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International audience; Introduction/aims: Respiratory status is a key determinant of prognosis in patients with Duchenne muscular dystrophy (DMD). We aimed to evaluate the determinants of diaphragm ultrasound and its performance in predicting restrictive respiratory patterns in DMD.Methods: This was a retrospective study of DMD patients followed in our center and admitted for an annual checkup from 2015 to 2018. We included DMD patients who underwent diaphragm ultrasound and pulmonary functional tests.Results: This study included 74 patients with DMD. The right diaphragm thickening fraction (TF) was significantly associated with age (P = .001), Walton score (P = .012), inspiratory capacity (IC) (P = .004), upright forced vital capacity (FVC) (P < .0001), supine FVC (P = .038), and maximal inspiratory pressure (MIP) (P = .002). Right diaphragm excursion was significantly associated with age (P < .0001), steroid use (P = .008), history of spinal fusion (P < .0001), body mass index (BMI) (P = .002), Walton score (P < .0001), IC (P < .0001), upright FVC (P < .0001), supine FVC (P < .0001), and MIP (P < .0001). A right diaphragm TF >28% and a right diaphragm excursion>25.4 mm were associated with an FVC >50% with, respectively, an area under the curve (AUC) of 0.95 (P = .001) and 0.93 (P < .001). A left diaphragm TF >26.8% and a left diaphragm excursion >21.5 mm were associated with an FVC >50% with, respectively, an AUC of 0.95 (P = .011) and 0.97 (P < .001).Discussion: Diaphragm excursion and diaphragm TF can predict restrictive pulmonary insufficiency in DMD.

Aims To estimate the effect of prophylactic angiotensin-converting enzyme inhibitors (ACEi) on survival in Duchenne muscular dystrophy (DMD). Methods and results We analysed the data from the French multicentre DMD Heart Registry (ClinicalTrials.gov: NCT03443115). We estimated the association between the prophylactic prescription of ACEi and event-free survival in 668 patients aged 8 to 13 years, with normal left ventricular function, using (i) a Cox model with intervention as a time-dependent covariate, (ii) a propensity-based analysis comparing ACEi treatment vs. no treatment, and (iii) a set of sensitivity analyses. The study outcomes were overall survival and hospitalizations for heart failure (HF) or acute respiratory failure. Among the 668 patients included in the DMD Heart Registry, 576 (mean age 6.1 ± 2.8 years) were eligible for this study, of whom 390 were treated with ACEi prophylactically. Death occurred in 53 patients (13.5%) who were and 60 patients (32.3%) who were not treated prophylactically with ACEi, respectively. In a Cox model with intervention as a time-dependent variable, the hazard ratio (HR) associated with ACEi treatment was 0.49 [95% confidence interval (CI) 0.34–0.72] and 0.47 (95% CI 0.31–0.17) for overall mortality after adjustment for baseline variables. In the propensity-based analysis, 278 patients were included in the treatment group and 834 in the control group, with 18.5% and 30.4% 12-year estimated probability of death, respectively. ACEi were associated with a lower risk of death (HR 0.39; 95% CI 0.17–0.92) and hospitalization for HF (HR 0.16; 95% CI 0.04–0.62). All other sensitivity analyses yielded similar results. Conclusion Prophylactic ACEi treatment in DMD was associated with a significantly higher overall survival and lower rates of hospitalization for HF.

Validation of transcranial direct current stimulation (tDCS) to treat obesity is hampered by evidence that participants can distinguish real from the traditional-control condition. Correctly guessing the real condition precludes knowing if it is neuromodulation or expectation that suppresses food craving and eating. Therefore, this study tested the putative efficacy of tDCS to the dorsolateral prefrontal cortex (DLPFC) to reduce food craving and eating when an alternative control condition was used that would be difficult to distinguish from the real condition. N = 28 adults with a 26–50 BMI range received a typical 20-min 2 mA current session of tDCS targeting the DLPFC as the real condition and a same duration/current tDCS session targeting the sensorimotor cortex (SMC), a region not expected to affect appetite, as the control. Food image craving ratings, in-lab food consumption, and momentary ratings of physical sensations were measured. DLPFC failed to reduce food craving and consumption compared to SMC stimulation. When interviewed, 71% of participants were unable to guess real from control conditions. Those who guessed DLPFC tDCS as real attributed their guess to increased number and frequency of sensations. However, their sensation ratings during tDCS did not differ between conditions. The results question if tDCS suppresses craving and eating at all, or if the DLPFC is the best target to do so. The results also indicate that alternate-site constant stimulation as the control method may strengthen the scientific evaluation of tDCS to treat obesity. Level I, experimental study.

