'Care and Prevent': rationale for investigating skin and soft tissue infections and AA amyloidosis among people who inject drugs in London.

BACKGROUND: Skin and soft tissue infections (SSTIs) are a leading cause of morbidity and mortality among people who inject drugs (PWID). International data indicate up to one third of PWID have experienced an SSTI within the past month. Complications include sepsis, endocarditis and amyloid A (AA) amyloidosis. AA amyloidosis is a serious sequela of chronic SSTI among PWID. Though there is a paucity of literature reporting on AA amyloidosis among PWID, what has been published suggests there is likely a causal relationship between AA amyloidosis and injecting-related SSTI. If left untreated, AA amyloidosis can lead to renal failure; premature mortality among diagnosed PWID is high. Early intervention may reverse disease. Despite the high societal and individual burden of SSTI among PWID, empirical evidence on the barriers and facilitators to injecting-related SSTI prevention and care or the feasibility and acceptability of AA amyloidosis screening and treatment referral are limited. This study aims to fill these gaps and assess the prevalence of AA amyloidosis among PWID. METHODS: Care and Prevent is a UK National Institute for Health Research-funded mixed-methods study. In five phases (P1-P5), we aim to assess the evidence for AA amyloidosis among PWID (P1); assess the feasibility of AA amyloidosis screening, diagnostic and treatment referral among PWID in London (P2); investigate the barriers and facilitators to AA amyloidosis care (P3); explore SSTI protection and risk (P4); and co-create harm reduction resources with the affected community (P5). This paper describes the conceptual framework, methodological design and proposed analysis for the mixed-methods multi-phase study. RESULTS: We are implementing the Care and Prevent protocol in London. The systematic review component of the study has been completed and published. Care and Prevent will generate an estimate of AA amyloidosis prevalence among community recruited PWID in London, with implications for the development of screening recommendations and intervention implementation. We aim to recruit 400 PWID from drug treatment services in London, UK. CONCLUSIONS: Care and Prevent is the first study to assess screening feasibility and the prevalence of positive proteinuria, as a marker for AA amyloidosis, among PWID accessing drug treatment services. AA amyloidosis is a serious, yet under-recognised condition for which early intervention is available but not employed.

Endovascular treatment for acute ischaemic stroke with large vessel occlusion: the experience of a regional stroke service.

AIM: To report the experience of a regional stroke referral service with endovascular treatment for patients with acute ischaemic stroke (AIS) and large vessel occlusion. MATERIALS AND METHODS: A prospective review was undertaken of 93 consecutive cases receiving endovascular treatment for AIS over a 42-month period (January 2010 to June 2013). The National Institutes of Health Stroke Scale (NIHSS), location of large vessel occlusion, details of endovascular procedure, and degree of reperfusion achieved (Thrombolysis In Cerebral Infarction [TICI] score) were recorded. Mortality and functional outcome (modified Rankin Scale [mRS]) were measured at 90 days. RESULTS: The mean patient age was 62 years (range 26-87 years). The mean NIHSS at presentation was 16 (range 6-29). All patients had confirmed proximal large-artery occlusion on computed tomography (CT) angiography: 87 in the anterior circulation, six in the posterior circulation. Of the 93 patients treated, 64 (69%) received intravenous thrombolysis. Successful reperfusion (TICI grade 2a to 3) was achieved in 80 (86%) cases. There were 13 (14%) cases of failed vessel recanalisation (TICI grade 0). Good functional outcome (mRS ≤2) was achieved in 51 (55%) cases. The 90-day mortality was 20 (22%) cases. Fifty-seven (61%) cases were transferred from outside centres. There was no significant increase in morbidity or mortality for transferred patients. CONCLUSION: Successful endovascular recanalisation can result in good functional outcomes for patients with AIS and large vessel occlusion. Our interventional neuroradiology service provides endovascular treatment as part of a regional stroke service without increase in morbidity or mortality for patients transferred from outside institutions.

Barcoding Atlantic Canada's commonly encountered marine fishes.

