BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a complex disease with a highly variable clinical course and generally poor prognosis. Classified as a rare disease, significant increases in incidence have been recorded worldwide in recent years. Left untreated IPF is extremely debilitating with substantial personal, social and economic implications. OBJECTIVES:To discuss how IPF is diagnosed and managed in real life clinical practice with particular reference to Italy and to determine how new and effective therapies can be incorporated into a patient-centred management approach in order to improve the lives of patients with IPF. OUTCOMES:Barriers to early diagnosis are discussed. Cited reasons for delays in diagnosing IPF in Italy include: inherent difficulties in diagnosis; lack of knowledge/awareness of the condition among point-of-contact healthcare professionals; delays in referral to centres of excellence and underestimation of symptoms by both patients and healthcare workers. Valid therapeutic options with demonstrated efficacy in slowing the decline in lung function are now available for patients with IPF. The ASCEND trial confirmed the effects of pirfenidone, approved for the treatment of IPF on the basis of the four phase III trials. Nintedanib, a tyrosine kinase inhibitor that targets the PDGF receptors α/β, FGF receptors 1 to 3, and VEGF receptors 1-3, is approved in the USA and the EU for the treatment of IPF. The TOMORROW and the INPULSIS placebo controlled trials in patients with IPF confirm the efficacy and safety of nintedanib and recent interim analyses endorse its long-term effects in slowing disease progression. CONCLUSIONS:The importance of early and accurate diagnosis of IPF cannot be underestimated and it is the duty of all healthcare professionals to be vigilant to the symptoms of IPF and to involve a multidisciplinary team in diagnosing and managing IPF early in the course of disease.

We present a case of a 85-year-old man who suffered from several chronic obstructive pulmonary disease (COPD) related exacerbations and hospitalizations. Traditional therapy, which also included intramuscular steroid therapy, did not help and caused several drug related adverse events. After yet another exacerbation followed by hospitalization at the intensive care unit, it was decided to start roflumilast treatment. In the year after beginning treatment, the patient did not experience any more exacerbations and his lung function also improved, as recorded by the COPD assessment test (CAT) score and improved forced expiratory volume in the first second (FEV1) value. In this patient roflumilast seems to be effective in reducing exacerbations, an important goal to be achieved in COPD patients.

Skeletal muscles are composed of fibres of different types, each type being identified by the isoform of myosin heavy chain which is expressed as slow 1, fast 2A, fast 2X, and fast 2B. Slow fibres are resistant to fatigue due to their highly oxidative metabolism whereas 2X and 2B fibres are easily fatiguable and fast 2A fibres exhibit intermediate fatigue resistance. Slow fibres and fast fibres are present in equal proportions in the adult human diaphragm while intercostal muscles contain a higher proportion of fast fibres. A small fibre size, abundance of capillaries, and a high aerobic oxidative enzyme activity are typical features of diaphragm fibres and give them the resistance to fatigue required by their continuous activity. Because of their fibre composition, intercostal muscles are less resistant to fatigue. The structural and functional characteristics of respiratory muscle fibres are not fixed, however, and can be modified in response to several physiological and pathological conditions such as training (adaptation to changes in respiratory load), adaptation to hypoxia, age related changes, and changes associated with respiratory diseases. The properties of respiratory muscle fibres can also be modified by pharmacological agents such as b2 agonists and corticosteroids used for the treatment of respiratory diseases.

