Two cases of culture proven Mycobacterium tuberculosis presenting with a broad-complex tachycardia and non-caseating granulomas.

Tuberculosis is a leading cause of death worldwide. It affects pulmonary and extra-pulmonary sites with a multitude of differing presentations. In this report, we describe two cases in which TB causes myopericarditis and presents with a broad-complex tachycardia that did not respond typically to standard anti-arrhythmic therapy; a very rare presentation with limited description in the literature. Both patients required extensive investigation culminating in identifying lymph nodes amenable to biopsy under endobronchial ultrasound guidance. It was not until both patients received anti-tuberculous chemotherapy alongside anti-arrhythmic management that any improvement to their condition was witnessed. Therefore, we recommend that the clinician should have a high index of suspicion for TB in any patient presenting with a broad-complex tachycardia that is not responding to standard first line management, especially if the patient is from a high risk background. We recommend an active diagnostic pursuit, and lymph node biopsy under endobronchial ultrasound guidance.

Is air travel safe for those with lung disease?

Airlines commonly report respiratory in-flight emergencies; flight outcomes have not been examined prospectively in large numbers of respiratory patients. The current authors conducted a prospective, observational study of flight outcomes in this group. UK respiratory specialists were invited to recruit patients planning air travel. Centres undertook their usual pre-flight assessment. Within 2 weeks of returning, patients completed a questionnaire documenting symptoms, in-flight oxygen use and unscheduled healthcare use. In total, 616 patients were recruited. Of these, 500 (81%) returned questionnaires. The most common diagnoses were airway (54%) and diffuse parenchymal lung disease (23%). In total, 12 patients died, seven before flying and five within 1 month. Pre-flight assessment included oximetry (96%), spirometry (95%), hypoxic challenge (45%) and walk test (10%). Of the patients, 11% did not fly. In those who flew, unscheduled respiratory healthcare use increased from 9% in the 4 weeks prior to travel to 19% in the 4 weeks after travel. However, when compared with self-reported data during the preceding year, medical consultations increased by just 2%. In patients flying after careful respiratory specialist assessment, commercial air travel appears generally safe.

Localisation of transforming growth factor beta1 and beta3 mRNA transcripts in normal and fibrotic human lung.

BACKGROUND: Transforming growth factor beta1 is implicated in the pathogenesis of lung fibrosis. It promotes extracellular matrix accumulation by increasing procollagen synthesis and reducing degradation. TGFbeta1 gene and protein expression increase in experimental lung fibrosis, and TGFbeta1 antibodies attenuate fibrosis in mice. The role of other TGFbeta isoforms is unclear. This study aimed to localise TGFbeta1 and TGFbeta3 gene expression in fibrotic human lung and compare it with that in normal human lung. METHODS: Lung tissue from patients with cryptogenic fibrosing alveolitis and fibrosis associated with systemic sclerosis was examined by in situ hybridisation. Macroscopically normal lung from carcinoma resections was used as control tissue. Digoxigenin labelled riboprobes were synthesised from TGFbeta isoform specific cDNA templates. RESULTS: The digoxigenin labelled riboprobes were sensitive and permitted precise cellular localisation of mRNA transcripts. TGFbeta1 and TGFbeta3 mRNA transcripts were widespread in normal lung and localised to alveolar macrophages and bronchiolar epithelium. TGFbeta1 but not TGFbeta3 mRNA was detected in mesenchymal and endothelial cells. In fibrotic lung tissue mRNA transcripts for both isoforms were also detected in metaplastic type II cells. TGFbeta1 gene expression was enhanced in some patients. TGFbeta3 was expressed in fibrotic lung but was not consistently altered compared with controls. CONCLUSION: TGFbeta1 mRNA transcripts were localised in normal and fibrotic human lung and TGFbeta3 gene expression in human lung fibrosis was shown for the first time. The results suggest that TGFbeta1 may play the predominant role in pathogenesis. It is suggested that TGFbeta1 should be the primary target of anticytokine treatments for pulmonary fibrosis.

Assessing the risk of hypoxia in flight: the need for more rational guidelines.

