Tiotropium improves walking endurance in COPD.

The primary objective of this study was to evaluate the effects of a 3-week treatment with tiotropium on walking capacity in chronic obstructive pulmonary disease (COPD). After familiarisation with study procedures, 36 patients were randomised to receive tiotropium 18 µg once daily or a matching placebo in a double-blind, parallel-group study. Pre- (trough) and 2-h post-dose pulmonary function was measured. An endurance shuttle walk was then completed. The same procedures were repeated after 3 weeks of treatment. Ventilatory parameters were monitored during exercise. At 3 weeks, tiotropium significantly improved walking endurance time in comparison with placebo, with a mean±sd between-group difference of 128±141 s (p=0.017). At 3 weeks, trough values for forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC) were significantly improved with tiotropium in comparison with placebo. The post-dose response to tiotropium was statistically superior to placebo after the first dose and after 3 weeks of treatment for FEV(1), FVC and inspiratory capacity. Ventilation and tidal volume at the end of walking were significantly improved with tiotropium. 3 weeks of tiotropium resulted in a greater walking endurance in patients with COPD. Improvements in FEV(1), maximal ventilation and tidal volume may contribute to this enhanced exercise capacity.

From commodity to money: The rise of silver coinage around the Ancient Mediterranean (sixth-first centuries bce).

The reasons why the Western Mediterranean, especially Carthage and Rome, resisted monetization relative to the Eastern Mediterranean are still unclear. We address this question by combining lead (Pb) and silver (Ag) isotope abundances in silver coinage from the Aegean, Magna Graecia, Carthage and Roman Republic. The clear relationships observed between 109Ag/107Ag and 208Pb/206Pb reflect the mixing of silver ores or silver objects with Pb metal used for cupellation. The combined analysis of Ag and Pb isotopes reveals important information about the technology of smelting. The Greek world extracted Ag and Pb from associated ores, whereas, on the Iberian Peninsula, Carthaginians and Republican-era Romans applied Phoenician cupellation techniques and added exotic Pb to Pb-poor Ag ores. Massive Ag recupellation is observed in Rome during the Second Punic War. After defeating the Carthaginians and the Macedonians in the late second century bce, the Romans brought together the efficient, millennium-old techniques of silver extraction of the Phoenicians, who considered this metal a simple commodity, with the monetization of the economy introduced by the Greeks.

Monitoring sputum eosinophils in mucosal inflammation and remodelling: a pilot study.

Normalisation of eosinophil counts in sputum of asthmatic patients reduces eosinophilic exacerbations. However, the effect of this strategy on airway remodelling remains to be determined. We compared bronchial inflammation and collagen deposition after 2 yrs of treatment guided by either sputum eosinophils (sputum strategy, SS) or by clinical criteria (clinical strategy, CS). As a pilot study, 20 mild asthmatic patients were randomly assigned to CS or SS strategies. Bronchial biopsies were obtained when minimum treatment needed to maintain control was identified and this was continued for 2 yrs. Biopsies were immunostained for inflammatory cells, mucin 5A (MUC5A) and collagen. The mean dose of inhaled corticosteroids at the start and end of the study was similar in both SS and CS groups. Forced expiratory volume in 1 s increased in both groups at the study end. In SS, mucosal lymphocyte and eosinophil counts, but not neutrophils, were reduced at the end of the study. In CS, only activated eosinophil and neutrophil counts decreased. MUC5A staining decreased in SS but not CS. No change in collagen deposition underneath the basement membrane was observed in either strategy. Treatment strategies that normalise sputum eosinophils also reduce mucosal inflammatory cells and MUC5A expression, but do not change subepithelial collagen deposition in mild to moderate asthma.

Regulation of epithelial cell proliferation by bronchial fibroblasts obtained from mild asthmatic subjects.

