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Cognitive and physical limitations are common in individuals with chronic lung diseases, but their interactions with physical function and activities of daily living are not well characterized. Understanding these interactions and potential contributors may provide insights on disability and enable more tailored rehabilitation strategies.

Chronic obstructive pulmonary disease patient care must include confirming a diagnosis with postbronchodilator spirometry. Because of the clinical heterogeneity and the reality that airflow obstruction assessed by spirometry only partially reflects disease severity, a thorough clinical evaluation of the patient should include assessment of symptom burden and risk of exacerbations that permits the implementation of evidence-informed pharmacologic and nonpharmacologic interventions. This guideline provides recommendations from a comprehensive systematic review with a meta-analysis and expert-informed clinical remarks to optimize maintenance pharmacologic therapy for individuals with stable COPD, and a revised and practical treatment pathway based on new evidence since the 2019 update of the Canadian Thoracic Society (CTS) Guideline. The key clinical questions were developed using the Patients/Population (P), Intervention(s) (I), Comparison/Comparator (C), and Outcome (O) model for three questions that focuses on the outcomes of symptoms (dyspnea)/health status, acute exacerbations, and mortality. The evidence from this systematic review and meta-analysis leads to the recommendation that all symptomatic patients with spirometry-confirmed COPD should receive long-acting bronchodilator maintenance therapy. Those with moderate to severe dyspnea (modified Medical Research Council ≥ 2) and/or impaired health status (COPD Assessment Test ≥ 10) and a low risk of exacerbations should receive combination therapy with a long-acting muscarinic antagonist/long-acting ẞ2-agonist (LAMA/LABA). For those with a moderate/severe dyspnea and/or impaired health status and a high risk of exacerbations should be prescribed triple combination therapy (LAMA/LABA/inhaled corticosteroids) azithromycin, roflumilast or N-acetylcysteine is recommended for specific populations; a recommendation against the use of theophylline, maintenance systemic oral corticosteroids such as prednisone and inhaled corticosteroid monotherapy is made for all COPD patients.

Calls have been made to discontinue the routine use of race and ethnicity in medicine. Specific to respiratory medicine, the use of race- and ethnicity-specific reference equations for the interpretation of pulmonary function test (PFT) results has been questioned.

Background. Exercise is recommended for people with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD), yet there is little information to guide safe and effective mobilization and exercise for these patients. Objectives. The purpose of this study was to develop a clinical decision-making tool to guide health care professionals in the assessment, prescription, monitoring, and progression of mobilization and therapeutic exercise for patients with AECOPD. Design and Methods. A 3-round interdisciplinary Delphi panel identified and selected items based on a preselected consensus of 80%. These items were summarized in a paper-based tool titled Mobilization in Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD-Mob). Focus groups and questionnaires were subsequently used to conduct a sensibility evaluation of the tool. Results. Nine researchers, 13 clinicians, and 7 individuals with COPD identified and approved 110 parameters for safe and effective exercise in AECOPD. These parameters were grouped into 5 categories: (1) 'What to Assess Prior to Mobilization,' (2) 'When to Consider Not Mobilizing or to Discontinue Mobilization,' (3) 'What to Monitor During Mobilization for Patient Safety,' (4) 'How to Progress Mobilization to Enhance Effectiveness,' and (5) 'What to Confirm Prior to Discharge.' The tool was evaluated in 4 focus groups of 18 health care professionals, 90% of whom reported the tool was easy to use, was concise, and would guide a health care professional who is new to the acute care setting and working with patients with AECOPD. Limitations. The tool was developed based on published evidence and expert opinion, so the applicability of the items to patients in all settings cannot be guaranteed. The Delphi panel consisted of health care professionals from Canada, so items may not be generalizable to other jurisdictions. Conclusions. The AECOPD-Mob provides practical and concise information on safe and effective exercise for the AECOPD population for use by the new graduate or novice acute care practitioner., The majority of individuals with chronic obstructive pulmonary disease (COPD) experience at least one acute exacerbation of COPD (AECOPD) per year; many have multiple exacerbations. (1) Many of these exacerbations [...]

