Impact of lung function changes after induction radiochemotherapy on resected T4 non-small cell lung cancer outcome.

BACKGROUND: Induction radiochemotherapy, followed by resection, for T4 non-small cell lung cancer, has shown promising long-term survival but may be associated with increased postoperative morbidity and death, depending on patient selection. Here, we determined the effect of induction radiochemotherapy on pulmonary function and whether postinduction pulmonary function changes predict hospital morbidity and death and long-term survival. METHODS: A consecutive prospective cohort of 72 patients with T4 N0-2 M0 non-small cell lung cancer managed by radiochemotherapy, followed by resection, is reported. All patients underwent thoracoabdominal computed tomography or fusion positron emission tomography-computed tomography, brain imaging, mediastinoscopy, echocardiography, ventilation-perfusion scintigraphy, and pulmonary function testing before and after induction therapy. Resection was performed if the postoperative forced expiratory volume in 1 second and diffusion capacity of the lung for carbon monoxide exceeded 30% predicted and if the postoperative maximum oxygen consumption exceeded 10 mL/kg/min. RESULTS: The postoperative 90-day mortality rate was 8% (lobectomy, 2%; pneumonectomy, 21%; p=0.01). All deaths after pneumonectomy occurred after right-sided procedures. The 3-year and 5-year survival was 50% (95% confidence interval, 36% to 62%) and 45% (95% confidence interval, 31% to 57%) and was significantly associated with completeness of resection (p=0.004) and resection type (pneumonectomy vs lobectomy, p=0.01). There was no correlation between postinduction pulmonary function changes and postoperative morbidity or death or long-term survival in patients managed by lobectomy or pneumonectomy. CONCLUSIONS: In properly selected patients with T4 N0-2 M0 non-small cell lung cancer, resection after induction radiochemotherapy can be performed with a reasonable postoperative mortality rate and long-term survival, provided the resection is complete and a right-sided pneumonectomy is avoided. Postinduction pulmonary function changes did not correlate with postoperative morbidity or death or with long-term outcome.

Fetal programming of pulmonary vascular dysfunction in mice: role of epigenetic mechanisms.

Insults during the fetal period predispose the offspring to systemic cardiovascular disease, but little is known about the pulmonary circulation and the underlying mechanisms. Maternal undernutrition during pregnancy may represent a model to investigate underlying mechanisms, because it is associated with systemic vascular dysfunction in the offspring in animals and humans. In rats, restrictive diet during pregnancy (RDP) increases oxidative stress in the placenta. Oxygen species are known to induce epigenetic alterations and may cross the placental barrier. We hypothesized that RDP in mice induces pulmonary vascular dysfunction in the offspring that is related to an epigenetic mechanism. To test this hypothesis, we assessed pulmonary vascular function and lung DNA methylation in offspring of RDP and in control mice at the end of a 2-wk exposure to hypoxia. We found that endothelium-dependent pulmonary artery vasodilation in vitro was impaired and hypoxia-induced pulmonary hypertension and right ventricular hypertrophy in vivo were exaggerated in offspring of RDP. This pulmonary vascular dysfunction was associated with altered lung DNA methylation. Administration of the histone deacetylase inhibitors butyrate and trichostatin A to offspring of RDP normalized pulmonary DNA methylation and vascular function. Finally, administration of the nitroxide Tempol to the mother during RDP prevented vascular dysfunction and dysmethylation in the offspring. These findings demonstrate that in mice undernutrition during gestation induces pulmonary vascular dysfunction in the offspring by an epigenetic mechanism. A similar mechanism may be involved in the fetal programming of vascular dysfunction in humans.

Successful bilateral lung transplantation after previous pneumonectomy.

We report successful bilateral lung transplantation for end-stage suppurative lung disease after a previous right-sided pneumonectomy performed for a destroyed lung. Our results demonstrate the feasibility of the procedure even in the context of mechanical ventilation and extracorporeal artificial oxygenation. Posttransplantation follow-up revealed excellent gas exchanges, no airway complications, and well-functioning grafts with right-sided ventilation and perfusion of 37% and 22%, respectively.

Pulmonary and systemic vascular dysfunction in young offspring of mothers with preeclampsia.

