Natural allergen exposure does not diminish the sensitivity of cytokine production to glucocorticosteroids in blood cells of seasonal allergic asthma and rhinitis patients

Glucocorticosteroid (GCS) inhibition of cytokine production is a major anti-inflammatory mechanism. However, increased production of pro-inflammatory cytokines during allergic airway inflammation has been proposed to reduce GCS effects. This study aimed to investigate whether allergic airway inflammation due to natural allergen exposure might decrease the sensitivity of granulocyte-macrophage colony-stimulating factor (GM-CSF) production to GCS in blood cells. Blood samples were collected from patients with seasonal allergic asthma (n = 10) and rhinitis (n = 8) and healthy subjects (n = 9), before, during, and after the birch pollen season. Whole blood cultures were stimulated with LPS (10 ng/ml) and treated with budesonide (10(-11)-10(-7) M) for 20 h. GM-CSF levels were analysed using immunoassay. Birch pollen exposure did not alter LPS-stimulated GM-CSF production, although disease symptoms and blood eosinophils increased in the patients. There were no significant differences in budesonide inhibition of GM-CSF production by blood cells of asthma and rhinitis patients compared with cells of healthy subjects before, during or after the birch pollen season and no change in response to allergen exposure. A concentration of 1 nM budesonide inhibited GM-CSF production by more than 50% at all time points. In conclusion, natural allergen exposure did not reduce the sensitivity of GM-CSF production to GCS inhibition in blood cells of seasonal allergic asthma and rhinitis patients.     

Nitric oxide metabolites in allergic rhinitis: The effect of pollen allergen exposure

BackgroundSeasonal allergic rhinitis (SAR) is characterised by an inflammation consequent to allergen exposure. Nitric oxide may be involved in allergic inflammation.ObjectiveThis study evaluated the serum nitrite concentrations in SAR patients during and outside pollen exposure in order to estimate activity of nitric oxide synthases.MethodsOne hundred and two (56 females, 46 males, median age: 28.7 years) were included in this study: 56 with SAR evaluated outside the pollen season and so without allergic inflammation and symptoms, and 46 with SAR evaluated during the pollen season with symptoms. Serum concentrations of nitrite were measured and in those patients exposed to pollens, results were compared to scores of the Visual Analogue Scale for nasal obstruction perception.ResultsSerum nitrite concentrations were higher in SAR patients evaluated outside the pollen season (U = ?6.78; p < 0.0001), moreover, there was a significant relationship between nasal obstruction perception and nitrite in patients evaluated during the pollen season.ConclusionThis preliminary study demonstrates that serum nitric oxide metabolism depends on allergen exposure.     

Pyridostigmine enhances, but does not normalise, the GH response to GH-releasing hormone in obese subjects

Obese patients are characterised by several neuroendocrine abnormalities, including characteristically a decrease in growth hormone responsiveness to GH-releasing hormone. In normal subjects, the GH response to GHRH is enhanced by the acetylcholinesterase inhibitor, pyridostigmine. We have studied the effect of this drug on GH secretion in gross obesity. Twelve obese patients were studied (mean weight 156% of ideal) and compared with a group of 8 normal volunteers. Each subject was initially studied on two occasions, in random order, with GHRH (1-29) NH2 100 micrograms iv alone and following pretreatment with pyridostigmine 120 mg orally one hour prior to GHRH. In obese patients, the GH response to GHRH was significantly blunted when compared to controls (GH peak: 20 +/- 4 vs 44 +/- 16 micrograms/l; mean +/- SEM). After pyridostigmine, the response to GHRH was enhanced in the obese subjects, but remained significantly reduced compared to non-obese subjects treated with GHRH and pyridostigmine (GH peak: 30 +/- 5 vs 77 +/- 20 micrograms/l, respectively). In 6 subjects, higher doses of GHRH or pyridostigmine did not further increase GH responsiveness in obese patients. Our results suggest that obese patients have a disturbed cholinergic control of GH release, probably resulting from increased somatostatinergic tone. This disturbed regulation may be responsible, at least in part, for the blunted GH responses to provocative stimuli.     

Experimental and seasonal exposure to birch pollen in allergic rhinitis and allergic asthma with regard to the inflammatory response

Background and Aims: Seasonal allergy is an interesting model to study the pathophysiological mechanisms involved in allergic inflammation. However, experimental allergen exposure is easier to perform and standardise. The primary aim of this study was to compare the inflammatory responses to high‐dose bronchial challenge and natural exposure during birch pollen season. The second aim was to compare the responses of patients with allergic rhinitis and allergic asthma, respectively to both types of allergen exposure. Methods: Fifteen birch pollen‐allergic patients (seven with asthma and eight with rhinitis) and five healthy individuals were studied during pollen season and after challenge with birch allergen. Symptoms, medication and peak expiratory flow rate (PEFR) were recorded, and blood samples, spirometry and induced sputum were analysed during season and after challenge. Results: Patients with allergic asthma demonstrated a greater bronchial responsiveness to bronchial provocation with birch allergen than patients with rhinitis (P = 0.04) whereas no difference was found regarding nasal challenge. No significant association was found between the level of responsiveness and the inflammatory response after seasonal exposure. Seasonal exposure was related to a more marked systemic inflammatory blood–eosinophil increase than bronchial challenge [(median) (0.25 vs 0.11 × 109/L, P = 0.03)] and after nasal challenge, respectively [(median) (0.25 vs 0.04 × 109/L, P = 0.003)]. A significant correlation in eosinophil cationic protein in induced sputum was found between the experimental and seasonal exposure (rho = 0.62, P = 0.02). Conclusions: Bronchial allergen challenge with inhalation of birch pollen gives a similar inflammatory response in the airway but less systemic inflammation than seasonal exposure in birch pollen allergic patients with asthma and rhinitis. Please cite this paper as: Kämpe M, Janson C, Stålenheim G, Stolt I and Carlson M. Experimental and seasonal exposure to birch pollen in allergic rhinitis and allergic asthma with regard to the inflammatory response. The Clinical Respiratory Journal 2009; DOI:10.1111/j.1752‐699X.2009.00140.x.     

The effect of exposure to sulphuric acid on the early asthmatic response to inhaled grass pollen allergen.

Particulate sulphates, including sulphuric acid (H2SO4), are important components of the ambient aerosol in some areas and are regarded as air pollutants with potentially important human health effects. Challenge studies suggest little or no effect of H2SO4 exposure on lung function in asthmatic adults, although some epidemiological studies demonstrate an effect of acid species on symptoms in subjects with asthma. To date, the effect of H2SO4 on allergen responsiveness has not been studied. The effect of exposure to particulate H2SO4 on the early asthmatic response to grass pollen allergen has been investigated in 13 adults with mild asthma. After establishment of the provocative dose of allergen producing a 15% fall in forced expiratory volume in one second (FEVI) (PD15) for each subject, they were exposed to air, 100 microg m(-3) or 1,000 g x m(-3) H2SO4 for 1 h, double-blind in random order > or =2 weeks apart, through a head dome delivery system 14 h after each exposure subject underwent a fixed-dose allergen challenge (PD15). Ten subjects completed the study. The mean early asthmatic responses (maximum percentage change in FEV1 during the first 2 h after challenge) following air, 100 microg x m(-3) H2SO4, and 1,000 microg m(-3) H2SO4, were -14.1%, -16.7%, and -18.4%, respectively. The difference between 1,000 microg x m(-3) H2SO4 and air was significant (mean difference: -4.3%, 95% confidence interval (CI: -1.2-7.4%, p=0.013). The difference between air and 100 microg m(-3) H2SO4 approached significance (mean difference: -2.6%, 95% CI: 0.0-5.3%, p = 0.051). These results suggest that, at least at high mass concentration, sulphuric acid can potentiate the early asthmatic response of mild asthmatic subjects to grass pollen allergen, although the effect is limited.     

Artesunate reduces but does not prevent posttreatment transmission of Plasmodium falciparum to Anopheles gambiae

Combination therapy that includes artemisinin derivatives cures most falciparum malaria infections. Lowering transmission by reducing gametocyte infectivity would be an additional benefit. To examine the effect of such therapy on transmission, Gambian children with Plasmodium falciparum malaria were treated with standard regimens of chloroquine or pyrimethamine-sulfadoxine alone or in combination with 1 or 3 doses of artesunate. The infectivity to mosquitoes of gametocytes in peripheral blood was determined 4 or 7 days after treatment. Infection of mosquitoes was observed in all treatment groups and was positively associated with gametocyte density. The probability of transmission was lowest in those who received pyrimethamine-sulfadoxine and 3 doses of artesunate, and it was 8-fold higher in the group that received pyrimethamine-sulfadoxine alone. Artesunate reduced posttreatment infectivity dramatically but did not abolish it completely. The study raises questions about any policy to use pyrimethamine-sulfadoxine alone as the first-line treatment for malaria.     

Adrenalectomy reduces but does not reverse obesity in ob/ob mice

Bilateral adrenalectomy (ADX) of 4-month-old ob/ob mice led to reduced rates of body weight gain, a complete cessation of fat deposition and increased percentage carcass protein and ash during a 2-month observation period after surgery. However, ADX obese mice were still heavier and had more body fat and lower concentrations of carcass protein and ash than intact sex-matched littermate lean mice at the end of the experiment. When adrenalectomy was performed in younger obese mice before the syndrome was fully expressed (23 +/- 2 days of age), body weight gain was reduced by 40 per cent and fat deposition by 50 per cent during the next 3.5 months, but each was still greater than that of littermate lean mice. Despite the lower rate of weight gain after adrenalectomy, the skeletal and lean body growth of the early ADX obese mice equalled that of both obese and lean mice fed ad libitum. When the carcass composition of early ADX obese mice was compared with that of intact obese mice which were calorically restricted to the same rate of body weight gain, the ADX group had significantly less carcass fat (28 per cent) and more protein (50 per cent) and ash (20 per cent) than the dieted obese mice. In both experiments adrenalectomy led to reduced circulating immunoreactive insulin levels, although hyperinsulinemia persisted. The present results show that adrenalectomy is an effective tool for ameliorating the severity of many aspects of the ob/ob syndrome, particularly when compared with caloric restriction, but the procedure does not entirely reverse the deranged metabolism or abnormal carcass composition of these mice.     

Acute exposure to sawdust does not alter airway calibre and responsiveness to histamine in asthmatic subjects

We investigated the effects of particles of sawdust delivered through a special device at known concentrations (close to the threshold limit value-short term exposure limit (TLV-STEL) of 10 mg.m-3) on FEV1 and PC20 in 12 asthmatic subjects free of clinical sensitization to this product. Subjects were studied over two days (day 1: exposure to sawdust; day 2: sham exposure) in random order with a maximum interval of 1 week. On each day, after the assessment of spirometry and PC20, subjects underwent exposure to sawdust or sham exposure. Sawdust was inhaled for a total of 30 min at average concentrations varying from 8.0 to 19.3 mg.m-3 (mean = 11.5 mg.m-3). Twenty-five to 39.7% (mean = 34.6%) of inhaled particles had a diameter less than 10 mu (diameter allowing deposition in the trachea and lower respiratory tract). At the end of each period of exposure, FEV1 was assessed. After recovery, the second PC20 was obtained. Serial measurements of FEV1 were carried out every hour for up to 6 h after the end of exposure. At that time, PC20 was reassessed. Only one subject showed an acute bronchoconstriction immediately after exposure to sawdust (maximum fall of 14% in FEV1) with complete recovery 10 min later. Overall, inhalation of sawdust did not modify PC20 by comparing the mean result of the first test with the second and the third assessments. Also, the mean changes in PC20 at each interval after exposure to sawdust were not significantly different from the variations in PC20 on the sham day.(ABSTRACT TRUNCATED AT 250 WORDS)     

Omeprazole reduces the response to capsaicin but not to methacholine in asthmatic patients with proximal reflux

Objective. To study the relationships between airway responsiveness to methacholine and capsaicin, proximal or distal reflux and the effects of short-term acid inhibition. Material and methods. Twenty-nine asthmatics, not taking steroids regularly, underwent respiratory symptom measurements, 24-h dual-probe pH monitoring, and challenges with methacholine and capsaicin. Challenges and symptom measurements were repeated after 12 days’ omeprazole treatment (20 mg b.i.d.). The results (median and range) were expressed as PD20 methacholine (mg) and PD5 capsaicin (dose causing five coughs, nmol). Results. Seventeen patients presented pathological reflux in the distal esophagus, and 17 in the proximal esophagus. At baseline no correlation was found between PD20 or PD5 and reflux. Treatment with omeprazole did not change bronchial responsiveness to methacholine (basal: 0.16 mg, 0.02–1.27; omeprazole: 0.15 mg, 0.02–1.60); omeprazole decreased the tussive response to capsaicin (basal: 0.08 nmol, 0.08–2.46; omeprazole: 0.61 nmol, 0.08–9.84, p<0.001) only in patients with pathological reflux. The decrease was positively correlated with proximal acid exposure (r²=0.70, p<0.001). Omeprazole reduced asthma symptoms in patients with proximal reflux, cough in those with proximal or distal reflux. Conclusions. In asthmatics, inhibition of gastric acid secretion does not influence bronchial hyperresponsiveness but decreases tussive sensitivity and this effect is related to proximal reflux.     

Omeprazole reduces the response to capsaicin but not to methacholine in asthmatic patients with proximal reflux

OBJECTIVE: To study the relationships between airway responsiveness to methacholine and capsaicin, proximal or distal reflux and the effects of short-term acid inhibition. MATERIAL AND METHODS: Twenty-nine asthmatics, not taking steroids regularly, underwent respiratory symptom measurements, 24-h dual-probe pH monitoring, and challenges with methacholine and capsaicin. Challenges and symptom measurements were repeated after 12 days' omeprazole treatment (20 mg b.i.d.). The results (median and range) were expressed as PD20 methacholine (mg) and PD5 capsaicin (dose causing five coughs, nmol). RESULTS: Seventeen patients presented pathological reflux in the distal esophagus, and 17 in the proximal esophagus. At baseline no correlation was found between PD20 or PD5 and reflux. Treatment with omeprazole did not change bronchial responsiveness to methacholine (basal: 0.16 mg, 0.02-1.27; omeprazole: 0.15 mg, 0.02-1.60); omeprazole decreased the tussive response to capsaicin (basal: 0.08 nmol, 0.08-2.46; omeprazole: 0.61 nmol, 0.08-9.84, p<0.001) only in patients with pathological reflux. The decrease was positively correlated with proximal acid exposure (r2=0.70, p<0.001). Omeprazole reduced asthma symptoms in patients with proximal reflux, cough in those with proximal or distal reflux. CONCLUSIONS: In asthmatics, inhibition of gastric acid secretion does not influence bronchial hyperresponsiveness but decreases tussive sensitivity and this effect is related to proximal reflux.     

Direct and prolonged exposure to dogs does not influence the degree of skin prick test positivity to dog allergen.

BACKGROUND: The relationship between pet ownership and the risk of developing allergic sensitization to pet allergens is still controversial. We assessed the possible effect of direct exposure to dog allergen on skin reactivity in dog-sensitized patients. METHODS: We studied, in a case-control trial, 116 adults sensitized to dog allergens (55 with a dog at home for at least 10 years and 61 without it). The degree of response was assessed by skin prick test, performed in quadruplicate with three concentrations of allergenic extract: A (1:20 w/v), B (1:200 w/v) and C (1:2000 w/v). The mean diameter of each wheal was assessed using a visilog image analysis software. RESULTS: No significant difference between the two groups in the wheal diameters induced by the three concentrations of dog allergen could be demonstrated. CONCLUSION: The results of this study suggest that direct dog exposure in adults with respiratory allergy is not associated with greater cutaneous response to dog allergens, as compared to non exposed subjects.     

Low-fat dairy consumption reduces systolic blood pressure, but does not improve other metabolic risk parameters in overweight and obese subjects

Background and aims

Epidemiological studies have indicated a negative relation between low-fat dairy consumption and the metabolic syndrome. However, evidence from intervention studies is scarce. Our aim was to investigate the effects of daily consumption of low-fat dairy products on metabolic risk parameters in overweight and obese men and women.

Methods and results

Thirty-five healthy subjects (BMI > 27 kg/m²) consumed low-fat dairy products (500 mL low-fat milk and 150 g low-fat yogurt) or carbohydrate-rich control products (600 mL fruit juice and 3 fruit biscuits) daily for 8 weeks in random order. Compared with the control period, systolic blood pressure was decreased by 2.9 mmHg (95% confidence interval (CI), −5.5 to −0.3 mmHg; P = 0.027), while the difference in diastolic blood pressure did not reach statistical significance (95% CI, −3.4 to 0.3 mmHg; P = 0.090). Low-fat dairy consumption decreased HDL-cholesterol concentrations by 0.04 mmol/L (95% CI, −0.07 to −0.01 mmol/L; P = 0.021) and apo A-1 concentrations by 0.04 g/L (95% CI, −0.07 to −0.01 g/L; P = 0.016) compared with control. Serum total cholesterol, LDL-cholesterol, apo B, triacylglycerols, non-esterified fatty acids, glucose, insulin, C-reactive protein and plasminogen activator inhibitor-1 were unchanged.

Conclusion

We conclude that in overweight and obese subjects, daily intake of low-fat dairy products for 8 weeks decreased systolic blood pressure, but did not improve other metabolic risk factors related to the metabolic syndrome.     

Interferon-a plus lamivudine vslamivudine reduces breakthroughs, but does not affect sustained response in HBeAg negative chronic hepatitis B

AIM: To investigate the efficacy of combination treatment of IFN-α and lamivudine compared to lamivudine monotherapy, after 24 mo of administration in HBeAgnegative hepatitis B patients. METHODS: Fifty consecutive patients were randomly assigned to receive IFN-α-2b (5MU thrice per week, n=24) plus lamivudine (100mg daily) or lamivudine only (n=26) for 24 mo. Patients were followed up for further 6 mo. The primary outcome was the proportion with sustained virological response (undetectable serum HBV DNA concentrations) and or sustained biochemical response (transaminase levels within normal range) at 30 mo (6 mo after the end of therapy). Secondary end-points were timed from initial virological (biochemical) response to VBR (BBR, respectively) and the emergence of YMDD mutants across the two arms. RESULTS: Five of twenty-four (21%) patients in the combination arm vs 3/26 (12%) in the lamivudine arm had sustained response (i.e., normal serum transaminase levels and undetectable HBV DNA by PCR assay) 6 mo after treatment discontinuation. A reduction in the emergence of YMDD mutants and in the development of virological breakthroughs was observed in patients receiving combination treatment (10% vs 46%, P=0.01 and 14% vs 46%, P=0.03, respectively). Time from initial virologic response to virologic breakthrough (VBR) was greater among initial responders receiving combination treatment compared to those receiving lamivudine (22.9 mo vs 15.9 mo, respectively; P=0.005). CONCLUSION: Our results demonstrate that IFN-α plus lamivudine combination therapy does not increase the sustained response, compared to lamivudine. However, combination therapy reduces the likelihood of VBR due to YMDD mutants and prolongs the time period until the breakthrough development.     

Budesonide reduces neutrophilic but not functional airway response to ozone in mild asthmatics.

Ambient ozone concentration is related to asthma exacerbation, but few findings are available regarding the effects of pharmacologic asthma treatment on this relationship. The purpose of this study was to investigate whether inhaled corticosteroids inhibit ozone-induced airway neutrophilic inflammation, as detected in induced sputum, and reduce functional response to ozone exposure. Eleven subjects with mild persistent asthma were exposed for 2 h, on separate days, to 0.27 ppm ozone and to air in random order, before and after 4 wk of treatment with budesonide (400 microg twice daily). Before exposure, 1 and 2 h after the beginning of exposure, and 6 h after the end of exposure, pulmonary function was measured, and a total symptom score questionnaire was completed; 6 h after exposure, sputum was induced with hypertonic saline. Budesonide treatment did not inhibit the functional response to ozone exposure, as determined by reduction in FEV(1) and increase in total symptom score, but it significantly blunted the increase in the percentage of sputum neutrophils and interleukin-8 concentrations in the supernatant (p < 0.05). Therefore, 4 wk of inhaled budesonide blunted the airway neutrophilic inflammatory response but did not prevent the functional impairment of the airways after ozone exposure.     

IL-3 does not affect the allergic airway responses and leukotriene production after allergen challenge in rats.

T cell cytokines are important in asthma. Interleukin (IL)-3, an important growth factor for mast cells and eosinophils has been shown to be increased in the airways of asthmatic subjects, but its precise functions are uncertain. The aim of this study was to determine whether recombinant human (rh) IL-3 affected airway responses, inflammation and leukotriene production after antigen challenge in Brown Norway (BN) rats. Having established that rhIL-3 (>12.5 microg subcutaneously b.i.d. for 4 days) caused a doubling of mast cell numbers in the airways of BN rats, sensitized rats were pretreated with rhIL-3 (50 microg) or vehicle subcutaneously b.i.d. for 4 days. Ovalbumin (OA) challenge was performed and the early (EAR), and late (LAR) airway response and the associated biliary leukotriene (LT) excretion measured. The pulmonary cellularity was evaluated by means of lung digestion 8 h after challenge. IL-3 increased the number of eosinophils isolated from the lungs after antigen challenge (0.77+/-0.23 versus 0.38+/-0.12 x 10(6) cells, p=0.03). However, there were no effects on the numbers of neutrophils, lymphocytes and macrophages. Neither the EAR nor the LAR after OA challenge were altered by IL-3. Likewise biliary cysteinyl-LT excretion was similar in IL-3-treated animals and controls after challenge. In conclusion, interleukin-3 caused an increase in the numbers of mast cells and eosinophils around the airways without affecting the magnitude of either early or late airway responses or mediator release after antigen challenge. The present results suggest that airway inflammation can occur in rats without increasing the allergic asthmatic response.     

Oral imatinib treatment reduces early fibrogenesis but does not prevent progression in the long term

BACKGROUND/AIMS: Transactivated hepatic stellate cells (HSCs) represent the key source of extra cellular matrix (ECM) in fibrotic liver. Imatinib, a potent inhibitor of the PDGF receptor tyrosine kinase, reduces HSC proliferation and fibrogenesis when treatment is initiated before fibrosis has developed. We tested the antifibrotic potential of imatinib in ongoing liver injury and in established fibrosis. METHODS: BDL-rats were gavage fed with 20 mg/kg/d imatinib either early (days 0-21) or late (days 22-35) after BDL. Untreated BDL-rats served as controls. ECM and activated HSCs were quantified by morphometry. Tissue activity of MMP-2 was determined by gelatin zymography. mRNA expression of TIMP-1 and procollagen alpha1(I) were measured by RT-PCR. Liver tissue concentration of imatinib was measured by tandem mass spectrometry. RESULTS: Early imatinib reduced ECM formation by 30% (P=0.0455) but left numbers of activated HSCs and procollagen I expression unchanged. MMP-2 activity and TIMP-1 expression were reduced by 50%. Late imatinib treatment did not alter histological or molecular markers of fibrogenesis despite high imatinib tissue levels. CONCLUSIONS: The antifibrotic effectiveness of imatinib is limited to the early phase of fibrogenesis. In ongoing liver injury other mediators most likely compensate for the inhibited PDGF effect.     

Low-dose acarbose does not delay digestion of starch but reduces its bioavailability.

AIMS: Slowly digestible starch is associated with beneficial health effects. The glucose-lowering drug acarbose has the potential to retard starch digestion since it inhibits alpha-amylase and alpha-glucosidases. We tested the hypothesis that a low dose of acarbose delays the rate of digestion of rapidly digestible starch without reducing its bioavailability and thereby increasing resistant starch flux into the colon. METHODS: In a crossover study, seven healthy males ingested corn pasta (50.3 g dry weight), naturally enriched with (13)C, with and without 12.5 mg acarbose. Plasma glucose and insulin concentrations, and (13)CO(2) and hydrogen excretion in breath were monitored for 6 h after ingestion of the test meals. Using a primed continuous infusion of D-[6,6-(2)H(2)] glucose, the rate of appearance of starch-derived glucose was estimated, reflecting intestinal glucose absorption. RESULTS: Areas under the 2-h postprandial curves of plasma glucose and insulin concentrations were significantly decreased by acarbose (-58.1 +/- 8.2% and -72.7 +/- 7.4%, respectively). Acarbose reduced the overall 6-h appearance of exogenous glucose (bioavailability) by 22 +/- 7% (mean +/-se) and the 6-h cumulative (13)CO(2) excretion by 30 +/- 6%. CONCLUSIONS: These data show that in healthy volunteers a low dose of 12.5 mg acarbose decreases the appearance of starch-derived glucose substantially. Reduced bioavailability seems to contribute to this decrease to a greater extent than delay of digestion. This implies that the treatment effect of acarbose could in part be ascribed to the metabolic effects of colonic starch fermentation.