BACKGROUND: Bronchial epithelium is considered a key player in coordinating airway wall remodelling. The function of epithelial cells can be modulated by the underlying fibroblasts through autocrine and paracrine mechanisms. OBJECTIVE: To investigate the effect of phenotypic changes in bronchial fibroblasts from asthmatic subjects on epithelial cell proliferation. METHODS: Epithelial cells and fibroblasts derived from bronchial biopsies of asthmatic and healthy controls were cultured in an engineered model. Proliferation was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium-bromid (MTT). Epidermal growth factor receptor (EGFR), cyclin-dependent kinase inhibitors p21 and p27 were measured by western blots. Total and active forms of transforming growth factor (TGF)-ß1 were measured using ELISA and bioassay. TGF-ß was inhibited using a recombinant TGF-ß soluble receptor II protein. RESULTS: Proliferation of epithelial cells from asthmatics (AE) is increased when cells were cultured with fibroblasts from normal controls (NF). Fibroblasts from asthmatics (AF) significantly decreased the proliferation of epithelial cells from healthy subjects (NE). Activation of p21, p27, EGFR and TGF-ß1 reflects the proliferation data by decreasing in AE cultured with NF and increasing in NE cultured with AF. Neutralization of TGF-ß increased proliferation of epithelial cells cultured in the asthmatic model. CONCLUSION: Fibroblasts from asthmatic subjects regulate epithelial cell prolifearation, and TGF-ß signalling may represent one of the pathway involved in these interactions.

Endurance shuttle walking test: responsiveness to salmeterol in COPD.

Few studies have shown that the endurance shuttle walking test (ESWT) is responsive to treatment in patients with chronic obstructive pulmonary disease (COPD). This exercise test needs to be further investigated because of its relevance for activity of daily living. The aim of the present study was to evaluate, in patients with COPD, the responsiveness of the ESWT in detecting improvement in walking performance after a single dose of salmeterol. In a randomised, double-blind, placebo-controlled crossover trial, 20 patients with COPD performed two ESWT at 80% of peak capacity 2.5 h after inhaling either a placebo or 50 microg of salmeterol. Cardiorespiratory parameters were monitored during each walking test. Inspiratory capacities and Borg ratings for dyspnoea were obtained every other minute throughout the tests. Compared with placebo, salmeterol produced a significant change in lung function and a significant improvement in walking performance (mean+/-sd difference in time: 117+/-20 s; difference in distance: 160+/-277 m). At isotime (the latest exercise time that was reached on both ESWT), a significant reduction in dyspnoea was observed after bronchodilation. Bronchodilation with salmeterol reduced dyspnoea during walking and improved walking capacity in patients with chronic obstructive pulmonary disease. These findings provide further support for the use of the endurance shuttle walking test as an evaluative tool in chronic obstructive pulmonary disease.

The effect of IVX-0142, a heparin-derived hypersulfated disaccharide, on the allergic airway responses in asthma.

BACKGROUND: IVX-0142 is a heparin-derived hypersulfated disaccharide devoid of anticoagulant activity while possessing anti-allergic and anti-inflammatory activity in preclinical studies. In a proof-of-concept study, the allergen inhalation challenge model was used to investigate the effect of IVX-0142 in mild atopic asthma. METHODS: Nineteen subjects, not on controller medications, were randomized to an evaluator-blind, placebo-controlled, cross-over study. The effect of a single nebulized dose of IVX-0142 (80 mg) or placebo administered 30 min prior to allergen inhalation was evaluated on the allergic airway responses, airway responsiveness, and airway inflammation. RESULTS: When compared with placebo, 14 and 13 subjects experienced a relatively smaller maximum fall in forced expiratory volume in 1 s (maxFEV(1)%) for the early airway response (EAR) and late airway response (LAR) with IVX-0142, respectively (P < 0.01). The degree of attenuation in the EAR [maxFEV(1)% (mean +/- SE) 26.5 +/- 2.8%vs placebo 31.0 +/- 2.8%, P = 0.059] and LAR (15.6 +/- 2.9%vs placebo 19.0 +/- 2.9%, P = 0.24) with IVX-0142, however, was small and did not reach statistical significance compared with placebo. Similarly, a trend in the attenuation of allergen-induced increase in the absolute sputum cell counts was also observed. No difference in the allergen-induced increase in airway hyper-responsiveness and exhaled nitric oxide was noticed. CONCLUSIONS: The majority of mild atopic asthmatics demonstrated a reduction in the EAR and LAR to IVX-0142. However, the treatment effect observed with a single prechallenge dose of IVX-0142 was small and heterogeneous. The potential anti-allergic and anti-inflammatory effects using multiple higher doses need to be evaluated.

