RESUMO
Promiscuous expression of tissue-restricted auto-antigens in the thymus imposes T-cell tolerance and provides protection from autoimmune diseases. Promiscuous expression of a set of self-antigens occurs in medullary thymic epithelial cells and is partly controlled by the autoimmune regulator (AIRE), a nuclear protein for which loss-of-function mutations cause the type 1 autoimmune polyendocrine syndrome. However, additional factors must be involved in the regulation of this promiscuous expression. Here we describe a mechanism controlling thymic transcription of a prototypic tissue-restricted human auto-antigen gene, CHRNA1. This gene encodes the alpha-subunit of the muscle acetylcholine receptor, which is the main target of pathogenic auto-antibodies in autoimmune myasthenia gravis. On re-sequencing the CHRNA1 gene, we identified a functional bi-allelic variant in the promoter that is associated with early onset of disease in two independent human populations (France and United Kingdom). We show that this variant prevents binding of interferon regulatory factor 8 (IRF8) and abrogates CHRNA1 promoter activity in thymic epithelial cells in vitro. Notably, both the CHRNA1 promoter variant and AIRE modulate CHRNA1 messenger RNA levels in human medullary thymic epithelial cells ex vivo and also in a transactivation assay. These findings reveal a critical function of AIRE and the interferon signalling pathway in regulating quantitative expression of this auto-antigen in the thymus, suggesting that together they set the threshold for self-tolerance versus autoimmunity.
Assuntos
Regulação da Expressão Gênica , Fatores Reguladores de Interferon/metabolismo , Regiões Promotoras Genéticas/genética , Receptores Nicotínicos/genética , Timo/metabolismo , Fatores de Transcrição/metabolismo , Idade de Início , Alelos , Linhagem Celular , Células Epiteliais/metabolismo , França/epidemiologia , Humanos , Miastenia Gravis/epidemiologia , Miastenia Gravis/genética , Polimorfismo de Nucleotídeo Único/genética , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Timo/citologia , Fatores de Transcrição/genética , Transcrição Gênica/genética , Reino Unido/epidemiologia , Proteína AIRERESUMO
BACKGROUND: Myasthenia gravis is an autoimmune disease in which autoantibodies interfere with neuromuscular transmission. As with other autoimmune diseases, people with myasthenia gravis would be expected to benefit from intravenous immunoglobulin (IVIg). This is an update of a review first published in 2003 and last updated in 2007. OBJECTIVES: To examine the efficacy of IVIg for treating exacerbations of myasthenia gravis or for chronic myasthenia gravis. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (11 October 2011), CENTRAL (2011, Issue 3), MEDLINE (January 1966 to September 2011) and EMBASE (January 1980 to September 2011) using 'myasthenia gravis' and 'intravenous immunoglobulin' as the search terms. SELECTION CRITERIA: All randomised controlled trials (RCTs) or quasi-RCTs in which IVIg was compared with no treatment, placebo or plasma exchange, in people with myasthenia gravis. DATA COLLECTION AND ANALYSIS: One review author extracted the data and two others checked these data. For methodological reasons, no formal meta-analysis was performed. MAIN RESULTS: We identified seven RCTs. These trials differ in inclusion criteria, comparison with alternative treatment and outcomes. In a trial comparing IVIg with placebo, including 51 participants with myasthenia gravis worsening, the mean difference (MD) in quantitative myasthenia gravis score (QMGS) (MD 95% CI) after 14 days was: -1.60 (95% CI - 3.23 to 0.03) this result being borderline statistically significant in favour of IVIg. In an unblinded study of 87 participants with exacerbation comparing IVIg and plasma exchange there was no difference in myasthenic muscle score (MMS) after 15 days (MD -1.00; 95% CI -7.72 to 5.72). In a study of 84 participants with worsening myasthenia gravis there was no difference in change in QMGS 14 days after IVIg or plasma exchange (MD -1.50; 95% CI -3.43 to 0.43). In a study of 12 participants with moderate or severe myasthenia gravis, which was at high risk of bias from skewed allocation, the mean fall in QMGS both for IVIg and plasma exchange after four weeks was significant (P < 0.05). A study with 15 participants with mild or moderate myasthenia gravis found no difference in change in QMGS 42 days after IVIg or placebo (MD 1.60; 95% CI -1.92 to 5.12). A study included 33 participants with moderate exacerbations of myasthenia gravis and showed no difference