Beate Rassler

The effect of respiratory muscle endurance training in patients with myasthenia gravis

We tested the effect of a home-based respiratory muscle endurance training in patients with mild to moderate generalized myasthenia gravis (MG) on Besinger score, lung function and respiratory muscle endurance. Ten patients performed respiratory muscle endurance training in form of normocapnic hyperpnea training at 50-60% of their maximal voluntary ventilation over 4-6 weeks. MG score, lung function and respiratory endurance were assessed before and after training period. The training significantly increased respiratory endurance from 8.4+/-0.9 min to 17.1+/-1.3 min (p<0.001) and total ventilatory volume from 555+/-87 L to 1081+/-127 L (p=0.004). About 25% of this gain was lost after 3-5 months of detraining. The remaining 75% gain might result from improved neuromuscular coordination rather than muscular training. MG score and lung function, however, did not change. Patients assessed the training effects on physical fitness and respiration as positive. In conclusion, respiratory muscle endurance training can be useful for MG patients as it is enhancing respiratory muscle endurance.

Coordination between breathing and forearm movements during sinusoidal tracking.

Abstract Time relationships (coordination) between breathing and rhythmical limb movements were analyzed during sinusoidal tracking movements of the forearm in 11 healthy subjects. The tracking rate was varied systematically between 0.1 and 1.0 Hz in 0.1-Hz steps. The aim of the study was to elucidate whether rhythmical tracking movements can entrain breathing, and whether this entrainment depends upon the movement rate. Subjects exhibited coordination between tracking movements and breathing at various rate ratios (1:1, 1:2, 1:3). At tracking rates of between 0.2 and 0.6 Hz, 1:1 coordination occurred with a maximum at 0.3 Hz; this rate range was called the 1:1 entrainment band. Coordination of 1:2 occurred at between 0.5 and 1.0 Hz (the 1:2 coordination band) with a maximum at 0.7 Hz. Coordination of 1:3 could be detected at between 0.5 and 1.0 Hz. Different subjects showed 1:n entrainment bands at similar locations but different widths of the rate range studied. The breathing rate during tracking was significantly higher than at rest, and it was correlated positively with tracking rate. This correlation, however, depended upon the width of the entrainment bands. Breathing rates varied between 0.2 and 0.6 Hz for all coordination patterns. We conclude that the occurrence of fixed time relationships is an expression of the strength of central nervous system coupling between the two processes. The frequency of coordination between breathing and rhythmical tracking movements depends critically upon the movement rate.

Pulmonary edema and pleural effusion in norepinephrine-stimulated rats--hemodynamic or inflammatory effect?

Stimulation with norepinephrine (NE) leads to pulmonary edema and pleural effusion in rats. These pulmonary fluid shifts may result from pulmonary congestion due to the hemodynamic effects of NE and/or inflammation with an increase in vascular permeability. The contribution of these two factors were investigated in the present study. Female Sprague–Dawley rats received continuous i.v. NE infusion (0.1 mg/kg/h) over time intervals between 90 min and 72 h. After heart catheterization, pleural fluid (PF) and lung tissue were obtained. In some of the animals, a bronchoalveolar lavage (BAL) was performed. Pulmonary edema and inflammation were shown histologically. We determined the expression of interleukin (IL)-6 as one of the most potent acute-phase protein mediators in serum, PF and BAL supernatant fluid (BALF) using ELISA as well as in the lung tissue using Western blotting. Total protein concentration in BALF and PF served as indicators of increased capillary permeability. Pulmonary edema and pleural effusion appeared coincidentally with an increase in total peripheral resistance (TPR) after 6 h of NE infusion. PF reached a maximum between 8 and 16 h (2.2 ± 0.3 ml, controls < 0.5 ml) and disappeared within 48 h. Activation of IL-6 in the fluids was observed after 8 h of NE stimulation. In the lung tissue it started after 12 h and reached 330% of the control value after 48 h. Pulmonary inflammation was documented histologically. It was accompanied by increased protein concentration in BALF after 24 h of NE treatment. Hemodynamic effects of NE are the main causative factors in the initial phase of the pulmonary fluid shifts. Additionally, NE leads to an activation of cytokines such as IL-6 and to inflammation and to an increase in capillary permeability. However, inflammation and increased capillary permeability occurred later than pulmonary edema and pleural effusion. Hence, we conclude that they are secondary factors which may contribute to maintain the fluid shifts over a longer period of time.

The expression of mRNA of cytokines and of extracellular matrix proteins in triiodothyronine-treated rat hearts

In various models of cardiac hypertrophy, e.g. treatment of rats with norepinephrine infusion or pressure overload, increased expression of cytokines together with increase in extracellular matrix proteins (ECMP) was reported. In this study the effect of triiodothyronine (T3) on the expression of mRNA for cytokines and ECMP was investigated. Female Sprague-Dawley rats were treated daily with T3 in a dose of 0.2 mg.kg−1 of body weight s.c. Changes in the left (LV) and right (RV) ventricular function were measured 6, 24, 48, 72 h and 7 and 14 days after the first T3-injection using Millar ultraminiature pressure catheter transducers. RNA was isolated from LV and RV tissue, and the expression of cytokines and ECMP was measured using the ribonuclease protection assay. T3-treatment induced a significant increase in LV dP/dtmax and RV dP/dtmax, (p < 0.05) 24 h after the first injection of T3 together with an increase in heart rate (p < 0.01). The RV systolic pressure increased 48 h after the first T3 injection, whereas the LV systolic pressure remained unchanged. After 48 h the heart weight to body weight ratio was increased (p< 0.01). Hypertrophy of the RV was more prominent than that of the LV (155.9 vs. 137.7%).In all groups the expression of mRNA for interleukins (IL) IL-6, IL-1β, IL-1α and tumour necrosis factor (TNF)-α in both ventricles did not change (p > 0.05). There was a significant increase in the mRNA for colligin 24 h after the T3 injection in both LV (p < 0.01) and RV (p< 0.05). This was followed by an increase in the mRNA for collagen I and III 72 h after the first T3-dose (p < 0.05 in RV; p < 0.01 in LV). At this point, the mRNA for tissue inhibitor of matrix metalloproteinases-2 (TIMP-2) was increased (p < 0.01) in the LV only. Moreover, after 7 days also the mRNA for matrix metalloproteinase (MMP)-2 increased (p < 0.01) in the LV. Both, TIMP-2 and MMP-2 were increased in the RV only after 14 days (p < 0.05). The gelatinase activity of MMP-2, however, was unchanged in both ventricles. The T3-induced cardiac hypertrophy was not accompanied by fibrosis as measured by the Sirius red staining after 14-days of T3-treatment. The moderate increase in mRNA for ECMP and MMP may be attributed more to the increasing mass of the ventricles with the accompanying remodelling of the ECM than to increased fibrosis.

cardiac remodeling in Erythropoietin-transgenic mice

Background: Transgenic (tg) mice with chronic overexpression of the human erythropoietin gene are characterized by an increased hematocrit of about 0.80 in adulthood. This is accompanied by cardiac dysfunction and premature death. The aim of this study was to examine whether this cardiac dysfunction was accompanied by hypertrophy of the heart with remodeling of the extracellular matrix (ECM). Methods: 3-months-old wild type (wt) and tg mice without cardiac hypertrophy were compared with the respective 7-months-old mice. The mRNA of brain natriuretic peptide (BNP), of the matrix metalloproteinases (MMP)-2, -8, -9, -13, of the tissue inhibitor of metalloproteinase (TIMP)-1, -2, -3, -4 and of collagen I and III was detected by ribonuclease protection assay. The activity of MMPs was measured by zymography. Results: There was hypertrophy of both ventricles in 7-months-old tg mice, which was accompanied by elevated mRNA expression of BNP. MMP-2 activity was increased and MMP-9 activity was decreased in the left ventricle (LV) of 3-months-old tg mice. This was accompanied by elevated TIMP-4 expression, followed by a shift of collagen mRNA expression from type III to type I in this ventricle. Conclusion: The shift to collagen I in the heart of tg mice might be associated with a stiffer ventricle resulting in diastolic dysfunction. This may be responsible for a relative and intermittent LV- and right ventricle (RV)-insufficiency which was likely to have occurred as evidenced by the elevation of lung and liver weight with hemorrhage and interstitial fibrosis after 7 months..

Time course of hypoxia-induced lung injury in rats.

We investigated the effects of normobaric hypoxia on rat lungs and hypothesized that the hypoxic exposure would induce lung injury with pulmonary edema and inflammation ensued by development of fibrosis. Rats were exposed to 10% O(2) in nitrogen over 6-168h. We analyzed cardiovascular function and pulmonary changes, lung histology and mRNA expression of extracellular matrix (ECM) molecules in the lung. Significant hemodynamic changes occurred after 168h of hypoxic exposure. Moderate pulmonary edema appeared after 8h and peaked after 16h of hypoxia. It was accompanied by inflammation, fibrosis and vascular hypertrophy. mRNA expression of transforming growth factor-beta2 and -beta3 was up-regulated in lung tissue after 8h of hypoxia. After 8-16h, mRNA expression of collagen types I and III and of other ECM molecules was significantly elevated and increased further with longer exposure to hypoxia. The time course of hypoxia-induced pulmonary injury resembled that previously observed after continuous norepinephrine infusion in rats.

Mutual nervous influences between breathing and precision finger movements.

