bluuebunny/crossref_metadata_2025 huggingface dataset:
Malaria and the Red Cell
Authors: Weatherall David J. , Miller Louis H. , Baruch Dror I. , Marsh Kevin , Doumbo Ogobara K. , Casals-Pascual Climent , Roberts David J.
Published: August 2003

Because of the breakdown of malaria control programs, the constant emergence of drug resistant parasites, and, possibly, climatic changes malaria poses a major problem for the developing countries. In addition, because of the speed of international travel it is being seen with increasing frequency as an imported disease in non-tropical countries. This update explores recent information about the pathophysiology of the disease, its protean hematological manifestations, and how carrier frequencies for the common hemoglobin disorders have been maintained by relative resistance to the malarial parasite.

In Section I, Dr. Louis Miller and colleagues consider recent information about the pathophysiology of malarial infection, including new information about interactions between the malarial parasite and vascular endothelium.

In Section II, Dr. David Roberts discusses what is known about the complex interactions between red cell production and destruction that characterize the anemia of malaria, one of the commonest causes of anemia in tropical countries.

In Section III, Dr. David Weatherall reviews recent studies on how the high gene frequencies of the thalassemias and hemoglobin variants have been maintained by heterozygote advantage against malaria and how malaria has shaped the genetic structure of human populations.
Stem Cells: Hype and Reality
Authors: Verfaillie Catherine M. , Pera Martin F. , Lansdorp Peter M.
Published: August 2003

This update discusses what is known regarding embryonic and adult tissue-derived pluripotent stem cells, including the mechanisms underlying self-renewal without senescence, differentiation in multiple cell types both in vitro and in vivo, and future potential clinical uses of such stem cells.

In Section I, Dr. Lansdorp reviews the structure and function of telomerase, the enzyme that restores telomeric ends of chromosomes upon cell division, highly present in embryonic stem cells but not adult stem cells. He discusses the structure and function of telomerase and signaling pathways activated by the enzyme, with special emphasis on normal and leukemic hematopoietic stem cells.

In Section II, Dr. Pera reviews the present understanding of mammalian pluripotent embryonic stem cells. He discusses the concept of pluripotentiality in its embryonic context, derivation of stem cells from embryonic or fetal tissue, the basic properties of the stem cells, and methods to produce specific types of differentiated cell from stem cells. He examines the potential applications of stem cells in research and medicine and some of the barriers that must be crossed to achieve these goals.

In Section III, Dr. Verfaillie reviews the present understanding of pluripotency of adult stem cells. She discusses the concept of stem cell plasticity, a term used to describe the greater potency described by several investigators of adult tissue-derived stem cells, critically reviews the published studies demonstrating stem cell plasticity, and possible mechanisms underlying such plasticity, and examines the possible role of pluripotent adult stem cells in research and medicine.
Non-Myeloablative Transplantation
Authors: Maloney David G. , Sandmaier Brenda M. , Mackinnon Stephen , Shizuru Judith A.
Published: August 2003

The concept of utilizing enhanced immunosuppression rather than myeloablative cytotoxic conditioning has allowed the engraftment of allogeneic stem cells from related and unrelated donors with lower early transplant-related mortality (TRM) and morbidity. This approach shifts tumor eradication to the graft-vs-host immune response directed against minor histocompatibility antigens expressed on tumor cells. This is not without risk, as the long-term effects of graft-versus-host disease (GVHD), it’s treatment, or resulting complications and immunodeficiency may be life threatening. However, this approach does allow the application of a potentially curative procedure to elderly or medically infirm patients who would not tolerate high-dose conditioning regimens.

Section I, by Dr. Sandmaier, describes the current use of nonmyeloablative regimens and matched related or unrelated donors for the treatment of patients with CLL, CML, acute leukemia, MDS, lymphoma, and myeloma.

In Section II, Dr. Maloney discusses the use of cytoreductive autologous followed by planned non-myeloablative allografts as treatment for patients with myeloma or NHL. This tandem transplant approach has a lower TRM than conventional high dose allografting. The nonmyeloablative allograft may allow the graft-versus-tumor (GVT) immune response to eradicate the minimal residual disease that causes nearly all patients with low-grade NHL or myeloma to relapse following autologous transplantation.

In Section III, Dr. Mackinnon discusses the risks and benefits of T cell depletion strategies to prevent acute GVHD, while retaining GVT activity by planned donor lymphocyte infusions.

Finally, in Section IV, Dr. Shizuru discusses the relationship between GVHD and GVT activity. Future studies, employing a greater understanding of these issues and the separation of GVHD from GVT activity by immunization or T cell cloning, may allow nonmyeloablative allogeneic transplantation to be safer and more effective.
Stem Cell Transplantation: Supportive Care and Long-Term Complications
Authors: Wingard John R. , Vogelsang Georgia B. , Deeg H. Joachim
Published: August 2003

With increasing hematopoietic stem cell transplant (HSCT) activity and improvement in outcomes, there are many thousands of HSCT survivors currently being followed by non-transplant clinicians for their healthcare. Several types of late sequelae from HSCT have been noted, and awareness of these complications is important in minimizing late morbidity and mortality. Late effects can include toxicities from the treatment regimen, infections from immunodeficiency, endocrine disturbances, growth impairment, psychosocial adjustment disorders, second malignancies, and chronic graft-versus-host disease (GVHD). A variety of risk factors for these complications have been noted. The clinician should be alert to the potential for these health issues. Preventive and treatment strategies can minimize morbidity from these problems and optimize outcomes.
Red Cell Antigens as Functional Molecules and Obstacles to Transfusion
Authors: Garratty George , Telen Marilyn J. , Petz Lawrence D.
Published: August 2003

Blood group antigens (BGAs) can act as functional molecules but also can evoke autoantibodies and alloantibodies, causing autoimmune hemolytic anemia, hemolytic disease of the newborn and hemolytic transfusion reactions.