BACKGROUND: Adverse events in utero may predispose to cardiovascular disease in adulthood. The underlying mechanisms are unknown. During preeclampsia, vasculotoxic factors are released into the maternal circulation by the diseased placenta. We speculated that these factors pass the placental barrier and leave a defect in the circulation of the offspring that predisposes to a pathological response later in life. The hypoxia associated with high-altitude exposure is expected to facilitate the detection of this problem. METHODS AND RESULTS: We assessed pulmonary artery pressure (by Doppler echocardiography) and flow-mediated dilation of the brachial artery in 48 offspring of women with preeclampsia and 90 offspring of women with normal pregnancies born and permanently living at the same high-altitude location (3600 m). Pulmonary artery pressure was roughly 30% higher (mean+/-SD, 32.1+/-5.6 versus 25.3+/-4.7 mm Hg; P<0.001) and flow-mediated dilation was 30% smaller (6.3+/-1.2% versus 8.3+/-1.4%; P<0.0001) in offspring of mothers with preeclampsia than in control subjects. A strong inverse relationship existed between flow-mediated dilation and pulmonary artery pressure (r=-0.61, P<0.001). The vascular dysfunction was related to preeclampsia itself because siblings of offspring of mothers with preeclampsia who were born after a normal pregnancy had normal vascular function. Augmented oxidative stress may represent an underlying mechanism because thiobarbituric acid-reactive substances plasma concentration was increased in offspring of mothers with preeclampsia. CONCLUSIONS: Preeclampsia leaves a persistent defect in the systemic and the pulmonary circulation of the offspring. This defect predisposes to exaggerated hypoxic pulmonary hypertension already during childhood and may contribute to premature cardiovascular disease in the systemic circulation later in life.

High altitude, a natural research laboratory for the study of cardiovascular physiology and pathophysiology.

High altitude constitutes an exciting natural laboratory for medical research. Although initially, the aim of high-altitude research was to understand the adaption of the organism to hypoxia and find treatments for altitude-related diseases, during the past decade or so, the scope of this research has broadened considerably. Two important observations led the foundation for the broadening of the scientific scope of high-altitude research. First, high-altitude pulmonary edema represents a unique model that allows studying fundamental mechanisms of pulmonary hypertension and lung edema in humans. Second, the ambient hypoxia associated with high-altitude exposure facilitates the detection of pulmonary and systemic vascular dysfunction at an early stage. Here, we will review studies that, by capitalizing on these observations, have led to the description of novel mechanisms underpinning lung edema and pulmonary hypertension and to the first direct demonstration of fetal programming of vascular dysfunction in humans.

New insights in the pathogenesis of high-altitude pulmonary edema.

High-altitude pulmonary edema is a life-threatening condition occurring in predisposed but otherwise healthy individuals. It therefore permits the study of underlying mechanisms of pulmonary edema in the absence of confounding factors such as coexisting cardiovascular or pulmonary disease, and/or drug therapy. There is evidence that some degree of asymptomatic alveolar fluid accumulation may represent a normal phenomenon in healthy humans shortly after arrival at high altitude. Two fundamental mechanisms then determine whether this fluid accumulation is cleared or whether it progresses to HAPE: the quantity of liquid escaping from the pulmonary vasculature and the rate of its clearance by the alveolar respiratory epithelium. The former is directly related to the degree of hypoxia-induced pulmonary hypertension, whereas the latter is determined by the alveolar epithelial sodium transport. Here, we will review evidence that, in HAPE-prone subjects, impaired pulmonary endothelial and epithelial NO synthesis and/or bioavailability may represent a central underlying defect predisposing to exaggerated hypoxic pulmonary vasoconstriction and, in turn, capillary stress failure and alveolar fluid flooding. We will then demonstrate that exaggerated pulmonary hypertension, although possibly a conditio sine qua non, may not always be sufficient to induce HAPE and how defective alveolar fluid clearance may represent a second important pathogenic mechanism.

Exaggerated pulmonary hypertension during mild exercise in chronic mountain sickness.