in change in QMGS 14 days after IVIg or methylprednisolone (MD -0.42; 95% CI -1.20 to 0.36). All these three smaller studies were underpowered. The last trial, including 168 people with exacerbations, showed no evidence of superiority of IVIg 2 g/kg over IVIg 1 g/kg on the change of MMS after 15 days (MD 3.84; 95% CI -0.98 to 8.66). Adverse events due to IVIg were moderate (fever, nausea, headache), self-limiting and subjectively less severe than with plasma exchange (although, given the available data, no statistical comparison was possible). Other than where specific limitations are mentioned the trials were generally at low risk of bias. AUTHORS' CONCLUSIONS: In exacerbation of myasthenia gravis, one RCT of IVIg versus placebo showed some evidence of the efficacy of IVIg and two did not show a significant difference between IVIg and plasma exchange. Another showed no significant difference in efficacy between 1 g/kg and 2 g/kg of IVIg. A further, but underpowered, trial showed no significant difference between IVIg and oral methylprednisolone. In chronic myasthenia gravis, there is insufficient evidence from RCTs to determine whether IVIg is efficacious.
Assuntos
Imunoglobulinas Intravenosas/uso terapêutico , Miastenia Gravis/terapia , Doença Crônica , Progressão da Doença , Humanos , Metilprednisolona/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Troca Plasmática , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
The results of four randomized controlled trials were examined to assess the efficacy of intravenous immunoglobulin (IVIG) for myasthenia gravis (MG) acute exacerbations. The first trial compared plasma exchange (PE) and IVIG in 87 patients. At day 15, the mean change in the Myasthenic Muscular Score (MMS) was 16.6 (95% CI 11.6-21.6) in the PE group and 15.6 (95% CI 10.9-20.3) in the IVIG group (Wilcoxon signed rank test, P = 0.65). The second trial compared IVIG to oral methylprednisolone, and 33 patients were included. The mean (SD) sum of the two most pathological items of the Quantitative Myasthenia Gravis Score (QMGS) at day 0 was 3.9 (1.1) for the IVIG group and 4.2 (0.7) for the methylprednisolone group. At day 14, these values were 2.9 (1.4) for the IVIG group and 2.8 (1.1) for the methylprednisolone group. The third trial compared IVIG 2 g/kg versus placebo for MG worsening. The mean change in QMGS at day 14 was -2.54 in the IVIG group and -0.89 in the placebo group (P = 0.047). A significant IVIG treatment effect was observed only in patients with more severe disease; the mean difference was -0.10 for mild MG (P = 0.914) and -3.39 for moderate to severe MG (P = 0.010). The last trial compared IGIV 2 g/kg versus 1 g/kg for MG acute exacerbation in 173 patients. The mean MMS change in both groups was similar (difference = 3.84; 95% CI -1.03 to 8.71; P = 0.12). In conclusion, IVIG may be used as treatment for MG acute exacerbations. IVIG at a dose of 1 g/kg may be sufficient.
Assuntos
Imunoglobulinas Intravenosas/imunologia , Imunoglobulinas Intravenosas/uso terapêutico , Miastenia Gravis/imunologia , Miastenia Gravis/terapia , Progressão da Doença , Humanos , Miastenia Gravis/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de TempoRESUMO
PURPOSE: To determine the efficacy and safety of hyperbaric oxygen therapy (HBO) for overt mandibular osteoradionecrosis. PATIENTS AND METHODS: This prospective, multicenter, randomized, double-blind, placebo-controlled trial was conducted at 12 university hospitals. Ambulatory adults with overt osteoradionecrosis of the mandible were assigned to receive 30 HBO exposures preoperatively at 2.4 absolute atmosphere for 90 minutes or a placebo, and 10 additional HBO dives postoperatively or a placebo. The main outcome measure was 1-year recovery rate from osteoradionecrosis. Secondary end points included time to treatment failure, time to pain relief, 1-year mortality rate, and treatment safety. RESULTS: At the time of the second interim analysis, based on the triangular test, the study was stopped for potentially worse outcomes in the HBO arm. A total of 68 patients were enrolled and analyzed. At 1 year, six (19%) of 31 patients had recovered in the HBO arm and 12 (32%) of 37 in the placebo arm (relative risk = 0.60; 95% CI, 0.25 to 1.41; P = .23). Time to treatment failure (hazard ratio = 1.33; 95% CI, 0.68 to 2.60; P = .41) and time to pain relief (hazard ratio = 1.00; 95% CI, 0.52 to 1.89; P = .99) were similar between the two treatment arms. CONCLUSION: Patients with overt mandibular osteoradionecrosis did not benefit from hyperbaric oxygenation.