In Section I, Dr. Marilyn Telen discusses physiologic and pathologic functions of RBC BGA-bearing molecules. She reviews some associations of BGAs with RBC membrane integrity and hemolytic anemia; association of BGAs with enzymatic and transport functions; and adhesion molecules expressed by RBCs, especially with reference to their pathophysiological role in sickle cell disease.

In Section II, Dr. Lawrence Petz discusses the problems of providing blood for patients who have RBC autoantibodies. He provides an algorithm for excluding the presence of “hidden” alloantibodies, when all units appear to be incompatible due to the autoantibody. He emphasizes that clinicians should be aware of these approaches and not accept “the least incompatible unit.”

In Section III, Dr. George Garratty describes two processes, in development, that produce RBCs that result in RBCs that can be described as “universal” donor or “stealth” RBCs. The first process involves changing group A, B, or AB RBCs into group O RBCs by removing the immunospecific sugars responsible for A and B specificity by using specific enzymes. The second process involves covering all BGAs on the RBC surface using polyethylene glycol (PEG). Results of in vitro and in vivo studies on these modified RBCs are discussed.
Enhancing Physician-Patient Communication
Authors: Lee Stephanie J. , Back Anthony L. , Block Susan D. , Stewart Susan K.
Published: August 2003

Physician-patient communication encompasses the verbal and nonverbal interactions that form the basis for the doctor-patient relationship. A growing body of research and guidelines development acknowledges that physicians do not have to be born with excellent communication skills, but rather can learn them as they practice the other aspects of medicine. Improvement in physician-patient communication can result in better patient care and help patients adapt to illness and treatment. In addition, knowledge of communication strategies may decrease stress on physicians because delivering bad news, dealing with patients’ emotions, and sharing decision making, particularly around issues of informed consent or when medical information is extremely complex, have been recognized by physicians as communication challenges. This paper will provide an overview of research aimed at improving patient outcome through better physician-patient communication and discuss guidelines and practical suggestions immediately applicable to clinical practice.
Marrow Failure
Authors: D’Andrea Alan D. , Dahl Niklas , Guinan Eva C. , Shimamura Akiko
Published: August 2003

This chapter describes the clinical presentation and molecular basis of two inherited bone marrow failure syndromes, Fanconi anemia (FA), and Diamond-Blackfan anemia (DBA). It also provides an update on diagnostic and therapeutic approaches to bone marrow failure of all types (inherited and acquired) in pediatric patients.

In Section I, Dr. Alan D’Andrea reviews the wide range of clinical manifestations of Fanconi anemia. Significant advances have been made in understanding the molecular pathogenesis of FA. On the basis of these advances, new diagnostic assays and treatment options are now available.

In Section II, Dr. Niklas Dahl examines the clinical features and molecular pathogenesis of Diamond-Blackfan anemia. The possible links between the RPS19 gene (DBA gene) and the erythropoiesis defect are considered.

In Section III, Drs. Eva Guinan and Akiko Shimamura provide an algorithm for the diagnostic evaluation and treatment of children with inherited or acquired aplastic anemia. Through the presentation of a case study of a pediatric patient with bone marrow failure, he provides an overview of the newest tests and treatment options.
Acute Myeloid Leukemia
Authors: Giles Francis J. , Keating Armand , Goldstone Anthony H. , Avivi Irit , Willman Cheryl L. , Kantarjian Hagop M.
Published: August 2003

In this chapter, Drs. Keating and Willman review recent advances in our understanding of the pathophysiology of acute myeloid leukemia (AML) and allied conditions, including the advanced myelodysplastic syndromes (MDS), while Drs. Goldstone, Avivi, Giles, and Kantarjian focus on therapeutic data with an emphasis on current patient care and future research studies.

In Section I, Dr. Armand Keating reviews the role of the hematopoietic microenvironment in the initiation and progression of leukemia. He also discusses recent data on the stromal, or nonhematopoietic, marrow mesenchymal cell population and its possible role in AML.

In Section II, Drs. Anthony Goldstone and Irit Avivi review the current role of stem cell transplantation as therapy for AML and MDS. They focus on data generated on recent Medical Research Council studies and promising investigation approaches.

In Section III, Dr. Cheryl Willman reviews the current role of molecular genetics and gene expression analysis as tools to assist in AML disease classification systems, modeling of gene expression profiles associated with response or resistance to various interventions, and identifying novel therapeutic targets.

In Section IV, Drs. Hagop Kantarjian and Francis Giles review some promising agents and strategies under investigation in the therapy of AML and MDS with an emphasis on novel delivery systems for cytotoxic therapy and on targeted biologic agents.
Incidence of probable occupational asthma and changes in airway calibre and responsiveness in apprentice welders
Authors: El-Zein M. , Malo J-L. , Infante-Rivard C. , Gautrin D.
Published: August 2003

The majority of cross-sectional studies have shown a higher prevalence of ventilatory impairment in welders while only few longitudinal studies were able to detect chronic effects on spirometry or bronchial responsiveness.

