Respiratory bronchiolitis associated interstitial lung disease (RB-ILD) presenting with haemoptysis.

Respiratory bronchiolitis associated interstitial lung disease is an uncommon condition in current or ex-smokers. The presentation is non-specific, but haemoptysis is uncommonly reported in this condition. We report the case of a 25-year-old woman who presented with significant haemoptysis, dyspnoea, reduced transfer factor and normal clinical examination. In addition, a Medline literature search was performed to review the clinical features and prognosis of this disease. Other causes of haemoptysis were excluded with extensive investigation. The diagnosis was made on thoracoscopic lung biopsy. The patient had significant postoperative complications of prolonged air leak and hydropneumothorax requiring further surgery and prolonged hospital stay. Advice regarding smoking cessation was given. Her pulmonary physiology remains abnormal on follow up but symptoms have improved. Respiratory bronchiolitis-ILD may present with normal examination and radiology. Haemoptysis in this case may have been associated with the underlying disease but could have been incidental. Diagnosis, in general, requires lung biopsy. As in this patient, lung function does not appear to improve significantly on follow up.

Diaphragm inhibition with positive pressure ventilation: quantification of mechanical effects.

To quantify any mechanical inhibitory effect of nasal intermittent positive pressure ventilation (IPPV) on inspiratory activity of the diaphragm we ventilated five conscious relaxed subjects on two occasions at respiratory rates similar to quiet breathing (QB) and at three levels of applied pressure (Pappl)--6, 9 and 12 cmH2O, each during hypocapnia (P(CO2) allowed to decrease) and eucapnia (CO2 added to inspired gas). Diaphragm activity was assessed from transdiaphragmatic pressure (esophageal and gastric balloons) and diaphragm EMG (surface electrodes) both integrated with time (integral(Pdi x dt) and integral(EMGdi x dt), respectively). Neural inspiratory time (Tin) was measured as onset to peak of the integral(EMGdi x dt) signal. Relative to QB, integral(Pdi x dt) was 50-69% less during eucapnic IPPV 6-12 cmH2O (P < 0.005) and 67-85% less during hypocapnic IPPV (P < 0.005). Tin decreased (P < 0.05) with IPPV and, on ceasing IPPV, there was apnoea (prolonged expiratory time) on 23 of 27 occasions; these changes were independent of P(CO2). Integral(EMGdi x dt) decreased (P < 0.05) at Pappl 12 cmH2O during eucapnia and at all Pappl during hypocapnia. The repeatability of integral(EMGdi x dt) was substantially less than integral(Pdi x dt) (F = 42, P << 0.01). We conclude that, during non-invasive IPPV in awake healthy subjects mechanical factors are of major importance in inhibiting inspiratory activity of the diaphragm.

Cooperative signaling by tumor necrosis factor receptors CD120a (p55) and CD120b (p75) in the expression of nitric oxide and inducible nitric oxide synthase by mouse macrophages.

Tumor necrosis factor-alpha (TNFalpha) is recognized by the cell-surface receptors CD120a (p55) and CD120b (p75). In the present study, we have investigated the role of these receptors in the expression of NO2-, a stable metabolite of nitric oxide, and inducible nitric oxide synthase (iNOS) by mouse macrophages. Specific antibody-mediated aggregation of CD120a (p55) induced NO2- accumulation in culture supernatants and iNOS mRNA expression in macrophage lysates, whereas cross-linking of CD120b (p75) had a minimal effect. In contrast, simultaneous cross-linking of both receptors led to a marked augmentation in NO2- and iNOS mRNA expression. Antibody-mediated blockade of CD120a (p55) completely inhibited NO2- expression in response to TNFalpha, whereas blockade of CD120b (p75) reduced NO2- accumulation by approximately 50%. Specific ligation of CD120a (p55) with either (i) human TNFalpha or (ii) by incubation with mouse TNFalpha following pretreatment of macrophages with blocking concentrations of anti-CD120b (p75) antibody resulted in a similar reduction in NO2- production in response to TNFalpha. Quantification of iNOS mRNA, protein, and NO2- expression during independent and co-ligation of CD120a (p55) and CD120b (p75) indicated that iNOS mRNA and protein expression was transient in nature when CD120a (p55) was cross-linked alone but was prolonged when both receptors were simultaneously cross-linked. In addition, cross-linking both receptors also led to a potentiation of NO2- accumulation in culture supernatants that was more pronounced at later time points. These findings suggest that while cross-linking of CD120a (p55) is necessary and sufficient for iNOS mRNA and NO2- expression, CD120b (p75) participates by (i) increasing the sensitivity of the cells to TNFalpha, probably by "passing" ligand to CD120a (p55), and (ii) initiating a signaling event that results in a more sustained induction of iNOS mRNA and protein and thereby augments the production of nitric oxide.