Assuntos
Neoplasias de Cabeça e Pescoço/radioterapia , Oxigenoterapia Hiperbárica , Doenças Mandibulares/etiologia , Doenças Mandibulares/terapia , Osteorradionecrose/etiologia , Osteorradionecrose/terapia , Método Duplo-Cego , Feminino , Humanos , Masculino , Doenças Mandibulares/patologia , Pessoa de Meia-Idade , Placebos , Resultado do TratamentoRESUMO
BACKGROUND: The optimal dose of intravenous immunoglobulin (IVIG) in acute exacerbation of myasthenia gravis remains unknown. Increasing the treatment duration might provide added efficacy. OBJECTIVE: To determine the optimal dose of IVIG for treating myasthenia gravis exacerbation. DESIGN: Randomized double-blind placebo-controlled multicenter trial designed to demonstrate superiority of the 2 g/kg dose over the 1 g/kg dose of IVIG, conducted between November 13, 1996, and October 26, 2002. PARTICIPANTS: One hundred seventy-three patients aged 15 to 85 years with acute exacerbation of myasthenia gravis. INTERVENTION: Participants were randomly assigned to receive 1 g/kg of IVIG on day 1 and placebo on day 2 (group 1) vs 1 g/kg of IVIG on 2 consecutive days (group 2). MAIN OUTCOME MEASURE: Improvement in the myasthenic muscular score after 2 weeks. RESULTS: The mean improvements in the myasthenic muscular scores after 2 weeks were 15.49 points (95% confidence interval, 12.09-18.90 points) in group 1 and 19.33 points (95% confidence interval, 15.82-22.85 points) in group 2. However, the difference between the 2 groups was not significant (effect size, 3.84 [95% confidence interval, -1.03 to 8.71]; P = .12). CONCLUSION: This trial found no significant superiority of 2 g/kg over 1 g/kg of IVIG in the treatment of myasthenia gravis exacerbation.
Assuntos
Imunoglobulinas Intravenosas/uso terapêutico , Miastenia Gravis/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Estudos Retrospectivos , Estatísticas não Paramétricas , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Results of experimental and clinical studies have shown that septic shock is associated with cardiovascular autonomic failure. Thus, we aimed to investigate the existence of ischaemia and apoptosis within the cerebral autonomic centres that control the cardiovascular system in patients with septic shock. METHODS: In a prospective cohort study, we did post-mortem examinations of supraoptic and paraventricular nuclei, cerebral amygdala, locus coeruleus, and medullary autonomic nuclei in 19 patients with septic shock, seven with non-septic shock and five who died suddenly from extracranial injury. Ischaemic and apoptotic neurons and microglial cells, and expression of tumour necrosis factor alpha (TNFalpha) and inducible nitric oxide synthase (iNOS) were scored. FINDINGS: Ischaemic, neuronal, and microglial apoptosis scores differed between groups (p=0.0007, p<0.0001, and p=0.0037, respectively) and were higher in patients with septic shock than in those with non-septic shock (p=0.0033, p=0.0005, and p=0.0235, respectively), and extra-cranial injury related deaths (p=0.0027, p=0.0007, and p=0.0045, respectively). There was little microglial activation and glial expression of TNFalpha. The scores for endothelial iNOS expression were different between the three groups (p<0.0001), and were higher in septic shock than in non-septic shock (p=0.0009) and than in extracranial injury related deaths (p=0.0007). Vascular expression of iNOS also correlated (Spearman tau=0.57) with autonomic-centre neuronal apoptosis in the combined septic and non-septic shock group. INTERPRETATION: Septic shock is associated with neuronal and glial apoptosis within the autonomic centres, which is strongly associated with endothelial iNOS expression.
