude do Pessoal de Saúde , Conscientização , Tomada de Decisões , Feminino , Hábitos , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória/estatística & dados numéricos , Motivação , Enfermeiros Anestesistas/educação , Propofol/administração & dosagem , Sevoflurano , Método Simples-Cego , Tiopental/administração & dosagemRESUMO
Liberal pre-operative fasting routines have been implemented in most countries. In general, clear fluids are allowed up to 2 h before anaesthesia, and light meals up to 6 h. The same recommendations apply for children and pregnant women not in labour. In children <6 months, most recommendations now allow breast- or formula milk feeding up to 4 h before anaesthesia.Recently, the concept of pre-operative oral nutrition using a special carbohydrate-rich beverage has also gained support and been shown not to increase gastric fluid volume or acidity. Based on the available literature, our Task Force has produced new consensus-based Scandinavian guidelines for pre-operative fasting. What is still not clear is to what extent the new liberal fasting routines should apply to patients with functional dyspepsia or systematic diseases such as diabetes mellitus. Other still controversial areas include the need for and effect of fasting in emergency patients, women in labour and in association with procedures done under deep sedation. We think more research on the effect of various fasting regimes in subpopulations of patients is needed before we can move one step further towards completely evidence-based pre-operative fasting guidelines.
Assuntos
Humanos , Cuidados Pré-Operatórios/normas , Jejum , Conteúdo Gastrointestinal , Pneumonia Aspirativa/prevenção & controleRESUMO
Despite significant advances in prevention and therapy, cytomegalovirus (CMV) infection continues to be an important cause of morbidity and mortality in the hematopoietic stem cell transplant (HSCT) recipient. The standard drug for pre-emptive therapy is intravenous ganciclovir (GCV). Valganciclovir (VGC), the oral pro-drug of GCV, has excellent bioavailability and is ideal for oral therapy. Since March 2002, VGC was adopted in our center for outpatient pre-emptive therapy in all patients undergoing allogeneic HSCT. Fifty-two allogeneic HSCT recipients were followed weekly via Digene hybrid capture assay. Patients with a positive assay were treated with VGC 900 mg p.o. b.i.d. x 14 days followed by 900 mg p.o. QD until at least 7 days after a negative test. Eighteen patients (14 sib, four MUD) had 30 episodes of CMV DNA detection treated with oral VGC. Median duration of therapy was 21 days (range 10-21 days). The rate of response was 93% (28/30) as confirmed by a negative assay within 14 days. No significant toxicity was encountered. Two patients failed oral VGC. One case of CMV enteritis was diagnosed in a patient with acute GVHD. Pre-emptive therapy of CMV infection with oral VGC is safe and effective in allogeneic HSCT recipients.
Assuntos
Antivirais/uso terapêutico , Infecções por Citomegalovirus/prevenção & controle , Ganciclovir/análogos & derivados , Leucemia/terapia , Transplante de Células-Tronco/métodos , Administração Oral , Adulto , Antivirais/administração & dosagem , Antivirais/farmacocinética , Disponibilidade Biológica , Infecções por Citomegalovirus/tratamento farmacológico , Feminino , Ganciclovir/administração & dosagem , Ganciclovir/farmacocinética , Ganciclovir/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/terapia , Síndromes Mielodisplásicas/terapia , Estudos Retrospectivos , Transplante de Células-Tronco/efeitos adversos , Transplante Homólogo , Falha de Tratamento , Resultado do Tratamento , Valganciclovir , Irradiação Corporal TotalRESUMO
Between 0.1% and 0.2% of surgical patients given general anesthesia remember having been aware during the procedure. Not all, but some of these patients have experienced pain, anxiety or both while being aware. In addition, there is a risk for developing anxiety symptoms. These symptoms can constitute a posttraumatic stress syndrome or parts thereof. The anxiety symptoms may be transient, but can persist in some patients. The majority of available studies on suffering due to awareness are retrospective, and potential selection bias in the studied cohorts should be considered when the likelihood for negative experiences of awareness are discussed.
Assuntos
Conscientização , Rememoração Mental , Dor/psicologia , Pânico , Transtornos de Estresse Pós-Traumáticos/etiologia , Anestesia Geral , Humanos , Período Intraoperatório , Transtornos de Estresse Pós-Traumáticos/psicologiaRESUMO
Liberal pre-operative fasting routines have been implemented in most countries. In general, clear fluids are allowed up to 2 h before anaesthesia, and light meals up to 6 h. The same recommendations apply for children and pregnant women not in labour. In children <6 months, most recommendations now allow breast- or formula milk feeding up to 4 h before anaesthesia. Recently, the concept of pre-operative oral nutrition using a special carbohydrate-rich beverage has also gained support and been shown not to increase gastric fluid volume or acidity. Based on the available literature, our Task Force has produced new consensus-based Scandinavian guidelines for pre-operative fasting. What is still not clear is to what extent the new liberal fasting routines should apply to patients with functional dyspepsia or systematic diseases such as diabetes mellitus. Other still controversial areas include the need for and effect of fasting in emergency patients, women in labour and in association with procedures done under 'deep sedation'. We think more research on the effect of various fasting regimes in subpopulations of patients is needed before we can move one step further towards completely evidence-based pre-operative fasting guidelines.
