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Solid tumors are often characterized by a hypoxic microenvironment which contributes, through the hypoxia-inducible factor HIF-1, to the invasion-metastasis cascade. Endoplasmic reticulum (ER) stress also leads tumor cells to thrive and spread by inducing a transcriptional and translational program, the Unfolded Protein Response (UPR), aimed at restoring ER homeostasis. We studied ERO1 alpha (henceforth ERO1), a protein disulfide oxidase with the tumor-relevant characteristic of being positively regulated by both ER stress and hypoxia. Analysis of the redox secretome indicated that pro-angiogenic HIF-1 targets, were blunted in ERO1-devoid breast cancer cells under hypoxic conditions. ERO1 deficiency reduced tumor cell migration and lung metastases by impinging on tumor angiogenesis, negatively regulating the upstream ATF4/CHOP branch of the UPR and selectively impeding oxidative folding of angiogenic factors, among which VEGF-A. Thus, ERO1 deficiency acted synergistically with the otherwise feeble curative effects of anti-angiogenic therapy in aggressive breast cancer murine models and it might be exploited to treat cancers with pathological HIF-1-dependent angiogenesis. Furthermore, ERO1 levels are higher in the more aggressive basal breast tumors and correlate inversely with the disease- and metastasis-free interval of breast cancer patients. Thus, taking advantage of our in vitro data on ERO1-regulated gene products we identified a gene set associated with ERO1 expression in basal tumors and related to UPR, hypoxia, and angiogenesis, whose levels might be investigated in patients as a hallmark of tumor aggressiveness and orient those with lower levels toward an effective anti-angiogenic therapy.

The expression of nuclear factor (NF)-kappaB is an indicator of cellular activation and of inflammatory mediator production. The aim of the present study was to characterise the expression and localisation of p65, the major subunit of NF-kappaB, in the bronchial mucosa of patients with chronic obstructive pulmonary disease (COPD), and to examine the relationship between p65 expression and disease status. Bronchial biopsies were obtained from 14 smokers with COPD, 17 smokers with normal lung function and 12 nonsmokers with normal lung function. The number of p65 positive (+) cells was quantified by immunohistochemistry and the expression of p65 in bronchial biopsies from the three groups was examined by Western blotting (WB). Smokers with normal lung function and patients with COPD had increased numbers of p65+ cells in the epithelium and increased p65 nuclear expression. In COPD patients the number of epithelial p65+ cells correlated with the degree of airflow limitation. WB analysis showed an increase in p65 in smokers with normal lung function and COPD patients (p<0.05). Bronchial biopsies in smokers with normal lung function and chronic obstructive pulmonary disease patients show increased expression of p65 protein, predominantly in the bronchial epithelium. Disease severity is associated with an increased epithelial expression of nuclear factor-kappaB.

Therapy of patients with chronic respiratory failure is mainly directed at minimizing symptoms in order to improve, or at least to prevent a deterioration of, patients' well-being. Under such circumstances, the perceived effect of therapies on patients' well-being and daily life represents the most important subjective outcome of treatment. Therefore, there is a need to provide a global estimate of health in patients on long term oxygen therapy or overnight home mechanical ventilation. The Maugeri Foundation Respiratory Failure Questionnaire (MRF28) is the first health status ("quality of life") questionnaire specifically developed for use in CRF and its items were selected to be applicable to patients with both obstructive and restrictive diseases. The Quality of Life Evaluation and Survival Study (QuESS) is a multinational study with the aim of re-evaluating the natural history of chronic respiratory failure in about 300 patients. To the authors knowledge, the Quality of Life Evaluation and Survival Study is the first study to evaluate the natural history of chronic respiratory failure in such a large number of subjects and with a complete set of data. In fact, both pathophysiologic and health status assessments will be made. Moreover, by collecting data on mortality, disease exacerbations and hospitalization, it will also be possible to verify the predictive ability of health status versus pathophysiology in terms of mortality and healthcare utilization.