AbstractBACKGROUNDOptimal chronic obstructive pulmonary disease (COPD) management includes both pharmacologic therapy and non-pharmacologic interventions including smoking cessation, vaccination, patient education/self-management and pulmonary rehabilitation. All of these elements should be optimized prior to hospital discharge in patients admitted for acute exacerbations of COPD (AECOPD).OBJECTIVES AND METHODS: We conducted a retrospective review of all patients admitted with an AECOPD in Saskatoon, Saskatchewan during 2016 to determine the proportion discharged on medical therapy consistent with the Global Initiative for Obstructive Lung Disease (GOLD) and Canadian Thoracic Society (CTS) guidelines, as well as the proportion who received appropriate non-pharmacologic interventions while in hospital — namely, nicotine replacement therapy (NRT), pneumococcal and influenza vaccination, COPD Nurse-Clinician and Respirologist involvement and pulmonary rehabilitation program (PRP) referral.RESULTSA total of 222 admissions were evaluated. Regarding non-pharmacologic management, 48% of smokers were prescribed NRT, while 3% and 24% of patients were vaccinated against pneumococcus and influenza, respectively, while in hospital. A total of 37% of patients were seen by a Respirologist and 66% were assessed by a COPD Nurse-Clinician, but only 8% were referred to PRP prior to discharge. In contrast, 86% of patients were discharged on guideline-adherent pharmacologic therapy. COPD Nurse-Clinician involvement, but not Respirologist involvement, was associated with guideline-adherent medical therapy on discharge.CONCLUSIONWhile most patients were discharged on appropriate pharmacologic therapy, the low rates of NRT prescription, pneumococcal and influenza vaccination, and PRP referral in these patients highlight meaningful opportunities for further optimizing care and warrant significant improvement. Given the documented benefits of these therapies in COPD, quality improvement initiatives should be undertaken to promote in-hospital COPD optimization.

Study objectives: Validation of test-shortening procedures for the 2-min tidal breathing methacholine challenge method. Design: Retrospective chart review. Setting: Tertiary-care university clinical pulmonary function laboratory. Patients: One thousand subjects aged [...]

Study design: We tested the hypothesis that maximal exercise performance in subjects with interstitial lung disease (ILD) is limited by respiratory factors. Assuming this is so, ventilatory stimulation by added [...]

A 56-year-old woman of average build (height 1.6 m, body mass index 26.4) was referred to the respirology clinic for assessment of recurrent, bilateral, spontaneous pneumothoraces of unknown cause. She [...]

AbstractRATIONALE: Pulmonary rehabilitation (PR) is recommended in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) to reduce the risk of future exacerbations. Previous review in this health region demonstrated 9% of inpatients with AECOPD were being referred to PR following discharge, and 4% were attending, none within 30 days post-discharge.OBJECTIVEEvaluate referral and attendance rates to PR after implementation of a physician-led recruitment method.MEASUREMENTS AND MAIN RESULTS: All inpatients admitted to medicine wards were systematically screened for AECOPD utilizing a Drug Use Evaluation report for prescribed inhalers/nebulizers. Investigators met with identified eligible patients, delivered education and provided a pre-booked appointment card to attend PR within 4 weeks of discharge. PR attendance and barriers to attendance were documented.A total of 296 patients receiving inhalers/nebulizers were screened: 135 patients did not have clinical COPD. Of the remaining 161 patients, 50 were deemed eligible for the intervention. Reasons for exclusion included significant co-morbid conditions (n = 71), distance (n = 34) and preexisting attendance (n = 6). Of eligible patients, 12 declined referral with the main reason being lack of transportation; 38 patients accepted referral to PR, with 16 attending their first appointment.CONCLUSIONA physician-led referral strategy improved PR referral rates, with 24% of patients admitted with “clinical COPD” being formally referred to PR compared to only 9% with prior clinical practice. Moreover, physician-led recruitment increased PR attendance to 10% from prior 4%. Of the patients with clinical AECOPD, only 31% were eligible for referral to PR, and of those, only 32% attended their first appointment.

Very low birthweight or preterm infants are at increased risk of adverse outcomes including sepsis, necrotising enterocolitis, and death. We assessed whether supplementing the enteral diet of very low-birthweight infants with lactoferrin, an antimicrobial protein, reduces all-cause mortality or major morbidity.

COPD has a substantial burden seen in both patient quality of life and health-care costs. One method of minimizing this burden is the implementation of clinical pathways (CPWs). CPWs bring the best available evidence to a range of health-care professionals by adapting guidelines to a local context and detailing essential steps in care.

