Inflammatory proteins in nasal lavage of workers exposed to occupational agents.

BACKGROUND: Low-molecular-weight (LMW) and high-molecular-weight (HMW) agents have been recognized as causes of occupational rhinitis (OR). Immunological mechanisms underlying OR differ according to the type of exposure. While HMW agents act mainly through IgE-mediated mechanisms, LMW agents appear to act through both immunological and non-immunological mechanisms. OBJECTIVE: The objective of this study was to identify potential differences in the upper airways inflammatory response after exposure to LMW and HMW agents by specific inhalation challenge test (SIC). METHODS: Nasal lavage (NL) samples from 20 subjects who were exposed to HMW (n = 10, Group I) and LMW (n = 10, Group II) at their workplaces were collected after SIC with control and specific occupational agents. These samples were analysed for 47 inflammatory markers using multiplex bead technology. RESULTS: After exposure to specific agent, Group I exhibited higher concentrations of the following proteins compared to Group II: fibrinogen (median (interquartile range) Group I: 0.09 (0.00) µg/mL, Group II: 0.04 (0.05) µg/mL, P = .05); haptoglobin (Group I: 0.86 (0.01) µg/mL, Group II: 0.14 (0.20) µg/mL, P = .02); vascular cell adhesion molecule-1 (VCAM-1) (Group I: 0.34 (0.67) ng/mL, Group II: 0.11 (0.11) ng/mL, P = .01); vascular endothelial growth factor (VEGF) (Group I: 157.0 (154.0) pg/mL, Group II: 98.0 (20.25) pg/mL, P = .01); and vitamin D (VDBP) (Group I: 0.06 (0.13) µg/mL, Group II: 0.03 (0.03) µg/mL, P = .04). No statistically significant differences in proteins profiles were observed between the groups after exposure to control agent. Also, subjects exposed to HMW agents showed a significant increase in NL levels of C-reactive protein compared to control-day exposure. CONCLUSIONS AND CLINICAL RELEVANCE: Exposure to HMW and LMW agents by SIC induced a differential nasal airway response including acute-phase reactants proteins (fibrinogen, haptoglobin and CRP), cell adhesion molecules (VCAM-1), endothelial growth factors (VEGF) and VDBP.

Gene expression in a rarely studied intraabdominal adipose depot, the round ligament, in severely obese women: A pilot study.

Gene expression (qPCR) was compared in round ligament (RL), omental (OME) and mesenteric (MES) ATs from 48 severely obese women (BMI, 54±11 kg/m(2); 38±9 yrs). The mRNA levels of enzymes of lipid metabolism (LPL, HSL, and PDE-3B), cortisol production (11ßHSD-1), adipogenesis (PPAR-γ1/2), thrombosis and inflammation (PAI-1, IL-6, TNF-α and adiponectin) were determined. AT-LPL mRNA was highest in RL. The highest PDE-3B and lowest PAI-1 mRNA levels were observed in RL and MES. The lowest IL-6 and TNF-α and the highest adiponectin and PPAR-g1/2 mRNA levels were found in RL AT. 11ßHSD-1 was highest in RL and OME. A higher lipogenic and adipogenic, and lower pro-inflammatory and pro-thrombotic profiles of the RL suggest a lesser deleterious impact on obesity-related complications.

Gene expression of different adipose tissues of severely obese women with or without a dysmetabolic profile

Despite well-established variations in the health risks posed by visceral vs. subcutaneous abdominal (SCABD) fat depots, surprisingly little is known on the differences within a given adipose tissue (AT) among severely obese patients displaying varying metabolic dysfunction. We thus compared, by quantitative PCR, the expression profile of a number of genes in the SCABD, omental (OME), and mesenteric (MES) depots of severely obese women with (DYS; n = 25) or without (NDYS; n = 23) a dysmetabolic profile. Fasting insulinemia and HOmeostasis Model Assessment-insulin resistance (HOMA-IR) were higher and plasma adiponectin level lower in DYS women (p < 0.05). Among enzymes involved in fatty acid metabolism and local cortisol production, phosphodiesterase-3B expression was lower in SCABD and MES fat, while 11Beta-hydroxysteroid dehydrogenase type 1 mRNA levels were higher in visceral depots of DYS women (p < 0.05). Regarding vascular homeostasis and inflammation, plasminogen activator inhibitor-1 and interleukin-6 mRNA levels were higher in OME fat, while adiponectin expression was lower in SCABD and OME ATs of DYS women (p < 0.05). Finally, HOMA-IR was positively associated with SCABD AT IL6 mRNA, only in DYS women (r = 0.47; p < 0.05). In conclusion, although metabolic and secretory characteristics of all depots vary with subjects’ metabolic profile, we find little evidence for a protective role of SCABD AT and no evidence for a further deleterious role of MES fat in DYS vs. NDYS severely obese women. Regional variation in the overall gene expression revealed that OME and MES fat were more closely related to each other in DYS women, while SCABD and MES depots showed greater resemblance in NDYS women

Gene expression of different adipose tissues of severely obese women with or without a dysmetabolic profile.