Data on the outcome of patients with chronic obstructive pulmonary disease (COPD) are limited. We know that the prognosis is poor when respiratory insufficiency develops, but we have little information on the actual cause of death. Epidemiological studies are suitable for the assessment of the prevalence of the disease, but give no details on the actual cause of death. Age and forced expiratory volume in one second (FEV1) have been recognized as the best predictors of mortality in studies designed to quantify survival of COPD patients, particularly when the post-brochodilator value is used, as this provides a better estimate of airway and parenchymal damage. Data from Intensive Care Units on acute respiratory failure have several significant limitations. Firstly, it is probable that some patients elect not to undergo intensive treatment for a terminal bout of respiratory failure, particularly if it is not first episode. Secondly, the actual cause of death is often not described in adequate detail. Hypoxaemia and acidaemia are the main risk factors in acute exacerbation of the disease and the presence of pulmonary infiltrates on chest radiographs worsens the prognosis. A single bout of respiratory failure appears to have no effect on the prognosis of COPD patients after recovery, but there is a consistent increase in mortality after the second episode. It seems possible to manage the majority of episodes of acute respiratory failure with mechanical ventilation administered with noninvasive techniques. When endotracheal intubation is necessary, the prognosis is usually poor and the survival after 1 yr is usually lower than 40%. The role of long-term home mechanical ventilation is still unclear. Results from pivotal studies have been encouraging, although survival is far less impressive than in neuromuscular disorders. In patients with end-stage lung disease, lung transplantation can be considered the only possibility of increasing pulmonary functional capacity. However the technique is reserved only for a highly selected group of patients and data on the long-term outcome are awaited.

Some patients with disabling and potentially fatal lung disease, who are nonresponders to conventional treatment, could benefit from lung transplantation (LT). It is, therefore, necessary to know the number of patients who are potentially eligible for such a therapeutic procedure. A retrospective study of the mortality rate of the Italian population from 1989-1991 was carried out. Groups of non-neoplastic chronic respiratory diseases, for which LT is indicated, were identified according to the Italian Central Statistical Institute (ISTAT), analytical international classification of diseases, trauma and causes of death (9th revision of 1975). The distribution of these diseases was considered both in terms of the total number of deaths (all ages) and in the relative number prior to 60 yrs of age (the maximum acceptable age for LT). Twenty five ISTAT codes referring to chronic non-neoplastic lung diseases for which LT is indicated were identified, and grouped according to disease type. The total national mortality rate from 1989-1991 due to selected lung diseases for which transplant is indicated was 44,915 (14,335 in 1989, 15,271 in 1990, and 15,309 in 1991), and 2,774 (6%) of these deaths occurred below the age limit of 60 yrs (986 in 1989, 889 in 1990, and 899 in 1981). Considering the normal limitations of retrospective studies on mortality rate, and the fact that only one eligibility criterion for LT (age) was considered, the results obtained provide an indirect evaluation and overestimation of the potential candidates for such treatment in Italy, and the relative need for organ donation.

Total cases of fatal asthma in the occupational setting reported in the literature are reviewed and the case of a 39-year-old foundry worker who died at work is described. A diagnosis of occupational asthma induced by diphenylmethane diisocyanate (MDI) had been assessed 5 years in advance through a 0.005-ppm exposure inhalation challenge. Postmortem microscopic examination of the lung showed epithelial desquamation, eosinophilic/neutrophilic infiltration of the mucosa, dilatation of bronchial vessels, edema, hypertrophy and disarray of smooth muscle. Fatal asthma attack in a MDI-sensitized individual, to our knowledge, has not been previously described.

