VEGFR-2, CXCR-2 and PAR-1 germline polymorphisms as predictors of survival in pancreatic carcinoma.

BACKGROUND: Hypoxic environment of pancreatic cancer (PC) implicates high vascular in-growth, which may be influenced by angiogenesis-related germline polymorphisms. Our purpose was to evaluate polymorphisms of vascular endothelial growth factor receptor 2 (VEGFR-2), CXC chemokine receptor 2 (CXCR-2), proteinase-activated receptor 1 (PAR-1) and endostatin (ES) as prognostic markers for disease-free (DFS) and overall survival (OS) in PC. PATIENTS AND METHODS: Genotyping of 173 patients, surgically treated for PC between 2004 and 2011, was carried out by TaqMan(®) genotyping assays or polymerase chain reaction. Chi-square test, Kaplan-Meier estimator and Cox regression hazard model were used to assess the prognostic value of selected polymorphisms. RESULTS: VEGFR-2 -906 T/T and PAR-1 -506 Del/Del genotypes predicted longer DFS (P = 0.003, P = 0.014) and OS (VEGFR-2 -906, P = 0.011). CXCR-2 +1208 T/T genotype was a negative predictor for DFS (P < 0.0001). Combined analysis for DFS and OS indicated that patients with the fewest number of favorable genotypes simultaneously present (VEGFR-2 -906 T/T, CXCR-2 +1208 C/T or C/C and PAR-1 -506 Del/Del) were at the highest risk for recurrence or death (P < 0.0001). CONCLUSION: VEGFR-2 -906 C>T, CXCR-2 +1208 C>T and PAR-1 -506 Ins/Del polymorphisms are potential predictors for survival in PC.

Comparison of recommendations for radiotherapy from two contemporaneous thoracic multidisciplinary meeting formats: co-located and video conference.

BACKGROUND: Thoracic multidisciplinary meetings (TMDM) are a key component of lung cancer patient management. The optimal design, organisation and function of TMDM are uncertain, and different models may serve different purposes. In the Auckland/Northland region, there are two contemporaneous weekly TMDM using different formats; one is a co-located TMDM (C-TMDM), and the other is a video conference TMDM (V-TMDM) connecting different locations. AIMS: To determine whether the rates of referral for radiotherapy (RT) and concordance between recommendations for RT and actual treatment received differed between the two TMDM formats. METHOD: A retrospective review of demographical and clinical data for cases referred for RT from both TMDM between January-June 2009 and the actual RT delivered. RESULTS: Seventy-nine and 31 lung cancers were referred for RT from the co-located TMDM and the video conference TMDM respectively. While there were significant differences in demographics related to areas of domicile, there were no significant differences between the TMDM in (i) the proportion of cases referred for RT that received RT, (ii) the intent of treatment recommended by the TMDM and the intent of RT delivered, or (iii) transit times to commencement of RT between cases referred from the different TMDM. CONCLUSION: The similar results from the different formats of TMDM indicate that cases discussed with the use of e-health technologies are not disadvantaged with respect to recommended therapy nor in the appropriateness of decisions of the TMDM. Use of such technology may reduce the existing disparities in health outcomes between urban and rural patients.

Inhaled dry powder mannitol in cystic fibrosis: an efficacy and safety study.

This international phase III study of inhaled dry powder mannitol was a randomised, double-blind, 26-week study, followed by a further 26-week, open-label (OL) extension. 324 cystic fibrosis (CF) patients were randomised, in a 3:2 ratio, to mannitol (400 mg b.i.d.) and control groups. The primary efficacy end-point was to determine the change in forced expiratory volume in 1 s (FEV1) over the double-blind phase. Secondary end-points included changes in forced vital capacity and pulmonary exacerbations. A significant improvement in FEV1 was seen over 26 weeks (p<0.001) and was apparent by 6 weeks, irrespective of concomitant recombinant human deoxyribonuclease (rhDNase) use. At 26 weeks, there was a significant improvement in FEV1 of 92.9 mL for subjects receiving mannitol compared with controls (change from baseline 118.9 mL (6.5%) versus 26.0 mL (2.4%); p<0.001). Improvements in FEV1 were maintained up to 52 weeks in the OL part of the study. There was a 35.4% reduction in the incidence of having an exacerbation on mannitol (p=0.045). The incidence of adverse events (AEs) was similar in both groups, although treatment-related AEs were higher in the mannitol compared with the control group. The most common mannitol-related AEs were cough, haemoptysis and pharyngolaryngeal pain. Mannitol showed sustained, clinically meaningful benefit in airway function in CF, irrespective of concomitant rhDNase use. Mannitol appears to have an acceptable safety profile for patients with CF.