Transcranial direct current stimulation (tDCS) is a neuromodulation technique with potential to treat eating disorders and obesity. As for any potential treatment, it is important to assess the degree to which expectation effects contribute to its reported efficacy. This study assessed the effect of tDCS on amount of food craving and eating while tightly controlling treatment expectation. N=74 adults with overweight or obesity were informed of the known effects of tDCS to suppress craving and eating. Once electrodes were on the head, half of the participants were told they were receiving real, and the other half sham tDCS. Within these groups, approximately half actually received real and the other half sham tDCS. Stimulation parameters used were those previously found to reduce craving and eating, including in our lab: 2mA, anode right/cathode left targeting the dorsolateral prefrontal cortex for 20 minutes (real), or only for the first and last minute (sham). Analyses controlled for demographics, hunger, trait impulsiveness, eating motives, dieting, binge eating, suggestibility, and baseline craving and eating. Participants told they were receiving real tDCS craved and ate less than participants told they were receiving sham tDCS (both p

Background: LAMA2-related muscular dystrophy (LAMA2-RD) encompasses a group of recessive muscular dystrophies caused by mutations in the LAMA2 gene, which codes for the alpha-2 chain of laminin-211 (merosin). Diagnosis is straightforward in the classic congenital presentation with no ambulation and complete merosin deficiency in muscle biopsy, but is far more difficult in milder ambulant individuals with partial merosin deficiency. Objective: To investigate the diagnostic utility of muscle imaging in LAMA2-RD using whole-body magnetic resonance imaging (WBMRI). Results: 27 patients (2–62 years, 21–80% with acquisition of walking ability and 6 never ambulant) were included in an international collaborative study. All carried two pathogenic mutations, mostly private missense changes. An intronic variant (c.909 + 7A > G) was identified in all the Chilean cases. Three patients (two ambulant) showed intellectual disability, epilepsy, and brain structural abnormalities. WBMRI T1w sequences or T2 fat-saturated images (Dixon) revealed abnormal muscle fat replacement predominantly in subscapularis, lumbar paraspinals, gluteus minimus and medius, posterior thigh (adductor magnus, biceps femoris, hamstrings) and soleus. This involvement pattern was consistent for both ambulant and non-ambulant patients. The degree of replacement was predominantly correlated to the disease duration, rather than to the onset or the clinical severity. A “COL6-like sandwich sign” was observed in several muscles in ambulant adults, but different involvement of subscapularis, gluteus minimus, and medius changes allowed distinguishing LAMA2-RD from collagenopathies. The thigh muscles seem to be the best ones to assess disease progression. Conclusion: WBMRI in LAMA2-RD shows a homogeneous pattern of brain and muscle imaging, representing a supportive diagnostic tool.

International audience; Extracellular matrix remodelling is associated with muscle force increase in overloaded mouse plantaris muscle Aims: Transforming growth factor-b (TGF-b) signalling is thought to contribute to the remodelling of extracellular matrix (ECM) of skeletal muscle and to functional decline in patients with muscular dystrophies. We wanted to determine the role of TGF-b-induced ECM remodelling in dystrophic muscle. Methods: We experimentally induced the pathological hallmarks of severe muscular dystrophy by mechanically overloading the plantaris muscle in mice. Furthermore, we determined the role of TGF-b signalling on dystrophic tissue modulation and on muscle function by (i) overloading myostatin knockout (Mstn À/À) mice and (ii) by additional pharmacological TGF-b inhibition via halofuginone. Results: Transcriptome analysis of overloaded muscles revealed upregulation predominantly of genes associated with ECM, inflammation and metalloproteinase activity. Histology revealed in wild-type mice signs of severe muscular dystrophy including myofibres with large variation in size and internalized myonuclei, as well as increased ECM deposition. At the same time, muscle weight had increased by 208% and muscle force by 234%. Myostatin deficiency blunted the effect of overload on muscle mass (59% increase) and force (76% increase), while having no effect on ECM deposition. Concomitant treatment with halofuginone blunted overload-induced muscle hypertro-phy and muscle force increase, while reducing ECM depo-sition and increasing myofibre size. Conclusions: ECM remodelling is associated with an increase in muscle mass and force in overload-modelled dystrophic muscle. Lack of myostatin is not advantageous and inhibition of ECM deposition by halofuginone is disadvantageous for muscle plasticity in response to stimuli that induce dystrophic muscle.