AbstractIn this guideline update, we highlight important and new findings related to pharmacological therapy of chronic obstructive pulmonary disease (COPD) that should change clinical practice and improve disease management. We present updated evidence, recommendations and expert clinical remarks on maintenance pharmacotherapy in patients with stable COPD. The diagnosis and nonpharmacological therapy of COPD are out-of-scope for this update.In patients with COPD who have persistent shortness of breath, exercise intolerance and/or poor health status despite using inhaled LAMA or LABA monotherapy, we recommend augmenting treatment to LAMA/LABA dual therapy. In patients with high-risk exacerbations, LAMA/LABA is the preferred choice to ICS/LABA except in patients with previous exacerbations who have higher peripheral eosinophilia. There is no role for ICS monotherapy; when indicated, ICS should only be used in combination with bronchodilators. Treatment “step up” in COPD is proposed as a practical construct supported by evidence that inhaled combined therapy is superior to monotherapy and triple therapy to dual therapy in certain patient populations. Because the superiority of inhaled triple or dual bronchodilator therapy may not be achieved in every patient, “step down” may be considered for some patients (not at high risk for future exacerbations), but should be done with close medical supervision, as the risk of clinical deterioration is real and continues to exist. The decision of changing a therapy should always occur after a complete evaluation of the patient and the potential benefit to a change in therapy; as well as an assessment of any adverse effects of the therapy, and with a review of patient adherence, inhaler technique and patient preferences.Pharmacological therapy plays a foundational role in therapy, but it should never be the sole treatment in managing COPD patients. Clinicians should always combine and optimize pharmacological and nonpharmacological therapies with the dual goals of reducing symptoms and preventing acute exacerbations of COPD (AECOPD).

AbstractRATIONALE: Delivery of pulmonary rehabilitation (PR) varies widely across Canada. There is a need for evidence-based quality indicators (QI) that can be used to identify variations in the quality of PR with the aim of improving health outcomes.OBJECTIVES: To use an evidence-based, systematic process to develop QI that addresses the process, structure and outcomes of PR.METHODS: The development process was based on the modified RAND Appropriateness Method that included a systematic review of the literature to identify candidate QI and refinement of these QI by a Working Group before they were sent to a Delphi panel. Panel members rated the importance, scientific soundness, reliability, and feasibility of each candidate using an electronic survey. The results of the survey were distributed to panelists who deliberated by teleconference prior their re-rating the candidate QI.RESULTS: The literature review identified 5490 titles and abstracts. A total of 1653 articles were retained after initial screening. After full text screening, 190 articles remained and were used to generate 90 candidate QI. The Delphi panel identified 56 QI: 19 structural, 29 process, 8 outcome. The Working Group distilled these to a shorter list of 14 core QI that defined the minimal requirements for PR.CONCLUSIONS: This process resulted in a comprehensive set of 56 QI and a shorter list of 14 core QI that can be used for evaluation and feedback to improve PR and patient outcomes. Future research to determine standards for the QI will support the development and assessment of strategies to improve PR.

Background: Methacholine-induced bronchoconstriction is associated with significant hypoxemia, which can be assessed noninvasively by transcutaneous oxygen tension and pulse oximetry. Objectives: To assess the value of the monitoring of finger [...]

John K Reid, MD(*); Lisa Paus-Jenssen, MD; Darcy D Marciniuk, MD and Vernon H Hoeppner, MD. Medicine, U of Saskatchewan, Saskatoon, SK, Canada. PURPOSE: To describe the phamacokinetics of antituberculosis [...]

Objective: To test the hypothesis that respiratory function contributes to limit maximal exercise performance in patients with chronic heart failure by using the technique of dead space loading during exercise. [...]

To the Editor: Increased nonspecific bronchial hyperresponsiveness to pharmacologic agents such as methacholine is a hallmark of asthma. The measurement of airway reactivity is quite sensitive, but testing is tedious [...]