Isolated nocturnal desaturation in COPD: prevalence and impact on quality of life and sleep.

BACKGROUND AND AIMS: The clinical impact of nocturnal desaturation on health related quality of life (HRQL) and sleep in chronic obstructive pulmonary disease (COPD) has been little studied. The aim of this study was to evaluate the prevalence and clinical impact of nocturnal desaturation in a typical outpatient population with COPD. PATIENTS AND METHODS: Between 2002 and 2005, consecutive patients with COPD attending outpatient services at the study centre underwent resting oximetry if they were not on domiciliary oxygen therapy. If their resting saturations were less than 95%, overnight pulse oximetry was performed. Significant nocturnal desaturation was defined as spending more than 30% of at least one of two nights with a saturation of less than 90%. The Chronic Respiratory Questionnaire (CRQ) and Short Form 36 (SF36) were used to assess HRQL, and the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Score (ESS) and Functional Outcomes of Sleep (FOSQ) questionnaires were used to assess sleep quality and daytime function. RESULTS: Of 1104 patients, 803 underwent resting oximetry and 79 had resting oxygen saturations of less than 95%. Of these, 59 agreed to undergo overnight oximetry (mean age 70 years, forced expiratory volume in 1 s 37.2% predicted, resting Po(2) on air 8.9 kPa). Significant nocturnal desaturation was seen in 29 (49.2%) of the 59 subjects. Assuming the less hypoxic patients do not have nocturnal desaturation, the prevalence of nocturnal desaturation in the whole clinic population could be estimated at 4.8%. There were no significant differences in CRQ, SF36, PSQI, ESS or FOSQ scores for desaturators compared with non-desaturators. CONCLUSION: Significant nocturnal desaturation was common in patients with COPD with resting saturations of less than 95%, but was estimated to have a prevalence of less than 5% in the whole outpatient population. Nocturnal desaturation was not associated with impairment of HRQL, sleep quality or daytime function.

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.

Management of stages I and II non-small-cell lung cancer in a New Zealand study: divergence from international practice and recommendations.

BACKGROUND: Lung cancer survival statistics for New Zealand (NZ) are poor relative to Australia, USA, Canada and some European countries for reasons that are unknown. As patients with early-stage non-small-cell lung cancer (NSCLC) have the highest chance of survival, appropriate management disproportionately influences survival rates. The aim of this study was to assess management of stage I/II NSCLC, whether management differed from international practice, and factors influencing curative management. METHODS: Management of patients with stages I and II NSCLC was determined from an audit of secondary care in Auckland and Northland for patients with lung cancer diagnosed in 2004 (565). RESULTS: Of the 142 cases with stage I or II NSCLC, 79 patients (56%) were treated with curative intent and 61 (44%) were managed palliatively. Of those treated curatively, 69 underwent surgical resection, 9 received definitive radiation therapy and a single patient received concurrent chemo-irradiation. Of those managed palliatively, 21 received anticancer treatment and 40 received supportive care. Increasing age and comorbidity reduced the chances of receiving curative treatment (P < 0.001, P = 0.004, respectively); however, discussion at a multidisciplinary meeting was associated with increased likelihood of curative management (P < 0.001). Disparity between NZ and overseas practice increased with increasing age and comorbidity. Only half of those managed curatively commenced treatment within internationally recommended time frames. CONCLUSION: Relatively fewer patients received potentially curative treatment in this NZ study than in countries with better survival outcomes and many were not managed within recommended time frames. Management differences increased with increasing age and comorbidity, possibly suggesting more nihilistic attitudes in NZ.

Structure of the glycan chain from the surface layer glycoprotein of Clostridium thermohydrosulfuricum L77-66.