Assuntos
Apoptose/efeitos dos fármacos , Doenças do Sistema Nervoso Autônomo/patologia , Sistema Nervoso Autônomo/patologia , Encéfalo/patologia , Sistema Cardiovascular/inervação , Óxido Nítrico Sintase/biossíntese , Choque Séptico/patologia , Adulto , Doenças do Sistema Nervoso Autônomo/enzimologia , Doenças do Sistema Nervoso Autônomo/metabolismo , Encéfalo/metabolismo , Estudos de Coortes , Morte Súbita/patologia , Endotélio Vascular/enzimologia , Feminino , Humanos , Masculino , Neurônios/metabolismo , Neurônios/patologia , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Estudos Prospectivos , Choque Séptico/mortalidadeRESUMO
OBJECTIVE: To evaluate the physiological effects of decannulation on breathing patterns and respiratory mechanics by comparing mouth breathing (MB) to tracheal breathing (TB) in tracheostomized patients. DESIGN AND SETTING: Prospective cross-over study in a critical and neuromuscular care unit. PATIENTS AND METHODS: Nine consecutive neuromuscular tracheostomized patients. Flow, esophageal pressure, gastric pressure, expiratory gas, and arterial blood gases were measured during MB and TB. RESULTS: MB induced an increase in tidal volume (from 330+/-60 ml to 400+/-80 ml) without changing respiratory frequency, inspiratory time, or arterial CO(2) pressure. This ventilation increase was due to a significant increase in physiological dead space (from 156+/-67 to 230+/-82 ml) and was associated with significant increases in work of breathing (from 6.9+/-3.4 to 9.1+/-3.3 J/min), transdiaphragmatic pressure swing (from 10+/-4 to 12.5+/-7 cmH(2)O), diaphragmatic pressure-time product per minute (from 214+/-100 to 271+/-92 cmH(2)O s(-1) min(-1)), and oxygen uptake (from 206+/-30 to 229+/-34 ml/min). Upper airway resistance did not differ from in vitro tracheostomy tube resistance. In addition, total lung-airway resistance, dynamic pulmonary compliance, and intrinsic positive end-expiratory pressure were similar in both conditions. CONCLUSIONS: Decannulation resulted in a dead space increase with no other detectable additional loading. It increased work of breathing by more than 30%. Decannulation deserves special attention in patients with restrictive respiratory disease.
Assuntos
Mecânica Respiratória/fisiologia , Traqueostomia , Desmame do Respirador , Adolescente , Adulto , Idoso , Resistência das Vias Respiratórias , Gasometria , Dióxido de Carbono/metabolismo , Estudos Cross-Over , Feminino , Humanos , Complacência Pulmonar , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio , Respiração por Pressão Positiva Intrínseca , Pressão , Estudos Prospectivos , Espaço Morto Respiratório , Estatísticas não Paramétricas , Trabalho RespiratórioAssuntos
Pessoas com Deficiência , Assistência Pública , Tecnologia Assistiva , Família , Humanos , Previdência Social , Apoio SocialRESUMO
INTRODUCTION: Although hyperbaric oxygen therapy (HBO) is broadly used for carbon monoxide (CO) poisoning, its efficacy and practical modalities remain controversial. OBJECTIVES: To assess HBO in patients poisoned with CO. DESIGN: Two prospective randomized trial on two parallel groups. SETTING: Critical Care Unit, Raymond Poincaré Hospital, Garches, France. SUBJECTS: Three hundred eighty-five patients with acute domestic CO poisoning. INTERVENTION: Patients with transient loss of consciousness (trial A, n = 179) were randomized to either 6 h of normobaric oxygen therapy (NBO; arm A0, n = 86) or 4 h of NBO plus one HBO session (arm A1, n = 93). Patients with initial coma (trial B, n = 206) were randomized to either 4 h of NBO plus one HBO session (arm B1, n = 101) or 4 h of NBO plus two 2 HBO sessions (arm B2, n = 105). PRIMARY ENDPOINT: Proportion of patients with complete recovery at 1 month. RESULTS: In trial A, there was no evidence for a difference in 1-month complete recovery rates with and without HBO [58% compared to 61%; unadjusted odds ratio, 0.90 (95% CI, 0.47-1.71)]. In trial B, complete recovery rates were significantly lower with two than with one HBO session [47% compared to 68%; unadjusted odds ratio, 0.42 (CI, 0.23-0.79)]. CONCLUSION: In patients with transient loss of consciousness, there was no evidence of superiority of HBO over NBO. In comatose patients, two HBO sessions were associated with worse outcomes than one HBO session.