ABSTRACTRATIONALE: Since the last published Canadian Thoracic Society (CTS) COPD guideline in 2007 and the 2008 update – highlights for primary care, many new clinical trials have challenged COPD treatment practices. The current Canadian position statement provides the reader with an update on pharmacotherapy of patients with COPD as reviewed by the CTS.OBJECTIVES: The objectives of this position statement are: 1) to summarize the literature on topics relevant to the pharmacological therapy of patients with stable COPD; and 2) to provide clinical guidance with evidence-based recommendations and expert-informed key messages for the pharmacological therapy for patients with stable COPD.METHODS: The authors systematically reviewed the relevant literature focusing on randomized controlled trials and when available, systematic reviews of randomized controlled trials. The proposed key messages, based on scientific evidence and expert-informed opinion, were agreed upon by a majority consensus.MAIN RESULTS: There is typically a significant delay in seeking medical care by patients with dyspnea, often waiting until symptoms affect the performance of activities of daily living. The diagnosis of COPD requires spirometry to confirm the presence of airflow obstruction in any patient presenting with symptoms and/or risk factors of COPD. An effective management plan for individuals with COPD should include: smoking cessation, vaccination and education. A number of non-pharmacological treatments are available for COPD patients with symptoms to improve outcomes such as self-management with coaching from a health care professional; pulmonary rehabilitation; supplemental oxygen in selected patients; and surgery.Current pharmacotherapy for COPD has been shown to alleviate symptoms and prevent exacerbations and related complications such as hospital admissions. In symptomatic patients with stable COPD not having or having infrequent exacerbation, treatment should be started with inhaled LAMA or LABA monotherapy, and if experiencing persistent or increased dyspnea, exercise intolerance, and/or reduced health status despite use of monotherapy, patients should be considered for treatment “step up”with an inhaled LAMA plus LABA dual therapy. In this situation, the use of a single inhaler would be preferred to simplify the treatment regimen and minimize the cost. In patients with stable COPD experiencing exacerbations despite the use of LAMA or LABA monotherapy, treatment “step up”with inhaled LAMA plus LABA dual therapy should be considered unless a patient has concomitant asthma (Asthma/COPD overlap (ACO)). There has been recent interest in using biomarkers to identify patients who are more likely to respond to ICS. Most of the studies have demonstrated that high blood eosinophils could be valuable to predict an increase response in terms of reduction of exacerbation rate when treated with combination ICS/LABA; there is still uncertainty about the exact cut-off level of blood eosinophils having potential therapeutic value. If a patient is still experiencing exacerbations despite the use of LAMA and LABA dual therapy, treatment “step up”with LAMA plus ICS/LABA triple therapy can be considered. Because the superiority of inhaled triple or dual therapy may not be achieved in every patient, the notion of treatment “step down”may be a consideration in some patients. These patients would be those not demonstrating expected benefits or having side effects exceeding benefits. In any circumstance, when a physician decides using a treatment “step down”, this approach should be undertaken under close medical supervision.Individuals with ACO are a population of medical interest, however, the paucity of original studies precluded evidence-based recommendations. The position statement, therefore, presents key messages from a survey which at best reflects the practice in our Canadian community and academic respirologists on assessment, diagnosis, and pharmacotherapy of ACO patients.CONCLUSIONS: This position statement is an evolution towards personalized treatment, compared to the previous published CTS COPD guideline. It promotes approaches to match treatment decisions based on symptom burden and risk of future exacerbations. Personalized medicine becomes increasingly possible, but to make future progress, we will need clinical research to be more specific, including greater focus on or defining better subsets of patients that are characterized by specific biomarkers and disease severity.RÉSUMÉJUSTIFICATION: Depuis les dernières lignes directrices publiées par la Société canadienne de thoracologie (SCT) en 2007 et actualisées pour le médecin de famille en 2008, de nombreux essais cliniques ont remis en question les pratiques relatives au traitement de la MPOC. Cet énoncé de position canadien présente au lecteur les plus récentes informations concernant la pharmacothérapie destinée aux patients souffrant de MPOC, telle que revue par la SCT.OBJECTIFS: Les objectifs de cet énoncé de position sont : 1) résumer la littérature sur les sujets pertinents au traitement pharmacologique des patients souffrant