The thermophilic eubacterium Clostridium thermohydrosulfuricum L77-66 is covered by a crystalline surface layer composed of identical glycoprotein subunits which are arranged in a hexagonal lattice with centre-to-centre spacings of approx. 14.3 nm. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis of cell wall preparations showed the presence of several broadened, carbohydrate-containing bands in a molecular mass range of 90 to 200 kDa. A total carbohydrate content of approx. 14% was determined in the purified surface layer glycoprotein. Chemical deglycosylation of this material by trifluoromethanesulfonic acid resulted in the disappearance of the complex banding pattern. Only a single band with a molecular mass of 82 kDa remained visible upon Coomassie staining. After proteolytic digestion of the surface layer glycoprotein a single glycopeptide fraction with an apparent molecular mass of approx. 25 kDa was obtained by gel filtration. Composition analysis, methylation, periodate oxidation and a combination of homonuclear and 1H-detected heteronuclear shift-correlated nuclear magnetic resonance experiments established the following structure for the glycan chain of the surface layer glycoprotein.

Nitric oxide levels and ciliary beat frequency in indigenous New Zealand children.

New Zealand children's morbidity from respiratory disease is high. This study examines whether subclinical ciliary abnormalities underlie the increased prevalence of respiratory disease in indigenous New Zealand children. A prospective study enrolled a group of healthy children who were screened for respiratory disease by questionnaire and lung function. Skin-prick tests were performed to control for atopy. Exhaled and nasal NO was measured online by a single-breath technique using chemiluminescence. Ciliary specimens were obtained by nasal brushings for assessment of structure and function. The ciliary beat frequency (CBF) (median CBF, 12.5 Hz; range, 10.4-16.8 Hz) and NO values (median exhaled NO, 5.6 ppb; range, 2.3-87.7 ppb; median nasal NO, 403 ppb; range, 34-1,120 ppb) for healthy New Zealand European (n=58), Pacific Island (n=61), and Maori (n=16) children were comparable with levels reported internationally. No ethnic differences in NO, atopy, or CBF were demonstrated. Despite an apparently normal ciliary beat, the percentage of ciliary structural defects was 3 times higher than reported controls (9%; range, 3.6-31.3%), with no difference across ethnic groups. In conclusion, it is unlikely that subclinical ciliary abnormalities underlie the increased prevalence of respiratory disease in indigenous New Zealand children. The high percentage of secondary ciliary defects suggests ongoing environmental or infective damage.

Assessment of practical knowledge of self-management of acute asthma.

AIMS: To develop an instrument for the measurement of, and to determine the level of, practical knowledge of self-management of acute asthma. METHODS: Eighty patients with moderate/severe asthma attending a hospital-based asthma clinic responded to an interviewer-administered questionnaire. Subjects were asked to describe the action they would take in response to each of two hypothetical evolving attacks: (1) one of gradually increasing severity and (2) the other developing rapidly. Responses were scored according to the appropriateness of actions taken relevant to the stage of the attack. Transcripts of the responses were scored independently by three of the investigators according to a system based on Thoracic Society of Australia and New Zealand (TSANZ) and British Thoracic Society (BTS) consensus statements on asthma management. A 25-point scale was used on which 0 represented a total lack of appropriate responses and a score of 25 was an optimal response. RESULTS: Interrater and intrarater reliability were excellent. Mean (+/- SD) scores for the slow and rapid onset attacks were 12.8 +/- 4.0 and 13.9 +/- 4.8, respectively. The scores for the two scenarios were predicted by each other (p = 0.002) and by the interviewer's rating of asthma management knowledge (p = 0.0004, p = 0.0001), but not by age, sex, race, previous asthma morbidity, depression, or anxiety. In both scenarios, most patients indicated that they would increase inhaled beta-agonist (85% for slow-onset scenarios and 94% for rapid-onset scenarios, respectively) and use their action plan and/or seek urgent medical advice at an appropriate time (74% and 70%). Although some would measure peak expiratory flow (PEF) initially (54% and 30%), only a minority would continue to monitor PEF in the context of worsening acute asthma (30% and 24%). When a severe life-threatening situation was described, only 50% and 64%, respectively, indicated that they would call emergency services. CONCLUSIONS: Scenarios describing hypothetical asthma attacks are a useful and reproducible method of assessing practical knowledge of self-management of acute asthma. Patients presented with scenarios frequently made errors in their hypothetical responses. The errors made with scenarios, which parallel errors reported in real clinical situations, occurred despite the fact that this patient population had received considerable education and training about how to manage asthma. Most indicated they would not monitor PEF even in an exacerbation of asthma and would not call emergency services despite life-threatening asthma. These scenarios may allow us to explore the gap between knowledge about treatment and actual practice, and perhaps to help close that gap and thus reduce asthma morbidity and mortality.