BACKGROUND: Chronic mountain sickness (CMS) is an important public health problem and is characterized by exaggerated hypoxemia, erythrocytosis, and pulmonary hypertension. While pulmonary hypertension is a leading cause of morbidity and mortality in patients with CMS, it is relatively mild and its underlying mechanisms are not known. We speculated that during mild exercise associated with daily activities, pulmonary hypertension in CMS is much more pronounced. METHODS: We estimated pulmonary artery pressure by using echocardiography at rest and during mild bicycle exercise at 50 W in 30 male patients with CMS and 32 age-matched, healthy control subjects who were born and living at an altitude of 3,600 m. RESULTS: The modest, albeit significant difference of the systolic right-ventricular-to-right-atrial pressure gradient between patients with CMS and controls at rest (30.3 +/- 8.0 vs 25.4 +/- 4.5 mm Hg, P 5 .002) became more than three times larger during mild bicycle exercise (56.4 +/- 19.0 vs 39.8 +/- 8.0 mm Hg, P < .001). CONCLUSIONS: Measurements of pulmonary artery pressure at rest greatly underestimate pulmonary artery pressure during daily activity in patients with CMS. The marked pulmonary hypertension during mild exercise associated with daily activity may explain why this problem is a leading cause of morbidity and mortality in patients with CMS.

[High altitude and preexisting lung diseases]. / Affections pulmonaires et attitude.

Today, a growing number of people, some of them suffering from lung diseases, travel to high altitude resorts. It is sometimes not easy for the general practitioner to adequately counsel these patients. Based on our knowledge of physiopathology and clinical studies, the present paper addresses the effects of high altitude in patients with preexisting lung diseases and provides recommendations in order to optimize the sojourn at high altitude.

Respiratory nitric oxide and pulmonary artery pressure in children of aymara and European ancestry at high altitude.

Invasive studies suggest that healthy children living at high altitude display pulmonary hypertension, but the data to support this assumption are sparse. Nitric oxide (NO) synthesized by the respiratory epithelium regulates pulmonary artery pressure, and its synthesis was reported to be increased in Aymara high-altitude dwellers. We hypothesized that pulmonary artery pressure will be lower in Aymara children than in children of European ancestry at high altitude, and that this will be related to increased respiratory NO. We therefore compared pulmonary artery pressure and exhaled NO (a marker of respiratory epithelial NO synthesis) between large groups of healthy children of Aymara (n = 200; mean +/- SD age, 9.5 +/- 3.6 years) and European ancestry (n = 77) living at high altitude (3,600 to 4,000 m). We also studied a group of European children (n = 29) living at low altitude. The systolic right ventricular to right atrial pressure gradient in the Aymara children was normal, even though significantly higher than the gradient measured in European children at low altitude (22.5 +/- 6.1 mm Hg vs 17.7 +/- 3.1 mm Hg, p < 0.001). In children of European ancestry studied at high altitude, the pressure gradient was 33% higher than in the Aymara children (30.0 +/- 5.3 mm Hg vs 22.5 +/- 6.1 mm Hg, p < 0.0001). In contrast to what was expected, exhaled NO tended to be lower in Aymara children than in European children living at the same altitude (12.4 +/- 8.8 parts per billion [ppb] vs 16.1 +/- 11.1 ppb, p = 0.06) and was not related to pulmonary artery pressure in either group. Aymara children are protected from hypoxic pulmonary hypertension at high altitude. This protection does not appear to be related to increased respiratory NO synthesis.

Stimulation of peroxynitrite catalysis improves insulin sensitivity in high fat diet-fed mice.

Peroxynitrite synthesis is increased in insulin resistant animals and humans. Peroxynitirite-induced nitration of insulin signalling proteins impairs insulin action in vitro, but the role of peroxynitrite in the pathogenesis of insulin resistance in vivo is not known. We therefore assessed the effects of a 1-week treatment with the peroxynitrite decomposition catalyst FeTPPS on insulin sensitivity in insulin resistant high fat diet-fed (HFD) and control mice. FeTPPS normalized the fasting plasma glucose and insulin levels (P < 0.01), attenuated the hyperglycaemic response to an intraperitoneal glucose challenge by roughly 50% (P < 0.05), and more than doubled the insulin-induced decrease in plasma glucose levels in HFD-fed mice (P < 0.001). Moreover, FeTPPS restored insulin-stimulated Akt phosphorylation and insulin-stimulated glucose uptake in isolated skeletal muscle in vitro. Stimulation of peroxynitrite catalysis attenuates HFD-induced insulin resistance in mice by restoring insulin signalling and insulin-stimulated glucose uptake in skeletal muscle tissue.

Pulmonary-artery pressure and exhaled nitric oxide in Bolivian and Caucasian high altitude dwellers.

