Ion and fluid transport properties of small airways in cystic fibrosis

Rationale: Small airways constitute amajor site of pathology in cystic fibrosis (CF) and provide most of the surface area of the conducting airways of the lung. Little is known, however, about the impact of CF on ion and fluid transport in small (bronchiolar) airways. Objectives: To describe the ion and fluid transport properties of CF bronchiolar epithelium. Methods: Primary cultures of human bronchial and bronchiolar (non-CF and CF) epithelial cells were obtained. The bioelectric properties were studied in Ussing chambers and the airway surface liquid (ASL) height was measured with confocal microscopy. Main Results: Primary cultures of ΔF508 CF bronchiolar epithelial cells displayed higher transepithelial resistance than non-CF cultures, whereas baseline short circuit current and amiloride-inhibitable short circuit current were similar in both preparations. The ASL height was significantly smaller in CF compared with non-CF preparations. In the presence of amiloride, addition of forskolin increased short circuit current in non-CF but not in CF bronchiolar cultures, and the ATP-induced increase in short circuit current was lower in CF than in non-CF cultures. Non-CF bronchiolar preparations displayed larger short circuit current and fluid secretion in responses to forskolin than non-CF bronchial preparations, suggesting that CFTR-dependent Cl- transport may play a more important role in the regulation of fluid transport in small airways than in large airways. Conclusion: In CF small airways, defective Cl- secretion combined with unregulated (persistent) Na+ absorption results in ASLdepletion

The contribution of Swiss scientists to the assessment of energy metabolism

Although Switzerland is considered a small country, it has its share in discoveries, inventions and developments for the assessment of energy metabolism. This includes seminal contributions to respiratory and metabolic physiology and to devices for measuring energy expenditure by direct and indirect calorimetry in vivo in humans and small animals (as well as in vitro in organs/tissues), for the purpose of evaluating the basic nutritional requirements. A strong momentum came during World War II when it was necessary to evaluate the energy requirements of soldiers protecting the country by assessing their energy expenditure, as well as to determine the nutritional needs of the Swiss civil population in time of war when food rationing was necessary to ensure national neutrality and independence. A further impetus came in the 1970s at the start of the obesity epidemics, toward a better understanding of the metabolic basis of obesity, ranging from the development of whole-body concepts to molecular mechanisms. In a trip down memory lane, this review focuses on some of the earlier leading Swiss scientists who have contributed to a better understanding of the field

Clinical activity of a htert (vx-001) cancer vaccine as post-chemotherapy maintenance immunotherapy in patients with stage IV non-small cell lung cancer : final results of a randomised phase 2 clinical trial

The cancer vaccine Vx-001, which targets the universal tumour antigen TElomerase Reverse Transcriptase (TERT), can mount specific Vx-001/TERT CD8 + cytotoxic T cells; this immune response is associated with improved overall survival (OS) in patients with advanced/metastatic non-small cell lung cancer (NSCLC). A randomised, double blind, phase 2b trial, in HLA-A*201-positive patients with metastatic, TERT-expressing NSCLC, who did not progress after first-line platinum-based chemotherapy were randomised to receive either Vx-001 or placebo. The primary endpoint of the trial was OS. Results: Two hundred and twenty-one patients were randomised and 190 (101 and 89 patients in the placebo and the Vx-001 arm, respectively) were analysed for efficacy. There was not treatment-related toxicity >grade 2. The study did not meet its primary endpoint (median OS 11.3 and 14.3 months for the placebo and the Vx-001, respectively; p = 0.86) whereas the median Time to Treatment Failure (TTF) was 3.5 and 3.6 months, respectively. Disease control for >6months was observed in 30 (33.7%) and 26 (25.7%) patients treated with Vx-001 and placebo, respectively. There was no documented objective CR or PR. Long lasting TERT-specific immune response was observed in 29.2% of vaccinated patients who experienced a significantly longer OS compared to non-responders (21.3 and 13.4 months, respectively; p = 0.004). Vx-001 could induce specific CD8 immune response but failed to meet its primary endpoint. Subsequent studies have to be focused on the identification and treatment of subgroups of patients able to mount an effective immunological response to Vx-001. Clinical trial registration: NCT0193515

The role of the myosin ATPase activity in adaptive thermogenesis by skeletal muscle

Resting skeletal muscle is a major contributor to adaptive thermogenesis, i.e., the thermogenesis that changes in response to exposure to cold or to overfeeding. The identification of the “furnace” that is responsible for increased heat generation in resting muscle has been the subject of a number of investigations. A new state of myosin, the super relaxed state (SRX), with a very slow ATP turnover rate has recently been observed in skeletal muscle (Stewart et al. in Proc Natl Acad Sci USA 107:430–435, 2010). Inhibition of the myosin ATPase activity in the SRX was suggested to be caused by binding of the myosin head to the core of the thick filament in a structural motif identified earlier by electron microscopy. To be compatible with the basal metabolic rate observed in vivo for resting muscle, most myosin heads would have to be in the SRX. Modulation of the population of this state, relative to the normal relaxed state, was proposed to be a major contributor to adaptive thermogenesis in resting muscle. Transfer of only 20% of myosin heads from the SRX into the normal relaxed state would cause muscle thermogenesis to double. Phosphorylation of the myosin regulatory light chain was shown to transfer myosin heads from the SRX into the relaxed state, which would increase thermogenesis. In particular, thermogenesis by myosin has been proposed to play a role in the dissipation of calories during overfeeding. Up-regulation of muscle thermogenesis by pharmaceuticals that target the SRX would provide new approaches to the treatment of obesity or high blood sugar levels