Differential influences on asthma self-management knowledge and self-management behavior in acute severe asthma.

AIM: While asthma education increases knowledge, it is less clear whether education influences actual patient behavior. To determine whether there are differences between asthma self-management knowledge and the actual behavior of patients during an acute severe asthma attack and to determine which clinical and psychosocial factors are associated with knowledge and behavior. METHODS: Validated hypothetical scenarios describing the development of life-threatening asthma and patients' reported actual behavior were scored (out of 25) using a system based on Thoracic Society of Australia and New Zealand and British Thoracic Society criteria. RESULTS: In 137 patients admitted to the hospital with severe asthma, the pattern of the index attack was slow onset (> or = 6 h) in 96%. The score for the hypothetical attack (knowledge) was 13.8 +/- 4.6, while that for the timeline (behavior) was 10.2 +/- 3.9 (p < 0.001) with 56% and 84%, respectively, having a score of less than 15 (regarded as inadequate). Certain components showed marked discrepancy (eg, appropriately seeking medical help 82% vs 52% (p < 0.001) and calling ambulance 61% vs 23% (p < 0.001). Factors such as physician-patient relationship, previous asthma morbidity, availability of peak flowmeter, action plan, and oral steroids correlated positively with both measures. Knowledge was negatively associated with being non-European, with anxiety, pessimism, and stigmatization. Behavior (but not knowledge) was negatively associated with lack of knowledge of what to do in the index attack, previous emotional counseling, and business failure. Those factors associated with the difference between knowledge and behavior scores (knowledge-behavior gap) were being non-European, anxiety, pessimism, and stigmatization, concerns about medical costs, and the only income for the household being a Social Security benefit. CONCLUSION: There are marked differences between patients' self-management knowledge and their actual behavior, particularly in terms of potentially life-saving actions. Psychological, health-care, and socioeconomic factors have a powerful and differential influence on knowledge and behavior. Improved understanding of the discrepancies between knowledge and behavior and which factors influence them may lead to more effective asthma educational interventions.

The association between asthma drugs and severe life-threatening attacks.

OBJECTIVES: To measure the association between asthma drugs and death or ICU admission due to asthma (severe life-threatening attack of asthma [SLTA]), and to assess the possibility that these associations may not be causal but due to the prescription of these drugs to patients with more severe disease (confounding). DESIGN: Retrospective cohort study of 655 asthmatics who attended an emergency department in 1986 to 1987 followed till death or May 1989. METHODS: Outcome events were death or ICU admission due to asthma (SLTA). All hospital attendances were identified and patients classified at each according to drug exposure and a wide variety of measures of asthma severity. Incidence rates were computed as total outcome events divided by person-time contributed for each subject classified according to drug use and asthma severity. Rate ratio (RR) estimates for severe asthma outcomes associated with use as compared to nonuse of asthma drugs were calculated. Severity markers were identified and used to adjust the crude RR estimates. RESULTS: One hundred five SLTAs (15 deaths, 90 ICU admissions) occurred in 66 patients. Like inhaled fenoterol, oral beta-agonists, theophylline, cromolyn, inhaled steroids, and oral steroids were all associated with an increased risk of SLTA. When adjusted progressively for measures of severity, these increased risks became insignificant except for cromolyn. CONCLUSION: Unadjusted RR estimates for severe asthma events comparing exposure to a particular drug with nonuse are overestimates due to confounding. Control with two severity markers (hospital admission in the last year, use of oral corticosteroid at the time of previous admission) removes some confounding but control for additional severity markers not available in previous studies reduces the effect estimates further. These results suggest that the problem of confounding is substantial in nonrandomized epidemiologic studies of asthma drugs. Previous studies reporting RR estimates are likely to be confounded.

Rapid increase in mast cell numbers in canine central and peripheral airways.