Marine fishes from the northwest Atlantic Ocean were analysed to determine whether barcoding was effective at identifying species. Our data included 177 species, 136 genera, 81 families and 28 orders. Overall, 88% of nominal species formed monophyletic clusters based on >500 bp of the CO1 region, and the average bootstrap value for these species was 98%. Although clearly effective, the percentage of species that were distinguishable with barcoding based on the criterion of reciprocal monophyletic clusters was slightly lower than has been documented in other studies of marine fishes. Eelpouts, sculpins and rocklings proved to be among the most challenging groups for barcoding, although we suspect that difficult identifications based on traditional (morphology based) taxonomy played a role. Within several taxa, speciation may have occurred too recently for barcoding to be effective (e.g. within Sebastes, Thunnus and Ammodytes) or the designation of distinct species may have been erroneous (e.g. within Antimora and Macrourus). Results were consistent with previous work recognizing particularly high levels of divergence within certain taxa, some of which have been recognized as distinct species (e.g. Osmerus mordax and Osmerus dentex; and Liparis gibbus and Liparis bathyarcticus), and some of which have not (e.g. within Halargyreus johnsonii and within Mallotus villosus). The results from this study suggest that morphology-based identification and taxonomy can be challenging in marine fishes, even within a region as well characterized as Atlantic Canada. Barcoding proved to be a very useful tool for species identification that will likely find a wide range of applications, including the fisheries trade, studies of range expansion, ecological analyses and population assessments.

Co-morbid anxiety disorders in bipolar disorder and major depression: familial aggregation and clinical characteristics of co-morbid panic disorder, social phobia, specific phobia and obsessive-compulsive disorder.

BACKGROUND: Co-morbidity of mood and anxiety disorders is common and often associated with greater illness severity. This study investigates clinical correlates and familiality of four anxiety disorders in a large sample of bipolar disorder (BP) and major depressive disorder (MDD) pedigrees. METHOD: The sample comprised 566 BP families with 1416 affected subjects and 675 MDD families with 1726 affected subjects. Clinical characteristics and familiality of panic disorder, social phobia, specific phobia and obsessive-compulsive disorder (OCD) were examined in BP and MDD pedigrees with multivariate modeling using generalized estimating equations. RESULTS: Co-morbidity between mood and anxiety disorders was associated with several markers of clinical severity, including earlier age of onset, greater number of depressive episodes and higher prevalence of attempted suicide, when compared with mood disorder without co-morbid anxiety. Familial aggregation was found with co-morbid panic and OCD in both BP and MDD pedigrees. Specific phobia showed familial aggregation in both MDD and BP families, although the findings in BP were just short of statistical significance after adjusting for other anxiety co-morbidities. We found no evidence for familiality of social phobia. CONCLUSIONS: Our findings suggest that co-morbidity of MDD and BP with specific anxiety disorders (OCD, panic disorder and specific phobia) is at least partly due to familial factors, which may be of relevance to both phenotypic and genetic studies of co-morbidity.

Survey of medical students and junior house doctors on the effects of medical radiation: is medical education deficient?

BACKGROUND: We investigated the knowledge of ionising radiation among medical students and junior doctors in Ireland and assessed whether this knowledge improved with clinical experience. METHODS: A total of 269 subjects completed a questionnaire on the fundamentals of diagnostic imaging and patient doses. RESULTS: Overall knowledge was poor, 99% of subjects underestimated the dose of radiation involved in a barium enema, plain film of abdomen, lumbar spine X-ray and a PET scan. Almost 90% underestimated the dose of a CT abdomen/pelvis. 42% of subjects knew that PET involved ionising radiation while 27% thought that MRI did. There was a significant improvement in understanding after transition to a clinical environment, however, no further development. 1% had attended formal radiation protection courses. CONCLUSION: The knowledge of basic radiological procedures and patient doses was extremely limited. Current undergraduate teaching needs to be expanded and continued post-qualification to improve core understanding and facilitate safe practice.