The aim of the study was to determine the incidence of probable occupational asthma (OA), bronchial obstruction and hyperresponsiveness among 286 students entering an apprenticeship programme in the welding profession.

This epidemiological prospective cohort study consisted of a baseline assessment survey and two follow-up assessments. A respiratory symptom questionnaire was administered at each visit. Spirometry and methacholine bronchial challenge test results, conducted once prior to onset of exposure and later after an average of 15 months of apprenticeship, were available for 194 subjects.

The incidence of probable OA was ∼3% (6 of 194). The incidence of bronchial hyperresponsiveness, defined as a ≥3.2‐fold decrease in the provocative concentration causing a 20% fall in the forced expiratory volume in one second from baseline to the end of the study was 11.9%. A statistically significant difference was found between the baseline and end of study for the lung function values. In particular, the forced expiratory volume per cent predicted had significantly dropped by 8.4% on average.

The significance of these early pulmonary function changes in relation to possible chronic effects of exposure to welding fumes and gases remains to be explored.
Diagnostic implications of telomerase activity in pleural effusions
Authors: Dikmen G. , Dikmen E. , Kara M. , Şahin E. , Doğan P. , Özdemir N.
Published: August 2003

The aim of the present study was to investigate the diagnostic efficacy of telomerase activity for discrimination of malignant and benign pleural effusions.

Pleural effusions were collected from 109 consecutive patients in whom the diagnosis was confirmed with cytological and/or histological examinations. Cytological samples were classified as malignant (n=63) and benign (n=46). Telomerase activity was determined with the polymerase chain reaction-based telomeric repeat amplification protocol assay.

Telomerase activity was detected in 52 (82.5%) and nine (19.6%) samples from the malignant and benign groups, respectively, which was a significant difference. The sensitivity rate of cytological examination when combined with telomerase activity (92.1%) was significantly greater than that of cytological examination alone (53.9%). The sensitivity and specificity of telomerase activity were 82.5 and 80.4%, respectively. Diagnostic accuracy of telomerase activity was 81.6%.

Telomerase activity is a highly sensitive diagnostic biomarker for malignancy and may be used as an adjunct to cytological findings in determining malignant pleural effusions.
Trends in asbestos body counts in bronchoalveolar lavage fluid over two decades
Authors: Dumortier P. , Thimpont J. , de Maertelaer V. , De Vuyst P.
Published: August 2003

As in most western countries, the use of asbestos has decreased in Belgium since the mid 1970's. Successive regulations have lowered the permissible levels of exposure and prohibited the use of various asbestos products.

In order to assess the impact of these prevention measures on the pulmonary fibre burden of asbestos-exposed patients, the bronchoalveolar lavage fluid (BALF) asbestos body (AB) analysis database of the authors' laboratory was reviewed for the period 1983–2000.

A total of 4,772 cases were considered, of which 95% were males. AB concentration exceeded 1 AB·mL BALF−1in 36.1%. There was essentially no change in the mean concentration of AB over the period evaluated. However, the concentrations in individuals with very high levels decreased over time. This was associated with a shift in exposure categories from primary asbestos workers to those exposed during handling of asbestos-containing materials or to asbestos in place in buildings or industrial sites.

This is consistent with epidemiological data indicating that the number of severe cases of asbestosis caused by very high cumulated doses decreases but that benign pleural diseases and mesothelioma remain the most frequent asbestos-related diseases. Past prevention measures are not expected to have a measurable influence on the incidence of mesothelioma in the near future.
Spirometric reference values in a large Middle Eastern population
Authors: Golshan M. , Nematbakhsh M. , Amra B. , Crapo R.O.
Published: August 2003

Ethnic differences in pulmonary function have been frequently reported. The purposes of this study were to derive equations for the prediction of normative spirometry values for a large population of Persians in Isfahan and compare them to reference values from a White Euro-USA population.

Spirometry measurements were obtained from 4,341 randomly selected healthy nonsmoker subjects in Isfahan, Iran, utilising American Thoracic Society guidelines and a vigorous quality assurance program. Measured data from 3,213 subjects were analysed using multiple regression techniques to derive prediction equations for spirometric variables; the remaining 1,128 subjects were used as a control group to test the validity of the derived equations. In addition, predicted values were compared with values derived from recently published equations for the USA.

Derived prediction equations showed good performance for most spirometric parameters. Compared with USA Whites, adult Persians have minimally lower forced vital capacities, while the values for children are close to USA Whites.

In comparison with reference equations based on European or USA populations, local reference values are more biologically and technically suitable for the interpretation of spirometric data from Iranian populations.
Inflammatory markers in cystic fibrosis patients with transmissiblePseudomonas aeruginosa
Authors: Jones A.M. , Martin L. , Bright-Thomas R.J. , Dodd M.E. , McDowell A , Moffitt K.L. , Elborn J.S. , Webb A.K.
Published: August 2003

ChronicPseudomonas aeruginosainfection in cystic fibrosis (CF) leads to a damaging host inflammatory response. There are an increasing number of reports ofP. aeruginosacross-infection at CF centres. The clinical significance of acquisition of a transmissible strain for patients who already harbourP. aeruginosais unclear. In this study, levels of inflammatory markers in clinically stable adult CF patients who harbour transmissible and sporadic strains ofP. aeruginosahave been compared.