Interstitial lung disease in recent onset rheumatoid arthritis.

Interstitial lung disease (ILD) is associated with rheumatoid arthritis (RA); however, the prevalence and natural history are undefined. Our aim was to determine the prevalence of ILD associated with RA using a number of sensitive techniques in patients with joint disease of less than 2-yr duration. Patients who met ARA criteria for RA were recruited from community-based and hospital rheumatologists and assessed using the following measures: clinical, lung physiology, radiology (chest X-ray, high resolution CT [HRCT]), bronchoalveolar lavage (BAL) and 99mTc-DTPA nuclear scan. Thirty-six patients (25 female and 11 male) of joint disease duration of (mean +/- SD) 13.2 +/- 8.6 mo were studied. Abnormalities consistent with ILD were found in one or more investigations in 21 of 36 (58%), which were in lung physiology in 22%, CXR in 6%, HRCT in 33%, BAL in 52%, and 99mTc-DTPA nuclear scan in 15%. Based on the results, they were categorized as having clinically significant ILD (Group 1), abnormalities compatible with ILD, but no clinically significant ILD (Group 2) and no abnormalities compatible with ILD (Group 3). Five of 36 (14%) were in Group 1, 16 of 36 (44%) in Group 2, and 15 of 36 (42%) in Group 3. The only risk factor for the presence of abnormalities compatible with ILD was male gender (p < 0.04, Student's t test). In conclusion, changes consistent with ILD in early RA are frequent. The significance of these changes is being determined in a longitudinal study.

Cryptogenic fibrosing alveolitis: have we made any progress?

The interstitial lung diseases (ILD) are a heterogeneous group of disorders the most common of which is cryptogenic fibrosing alveolitis (CFA). This article has summarized recent work in particular on the diagnosis, pathogenesis and treatment of CFA, by reviewing published data accessed through Medline searching. Recent reports suggest a higher prevalence of CFA than previously documented (13.2-20.2/100,000 population) and a rising mortality rate. The prognosis is universally poor with 50% of patients dying within 5 years. Although approximately 30% of patients may live for long periods (> 10 years), morbidity is significant and quality of life in the long-term survivors is poor. Diagnosis is traditionally based on an open lung biopsy, however, more recently the high resolution computer tomography (HRCT) is often used; however, its use without a tissue diagnosis remains controversial. In conclusion, we know substantially more about the pathogenesis of the disease and from this work have a number of possibilities for new therapeutic strategies that will hopefully reach the bedside in the near future. Additionally we have some new non-invasive tests that offer hope for stratifying patients but require further evaluation. For assessing both therapy and investigations we will need substantial groups of patients in multicentre studies to provide sufficient power to allow a conclusion to be reached. To ensure any further progress we must collaborate and enter our patients into such trials.

Divergence in macrophage insulin-like growth factor-I (IGF-I) synthesis induced by TNF-alpha and prostaglandin E2.

Increased synthesis of insulin-like growth factor I (IGF-I), a fibroblast growth factor, is induced in murine macrophages by TNF-alpha. TNF-alpha also induces macrophages to express cytocidal activity, but only during costimulation with IFNs. Since prostaglandin E2 (PGE2) is known to inhibit macrophage cytocidal activity, its possible reciprocal enhancement of IGF-I synthesis was examined. PGE2 or dibutyryl cyclic AMP (dbcAMP) stimulated the synthesis of IGF-I similarly to TNF-alpha in magnitude and time course. TNF-alpha did not increase IGF-I synthesis by first inducing PGE2 synthesis, because indomethacin was unable to block the effect of TNF-alpha. PGE2 did not stimulate IGF-I synthesis by first inducing TNF-alpha production, because 1) anti-TNF-alpha Ab did not block PGE2-induced IGF-I synthesis, and 2) PGE2 down-regulated TNF-alpha mRNA levels and did not affect levels of the cytokine in supernatants. Moreover, the difference in the induction of IGF-I was observed at the level of signal transduction, in that PGE2 and dbcAMP increased cAMP-dependent protein kinase (PKA) activity, whereas TNF-alpha stimulated the mitogen-activated protein (MAP) kinase pathway. Divergence between the two pathways was also noted in the regulation of IGF-I at the mRNA level, and an additive effect on IGF-I synthesis was observed when cells were incubated with the combination of TNF-alpha plus PGE2 or dbcAMP. Collectively, these data suggest that TNF-alpha and PGE2 stimulate IGF-I synthesis in macrophages by two separate pathways, and that PGE2 acts as a positive stimulus for IGF-I synthesis through a cyclic AMP/PKA pathway.