Skeletal muscles are composed of fibres of different types, each type being identified by the isoform of myosin heavy chain which is expressed as slow 1, fast 2A, fast 2X, and fast 2B. Slow fibres are resistant to fatigue due to their highly oxidative metabolism whereas 2X and 2B fibres are easily fatiguable and fast 2A fibres exhibit intermediate fatigue resistance. Slow fibres and fast fibres are present in equal proportions in the adult human diaphragm while intercostal muscles contain a higher proportion of fast fibres. A small fibre size, abundance of capillaries, and a high aerobic oxidative enzyme activity are typical features of diaphragm fibres and give them the resistance to fatigue required by their continuous activity. Because of their fibre composition, intercostal muscles are less resistant to fatigue. The structural and functional characteristics of respiratory muscle fibres are not fixed, however, and can be modified in response to several physiological and pathological conditions such as training ( adaptation to changes in respiratory load), adaptation to hypoxia, age related changes, and changes associated with respiratory diseases. The properties of respiratory muscle fibres can also be modified by pharmacological agents such as beta(2) agonists and corticosteroids used for the treatment of respiratory diseases.

Beta‐agonists and glucocorticoids are frequently coprescribed for chronic asthma treatment. In this study the effects of 4 week treatment with beta‐agonist clenbuterol (CL) and glucocorticoid dexamethasone (DEX) on respiratory (diaphragm and parasternal) and limb (soleus and tibialis) muscles of the mouse were studied. Myosin heavy chain (MHC) distribution, fibres cross sectional area (CSA), glycolytic (phosphofructokinase, PFK; lactate dehydrogenase, LDH) and oxidative enzyme (citrate synthase, CS; cytochrome oxidase, COX) activities were determined. Muscle samples were obtained from four groups of adult C57/B16 mice: (1) Control (2) Mice receiving CL (CL, 1.5 mg kg −1 day −1 in drinking water) (3) Mice receiving DEX (DEX, 5.7 mg kg −1 day −1 s.c. ) (4) Mice receiving both treatments (DEX + CL). As a general rule, CL and DEX showed opposite effects on CSA, MHC distribution, glycolytic and mitochondrial enzyme activities: CL alone stimulated a slow‐to‐fast transition of MHCs, an increase of PFK and LDH and an increase of muscle weight and fibre CSA; DEX produced an opposite (fast‐to‐slow transition) change of MHC distribution, a decrease of muscle weight and fibre CSA and in some case an increase of CS. The response varied from muscle to muscle with mixed muscles, as soleus and diaphragm, being more responsive than fast muscles, as tibialis and parasternal. In combined treatments (DEX + CL), the changes induced by DEX or CL alone were generally minimized: in soleus, however, the effects of CL predominated over those of DEX, whereas in diaphragm DEX prevailed over CL. Taken together the results suggest that CL might counteract the unwanted effects on skeletal muscles of chronic treatment with glucocorticoids.

The aim of this study was to analyze the effects of chronic administration of the beta(2)-agonist clenbuterol (1.5 mg x kg(-1) x day(-1) for 4 wk in the drinking water) on respiratory (diaphragm and parasternal intercostal) and hindlimb (tibialis and soleus) muscles in young rats during postnatal development (21 to 49 postnatal days). The treatment resulted in very little stimulation of muscle growth. Significant slow-to-fast transitions in the expression of myosin heavy chain isoforms and significant increases in the myofibrillar ATPase activity were found in the diaphragm and soleus, whereas tibialis anterior and intercostal muscles did not show any significant fiber-type alteration. Decrease of oxidative enzyme activities and increase of glycolytic enzyme activities were also observed. It is concluded that whereas the growth stimulation is age dependent and only detectable in adult rats, the fiber-type transformation is also present in weaning rats and particularly evident in the soleus and diaphragm. The fiber-type transformation caused by clenbuterol might lead to an enhancement of contractile performance and also to a reduced resistance to fatigue.