Despite well-established variations in the health risks posed by visceral vs. subcutaneous abdominal (SCABD) fat depots, surprisingly little is known on the differences within a given adipose tissue (AT) among severely obese patients displaying varying metabolic dysfunction. We thus compared, by quantitative PCR, the expression profile of a number of genes in the SCABD, omental (OME), and mesenteric (MES) depots of severely obese women with (DYS; n = 25) or without (NDYS; n = 23) a dysmetabolic profile. Fasting insulinemia and HOmeostasis Model Assessment-insulin resistance (HOMA-IR) were higher and plasma adiponectin level lower in DYS women (p < 0.05). Among enzymes involved in fatty acid metabolism and local cortisol production, phosphodiesterase-3B expression was lower in SCABD and MES fat, while 11ß-hydroxysteroid dehydrogenase type 1 mRNA levels were higher in visceral depots of DYS women (p < 0.05). Regarding vascular homeostasis and inflammation, plasminogen activator inhibitor-1 and interleukin-6 mRNA levels were higher in OME fat, while adiponectin expression was lower in SCABD and OME ATs of DYS women (p < 0.05). Finally, HOMA-IR was positively associated with SCABD AT IL6 mRNA, only in DYS women (r = 0.47; p < 0.05). In conclusion, although metabolic and secretory characteristics of all depots vary with subjects' metabolic profile, we find little evidence for a protective role of SCABD AT and no evidence for a further deleterious role of MES fat in DYS vs. NDYS severely obese women. Regional variation in the overall gene expression revealed that OME and MES fat were more closely related to each other in DYS women, while SCABD and MES depots showed greater resemblance in NDYS women.

Occupational asthma: new low-molecular-weight causal agents, 2000-2010.

Background. More than 400 agents have been documented as causing occupational asthma (OA). The list of low-molecular-weight (LMW) agents that have been identified as potential causes of OA is constantly expanding, emphasizing the need to continually update our knowledge by reviewing the literature. Objective. The objective of this paper was to identify all new LMW agents causing occupational asthma reported during the period 2000-2010. Methods. A Medline search was performed using the keywords occupational asthma, new allergens, new causes, and low-molecular-weight agents. Results. We found 39 publications describing 41 new LMW causal agents, which belonged to the following categories: drugs (n = 12), wood dust (n = 11), chemicals (n = 8), metals (n = 4), biocides (n = 3), and miscellaneous (n = 3). The diagnosis of OA was confirmed through SIC for 35 of 41 agents, peak expiratory flow monitoring for three (3) agents, and the clinical history alone for three (3) agents. Immunological tests provided evidence supporting an IgE-mediated mechanism for eight (8) (20%) of the newly described agents. Conclusion. This paper highlights the importance of being alert to the occurrence of new LMW sensitizers, which can elicit OA. The immunological mechanism is explained by a type I hypersensitivity reaction in 20% of all newly described LMW agents.

Pro-inflammatory phospholipid arachidonic acid/eicosapentaenoic acid ratio of dysmetabolic severely obese women.