Assuntos
Intoxicação por Monóxido de Carbono/terapia , Oxigenoterapia Hiperbárica , Doença Aguda , Adulto , Intoxicação por Monóxido de Carbono/fisiopatologia , Coma , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Prospectivos , Adulto JovemAssuntos
Miastenia Gravis , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Inibidores da Colinesterase , Diagnóstico Diferencial , Edrofônio , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Recém-Nascido , Miastenia Gravis/classificação , Miastenia Gravis/diagnóstico , Miastenia Gravis/terapia , Miastenia Gravis Neonatal/diagnóstico , Neostigmina , Parassimpatomiméticos , Prognóstico , TimectomiaRESUMO
We investigated an association of the HLA-A locus in 78 French Caucasian patients with autoimmune myasthenia gravis (MG) and thymic epithelial tumours. The largest effect was a protection associated with HLA-A02 in MG patients with a B2 type thymoma (OR=0.323, 95% CI: 0.113-0.756, P=0.00041). The frequency of HLA-A25 was also increased in the whole group of patients (OR=3.62, 95% CI: 1.62-7.08, P=0.0041). Our findings emphasise the interest of the histological classification in the genetic study of thymomas.
Assuntos
Predisposição Genética para Doença/genética , Antígenos HLA-A/genética , Miastenia Gravis/genética , Miastenia Gravis/imunologia , Timoma/genética , Timoma/imunologia , Adulto , Autoanticorpos/análise , Autoanticorpos/sangue , Análise Mutacional de DNA , Feminino , França , Frequência do Gene , Marcadores Genéticos/genética , Testes Genéticos , Genética Populacional , Genótipo , Heterozigoto , Teste de Histocompatibilidade , Humanos , Masculino , Miastenia Gravis/etnologia , Timoma/patologia , Timo/imunologia , Timo/patologia , Timo/fisiopatologia , População BrancaRESUMO
OBJECTIVE: Our objective was to investigate a role of the intracellular tyrosine phosphatase PTPN22*R620W variant in autoimmune myasthenia gravis (MG), considering disease heterogeneity. METHODS: We used a case-control design, comparing 470 patients and 296 controls, all French whites. Patients were categorized depending on the presence of a thymoma and serum anti-titin antibodies. RESULTS: The 620W risk allele was increased in 293 nonthymoma patients without anti-titin antibodies (odds ratio, 1.97; 95% confidence interval, 1.32-2.97, p = 0.00059) but not in nonthymoma patients with anti-titin antibodies or in thymoma patients. INTERPRETATION: Our genetic findings strengthen the concept that these groups of patients correspond to etiologically distinct disease entities.