The aim of this study was to determine (i) whether phosphodiesterase inhibitors influenced ATPase activity of maximally calcium activated cardiac myofibrils and (ii) whether this effect varied in relation to isomyosin composition. Myofibrils were prepared from ventricular myocardium of 2- to 3-month-old rats. ATPase activity was determined at low ionic strength at high (> 7.5) and low (4.4) pCa. Five compounds (amrinone, milrinone, enoximone, piroximone, and rolipram) were examined at concentrations between 10 microM and 1 mM. The results obtained showed that only milrinone and amrinone inhibited ATPase activity; inhibition was dose dependent, and milrinone was more potent than amrinone. To assess whether isomyosin composition might influence the responsiveness of myofibrils to phosphodiesterase inhibitors, the effect of 1 mM milrinone was also determined in myofibrils from hypothyroid rats. According to previous observations hypothyroidism caused an isomyosin shift from V1 to V3 in rat ventricular myocardium. The inhibitory effect of milrinone was lower in myofibrils prepared from hypothyroid rats than in myofibrils from euthyroid rats.

This study aimed to investigate whether milrinone effect on cardiac muscle contractility undergoes to age-related changes. Experiments were carried out on papillary muscles isolated from right ventricle of Brown Norway rats belonging to two different age groups: 2 month old and 18 month old. The effect of milrinone (10-100 microM) on rat cardiac muscle in vitro preparations was characterized by a reduction of peak developed tension and of contraction duration. Furthermore, the recovery of contractility after a contractile cycle, i.e. the mechanical restitution was faster in the presence of milrinone than in control conditions. All these effects were reduced in preparations from 18 month old rats compared to preparations from 2 month old rats. The decrease of milrinone effect on the mechanical restitution was particularly pronounced. The reduction of the milrinone effects is likely connected with the reduction of the maximal effect of adrenergic stimulation, although the molecular basis of this link is not yet clearly understood.

In this study the effects of administration of cortisone acetate (100 mg kg-1 body weight subcutaneously for 11 days) on distribution and cross-sectional area of different fibre types of rat skeletal muscles were investigated. Diaphragm, parasternal intercostal (PI), extensor digitorum longus (EDL) and soleus muscles were examined in cortisone treated animals (CA) in comparison with ad libitum controls (CTRL) and pair-fed (PF) controls. Four fibre types (I or slow and IIA, IIX, IIB or fast) were identified on the basis of their myosin heavy chain composition using a set of monoclonal antibodies. In CA rats the reduction of cross-sectional area was above 30% in IIX fibres of diaphragm, IIB fibres of PI and in all fast fibres of EDL. In all muscles slow fibres were spared from atrophy. Significant variations in fibre type distribution were found in the muscles of CA rats when compared to CTRL. The percentage of IIB fibres decreased in EDL, PI and diaphragm. This decrease was accompanied by an increase in the percentage of IIA fibres in the same muscles. No changes in the percentage of slow fibres and of fast IIX fibres were observed in EDL, PI and diaphragm of CA rats in comparison with CTRL. In soleus of CA rats the proportion of IIA fibres was lower than in CTRL. In EDL of PF rats atrophy of IIA fibres and changes in fibre type distribution were similar to those observed in CA rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations of cardiac contractility caused by thiamine deficiency were studied on three groups of 2 month old male Wistar rats: B1, fed a thiamine deficient diet, PF pair fed, which received an amount of thiamine free diet determined on the daily consumption of B1 animals, supplemented with appropriate thiamine supply, C ad libitum fed controls. The animals were studied after 35 days of dietary treatment. Force-velocity curves were determined in right ventricle papillary muscles. Shortening velocity was significantly lower in B1 and PF than in C muscles and in B1 than in PF muscles. The ability to develop tension was not altered. Myosin ATPase activity was assayed in preparations of myofibrils and in preparations of purified myosin. Both CaMg activated myofibrillar ATPase activity and Ca-activated myosin ATPase activity were significantly reduced in B1 and PF compared to C myocardium. Furthermore Ca-activated ATPase activity was lower in B1 than in PF myocardium. Myosin isoenzyme distribution was determined by pyrophosphate gel electrophoresis of purified myosin preparations. When compared to C animals both B1 and PF animals showed a myosin electrophoretic pattern shifted towards the slow isoform V3; such a shift was more pronounced in B1 animals. Information concerning excitation-contraction coupling was obtained by determining the steady state and transient force-interval relation and by recording transmembrane action potential. B1 and PF myocardium exhibited, when compared to C, a less sensitivity to a reduction of the interval of stimulation, a faster mechanical restitution, a prolonged action potential duration. Such alterations were generally more pronounced in B1 than in PF myocardium. The results support the view that in the rat cardiac contractility is deeply affected by thiamine deficiency. The alterations of cardiac contractility seem to be caused by adaptive mechanisms rather than by cardiac failure and seem to be attributable for a big part to the reduction of food supply.