BACKGROUND: Fatty acids (FAs) and adipokines such as adiponectin or interleukin-6 (IL-6) are known to modulate inflammation and the development of metabolic syndrome. Whether FA composition assessed in plasma triacylglycerols (TAGs), phospholipids (PLs) and non-esterified fatty acids (NEFAs) and adipose tissue (AT) PLs differed between dysmetabolic and non-dysmetabolic severely obese women remains to be established. Whether the plasma and/or AT arachidonic acid (AA)/eicosapentaenoic acid (EPA) ratio in the PL sub-fraction may be associated with adipokine AT gene expression needs to be examined. METHODS: FA composition was measured in plasma lipid classes and in the TAG and PL sub-fractions of subcutaneous abdominal and omental ATs of severely obese women paired for age and adiposity but showing a dysmetabolic profile (n = 13) or not (n = 14). FA profile was assessed by gas chromatography. Plasma and AT mRNA concentrations of adiponectin and IL-6 were measured by ELISA and real-time polymerase chain reaction, respectively. RESULTS: Plasma adiponectin and FA concentrations in the NEFA sub-fraction were, respectively, lower and higher in dysmetabolic than in non-dysmetabolic women (p < 0.05). Despite similar FA levels in the PL sub-fraction, the AA/EPA ratio was higher in plasma and ATs (p < 0.005), because of an EPA decrease in plasma and subcutaneous abdominal fat vs. an AA increase in the omental depot. The AA/EPA ratio was negatively associated with adiponectin concentrations in plasma and subcutaneous abdominal AT (0.01 < p < 0.05). CONCLUSIONS: Metabolic dysfunction is associated with a pro-inflammatory phospholipid AA/EPA ratio in plasma and ATs, and an altered adiponectin secretion that could contribute to developing metabolic syndrome.

Hypoadiponectinemia is associated with valvular inflammation and faster disease progression in patients with aortic stenosis.

OBJECTIVES: Adiponectin is a protein secreted by adipocytes which has anti-inflammatory properties. The objective of this study was to examine the relationship between adiponectinemia and the hemodynamic progression of aortic stenosis (AS) as well as the degree of inflammation in the valve explanted at the time of aortic valve replacement (AVR). METHODS: The plasma level of adiponectin was measured in 122 patients undergoing AVR. The explanted aortic valves were analyzed and the density of leukocytes (CD45+), T cells (CD3+) and blood vessels (von Willebrand factor positive; vWF+) was documented. Also, a subset of patients (n = 67) had ≥2 echocardiographic studies separated by at least 6 months, thereby allowing assessment of the rate of progression of stenosis during the preoperative period. RESULTS: Patients with lower plasma levels of adiponectin (<5.4 µg/ml) had a faster progression rate of the mean transvalvular gradient before surgery than those with higher levels (9 ± 1 vs. 4 ± 1 mm Hg/year; p = 0.008). Moreover, these patients with hypoadiponectinemia had significantly more leukocytes (CD45+), T cells and blood vessels (vWF+) in their explanted valves compared to those with higher adiponectin levels. CONCLUSION: These findings support the concept that adiponectin may play a protective role against the inflammatory process and progression of calcific AS.

Occupational asthma and allergy in snow crab processing in Newfoundland and Labrador.

BACKGROUND: Risk factors and prevalence of occupational asthma (OA) and occupational allergy (OAl) in the snow crab-processing industry have been poorly studied. OBJECTIVE: To estimate the prevalence of OA and OAl in snow crab-processing workers and determine their relationship with exposure to snow crab allergens and other potential risk factors. METHODS: A total of 215 workers (120 female/95 male) were recruited from four plants in Newfoundland and Labrador, Canada in 2001-2002. Results from questionnaires, skin-prick tests to snow crab meat and cooking water, specific IgEs against the latter, spirometry and peak flow monitoring were used to develop a diagnostic algorithm. An index based on work history and exposure measurements of snow crab aeroallergens was developed to estimate the cumulative exposure for each worker. RESULTS: The prevalences of almost certain or highly probable OA and OAl were 15.8% and 14.9%, respectively. A high cumulative exposure to crab allergens, in jobs mostly held by women, was associated with OA (odds ratio (OR) = 14.0, 95% CI 3.0 to 65.8) (highest vs lowest Cumulative Exposure Index) and with OAl (OR = 7.1, 95% CI 1.9 to 29.0); job held when symptoms started (cleaning, packing, freezing) also predicted OA (OR = 3.9, 95% CI 1.6 to 8.7) and OAl (OR = 3.2, 95% CI 1.4 to 7.5). Atopy (OR = 2.8, 95% CI 1.2 to 6.8), female gender (OR = 10.7, 95% CI 3.6 to 32.1) and smoking were significant determinants for OA (OR = 3.1, 95% CI 1.3 to 7.4). CONCLUSIONS: The prevalences of OA and OAl are high in snow crab-processing workers of Canada's East Coast. Cumulative exposure to snow crab allergens was related to the prevalences of OA and OAl in a dose-response manner taking into account atopy, gender and smoking.

Malt can cause both occupational asthma and allergic alveolitis.

Specific inhalation challenge can help differentiate occupational asthma from allergic alveolitis caused by malt.

Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: associations with changes in metabolic risk factors.