Waardenburg syndrome--penetrance of major signs.

We have estimated that 83% of individuals carrying the gene for Waardenburg syndrome type I show penetrance of the gene as measured by dystopia canthorum. This is lower than previous estimates, which failed to consider the frequency of equivocal dystopia in the general population. The addition of three other major signs (hearing loss, white forelock, and premature graying of the hair or vitiligo) does not substantially increase the discrimination of gene carriers (85% versus 83%). We estimate that about 75% of the first-degree relatives of probands can be assigned as normal or a gene carrier on the basis of the four major signs.

Comparative safety and efficacy of single or twice daily administration of inhaled beclomethasone in moderate asthma.

OBJECTIVES: In the treatment of stable mild to moderate asthma, twice-daily administration of inhaled steroids may allow adequate control of the asthma; however, comparisons of the efficacy of once- or twice-daily administration brought contradictory results. This study is a randomized, double-blind crossover trial, set to determine if inhaled beclomethasone dipropionate given once daily in the late afternoon or at bedtime can be as effective as a twice-daily regimen in the treatment of moderate asthma. DESIGN: Subjects were randomly assigned to 3 different dosing regimens of inhaled beclomethasone: (1) regimen A, a twice-daily dose of 500 micrograms in the morning and at bedtime; (2) regimen B, a single dose of 1,000 micrograms in the late afternoon; and (3) regimen C, a single dose of 1,000 micrograms at bedtime. PATIENTS AND PARTICIPANTS: Enrolled in the study were 42 subjects who required 500 micrograms of inhaled beclomethasone dipropionate twice daily to control symptoms of asthma and to minimize use of beta 2-adrenergic agonists, according to criteria suggested in a recent international consensus on asthma therapy. Prior to receiving therapy with inhaled steroids, all of these patients either had chronic symptoms of asthma that required administration of a short-acting beta 2-agonist at least twice per day, or had nocturnal asthma symptoms at least once per week. THERAPY: After a 2-week baseline evaluation, each subject was given the 3 treatment regimens in randomized order, each for a period of 4 weeks. Subjects were asked to record daily symptoms of asthma and peak expiratory flows in the morning and evening. At the end of each treatment period, spirometric data and airway responsiveness to methacholine were measured. MEASUREMENTS AND RESULTS: Thirty-seven subjects completed the study. No significant difference was found among the 3 treatment regimens for asthma symptoms, FEV1, the provocative concentration of methacholine causing a 20 percent decrease in the FEV1 (PC20) (geometric means, 1.41, 1.09, and 1.09 mg/ml), and mean morning and evening peak expiratory flow rates (PEFR). The plasma cortisol level and the adrenocorticotropic hormone (ACTH) response were not significantly different among treatments, nor were side effects, which were minimal. CONCLUSION: In moderate asthma controlled with a twice-daily dose of inhaled beclomethasone, a single total daily dose administered in the late afternoon or in the evening provides as good control of asthma for 2 months.

Influence of beclomethasone and salmeterol on the perception of methacholine-induced bronchoconstriction.