Abstract The precision of short-term finger tracking flexions has been shown to vary with the respiratory cycle. In the present study, we analysed the mutual effects between breathing and short-term finger tracking movements (SFTM) – both flexions and extensions. Moreover, we investigated the preferred phase relationships between breathing and spontaneous single finger flexions and extensions. Two types of experiments were carried out. Fifteen volunteers participated in the finger tracking experiments. In one experimental session, a square-wave function served as a tracking signal that required a rapid finger flexion, and in another session it required a finger extension. In the second type of experiment, 14 volunteers performed spontaneous short-term finger flexions and extensions of a pre-defined amplitude, with the starting point chosen at their convenience. SFTM were associated with modulations in the time course of the respiratory cycle. These were more pronounced for finger flexions than for extensions. Likewise, the precision of finger flexions, but not extensions, showed significant respiratory-phase-dependent differences. The largest tracking errors occurred at the end of expiration in finger flexions and at the end of inspiration in finger extensions. Spontaneous finger flexions tended to start at around the respiratory phase transitions. Spontaneous extensions, however, tended to start at early expiration (12.5–37.5% of expiration time). The results demonstrate that both spontaneous and tracking finger flexions and extensions are influenced by different stages of a breath. However, spontaneous finger movements did not tend to start at the stages of breaths that were associated with the highest movement precision in the tracking tests. Moreover, these results suggest that finger flexions are more closely related to the respiratory rhythm than are finger extensions.

Long-Term Respiratory Muscle Endurance Training in Patients with Myasthenia Gravis: First Results after Four Months of Training

Myasthenia gravis (MG) is characterized by reduced muscle endurance and is often accompanied by respiratory complications. Improvement of respiratory function is therefore an important objective in MG therapy. A previous study demonstrated that respiratory muscle endurance training (RMET) over four weeks increased respiratory muscle endurance of MG patients to about 200% of baseline. The purpose of the present study was to establish an appropriate maintenance training and to test its effects over four months. Ten patients with mild to moderate MG participated in this study. During the first month, they performed five training sessions per week. For the following 3 months, training frequency was reduced to five sessions per two weeks. Myasthenia score, lung function, and respiratory endurance were determined prior to training, after the first month, and after 4 months. Myasthenia score improved from 0.71 ± 0.1 to 0.56 ± 0.1 (P = 0.007). Respiratory endurance time increased from 6.1 ± 0.8 to 20.3 ± 3.0 min (P < 0.001). In conclusion, this RMET maintenance program is feasible and is significantly beneficial for MG patients.

Norepinephrine-induced cardiac hypertrophy and fibrosis are not due to mast cell degranulation.

The norepinephrine (NE)-induced hypertrophy of the left ventricle (LV) in the rat is preceded by increased interleukin (IL)-6 expression and associated with LV fibrosis. We have examined whether the elevated level of IL-6 may be due to mast cell degranulation. Therefore we tested the effect of cromoglycate sodium salt (cromolyn), an inhibitor of mast cell degranulation with anti-inflammatory and membrane-stabilizing activity, on the increased expression of IL-6 mRNA and of mRNAs of proteins involved in the remodelling of the extracellular matrix (ECM) which is induced by NE (0.1 mg/kg·h). After 4 h, the NE-induced increase in IL-6 mRNA expression was not influenced by cromolyn (20 mg/kg·h). Cromolyn-infusion for 3 days did not affect the extent of LV hypertrophy induced by NE, as measured by the LV weight/body weight (LVW/BW) ratio and by atrial natriuretic peptide (ANP) expression. Cromolyn induced a slight depression of the NE-induced elevation of the matrix metalloproteinase (MMP)-2. However, it did not affect the NE-induced elevated levels of mRNAs of collagen I and III and the tissue inhibitor of matrix metalloproteinase (TIMP)-2. Since cromolyn did not reduce the NE-effects in rat hearts in vivo we conclude that mast cell degranulation seems not to be involved in them.

Contribution of α - and β -Adrenergic Mechanisms to the Development of Pulmonary Edema.

Endogenous or exogenous catecholamines can induce pulmonary edema (PE). This may occur in human pathologic conditions such as in pheochromocytoma or in neurogenic pulmonary edema (NPE) but can also be provoked after experimental administration of adrenergic agonists. PE can result from stimulation with different types of adrenergic stimulation. With α-adrenergic treatment, it develops more rapidly, is more severe with abundant protein-rich fluid in the alveolar space, and is accompanied by strong generalized inflammation in the lung. Similar detrimental effects of α-adrenergic stimulation have repeatedly been described and are considered to play a pivotal role in NPE or in PE in patients with pheochromocytoma. Although β-adrenergic agonists have often been reported to prevent or attenuate PE by enhancing alveolar fluid clearance, PE may also be induced by β-adrenergic treatment as can be observed in tocolysis. In experimental models, infusion of β-adrenergic agonists induces less severe PE than α-adrenergic stimulation. The present paper addresses the current understanding of the possible contribution of α- and β-adrenergic pathways to the development of PE.