Hazardous and harmful drinking: a comparison of the AUDIT and CAGE screening questionnaires.

BACKGROUND: Hazardous and harmful use of alcohol remains a public health concern, and many general hospital admissions are alcohol-related. AIM: To compare the CAGE and Alcohol Use Disorders Identification Test (AUDIT) questionnaires in screening general medical admissions for harmful or hazardous drinking. DESIGN: Prospective questionnaire-based study. METHODS: Both questionnaires were administered, and demographic data collected. RESULTS: One hundred and three patients were included. Of these, 36% were identified by the AUDIT to be drinking hazardously or harmfully, and 22% were identified as CAGE cases. All CAGE cases were also AUDIT cases. DISCUSSION: As the CAGE and the AUDIT are designed to identify different populations, it is not surprising that significantly fewer cases were identified using the CAGE. The AUDIT identifies not just the harmful drinkers detected by the CAGE, but also hazardous drinkers, who have not yet reached that level of harm. As drinkers at an earlier stage may respond better to interventions aimed at reducing their consumption, the AUDIT is preferable in clinical practice.

Influence of hepatitis C status on alcohol consumption in opiate users in treatment.

AIMS: To estimate the prevalence of (a) hazardous and/or harmful drinking, (b) alcohol consumption, (c) perceived hepatitis C status (HCV) in opiate users in treatment and (d) assess the influence of perceived HCV status on consumption and attitudes to risk. DESIGN: Cross-sectional survey. SETTING: A methadone maintenance clinic and a drug treatment centre within a British substance misuse service in London. PARTICIPANTS: A random sample of 93 opiate users in treatment. MEASUREMENTS: Hazardous and/or harmful drinking was assessed using the Alcohol Use Disorders Identification Test (AUDIT). Alcohol consumption was assessed using several indicators. Data on clinical and demographic characteristics, perceived HCV status, change in consumption and attitudes to alcohol consumption were also collected. FINDINGS: A third of the sample were identified as AUDIT cases, 17% drank more than one unit/day and 15% were drinking above the weekly, recommended units for safe drinking (21 for men, 14 for women). Perceived HCV positive status was estimated at 70%. HCV status influenced consumption with fewer HCV positive than HCV negative clients drinking any alcohol in the previous year. Also, more HCV positive clients than HCV negative clients, reduced their consumption after the HCV test result. HCV status had some influence on attitudes to drinking for HCV positive people, although most were aware that abstinence was important for those with HCV positive status. CONCLUSION: Perceived HCV positive status has some influence on alcohol consumption. Despite these findings, training on harm reduction advice on alcohol consumption, particularly in HCV positive clients, should be extended. More intense interventions, within drug treatment services, may be required for those drinkers for whom advice is insufficient.

Morphological analysis of nevoid melanoma: a study of 20 cases with a review of the literature.

Nevoid melanoma is a rare variant of melanoma characterized by deceptive morphologic features reminiscent of a benign melanocytic nevus. Twenty (13 nodular, 7 verrucous) nevoid melanomas were reviewed with the goal of identifying the predominant architectural patterns, cytologic features, and prognostic indicators. Although at scanning magnification, many lesions showed a strong resemblance to banal compound or dermal nevi, careful inspection in all cases demonstrated subtle pleomorphism and impaired maturation with depth, invariably accompanied by multiple dermal mitoses. Four tumors recurred and three metastasized, with subsequent death of the patients. Follow-up information for a period of at least 3 years was available in eight cases. In this group, mortality was 37.5%, the metastasis rate was 37.5%, and the local recurrence rate was 75%, with an average tumor thickness of 2.5 mm. We conclude that nevoid melanoma may be distinguished from a benign melanocytic nevus by a high index of suspicion, a careful analysis of architecture, and attention to cytologic features. Our data and a review of the literature do not support the notion that nevoid melanoma has a better prognosis than ordinary melanoma.

Mitochondrial DNA variation in rainbow trout (Oncorhynchus mykiss) across its native range: testing biogeographical hypotheses and their relevance to conservation.