Assuntos
Arginina/genética , Predisposição Genética para Doença , Miastenia Gravis/genética , Polimorfismo Genético , Proteínas Tirosina Fosfatases/genética , Triptofano/genética , Adulto , Idoso , Alelos , Intervalos de Confiança , Conectina , Análise Mutacional de DNA/métodos , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/metabolismo , Miastenia Gravis/classificação , Razão de Chances , Proteínas Quinases/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 22RESUMO
OBJECTIVE: To assess the frequency of vasopressin deficiency in septic shock. DESIGN: Prospective cohort study. SETTING: Intensive care unit at Raymond Poincaré University Hospital. PATIENTS: A cohort of 44 patients who met the usual criteria for septic shock for < 7 days. A second cohort of 18 septic shock patients were enrolled within the first 8 hrs of disease onset. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: General demographics, severity scores, vital signs, standard biochemical data, and circulating vasopressin levels were systematically obtained at baseline in the two cohorts. Vasopressin deficiency was defined by a normal plasma vasopressin level in the presence of a systolic blood pressure of <100 mm Hg or in the presence of hypernatremia. Baroreflex sensitivity was systematically evaluated in patients of the first cohort when vasopressin deficiency was noted. In the second cohort of patients, plasma levels of vasopressin were obtained at baseline, 6, 24, 48, and 96 hrs after shock onset. In the first population, plasma vasopressin levels were inversely correlated to the delay from shock onset. Fourteen patients had relative vasopressin deficiency: 12 patients had systolic blood pressure <100 mm Hg, with impaired baroreflex sensitivity in four, and three patients had hypernatremia. In the second population, only two patients had relative vasopressin deficiency. The plasma levels of vasopressin significantly decreased over time (p < 10-3). CONCLUSIONS: Plasma vasopressin levels are almost always increased at the initial phase of septic shock and decrease afterward. Relative vasopressin deficiency is seen in approximately one-third of late septic shock patients.
Assuntos
Síndrome de Secreção Inadequada de HAD/etiologia , Choque Séptico/sangue , Vasopressinas/deficiência , Análise de Variância , Barorreflexo , Pressão Sanguínea , Feminino , França/epidemiologia , Humanos , Síndrome de Secreção Inadequada de HAD/epidemiologia , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Estudos Prospectivos , Choque Séptico/complicações , Sódio/sangue , Estatísticas não Paramétricas , Fatores de Tempo , Equilíbrio HidroeletrolíticoRESUMO
OBJECTIVE: Multifocal necrotizing leukoencephalopathy, characterized by multiple microscopic foci of necrosis involving the white matter of the pons, has been described mainly after chemotherapy or radiotherapy for brain cancer and in HIV infection. The role of circulating cytokines has been suggested but remains to be assessed. DESIGN: Prospective case series. SETTING: A 26-bed general medical intensive care unit at a university hospital. PATIENTS: Septic shock patients. MEASUREMENTS AND PATIENTS: In three patients who died from septic shock, careful postmortem examination of the brain was performed, including studies of neuronal apoptosis and cytokine expression. MAIN RESULTS: In one patient, typical lesions of multifocal necrotizing leukoencephalopathy were seen. As compared with control 1 and control 2 who did not have multifocal necrotizing leukoencephalopathy, marked lesions of the pons, including vacuolization, apoptosis, microglial activation, and expression of tumor necrosis factor-alpha and interleukin-1beta, were observed in the case. Simultaneously, case 1 had markedly increased circulating levels for tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, interleukin-8, interleukin-10, soluble tumor necrosis factor receptor II, and for interleukin-1 receptor antagonist. CONCLUSION: Septic shock is a newly described cause of multifocal necrotizing leukoencephalopathy, probably mediated by an excessive systemic inflammatory response.
Assuntos
Leucoencefalopatia Multifocal Progressiva/etiologia , Choque Séptico/complicações , Adulto , Apoptose , Citocinas/sangue , Feminino , Humanos , Leucoencefalopatia Multifocal Progressiva/patologia , Masculino , Pessoa de Meia-Idade , Necrose , Ponte/patologia , Choque Séptico/sangueRESUMO
OBJECTIVE: Continuous positive airway pressure (CPAP) is considered an effective nonpharmacologic method of treating patients with severe acute cardiogenic pulmonary edema. However, we hypothesized that bilevel noninvasive positive-pressure ventilation (NPPV), which combines both inspiratory pressure support and positive expiratory pressure, would unload the respiratory muscles and improve cardiac and hemodynamic function more effectively than CPAP. DESIGN: Randomized crossover study. SETTING: Critical care unit, Raymond Poincaré Hospital. PATIENTS: Six consecutive patients with acute cardiogenic pulmonary edema. INTERVENTIONS: Patients were sequentially treated with 5 cm H2O CPAP, 10 cm H2O CPAP, and NPPV in a random order. MEASUREMENTS AND MAIN RESULTS: Cardiac and hemodynamic function and indexes of respiratory mechanics were measured at each treatment sequence. NPPV reduced the esophageal pressure swing and esophageal pressure-time product compared with baseline (p <.05). There was no reduction in esophageal pressure swing or esophageal pressure-time product with CPAP. NPPV and 10 cm H2O CPAP reduced the mean transmural right and left atrial filling pressures without a change in cardiac index. CONCLUSIONS: This study demonstrates that NPPV was more effective at unloading the respiratory muscles than CPAP in acute cardiogenic pulmonary edema. In addition, NPPV and 10 cm H2O CPAP produced a reduction in right and left ventricular preload, which suggests an improvement in cardiac performance.
