Genetic disorders of GH action pathway.

While insensitivity to GH (GHI) is characterized by low IGF-I levels, normal or elevated GH levels, and lack of IGF-I response to GH treatment, IGF-I resistance is characterized by elevated IGF-I levels with normal/high GH levels. Several genetic defects are responsible for impairment of GH and IGF-I actions resulting in short stature that could affect intrauterine growth or be present in the postnatal period. The genetic defects affecting GH and/or IGF-I action can be divided into five different groups: GH insensitivity by defects affecting the GH receptor (GHR), the intracellular GH signaling pathway (STAT5B, STAT3, IKBKB, IL2RG, PIK3R1), the synthesis of insulin-like growth factors (IGF1, IGF2), the transport/bioavailability of IGFs (IGFALS, PAPPA2), and defects affecting IGF-I sensitivity (IGF1R). Complete GH insensitivity (GHI) was first reported by Zvi Laron and his colleagues in patients with classical appearance of GH deficiency, but presenting elevated levels of GH. The association of GH insensitivity with several clinical sings of immune-dysfunction and autoimmune dysregulation are characteristic of molecular defects in the intracellular GH signaling pathway (STAT5B, STAT3, IKBKB, IL2RG, PIK3R1). Gene mutations in the IGF1 and IGF2 genes have been described in patients presenting intrauterine growth retardation and postnatal short stature. Molecular defects have also been reported in the IGFALS gene, that encodes the acid-labile subunit (ALS), responsible to stabilize circulating IGF-I in ternary complexes, and more recently in the PAPPA2 gen that encodes the pregnancy-associated plasma protein-A2, a protease that specifically cleaves IGFBP-3 and IGFBP-5 regulating the accessibility of IGFs to their target tissues. Mutations in the IGF1R gene resulted in IGF-I insensitivity in patients with impaired intrauterine and postnatal growth. These studies have revealed novel molecular mechanisms of GH insensitivity/primary IGF-I deficiency beyond the GH receptor gene. In addition, they have also underlined the importance of several players of the GH-IGF axis in the complex system that promotes human growth.

Responsiveness of continuous ratings of dyspnea during exercise in patients with COPD.

PURPOSE: To examine the responsiveness of a new computerized method for patients to provide continuous ratings of dyspnea during exercise in patients with chronic obstructive pulmonary disease (COPD). METHODS: In this randomized, double-blind study the effects of an inhaled bronchodilator (BD), albuterol/ipratropium bromide solution, were compared with normal saline (NS) in 30 patients with COPD (age, 66+/-9 yr; forced expiratory volume in 1 s, 48+/-14% pred). At visit 1, patients were familiarized with the cycle ergometer and computer, monitor, and mouse system to provide continuous ratings of dyspnea during exercise. At subsequent visits 2-3 d apart, patients performed pulmonary function tests followed by incremental ramp (15 W.min-1) and, 1 h later, constant work (at 55% of maximal work capacity) exercise tests. RESULTS: During incremental exercise the slopes of VO2:dyspnea and VE:dyspnea regressions were significantly lower, and patients exercised longer (Delta=0.4 min; P=0.003) with BD therapy compared with NS. During constant work exercise there was a significant reduction in dyspnea at the same exercise duration (5.0+/-2.8 vs 6.2+/-2.8 units on the 0-10 category-ratio scale; P=0.02) and patients exercised longer (Delta=0.9 min; P=0.04) with BD therapy. Changes in lung function at rest did not correlate significantly with changes in dyspnea ratings during exercise. CONCLUSIONS: Continuous ratings of dyspnea were responsive to inhaled bronchodilator therapy during both incremental and constant work exercise tests in patients with symptomatic COPD.

Comparison of continuous and discrete measurements of dyspnea during exercise in patients with COPD and normal subjects.

STUDY OBJECTIVES: The objectives of this study were as follows: (1) to compare results of the discrete and the continuous methods for measuring breathlessness; (2) to examine test-retest reliability; (3) and to test the hypothesis that patients with COPD have higher slopes and lower x-intercepts and absolute thresholds for power production, oxygen consumption (O(2)), and minute ventilation as independent variables and breathlessness ratings as the dependent variable, as compared with healthy subjects. DESIGN: Visit 1 (familiarization) and visit 2 and visit 3 (2 days apart) with randomized assignment of the discrete and continuous methods for subjects rating breathlessness during cycle ergometry. SETTING: Cardiopulmonary exercise laboratory in a university medical center. PARTICIPANTS: Twenty-four patients with COPD (mean age, 66 +/- 8 years [+/- SD]) and 24 healthy subjects (mean age, 66 +/- 10 years). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Ratings of breathlessness on the Borg scale on cue with subjects moving and pressing the computer mouse button to indicate a rating (discrete method) or by moving the position of the mouse to adjust a vertical bar to indicate a change in breathlessness (continuous method). There were no significant differences in results between visit 2 and visit 3. Although peak exercise variables were similar with the discrete and continuous methods, both groups provided significantly more ratings of breathlessness with the continuous method. Patients with COPD exhibited higher slopes, lower x-intercepts, and lower absolute thresholds (breathlessness rating >/==" BORDER="0"> 0.5 ["just noticeable"] on the Borg scale) for power production and O(2)-breathlessness compared with healthy subjects (p < 0.05). CONCLUSIONS: Elderly patients with COPD and healthy subjects are able to use the continuous method successfully. Reliability is excellent for both methods. The continuous method provides a greater number of breathlessness ratings over the course of exercise, and allows the clinician to calculate an absolute threshold and just-noticeable differences. Regression parameters and absolute thresholds discriminate between patients with COPD and healthy subjects.

Development of self-administered versions of modified baseline and transition dyspnea indexes in COPD.

In this study we developed self-administered versions of modified baseline and transition dyspnea indexes and compared the scores obtained by this method with the mean value obtained by two trained interviewers. Twenty-five patients (14 males/11 females) with chronic obstructive disease who had a chief complaint of "breathlessness" were tested. Age was 66+/-11 years; forced expiratory volume in one second was 48+/-23% predicted. The baseline total scores were 5.0+/-1.8 for the interviewers and 5.4+/-2.0 for the self-administered method. For the baseline dyspnea scores the correlations were 0.83 (p<0.0001) between self-administration and the mean value of two interviewers and 0.75 (p<0.0001) between the two interviewers. The transition total scores, obtained an average of 102 days (range, 7-377 days) later, were - 0.1+/-3.0 for the interviewers and - 0.4+/-3.0 for the self-administered method. For the transition dyspnea scores the correlations were 0.94 (p<0.0001) between self-administration and the mean value of two interviewers and 0.83 (p<0.0001) between the two interviewers. The self-administered dyspnea scores had similar correlations with measures of lung function as did the interview dyspnea scores. We conclude that self-administered versions of the modified baseline and transition dyspnea indexes provide comparable scores as those obtained by trained and experienced interviewers. The advantages of the self-administered versions include standardized methodology and computerized scoring.

Evaluation of dyspnea in the elderly.

The word "dyspnea" encompasses many different features. It can be considered to be a sensation, a symptom, or an illness. From a practical perspective many physicians and nurses use dyspnea to refer to difficult or labored breathing or an uncomfortable awareness of breathing. The American Thoracic Society recently defined dyspnea as a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity.