Cardio-selective and non-selective beta-blockers in chronic obstructive pulmonary disease: effects on bronchodilator response and exercise.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) often have co-existing cardiovascular disease and may require beta-blocker treatment. There are limited data on the effects of beta-blockers on the response to inhaled beta2-agonists and exercise capacity in patients with COPD. OBJECTIVE: To determine the effects of different doses of cardio-selective and non-selective beta-blockers on the acute bronchodilator response to beta-agonists in COPD, and to assess their effects on exercise capacity. METHODS: A double-blind, randomized, three-way cross-over (metoprolol 95 mg, propranolol 80 mg, placebo) study with a final open-label high-dose arm (metoprolol 190 mg). After 1 week of each treatment, the bronchodilator response to salbutamol was measured after first inducing bronchoconstriction using methacholine. Exercise capacity was assessed using the incremental shuttle walk test. RESULTS: Eleven patients with moderate COPD were recruited. Treatments were well-tolerated although two did not participate in the high-dose metoprolol phase. The area under the salbutamol-response curve was lower after propranolol compared with placebo (P=0.0006). The area under the curve also tended to be lower after high-dose metoprolol (P=0.076). The per cent recovery of the methacholine-induced fall was also lower after high-dose metoprolol (P=0.0018). Low-dose metoprolol did not alter the bronchodilator response. Oxygen saturation at peak exercise was lower with all beta-blocker treatments (P=0.046). CONCLUSION: Non-selective beta-blockers and high doses of cardio-selective beta-blockers may inhibit the bronchodilator response to beta2-agonists in patients with COPD. Beta-blockers were also associated with lower oxygen saturation during exercise. The clinical significance of these adverse effects is uncertain in view of the benefits of beta-blocker treatment for cardiovascular disease.

A gene-based risk score for lung cancer susceptibility in smokers and ex-smokers.

BACKGROUND: Epidemiological and family studies suggest that lung cancer results from the combined effects of age, smoking and genetic factors. Chronic obstructive pulmonary disease (COPD) is also an independent risk factor for lung cancer and coexists in 40-60% of lung cancer cases. METHODS: In a two-stage case-control association study, genetic markers associated with either susceptibility or protection against lung cancer were identified. In a test cohort of 439 Caucasian smokers or ex-smokers, consisting of healthy smokers and lung cancer cases, 157 candidate single nucleotide polymorphisms (SNPs) were screened. From this, 30 SNPs were identified, the genotypes (codominant or recessive model) of which were associated with either the healthy smokers (protective) or lung cancer (susceptibility) phenotype. After genotyping of this 30-SNP panel in a second validation cohort of 491 subjects and using the same protective and susceptibility genotypes from our test cohort, a 20-SNP panel was selected on the basis of independent univariate analyses. RESULTS: Using multivariate logistic regression, including the 20 SNPs, it was also found that age, history of COPD, family history of lung cancer and gender were significantly and independently associated with lung cancer. CONCLUSIONS: When numeric scores were assigned to both the SNP and demographic data, and sequentially combined by a simple algorithm in a risk model, the composite score was found to be linearly related to lung cancer risk with a bimodal distribution. Genetic data may therefore be combined with other risk variables from smokers or ex-smokers to identify individuals who are most susceptible to developing lung cancer.

Pseudomonas aeruginosa transmission is infrequent in New Zealand cystic fibrosis clinics.

Pseudomonas aeruginosa is an important pathogen in cystic fibrosis (CF). Although most patients harbour unique P. aeruginosa isolates, some clinics report patients sharing common strains. The overall importance of person-to-person transmission in P. aeruginosa acquisition and whether routine patient segregation is necessary remains uncertain. The present authors therefore investigated the extent of P. aeruginosa transmission in New Zealand CF clinics. New Zealand's seven major CF centres were assessed, combining epidemiological data with computer-assisted SalI DNA fingerprinting of 496 isolates from 102 patients. One cluster of related isolates was significantly more prevalent in the largest clinic than expected by chance. The seven patients with isolates belonging to this cluster had more contact with each other than the remaining patients attending this centre. No other convincing evidence of transmission was found in any of the other smaller clinics. Three P. aeruginosa strains believed to be transmissible between patients in Australian and British CF clinics are present in New Zealand, but there was no definite evidence they had spread. Pseudomonas aeruginosa transmission is currently infrequent in New Zealand cystic fibrosis clinics. This situation could change rapidly and ongoing surveillance is required. The current results confirm that computer-assisted SalI DNA fingerprinting is ideally suited for such surveillance.

Audit of acute admissions of chronic obstructive pulmonary disease: inpatient management and outcome.

BACKGROUND: Despite the publication of several management guidelines for exacerbations of chronic obstructive pulmonary disease (COPD), there is little information on standards of care in clinical practice. The aim of this audit was to examine the assessment, management and outcome of COPD admissions to a secondary and tertiary referring New Zealand hospital during two different seasons. Compliance to current recommendations was examined and compared with the available international published work. METHODS: All COPD-related admissions to Waikato Hospital during the months of May and October 2004 were reviewed. Ninety-four cases (from 84 patients) were audited. RESULTS: General characteristics, clinical features and lung function tests were similar to that of other cohorts. Twenty-three per cent of the admissions were Maori and the mean age of Maori admissions were significantly less than that of the non-Maori admissions (57 and 72 years, respectively; P = 0.0001). The geometric mean length of stay was 3.4 days, which is significantly less than most other reported hospital lengths of stays related to exacerbations of COPD. Fifty-five per cent of the cohort was admitted more than once to the hospital for COPD in the 12 months before the index admission. Thirteen per cent of all admissions received assisted ventilation. Overall 30-day mortality was 8% and the 12-month mortality was 31%. Decreased body mass index was a risk factor for death as was an increased CURB-65 (confusion, urea, respiratory rate, blood pressure age) score--a simple bedside assessment score, which has previously been used to predict mortality in patients with community-acquired pneumonia. CONCLUSION: This audit documented the general characteristics, assessment, management and outcome of the COPD admissions to a secondary New Zealand hospital. Further investigations into factors contributing to shorter length of stay and predictors of mortality are needed.

Elevated procalcitonin as a diagnostic marker in meningococcal disease.

Patients with meningococcal disease who seek medical attention can create a diagnostic dilemma for clinicians due to the nonspecific nature of the disease's presentation. This study assesses the diagnostic accuracy of procalcitonin levels in the setting of meningococcal disease. Two emergency department cohorts (A and B) were studied between 2002 and 2005, during the current epidemic of serogroup B meningococcal disease in New Zealand. Cohort A consisted of 171 patients, all with confirmed meningococcal disease (84 children, 87 adults). Cohort B consisted of a large (n=1,524) consecutively recruited population of febrile patients who presented to the emergency department, 28 of whom had confirmed meningococcal disease. Within the meningococcal disease cohort (cohort A), the geometric mean procalcitonin level was 9.9 ng/ml, with levels being higher in children than in adults (21.6 vs. 4.6 ng/ml, p=0.01). The overall sensitivity of elevated procalcitonin, using a cutoff of 2.0 ng/ml in children and 0.5 ng/ml in adults, was 0.93 (95%CI: 0.88-0.96). Despite the higher cutoff level for paediatric patients, a trend towards greater sensitivity existed in children (0.96 vs. 0.90; p=0.08). Elevated procalcitonin was correlated with whole blood meningococcal load (r=0.50) and Glasgow Meningococcal Sepsis Prognostic Score (r=0.40). Within the cohort of patients who were febrile on presentation (cohort B), the specificity of elevated procalcitonin in meningococcal disease was 0.85 (95% CI: 0.83-0.87), the positive and negative likelihood ratios were 6.1 and 0.08, respectively, and the sensitivity of elevated procalcitonin (0.93; 95% CI: 0.76-0.99) was corroborated. Measurement of procalcitonin is a useful tool in patients with nonspecific febrile illnesses when the possibility of meningococcal disease is present. The diagnostic accuracy surpasses that of current early laboratory markers, allowing results to be used to guide decisions about patient management.

Functional variants of antioxidant genes in smokers with COPD and in those with normal lung function.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is predominantly the consequence of chronic smoking exposure, but its development may be influenced by genetic variants that affect lung remodelling, inflammation, and defence from oxidant stress. A study was undertaken to determine whether genetic variants within genes encoding the antioxidant enzymes superoxide dismutase (SOD) and catalase may be associated with the development of impaired lung function. METHODS: In a case-control study, the allele and genotype frequencies of functional polymorphisms from SOD1 (CuZnSOD), SOD2 (MnSOD), SOD3 (extracellular SOD), and catalase (CAT) were compared in chronic smokers with normal lung function (resistant smokers) and in those with COPD. RESULTS: Significantly higher frequencies of the G allele and CG/GG genotype of the 213 SOD3 polymorphism were found in resistant smokers (odds ratios (ORs) 4.3 (95% CI 1.5 to 13.3) and 4.2, 95% CI 1.4 to 13.3), Bonferroni corrected p = 0.02 and p = 0.02, respectively) than in those with COPD. There were no differences between the COPD and resistant smokers for the SOD1, SOD2, or CAT polymorphisms tested. CONCLUSIONS: The 213Gly variant of the SOD3 gene may, through antioxidant or anti-inflammatory effects, confer a degree of resistance in some smokers to the development of COPD.

Transforming growth factor-beta1 genotype and susceptibility to chronic obstructive pulmonary disease.

BACKGROUND: Only a few long term smokers develop symptomatic chronic obstructive pulmonary disease (COPD) and this may be due, at least in part, to genetic susceptibility to the disease. Transforming growth factor beta1 (TGF-beta1) has a number of actions that make it a candidate for a role in the pathogenesis of COPD. We have investigated a single nucleotide polymorphism at exon 1 nucleotide position 29 (T-->C) of the TGF-beta1 gene that produces a substitution at codon 10 (Leu-->Pro). METHODS: The frequency of this polymorphism was determined in 165 subjects with COPD, 140 healthy blood donors, and 76 smokers with normal lung function (resistant smokers) using the polymerase chain reaction and restriction enzyme fragment length polymorphism. RESULTS: The distribution of genotypes was Leu-Leu (41.8%), Leu-Pro (50.3%), and Pro-Pro (7.9%) for subjects with COPD, which was significantly different from the control subjects (blood donors: Leu-Leu (29.3%), Leu-Pro (52.1%) and Pro-Pro (18.6%), p=0.006; resistant smokers: Leu-Leu (28.9%), Leu-Pro (51.3%) and Pro-Pro (19.7%), p=0.02). The Pro10 allele was less common in subjects with COPD (33%) than in blood donors (45%; OR=0.62, 95% CI 0.45 to 0.86, p=0.005) and resistant smokers (45%; OR=0.59, 95% CI 0.40 to 0.88, p=0.01). CONCLUSIONS: The proline allele at codon 10 of the TGF-beta1 gene occurs more commonly in control subjects than in individuals with COPD. This allele is associated with increased production of TGF-beta1 which raises the possibility that TGF-beta1 has a protective role in COPD.

Evaluation of a rapid immunochromatographic test for detection of Streptococcus pneumoniae antigen in urine samples from adults with community-acquired pneumonia.

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia but is undoubtedly underdiagnosed. Isolation of S. pneumoniae from blood is specific but lacks sensitivity, while isolation of S. pneumoniae from sputum may represent colonization. We evaluated a new immunochromatographic test (NOW S. pneumoniae urinary antigen test; Binax, Portland, Maine) that is simple to perform and that can detect S. pneumoniae antigen in urine within 15 min. Urine samples from 420 adults with community-acquired pneumonia and 169 control patients who did not have pneumonia were tested. Urine from 315 (75%) of the pneumonia patients and all controls was tested both before and after 25-fold concentration, while the remaining 105 samples were only tested without concentration. S. pneumoniae urinary antigen tests were positive for 120 (29%) patients with pneumonia and for none of the controls. Of the urine samples tested with and without concentration, 96 were positive, of which 6 were positive only after concentration. S. pneumoniae antigen was detected in the urine from 16 of the 20 (80%) patients with blood cultures positive for S. pneumoniae and from 28 of the 54 (52%) patients with sputum cultures positive for S. pneumoniae. The absence of S. pneumoniae antigen in the urine from controls suggests that the specificity is high. Concentration of urine prior to testing resulted in a small increase in yield. The NOW S. pneumoniae urinary antigen test should be a useful adjunct to culture for determining the etiology of community-acquired pneumonia in adults.

Trial of roxithromycin in subjects with asthma and serological evidence of infection with Chlamydia pneumoniae.

An association has been reported between chronic infection with Chlamydia pneumoniae and the severity of asthma, and uncontrolled observations have suggested that treatment with antibiotics active against C. pneumoniae leads to an improvement in asthma control. We studied the effect of roxithromycin in subjects with asthma and immunoglobulin G (IgG) antibodies to C. pneumoniae > or = 1:64 and/or IgA antibodies > or = 1:16. A total of 232 subjects, from Australia, New Zealand, Italy, or Argentina, were randomized to 6 wk of treatment with roxithromycin 150 mg twice a day or placebo. At the end of 6 wk, the increase from baseline in evening peak expiratory flow (PEF) was 15 L/min with roxithromycin and 3 L/min with placebo (p = 0.02). With morning PEF, the increase was 14 L/min with roxithromycin and 8 L/min with placebo (NS). In the Australasian population, the increase in morning PEF was 18 L/min and 4 L/min, respectively (p = 0.04). At 3 mo and 6 mo after the end of treatment, differences between the two groups were smaller and not significant. Six weeks of treatment with roxithromycin led to improvements in asthma control but the benefit was not sustained. Further studies are necessary to determine whether the lack of sustained benefit is due to failure to eradicate C. pneumoniae.

Chlamydia pneumoniae serological status is not associated with asthma in children or young adults.

BACKGROUND: The factors that cause the allergic sensitization and inflammation in asthma still remain to be clarified. A role for Chlamydia pneumoniae has been suggested although serological studies have produced conflicting findings. This study aims to clarify the relationship between asthmatic variables and C. pneumoniae serological status. METHODS: A case-control study was undertaken on an asthma-enriched subset from a longitudinal birth cohort. In all, 198 subjects (96 with self-reported asthma) had C. pneumoniae serology (microimmunofluorescence [MIF] IgG, IgA) undertaken at age 11 and age 21 and assessment made in relation to a number of asthma variables. RESULTS: The only statistically significant finding was in subjects self-reporting asthma at age 21 who had evidence of lower IgG titres (P = 0.046), a finding in the opposite direction to that expected from the hypothesis. Subjects with high IgG titres (> or =128) were less likely to have reported ever having asthma; odds ratio (OR) = 0.29, (95% CI: 0.10-0.87). No association existed between symptoms suggestive of asthma in the previous 12 months and either IgG (P = 0.127) or IgA (P = 0.189) antibody titres at age 21. Likewise, no association was found between symptoms suggestive of asthma in the previous two years and C. pneumoniae IgG antibody titre (P = 0.81) at age 11. There was no evidence of an association with any of the other variables examined at either age 11 or age 21. These included use of inhaled steroids, serum IgE levels, airway responsiveness, skin test evidence of atopy, or smoking status. CONCLUSION: The results of this study suggest that C. pneumoniae infection when diagnosed by MIF serology is not a major risk factor for the development of asthma in children and young adults. The study has not, however, addressed the role this organism may play in specific asthmatic subsets or asthma exacerbations.

Chlamydia pneumoniae DNA is not detectable within sarcoidosis tissue.

Sarcoidosis is a granulomatous disease of unknown etiology. Recent studies have suggested the possibility of a bacterial origin with Chlamydia pneumoniae being one of the many bacteria considered. The aim of this study was to use the polymerase chain reaction (PCR) in an attempt to identify C. pneumoniae within fresh/frozen sarcoidosis tissue. Tissue from 20 sarcoidosis patients and 17 controls was evaluated. DNA was extracted from all tissue specimens and PCR amplified with primers specific for C. pneumoniae. All study tissues were negative for the presence of DNA sequences from C. pneumoniae. These findings could not be attributed to PCR inhibition or to lack of sensitivity of the PCR assay. The negative finding suggests either that there is no involvement between C. pneumoniae and sarcoidosis or that, having incited granulomata formation, it is no longer present in detectable amounts.

Patterns of activity in host-seeking adult Ixodes scapularis (Acari: Ixodidae) and host-produced kairomones.

Adult blacklegged ticks, Ixodes scapularis Say, were confined to clay islands each surmounted with a vertical glass rod, and tick activities were videotaped continuously for 48 h. Some rods were treated basally or apically with substances rubbed from pelage associated with the tarsal or interdigital glands of white-tailed deer, Odocoileus virginianus (Zimmermann). Except for the activity immediately following their release, tick activity on both days was greatest during the period from 1700 to 2300 hours, which coincided with the onset of scotophase. Ticks were most active when rods had interdigital gland substances applied to their basal 2 cm, whereas they were least active when confined with rods treated with tarsal gland substances on their apical 2 cm. Overall, ticks spent more time on the apical 2 cm of the glass rods during the scotophase than during the photophase. The highest level of apical arrestment among treated and untreated rods occurred when the rod tips were treated with tarsal gland substances, with female ticks on the apical 2 cm of the rods 70-100% of every 3-h period beginning with the period from 2000 to 2300 hours on day 1. In contrast, when tarsal gland substances were applied to the basal 2 cm of the rods, the ticks spent < 40% of every period on day 2 on the rod tips.

Field and laboratory responses of adult Ixodes scapularis (Acari: Ixodidae) to kairomones produced by white-tailed deer.

In a field test, adult blacklegged ticks, Ixodes scapularis Say, of both sexes exhibited an arrestant response to substances associated with external glands on the legs of white-tailed deer, Odocoileus virginianus (Zimmermann), their principal host. Substances rubbed from the pelage covering tarsal and interdigital glands were applied to artificial vantage points simulating vegetation on which I. scapularis adults wait for host contact. A combination of tarsal substances (applied to the apex of the simulated vantage point) and interdigital gland substances (applied to the horizontal base) elicited a greater response than either treatment alone. A minimal response was observed on untreated vantage points. In laboratory bioassays using glass tubing as vantage points, substances associated with preorbital glands of deer elicited a strong arrestant response among I. scapularis females, whereas samples rubbed from the forehead, back, and a nonglandular area on deer tarsi evoked weak arrestant responses. These results support the hypothesis that the kairomonal properties of host-generated residues, either in conjunction with or in lieu of the effects of carbon dioxide, help account for the prevalence of host-seeking ticks along animal trails.

Traps and baits for flies (Diptera) on Pacific Islands.

Studies conducted on Oahu, HI, and on islands of the Kwajalein Atoll, Marshall Islands, demonstrated that adult house flies, Musca domestica L., were attracted to a mixture of cooked rice and chicken and to a commercial bait, whereas adults of Chrysomya megacephala F. and Musca sorbens Wiedemann were attracted to shark fluids or to ripe breadfruit. M. domestica and M. sorbens could be captured in standard inverted-cone traps, whereas C. megacephala could be captured in traps fitted with horizontal entry cones or in cone traps in which the bait was placed inside the cone chamber. M. sorbens and C. megacephala were killed by horizontal electric grids placed over yellow plastic or paper at ground level. M. sorbens was attracted to 15-cm cubes, but not to larger objects.

Relationship between CD4 lymphocyte count and AIDS mortality, 1986-1991.

OBJECTIVE: To determine the relationship between CD4 lymphocyte count and short-term AIDS mortality, and to determine whether this relationship changed during 1986-1991. DESIGN: A retrospective analysis of CD4 lymphocyte counts in patients dying with AIDS and estimation of median survival in patients with a CD4 count < .50 x 10(6)/l. METHODS: Absolute CD4 lymphocyte count in the 6 months before death was available for 178 patients. The terminal CD4 count was compared in five cohorts of patients dying in 12-month periods from July 1986. Kaplan-Meier survival curves were constructed using survival from date of first absolute CD4 count < 50 x 10(6)/l in 271 patients and compared for each yearly cohort. RESULTS: The median terminal CD4 lymphocyte count for all patients was 10 x 10(6)/l. The median terminal CD4 counts for each yearly cohort were: 1986/1987, 100 (n = 13); 1987-1988, 10 (n = 27); 1988-1989, 10 (n = 30); 1989/1990, 20 (n = 59); 1990-1991, 10 (n = 58). There was a significant difference in the terminal CD4 count in the 1986-1987 period compared with all other years combined, but no further changes after 1987-1988. The median survival of all patients from date of first CD4 count < 50 x 10(6)/l was 11.9 months. There was no significant difference in median survival in each yearly cohort. CONCLUSIONS: There is a close correlation between CD4 lymphocyte count and short-term mortality in AIDS. Therapeutic advances over the past 5 years are not reflected by changes in CD4 count before death or improved survival in patients with very low CD4 counts.

Solar-powered electrocuting trap for controlling house flies and stable flies (Diptera: Muscidae).

A portable trap was constructed that was visually attractive to house flies, Musca domestica L., and stable flies, Stomoxys calcitrans (L.), outdoors. The trap was made of a white and yellow pyramid placed on top of a white vertical base that had large cutouts in each side. Attracted flies were killed by means of solar-powered electrocuting grids. Three traps killed an average of 1,360 house flies and 1,190 stable flies per day at a manure dump and were effective in attracting flies under both cool (< 23 degrees C) and warm (> 30 degrees C) temperatures. Both species of flies were most attracted to the eastern side of the trap, but house flies preferred yellow in cool mornings and white in warm afternoons. When air temperatures were > 30 degrees C, both house flies and stable flies went into the shaded base of the trap or into tunnels. Most house flies were killed on the pyramidal top of the trap, whereas most stable flies were killed on the vertical base. Opaque fiberglass tunnels with central electrocuting grids were simpler and cheaper, although less effective, for stable flies.

Clinical spectrum of dengue fever in travellers.

Dengue fever is a mosquito borne viral disease endemic throughout the tropics. Three cases are presented which illustrate the clinical spectrum of dengue fever in travellers. The discussion centres on diagnostic and preventive aspects.

Circadian rhythm of trehalose in the face fly Musca autumnalis de Geer.

Trehalose levels were determined over two 24 hr spans in groups of face fly adults 3-4 days after emergence from the puparium. Face fly pupae were placed in rearing chambers at 27 degrees C in a staggered light-dark regimen, LD 16:8, so that at a given clock hour, samples could be obtained at several different hours after lights on (HALO). Trehalose was determined in hemolymph collected from a puncture in the intersegmental membrane of the abdomen. Treated hemolymph samples were passed through a Bio-Rad Amino 5-S disaccharide column and a Waters 410 refractive index detector was used to differentiate among sugars. The circadian acrophase derived by cosinor analysis in hemolymph trehalose (when the values were 25.49 and 26.86 micrograms/microliters on the first and second days respectively) occurred at -226 degrees (ca 15 HALO) and the bathyphase at 24 HALO. The mesor = 11.82 micrograms/microliters trehalose, the amplitude = 8.57 micrograms/microliters trehalose and the P-value for presence of a rhythm was 0.003. Based on these data, differences between control and test flies in a bioassay of hypertrehalosemic activity would be most easily observed at 0-8 HALO, while exogenous hypotrehalosemic activity would be best assayed at 12-20 HALO.

Reimer-Tiemann adducts as potential insect antifeedant agents Reviewing the structure-activity relationship theory of the antifeedant, warburganal.

Structure-activity relationships of naturally occurring enedials with antifeedant activity againstSpodoptera species have been extended via the synthesis and bioassay of a series of Reimer-Tiemann adducts. The activities attributed to the different chemical structures of these and other analogs interacting with the chemoreceptor site have been observed; a three-pronged mode of substrate binding via aromatic pyrrole formation, Michael addition of free sulfhydryl moieties, and van der Waals interactions of the A ring has been postulated to account for these observations.