Patients with CF and chronicP. aeruginosainfection were grouped into those who harbour a transmissibleP. aeruginosaand those who harbour their own sporadic strains. Total white cell and differential counts, sputum neutrophil elastase (NE), interleukin (IL)‐8, tumour necrosis factor (TNF)‐α, plasma IL‐6 and NE/α1‐antitrypsin complexes, serum C‐reactive protein, and urine TNF receptor 1 were all measured in clinically stable patients 4–6 weeks following completion of intravenous antibiotic therapy.

The two groups (both n=20) were well matched for per cent predicted forced expiratory volume in one second, per cent predicted forced vital capacity and body mass index. There were no significant differences in levels of white cell counts or inflammatory markers between the two groups.

At times of clinical stability, cystic fibrosis patients infected with transmissiblePseudomonas aeruginosado not have a heightened inflammatory response above that of those harbouring sporadic strains.
Is bronchoscopic photodynamic therapy a therapeutic option in lung cancer?
Authors: Moghissi K. , Dixon K.
Published: August 2003

This study addresses whether photodynamic therapy (PDT) is a valid therapeutic option in lung cancer treatment.

A total of 24 articles were reviewed in two categories: advanced (G1) and early (G2) disease. Details considered included the following: 1) number of patients in each series; 2) staging; 3) methodology; 4) mortality; 5) morbidity; 6) survival; 7) relief of symptoms; and 8) concomitant treatments. G1 (636 patients) had severe endobronchial obstructive cancer and PDT was primarily for symptom relief. G2 (517 patients) had early stage cancer and were treated with PDT for curative intent.

There was no procedure-related mortality in either group. G1 had a 5–28% incidence of skin sensitivity. Haemoptysis occurred in two series; one fatal, an incidence of 2.2%. Almost all patients had symptomatic relief. Patients with lower disease stage and better performance status had improved survival rates. G2 had a 8–28% incidence of sunburn. Three patients in one series (38 patients) had haemoptysis. Survival after 5 yrs in complete remission/response patients was 70%.

This review suggests that bronchoscopic photodynamic therapy has indications in selected lung cancer patients with early or advanced stage disease. However, in the absence of a formal comparative study, no claim can be made of its superiority over other endobronchial therapies.
Melioidosis: an important cause of pneumonia in residents of and travellers returned from endemic regions
Authors: Currie B.J.
Published: August 2003

Melioidosis is endemic in South East Asia, Asia and northern Australia. Infection usually follows percutaneous inoculation or inhalation of the causative bacterium,Burkholderia pseudomallei, which is present in soil and surface water in the endemic region. While 20–36% of melioidosis cases have no evident predisposing risk factor, the vast majority of fatal cases have an identified risk factor, the most important of which are diabetes, alcoholism and chronic renal disease.

Half of all cases present with pneumonia, but there is great clinical diversity, from localised skin ulcers or abscesses without systemic illness to fulminant septic shock with multiple abscesses in the lungs, liver, spleen and kidneys. At least 10% of cases present with a chronic respiratory illness (sick >2 months) mimicking tuberculosis and often with upper lobe infiltrates and/or cavities on chest radiography. As with tuberculosis, latency with reactivation decades after infection can also occur, although this is rare.

Confirmation of diagnosis is by culture ofB. pseudomalleifrom blood, sputum, throat swab or other samples. Microbiology laboratories need to be informed of the possibility of melioidosis, as those not familiar with it can misidentify the organism. Antibiotic therapy is initial intensive therapy withi.v.ceftazidime or meropenem or imipenem +/− cotrimoxazole for ≥10 days, followed by eradication therapy with cotrimoxazole +/− doxycycline +/− chloramphenicol (first 4 weeks only) for ≥3 months.

Melioidosis has been increasingly recognised in returning travellers in Europe and recently melioidosis and colonisation withB. pseudomalleihave been documented in cystic fibrosis patients visiting or resident in endemic areas.
Primary pulmonary hypertension, Castleman's disease and human herpesvirus‐8
Authors: Bull T.M. , Cool C.D. , Serls A.E. , Rai P.R. , Parr J. , Neid J.M. , Geraci M.W. , Campbell T.B. , Voelkel N.F. , Badesch D.B.
Published: August 2003

Primary pulmonary hypertension (PPH) and Castleman's disease (CD) are rare conditions infrequently encountered in clinical practice.

In this paper, two patients diagnosed with both of these diseases are reported. The authors speculate that rather than being a chance occurrence, these conditions are linked by a common angio-proliferative mechanism. Therefore, an association between infection with the human herpesvirus‐8 and the diseases of PPH and CD was sought.

Evidence of human herpesvirus‐8 infection was found in the lung tissue and, specifically, in the plexiform lesions from one of the patients.
Bleomycin induces cellular senescence in alveolar epithelial cells
Authors: Aoshiba K. , Tsuji T. , Nagai A.
Published: August 2003

Cellular senescence is a state of irreversible growth arrest. In this paper the authors examined whether bleomycin, an agent that causes pulmonary fibrosis, induces the senescence of alveolar epithelial cells.

Type II-like alveolar epithelial (A549) cells or rat primary type II cells were exposed to bleomycin and then evaluated for markers of cellular senescence. Bleomycin was also administered intratracheally in C57BL/6 mice.