Functional switching of macrophage responses to tumor necrosis factor-alpha (TNF alpha) by interferons. Implications for the pleiotropic activities of TNF alpha.

Recent work conducted in our laboratory has been directed towards understanding the role of TNF alpha in stimulating the synthesis of two macrophage gene products, namely IGF-1, a growth factor implicated in wound repair and fibrosis, and complement component factor B (Bf), an alternative pathway complement component. The expression of these proteins is induced by hyaluronic acid and poly (I:C), respectively, although TNF alpha plays a requisite role in the expression of both proteins. The objective of this study was to determine the mechanism governing the dichotomy in the expression of IGF-1 and Bf by TNF alpha. First, we questioned if the diversity in IGF-1 and Bf synthesis was regulated at the level of TNF receptor usage. Second, based on earlier findings that IFNs contribute to the initiation of Bf expression, we determined if IFNs modulate the response of macrophages to TNF alpha. Our data show that differences in TNF receptor usage cannot fully explain the dichotomy in the expression of IGF-1 and Bf. However, prior exposure to IFN-beta or IFN-gamma was found to be a dominant factor controlling the expression of these proteins, suppressing IGF-1, and enhancing Bf. These findings indicate that IFNs mediate a functional "switch" in the response of macrophages to TNF alpha and suggest that the pattern of cytokine expression by diverse macrophage stimuli is an important determinant of the eventual responses of macrophages to TNF alpha.

Involvement of protein kinase C in macrophage activation by poly(I.C).

The expression of cytocidal activity is initiated by the interaction of macrophages with priming [e.g., interferon (IFN)] and triggering stimuli (polyinosinic-polycytidylic acid). We have shown that the triggering step can be initiated in a Ca(2+)-dependent fashion and hypothesized that protein kinase C (PKC) may couple the Ca2+ signal to the expression of a gene product, Bf, that accompanies the expression of macrophage cytocidal activity. Exposure of IFN-primed macrophages to polyinosinic-polycytidylic acid in the presence of the PKC inhibitors H-7 or sphingosine or after downregulation of PKC with phorbol myristate acetate markedly inhibited Bf synthesis. Western blots of macrophage lysates revealed the presence of the alpha-, delta-, and zeta-isozymes of PKC, and all were found to be downregulated by phorbol myristate acetate. Inhibition of PKC also prevented the increase in IFN-beta mRNA levels and partially blocked the response to IFN-beta. These data suggest that the alpha-, delta-, and zeta-isozymes of PKC are involved in signaling leading to Bf expression and that the level of involvement is restricted to the induction and response to IFN-beta.

Hyaluronate activation of CD44 induces insulin-like growth factor-1 expression by a tumor necrosis factor-alpha-dependent mechanism in murine macrophages.

Macrophages participate in inflammatory and repair processes in part through the selective release of cytokines that contribute to tissue remodeling. Extracellular matrix components generated at inflammatory sites may influence tissue remodeling by effects on leukocyte adherence and local cytokine production. In murine bone marrow-derived macrophages, we found that soluble hyaluronic acid stimulated IL-1 beta, TNF alpha, and insulin-like growth factor-1 (IGF-1) mRNA transcript expression as well as IGF-1 protein synthesis. Monoclonal antibodies to the hyaluronic acid receptor CD44 blocked the effects of hyaluronic acid on IL-1 beta, TNF alpha, and IGF-1 expression. TNF alpha and IL-1 beta mRNA expression preceded IGF-1 protein synthesis, and TNF alpha, but not IL-1 beta, was found to directly stimulate IGF-1. Furthermore, IGF-1 induction was dependent on endogenous TNF alpha production since IGF-1 protein synthesis was inhibited in the presence of anti-TNF alpha antiserum. In addition, IL-1 beta was found to exert a regulatory role on IGF-1 production by enhancing the TNF alpha effect. IL-1 beta and TNF alpha mRNA transcript expression as well as IGF-1 protein synthesis were also stimulated by chrysotile asbestos. Anti-CD44 antibodies had no effect whereas anti-TNF alpha antiserum blocked asbestos-stimulated IGF-1 production. These results indicate that hyaluronate activation of CD44 induces cytokine expression and macrophage-derived IGF-1 production is dependent on TNF alpha expression.