BACKGROUND: Patient evaluation of asthma severity and medication needs is mostly based on respiratory symptoms and may be influenced by changes in perception of bronchoconstriction-induced sensations. However, the influence of asthma medication on the ability to perceive symptoms is still to be documented. This study evaluated the effects of short-term and regular use of salmeterol on the perception of methacholine-induced bronchoconstriction (MIB) in subjects with mild asthma, using inhaled salbutamol on an "as required" basis (n=15), and in subjects with moderate asthma, using daily inhaled beclomethasone (mean daily dose, 640 microg; n=15) in addition to salbutamol to control their asthma. METHODS: Methacholine challenges (MC) were performed at entry into the study, and then before, 1, and 12 h following inhalation of 50 microg of salmeterol or a placebo, after a 15-day baseline period; and after 4 weeks of twice daily use of those treatments. The measurements were then repeated with the alternate treatment after a 15-day washout period. Finally, a last MC was performed after another 15-day washout period. For each MC, the perception score of bronchoconstriction-associated breathlessness at 20% fall in FEV1 (PS20) was evaluated on a modified Borg scale from 0 to 10. RESULTS: Subjects using regular beclomethasone had a higher baseline PS20 than those using only salbutamol (means: 3.06 0.06 and 2.01+/-0.07, p=0.0001). Short- and long-term use of salmeterol did not change significantly the PS20 compared with placebo (p>0.05) in either group (with or without corticosteroid). Although there were some intraindividual variations, mean PS20 did not vary significantly throughout the study. CONCLUSION: These observations show that the perception of bronchoconstriction-associated breathlessness is not influenced by regular use of salmeterol. Patients using inhaled corticosteroids show a greater perception of MIB.

Incidence and predictors of ARDS after cardiac surgery.

BACKGROUND: Severe pulmonary injury with the development of ARDS is a potential complication of cardiac surgery and cardiopulmonary bypass (CPB). STUDY OBJECTIVES: This retrospective, case-control study was designed to determine the incidence and mortality of ARDS after cardiac surgery and CPB, as well as to identify preoperative and perioperative predisposing factors of this complication. METHODS: Of 3,278 patients who underwent cardiac surgery and CPB between January 1995 and December 1998, 13 patients developed ARDS during the postoperative period. Each patient was matched with four or five control subjects who had the same type of surgery on the same day but did not develop postoperative respiratory complications. RESULTS: The incidence of ARDS was 0.4%, with an ARDS mortality of 15%. In the ARDS group, 38% had previous cardiac surgery, as compared to 3.5% in the control group (p < 0.002). During the postoperative period, ARDS patients received more blood products (4 +/- 5 vs 2 +/- 3; p < 0.01) and developed shock more frequently (31% vs 5%; p < 0.02) than patients in the control group. Multivariate regression analysis identified previous cardiac surgery, shock, and the number of transfused blood products as significant independent predictors for ARDS, with odds ratios of 31.5 (p = 0.015), 10.8 (p = 0.03), and 1.6 (p = 0.03), respectively. CONCLUSIONS: ARDS following cardiac surgery and CPB was a rare complication that carried a 15% mortality rate. Previous cardiac surgery, shock, and number of blood products received are important predicting factors for this complication.

Ocular manifestations of nephropathic cystinosis. The French-Canadian experience in a genetically homogeneous population.

A large spectrum of ocular pathologic features have been described in infantile cystinosis. Reported symptoms may require corneal transplantation and therapeutic efforts to solubilize cystine crystals with hourly administration of cysteamine (mercaptamine) drops. French Canada has the highest incidence of cystinosis in the world. We studied 18 patients with cystinosis who appeared to have much milder ocular involvement than that in other reported series. No operative interventions were required. Relatively mild photophobia was the most common ocular manifestation of cystinosis.

Detection by electron microscopy of a small subband 13q14.11 deletion in an hereditary retinoblastoma.

High-resolution banding, specific for electron microscopy, was applied to chromosomes of synchronized blood lymphocytes obtained from a child with bilateral retinoblastoma. Ultrastructural analysis of the subbands in region q14.1, after synchronization and immunochemical banding, showed that the deletion in the abnormal chromosome 13 corresponds to subband 14.11, thus evidencing that the retinoblastoma gene is located within subband q14.11. This first application to a diagnostic problem of immunochemical banding suggests that, coupled with electron microscopy, this banding provides a higher resolution than that obtained with light microscopy and should be useful to pinpoint important localizations.

First cytogenetic evidence of homozygosity for the retinoblastoma deletion in chromosome 13.