BACKGROUND Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic muscle disorder. Respiratory muscle function is classically affected in this disease. Ultrasound recently emerged as a non-invasive tool to assess diaphragm function. However, there are only a few studies using diaphragm ultrasound (US) in DMD. PURPOSE We aimed to assess diaphragm ultrasound patterns in DMD, their relationship with age and their association with home mechanical ventilation (HMV). METHODS We included DMD patients followed at Raymond Poincare Hospital who benefited from diaphragm ultrasound and pulmonary function tests. RESULTS There were 110 DMD patients and 17 male sex-matched healthy subjects included. In all, 94% of patients were permanent wheelchair users. Median body mass index (BMI) was 18 kg/m2. DMD patients disclosed a reduced forced vital capacity (VC) (12% of predicted value), and 78% of patients were on HMV. In patients, right and left diaphragmatic motions on deep inspiration were reduced and end expiratory diaphragm thickness was borderline normal. In patients, right and left diaphragmatic thickening fractions (TF) were reduced 12.7% and 15.5%, respectively. Age and end expiratory thickness were significantly inversely associated (p = 0.005 for the right diaphragm, p = 0.018 for the left diaphragm). Diaphragm TF was significantly inversely associated with age (p = 0.001 for the right side, p

International audience; Numerous approaches are being developed to promote post-natal muscle growth based on attenuating Myostatin/Activin signalling for clinical uses such as the treatment neuromuscular diseases, cancer cachexia and sarcopenia. However there have been concerns about the effects of inhibiting Activin on tissues other than skeletal muscle. We intraperitoneally injected mice with the Activin ligand trap, sActRIIB, in young, adult and a progeric mouse model. Treatment at any stage in the life of the mouse rapidly increased muscle mass. However at all stages of life the treatment decreased the weights of the testis. Not only were the testis smaller, but they contained fewer sperm compared to untreated mice. We found that the hypertrophic muscle phenotype was lost after the cessation of sActRIIB treatment but abnormal testis phenotype persisted. In summary, attenuation of Myostatin/Activin signalling inhibited testis development. Future use of molecules based on a similar mode of action to promote muscle growth should be carefully profiled for adverse side-effects on the testis. However the effectiveness of sActRIIB as a modulator of Activin function provides a possible therapeutic strategy to alleviate testicular seminoma development.

Respiratory muscles are classically involved in neuromuscular disorders, leading to a restrictive respiratory pattern. The diaphragm is the main respiratory muscle involved during inspiration. Ultrasound imaging is a noninvasive, radiation-free, accurate and safe technique allowing assessment of diaphragm anatomy and function. The authors review the pathophysiology of diaphragm in neuromuscular disorders, the methodology and indications of diaphragm ultrasound imaging as well as possible pitfalls in the interpretation of results.

ObjectiveTo characterize 2 unrelated patients with either asymmetric or unilateral muscle weakness at the clinical, genetic, histologic, and ultrastructural level.MethodsThe patients underwent thorough clinical examination, whole-body MRI, and exome sequencing. Muscle morphology was assessed by histology and electron microscopy.ResultsBoth patients presented with early-onset hypotonia, delayed motor milestones, scoliosis, and reduced pulmonary function. Patient P1 manifested unilateral muscle weakness exclusively affecting the left side of the body; the asymmetry was less pronounced in patient P2. Muscle biopsies from both patients showed nemaline rods as the main histopathologic hallmark, and MRI revealed major fatty infiltrations in selective head, proximal, and distal muscles, correlating with the degree of muscle weakness asymmetry. Exome sequencing on blood DNA from both patients identified de novo ACTA1 missense mutations in a small number of reads, suggesting mutation mosaicism. Subsequent Sanger sequencing confirmed the presence of the mutations on muscle DNA, while they were barely detectable on blood DNA.ConclusionsDe novo mutations can occur anytime during embryonic development and may result in a mosaic pattern of affected cells and tissues and lead to the development of an asymmetric clinical picture. The present study points out that mosaic mutations might not be easily detectable on leukocyte DNA and thereby escape routine genetic analysis, and possibly account for a significant number of molecularly undiagnosed patients.