North-western North America has been repeatedly glaciated over most of the past two million years, with the most recent glaciation occurring between 60 000 and 10 000 years ago. Intraspecific genetic variation in many species has been shaped by where they survived glaciation and what postglacial recolonization routes were used. In this study, molecular techniques were used to investigate biogeographical, taxonomic and conservation issues in rainbow trout, Oncorhynchus mykiss. Mitochondrial DNA (mtDNA) variation was assessed using a restriction fragment length polymorphism (RFLP) analysis, focusing mainly on the previously understudied northern extent of the species' range. Two phylogenetically distinct mitochondrial lineages were found that differed from each other by up to 1.8% in sequence. Although the geographical distributions of the two clades overlap extensively, diversity and distributional analyses strongly suggest that trout survived glaciation in both coastal and inland refugia followed by postglacial gene flow and secondary contact. Postglacial dispersal into British Columbia most likely occurred from the Queen Charlotte Islands and the Columbia River. Although trout most likely also survived glaciation along the coast of Washington, Oregon and California, as well as near the Bering Strait, evidence suggests that dispersal into British Columbia from these areas was limited. Sequence analysis of mitochondrial haplotypes revealed higher diversity in California than in the northern part of the species' range, indicating an ancient presence of the species in the south. Phylogeographic divergence probably predates adaptive variation in the species as suggested by evidence for parallel evolution of life history types across the range of O. mykiss.

Negative regulation of the Pseudomonas aeruginosa outer membrane porin OprD selective for imipenem and basic amino acids.

Pseudomonas aeruginosa OprD is a specific porin which facilitates the uptake of basic amino acids and imipenem, a carbapenem antibiotic. Resistance to imipenem due to the loss of OprD is an important mechanism for the loss of clinical effectiveness. To investigate the negative regulatory mechanisms influencing oprD expression, a gene upstream of the coregulated mexEF-oprN efflux operon, designated mexT, was cloned. The predicted 304-amino-acid mature MexT protein showed strong homology to LysR-type regulators. When overexpressed it induced the expression of the mexEF-oprN efflux operon while decreasing the level of expression of OprD. The use of an oprD::xylE transcriptional fusion indicated that it acted by repressing the transcription of oprD. Salicylate, a weak aromatic acid known to reduce porin expression and induce low levels of multiple antibiotic resistance in Escherichia coli, was able to induce imipenem resistance and reduce the expression of OprD but not multiple antibiotic resistance or OprN expression in P. aeruginosa. This was also demonstrated to occur at the level of transcription. Acetyl salicylate and benzoate, but not catechol, were also able to reduce the levels of OprD in the P. aeruginosa outer membranes. These OprD-suppressing compounds increased imipenem resistance even in a mexT-overexpressing and nfxC mutant backgrounds, suggesting that such resistance is independent of the MexT repressor and that oprD is influenced by more than a single mechanism of repression.

Sezary lineage cells can be induced to proliferate via CD28-mediated costimulation.

Sezary syndrome and mycosis fungoides are related chronic lymphoproliferative diseases caused by the malignant growth of CD4+ T lymphocytes that display hyperconvoluted nuclei and a predilection for skin homing. Despite the malignant nature of these cells, they paradoxically do not grow in vitro, either spontaneously or following exposure to mitogens. Partly because of this technical limitation, the cellular lineage and causes of abnormal growth resulting in a classical hyperconvoluted Sezary cell are poorly characterized. To better understand these aspects, we examined Sezary lineage cell growth in vitro. We found that, contrary to previous reports, Sezary lineage cells are capable of in vitro proliferation in response to either PHA or anti-CD3 mAb, if exogenous costimulation is provided. The CD28-B7 interaction provides at least one of the costimulatory signals capable of inducing Sezary lineage cell growth. Namely, Sezary lineage cells from three of six Sezary syndrome patients proliferated in response to PHA if an anti-CD28 mAb was also added to the in vitro culture. The remaining three patients' Sezary lineage cells were dependent upon CD28-B7-mediated costimulation, but in addition required other intercellular signals present on blood mononuclear cells. The relative lack of costimulation from the patients' own PBMC is not due to an intrinsic defect in the mycosis fungoides/Sezary syndrome patients' immune accessory cells. Rather, it appears primarily due to an inability of Sezary cells to significantly up-regulate CD40 ligand (gp39) following in vitro exposure to PHA.