d'une MPOC stable; et 2) présenter des directives comprenant des recommandations fondées sur les données probantes et des messages-clés fondés sur l'avis d'experts pour le traitement pharmacologique des patients souffrant d'une MPOC stable.MÉTHODES: Les auteurs ont revu la littérature pertinente de manière systématique en privilégiant les essais contrôlés randomisés et, lorsque disponibles, les revues systématiques d'essais randomisés. Les messages-clés proposés, qui se fondent sur les données probantes et sur l'opinion d'experts, ont été approuvés par consensus obtenu à la majorité.PRINCIPAUX RÉSULTATS: Les patients souffrant de dyspnée retardent généralement leur quête de soins médicaux jusqu'au moment où les symptômes commencent à affecter leurs activités quotidiennes. Le diagnostic de MPOC nécessite une spirométrie pour confirmer la présence d'une obstruction des voies respiratoires chez un patient qui présente des symptômes ou des facteurs de risque de MPOC. Un plan de prise en charge efficace pour les individus souffrant de MPOC devrait comprendre : la cessation du tabagisme, la vaccination et l’éducation. Un certain nombre de traitements non pharmacologiques sont disponibles pour les patients atteints de MPOC symptomatique afin d'optimiser les résultats, dont l'auto-prise en charge accompagnée des conseils d'un professionnel de la santé; la réadaptation pulmonaire; l'oxygène d'appoint chez certains patients; et la chirurgie.Il a été démontré que la pharmacothérapie actuelle pour la MPOC soulage les symptômes et prévient les exacerbations ainsi que les complications qui en découlent, comme les hospitalisations. Chez les patients atteints de MPOC symptomatique stable avec ou sans exacerbations occasionnelles, le traitement devrait commencer par l'inhalation d'un anticholinergique à longue durée d'action (ACLA) ou d'un Beta2agoniste à longue durée d'action (BALA) en monothérapie, et dans les cas où la dyspnée, l'intolérance à l'exercice et la détérioration de l’état de santé persistent ou augmentent, une intensification  du traitement devrait être envisagée pour ces patients en combinant l'inhalation d'un ACLA à celle d'un BALA en double thérapie. Dans une telle situation, l'usage d'un seul inhalateur devrait être privilégié afin de simplifier le régime de traitement et minimiser les coûts. Chez les patients atteints de MPOC stable qui ont des exacerbations malgré l'utilisation d'un ACLA ou d'un BALA en monothérapie, l'intensification du traitement par l'inhalation d'un ACLA associé au BALA en double thérapie devrait être envisagée, sauf dans les cas où le patient souffre d'asthme concomitant (chevauchement asthme/MPOC). Récemment, on assiste à un accroissement de l'intérêt pour l'utilisation de biomarqueurs afin de déterminer les patients qui sont les plus susceptibles de répondre aux CSI. La plupart des études ont démontré qu'un nombre élevé d’éosinophiles dans le sang pourrait être utile pour prédire une meilleure réponse en ce qui a trait à la réduction du taux d'exacerbation lorsque traité par une combinaison de CSI et de BALA; toutefois, l'incertitude demeure quant au seuil d’éosinophiles dans le sang pouvant avoir une valeur thérapeutique. Si le patient connaît encore des exacerbations malgré un double traitement par ACLA et BALA, l'intensification du traitement par l'ajout d'un ACLA au traitement CSI/BALA en trithérapie peut être envisagé. Puisque la supériorité du traitement par inhalation double ou triple pourrait ne pas être réalisable pour chaque patient, la notion de « diminution graduelle » du traitement pourrait être envisagée pour certains patients. Ces patients seraient ceux qui ne démontrent pas les bénéfices attendus ou qui ont des effets secondaires qui dépassent les bénéfices. Dans toute circonstance, lorsqu'un médecin décide d'avoir recours à une « diminution graduelle » du traitement, cette approche devrait être entreprise sous supervision médicale étroite.Les personnes souffrants de chevauchement asthme/MPOC sont une population de grand intéretê médical. Toutefois, le nombre limité d’études originales empêche la formulation de recommandations fondées sur des données probantes. Cet énoncé de position présente donc des messages-clés issus d'une enquête qui, au mieux, reflète la pratique dans notre communauté canadienne et chez les pneumologues universitaires en ce qui concerne l'evaluation, le diagnostic et la pharmacothérapie dans le cas des patients souffrant de chevauchement asthma/MPOC.CONCLUSION: Cet énoncé de position constitue une évolution vers le traitement personnalisé, comparativement aux lignes directrices de la SCT relatives à la MPOC publiées précédemment. Il favorise les approches qui visent à établir une correspondance entre les décisions thérapeutiques fondées sur le fardeau des symptômes et le risque d'exacerbations futures. La médecine personnalisée devient de plus en plus possible, mais pour progresser, la recherche clinique doit être plus spécifique, notamment en ciblant ou en définissant plus clairement des sous-ensembles de patients caractérisés par des biomarqueurs précis et par le degré de gravité de leur maladie.