The effect of constitutive inactivation of the gene encoding myostatin on the gain in muscle performance during postnatal growth hsa not been well characterized. Methods. We analyzed 2 murine myostatin knockout (KO) models: i) the Lee model (KOLee) and ii) the Grobet model (KOGrobet), and measured the contraction of tibialis anterior muscle in situ. Results. Absolute maximal isometric force was increased in 6-month old KOLee and KOGrobet mice, as compared to wild-type mice. Similarly, absolute maximal power was increased in 6-month old KOLee mice. In contrast, specific maximal force (relative maximal force per unit of muscle mass was decreased in all 6-month old male and female KO mice, except in 6-month old female KOGrobet mice, whereas specific maximal power was reduced only in male KOLee mice. Discussion. Genetic inactivation of myostatin increases maximal force and power, but in return it reduces muscle quality, particularly in male mice.

Objective To investigate the effect of transcranial direct current stimulation (tDCS) on food craving, intake, binge eating desire, and binge eating frequency in individuals with binge eating disorder (BED). Method N = 30 adults with BED or subthreshold BED received a 20-min 2 milliampere (mA) session of tDCS targeting the dorsolateral prefrontal cortex (DLPFC; anode right/cathode left) and a sham session. Food image ratings assessed food craving, a laboratory eating test assessed food intake, and an electronic diary recorded binge variables. Results tDCS versus sham decreased craving for sweets, savory proteins, and an all-foods category, with strongest reductions in men (p

Satellite cells are dysfunctional in several neuromuscular disorders. Some muscles are more susceptible than others to disease and ageing. In vitro and in vivo model systems have shed light on many of the processes involved. in satellite cell function and dysfunction, but the drawbacks of each model system must be considered. Skeletal muscle pathology in mouse models of neuromuscular disease are affected by genetic background. A single cell approach will be useful to identify dysfunction in subsets of cell populations.

SH3 and cysteine-rich domain-containing protein 3 (STAC3) is an essential component of the skeletal muscle excitation-contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, we report 18 patients carrying a homozygous p.(Trp284Ser) STAC3 variant in addition to a patient compound heterozygous for the p.(Trp284Ser) and a novel splice site change (c.997-1G > T). Clinical severity ranged from prenatal onset with severe features at birth, to a milder and slowly progressive congenital myopathy phenotype. A malignant hyperthermia (MH)-like reaction had occurred in several patients. The functional analysis demonstrated impaired ECC. In particular, KCl-induced membrane depolarization resulted in significantly reduced sarcoplasmic reticulum Ca2+ release. Co-immunoprecipitation of STAC3 with CaV 1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and CaV 1.1 was not significantly affected by the STAC3 variants. This study demonstrates that STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy, in particular if a history of MH-like episodes is reported. While the precise pathomechanism remains to be elucidated, our functional characterization of STAC3 variants revealed that defective ECC is not a result of CaV 1.1 sarcolemma mislocalization or impaired STAC3-CaV 1.1 interaction.

International audience; Antisense oligonucleotides (AONs) hold promise for therapeutic correction of many genetic diseases via exon skipping, and the first AON-based drugs have entered clinical trials for neuromuscular disorders. However, despite advances in AON chemistry and design, systemic use of AONs is limited because of poor tissue uptake, and recent clinical reports confirm that sufficient therapeutic efficacy has not yet been achieved. Here we present a new class of AONs made of tricyclo-DNA (tcDNA), which displays unique pharmacological properties and unprecedented uptake by many tissues after systemic administration. We demonstrate these properties in two mouse models of Duchenne muscular dystrophy (DMD), a neurogenetic disease typically caused by frame-shifting deletions or nonsense mutations in the gene encoding dystrophin and characterized by progressive muscle weakness, cardiomyopathy, respiratory failure and neurocognitive impairment. Although current naked AONs do not enter the heart or cross the blood-brain barrier to any substantial extent, we show that systemic delivery of tcDNA-AONs promotes a high degree of rescue of dystrophin expression in skeletal muscles, the heart and, to a lesser extent, the brain. Our results demonstrate for the first time a physiological improvement of cardio-respiratory functions and a correction of behavioral features in DMD model mice. This makes tcDNA-AON chemistry particularly attractive as a potential future therapy for patients with DMD and other neuromuscular disorders or with other diseases that are eligible for exon-skipping approaches requiring whole-body treatment.