There is evidence that high altitude populations may be better protected from hypoxic pulmonary hypertension than low altitude natives, but the underlying mechanism is incompletely understood. In Tibetans, increased pulmonary respiratory NO synthesis attenuates hypoxic pulmonary hypertension. It has been speculated that this mechanism may represent a generalized high altitude adaptation pattern, but direct evidence for this speculation is lacking. We therefore measured systolic pulmonary-artery pressure (Doppler chocardiography) and exhaled nitric oxide (NO) in 34 healthy, middle-aged Bolivian high altitude natives and in 34 age- and sex-matched, well-acclimatized Caucasian low altitude natives living at high altitude (3600 m). The mean+/-SD systolic right ventricular to right atrial pressure gradient (24.3+/-5.9 vs. 24.7+/-4.9 mmHg) and exhaled NO (19.2+/-7.2 vs. 22.5+/-9.5 ppb) were similar in Bolivians and Caucasians. There was no relationship between pulmonary-artery pressure and respiratory NO in the two groups. These findings provide no evidence that Bolivian high altitude natives are better protected from hypoxic pulmonary hypertension than Caucasian low altitude natives and suggest that attenuation of pulmonary hypertension by increased respiratory NO synthesis may not represent a universal adaptation pattern in highaltitude populations.

Endothelial nitric oxide synthase (eNOS) knockout mice have defective mitochondrial beta-oxidation.

OBJECTIVE: Recent observations indicate that the delivery of nitric oxide by endothelial nitric oxide synthase (eNOS) is not only critical for metabolic homeostasis, but could also be important for mitochondrial biogenesis, a key organelle for free fatty acid (FFA) oxidation and energy production. Because mice deficient for the gene of eNOS (eNOS(-/-)) have increased triglycerides and FFA levels, in addition to hypertension and insulin resistance, we hypothesized that these knockout mice may have decreased energy expenditure and defective beta-oxidation. RESEARCH DESIGN AND METHODS: Several markers of mitochondrial activity were assessed in C57BL/6J wild-type or eNOS(-/-) mice including the energy expenditure and oxygen consumption by indirect calorimetry, in vitro beta-oxidation in isolated mitochondria from skeletal muscle, and expression of genes involved in fatty acid oxidation. RESULTS: eNOS(-/-) mice had markedly lower energy expenditure (-10%, P < 0.05) and oxygen consumption (-15%, P < 0.05) than control mice. This was associated with a roughly 30% decrease of the mitochondria content (P < 0.05) and, most importantly, with mitochondrial dysfunction, as evidenced by a markedly lower beta-oxidation of subsarcolemmal mitochondria in skeletal muscle (-30%, P < 0.05). Finally, impaired mitochondrial beta-oxidation was associated with a significant increase of the intramyocellular lipid content (30%, P < 0.05) in gastrocnemius muscle. CONCLUSIONS: These data indicate that elevated FFA and triglyceride in eNOS(-/-) mice result in defective mitochondrial beta-oxidation in muscle cells.

Enhanced expression of three monocarboxylate transporter isoforms in the brain of obese mice.

Monocarboxylate transporters (MCTs) are membrane carriers for lactate and ketone bodies. Three isoforms, MCT1, MCT2 and MCT4, have been described in the central nervous system but little information is available about the regulation of their expression in relation to altered metabolic and/or nutritional conditions. We show here that brains of mice fed on a high fat diet (HFD) up to 12 weeks as well as brains of genetically obese (ob/ob) or diabetic (db/db) mice exhibit an increase of MCT1, MCT2 and MCT4 expression as compared to brains of control mice fed a standard diet. Enhanced expression of each transporter was visible throughout the brain but most prominently in the cortex and in the hippocampus. Using immunohistochemistry, we observed that neurons (expressing mainly MCT2 but also sometimes low levels of MCT1 under normal conditions) were immunolabelled for all three transporters in HFD mice as well as in ob/ob and db/db mice. At the subcellular level, changes were most remarkable in neuronal cell bodies. Western blotting performed on brain structure extracts allowed us to confirm quantitatively the enhancement of MCT1 and MCT2 expression. Our data demonstrate that the expression of cerebral MCT isoforms can be modulated by alterations of peripheral metabolism, suggesting that the adult brain is sensitive and adapts to new metabolic states. This observation could be relevant in the context of obesity development and its consequences for brain function.

[High altitude pulmonary edema. An experiment of nature to study the underlying mechanisms of hypoxic pulmonary hypertension and pulmonary edema in humans]. / Edema pulmonar de altura. Modelo de estudio de la fisiopatologia del edema pulmonar y de la hipertension pulmonar hipoxica en humanos.