Journal Article Effects of thyroid state and beta adrenergic stimulation on mechanical restitution of rat ventricular myocardium Get access R BOTTINELLI, R BOTTINELLI From the Institute of Human Physiology, University of Pavia, Pavia, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar C POGGESI, C POGGESI From the Institute of Human Physiology, University of Pavia, Pavia, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar B POLLA, B POLLA From the Institute of Human Physiology, University of Pavia, Pavia, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar C REGGIANI C REGGIANI From the Institute of Human Physiology, University of Pavia, Pavia, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 22, Issue 8, August 1988, Page 597, https://doi.org/10.1093/cvr/22.8.597 Published: 01 August 1988

This study was designed to investigate the changes in cardiac contractile properties induced by triiodothyronine (T3) administration in adult rats. Myofibrils and myosin were isolated from ventricular muscles from euthyroid and hyperthyroid animals and enzymatically and electrophoretically characterized. The time course of the isometric response, the force velocity curve, the force interval relation were studied in papillary muscles isolated from the right ventricles of euthyroid and hyperthyroid rats. T3 administration induced significant increases in Mg2+ activated myofibrillar ATPase activity (+11.4%) and in Ca2+ activated myosin ATPase activity (+20.1%). Significant increases in shortening velocity at low and zero loads (+20.4%) were found in papillary muscles from treated animals when compared with the control muscles. These variations in enzymatic activity and shortening velocity could be related to the increase in the amount of the fast isomyosin V1, as shown by pyrophosphate gel electrophoresis. The negative force-frequency relation at steady state, typical of rat cardiac preparations, was observed in treated and control animals; its slope was, however, halved in hyperthyroid papillary muscles when compared with control ones. In accordance with this finding, the potentiating effect of a prolonged diastolic interval was significantly reduced in hyperthyroid papillary muscles. In the frame of an interpretation of the force interval relation on the basis of the excitation contraction coupling processes, these latter observations might indicate an enhanced activity of the sarcoplasmic reticulum. We conclude that thyroid hormone administration has a dual effect on cardiac contractility, on one hand regulating the synthesis of the different isomyosin and, on the other hand, stimulating the activity of the sarcoplasmic reticulum.

The purpose of this study was to determine whether thyroid state affects the beat-to-beat regulation of contractile strength in cardiac muscle. Transmembrane action potential and isometric force were simultaneously recorded in right ventricular papillary muscles from euthyroid, hypothyroid, and hyperthyroid rats. Large thyroid state-dependent alterations in the contractile response of the muscles were not accompanied by any significant difference in the action potential. During steady-state stimulation, single test stimuli were interpolated at varying intervals. Action potential duration and peak force of the test responses were plotted against the test stimulus interval to produce electrical and mechanical restitution curves. In all muscles studied, electrical and mechanical restitution followed different time courses; over a wide range of test intervals, action potential duration and peak force of the test responses changed in opposite directions. Thyroid state profoundly affected the recovery of contractile strength, while only minor differences were found among the electrical restitution curves of the three groups of preparations. Mechanical recovery was much faster in hyperthyroid and slower in hypothyroid than in euthyroid muscles. We conclude that electrical and mechanical restitutions occur through separate processes and that the thyroid state affects only the mechanisms responsible for the contractile recovery of rat myocardium. The modifications induced by thyroid dysfunction on contractile recovery might be accounted for by an effect of thyroid state on a time-dependent recycling of calcium by the sarcoplasmic reticulum.