Postnatal growth of skeletal muscle largely depends on the expansion and differentiation of resident stem cells, the so-called satellite cells. Here, we demonstrate that postnatal satellite cells express components of the bone morphogenetic protein (BMP) signaling machinery. Overexpression of noggin in postnatal mice (to antagonize BMP ligands), satellite cell-specific knockout of Alk3 (the gene encoding the BMP transmembrane receptor) or overexpression of inhibitory SMAD6 decreased satellite cell proliferation and accretion during myofiber growth, and ultimately retarded muscle growth. Moreover, reduced BMP signaling diminished the adult satellite cell pool. Abrogation of BMP signaling in satellite cell-derived primary myoblasts strongly diminished cell proliferation and upregulated the expression of cell cycle inhibitors p21 and p57. In conclusion, these results show that BMP signaling defines postnatal muscle development by regulating satellite cell-dependent myofiber growth and the generation of the adult muscle stem cell pool.

Many stroke survivors suffer from poststroke fatigue (PSF) and poststroke depression (PSD), indicating the importance of increasing the base of knowledge about the mechanisms underlying these sequelae. The primary aim of this study was to determine whether activation of the kynurenine (KYN) pathway predicts subsequent fatigue or depression in acute ischemic stroke (AIS) patients. Acute serum levels of 5-hydroxytryptamine (5-HT), tryptophan (TRP) catabolites (TRYCATs), and competing amino acids, as well as subsequent fatigue and depression, were measured in 45 stroke patients. TRP index [=100 x TRP / (tyrosine + valine + phenylalanine + leucine + isoleucine)] was significantly lower in patients with a Fatigue Severity Scale (FSS) score of a parts per thousand yen4 at 12 months than in those with an FSS score of < 4 (p = 0.039). Furthermore, the serum level of kynurenic acid in the acute stroke phase was significantly higher in patients with an FSS of score a parts per thousand yen4 at 18 months than in those with an FSS score of < 4 (p = 0.026). These findings indicate that stroke patients with PSF have a lower bioavailability of TRP for 5-HT synthesis in the brain in the acute stroke phase. However, they also appear to have greater neuroprotective potential in that phase. In contrast to PSF, no predictors of PSD were found. These findings together with those of previous studies suggest that the immune response and indoleamine 2,3-dioxygenase activation that follows AIS can predict PSF but not PSD.

Whether the inflammatory response that accompanies acute ischemic stroke induces the kynurenine pathway is currently a matter of conjecture. Activation of this pathway may disturb active metabolites. The aim of this study was thus to characterize the catabolism of tryptophan and tyrosine in acute ischemic stroke (AIS) patients, and its association with cytokines, C-reactive protein, and glucose. Serum levels of 5-hydroxytryptamine, tryptophan catabolites, and competing amino acids and significant ratios of these were measured in 45 AIS patients and compared to those of 40 control subjects. Furthermore, associations between the serum levels of these biomarkers and serum levels of cytokines, C-reactive protein, and glucose were determined. Significantly lower levels of tryptophan and tyrosine in the stroke group indicate increased tryptophan and tyrosine oxidation in acute ischemic stroke, while significantly lowered tryptophan index and tyrosine index indicate a reduced capacity for the synthesis of 5-hydroxytryptamine and catecholamines in the brain, respectively. Furthermore, our findings indicate that the proinflammatory response in acute ischemic stroke may be responsible for a reduced capacity for the biosynthesis of brain catecholamines and mediate neurotoxic effects. Meanwhile, the anti-inflammatory IL-10 may exert a neuroprotective effect and prevent the putative reduced capacity for 5-hydroxytryptamine synthesis in the brain. These mechanisms may be involved in several sequelae following stroke, such as cognitive impairment, depression, and fatigue.

International audience; The prolonged effect of myostatin deficiency on muscle performance in knockout mice has as yet been only poorly investigated. We have demonstrated that absolute maximal force is increased in 6-month old female and male knockout mice and 2-year old female knockout mice as compared to age- and sex-matched wildtype mice. Similarly, absolute maximal power is increased by myostatin deficiency in 6-month old female and male knockout mice but not in 2-year old female knockout mice. The increases we observed were greater in 6-month old female than in male knockout mice and can primarily result from muscle hypertrophy. In contrast, fatigue resistance was decreased in 6-month old knockout mice of both sexes as compared to age- and sex-matched wildtype mice. Moreover, in contrast to 2-year old female wildtype mice, aging in 2-year old knockout mice reduced absolute maximal force and power of both sexes as compared to their younger counterparts, although muscle weight did not change. These age- related decreases were lower in 2-year old female than in 2-year old male knockout mice. Together these results suggest that the beneficial effect of myostatin deficiency on absolute maximal force and power is greater in young (versus old) mice and female (versus male) mice. Most of these effects of myostatin deficiency are related neither to changes in the concentration of myofibrillar proteins nor to the slow to fast fiber type transition.