Synchronization modulation increases transepithelial potentials in MDCK monolayers through Na/K pumps

Peer reviewedPublisher PD

Measuring substance use in the club setting: a feasibility study using biochemical markers

<p>Abstract</p> <p>Background</p> <p>During the last few decades the use of club drugs (e.g., cocaine, amphetamines) has been of increased concern in nightlife settings. Traditionally, surveys have been used to estimate the use of club drugs, however, they mostly rely on self-reports which may not be accurate. Recent advances have allowed for readily accessible drug testing methods such as oral fluid drug testing. Nevertheless, research using oral fluid sampling to measure the frequency of drug use in the club environment is scarce. The objective of this study is to evaluate the feasibility of measuring the frequency of alcohol and drug use among Swedish clubbers using breath alcohol and oral fluid drug testing.</p> <p>Method</p> <p>The setting was a 40 hour electronic music dance event (EMDE) on a cruise ship on the Baltic Sea, departing from Sweden, with 875 passengers. Groups of participants at the EMDE were randomly invited to participate. Data were collected with face-to-face and self-administered questionnaires. Further, oral fluid samples were collected to determine illicit drug use, and blood alcohol concentration (BAC) levels were measured using a breath analyzer.</p> <p>Results</p> <p>A total of 422 passengers were asked to participate in the study whereof 21 declined (5.0% refusal rate). Of the 401 study participants (accounting for 45.8% of all attendees), 5 declined oral fluid drug testing. Results show that there was a discrepancy between self-reported and actual drug use as 10.1% of the participants were positive on illicit drug use (amphetamines, ecstasy/MDMA, cannabis, cocaine), while only 3.7% of the participants reported drug use during the last 48 hours. The average BAC level was 0.10% and 23.7% had BAC levels ≥ 0.15%, while 5.9% had levels below the detection limit. The mean BAC levels for the illicit drug users were significantly higher (<it>p </it>= 0.004) than for non-drug users (0.13% vs. 0.10%). Self-reported AUDIT-C scores (using a threshold of ≥ 5 for men and ≥ 4 for women) revealed that 76.0% of the men and 80.7% of the women had risky alcohol consumption patterns.</p> <p>Conclusion</p> <p>This study indicates that it is feasible to conduct breath alcohol and oral fluid drug testing in a Swedish club setting.</p

CD(8+ )T lymphocytes in lung tissue from patients with idiopathic pulmonary fibrosis

BACKGROUND: Several studies have implicated a role of inflammation in the pathogenesis of lung damage in idiopathic pulmonary fibrosis (IPF). Parenchymal lung damage leads to defects in mechanics and gas exchange and clinically manifests with exertional dyspnea. Investigations of inflammatory cells in IPF have shown that eosinophils, neutrophils and CD(8+ )TLs may be associated with worse prognosis. We wished to investigate by quantitative immunohistochemistry infiltrating macrophages, neutrophils and T lymphocytes (TLs) subpopulations (CD(3+), CD(4+ )and CD(8+)) in lung tissue of patients with IPF and their correlation with lung function indices and grade of dyspnoea. METHODS: Surgical biopsies of 12 patients with IPF were immunohistochemically stained with mouse monoclonal antibodies (anti-CD(68 )for macrophages, anti-elastase for neutrophils, and anti-CD(3), anti-CD(4), anti-CD(8 )for CD(3+)TLs, CD(4+)TLs, and CD(8+)TLs respectively). The number of positively stained cells was determined by observer-interactive computerized image analysis (SAMBA microscopic image processor). Cell numbers were expressed in percentage of immunopositive nuclear surface in relation to the total nuclear surface of infiltrative cells within the tissue (labeling Index). Correlations were performed between cell numbers and physiological indices [FEV(1), FVC, TLC, DLCO, PaO(2), PaCO(2 )and P(A-a)O(2))] as well as dyspnoea scores assessed by the Medical Research Council (MRC) scale. RESULTS: Elastase positive cells accounted for the 7.04% ± 1.1 of total cells, CD(68+ )cells for the 16.6% ± 2, CD(3+ )TLs for the 28.8% ± 7, CD(4+ )TLs for the 14.5 ± 4 and CD(8+ )TLs for the 13.8 ± 4. CD(8+)TLs correlated inversely with FVC % predicted (r(s )= -0.67, p = 0.01), TLC % predicted (r(s )= -0.68, p = 0.01), DLCO % predicted (r(s )= -0.61, p = 0.04), and PaO(2 )(r(s )= -0.60, p = 0.04). Positive correlations were found between CD(8+)TLs and P(A-a)O(2 )(r(s )= 0.65, p = 0.02) and CD(8+)TLs and MRC score (r(s )= 0.63, p = 0.02). Additionally, CD(68+ )cells presented negative correlations with both FVC % predicted (r(s )= -0.80, p = 0.002) and FEV(1 )% predicted (r(s )= -0.68, p = 0.01). CONCLUSION: In UIP/IPF tissue infiltrating mononuclear cells and especially CD(8+ )TLs are associated with the grade of dyspnoea and functional parameters of disease severity implicating that they might play a role in its pathogenesis