The authors found that exposure to bleomycin induced cellular senescence in A549 cells and rat primary type II cells. The senescence was characterised by a dose- and time-dependent increase in senescence-associated β‐galactosidase activity, senescence-associated changes in cell morphology, an increase in cell size and lysosomal mass, the overexpression of p21 protein, and irreversible growth arrest. The intratracheal injection of bleomycin in mice induced an increase in senescence-associated β‐galactosidase activity in type II epithelial cells, reaching a maximum at day 7.

These results suggest that bleomycin induces a phenotype that is indistinguishable from that of senescence in alveolar epithelial cells. The induction of epithelial senescence by bleomycin may contribute to the pathway of impaired re-epithelialisation leading to pulmonary fibrosis.
Expression of the serotonin 1b receptor in experimental pulmonary hypertension
Authors: Rondelet B. , Van Beneden R. , Kerbaul F. , Motte S. , Fesler P. , McEntee K. , Brimioulle S. , Ketelslegers J-M. , Naeije R.
Published: August 2003

The pathogenesis of pulmonary arterial hypertension (PAH) remains uncertain. Both the serotonin and endothelin (ET) systems are believed to be involved. Recent studies pointed to the importance of the serotonin 2B receptor as a limiting step.

The current authors investigated the lung tissue expression of serotonin receptors and of the serotonin transporter (5‐HTT) by real-time-quantitative polymerase chain reaction in chronic overcirculation-induced PAH in growing piglets, with and without treatment with the dual ET receptor blocker bosentan. Pulmonary haemodynamic changes were described by pulmonary arterial impedance spectra.

Three months after the surgical anastomosis of the left subclavian artery to the pulmonary arterial trunk, there was a shift of the impedance spectra to higher ratios of pressure and flow moduli, with increases in both 0 Hz impedance and characteristic impedance, and these changes were completely prevented by bosentan therapy. There was an increase in the expression of the serotonin 1B receptor. There was no change in the expression of the 5‐HTT, and of the serotonin 2B, 1D, and 4 receptors. The overexpression of the serotonin 1B receptor was partially prevented by bosentan therapy.

The present authors conclude that this early pulmonary arterial hypertension model is characterised by an endothelin receptor-dependent increased expression of the serotonin 1B receptor.
Cellular profiles of induced sputum in children with stable cystic fibrosis: comparison with BAL
Authors: Reinhardt N. , Chen C.I.U. , Loppow D. , Schink T. , Kleinau I. , Jörres R.A. , Wahn U. , Magnussen H. , Paul K.P.
Published: August 2003

Neutrophil-dominated endobronchial inflammation is a major characteristic of cystic fibrosis (CF) and there is increasing demand for easy-to-perform noninvasive monitoring for prediction and intervention.

Fourteen stable paediatric CF patients (8–17 yrs; mean forced expiratory volume in one second 86.7% of the predicted value) were investigated once by fractional bronchoalveolar lavage (BAL) and by sputum induction on three occasions, 2–6 weeks apart. Sputum was induced by consecutive 10‐min inhalations of 3, 4 and 5% saline. CFsputum cellular profiles were compared with BAL fluid cell counts and samples from age-matched healthy children, and between different time points to assess reproducibility.

Adequate sputum was recovered on >95% of occasions. In all sputum fractions, CF patients showed higher neutrophil counts than healthy children. Neutrophil percentages were highest in the first BAL fraction (median 92%), followed by sputum, in which the percentages decreased in consecutive fractions (72, 66 and 64%), whereas counts were lowest in the pooled BAL fraction (53%). Increasing percentages of macrophages mirrored the decreases in neutrophil percentage. Results of sputum induction at different time points in the CF patients showed good reproducibility and nonoverlap with counts from healthy children.

In conclusion, the results of sputum induction in children with mild stable cystic fibrosis adequately describe airway inflammation by providing cellular profiles with lower relative neutrophil counts than in the first (“bronchial”) bronchoalveolar lavage fraction and higher relative neutrophil counts than in subsequent pooled (“more peripheral”) bronchoalveolar lavage fractions.
Controversies in epidemiology of occupational asthma
Authors: Gautrin D. , Newman-Taylor A.J. , Nordman H. , Malo J-L.
Published: August 2003

Epidemiology is the study of the distribution, determinants and outcome of disease. In this article, the recently acquired knowledge of the epidemiology of occupational asthma is described, as well as current areas of controversy.

Incidence figures obtained from field studies in high-risk workplaces, medicolegal statistics and sentinel programmes indicate that ∼10% of adult-onset asthma is attributable to the workplace. The strategy to identify cases through questionnaires and tools that address functional, immunological and physiopathological issues needs to be improved.

Although few in number and limited to a handful of workplaces, cohort studies found that the risk of developing occupational asthma is determined less by individual susceptibility (e.g.atopy, tobacco smoking, human leukocyte antigen phenotype) and more by the level of exposure to its causes; in general, the higher the exposure, the greater the risk, and, by implication, lowering the level of exposure reduces the incidence of disease.

Occupational asthma can be used as a satisfactory model for the development of adult-onset asthma. There is a great need to develop intervention strategies through adequate surveillance programmes in high-risk workplaces.
Predominant emphysema phenotype in chronic obstructive pulmonary disease patients
Authors: Boschetto P. , Miniati M. , Miotto D. , Braccioni F. , De Rosa E. , Bononi I. , Papi A. , Saetta M. , Fabbri L.M. , Mapp C.E.
Published: August 2003

Patients with fixed airflow limitation are grouped under the heading of chronic obstructive pulmonary disease (COPD). The authors investigated whether COPD patients have distinct functional, radiological and sputum cells characteristics depending on the presence or absence of emphysema.