Retinoblastoma (Rb) provided the first model in which both normal alleles of a recessive gene had to be lost as a prerequisite for tumorigenicity. However, region q14 of chromosome 13 appears cytogenetically normal in the majority of Rb tumors, and no homozygotic deletion had previously been observed. High-resolution cytogenetics of an Rb tumor revealed a homozygotic deletion in bands q13.3-14.2 of chromosomes 13 in 35% of the cells and a heterozygotic deletion, involving the same region, in 17%. In one third of the cells, although random chromosome loss occasionally occurred, no specific anomaly was detected. The remaining cells showed either monosomy 13, tetraploidy, or an i(1p). Revealing a homozygotic deletion in subbands 14.1 and 14.2 of chromosomes 13 provides the first cytogenetic evidence of the two somatic mutations considered essential to inactivate the Rb gene. These results allow insight into the succession of events necessary for tumor development.

Ophthalmic manifestations of Aarskog (facial-digital-genital) syndrome.

Four boys with facial-digital-genital or Aarskog syndrome were whort with triangular faces, characteristic deformities of the hands and feet, and anomalies of the external genitalia. The syndrome appears to be inherited in an X-chromosomes-limked recessive manner. Previous reports emphasized the presence of hypertelorism but careful measurements of the interorbital dimensions revealed primary telecanthus in addition to hypertelorism. The palpebral fissures had a marked antimongoloid obliquity and in half the reported cases, there was unilateral or bilateral congenital blepharoptosis. Strabismus, hyperopic astigmatism, and large corneas may be additional features.

Relationship between changes in diurnal variation of expiratory flows, lung volumes and respiratory symptoms after acute asthma.

We looked at the comparative recovery of asthma symptoms and changes in airflow obstruction after an acute exacerbation of asthma in 26 asthmatics, aged 18-69 years (mean = 43). In the 4 weeks following the acute episode, they recorded their respiratory symptoms and twice-daily peak expiratory flow rates (PEFR). In 14 subjects, lung volumes were also measured on days 1, 7 and 30. Mean initial FVC and FEV1 [+/- SEM (% predicted)] were 2.30 +/- 0.16 (61%) and 1.18 +/- 0.08 (39%). The rate of improvement of airflow obstruction initially paralleled that of asthma symptoms in subjects with mild or with a recent onset of asthma. On the first study day, diurnal variation of PEFR was minimal, increased rapidly during the first week of treatment and stabilized thereafter. Mean daily delta PEFR was significantly higher in the first than at the fourth week (P = 0.005). Recovery of asthma symptoms was associated with an overall reduction in FRC and RV but there was no significant correlation between FRC or RV and dyspnea score or PEFR. Perception of airflow obstruction was generally lower, improvement of symptoms slower and of smaller amplitude in those with long-standing asthma. In conclusion, during recovery from acute asthma: (1) diurnal variation of PEFR is initially minimal, increases rapidly after beginning steroids and stabilize in the two following weeks; (2) in patients with more than mild or long-standing asthma, and magnitude and range of perception of asthma symptoms is reduced and correlates less with PEFR; and (3) no significant correlation could be found between FRC or RV and dyspnea score or PEFR.

Recombinant interferon alfa-2b in the treatment of vision-threatening capillary hemangiomas in childhood.

INTRODUCTION: Hemangiomas of the orbit and eyelids may cause serious ocular problems usually related to amblyopia and astigmatism. Steroids have become the accepted treatment. However, some hemangiomas are resistant to steroids or require prolonged use,with unacceptable side effects. Interferon alfa-2b, an antiangiogenic protein, was used in this prospective study to treat visually threatening hemangiomas that were unresponsive to oral or intralesional steroid treatment. METHODS: Forty patients aged 2 to 36 months with life- or organ-threatening hemangiomas were prospectively enrolled to evaluate the efficacy and safety of interferon alfa treatment for hemangiomas. Sixteen of these 40 patients had hemangiomas causing serious ocular dysfunction. The patients were treated with 3 x 10(6) U/m2 interferon alfa-2b subcutaneously daily for 3 months; treatment was then tapered or retreated according to response and protocol. Therapeutic responses were documented. RESULTS: Fifteen patients with ocular hemangiomas have finished treatment. The pretreatment volume measured by computed axial tomographywas an average of 22.3 cm3. Clinical response with eye opening was observed at an average of 6 weeks. There was a significant regression of the hemangioma in all patients, with an average 82% reduction in volume. Patients were treated with glasses and occlusion therapy as appropriate. Final visual acuities with a follow-up averaging 14 months after cessation of interferon treatment were normal, except that five of 15 patients had amblyopia; one of these patients had 20/40, two had 20/60, and two had 20/70. There were no major illnesses or serious adverse side effects. CONCLUSION: Interferon alfa-2b treatment resulted in good to excellent regression of all the hemangiomas. This regression was clinically significant,with patients able to open the affected eye an average of 6 weeks into treatment. Visual results were good, with moderate amblyopia occurring only in patients treated at a later age. Interferon alfa-2b was well tolerated by these young patients, and no significant illness or side effect has occurred.