Immunophenotypic identification of Sezary cells in peripheral blood.

Despite anecdotal literature that Sezary cells express the CD4+ CD7- immunophenotype, no formal validation has been published establishing the use of this immunophenotype for clinical or experimental purposes. Consequently, the only method presently available for Sezary cell identification is nuclear contour analysis, a labor-intensive procedure not generally available at most major medical centers. In this study, the accuracy of CD4+ CD7- subset quantitation for the identification of Sezary cells was examined. The study found that the percentage of CD4+ CD7- cells is elevated in many Sezary syndrome/MF patients relative to normal, healthy individuals. In addition, CD4+ CD7- enumeration correlates with enumeration by nuclear contour analysis in most patients (11 of 15) with elevated CD4/CD8 ratios. The CD4+ CD7- subset also correlates with the expression of other aberrant immunophenotypes, such as CD3low or CD4low. Lastly, CD4+ CD7- subset quantitation correlates with the number of clonal T lymphocytes, as measured using V beta-specific T-cell receptor monoclonal antibodies. The study found this method to be exceptionally accurate, with two caveats: (1) the absence of an expanded CD4+ CD7- subset in patients with a normal CD4/CD8 ratio is uninformative; and (2) in approximately 25% of patients with an elevated CD4/CD8 ratio, the Sezary cells are CD7+.

In situ analysis of cytokine responses in experimental murine schistosomiasis.

BACKGROUND: Infection with schistosomiasis results in CD4+ T helper (Th) cell-dependent granulomatous inflammation around parasite eggs. T cell-derived cytokines play a critical role in the induction and subsequent down-modulation of the granulomas. These cytokine responses have been previously examined in lymphoid cell supernatants or in tissue homogenates but have not been examined directly in the local microenvironment of the lesions or in the reacting lymphoid tissues. EXPERIMENTAL DESIGN: With the use of specific mAb, the cytokines IL-2, IFN gamma, IL-4, and IL-10 were investigated by direct immunocytochemical analysis in situ in hepatic egg granulomas and lymphoid organs from acutely and chronically infected mice. Cytokine expression in situ was compared with cytokine production during a secondary response in vitro. RESULTS: All cytokines examined were detected in various amounts in both the hepatic egg granulomas as well as in mesenteric lymph nodes and spleen. The majority of cells expressing the cytokines was found in lymph nodes, and very few were found in granulomas. Relatively small numbers of granulomas contained most of the cytokine-expressing cells, which tended to localize in their periphery. Granulomas and lymphoid organs in the acute disease contained significantly more cytokine-expressing cells in comparison with those from the chronic disease. This observation correlated well with cytokine production in vitro. CONCLUSIONS: Direct immunocytochemical examination in situ was used to detect and measure cytokine-producing cells in hepatic egg granulomas and reacting lymphoid organs of acute and chronic experimental murine schistosomiasis. Observed cytokine patterns suggest that granulomas contain T lymphocytes of both the Th-1 and Th-2 types and that cytokine production occurs during a limited time in the early granuloma. The immunocytochemical technique affords a direct appraisal of amount, dynamics, and localization of cytokine-producing cells in the unperturbed local environment.

Enhancing infection control for elderly and medically compromised patients.

Some patients may be at risk for complications from relatively common infectious diseases. Influenza, tuberculosis and methicillin-resistant Staphylococcus aureus infection can lead to illness and even death in elderly, medically compromised and institutionalized individuals. Dental personnel caring for these individuals should adopt preventive strategies that are simple and inexpensive in addition to standard infection control guidelines.