Twenty-four COPD outpatients, 12 with and 12 without emphysema on high-resolution computed tomography scan of the chest, were examined. Patients underwent chest radiography, pulmonary function tests and sputum induction and analysis.

Subjects with documented emphysema had lower forced expiratory volume in one second (FEV1), FEV1/forced vital capacity ratio, and lower carbon monoxide diffusion constant (KCO), compared with subjects without emphysema. Chest radiograph score of emphysema was higher, chest radiograph score of chronic bronchitis was lower, and the number of sputum lymphocytes was increased in patients with emphysema, who also showed a negative correlation betweenKCOand pack-yrs.

Chronic obstructive pulmonary disease patients with emphysema, documented by high-resolution computed tomography scan, have a different disease phenotype compared with patients without emphysema. Identification of chronic obstructive pulmonary disease-related phenotypes may improve understanding of the natural history and treatment of the disease.
Treatment of chronic respiratory failure in kyphoscoliosis: oxygen or ventilation?
Authors: Buyse B. , Meersseman W. , Demedts M.
Published: August 2003

Patients with kyphoscoliosis and chronic respiratory insufficiency are treated either with home oxygen therapy or ventilation. Kyphoscoliotic patients demonstrate impaired ventilatory mechanics, consequently ventilation seems to be the treatment of choice. Yet, no randomised controlled trials (CRT) exist to prove it.

Most investigators find it difficult to ethically justify a CRT. Therefore, the current authors performed the following retrospective study: survival and pulmonary function were analysed in all consecutive kyphoscoliotic patients who started long-term oxygen therapy (LTO group; n=15, aged 62±11 yrs (mean±sd)) or LTO plus nocturnal nasal intermittent positive pressure ventilation (nNIPPV group; n=18, aged 61±7 yrs) in the Dept of Pulmonology (University Hospital Gasthuisberg, Leuven) between 1990–2002.

Prior to treatment partial pressure of oxygen (PO2) was lower, partial pressure of carbon dioxide (PCO2) tended to be higher and vital capacity (VC) tended to be lower in the nNIPPV group than in the LTO group (PO25.9±1versus6.7±0.9 kPa (44±8versus50±7 mmHg),PCO28±1versus7.3±0.9 kPa (60±8versus55±7 mmHg), VC 32±12versus40±16% predicted, or 645±244versus970±387 mL). In the nNIPPV group the 1‐yr survival was higher (100%versus66%). nNIPPV patients demonstrated an improvement inPO2(breathing air) +54%,PCO2(breathing air) −21%, VC +47% and maximal static inspiratory mouth pressure +33%; these improvements were absent in the LTO group.

In conclusion, nocturnal nasal intermittent positive pressure ventilation, plus long-term oxygen therapy results in more favourable survival and changes in blood gases and respiratory function than long-term oxygen therapy alone.
The occupational burden of chronic obstructive pulmonary disease
Authors: Trupin L. , Earnest G. , San Pedro M. , Balmes J.R. , Eisner M.D. , Yelin E. , Katz P.P. , Blanc P.D.
Published: August 2003

Although chronic obstructive pulmonary disease (COPD) is attributed predominantly to tobacco smoke, occupational exposures are also suspected risk factors for COPD. Estimating the proportion of COPD attributable to occupation is thus an important public health need.

A randomly selected sample of 2,061 US residents aged 55–75 yrs completed telephone interviews covering respiratory health, general health status and occupational history. Occupational exposure during the longest-held job was determined by self-reported exposure to vapours, gas, dust or fumes and through a job exposure matrix. COPD was defined by self-reported physician's diagnosis.

After adjusting for smoking status and demography, the odds ratio for COPD related to self-reported occupational exposure was 2.0 (95% confidence interval (CI) 1.6–2.5), resulting in an adjusted population attributable risk (PAR) of 20% (95% CI 13–27%). The adjusted odds ratio based on the job exposure matrix was 1.6 (95% CI 1.1–2.5) for high and 1.4 (95% CI 1.1–1.9) for intermediate probability of occupational dust exposure; the associated PAR was 9% (95% CI 3–15%). A narrower definition of COPD, excluding chronic bronchitis, was associated with a PAR based on reported occupational exposure of 31% (95% CI 19–41%).

Past occupational exposures significantly increased the likelihood of chronic obstructive pulmonary disease, independent of the effects of smoking. Given that one in five cases of chronic obstructive pulmonary disease may be attributable to occupational exposures, clinicians and health policy-makers should address this potential avenue of chronic obstructive pulmonary disease causation and its prevention.
Primary pulmonary hypertension after amfepramone (diethylpropion) with BMPR2 mutation
Authors: Abramowicz M.J. , Van Haecke P. , Demedts M. , Delcroix M.
Published: August 2003

Primary pulmonary hypertension (PPH) is characterised by sustained elevations of pulmonary arterial pressure without a demonstrable cause, leading to right ventricular failure and death. Hereditary mutations in the bone morphogenetic protein receptor type II (BMPR2) gene result in familial PPH transmitted as an autosomal dominant trait, albeit with low penetrance. The causes in cases without a BMPR2 mutation are unknown, but a syndrome of pulmonary arterial hypertension (PAH) similar to hereditary PPH is associated with systemic connective tissue disease, congenital heart disease, portal hypertension, and human immunodeficiency virus infection, or with the use of appetite‐suppressant drugs.