The Aims of Our Study Were: 1) to evaluate the long-term efficacy of nocturnal IPPV either via tracheostomy (tIPPV) or a nasal mask (nIPPV) as a means to improve alveolar ventilation in patients with chronic severe hypercapnia caused by kyphoscoliosis; and 2) to assess the effect of MV on hospitalizations and life-style. Twenty six patients with kyphoscoliosis in chronic respiratory failure were enrolled in the study. Patients were divided into two groups. The first group comprised 13 subjects who had been clinically stable for at least 1 month (arterial carbon dioxide tension (Pa,CO2) 81 +/- 1.5 kPa (60.8 +/- 10.9 mmHg), arterial oxygen tension (Pa,O2) 7.3 +/- 0.8 kPa (54.6 +/- 6.1 mmHg)). The second group comprised 13 patients who were either suffering or recovering from an episode of acute respiratory insufficiency (Pa,CO2 9.0 +/- 1.8 kPa (67.8 +/- 13.3 mmHg), Pa,O2 6.8 +/- 1.1 kPa (51.2 +/- 8.2 mmHg), breathing supplemental oxygen in seven cases). Patients in the first group were treated with nocturnal IPPV via a nasal mask, whilst those in the second received nocturnal IPPV via tracheostomy. Similar improvements in arterial blood gases (ABGs) were achieved with both methods. Despite the differences in the degree of severity at baseline, after 1 month, ABG values were: Pa,CO2 6.2 +/- 0.6 kPa (46.6 +/- 4.4 mmHg), Pa,O2 9.0 +/- 1.3 kPa (67.5 +/- 9.6 mmHg) (nIPPV patients); Pa,CO2 6.1 +/- 0.9 kPa (46.1 +/- 6.8 mmHg), Pa,O2 9.8 +/- 1.3 kPa (73.6 +/- 9.8 mmHg) (tIPPV patients). After 1 yr, this improvement was still evident. Days of hospitalization were significantly reduced in both groups during the first year of MV. We conclude that both tIPPV and nIPPV are effective in the long-term treatment of respiratory failure in patients with kyphoscoliosis. It would appear from our data that if nIPPV is initiated early in the evolution of chronic respiratory failure in patients with kyphoscoliosis it will delay the necessity to use an invasive technique; however, long-term follow-up studies and larger case series are needed to demonstrate this.

The ventilator assisted individual (VAI) represents a complex set of medical and social issues that call for the involvement of multiple interest groups. The success of treatment for VAI depends on many factors. These include: appropriate selection of patients for care outside the hospital, clinical and physiological stability of patients, patient and family motivation, and their ability to learn. Assisted ventilation in chronic respiratory failure secondary to chest-wall deformities and neuromuscular disease has shown promising results. Less satisfactory have been those reported in patients with chronic obstructive pulmonary disease (COPD). COPD candidates for chronic mechanical ventilation should be carefully selected. Patients should not be discharged on ventilators to nonhospital environments before they are clinically stable. It is also crucial to rule out other medical diseases that could interfere with successful discharge and home-care. Discharge planning requires the support and involvement of the physicians, nurses, and other allied health professionals. Education is of vital importance and, as such, needs to begin early in the patient's hospital stay. A basic checklist of skills that the VAI and the family will need to know should be developed, as well as an individual rehabilitation programme planned according to the patient's primary problem, with realistic short- and long-term goals. The aim is to restore and maintain the best possible quality of life for the individual.

Controlled studies have demonstrated that the correction of tissue hypoxia increases survival and reduces pulmonary hypertension in patients with chronic obstructive pulmonary disease (COPD) receiving oxygen therapy 15 h/day or longer. Long-term oxygen therapy (LTOT) is recommended to any patient with COPD who has a PaO2 of < or = 7.3 kPa. In most countries, the PaO2 threshold is 8kPa in patients with chronic hypoxemia (PaO2 > or = 55 mm Hg) with associated hematocrit > or = 55%, pulmonary hypertension or cor pulmonale. Desaturations during sleep or exercise should be investigated, although a consensus as to whether and how these episodes should be treated has yet to be reached. The indications for LTOT in restrictive lung diseases, such as interstitial pulmonary fibrosis and pneumoconiosis, remain controversial. In many countries, oxygen is not prescribed if the patient is a current smoker. Breathlessness without hypoxemia should not be considered an indication for LTOT. The oxygen is usually administered through nasal cannula. Venturi type masks, nasopharyngeal and transtracheal catheters are associated with several drawbacks. Oxygen is usually supplied by the relatively cheap oxygen concentrator. Liquid oxygen is favored when a portable source is an important requirement. Many questions remain unanswered concerning the duration of added survival, the effect of LTOT on physiological parameters such as pulmonary artery pressure, respiratory failure in non-COPD patients, exercise and nocturnal desaturations.