High altitude constitutes an exciting natural laboratory for medical research. Over the past decade, it has become clear that the results of high-altitude research may have important implications not only for the understanding of diseases in the millions of people living permanently at high altitude, but also for the treatment of hypoxemia-related disease states in patients living at low altitude. High-altitude pulmonary edema (HAPE) is a life-threatening condition occurring in predisposed, but otherwise healthy subjects, and, therefore, allows to study underlying mechanisms of pulmonary edema in humans, in the absence of confounding factors. Over the past decade, evidence has accumulated that HAPE results from the conjunction of two major defects, augmented alveolar fluid flooding resulting from exaggerated hypoxic pulmonary hypertension, and impaired alveolar fluid clearance related to defective respiratory transepithelial sodium transport. Here, after a brief presentation of the clinical features of HAPE, we review this novel concept. We provide experimental evidence for the novel concept that impaired pulmonary endothelial and epithelial nitric oxide synthesis and/or bioavailability may represent the central underlying defect predisposing to exaggerated hypoxic pulmonary vasoconstriction and alveolar fluid flooding. We demonstrate that exaggerated pulmonary hypertension, while possibly a condition sine qua non, may not be sufficient to cause HAPE, and how defective alveolar fluid clearance may represent a second important pathogenic mechanism. Finally, we outline how this insight gained from studies in HAPE may be translated into the management of hypoxemia related disease states in general.

Edema pulmonar de altura: Modelo de estudio de la fisiopatología del edema pulmonar y de la hipertensión pulmonar hipóxica en humanos / High altitude pulmonary edema. An experiment of Nature to study the underlying mechanisms of hypoxic pulmonary hypertension and pulmonary edema in humans

La altura, fascinante laboratorio natural de investigación médica, provee resultados con importantes implicancias para la comprensión de enfermedades que afectan a millones de personas que viven en ella, asi como para el tratamiento de enfermedades ligadas a la hipoxemia en pacientes que viven en baja altitud. El edema pulmonar de altura (EPA) es una entidad que pone en peligro la vida y que ocurre en sujetos predispuestos pero sanos. Esto permite estudiar los mecanismos subyacentes del edema pulmonar en humanos, sin la presencia de factores que presten a la confusión como enfermedades concomitantes. El EPA resulta de la conjunción de dos defectos mayores: acumulación de líquido en el espacio alveolar debido a una hipertensión pulmonar hipóxica exagerada, y alteración en la eliminación del mismo por un defecto en el transporte transepitelial alveolar de sodio. En esta revisión, describimos brevemente las características clínicas y revisaremos este novedoso concepto. Proveemos evidencia experimental de como la síntesis alterada de óxido nítrico y/o la disminución de su biodisponibilidad representan el defecto central que predispone a la vasoconstricción pulmonar hipóxica exagerada y a la acumulación de líquido en el espacio alveolar. Mostramos que la hipertensión pulmonar hipóxica exagerada, per se, no es suficiente para producir un EPA, y que una alteración en la eliminación del fluido del espacio alveolar representa un segundo mecanismo fisiopatológico importante. Finalmente, describimos cómo los nuevos aportes obtenidos de los estudios del EPA pueden ser trasladados al manejo de otros estados patológicos ligados a la hipoxemia.

High altitude constitutes an exciting natural laboratory for medical research. Over the past decade, it has become clear that the results of high-altitude research may have important implications not only for the understanding of diseases in the millions of people living permanently at high altitude, but also for the treatment of hypoxemia-related disease states in patients living at low altitude. High-altitude pulmonary edema (HAPE) is a life-threatening condition occurring in predisposed, but otherwise healthy subjects, and, therefore, allows to study underlying mechanisms of pulmonary edema in humans, in the absence of confounding factors. Over the past decade, evidence has accumulated that HAPE results from the conjunction of two major defects, augmented alveolar fluid flooding resulting from exaggerated hypoxic pulmonary hypertension, and impaired alveolar fluid clearance related to defective respiratory transepithelial sodium transport. Here, after a brief presentation of the clinical features of HAPE, we review this novel concept. We provide experimental evidence for the novel concept that impaired pulmonary endothelial and epithelial nitric oxide synthesis and/or bioavailability may represent the central underlying defect predisposing to exaggerated hypoxic pulmonary vasoconstriction and alveolar fluid flooding. We demonstrate that exaggerated pulmonary hypertension, while possibly a condition sine qua non, may not be sufficient to cause HAPE, and how defective alveolar fluid clearance may represent a second important pathogenic mechanism. Finally, we outline how this insight gained from studies in HAPE may be translated into the management of hypoxemia related disease states in general.