To the Editor:In June 1983, Ciment et al reported two cases of contralateral effusions secondary to subclavian venous catheters (Chest 1983; 83:926–27). We recently observed right chylothorax in a 75-year-old man 15 days after problematic insertion of a definitive endovenous pacemaker into the left subclavian vein. Other potential causes of chylothorax, especially neoplasm, were excluded. The chylothorax resolved spontaneously and did not recur.To our knowledge, this is the first report of a chylothorax secondary to endovenous pacemaker insertion (Acta Clin Belgica, in press). However, subclavian vein puncture has already been mentioned by Marsac as a possible cause of chylothorax.1Marsac J. Frija G. Bismuth V. Chylothorax et pathologie lymphatique de la plèvre.Rev fr Mal Resp. 1982; 10: 227-241PubMed Google Scholar The mechanism is similar to that described by Ciment et al. Mediastinal leakage of chyle occurs first, and the pleural effusion (homolateral or contralateral) may appear as late as two weeks after the puncture, as in our case. As central venous catheters are used more and more, it is important to be aware of potential complications, either classic or rare. Late-appearing contralateral effusion or chylothorax may represent a diagnostic challenge. As Ciment et al point out, the more frequent use of right internal jugular vein for central catheters may significantly reduce complications, and subclavian venous catheters should be reserved for emergencies or profoundly hypovolemic patients.2Stevens J.C. Hamit H.F. A simple method for percutaneous cannulation of the internal jugular vein.Am J Surg. 1978; 135: 722-723Abstract Full Text PDF PubMed Scopus (7) Google Scholar Pneumothoraces and hydrothoraces are less frequent with the internal jugular vein approach and chylothorax has not been reported using this insertion route.3Bernard R.W. Stahl W.M. Subclavian vein catheterization: a prospective study.Ann Surg. 1971; 173: 184-200Crossref PubMed Scopus (216) Google Scholar To the Editor: In June 1983, Ciment et al reported two cases of contralateral effusions secondary to subclavian venous catheters (Chest 1983; 83:926–27). We recently observed right chylothorax in a 75-year-old man 15 days after problematic insertion of a definitive endovenous pacemaker into the left subclavian vein. Other potential causes of chylothorax, especially neoplasm, were excluded. The chylothorax resolved spontaneously and did not recur. To our knowledge, this is the first report of a chylothorax secondary to endovenous pacemaker insertion (Acta Clin Belgica, in press). However, subclavian vein puncture has already been mentioned by Marsac as a possible cause of chylothorax.1Marsac J. Frija G. Bismuth V. Chylothorax et pathologie lymphatique de la plèvre.Rev fr Mal Resp. 1982; 10: 227-241PubMed Google Scholar The mechanism is similar to that described by Ciment et al. Mediastinal leakage of chyle occurs first, and the pleural effusion (homolateral or contralateral) may appear as late as two weeks after the puncture, as in our case. As central venous catheters are used more and more, it is important to be aware of potential complications, either classic or rare. Late-appearing contralateral effusion or chylothorax may represent a diagnostic challenge. As Ciment et al point out, the more frequent use of right internal jugular vein for central catheters may significantly reduce complications, and subclavian venous catheters should be reserved for emergencies or profoundly hypovolemic patients.2Stevens J.C. Hamit H.F. A simple method for percutaneous cannulation of the internal jugular vein.Am J Surg. 1978; 135: 722-723Abstract Full Text PDF PubMed Scopus (7) Google Scholar Pneumothoraces and hydrothoraces are less frequent with the internal jugular vein approach and chylothorax has not been reported using this insertion route.3Bernard R.W. Stahl W.M. Subclavian vein catheterization: a prospective study.Ann Surg. 1971; 173: 184-200Crossref PubMed Scopus (216) Google Scholar