The interbranchial lymphoid tissue (ILT) of Atlantic salmon originates from an embryological location that in higher vertebrates gives rise to both primary and secondary lymphoid tissues. Still much is unknown about the morphological and functional development of the ILT. In the present work a standardized method of organ volume determination was established to study its development in relation to its containing gill and the thymus. Based on morphological findings and gene transcription data, the ILT shows no signs of primary lymphoid function. In contrast to the thymus, an ILT-complex first became discernible after the yolk-sac period. After its appearance, the ILT-complex constitutes 3-7% of the total volume of the gill (excluding the gill arch) with the newly described distal ILT constituting a major part, and in adult fish it is approximately 13 times larger than the thymus. Confined regions of T-cell proliferation are present within the ILT. Communication with systemic circulation through the distal ILT is also highly plausible thus offering both internal and external recruitment of immune cells in the growing ILT.

Myostatin regulates both muscle mass and muscle metabolism. The myostatin null (MSTN(-/-)) mouse has a hypermuscular phenotype owing to both hypertrophy and hyperplasia of the myofibres. The enlarged muscles display a reliance on glycolysis for energy production; however, enlarged muscles that develop in the absence of myostatin have compromised force-generating capacity. Recent evidence has suggested that endurance exercise training increases the oxidative properties of muscle. Here, we aimed to identify key changes in the muscle phenotype of MSTN(-/-) mice that can be induced by training. To this end, we subjected MSTN(-/-) mice to two different forms of training, namely voluntary wheel running and swimming, and compared the response at the morphological, myocellular and molecular levels. We found that both regimes normalized changes of myostatin deficiency and restored muscle function. We showed that both exercise training regimes increased muscle capillary density and the expression of Ucp3, Cpt1α, Pdk4 and Errγ, key markers for oxidative metabolism. Cross-sectional area of hypertrophic myofibres from MSTN(-/-) mice decreased towards wild-type values in response to exercise and, in this context, Bnip3, a key autophagy-related gene, was upregulated. This reduction in myofibre size caused an increase of the nuclear-to-cytoplasmic ratio towards wild-type values. Importantly, both training regimes increased muscle force in MSTN(-/-) mice. We conclude that impaired skeletal muscle function in myostatin-deficient mice can be improved through endurance exercise-mediated remodelling of muscle fibre size and metabolic profile.

Dans le cas de brulure a la face dorsale de la main, l’atteinte des tendons extenseurs est frequente, avec dans environ 20 % des cas apparition d’une deformation en boutonniere [1]. Dans cet article, nous relatons notre experience clinique quant a la prise en charge de ce type de deformation en maillet ou en boutonniere, en sachant qu’elle doit etre la plus precoce possible pour ameliorer le pronostic fonctionnel. Dans le cas d’atteinte des tendons extenseurs, nous proposons le port d’attelles statiques digitales en extension maintenues 24 heures/24 pendant six semaines. Apres ces six semaines, en fonction de l’evolution, l’immobilisation peut etre maintenue pendant trois mois au maximum. Avec le protocole que nous utilisons, nous avons pu observer la recuperation d’une extension active au niveau de l’articulation concernee, ce qui suggere la reconstitution possible d’un tissu de type neotendon.

There is increasing evidence that inflammation plays an important role in the progression of acute ischemic stroke (AIS). The primary aims of this study were to examine the serum levels of 13 cytokines, C-reactive protein (CRP), glucose, and hemoglobin in AIS patients, and their relationship to stroke lateralization, type, and infarct volume. Forty-five patients with AIS were evaluated. Blood samples were taken within 72 h, and volumetric analyses performed within 1–7 days after AIS onset. Cytokines were measured in serum from all patients and from 40 control subjects using Luminex Bio-Plex XMap technology. The levels of interleukin (IL)-1ra (p