AIMS/HYPOTHESIS: We previously reported that the plasma levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), in a cohort of viscerally obese men are directly correlated with visceral adipose tissue (VAT) accumulation and metabolic risk factors including low HDL-cholesterol and high triacylglycerol. It is not known, however, if such correlations persist after vigorous lifestyle interventions that reduce metabolic risk factors. We analysed the changes in endocannabinoid levels in a subsample from the same cohort following a 1 year lifestyle modification programme, and correlated them with changes in VAT and metabolic risk factors. METHODS: Forty-nine viscerally obese men (average age 49 years, BMI 30.9 kg/m(2), waist 107.3 cm) underwent a 1 year lifestyle modification programme including healthy eating and physical activity. Plasma levels of 2-AG and the other most studied endocannabinoid, anandamide, were measured by liquid chromatography-mass spectrometry. Anthropometric and metabolic risk factors, including VAT, insulin resistance and glucose intolerance, HDL-cholesterol and triacylglycerol, were measured. RESULTS: Most risk factors were improved by the intervention, which led to a significant decrease in body weight (-6.4 kg, p < 0.0001), waist circumference (-8.0 cm, p < 0.0001) and VAT (-30%, p < 0.0001), and in plasma 2-AG (-62.3%, p < 0.0001) and anandamide (-7.1%, p = 0.005) levels. The decrease in levels of 2-AG but not those of anandamide correlated with decreases in VAT and triacylglycerol levels, and with the increase in HDL(3)-cholesterol levels. Multivariate analyses suggested that decreases in 2-AG and VAT were both independently associated with decreases in triacylglycerol. CONCLUSIONS/INTERPRETATION: This study shows that a strong correlation exists between 2-AG levels and high plasma triacylglycerol and low HDL(3)-cholesterol in viscerally obese men.

Association between circulating oxidised low-density lipoprotein and fibrocalcific remodelling of the aortic valve in aortic stenosis.

INTRODUCTION: Aortic stenosis (AS) is the most common valvular heart disease in westernized societies. AS is a disease process akin to atherosclerosis in which calcification and tissue remodelling play a crucial role. In patients with moderate/severe AS, we sought to determine whether the remodelling process would be in relationship with transvalvular gradients and circulating oxidised low-density lipoprotein (ox-LDL) levels. METHODS: In 105 patients with AS, the aortic valve and blood plasma were collected at the time of valve replacement surgery. The degree of valve tissue remodelling was assessed using a scoring system (Score: 1-4) and the amount of calcium within the valve cusps was determined. The standard plasma lipid profile, the size of LDL particles and the plasma level of circulating ox-LDL (4E6 antibody) were determined. RESULTS: After adjustment for covariables, aortic remodelling score was significantly related to transvalvular gradients measured by Doppler echocardiography before surgery. Patients with higher valve remodelling score had higher circulating ox-LDL levels (score 2: 27.3 (SEM 2.6) U/l; score 3: 32.2 (SEM 2.3) U/l; score 4: 38.3 (SEM 2.3) U/l; p = 0.02). After correction for age, gender, hypertension and HDL-C, the plasma level of ox-LDL remained significantly associated with the aortic valve remodelling score (p<0.001). The plasma level of ox-LDL was significantly associated with LDL-C (r = 0.41; p<0.001), apoB (r = 0.59; p<0.001), triglyceride (r = 0.39; p<0.001), Apo A-I (r = 0.23; p = 0.01) and cholesterol in small (<255 A) LDL particles (r = 0.22; p = 0.02). After correction for covariables, circulating ox-LDL levels remained significantly associated with apoB (p<0.001) and triglyceride (p = 0.01) levels. CONCLUSION: Increased level of circulating ox-LDL is associated with worse fibrocalcific remodelling of valvular tissue in AS. It remains to be determined whether circulating ox-LDL is a risk marker for a highly atherogenic profile and/or a circulating molecule which is actively involved in the pathogenesis of calcific aortic valve disease.

Cell detachment modulates TRAIL resistance in ovarian cancer cells by downregulating the phosphatidylinositol 3-kinase/Akt pathway.

TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a potent inducer of apoptosis but many ovarian cancer cells display intrinsic resistance to TRAIL. The molecular determinants regulating TRAIL sensitivity in these resistant tumor cells are still incompletely understood. We observed that cell detachment enhances TRAIL-induced apoptosis in two TRAIL-resistant ovarian cancer cell lines. This process was accompanied by an increase of caspase activation, which could be blocked by caspase-8 inhibitor IETD. Cell detachment inhibited Akt phosphorylation. Phosphatidylinositol 3-kinase inhibition by LY294002 also enhanced TRAIL-induced apoptosis. Further decreased Akt activity by LY294002 in detached cells translated to increased cell death after TRAIL treatment. Our data indicate that cell detachment enhances TRAIL-induced killing by decreasing Akt activity in TRAIL-resistant ovarian carcinoma cells and suggest that Akt inhibition primes TRAIL-resistant cells to TRAIL-induced apoptosis.