Between January 1989 and February 1993, 52 patients were evaluated at Niguarda Hospital for lung or heart and lung transplantation. Of the 35 that entered the waiting list, a total of 19 were transplanted (14 at other institutes before our surgical programme became operative, and 5 at our hospital). Recipient selection and evaluation criteria, and timing of transplantation in the different diseases are discussed.

Though exercise training is part of most pulmonary rehabilitation programs, whether there is a physiologic basis for increased exercise tolerance is unclear. We sought to determine whether patients with chronic obstructive pulmonary disease (COPD) are capable of obtaining a physiologic training effect, as manifested by a reduction in blood lactate and ventilation (VE) at a given level of exercise. We also sought to determine whether training work rate determines the size of the training effect. Nineteen participants with COPD of predominantly moderate severity in an inpatient rehabilitation program performed two cycle ergometer exercise tests at a low and a high work rate for 15 min or to tolerance and also an incremental exercise test to tolerance. Arterial blood was sampled for blood gas and lactate analyses. Identical tests were performed before and after 5-day-per-week cycle ergometer training for 8 wk either for 45 min/day at a high work rate (average, 71 W) or for a proportionally longer time at a low work rate (average, 30 W). Average FEV1 was 56 +/- 12% predicted and did not change with training. Peak exercise lactate (average, 6.5 mEq/L) was not correlated with FEV1. For the high work rate training group, identical work rates engendered less lactate (4.5 versus 7.2 mEq/L) and less VE (48 versus 55 L/min) after training; the low work rate training group had significantly less lactate and VE decrease (p less than 0.01). Further, endurance time for the high constant work rate increased 73% in the high work rate training group but only 9% in the low work rate training group. At identical work rates, VE decrease average 2.5 L/min per mEq/L decrease in lactate (r = 0.75). We conclude that most COPD subjects studied increased blood lactate at low work rates. Many of these patients were able to achieve a physiologic training effect. Though total work was the same, training at a high work rate was more effective than was training at a low work rate. The lower VE requirement to perform exercise was in proportion to the lower lactate level, but the VE decrease for a given decrease in lactate was smaller than that seen in normal subjects (7.2 L/min/mEq/L), apparently because patients with COPD fall to hyperventilate in response to lactic acidosis (PaCO2 does not drop). These findings provide a physiologic rationale for exercise training of patients with COPD.

Long-term O2 prescription in chronic non-COPD hypoxic lung disease is, at present, based largely on physiological rather than on clinical studies. Controlled long-term studies in this field are difficult to perform. The cooperation of many centers is necessary to obtain a large and homogeneous population as the incidence of these diseases is significantly lower than COPD.

At first Authors explain the stages of tubercular disease in which a programme of functional respiratory rehabilitation can be advised. Then they deal with the main aspects of rehabilitating treatment in some tubercular manifestations, as sero-fibrinous pleural effusion, tubercular empyema, parenchymal fibrosis and surgical reliquates. With regard to surgical reliquates, we mostly consider pulmonary resections and pleural skinning. At last Authors recall the indications to physical exercise training, that are constituted by some reliquates of tubercular pathology, and they resume the accomplishment modalities of such a programme in order to allow every patient wide possibilities of social reintroduction.

We investigated the relationship between the sensation of breathlessness and progressively higher resistive inspiratory loadings in nine normal subjects (31 +/- 17 yr; forced expiratory volume in one second (FEV1) = 105 +/- 9% of predicted) and in eighteen chronic obstructive pulmonary disease (COPD) patients (63 +/- 7 yr; FEV1 = 43 +/- 17% of predicted). The sensation of breathlessness correlated with mouth pressure both in normals (r = 0.94) and in COPD patients (r = 0.95), with a steeper slope in patients. On this basis we studied the effect of inspiratory muscle training on the sensation of breathlessness in sixteen COPD patients (63 +/- 8 yr; FEV1 = 52 +/- 19% of predicted). After a baseline assessment of lung function, MIP (maximal inspiratory pressure), inspiratory muscle endurance and the sensation of breathlessness (Borg scale) at different inspiratory loads, the patients were divided into two groups: the first was trained by means of resistive breathing, the second used a placebo device. At the end of the training, MIP increased more in the trained group (56 +/- 10 to 69 +/- 15 cmH2O; p less than 0.001) than in the placebo group (50 +/- 17 to 56 +/- 22 cmH2O; p = NS). The Borg score fell significantly at all the considered inspiratory loads in trained patients, but not in the placebo group. We conclude that the training with inspiratory resistances decreased the sensation of breathlessness via an increase in inspiratory muscle strength and endurance.