The authors identified a BMPR2 gene mutation in a 27‐yr‐old female who developed PAH after a short course of the appetite‐suppressant drug amfepramone (diethylpropion). This allowed molecular genetic counselling and prevention of potentially harmful drug exposure in the patient's son treated for attention deficit disorder with methylphenidate, an amphetamine‐related drug. No BMPR2 mutation was found in four additional, unrelated patients with appetite suppressant‐related PPH.

The findings provide strong evidence that amfepramone can trigger primary pulmonary hypertension in a bone morphogenetic protein receptor type II gene mutation carrier, and indicate that other genes are probably implicated in genetic susceptibility to appetite suppressants.
Do GOLD stages of COPD severity really correspond to differences in health status?
Authors: Antonelli-Incalzi R. , Imperiale C. , Bellia V. , Catalano F. , Scichilone N. , Pistelli R. , Rengo F. ,   the SaRA investigators
Published: August 2003

The purpose of this study was to assess whether different stages of chronic obstructive pulmonary disease (COPD) severity defined according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria correlate with meaningful differences in health status.

A total of 381 COPD patients, aged 73±6 yrs, were classified in the five GOLD stages. Disease-specific (St George Respiratory Questionnaire (SGRQ)) and generic indexes of health status were measured in all patients. Multivariate analysis of covariance or Kruskal Wallis tests were used to compare health status indexes across the spectrum of GOLD stages of COPD severity.

GOLD stages of COPD severity significantly differed in SGRQ components and Barthel's index, but not in the indexes assessing cognitive and affective status and quality of sleep. The largest variation in health status was observed at the transition from stage IIa to stage IIb, while there were no other significant differences between consecutive stages. Both female sex and comorbidity were associated with a greater impact of COPD on the health status.

In conclusion, the upper limit of stage IIb (forced expiratory volume in one second of 49%) marks a threshold for dramatic worsening of health status. Progression of chronic obstructive pulmonary disease severity from stage 0 to stage IIa does not correspond to any meaningful difference in health status.
Upregulation of MCAM in primary bronchial epithelial cells from patients with COPD
Authors: Schulz C. , Petrig V. , Wolf K. , Krätzel K. , Köhler M. , Becker B. , Pfeifer M.
Published: August 2003

An increasing body of evidence indicates that the bronchial epithelium plays a crucial role in the pathophysiology of chronic obstructive pulmonary disease (COPD). The aim of this study was to identify new genes whose bronchoepithelial expression is specifically altered in COPD patients.

Primary bronchial epithelial cell (PBEC) cultures were established from exsmokers with stable airflow limitation and never smokers. Complementary deoxyribonucleic acid array technology was used to investigate the differential expression of 847 cytokine and cytokine-related genes between the two groups. Statistical analysis was performed by means of significance analysis of microarrays and Bonferroni-corrected analysis of variance on ranks. Discriminant analysis and light cycler measurements as well as flow cytometry and Western blotting were used to confirm the significance of the array results at both the messenger ribonucleic acid (mRNA) and protein expression levels.

With respect to array experiments, melanoma cell adhesion molecule (MCAM) was identified as the sole gene showing highly significant upregulation in PBECs from COPD patients compared to never smokers. Light cycler measurements confirmed these results, revealing a 2.9‐fold and 2.0‐fold increase in MCAM mRNA expression in COPD patients compared to nonsmokers and smokers, respectively. In addition, these differences are associated with higher median protein expression levels.

These results strongly suggest involvement of melanoma cell adhesion molecule in the pathophysiology of the chronic airway inflammation seen in patients with chronic obstructive pulmonary disease.
Carcinoembryonic antigen mRNA analysis detects micrometastatic cells in blood from lung cancer patients: Table 1
Authors: Castaldo G. , Tomaiuolo R. , Sanduzzi A. , Ponticiello A. , Marchetiello I. , Salvatore F.
Published: August 2003

The current authors previously identified circulating cells expressing carcinoembryonic antigen (CEA) messenger ribonucleic acid (mRNA) in 80% of lung cancer patients bearing distant metastases. The current study prospectively validated the data on a novel cohort and extended the study to other mRNAs expressed by neoplastic cells.

CEA, cytokeratin 19 and 20, aldolase A and epithelial glycoprotein 2 (EPG2) mRNA was analysed by reverse transcriptase-polymerase chain reaction in circulating cells from 19 healthy controls, and in biopsies and blood at diagnosis from 32 lung cancer patients monitored for 24 months.

Aldolase A and cytokeratin 19 mRNA occurred in circulating cells of all controls; cytokeratin 20 was not expressed by any lung cancer biopsy. EPG2 mRNA occurred in all biopsies but not in the patients' circulating cells. CEA mRNA occurred in 29/32 (90.6%) biopsies and in 17/32 mRNA samples from circulating cells from lung cancer patients. Of these positive patients 12/17 developed metastases within 9 months of mRNA analysis. Three positive patients died, one was lost to follow-up, and one did not develop metastases within 24 months. Of the negative patients 12/15 did not develop metastases during the 24-month follow-up; one patient was lost to follow-up, one did not express CEA, and another developed metastases.