Substance-Related Health Problems during Rave Parties in the Netherlands (1997–2008)

The objective of this study was to describe a 12-year (1997–2008) observation of substance-related incidents occurring at rave parties in the Netherlands, including length of visits to first-aid stations, substances used, and severity of the incidents. During rave parties, specifically trained medical and paramedical personnel staffed first aid stations. Visitors were diagnosed and treated, and their data were recorded using standardized methods. During the 12-year period with 249 rave parties involving about 3,800,000 visitors, 27,897 people visited a first aid station, of whom 10,100 reported having a substance-related problem. The mean age of these people was 22.3+/−5.4 years; 52.4% of them were male. Most (66.7%) substance-related problems were associated with ecstasy or alcohol use or both. Among 10,100 substance-related cases, 515 required professional medical care, and 16 of these cases were life threatening. People with a substance-related problem stayed 20 min at the first aid station, which was significantly longer than the 5 min that those without a substance-related health problem stayed. These unique data from the Netherlands identify a variety of acute health problems related to the use of alcohol, amphetamines, cannabis, cocaine, ecstasy, and GHB. Although most problems were minor, people using GHB more often required professional medical care those using the other substances. We recommended adherence to harm and risk reduction policy, and the use of first aid stations with specially trained staff for both minor and serious incidents

Influence of the technique of re-educating thoracic and abdominal muscles on respiratory muscle strength in patients with cystic fibrosis

OBJETIVO: Avaliar o efeito do método Reequilíbrio Toracoabdominal na força dos músculos respiratórios de pacientes com fibrose cística, acompanhados no Ambulatório de Fibrose Cística da Universidade Católica de Brasília. MÉTODOS: A amostra, constituída de 29 fibrocísticos, foi caracterizada com base em dados antropométricos, genéticos e de colonização bacteriana. Espirometria, manovacuometria e antropometria foram realizadas antes e depois do tratamento fisioterapêutico, no qual se utilizou o método Reequilíbrio Toracoabdominal, duas vezes por semana, durante quatro meses. RESULTADOS: Houve aumento da pressão inspiratória máxima e da pressão expiratória máxima após o tratamento fisioterapêutico em todos os pacientes, naqueles sem distúrbio ventilatório obstrutivo e naqueles com distúrbio ventilatório obstrutivo leve (p < 0,05). Foi encontrada correlação positiva entre a idade e a pressão expiratória máxima para a maioria dos grupos. A pressão inspiratória máxima só apresentou correlação positiva com a idade no grupo com distúrbio ventilatório obstrutivo leve (p = 0,012; r = 0,817). Para o sexo feminino e para o grupo sem distúrbio ventilatório obstrutivo houve correlação negativa entre a pressão expiratória máxima e a colonização por Pseudomonas aeruginosa (p = 0,036; r = -0,585). CONCLUSÃO: Para os fibrocísticos avaliados, o método Reequilíbrio Toracoabdominal aumentou a força dos músculos respiratórios, o que reafirma a importância do tratamento fisioterapêutico para estes pacientes.OBJECTIVE: To determine the effect that re-education of the thoracic and abdominal muscles has on the respiratory muscle strength of patients with cystic fibrosis evaluated over time at the Cystic Fibrosis Outpatient Clinic of the Universidade Católica de Brasília (Catholic University of Brasília). METHODS: The sample consisted of 29 cystic fibrosis patients, characterized based on anthropometric, genetic and bacterial colonization data. The patients were submitted to physical therapy sessions, involving re-education of the respiratory muscles, twice a week for four months. Spirometry, pressure manometry and anthropometry were performed before and after each session. RESULTS: Comparing baselines values to those obtained after physical therapy, increases in maximum inspiratory pressure and maximum expiratory pressure were observed in all patients, those without any obstructive respiratory disease and those with mild obstructive respiratory disease (p < 0.05). A positive correlation between age and maximum expiratory pressure was observed for most of the patients. Maximum inspiratory pressure correlated positively with age only in the group with mild obstructive respiratory disease (p = 0.012; r = 0.817). In female patients and in the group of patients without obstructive respiratory disease, a negative correlation was observed between maximum expiratory pressure and colonization with Pseudomonas aeruginosa (p = 0.036; r = -0.585). CONCLUSION: Use of the thoracic and abdominal muscle re-education technique increased respiratory muscle strength in the cystic fibrosis patients studied, a finding that underscores the importance of including physical therapy in the treatment of these patients