The COPD Assessment Test (CAT) is a valid disease-specific questionnaire measuring health status. However, knowledge concerning its use regarding patient and disease characteristics remains limited. Our main objective was to assess the degree to which the CAT score varies and can discriminate between specific patient population groups.

This article provides an update on progress toward establishing pulmonary and critical care medicine (PCCM) fellowship training as one of the first four subspecialties to be recognized and supported by the Chinese government. Designed and implemented throughout 2013 and 2014 by a collaborative effort of the Chinese Thoracic Society (CTS) and the American College of Chest Physicians (CHEST), 12 leading Chinese hospitals enrolled a total of 64 fellows into standardized PCCM training programs with common curricula, educational activities, and assessment measures. Supplemental educational materials, online assessment tools, and institutional site visits designed to evaluate and provide feedback on the programs’ progress are being provided by CHEST. As a result of this initial progress, the Chinese government, through the Chinese Medical Doctor’s Association, endorsed the concept of subspecialty fellowship training in China, with PCCM as one of the four pilot subspecialties to be operationalized nationwide in 2016, followed by implementation across other subspecialties by 2020. This article also reflects on the achievements of the training sites and the challenges they face and outlines plans to enhance and expand PCCM training and practice in China.

BACKGROUND:COPD is a major cause of morbidity and mortality in the United States as well as throughout the rest of the world. An exacerbation of COPD (periodic escalations of symptoms of cough, dyspnea, and sputum production) is a major contributor to worsening lung function, impairment in quality of life, need for urgent care or hospitalization, and cost of care in COPD. Research conducted over the past decade has contributed much to our current understanding of the pathogenesis and treatment of COPD. Additionally, an evolving literature has accumulated about the prevention of acute exacerbations.

Objectives: To describe the early symptoms of pulmonary tuberculosis (TB) when the chest radiograph (CXR) is normal. Setting: Centralized, provincial TB control program. Subjects: Twenty-five patients with culture-positive pulmonary TB [...]

We investigate the bias-stress effect in field-effect transistors (FETs) consisting of 1,2-ethanedithiol-treated PbS quantum dot (QD) films as charge transport layers in a top-gated configuration. The FETs exhibit ambipolar operation with typical mobilities on the order of μe= 8 × 10–3cm2V–1s–1in n-channel operation and μh= 1 × 10–3cm2V–1s–1in p-channel operation. When the FET is turned on in n-channel or p-channel mode, the established drain–source current rapidly decreases from its initial magnitude in a stretched exponential decay, manifesting the bias-stress effect. The choice of dielectric is found to have little effect on the characteristics of this bias-stress effect, leading us to conclude that the associated charge-trapping process originates within the QD film itself. Measurements of bias-stress-induced time-dependent decays in the drain–source current (IDS) are well fit to stretched exponential functions, and the time constants of these decays in n-channel and p-channel operation are found to follow thermally activated (Arrhenius) behavior. Measurements as a function of QD size reveal that the stressing process in n-channel operation is faster for QDs of a smaller diameter while stress in p-channel operation is found to be relatively invariant to QD size. Our results are consistent with a mechanism in which field-induced nanoscale morphological changes within the QD film result in screening of the applied gate field. This phenomenon is entirely recoverable, which allows us to repeatedly observe bias stress and recovery characteristics on the same device. This work elucidates aspects of charge transport in chemically treated lead chalcogenide QD films and is of relevance to ongoing investigations toward employing these films in optoelectronic devices.

Background The metabolism of pyrimidine deoxynucleosides and nucleoside reverse transcriptase inhibitors has been studied in growing cells. However, many of these drugs are associated with mitochondrial toxicities observed in non-replicating tissues, such as in the heart, where their metabolism has not been investigated.Methods The aims of this study were twofold. The first was to investigate the metabolism of the thymidine analogues 3’-azido-3'deoxythymidine (AZT) and 2’,3’-didehydrodideoxy-thymidine (d4T), and the deoxycytidine (dCyd) analogues 2’-deoxy-3’-thiacytidine (3TC) and 2’,3’-dideoxycytidine (ddC) with regard to phosphorylation and breakdown. The second was to investigate their potential effects, singly or in combination with AZT, on metabolism of the naturally occurring deoxynucleosides in the perfused rat heart and in isolated heart mitochondria.Results The analogue d4T was not metabolized in perfused heart or in isolated mitochondria, and had no effect on either thymidine or dCyd metabolism. The dCyd analogues were both phosphorylated in perfused heart to the triphosphate, but only at the limit of detection and they were not phosphorylated in isolated mitochondria. Neither ddC nor 3TC had any effect on thymidine or dCyd metabolism in either perfused heart or in isolated mitochondria. AZT has been previously shown to inhibit thymidine phosphorylation. When d4T, 3TC or ddC were given with AZT, only ddC caused a significant further decrease in thymidine phosphorylation.Conclusions These results indicate that with the exception of the competition between AZT and thymidine, there was little competition for phosphorylation among and between these other nucleoside reverse transcriptase inhibitors and the naturally occurring deoxynucleosides in cardiac tissue and isolated heart mitochondria.

ABSTRACTTo test whether zidovudine (3′-azido-3′-deoxythymidine) (AZT) inhibition of thymidine phosphorylation causes depletion of the TTP pool resulting in mitochondrial DNA depletion, 3T3-F442a cells were differentiated in the presence of AZT and analyzed to determine mitochondrial DNA content and deoxynucleotide levels. These results suggest that AZT toxicity may not be related to deoxynucleotide pool alterations.