In preliminary studies of antigen-induced airway inflammation, we noted an apparent increase in peribronchiolar mast cell number. Experiments were thus undertaken to investigate the nature of this migration of mast cells into the central and peripheral airway epithelium and to determine its time course. The tracheae and small airways of 10 anesthetized mongrel dogs were exposed via a bronchoscope to Ascaris suum antigen (Ag), fMet-Leu-Phe (fMLP), ovalbumin (OVA), and isotonic saline (SAL). In the central airways, all stimuli provoked a significant increase (P less than 0.05) in mast cell numbers at the base of the airway epithelium within 3 h. In the peripheral airways, only Ag aerosol stimulated a significant mast cell increase compared with unexposed tissue. In a second series of experiments, the trachea of seven dogs were exposed to 0.026, 0.26, and 2.6 micrograms of Ag. The tissue was collected at 1, 3, 6, and 10 h after exposure. In these experiments, there was a significant mast cell increase seen within 1 h but it was not dose dependent. By 6-10 h after exposure, mast cell counts were not significantly different from the unexposed condition, which is consistent with the idea that some of the cells either degranulated or migrated into the airway lumen. We conclude that mast cell migration is an acute response that can be demonstrated within 1 h of stimulation with Ag. The observation that nonimmunological stimuli may, in some cases, also stimulate mast cell movement affords the possibility that this process represents a generalized response to airway irritation.

Hypocapnia-induced constriction of the canine peripheral airways exhibits tachyphylaxis.

Hypocapnia-induced constriction of peripheral airways may be important in regulating the distribution of ventilation in pathological conditions. We studied the response of the peripheral lung to hypocapnia in anesthetized, paralyzed, mechanically ventilated dogs using the wedged bronchoscope technique to measure resistance of the collateral system (Rcs). A 5-min hypocapnic challenge produced a 161 +/- 19% (mean +/- SE) increase in Rcs. The magnitude of this response was not diminished with repeated challenge or by atropine sulfate (1 mg base/kg iv), chlorpheniramine maleate (5 mg base/kg iv), or indomethacin (5 mg/kg iv). The response was reduced by 75% by isoproterenol (5 micrograms/kg iv) (P less than 0.01) and reduced by 80% by nifedipine (20 micrograms/kg iv) (P less than 0.05). During 30-min exposure to hypocapnia the maximum constrictor response occurred at 4-5 min, after which the response attenuated to approximately 50% of the maximum response (mean = 53%, range 34-69%). Further 30-min challenges with hypocapnia resulted in significantly decreased peak responses, the third response being 50% of the first (P less than 0.001). The inability of indomethacin or propranolol to affect the tachyphylaxis or attenuation of the response suggests that neither cyclooxygenase products nor beta-adrenergic activity was involved. Hence, hypocapnia caused a prompt and marked constrictor response in the peripheral lung not associated with cholinergic mechanisms or those involving histamine H1-receptors or prostaglandins. With prolonged exposure to hypocapnia there was gradual attentuation of the constrictor response with continued exposure and tachyphylaxis to repeated exposure both of which would tend to diminish any compensatory effect of hypocapnic airway constriction on the distribution of ventilation.

Thromboxane contributes to the immediate antigenic response of canine peripheral airways.

The actions of specific humoral mediators in the immediate response of the canine peripheral airways to antigen challenge are not well understood. Using a method which allows localized exposure of the peripheral lung to antigen, we investigated the role of locally released thromboxane A2 (TxA2) in the immediate response of collateral airways to aerosolized antigen. In dogs with native sensitivity to Ascaris suum antigen, resistance to flow through the collateral system (Rcs) was measured using a wedged bronchoscope technique. Local administration of antigen aerosol (25 microliters, 1:10,000 dilution) produced a gradual increase in Rcs which reached a maximum of 365% of base line in 4-8 min. Analysis of bronchoalveolar lavage fluid obtained from the exposed segment at the peak of the response demonstrated significantly more TxB2 compared with control lavage samples (41.8 +/- 7.8 pg/ml vs. 27.9 +/- 8.3; P less than 0.025). After inhibition of thromboxane synthase with UK-37,248 (3 mg/kg iv) or OKY-046 (5 mg/kg iv), the increase in Rcs was significantly reduced at 40 s (P less than 0.001) and 2 min (P less than 0.01) after antigen delivery, and the maximal increase was attenuated by 41% (P less than 0.005). In contrast, the magnitude and time course of the airway response to aerosols of a stable thromboxane analog (U-46619) were not affected by blockade. Despite a similar attenuation (42%) of the maximal increase in Rcs by sodium meclofenamate (3 mg/kg iv), this cyclooxygenase inhibitor had no effect on the time course of the antigenic response.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchial blood flow affects recovery from constriction in dog lung periphery.