Diisocyanate conjugate and immunoassay characteristics influence detection of specific antibodies in HDI-exposed workers.

BACKGROUND: The structural characteristics of diisocyanate chemical protein antigens vary depending upon the methods of production, and may influence diisocyanate antigen immunoassays. The impact of different antigen preparation methods on immunoassay sensitivity, specificity, and predictive value for identifying workers with diisocyanate asthma (DA) has not been systematically evaluated. OBJECTIVE: Evaluate the influence of preparation methodology of hexamethylene diisocyanate human serum albumin (HDI-HSA) conjugates on the performance of specific antibody assays for identifying workers with confirmed HDI asthma. METHODS: Asthmatic reactions to HDI exposure were assessed in 80 autobody shop workers by specific inhalation challenge (SIC). HDI-specific IgE and IgG in serum were measured by RAST and ELISA with seven different HDI-HSA conjugates prepared in liquid phase with monomeric or polymeric HDI, or vapour-phase monomeric HDI. The HDI : HSA substitution ratios were determined by mass spectrometry. RESULTS: DA was confirmed by SIC in 23 subjects. The maximal sensitivity for detecting specific IgE among workers with positive SIC results was higher with RAST and with polymeric vs. monomeric HDI-albumin conjugates (21.7% vs. 8.7%) with a generally high specificity (>or=95%). HDI-HSA specific IgG antibody was also detected in 22-43% of HDI asthmatics depending upon the conjugate used. The specificity of specific IgG varied from 88% to 96%, and it was higher for monomeric (vs. polymeric) HDI-albumin conjugates with low (vs. high) substitution ratios. CONCLUSION: The test performance of specific IgE and IgG immunoassays for identifying a positive SIC response varied with different HDI-HSA conjugates. Standard test antigens and common immunoassays must be used to minimize inter-laboratory variability.

Can access to spirometry in asthma education centres influence the referral rate by primary physicians for education?

BACKGROUND AND OBJECTIVES: Asthma remains uncontrolled in a large number of asthmatic patients. Recent surveys have shown that a minority of asthmatic patients are referred to asthma educators. The objective of the present study was to assess the influence of increased access to spirometry in asthma education centres (AECs) on the rate of patient referrals to these centres by general practitioners. METHODS: A one-year, prospective, randomized, multicentric, parallel group study was conducted over two consecutive periods of six months each, with added spirometry being offered in the second six-month period to the experimental group. Ten AECs were enrolled in the project. An advertisement describing the AECs' services was sent by mail to a total of 303 general practitioners at the start of each period, inviting them to refer their patients. Measures of the frequency of medical referrals to the AECs were assessed for each period. RESULTS: The group of AECs randomly selected for spirometry in the second six-month period received 48 medical referrals during the first period and 32 during the second one, following proposed spirometry. AECs that had not offered spirometry received five referrals during the first period and seven during the second period. One AEC withdrew a few weeks after the study began and others encountered administrative problems, reducing their ability to provide interventions. CONCLUSIONS: Referral to AECs is not yet integrated into the primary care of asthma and offering more rapid access to spirometry in the AECs does not seem to be a significant incentive for such referrals.

Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations.

One important goal of asthma treatment is to reduce exacerbations. The current authors investigated if the use of sputum cell counts to guide treatment would achieve this goal. A total of 117 adults with asthma were entered into a multicentre, randomised, parallel group-effectiveness study for two treatment strategies over a 2-yr period. In one strategy (the clinical strategy: CS) treatment was based on symptoms and spirometry. In the other (the sputum strategy: SS) sputum cell counts were used to guide corticosteroid therapy to keep eosinophils250 microg, and was due to fewer eosinophilic exacerbations. The cumulative dose of corticosteroid during the trial was similar in both groups. Monitoring sputum cell counts was found to benefit patients with moderate-to-severe asthma by reducing the number of eosinophilic exacerbations and by reducing the severity of both eosinophilic and noneosinophilic exacerbations without increasing the total corticosteroid dose. It had no influence on the frequency of noneosinophilic exacerbations, which were the most common exacerbations.