We examine how thermal annealing affects the fullerene network in conjugated polymer bulk heterojunction (BHJ) solar cells. We begin by creating electron-only devices with a BHJ geometry by blending the fullerene derivative [6,6]-phenyl-C61-butyric-acid-methyl-ester (PCBM) with polystyrene (PS). These electron-only PS:PCBM diodes function even with a poly(ethylenedioxithiophene):poly(styrenesulfonate) (PEDOT:PSS) layer, indicating that PEDOT:PSS films do not serve as electron blocking layers. Atomic force microscopy shows that the degree of phase segregation in the PS:PCBM blend films is similar to that in the active layer of blends of PCBM with poly(3-hexylthiophene-2,5-diyl) (P3HT), so that the PS:PCBM blends provide a good model for the fullerene part of the BHJ network in P3HT:PCBM solar cells. We find that thermal annealing dramatically decreases the electron current that flows in the PS:PCBM diodes, suggesting that annealing leads to increased phase segregation that lowers the electron mobility on fullerenes in the BHJ geometry. We also find that annealing increases the photoluminesence of P3HT:PCBM blend films, indicating that thermal treatment produces increased phase segregation that leads to decreased exciton harvesting. The fact that annealing decreases both exciton harvesting and electron mobility implies that there is significant room to further improve polymer/fullerene photovoltaics by controlling the amount of phase segregation.

ABSTRACTZidovudine (AZT; 3′-azido-3′-deoxythymidine), a thymidine analog, has been a staple of highly active antiretroviral therapy. It is phosphorylated in the host to the triphosphate and functions by inhibiting the viral reverse transcriptase. However, long-term use of AZT is linked to various tissue toxicities, including cardiomyopathy. These toxicities are associated with mitochondrial DNA depletion, which is hypothesized to be caused by AZT triphosphate inhibition of mitochondrial DNA polymerase γ. In previous work with isolated heart mitochondria, we demonstrated that AZT phosphorylation beyond the monophosphate was not detected and that AZT itself was a potent inhibitor of thymidine phosphorylation. This suggests an alternative hypothesis in which depletion of the TTP pool may limit mitochondrial DNA replication. The present work extends these studies to the whole cell by investigating the metabolism of thymidine and AZT in the intact isolated perfused rat heart. [3H]thymidine is converted to [3H]TTP in a time- and concentration-dependent manner. The level of [3H]TMP is low, suggesting that the reaction catalyzed by thymidine kinase is the rate-limiting step in phosphorylation. [3H]AZT is converted in a time- and concentration-dependent manner to AZT monophosphate, the only phosphorylated product detected after 3 h of perfusion. Both compounds display negative cooperativity, similar to the observations with cloned and purified mitochondrial thymidine kinase 2. The presence of AZT in the perfusate inhibits the phosphorylation of [3H]thymidine with a 50% inhibitory concentration of 24 ± 4 μM. These data support the hypothesis that AZT-induced mitochondrial cardiotoxicity may be caused by a limiting pool of TTP that lowers mitochondrial DNA replication.

Background:Regular use of racemic salbutamol results in the partial loss of its bronchoprotective effect. The 2 enantiomers of salbutamol, the bronchodilator R-salbutamol and nonbronchodilator S-salbutamol, are now available. Objective:We sought to compare the effect of regular use of S-salbutamol, R-salbutamol, racemic salbutamol, and placebo on the bronchoprotective effect of a single dose of racemic salbutamol against methacholine-induced bronchoconstriction. Methods:Eleven of 13 well-controlled β2-agonist–free asthmatic subjects completed a double-blind, randomized study comparing racemic salbutamol 2.5 mg, S-salbutamol 1.25 mg, R-salbutamol 1.25 mg, and diluent placebo nebulized and inhaled 3 times daily for 6 days (≥6-day washout period). Ten to 12 hours after the last dose, the subjects performed measurement of FEV1, methacholine PC20, and a repeat methacholine PC20done 1 hour after the first methacholine test and 10 minutes after 2 puffs (200 μg) of racemic salbutamol administered from a metered-dose inhaler. The primary endpoint was the methacholine PC20dose shift (Δlog PC20÷ log 2) from before to after administration of 200 μg of racemic salbutamol. Results:The methacholine dose shift was 3.2 doubling doses (9-fold increase in methacholine PC20after 200 μg of racemic salbutamol) during the placebo treatment and was unaltered (3.2) after administration of S-salbutamol. The dose shift was significantly lower after both the R-salbutamol and racemic salbutamol treatments (2.2 and 2.6 doubling doses, respectively); there was no significant difference between R-salbutamol and racemic salbutamol. There was no treatment effect on baseline FEV1, baseline methacholine PC20, or bronchodilation. Conclusion:Regular treatment with racemic salbutamol or R-salbutamol, but not S-salbutamol, results in a partial loss of bronchoprotection, without loss of bronchodilation, compared with placebo. (J Allergy Clin Immunol 1999;103:1049-53.)