We investigated the effect of eliminating the bronchial circulation on recovery time from intravenous histamine challenge in canine lung periphery. Results from animals with intact bronchial circulations were compared with a second group in which the left lower lobe was isolated in situ. The pulmonary artery to this lobe was perfused and a bronchoscope was wedged in a small airway, which provided an index of resistance to airflow through the collateral system. The lobe was challenged with intravenous histamine, and the time constant of recovery (tau) from bronchoconstriction was measured. With or without pulmonary blood flow, elimination of the bronchial circulation increased tau 44.4 and 48.5%, respectively. This increase was similar to that found by stopping pulmonary blood flow alone (56.5%). Histamine challenges were also performed in sympathectomized or vagotomized animals with intact bronchial circulations. Neither of these conditions increased tau. We conclude that blood flow through the bronchial circulation affects the recovery time from intravenous histamine challenge in the lung periphery to a degree similar to that of the pulmonary circulation.

Central role of cyclooxygenase in the response of canine peripheral airways to antigen.

We studied the effects of antigen aerosol challenge on the airways of the canine peripheral lung and examined the roles of cyclooxygenase products, histamine, and cholinergic activity in the responses. One-minute deliveries of 1:10,000 or 1:100,000 concentrations of Ascaris suum antigen aerosol through a wedged bronchoscope resulted in mean maximal increases in collateral system resistance (Rcs) of 415 and 177%, respectively, after 4-8 min. Repeated antigen challenge (1:100,000) resulted in significantly decreased responsiveness to antigen after the initial exposure (P less than 0.005). Bronchoalveolar lavage fluid obtained from the isolated, challenged segment had a significant increase in mean (+/- SE) prostaglandin D2 (PGD2) concentration vs. control (222.0 +/- 65.3 vs. 72.7 +/- 19.5 pg/ml; P less than 0.05); histamine concentrations were variable and not significantly different (4.1 +/- 2.6 vs. 1.2 +/- 0.2 ng/ml; P greater than 0.05). In nine experiments, cyclooxygenase inhibition significantly attenuated the antigen-induced increase in Rcs by 53.4% (P less than 0.001), and the concentration of PGD2 in lavage fluid was reduced by 96.0% (P less than 0.01). Blockade of histamine H1-receptors (n = 8) or cholinergic receptors (n = 7) did not significantly affect the airway response (P greater than 0.05). These data indicate that the canine peripheral lung responds in a dose-dependent manner to antigen aerosol challenge and exhibits characteristics of antigen tachyphylaxis. Results also suggest that cyclooxygenase products play a central role in the acute bronchoconstrictive response of the lung periphery.

Expression of CD44 isoforms on isolated bone marrow plasma cells and peripheral CD19+ B cells of patients with multiple myeloma and healthy individuals.

The expression of certain isoforms of CD44 was shown to correlate with aggressiveness and metastatic potential of various tumour types. We analysed the expression of the adhesion molecule CD44 and its variant domains (v6, v7, v7/8, v10) on isolated bone marrow (BM) plasma cells and peripheral blood (PBL) CD19+ B cells of 21 patients with MM and 15 healthy donors. B cells and plasma cells were isolated by immunomagnetic sorting and analysed by two-colour flow cytometry. The expression of CD44 isoforms was significantly higher on PBL B cells of patients with MM than in healthy controls. The elevated expression of CD44 isoforms (v6, v7/8, v10) on PBL B cells correlated with reduced overall survival in MM. CD44 isoforms were more strongly expressed on "larger", activated B cells. Furthermore, CD44 isoforms were found to be simultaneously expressed with CD38hi and CD56 on both, B lymphocytes and plasma cells of patients with MM. The determination of CD44 isoforms on circulating B cells may be helpful in defining prognostically unfavourable subgroups in MM.

Multicenter, open-label study of recombinant human DNase in cystic fibrosis patients with moderate lung disease. DNase International Study Group.