Assuntos
Jejum/fisiologia , Cuidados Pré-Operatórios/normas , Anestesia/efeitos adversos , Esvaziamento Gástrico/fisiologia , Humanos , Pneumonia Aspirativa/prevenção & controle , Países Escandinavos e NórdicosRESUMO
In 21 patients given sevoflurane anesthesia, we simultaneously compared the abilities of Bispectral Index (BIS) and rapidly extracted auditory evoked potentials index (AAI) to display the effect of an increasing cerebral concentration of sevoflurane, with and without noxious stimulation. In addition to BIS/AAI, hemodynamic variables were monitored. After titrating sevoflurane to BIS = 50-55 during 15 min, the end-tidal concentration of sevoflurane (1.46% +/- 0.20%) was doubled followed by a noxious stimulus, laryngoscopy, applied at random time points within the following 15 min. After the end-tidal concentration of sevoflurane was doubled, a substantial reduction in BIS was observed, whereas only a slight reduction in AAI was seen (P < 0.0001). BIS/AAI responses to laryngoscopy were not attenuated with increasing wash-in of sevoflurane. After noxious stimulation, AAI exceeded the highest recommended value, 25, in 3 cases, whereas BIS did not exceed the recommended threshold, 60, in any of the patients. Response times for BIS and AAI were 44.5 +/- 26 and 47 +/- 31 s, respectively. These results suggest that, at a hypnotic level associated with surgical sevoflurane anesthesia, BIS better displays drug-related alterations in the level of hypnosis than AAI or hemodynamic variables but there is no difference between BIS and AAI in the time to response to a noxious stimulus.
Assuntos
Anestesia por Inalação , Anestésicos Inalatórios , Eletroencefalografia/efeitos dos fármacos , Potenciais Evocados Auditivos/efeitos dos fármacos , Éteres Metílicos , Monitorização Intraoperatória/métodos , Adulto , Artroscopia , Pressão Sanguínea/efeitos dos fármacos , Coleta de Dados , Feminino , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Joelho/cirurgia , Laringoscopia , Masculino , Estimulação Física , SevofluranoRESUMO
There is still no general vaccine for prevention of disease caused by group-B meningococcal strains. Meningococcal lipopolysaccharides (LPSs) have received attention as potential vaccine candidates, but concerns regarding their safety have been raised. Peptide mimics of LPS epitopes may represent safe alternatives to immunization with LPS. The monoclonal antibody (MoAb) 9-2-L3,7,9 specific for Neisseria meningitidis LPS immunotype L3,7,9 is bactericidal and does not cross-react with human tissue. To explore the possibility of isolating peptide mimics of the epitope recognized by MoAb 9-2-L3,7,9, we have constructed two phage display libraries of six and nine random amino acids flanked by cysteines. Furthermore, we developed a system for the easy exchange of peptide-encoding sequences from the phage-display system to a hepatitis B core (HBc) expression system. Cyclic peptides that specifically bound MoAb 9-2-L3,7,9 at a site overlapping with the LPS-binding site were selected from both libraries. Three out of four tested peptides which reacted with MoAb 9-2-L3,7,9 were successfully presented as fusions to the immunodominant loop of HBc particles expressed in Escherichia coli. However, both peptide conjugates to keyhole limpet haemocyanin and HBc particle fusions failed to give an anti-LPS response in mice.