Assuntos
Cardiopatias/terapia , Respiração com Pressão Positiva/métodos , Edema Pulmonar/terapia , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Feminino , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Mecânica Respiratória , Método Simples-Cego , Estatísticas não ParamétricasRESUMO
OBJECTIVES: To assess the mechanisms underlying the inappropriately low plasma vasopressin levels reported in septic shock. DESIGN: Prospective case series. SETTING: A 26-bed general medical intensive care unit at a university hospital. PATIENTS: Septic shock patients. MEASUREMENTS AND MAIN RESULTS: In three consecutive patients with septic shock, plasma vasopressin levels, circulating vasopressinase activity, baroreflex sensitivity, and neurohypophyseal vasopressin content were assessed. Plasma vasopressin concentration was unexpectedly within normal range in two patients (1.6 pg/mL and 1.8 pg/mL) and increased in one (16 pg/mL). In all cases, vasopressinase activity was undetectable, baroreflex sensitivity was decreased, and the high signal intensity of the posterior lobe of the pituitary gland on T1-weighted magnetic resonance images was absent. Magnetic resonance imaging and plasma vasopressin levels normalized after recovery from shock in the patient who survived. CONCLUSION: These data suggest that in septic shock, inappropriately low plasma levels of vasopressin are at least partly related to a depletion of vasopressin stores in the neurohypophysis.
Assuntos
Neuro-Hipófise/metabolismo , Choque Séptico/metabolismo , Vasopressinas/metabolismo , Idoso , Barorreflexo , Cistinil Aminopeptidase/sangue , Análise de Fourier , Gangrena Gasosa/metabolismo , Gangrena Gasosa/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuro-Hipófise/patologia , Pneumonia/metabolismo , Pneumonia/fisiopatologia , Estudos Prospectivos , Choque Séptico/fisiopatologia , Infecções dos Tecidos Moles/metabolismo , Infecções dos Tecidos Moles/fisiopatologia , Estatísticas não ParamétricasRESUMO
The 8.1 haplotype of the HLA complex has been reproducibly associated with several autoimmune diseases and traits, notably with thymus hyperplasia in patients with acquired generalized myasthenia gravis, an autoantibody-mediated disease directed at the muscle acetylcholine receptor. However, the strong linkage disequilibrium across this haplotype has prevented the identification of the causative locus, termed MYAS1. Here, we localized MYAS1 to a 1.2-Mb genome segment by reconstructing haplotypes and assessing their transmission in 73 simplex families. This segment encompasses the class III and proximal class I regions, between the BAT3 and C3-2-11 markers, therefore unambiguously excluding the class II loci. In addition, a case-control study revealed a very strong association with a core haplotype in this same region following an additive model (P=7 x 10(-11), odds ratio 6.5 for one copy and 42 for two copies of the core haplotype). Finally, we showed that this region is associated with a marked increase in serum titers of anti-acetylcholine receptor autoantibodies (P=8 x 10(-6)). Remarkably, this effect was suppressed by a second locus in cis on the 8.1 haplotype and located toward the class II region. Altogether, these data demonstrate the highly significant but complex effects of the 8.1 haplotype on the phenotype of myasthenia gravis patients and might shed light on its role in other autoimmune diseases.