Clinical exercise testing has become an important tool in the evaluation of the physiologic functions of patients with known and suspected interstitial lung disease (ILD), a diverse group of disorders that demonstrate common clinical, radiographic, and physiologic abnormalities. Exercise testing offers a sensitive means to aid in the early diagnosis and effective monitoring of therapeutic interventions in this population. Other indications for exercise testing in this population include objective assessment of symptoms, assessment of disease severity, assessment of factors contributing to exercise limitation, and disability assessment. Characteristic measurements during exercise testing in patients with ILD include reduced peak oxygen uptake and maximum work rate, high minute ventilation (V1) at submaximal work, low peak VI, high respiratory frequency and low tidal volume (VI) at submaximal work, normal peak VT/vital capacity, high peak VI/ maximum voluntary ventilation, low maximal heart rate, high wasted ventilation (VD/VT), arterial O2desaturation, and unchanged partial pressure of arterial carbon dioxide pressure from rest. Although the pattern of physiologic responses demonstrated during exercise is similar in the various disorders that present as the common entity known as ILD, it is important to remember that it is not entirely characteristic. However, the results from exercise testing may certainly be diagnostic when considered together with all other information usually available to the clinician.

Clinical exercise testing has become an essential tool used in the early diagnosis, in the monitoring of treatment effectiveness, and in the assessment of impairment owing to ILD. Despite the assorted causes, the responses to exercise demonstrated by these diseases are generally similar. Although much has been learned about how these diverse diseases functionally impair the exercise capacity of the patient, further study is required if we are to understand fully the various physiologic abnormalities manifested by patients with ILD during exercise.

A new fumonisin has been isolated from Fusarium moniliforme isolate MRC826 grown on corn. It was shown by NMR and mass spectrometry to be an isomer of fumonisin B2 that has free hydroxyl groups at C-3 and C-10 instead of the normal C-3 and C-5. This new fumonisin was detected in cultures of most isolates of F. moniliforme that were examined and was usually present at concentrations similar to those of fumonisin B2. Two isolates of F. moniliforme that produce significantly higher levels of this new isomer were identified.

We examined 25 strains of Fusarium moniliforme from eight states known to be associated with equine leukoencephalomalacia, a disease caused by the mycotoxin fumonisin B1. We determined the mating population, mating type, and vegetative compatibility group to which each of these strains belonged. All 25 strains were in the ‘A’ mating population; 12 were A+ and 13 were A-. Seventeen of the 25 strains were female fertile; these strains also averaged higher levels of fumonisin B1 production than did the strains that were female sterile. Nitrate non-utilizing (nit) mutants were generated in all 25 strains and each strain was assigned to a unique vegetative compatibility group based on the inability of the derived nit mutants to form a prototrophic heterokaryon with complementary nit mutants derived from any of the other strains examined. From these data, we concluded that the production of fumonisin B1 is a general characteristic of strains from the ‘A’ mating population of Gibberella fujikuroi associated with equine leukoencephalomalacia, since all 25 of the isolates that we examined were genetically distinct individuals.

Fumonisins were readily produced in cultures of Fusarium moniliforme using a defined liquid medium. Addition of 200 mg of d3-methyl L-methionine to 100-ml cultures of F. moniliforme gave increased overall yields and high levels of deuterium (2H) incorporation into fumonisin B1. Approximately 90% of the resulting fumonisin B1 contained 6 deuterium atoms, while 9% of the product contained 3 deuterium atoms. Deuterium was shown to be incorporated exclusively in the methyl groups of the fumonisin backbone. The addition of as little as 5 mg of labeled methionine stimulated fumonisin production, but only about 5% of the fumonisin produced contained 3 deuterium atoms.

A comparison has been made of the immunological properties of CEA (carcinoembryonic antigen) and another perchloric acid-soluble macromolecule which occurs in colonic and certain other carcinomata and which is here termed CEX. By using a variety of antisera it was shown that the two substances share common antigenic groups as well as having characteristic ones of their own. These latter groups have enabled the preparation of (a) antisera which give a gel diffusion line only with CEA and (b) and antiserum which gives a line only with CEX. No immunological difference could be found between CEX and the NGP of Mach or the NCA of von Kleist and Burtin. CEX was found in foetal gut, in plasma and associated with CEA in virtually all the tissues and fluids in which the latter occurs; the two appear to go hand-in-hand and no proof was found that CEX is either less or more cancer specific than CEA—it is merely found in greater quantity; neither substance showed absolute cancer specificity. The usefulness of a radioimmunoassay for CEX is discussed, and also the possibility of interference by CEX in the radioimmunoassay for CEA. Evidence of two molecular species of CEA has been found.