Allergic bronchopulmonary fungal disease caused by Bipolaris and Curvularia.

Allergic bronchopulmonary fungal disease (ABPFD) usually manifests in asthmatics as allergic bronchopulmonary aspergillosis. In a few instances other fungi have been implicated. Serological testing in Western Australia between 1979 and 1986 revealed precipitins to Bipolaris and Curvularia species in 40 of 503 patients tested. Eight of these were patients with ABPFD due to Bipolaris and/or Curvularia and are reported here. Geographical location appeared to be significant as seven of eight of those with ABPFD (and at least 18 of 40 with positive serology) were living in the more remote and sub-tropical northern part of the state. ABPFD due to fungi other than Aspergillus species may be more common than previously recognised and further epidemiological assessment is warranted.

Prevention of embolic complications in nonvalvular atrial fibrillation in the elderly.

Atrial fibrillation is common in elderly subjects, usually with coexistent underlying heart disease. Nonvalvular atrial fibrillation is associated with increased morbidity and mortality, especially due to embolic complications: it carries a 5.6-fold increased risk of stroke, compared with age-matched controls. Three recent trials have demonstrated that prophylactic anticoagulation (either 'full' or 'partial') decreases the rate of stroke significantly, with an acceptably low rate of complications. The benefits of aspirin prophylaxis are less clear, and currently there is no evidence for a beneficial effect in the elderly patient. At present, no factor apart from a previous symptomatic embolism predicts those who are at risk of embolism. The risk of stroke appears to continue for a long time and, until data are provided, therapy should be continued indefinitely in the absence of contraindications. All patients with nonvalvular atrial fibrillation should be considered for prophylactic anticoagulants. Further work is required to identify those at highest risk, and to clarify how long therapy should be continued and whether there are subgroups in whom full or partial anticoagulation would be preferable.

House dust mite-derived amylase: allergenicity and physicochemical characterization.

Amylase activity was found in extracts of both Dermatophagoides pteronyssinus whole mite (0.16 U/mg) and spent growth medium (0.01 U/mg) but not in unused growth medium. It was also detected in all extracts of house dust obtained from mattresses (n = 20; geometric mean, 1.95 U/gm) and in 18 extracts of dust obtained from lounge room carpets (n = 20; geometric mean, 0.54 U/gm). Although the origins of amylase in dust are unclear, enzyme activity correlated with mite counts (n = 40; r = 0.35; p less than 0.05) and Der p I concentrations (r = 0.41; p less than 0.01). Mite amylase was purified from spent growth medium by affinity chromatography, gel filtration, and chromatofocusing. It was physicochemically similar to mammalian amylase with regard to molecular weight (60,000), charge heterogeneity (isoelectric point, 5 to 7) and the capacity to bind to an organomercurial affinity matrix. The optimum pH for enzymatic activity was revealed to be 6.4. IgE immunoblot studies demonstrated that the enzyme was allergenic and that its expression was dependent on the integrity of intrachain disulfide bonds. Sera from 25% of mite-allergic children and 46% of mite-allergic adults contained specific IgE to mite amylase. IgE to amylase was associated (p less than 0.01) with increased concentrations of total mite-specific IgE determined with a direct RAST assay.

Allergenicity and physicochemical characterization of house dust mite derived amylase.

The enzyme amylase was shown to be present in extracts prepared from both house dust and spent growth medium used in the culture of the mite Dermatophagoides pteronyssinus. In dust, it was shown to correlate with both mite counts and concentrations of the faecally derived mite allergen, Der p I. Mite amylase was isolated from the culture medium and shown to be a single chain protein with a molecular weight of 56,000. The enzyme contained free sulphydryl groups and had the N-terminal sequence, KYXNPHFIGXRSVITXLME. It was found to be an allergen using sera from adults (46% positive) and children (25%) who were mite allergic. The expression of allergenicity was dependent on the integrity of intra-chain disulphide bonds.

Faecally derived hydrolytic enzymes from Dermatophagoides pteronyssinus: physicochemical characterisation of potential allergens.