Edema pulmonar de altura: Modelo de estudio de la fisiopatología del edema pulmonar y de la hipertensión pulmonar hipóxica en humanos / High altitude pulmonary edema. An experiment of Nature to study the underlying mechanisms of hypoxic pulmonary hypertension and pulmonary edema in humans

La altura, fascinante laboratorio natural de investigación médica, provee resultados con importantes implicancias para la comprensión de enfermedades que afectan a millones de personas que viven en ella, asi como para el tratamiento de enfermedades ligadas a la hipoxemia en pacientes que viven en baja altitud. El edema pulmonar de altura (EPA) es una entidad que pone en peligro la vida y que ocurre en sujetos predispuestos pero sanos. Esto permite estudiar los mecanismos subyacentes del edema pulmonar en humanos, sin la presencia de factores que presten a la confusión como enfermedades concomitantes. El EPA resulta de la conjunción de dos defectos mayores: acumulación de líquido en el espacio alveolar debido a una hipertensión pulmonar hipóxica exagerada, y alteración en la eliminación del mismo por un defecto en el transporte transepitelial alveolar de sodio. En esta revisión, describimos brevemente las características clínicas y revisaremos este novedoso concepto. Proveemos evidencia experimental de como la síntesis alterada de óxido nítrico y/o la disminución de su biodisponibilidad representan el defecto central que predispone a la vasoconstricción pulmonar hipóxica exagerada y a la acumulación de líquido en el espacio alveolar. Mostramos que la hipertensión pulmonar hipóxica exagerada, per se, no es suficiente para producir un EPA, y que una alteración en la eliminación del fluido del espacio alveolar representa un segundo mecanismo fisiopatológico importante. Finalmente, describimos cómo los nuevos aportes obtenidos de los estudios del EPA pueden ser trasladados al manejo de otros estados patológicos ligados a la hipoxemia. (AU)

High altitude constitutes an exciting natural laboratory for medical research. Over the past decade, it has become clear that the results of high-altitude research may have important implications not only for the understanding of diseases in the millions of people living permanently at high altitude, but also for the treatment of hypoxemia-related disease states in patients living at low altitude. High-altitude pulmonary edema (HAPE) is a life-threatening condition occurring in predisposed, but otherwise healthy subjects, and, therefore, allows to study underlying mechanisms of pulmonary edema in humans, in the absence of confounding factors. Over the past decade, evidence has accumulated that HAPE results from the conjunction of two major defects, augmented alveolar fluid flooding resulting from exaggerated hypoxic pulmonary hypertension, and impaired alveolar fluid clearance related to defective respiratory transepithelial sodium transport. Here, after a brief presentation of the clinical features of HAPE, we review this novel concept. We provide experimental evidence for the novel concept that impaired pulmonary endothelial and epithelial nitric oxide synthesis and/or bioavailability may represent the central underlying defect predisposing to exaggerated hypoxic pulmonary vasoconstriction and alveolar fluid flooding. We demonstrate that exaggerated pulmonary hypertension, while possibly a condition sine qua non, may not be sufficient to cause HAPE, and how defective alveolar fluid clearance may represent a second important pathogenic mechanism. Finally, we outline how this insight gained from studies in HAPE may be translated into the management of hypoxemia related disease states in general. (AU)

Pulmonary hypertension in high-altitude dwellers: novel mechanisms, unsuspected predisposing factors.