This study aimed to test the hypothesis that advice currently given by respiratory physicians to potentially hypoxic patients planning air travel varies and is not evidence-based. A prospective observational study was performed, surveying respiratory physicians in England and Wales. Sixty-two per cent responded. Nearly two-thirds worked in district general hospitals, a quarter in university hospitals, and the rest in tertiary referral (specialist) centres or a combination thereof. Most provide advice routinely; most of the remainder do on request or if concerned. Assessments comprise spirometry, blood gas level measurement, oximetry, predictive equations and hypoxic challenge tests. Twenty-five per cent of physicians measuring blood gas levels recommend in-flight oxygen when arterial oxygen tension (Pa,O2) <7.3 kPa, 50% when Pa,O2 is 7.3-8.0 kPa. Over two-thirds using spirometry recommend oxygen when the forced expiratory volume in one second <40% of the predicted value. Half recommend oxygen when arterial oxygen saturation (Sa,O2) <90%, 33% when Sa,O2 is 90-94%. Fewer than 10% of district hospital physicians (and none in other hospitals) use predictive equations. More than half of specialists but fewer than 10% of district hospital physicians perform hypoxic challenge tests. The risk of hypoxia at altitude is recognized by most respiratory physicians in England and Wales, but assessment methods and criteria for recommending oxygen vary widely. This suggests that most current advice is not evidence-based. Evidence-based guidelines are required.

Pulmonary fibrosis: cytokines in the balance.

Pulmonary fibrosis can complicate diverse pulmonary and systemic pathologies. In many cases the underlying cause remains unidentified. Mortality from the disease is increasing steadily in the UK and USA. The clinical features are well-described, but patients frequently present at an advanced stage, and current treatments have not improved the poor prognosis. There is a compelling need to identify the fibrotic process earlier and to develop new therapeutic agents. Increased collagen deposition is central to the pathology and interest over the last decade has focused on the role of cytokines in this process. These polypeptide mediators are believed to be released from both circulating inflammatory and resident lung cells in response to endothelial and epithelial injury. Key cytokines currently implicated in the fibrotic process are transforming growth factor-beta, tumour necrosis factor-alpha and endothelin-1. This article outlines the evidence implicating these mediators in the pathogenesis of pulmonary fibrosis and also considers the possible role of cytokines with antifibrotic effects, such as interferon-gamma. The "balance" of positively and negatively regulating cytokines is discussed, and the potential for interaction with other factors including viruses, hormones and altered antioxidant status is also considered. Finally, potential novel therapeutic approaches are discussed, together with suggestions for future studies and clinical trials. As the outcomes of different avenues of research over the last ten years are brought together, it is clear that there is now a hitherto unrivalled opportunity to begin to tackle the treatment of this devastating disease.

A novel transforming growth factor beta2 antisense transcript in mammalian lung.

Transforming growth factor (TGF) beta2 gene expression was examined in murine, rat and human lung by in situ hybridization with riboprobes. Hybridization signal was observed in a variety of cells with the sense probe, and Northern-blot analysis with this probe demonstrated the presence of a novel 3.5 kb transcript. This first report suggesting the existance of a natural TGFbeta2 antisense transcript raises the possibility that such a transcript may play a role in regulating TGFbeta2 production.

Transforming growth factors-beta 1, -beta 2, and -beta 3 stimulate fibroblast procollagen production in vitro but are differentially expressed during bleomycin-induced lung fibrosis.

Transforming growth factor (TGF)-beta 1 may potentiate wound healing and fibrosis by stimulating fibroblast collagen deposition. TGF-beta 1 is implicated in the pathogenesis of pulmonary fibrosis, but the role of TGF-beta 2 and TGF-beta 3 remains unclear. We examined their effects on lung fibroblast procollagen metabolism in vitro and localized their gene expression during bleomycin-induced lung fibrosis using in situ hybridization with digoxigenin-labeled riboprobes. All three isoforms stimulated fibroblast procollagen production. TGF-beta 3 was the most potent and also reduced procollagen degradation. In normal mouse lung, TGF-beta 1 and TGF-beta 3 mRNA transcripts were abundant in bronchiolar epithelium. After bleomycin, TGF-beta 1 gene expression was maximally enhanced at 10 days, with the signal being predominant in macrophages. Signal was also enhanced in mesenchymal, pulmonary endothelial, and mesothelial cells. After 35 days, the pattern of TGF-beta 1 gene expression returned to that of control lung. TGF-beta 3 gene expression remained unchanged throughout compared with controls. TGF-beta 2 mRNA was not detected with the antisense probe, but signal obtained with the sense probe suggests the presence of a naturally occurring antisense. This study demonstrates that TGF-beta 1, -beta 2, and -beta 3 all exert profibrotic effects in vitro. However, TGF-beta isoform gene expression is differentially controlled during experimental pulmonary fibrosis with TGF-beta 1 the predominant isoform expressed during pathogenesis.