Cystic fibrosis is characterized by the accumulation of thick viscous purulent secretions. Recombinant human deoxyribonuclease I (rhDNase) breaks down extracellular DNA, which contributes to the increased viscosity of sputum. A multinational, open-label study was conducted in 974 cystic fibrosis patients with moderate lung disease [forced vital capacity (FVC) 40-70% of predicted values] to examine the safety and efficacy of aerosolized rhDNase, 2.5 mg, once daily over a period of at least 12 weeks. Patients were assessed under conditions reflecting routine clinical practice. During rhDNase therapy, at least one respiratory tract infection (RTI) requiring intravenous antibiotics was experienced by 29.5% of patients. Forced expiratory volume in 1 second (FEV1) and FVC were significantly improved from baseline by a mean of 10.5% and 7.2%, respectively. Voice alteration and pharyngitis were the most frequent rhDNase-related adverse events, but only 2% of all patients discontinued treatment due to adverse events. The results obtained were similar to a subanalysis of data from the first 3 months of a placebo-controlled U.S. study. The patients in the present study had a similar frequency of RTIs and improvement in pulmonary function, and reported fewer rhDNase-related and cystic fibrosis-related adverse events than patients in the U.S. study. We conclude that administration of rhDNase is safe, well tolerated, and effective under conditions reflecting routine clinical practice in patients with cystic fibrosis and moderate lung disease.

Long-term oxygen therapy improves health-related quality of life.

Guidelines for the prescription of long-term oxygen therapy (LTOT) in hypoxemic COPD patients are based on two landmark studies in which survival was the primary outcome. Such patients are importantly symptomatic with poor health-related quality of life (HRQL) but the effect of LTOT on HRQL remains uncertain. We undertook a prospective longitudinal interventional study of consecutive COPD patients referred to our regional oxygen service; n = 43 fulfilling criteria and commenced on LTOT, n = 25 not fulfilling criteria and continued on standard care. HRQL was measured at baseline, 2 and 6 months. Both patient groups had severe COPD as defined by mean FEV1 < 35% predicted. At baseline the LTOT group demonstrated significantly worse HRQL as defined by the Chronic Respiratory Questionnaire (CRQ) (fatigue, emotional function, mastery and total scores), total generic Dartmouth COOP Charts and anxiety domain of the Hospital Anxiety and Depression scale. Significant improvements in HRQL were noted at 2 and 6 months in the LTOT group. Conversely the non-LTOT group demonstrated a progressive decline in HRQL. Using validated criteria for a minimal clinically significant improvement in CRQ, there were 28 (67%) and 26 (68%) 'responders' at 2 and 6 months respectively in the LTOT group. The introduction of LTOT to patients with severe COPD fulfilling standard criteria was associated with early significant improvements in HRQL with sustained or further response at 6 months.

Inhaled steroids for bronchiectasis.

BACKGROUND: Bronchiectasis is a progressive condition characterised by irreversible destruction and dilatation of airways, generally associated with chronic bacterial infection. The two distinct therapeutic goals are: symptom control and reduction in morbidity; and prevention of progression of the underlying disease. OBJECTIVES: To determine whether regular inhaled corticosteroids produce improvement in symptom control and whether they beneficially influence the natural history of the disease. SEARCH STRATEGY: The Cochrane Airways Group RCT register and Cochrane Controlled Clinical Trials Register were searched using the following search terms; bronchiectasis AND [corticosteroid* OR beclomethasone OR budesonide OR fluticasone OR triamcinolone OR flunisolide]. Bibliographies of each included RCT was searched for additional trials. Pharmaceutical companies that manufacture inhaled corticosteroids were also contacted. SELECTION CRITERIA: Only randomised double blind studies controlled trials were included. Patients with radiographic evidence of bronchiectasis were included, but patients with cystic fibrosis were excluded. DATA COLLECTION AND ANALYSIS: Data was extracted by one of the reviewers (FR). Continuous outcomes were analysed as effect sizes (weighted mean difference or as standardised mean difference with 95% confidence intervals). MAIN RESULTS: Only two trials on a total of 54 patients could be included. The studies were of 4 and 6 weeks duration. Inhaled corticosteroids had no significant effect on any of the outcomes included in this review, however there was a trend towards improving: FEV1, FVC, PEFR, RV and DLco. REVIEWER'S CONCLUSIONS: In bronchiectasis, regular use of inhaled corticosteroids may improve lung function. The available studies were too short and too small to provide any clear evidence to guide practice. Larger and longer studies should include rate of decline of lung function, exacerbation frequency, hospitalisations and healthy status as outcomes.