Anterior transposition of the inferior oblique for dissociated vertical deviation with inferior oblique overaction.

We reviewed the charts of 17 children (27 eyes) who underwent anterior transposition of the inferior oblique muscle for dissociated vertical deviation coexistent with inferior oblique overaction. All the eyes showed an improvement in the inferior oblique overaction. Twenty-one eyes had reduction in the dissociated vertical deviation, five eyes showed no change in the degree of dissociated vertical deviation, and in one case the hyperdeviation increased after surgery. No intraoperative or late postoperative complications were noted. Anterior transposition is an effective procedure for weakening inferior oblique overaction coexistent with dissociated vertical deviation.

Congenital miosis.

The inheritance of congenital miosis in 2 pedigrees is described. The inheritance was autosomal dominant in one and autosomal recessive in the other. The pupils were 0.5-2.5 mm diameter, reacted normally to light and accommodation but dilated poorly with mydriatics. In both pedigrees, the affected members had enlarged corneas. The five members in the autosomal dominant family were myopic and had translucent peripheral irides. Iridodonesis was presented in both members of the autosomal recessive pedigree. The embryology and innervation of the iris muscles together with the ocular abnormalities and syndromes associated with congenital miosis are reviewed.

Preschool vision testing with a new device, the Scolatest.

To determine the reliability of results obtained in preschool children by school nurses with a new device for testing vision, the Scolatest, 153 children aged 4 to 5 years were presented with the Snellen E on the standard American Optical projector and with five letters of the Sheridan test (H, O, V, T and X) on the Scolatest. Another 212 children aged 3 to 4 years were presented with the Allen symbols on the projector and with the Pigassou symbols on the Scolatest. The tests with the projector were given at 6 m by an experienced pediatric orthoptist, those with the Scolatest at 2.5 m by a school nurse. The proportion of good responses was higher with the Pigassou symbols than with the Allen symbols. The results with the Sheridan letters and the Snellen E were similar up to 20/30; beyond 20/30 the Snellen E appeared unreliable. The four vision-testing systems were also presented by a school nurse at 2.5 m on the Scolatest to 102 children aged 4 to 5 years (Snellen E and the five Sheridan letters) and 80 children aged 3 to 4 years (Allen and Pigassou symbols). The proportions of good responses were more comparable. The results suggest that a working distance of 2.5 m should be used in testing vision in preschool children. Visual screening at this distance should test acuity beyond the 20/30 equivalence if results comparable to those at 20 feet with the 20/30 standard requirement are to be obtained.

The concept of corticosteroid cataractogenic factor revisited.

Formation of posterior subcapsular cataracts is a known complication of systemic corticosteroid therapy. However, the relation between steroid dosage, cumulative dose and type of steroid on one hand and the subsequent formation of cataract on the other is unclear. We carried out a study to determine the incidence of posterior subcapsular cataracts in 64 children who had undergone renal transplantation and to attempt to determine what factors were associated with cataract formation. Cataracts were detected in 17 (26%) of the patients. The steroid dosage, cumulative dose and duration of therapy were not associated with cataract formation. There was a significant difference in the distribution of HLA-CW3 antigen between the patients with cataracts and those without cataracts. The reason for the link between corticosteroid therapy and formation of posterior subcapsular cataracts remains unclear.