Assuntos
Anticorpos Monoclonais/imunologia , Lipopolissacarídeos/imunologia , Neisseria meningitidis/imunologia , Peptídeos Cíclicos/imunologia , Animais , Anticorpos Antibacterianos/química , Anticorpos Antibacterianos/imunologia , Anticorpos Monoclonais/química , Sítios de Ligação/imunologia , Hemocianinas/imunologia , Camundongos , Biblioteca de Peptídeos , Peptídeos Cíclicos/química , Ligação ProteicaRESUMO
BACKGROUND: Explicit recall (ER) is evident in approximately 0.2% of patients given general anaesthesia including muscle relaxants. This prospective study was performed to evaluate if cerebral monitoring using BIS to guide the conduction of anaesthesia could reduce this incidence significantly. PATIENTS AND METHODS: A prospective cohort of 4945 consecutive surgical patients requiring muscle relaxants and/or intubation were monitored with BIS and subsequently interviewed for ER on three occasions. BIS values between 40 and 60 were recommended. The results from the BIS-monitored group of patients was compared with a historical group of 7826 similar cases in a previous study when no cerebral monitoring was used. RESULTS: Two patients in the BIS-monitored group, 0.04%, had ER as compared with 0.18% in the control group (P < 0.038). Both BIS-monitored patients with ER were aware during intubation when they had high BIS values (> 60) for 4 min and more than 10 min, respectively. However, periods with high BIS = 4 min were also evident in other patients with no ER. Episodes with high BIS, 4 min or more, were found in 19% of the monitored patients during induction, and in 8% of cases during maintenance. CONCLUSIONS: The use of BIS monitoring during general anaesthesia requiring endotracheal intubation and/or muscle relaxants was associated with a significantly reduced incidence of awareness as compared with a historical control population.
Assuntos
Anestesia Geral , Conscientização/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Monitorização Intraoperatória , Complicações Pós-Operatórias/psicologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Período Intraoperatório , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Bucais , Pneumotórax/cirurgia , Complicações Pós-Operatórias/epidemiologia , Período Pós-Operatório , Estudos Prospectivos , Suécia , Resultado do TratamentoRESUMO
We have constructed chimaeric (ch) mouse/human antibodies with identical binding regions isolated from the V-genes of two mouse parent hybridoma cell lines, with specificity against the P1.7 and P1.16 epitopes on the outer-membrane protein PorA on meningococci. The chimaeric antibodies can be used to analyse relationships between specificity, binding activity (avidity and kinetics), isotype (antibody class and antibody subclass) and in vitro anti-bacterial activity of meningococcal antibodies. The antibody sets represented the human isotypes IgG1, IgG3 and IgM, which dominate during immune response against protein antigens. The binding activities were quite similar for all these isotypes, surprisingly also for the pentameric IgM. Interestingly, monomeric IgM, prepared from pentameric IgM by partially reduction and alkylation, had similar binding activities as the original pentameric IgM. Regarding in vitro anti-bacterial activity, chIgG1 was superior in SBA (serum bactericidal activity) compared with chIgG3, while chIgG3 was more efficient in OP (opsonophagocytosis; measured by flow cytometry) than chIgG1. ChIgM showed slightly higher SBA than chIgG1 on molar basis, and much higher OP than chIgG3 and chIgG1. A lower concentration of antibodies was needed against the P1.16 than against the P1.7 epitope to induce SBA, but this was not the case for OP.
Assuntos
Antibacterianos/farmacologia , Imunoglobulina G/química , Imunoglobulina M/química , Neisseria meningitidis/metabolismo , Relação Dose-Resposta a Droga , Epitopos/química , Citometria de Fluxo , Vetores Genéticos , Humanos , Cinética , Leucócitos Mononucleares/microbiologia , Ligação Proteica , Proteínas Recombinantes de Fusão/metabolismoRESUMO
A serogroup B meningococcal outer membrane vesicle (OMV) vaccine was delivered either intranasally or intramuscularly to 12 and 10 volunteers, respectively. The mucosal vaccine was given as four weekly doses followed by a fifth dose after 5 months; each dose consisted of OMVs equivalent to 250 microg of protein. The intramuscular (i.m.) vaccine, consisting of the same OMVs but adsorbed to Al(OH)(3), was administered as three doses each of 25 microg of protein, with 6 weeks interval between first and second doses and the third dose after 10 months. Both groups of vaccinees demonstrated significant immune responses when measured as specific IgG antibodies against live meningococci, as serum bactericidal activity (SBA) and as opsonophagocytic activity. Two weeks after the last dose, the anti-meningococcal IgG concentrations were significantly higher in the i.m. group (median IgG concentration: 43.1 microg/ml) than in the intranasal group (10.6 microg/ml) (P=0.001). The corresponding opsonophagocytic activity was 7.0 and 3.0 (median log(2) titre) (P=0.001), and the SBA was 5.0 and 2.0 (median log(2) titre) (P=0.005), for the i.m. and intranasal groups, respectively. The last immunisation induced an enhanced immune response in the i.m. group, whereas the intranasal group showed no significant booster response. Accordingly, affinity maturation of anti-OMV-specific IgG antibodies was seen only after i.m. vaccination. The IgG1 subclass dominated the responses in both groups, whereas the significant IgG3 responses observed in the i.m. group were absent in the intranasal group. Although the intranasal OMV vaccination schedule used here induced functional immune responses relevant to protection, an improved vaccine formulation and/or a modified mucosal immunisation regimen may be needed to achieve a systemic effect comparable to that seen after three doses of intramuscular vaccination.