The previous findings that the group I and III mite allergens, and amylase present in mite faeces are hydrolytic enzymes has prompted a study to determine whether this material contains other enzymes which could be allergenic. Thus, spent growth medium devoid of whole Dermatophagoides pteronyssinus mites was shown to contain glucoamylase, lipase and lysozyme in addition to the cysteine protease, serine protease and amylase activities associated with the above allergens, respectively. All of these enzymes are probably associated with mite digestive processes. They were rapidly solubilised, heterogeneous with regard to charge (pI in the range 4-8) and demonstrated maximum biochemical activity in the neutral pH range. Three serine proteases were detected and comprised a chymotrypsin-like, a trypsin-like and an unclassified enzyme with pI of 4.1 and 5.3, 8.5 and 7.1, respectively. Only one cysteine protease was observed, which paralleled immunochemically identified Der p I in a variety of assays. It was shown to cleave at lysyl residues and could be inhibited by the specific cysteine protease inhibitor, E-64. The remaining serine proteases, glucoamylase, lipase and lysozyme represent potential allergens.

Mixed allergic bronchopulmonary fungal disease due to Pseudallescheria boydii and Aspergillus.

A 24 year old asthmatic woman with mixed allergic bronchopulmonary fungal disease due to Pseudallescheria boydii and Aspergillus is reported. No previous cases due to P boydii have been described. This patient provides evidence that fungi other than Aspergillus species may cause the condition.

Upper-limb and lower-limb exercise training in patients with chronic airflow obstruction.

We designed a randomized controlled study to evaluate the benefit of upper-limb exercise training, alone and in combination with walking training, in patients with severe CAO. In an outpatient department supervised by a physiotherapist, we evaluated 28 patients with severe stable CAO (FEV1, 32 percent of predicted). Patients were randomly allocated to either a control (eight), upper-limb (six), lower-limb (seven), or combined (seven) exercise group. The upper-limb group trained with a circuit of upper-limb exercises, the lower-limb group by walking, and the combined group with both. Exercise was for one hour three times per week for eight weeks. Assessment before and after training included pulmonary function, mouth pressures, respiratory muscle endurance, maximal bicycle exercise test, maximal and submaximal arm ergometer, six-minute walking distance, and a scale of well-being (Bandura scale). Twenty-six patients completed the program. There was a significant improvement (Wilcoxon rank sum test) in the following: six-minute walking distance in the lower-limb (p less than 0.005) and combined (p less than 0.003) groups; arm ergometer in the upper-limb (p less than 0.005) and combined (p less than 0.04) groups; and the scale of well-being in the combined (p less than 0.005) group. There was no significant change in any other parameter measured. We conclude that exercise training improves exercise performance in severe CAO, that the training is specific for the muscle group trained, and that upper-limb exercises should be included in training programs for these patients.

Atrial fibrillation and mortality in an elderly population.

Prospective data from Busselton, Western Australia, collected during triennial surveys from 1966-81 with follow-up of subjects to 1983, showed that atrial fibrillation (AF) was frequent in elderly people and associated with increased mortality. Of 1770 people aged over 60 years, 40 were in atrial fibrillation when first seen and a further 47 developed it during follow-up. Atrial fibrillation was positively associated with angina, history of a myocardial infarction and left bundle branch block. Relative mortality in those with atrial fibrillation compared with those without it, was 1.92 for all causes, 1.82 for death from cardiovascular causes (excluding stroke) and 3.78 for deaths from stroke, after adjustment by proportional hazards regression for confounding effects of age, sex, history of a myocardial infarction, an abnormal electrocardiogram, angina, cholesterol level systolic blood pressure and Quetelet's Index (weight/height2). The excess relative mortality declined with increasing age for both women and men. This raised relative mortality remained constant with time from the first detection of AF for all causes and cardiovascular causes but appeared to increase with time from detection for stroke death. The risk of death from stroke was greatest in the younger women. The observed risk of death from stroke in patients with AF suggests that anticoagulant use should be considered in selected patients.

Pulmonary mucormycosis without underlying systemic disease.

Mucormycosis (or zygomycosis) is an opportunistic fungal infection which usually is seen in patients who are immunosuppressed or who have diabetes. It is uncommon in healthy persons and also is uncommon in Australia. We report a case of a 45-year-old, otherwise-healthy man with an indolent lung infection that was caused by Absidia corymbifera, who was cured by a combination of surgical and medical therapy.