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Trigger for autoimmunity The human thymus is tasked to teach T-cells which antigens are foreign and which are 'self', a process that appears to go wrong in autoimmune disorders. A study of the variation in the promoter of one gene expressed in the thymus shows that a single nucleotide change can disrupt gene regulation, and increase susceptibility to autoimmune disease. The gene, CHRNA1 , encodes a subunit of the muscle acetylcholine receptor, a target for autoantibodies in the neuromuscular disease autoimmune myasthenia gravis. The human thymus is given the difficult task of teaching T-cells which antigens are 'foreign' and which are 'self', a process which seems to go wrong in autoimmune disorders. A study of variation in the promoter of one gene expressed in thymus shows that one nucleotide change can disrupt gene regulation, and might lead to increased risk for autoimmune disease. Promiscuous expression of tissue-restricted auto-antigens in the thymus imposes T-cell tolerance and provides protection from autoimmune diseases 1 , 2 , 3 . Promiscuous expression of a set of self-antigens occurs in medullary thymic epithelial cells 4 , 5 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 6 , 7 . 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 α-subunit of the muscle acetylcholine receptor, which is the main target of pathogenic auto-antibodies in autoimmune myasthenia gravis 8 , 9 . 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.

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× 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× 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.

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. Prospective cross-over study in a critical and neuromuscular care unit. Nine consecutive neuromuscular tracheostomized patients. Flow, esophageal pressure, gastric pressure, expiratory gas, and arterial blood gases were measured during MB and TB. 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. 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.

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.

To identify early predictors of recovery from mild carbon monoxide poisoning, and to search for qualitative interactions between subsets of patients and treatment effects. Inception cohort study from a 4-year, randomised, controlled trial, which compared normobaric oxygen therapy to the combination of normobaric plus hyperbaric oxygen therapy in 307 patients. Study was conducted at a hyperbaric oxygen therapy referral centre. Victims of unintentional, non-fire-related, domestic, carbon monoxide intoxication were evaluated if the time elapsed from end of exposure to hospital admission was less than 12 h, the carboxyhaemoglobin level was greater than or equal to 10% or 5% for smoker or non-smoker, respectively, and if they did not suffer a loss of consciousness. One course of hyperbaric oxygen therapy or 6-h normobaric oxygen therapy was given. The main outcome measure was status at the 1-month recovery. Of the 307 evaluated patients, 206 (67%, 95%CI: 62%-72%) had recovered at 1 month. None of the patients died or suffered severe sequelae. Apathy and headaches were the main moderate sequelae. The multivariate analysis selected dizziness before admission (OR=1.92, [1.17-3.15], p=0.010) and headaches upon hospital admission (OR=2.14, [1.09-4.17], p=0.026) as jointly associated with persistent neurological symptoms. No significant crossover interaction between each combination of these two predictors and treatment effects was observed. At 1 month after mild carbon monoxide intoxication, victims who presented with dizziness before hospital admission or headaches upon admission have an increased risk of minor persistent neurological symptoms, but almost all patients could resume their former occupation.

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. In a prospective cohort study, we did post-mortem examinations of supraoptic and paraventricular nuclei, cerebral amygdala, locus cœruleus, 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 α (TNFα) and inducible nitric oxide synthase (iNOS) were scored. 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 TNFα. 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 τ=0·57) with autonomic-centre neuronal apoptosis in the combined septic and non-septic shock group. Septic shock is associated with neuronal and glial apoptosis within the autonomic centres, which is strongly associated with endothelial iNOS expression.

Previous experimental studies support a role for inducible nitric-oxide synthase (iNOS) in the pathogenesis of severe sepsis. The aim of the study was to characterise iNOS activity in different tissues in patients with septic shock. 13 consecutive patients with septic shock caused by cellulitis were enrolled. Skin, muscle, fat, and artery samples were obtained from normal, inflamed, and putrescent areas to measure iNOS activity, and concentrations of tumour necrosis factor α (TNFα) and interleukin 1β (IL-1β). In two patients, iNOS activity was also assessed in peripheral blood mononuclear cells (PBMC) incubated with microorganisms causing the sepsis, or in macrophages isolated from suppurating peritoneal fluid incubated with IL-1β. Compared with normal and inflamed areas, iNOS activity was increased in putrescent areas for muscle (71-fold [95% CI 20–259] vs normal areas, 69-fold [19–246] vs inflammed areas; p<0·01 for each) and for fat (68-fold [23–199] and 49-fold [18–137], respectively; p<0·01), but not for skin. Compared with normal areas, putrescent areas of arteries showed increased iNOS expression (1280-fold [598–3153]; p<0·01). Compared with normal areas, TNFα and IL-1β were increased in putrescent areas of arteries (223-fold and 41-fold, respectively; p<0·01 for each). PBMCs and tissue macrophages expressed iNOS. Plasma nitrite/nitrate concentrations inversely correlated with mean arterial pressure and systemic vascular resistance. In human septic shock we found that iNOS activity is compartmentalised at the very site of infection and parallels expression of TNFα and IL-1β. PBMCs and tissue macrophages can be a cellular source for iNOS.

Valid and reliable measurements of muscle impairment are needed to assess therapeutic efficacy in patients with generalized myasthenia gravis (MG). In 22 patients we compared the validity and interobserver reliability of two scoring methods commonly used as main endpoints in clinical trials, i.e., the Myasthenic Muscle Score (MMS) ranging from 0 to 100 (normal) and the Quantified Myasthenia Gravis Strength Score (QMGSS) ranging from 0 (normal) to 39. Each score is correlated more with functional scale and less with the patient's self-evaluation. Using intraclass correlation we found strong agreement between observers for both the MMS (r = 0.906) and the QMGSS (r = 0.905). The correlation between MMS and QGMSS was high (r = 0.87). The reliability of neither score depended on any specific item, since the removal of individual items did not significantly alter the intraclass correlation coefficient (ranging from 0.86 to 0.93).

The muscle acetylcholine receptor is the major target of the autoimmune response in generalized myasthenia gravis. To investigate the role of the gene encoding the α subunit of the receptor (CHRNA), two stable polymorphic d[(GT)·(CA)]dinucleotide repeats, designated HB and BB, were characterized within the first intron of CHRNA. The HB*14 allele conferred a relative risk for myasthenia gravis of 2.5 in 81 unrelated patients compared with 100 control subjects. Very significantly, family analysis based on haplotype segregation data indicated that parental haplotypes associated with HB*14 always segregated to the child with myasthenia gravis (P < 0.0002 for the comparison with the transmission of haplotypes not bearing HB*14), whereas their transmission to unaffected siblings was equilibrated. Myasthenia gravis patients also showed a high frequency of microsatellite variants unseen in controls. These findings implicate the CHRNA in susceptibility to myasthenia gravis.

A study examined the role of the gene encoding the alpha subunit of the muscle acetylcholine receptor (CHRNA). The results show a significant contribution of one of its allelic forms to myasthenia gravis susceptibility.