Studies of high-altitude populations, and in particular of maladapted subgroups, may provide important insight into underlying mechanisms involved in the pathogenesis of hypoxemia-related disease states in general. Over the past decade, studies involving short-term hypoxic exposure have greatly advanced our knowledge regarding underlying mechanisms and predisposing events of hypoxic pulmonary hypertension. Studies in high altitude pulmonary edema (HAPE)-prone subjects, a condition characterized by exaggerated hypoxic pulmonary hypertension, have provided evidence for the central role of pulmonary vascular endothelial and respiratory epithelial nitric oxide (NO) for pulmonary artery pressure homeostasis. More recently, it has been shown that pathological events during the perinatal period (possibly by impairing pulmonary NO synthesis), predispose to exaggerated hypoxic pulmonary hypertension later in life. In an attempt to translate some of this new knowledge to the understanding of underlying mechanisms and predisposing events of chronic hypoxic pulmonary hypertension, we have recently initiated a series of studies among high-risk subpopulations (experiments of nature) of high-altitude dwellers. These studies have allowed to identify novel risk factors and underlying mechanisms that may predispose to sustained hypoxic pulmonary hypertension. The aim of this article is to briefly review this new data, and demonstrate that insufficient NO synthesis/bioavailability, possibly related in part to augmented oxidative stress, may represent an important underlying mechanism predisposing to pulmonary hypertension in high-altitude dwellers.

[Spirometry for the primary care physician? For which patient?]. / La spirométrie au cabinet du praticien? Pour quel patient?

Spirometry is the simplest pulmonary function test and recently became available to all physicians by means of economic and performing devices. Spirometry however requires a good knowledge of indications, realization and interpretation. Expert recommendations, regularly updated by the American and European respiratory societies, specify the necessary conditions for spirometry to provide useful information for the care of patients.

Reference values for methacholine reactivity (SAPALDIA study).

BACKGROUND: The distribution of airway responsiveness in a general population of non-smokers without respiratory symptoms has not been established, limiting its use in clinical and epidemiological practice. We derived reference equations depending on individual characteristics (i.e., sex, age, baseline lung function) for relevant percentiles of the methacholine two-point dose-response slope. METHODS: In a reference sample of 1567 adults of the SAPALDIA cross-sectional survey (1991), defined by excluding subjects with respiratory conditions, responsiveness during methacholine challenge was quantified by calculating the two-point dose-response slope (O'Connor). Weighted L1-regression was used to estimate reference equations for the 95th , 90th , 75th and 50th percentiles of the two-point slope. RESULTS: Reference equations for the 95th , 90th , 75th and 50th percentiles of the two-point slope were estimated using a model of the form a + b* Age + c* FEV1 + d* (FEV1)2 , where FEV1 corresponds to the pre-test (or baseline) level of FEV1. For the central half of the FEV1 distribution, we used a quadratic model to describe the dependence of methacholine slope on baseline FEV1. For the first and last quartiles of FEV1, a linear relation with FEV1 was assumed (i.e., d was set to 0). Sex was not a predictor term in this model. A negative linear association with slope was found for age. We provide an Excel file allowing calculation of the percentile of methacholine slope of a subject after introducing age--pre-test FEV1--and results of methacholine challenge of the subject. CONCLUSION: The present study provides equations for four relevant percentiles of methacholine two-point slope depending on age and baseline FEV1 as basic predictors in an adult reference population of non-obstructive and non-atopic persons. These equations may help clinicians and epidemiologists to better characterize individual or population airway responsiveness.

Passive smoking exposure among adults and the dynamics of respiratory symptoms in a prospective multicenter cohort study.

OBJECTIVES: The aim of this study was to measure the effects of past exposure to environmental tobacco smoke on the day-to-day dynamics of four respiratory-symptom classes in a diary study including adult never-smokers. METHODS: As part of SAPALDIA (Swiss study on air pollution and lung diseases in adults), a prospective multicenter cohort study, 1421 life-time adult nonsmokers were followed for 2 years with the use of daily questionnaires filled out during one to six periods of 4 weeks spread over 2 years (1992-1993). The hazard ratios (HR) of getting or losing respiratory symptoms from one day to another were determined in association with past exposure to environmental tobacco smoke. RESULTS: In a sample of adult never-smokers, an association between self-reported past exposure to environmental tobacco smoke and deteriorated average symptom dynamics was found for all of the outcomes considered, showing HR values from 1.09 to 1.21 for developing symptoms and HR values from 0.91 to 0.83 for getting rid of them. Exposure to environmental tobacco smoke, including the workplace, was negatively associated with the length of intervals without symptoms of bronchitis (HR 1.33) and asthma (HR 1.27), while exposure to environmental tobacco smoke confined to places outside work was positively associated with the length of episodes of any respiratory symptom and lower-respiratory-tract symptoms (HR 0.78-0.77). CONCLUSIONS: The results suggest that exposure to environmental tobacco smoke has adverse effects on the dynamics of respiratory symptoms, and the size (magnitude) and type of effects appear to depend on the place of exposure.