Exercise training is a mainstay of many pulmonary rehabilitation programmes. However, the physiologic basis for improved exercise tolerance is unclear. We hypothesized that since endurance training is known to reduce blood lactate at levels of work above the anaerobic threshold (AT), minute ventilation (VE) would also be lower. This might be an important benefit for the ventilatory-limited patient. We studied 10 normal subjects who performed 15 min of exercise at each of 4 work rates before and after 8 weeks of training. The lowest work rate was chosen to be below the AT; training produced a minimal decrease in VE (2.5 l.min-1). For the highest work rate, training produced a 4 mEq.l-1 decrease in lactate and a 37 l.min-1 decrease in VE. End-exercise VE reduction was well correlated with lactate reduction (r = 0.69). Seven men with chronic obstructive pulmonary disease (COPD) have also been studied. Each performed an incremental exercise test and two constant work rate tests (one above and one below AT) before and after an 8 week training period. Though responses were more variable than in normal subjects, training produced a reduced ventilatory requirement for exercise when blood lactate was reduced.

Epidemiological data show that chronic diseases of the respiratory apparatus have constantly increased over the last 20 years or so, often involving relatively young age classes. The increased survival rates due to chemotherapy also increase the importance of rehabilitation in such diseases. The officially accepted concept of a "global" rehabilitation is particularly significant in the case of patients of working age. The main rehabilitation procedures include chest physiotherapy, aerosol therapy, oxygen therapy (where selection criteria have been established and where there are new prospects related to long-term oxygen therapy), intermittent positive pressure breathing and physical retraining. Details on the methods of assessment and training and data concerning three groups of patients suffering from respectively chronic obstructive lung disease, silicosis and asbestosis, are given. The data show a general pattern of a decrease in ventilation (for an unchanged level of O2 uptake and CO2 output) and reflect a rise in muscular efficiency (exercising and respiratory) enabling the body to perform the same work load at a lower energy cost. The authors discuss the vocational rehabilitation of the patient with lung disease and illustrate the most useful procedures in the assessment of the subject, the environment and the place of work, including guidelines to achieve this. Rehabilitation treatment is also summarized into a number of stages, with the goals at different therapeutic levels and the ways to reach them.

The aim of the present study was to verify the effectiveness of procaterol, a recent and specific beta-2-adrenoceptor stimulant, in preventing exercise-induced asthma (EIA). Twelve asthmatic patients were selected aged 18.6 +/- 5.6 years with a positive response to EIA and a basal forced expiratory volume of the first second (FEV1) better than 80% of predicted. The patients underwent four bronchoprovocation challenges on four consecutive days. On the first day they performed an inclusion test, and, on the three subsequent days, they were submitted, to three identical standardized challenges according to a randomized design. Fifteen minutes before, procaterol (20 mcg), salbutamol (200 mcg) and a placebo were administered as metered aerosol. No pharmacological treatment was given for 24 h (48 h for antihistamines) before each challenge. The test was carried out running on treadmill (10% grade) for 7 min. Room temperature (20-25 degrees C) and relative humidity (40-55%) were maintained constant. At baseline, 15 min before, 5, 10, 15, 30 and 60 min after the exercise, lung function was assessed. Basal mean values of FEV1 were 94.7, 94.9, 90.7 and 91.5% of predicted for the inclusion and the three protected tests, respectively, without significant differences. The FEV1 mean values showed a mild bronchodilation 15 min after salbutamol (+13.2%, p less than 0.006) and procaterol (+8%, NS). At every considered time all indices showed a significant gap (p less than 0.01) between drugs and the placebo with no appreciable differences between procaterol and salbutamol.