Anticytokine approaches in pulmonary fibrosis: bringing factors into focus.

The prognosis of pulmonary fibrosis is poor and current therapies inadequate. Recent progress in understanding the mechanisms underlying the pathogenesis of this disease leads us to expect that inhibitors of cytokine and polypeptide growth factor will provide novel therapeutic agents. This paper outlines the role of cytokines in the pathogenesis of pulmonary fibrosis and concludes that there are compelling reasons to explore anticytokine therapeutic approaches. It also proposes criteria that will enable us to evaluate such agents in vivo and suggests approaches which might overcome the obstacles presented by control mechanisms which recruit a multiplicity of factors.

Indomethacin suppresses the anti-proliferative effects of transforming growth factor-beta isoforms on fibroblast cell cultures.

The transforming growth factor-beta (TGFbeta) family of mediators consists of five closely related isoforms, of which three are present in mammals. TGFbeta1 has been shown to exert a biphasic effect on the proliferation of several cell types, including fibroblasts, with stimulation at low concentrations and inhibition at higher concentrations. The stimulatory effects are well characterized, but the mechanisms by which TGFbeta1 inhibits cell proliferation are incompletely understood. In the present study we have compared the effects of all three mammalian TGFbeta isoforms on human lung fibroblast proliferation, and have elucidated the role of the TGFbeta-induced synthesis of prostaglandin E2 (PGE2) in mediating their actions. All three isoforms stimulated fibroblast proliferation with maximal effects at 5 pg/ml (0.2 pM) and an order of potency of TGFbeta3 > TGFbeta2 > TGFbeta1. At higher concentrations, proliferation declined, and at 40 pg/ml and above all isoforms inhibited fibroblast proliferation. Again TGFbeta3 was the most potent, but there were no significant differences between the inhibitory effects of TGFbeta1 and TGFbeta2. Addition of indomethacin, an inhibitor of PGE2 synthesis, did not alter the proliferative activity of any of the TGFbeta isoforms, but completely overcame their inhibitory effects, restoring the stimulatory actions observed at lower TGFbeta concentrations. All TGFbeta isoforms stimulated PGE2 synthesis; TGFbeta3 was approximately twice as potent as TGFbeta1 and TGFbeta2, each of which had similar effects. These data suggest that the inhibition of fibroblast proliferation at higher concentrations of TGFbeta isoforms may be mediated by autocrine stimulation of PGE2 synthesis.

Diverse cellular TGF-beta 1 and TGF-beta 3 gene expression in normal human and murine lung.

A role for transforming growth factor-beta 1, (TGF-beta 1) has been proposed in lung development and in the pathogenesis of pulmonary disease. However, previous studies have not delineated the cells expressing TGF-beta 1 in normal adult lung, nor compared its gene expression with that of other TGF-beta isoforms. We used digoxigenin-labelled riboprobes to localize TGF-beta 1 and TGF-beta 3 gene expression in normal adult human and mouse lung. This procedure was technically simple, providing excellent resolution. TGF-beta 1 and TGF-beta 3 messenger ribonucleic acid (mRNA) transcripts were detected in a wide variety of cells. In human lung, mRNA for both isoforms was localized to bronchiolar epithelium and alveolar macrophages. TGF-beta 1, but not TGF-beta 3 mRNA was detected in mesenchymal and endothelial cells. In murine tissue, TGF-beta 1, mRNA was localized to bronchiolar epithelium, Clara cells, mesenchymal cells, pulmonary endothelium and alveolar cells, including macrophages. TGF-beta 3 mRNA was similarly distributed but not detected in endothelium. In summary, using a nonisotopic technique in lung tissue, we have detailed the cells expressing the transforming growth factor-beta 1 and beta 3 genes in human and murine lung. There was widespread expression of these cytokines in normal lung consistent with autocrine or paracrine roles in regulating cellular turnover, immune defence and matrix protein metabolism.