Steroid naive eosinophilic asthma: anti-inflammatory effects of fluticasone and montelukast.

BACKGROUND: Inhaled corticosteroids and leukotriene receptor antagonists reduce airway eosinophilia and have been used as first line anti-inflammatory therapy for mild persistent asthma. METHODS: A multicentre, randomised, placebo controlled, parallel group study was performed to compare the anti-inflammatory effects of fluticasone propionate and montelukast as measured by sputum eosinophils in 50 adults with symptomatic steroid naive asthma and sputum eosinophilia of > or =3.5%. RESULTS: Eighteen patients received low dose fluticasone (250 mug/day), 19 received montelukast (10 mg/day), and 13 were given placebo for 8 weeks. Fluticasone treatment resulted in a greater reduction in sputum eosinophils (geometric mean (SD) 11.9 (2.3)% to 1.7 (5.1)%) than montelukast (10.7 (2.3)% to 6.9 (3.8)%; p = 0.04) or placebo (15.4 (2.4)% to 7.8 (4.2)%; p = 0.002), and improvement in FEV(1) (mean (SD) 2.6 (0.9) l to 3.0 (0.9) l) than montelukast (2.8 (0.7) l to 2.8 (0.9) l; p = 0.02) or placebo (2.4 (0.8) l to 2.4 (0.9) l; p = 0.01). Treatment with fluticasone suppressed sputum eosinophilia within a week while montelukast only attenuated it. The effect of montelukast was maximal at 1 week and was maintained over 4 weeks. The effect of fluticasone was maintained over 8 weeks while that of montelukast was not. CONCLUSIONS: Montelukast is not as effective as low dose fluticasone in reducing or maintaining an anti-inflammatory effect in steroid naive eosinophilic asthma.

Differential regulation of MHC class-I-restricted and unrestricted cytotoxicity by the Us3 protein kinase of herpes simplex virus-1.

Modulation of cytotoxic responses by viral immunoevasins plays an important role in the establishment of latent and persistent viral infections. Together with MHC class-I-restricted CD8T-lymphocytes, non-MHC-restricted natural killer (NK) and lymphokine-activated killer (LAK) cells participate in this anti-viral control. The Us3 protein kinase of herpes simplex virus-1 (HSV-1) inhibits CD8T-cell cytotoxicity, which correlates with the inhibition of granzyme-B (GrB)-induced activation of pro-apoptotic Bid. We have investigated the effect of Us3 on NK and LAK cytotoxicity, because these effectors are believed to share common mechanisms for inducing cell death. We show that, in contrast to their lower sensitivity to CD8T-cell lysis, HSV-1-infected cells are lysed by NK cells or LAK cells as efficiently as the uninfected controls. Both CD8T and NK/LAK effectors were dependent on the activity of GrB and were efficiently blocked by means of treatment with a GrB inhibitor. However, unlike CD8T cells, LAK cells and NK cells failed to induce Bid cleavage, suggesting that various GrB downstream targets be involved in the induction of cell lysis. This finding explains their various sensitivities to viral modulation, which is likely to be important for the respective role of MHC-restricted and non-restricted effectors in the control of HSV-1 infection.

Exaggerated bronchoconstriction due to inhalation challenges with occupational agents.

Inhalation challenges with occupational agents are used to confirm the aetiology of occupational asthma. It has been proposed that using closed-circuit equipment rather than the realistic challenge method would improve the methodology of these tests. Changes in forced expiratory volume in one second (FEV1) were examined in 496 subjects with "positive specific inhalation challenges", i.e. changes in FEVI of > or = 20% after exposure to an occupational agent, including 357 subjects exposed by the realistic method, 108 using the closed-circuit method and 31 by both methods. For immediate reactions, 18 of 95 (19%) showed changes in FEV1 of > or = 30% with the closed-circuit method, whereas a significantly larger proportion, i.e. 77 of 200 (38.5%), showed such changes using the realistic method. As regards nonimmediate reactions, changes in FEV1 of > or = 30% occurred in 16 of 43 (37%) cases with the closed-circuit method as compared to a larger proportion, i.e. 87 of 180 (48%) cases, using the realistic method. This favourable effect was significantly more pronounced in workers with higher levels of bronchial hyperresponsiveness to methacholine. It is concluded that, for agents that can be generated using the closed-circuit method, use of such apparatus results in a smaller proportion of exaggerated bronchoconstriction than does the realistic method, this being particularly true for low-molecular weight agents.