Unlike in other neoplasias, cytokeratin 19 and 20, aldolase A and epithelial glycoprotein 2 messenger ribonucleic acid are not useful for the detection of circulating cancer cells in lung cancer. Carcinoembryonic antigen messenger ribonucleic acid analysis in circulating cells helps to identify lung cancer patients at a greater risk of metastases.
Cathepsins in bleomycin-induced lung injury in rat
Authors: Koslowski R. , Knoch K. , Kuhlisch E. , Seidel D. , Kasper M.
Published: August 2003

Endogenous inhibitors tightly control the activity of proteinases in the extracellular space. Proteinase/antiproteinase imbalance may be caused by predominance of proteinases, resulting in severe tissue damage or abundance of proteinase inhibitors, leading to a shift in the balance of synthesis and degradation of extracellular matrix proteins and accumulation of these matrix components. Lung fibrosis is characterised by accumulation of fibrous matrix proteins in the alveolar interstitium.

The activity of cathepsin D and amounts of cathepsins D and B in bleomycin-injured rat lung tissue and alveolar macrophages were examined. In addition, the activities of cathepsins and cysteine proteinase inhibitors (CPIs) in bronchoalveolar lavage fluid (BALF) were determined.

No cathepsin but high CPI activity and large amounts of procathepsin B were detected in the BALF. In the alveolar lumen, the disturbed proteinase/antiproteinase balance for cysteine proteinases was clearly dominated by CPIs. In alveolar macrophages, the main source of increased cathepsin levels, large changes in cathepsin B and D content were observed during the inflammatory phase, corresponding to the occurrence of procathepsin B in BALF. With the end of the phase of tissue remodelling, imbalances in cathepsin and CPI activities were largely eliminated. Immunoblot data, revealing an increase in cathepsin D levels in myofibroblast-like cells compared to fibroblasts and in resting fibroblasts compared to proliferating cells, implicate this proteinase in the differentiation and conversion processes occurring at the beginning of the fibrotic phase of lung injury.

The results show that cathepsin amounts and activities are increased transiently in lung tissue during regeneration processes in bleomycin-induced lung injury. Imbalances of cathepsin and cysteine proteinase inhibitors activities are also a phenomenon of the phase of tissue remodelling initiated by lung injury.
Evidence of mast cell activation and leukotriene release after mannitol inhalation
Authors: Brannan J.D. , Gulliksson M. , Anderson S.D. , Chew N. , Kumlin M.
Published: August 2003

The aim of this study was to investigate if mannitol inhalation, as a model of exercise-induced bronchoconstriction (EIB), causes mast cell activation and release of mediators of bronchoconstriction.

Urinary excretion of previously identified mediators of EIB was investigated in association with mannitol-induced bronchoconstriction. Twelve asthmatic and nine nonasthmatic subjects inhaled mannitol and urine was collected 60 min before andfor90 min after challenge. The urinary concentrations of leukotriene (LT)E4, the prostaglandin (PG)D2metabolite and the mast cell marker 9α,11β‐PGF2weremeasured by enzyme immunoassay. Nτ‐methylhistamine was measured by radioimmunoassay.

In asthmatic subjects, inhalation of a mean±sem dose of 272±56 mg mannitol induced a reduction in forced expiratory volume in one second (FEV1) of 34.5±2.1%. This was associated with increases in urinary 9α,11β‐PGF2(91.9±8.2versus66.9±6.6 ng·mmol creatinine−1, peakversusbaseline) and LTE4(51.3±7.5versus32.9±4.7). In nonasthmatic subjects, the reduction in FEV1was 1.0±0.5% after inhaling 635 mg of mannitol. Although smaller than in the asthmatics, significant increases of urinary 9α,11β‐PGF2(68.4±6.9versus56.0±5.8 ng·mmol creatinine−1) and LTE4(58.5±5.3versus43.0±3.3 ng·mmol creatinine−1) were observed in the nonasthmatic subjects. There was also a small increase in urinary excretion of Nτ‐methylhistamine in the nonasthmatics, but not in the asthmatics.

The increased urinary levels of 9α,11β‐prostaglandin F2support mast cell activation with release of mediators following inhalation of mannitol. Increased bronchial responsiveness to the released mediators could explain the exclusive bronchoconstriction in asthmatic subjects.
Chronic cough and phlegm in young adults
Authors: Cerveri I. , Accordini S. , Corsico A. , Zoia M.C. , Carrozzi L. , Cazzoletti L. , Beccaria M. , Marinoni A. , Viegi G. , de Marco R.
Published: August 2003

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines underline that the presence of chronic cough and sputum production before airflow obstruction offers a unique opportunity to identify subjects at risk of chronic obstructive pulmonary disease for an early intervention. Current epidemiological data on these subjects are scant.

Between 1998–2000, the authors evaluated the prevalence and characteristics of these symptoms by a multicentre cross-sectional survey of Italian people aged between 20–44 yrs from the general population (Italian Study on Asthma in Young Adults (ISAYA)). Besides the questions on asthma, more than 18,000 subjects answered the question: “Have you had cough and phlegm on most days for as much as 3 months per year and for at least two successive years?”

The adjusted prevalence of subjects with chronic cough and phlegm was 11.9%, being 11.8% in males and 12.0% in females. From these subjects ∼20% reported coexisting asthma and ∼30%, predominately females, were nonsmokers. The survey showed thatsex (female), smoking and low socioeconomic status were significantly and independently associated with chronic cough and phlegm, current smoking playing the major role.

The prevalence of subjects with chronic cough and phlegm is startlingly high among young adults. Further follow-up studies are needed to establish how many of them will go on to develop chronic obstructive pulmonary disease.