Effects of prostacyclin on bronchoconstriction and neutropenia induced by inhaled platelet-activating factor in man.

We studied the effects of prostacyclin (PGI2) on the airway responses to platelet-activating factor (PAF) in a randomized and crossover study in eight normal subjects. PGI2 or diluent (glycine buffer) was continuously infused on 2 separate days. Two breaths of PAF (21 micrograms) were inhaled three times every 15 minutes and airflow at 30% of vital capacity from partial flow-volume curves (Vp30) was measured. PGI2 (4 ng/kg/min) had no effect on Vp30 or blood pressure, whereas heart rate increased from 70.3 +/- 3.9 to 73.7 +/- 4.0 beats/min (mean +/- SEM; p less than 0.01). Two subjects did not complete the study because of transient hypotension. PGI2 had no effect on PAF-induced bronchoconstriction with maximal decreases in Vp30 of 42.0 +/- 8.0% (p less than 0.01) during PGI2 and 49.8 +/- 14.2% (p less than 0.02) during diluent infusion. Ex vivo platelet aggregation to PAF (10(-9) to 10(-7) mol/L) was significantly inhibited by PGI2. Circulating neutrophils decreased from 4.7 +/- 0.9 x 10(9)/L to 1.5 +/- 0.3 x 10(9)/L (p less than 0.05) 5 minutes after the first PAF inhalation during diluent infusion, whereas there was no significant change with PGI2. Thus, PGI2 does not influence PAF-induced bronchoconstriction in man despite causing marked inhibition of ex vivo PAF-induced platelet aggregation and preventing the fall of neutrophils.

Effects of inhaled PAF in humans on circulating and bronchoalveolar lavage fluid neutrophils. Relationship to bronchoconstriction and changes in airway responsiveness.

We have compared the effect of inhaled platelet activating factor (PAF) on circulating neutrophils with its ability to induce bronchoconstriction and bronchial hyperresponsiveness in humans. Human volunteers inhaled PAF, given as six successive inhalations 15 min apart, followed by bronchoalveolar lavage (BAL) 4 h later. The mean density and volume of circulating neutrophils were measured by metrizamide gradients and flow cytometry, respectively. PAF caused a decrease in Vp20 of 38.2 +/- 4.5% at 5 min after the first inhalation (p less than 0.001). This was associated with a fall in the peripheral blood neutrophil count from 3.15 +/- 0.3 to 1.1 +/- 0.3 x 10(6) per ml (p less than 0.001), followed by a rebound neutrophilia (p less than 0.01). The mean density of peripheral blood neutrophils fell significantly at 15 min (p less than 0.02), with a return to baseline values despite further PAF inhalations; this was associated with an increase in neutrophil volume (n = 4; p less than 0.05). The numbers of neutrophils (x 10(5] in BAL fluid after PAF were significantly greater than after inhalation of lyso-PAF: 7.1 +/- 1.4 (n = 7) versus 1.3 +/- 0.3 (n = 5, p less than 0.01); eosinophil counts did not change significantly. The PC40 (the concentration of methacholine needed to cause a fall in Vp30) decreased from 17.1 (GSEM 1.40) to 8.7 (1.44) mg/ml (n = 12, p less than 0.02) 3 days after PAF. Inhaled lyso-PAF was inactive in all these respects.(ABSTRACT TRUNCATED AT 250 WORDS)

A muscarinic agonist inhibits reflex bronchoconstriction in normal but not in asthmatic subjects.

Muscarinic receptors of the M2 subtype, which inhibit acetylcholine release from cholinergic nerves (autoreceptors), have been described in animal and human bronchi in vitro. We investigated whether these receptors may be involved in feedback inhibition of cholinergic reflex bronchoconstriction induced by sulfur dioxide (SO2) in seven nonasthmatic atopic subjects and in six mild asthmatic subjects. In a control experiment, total respiratory resistance (Rrs) was increased by 30 +/- 5% in nonasthmatic and by 60 +/- 18% in asthmatic subjects. In nonasthmatic subjects, pilocarpine, an agonist of muscarinic M2-autoreceptors, increased Rrs by 15 +/- 5% and addition of SO2 increased Rrs to 21 +/- 5% above base line, which was not significantly greater than after pilocarpine alone. Histamine gave a comparable bronchoconstriction (25 +/- 3% increase in Rrs) and SO2 further increased Rrs to 39 +/- 6% above base line (P less than 0.05). Thus pilocarpine appears to inhibit SO2-induced bronchoconstriction in nonasthmatic subjects, and this effect is not explained by an increase in airway tone. In asthmatic subjects, pretreatment with pilocarpine increased Rrs by 31 +/- 8% and SO2 further increased Rrs to 88 +/- 17% above base line. SO2 alone gave a 60 +/- 18% increase in Rrs. Our results suggest that feedback inhibitory muscarinic receptors may be present on cholinergic nerves in normal airways and that there may be a dysfunction of this feedback mechanism in asthmatic airways. This might be contributory to exaggerated cholinergic reflex bronchoconstriction in asthma.

Effect of theophylline on airway responses to inhaled platelet-activating factor in man.

It has been suggested that theophylline may possess anti-inflammatory actions which underlie its antiasthma properties. We examined whether theophylline could inhibit the bronchoconstriction and the bronchial hyperresponsiveness induced by inhaled platelet-activating factor (PAF) in eight nonasthmatic subjects in a double-blind, cross-over study. After oral theophylline (6 mg.kg-1), plasma theophylline at 1 h was 10.4 +/- 1.8 mg.ml-1 (mean +/- SEM) compared to 0.39 +/- 0.19 mg.ml-1 on the placebo day (p less than 0.005). PAF, inhaled in five successive doses every 15 min, caused a 56 +/- 11% fall in Vp30 (flow at 30% of vital capacity from a partial expiratory manoeuvre) after the first dose at 5 min, and diminishing responses with successive doses. Theophylline had no significant effect on PAF-induced bronchoconstriction. PAF caused a significant decrease in PC40 (the concentration of methacholine needed to cause 40% fall in baseline Vp30) from a baseline of 12.8 mg.ml-1 (geometric standard error of mean (GSEM) 1.98) to 7.9 (1.79) mg.ml-1 on day 3 and 6.9 (1.74) on day 7 (p less than 0.02). There was no significant difference when mean PC40 values on corresponding days after PAF were compared between placebo and theophylline treatment periods. Our results suggest that theophylline has negligible influence on the airway effects of PAF.

Capsaicin-induced bronchodilation in mild asthmatic subjects: possible role of nonadrenergic inhibitory system.

We investigated whether stimulation of vagal afferent nerve fibers with inhaled capsaicin could induce a nonadrenergic inhibitory reflex in nine mild asthmatic subjects. Changes in total respiratory resistance (Rrs) were measured with a forced oscillation technique. First we induced a rise of 71 +/- 15% in Rrs (P less than 0.001) after leukotriene D4 aerosol. Subsequent inhalation of capsaicin (2 nmol) caused no significant change in mean Rrs of -1.1 +/- 8.2%. After the muscarinic receptor antagonist ipratropium bromide (120 micrograms) was inhaled, leukotriene D4 increased Rrs by 103 +/- 9% (P less than 0.001). Capsaicin subsequently caused bronchodilation in all subjects (Rrs = -22.3 +/- 2.7%, P less than 0.001). Ethanol-saline (diluent) alone caused a nonsignificant fall in Rrs (-9.9 +/- 4.7%) but a deep breath and coughing resulted in bronchodilation (-16.9 +/- 6.1%, P less than 0.05 and -11.6 +/- 2.9%, P less than 0.01, respectively). As observed in normal subjects, capsaicin may initiate an inhibitory reflex, presumably of nonadrenergic origin. This reflex could not be distinguished from that caused by coughing or by deep inhalation. A defect in nonadrenergic mechanisms, at least in mild asthma, seems unlikely.