Fatigue is a common but often overlooked symptom after stroke. This study investigated whether stroke type, infarct volume, and laterality, as well as the levels of various cytokines and other blood components in the acute phase of acute ischemic stroke (AIS), can predict the level of fatigue at 6, 12, and 18 months after its onset. In 45 patients with acute stroke, serum levels of C-reactive protein, hemoglobin, glucose, and 13 cytokines were measured within 72 h of stroke onset. The cytokine measurements were performed using BioPlex XMap technology (Luminex). The acute serum levels of interleukin (IL)-1β and glucose were positively correlated with the score on the Fatigue Severity Scale (FSS) at 6 months after the stroke (r = 0.37, p = 0.015, and r = 0.37, p = 0.017, respectively). The acute serum levels of IL-ra and IL-9 were negatively correlated with FSS score at 12 months after the stroke (r = −0.38, p = 0.013, and r = −0.36, p = 0.019, respectively). The FSS score at 12 months after stroke was significantly lower in patients with radiologically confirmed infarction than in those without such confirmation (p = 0.048). The FSS score at 18 months was not correlated with any of the measured variables. High acute serum levels of glucose and IL-1β, and low IL1-ra and IL-9 may predict fatigue after AIS, indicating that the development of poststroke fatigue can be accounted for by the proinflammatory response associated with AIS. These novel findings support a new cytokine theory of fatigue after stroke. However, more research is needed to validate the results of this study.

Myostatin-deficient mice (MSTN (-/-)) display excessive muscle mass and this is associated with a profound loss of oxidative metabolic properties. In this study we analysed the effect of two endurance-based exercise regimes, either a forced high-impact swim training or moderate intensity voluntary wheel running on the adaptive properties of the tibialis anterior and plantaris muscle from MSTN (-/-) mice. MSTN (-/-) and wild type (MSTN (+/+)) animals had comparable performances in the wheel running regime in terms of distance, average speed and time, but MSTN (-/-) mice showed a reduced ability to sustain a high-impact activity via swimming. Swim training elicited muscle specific adaptations on fibre type distribution in MSTN (-/-); the tibialis anterior displaying a partial transformation in contrast to the plantaris which showed no change. Conversely, wheel running induced similar changes in fibre type composition of both muscles, favouring transitions from IIB-to-IIA. Succinate dehydrogenase activity, an indicator of mitochondrial oxidative potential was increased in response to either exercise regime, with wheel running eliciting more robust changes in the MSTN (-/-) muscles. Examination of the cross sectional area of individual fibre types showed genotype-specific responses with MSTN (-/-) mice exhibiting an incapability of fibre enlargement following the wheel running regime, as opposed to MSTN (+/+) mice and a greater susceptibility to muscle fibre area loss following swimming. In conclusion, the muscle fibre hypertrophy, oxidative capacity and glycolytic phenotype of myostatin deficient muscle can be altered with endurance exercise regimes.

Myostatin, a member of the TGF-β family, has been identified as a powerful inhibitor of muscle growth. Absence or blockade of myostatin induces massive skeletal muscle hypertrophy that is widely attributed to proliferation of the population of muscle fiber-associated satellite cells that have been identified as the principle source of new muscle tissue during growth and regeneration. Postnatal blockade of myostatin has been proposed as a basis for therapeutic strategies to combat muscle loss in genetic and acquired myopathies. But this approach, according to the accepted mechanism, would raise the threat of premature exhaustion of the pool of satellite cells and eventual failure of muscle regeneration. Here, we show that hypertrophy in the absence of myostatin involves little or no input from satellite cells. Hypertrophic fibers contain no more myonuclei or satellite cells and myostatin had no significant effect on satellite cell proliferation in vitro, while expression of myostatin receptors dropped to the limits of detectability in postnatal satellite cells. Moreover, hypertrophy of dystrophic muscle arising from myostatin blockade was achieved without any apparent enhancement of contribution of myonuclei from satellite cells. These findings contradict the accepted model of myostatin-based control of size of postnatal muscle and reorient fundamental investigations away from the mechanisms that control satellite cell proliferation and toward those that increase myonuclear domain, by modulating synthesis and turnover of structural muscle fiber proteins. It predicts too that any benefits of myostatin blockade in chronic myopathies are unlikely to impose any extra stress on the satellite cells.

When the international community declared a famine in Malawi in January of 2006, emergency food aid reached only populations with pre-existing health care services. To treat the widespread childhood malnutrition in Machinga district, a rural area lacking health care facilities, in February 2006 five outpatient therapeutic programs were implemented that utilized home-based therapy and ready-to-use therapeutic food. Children with severe malnutrition, defined as the presence of edema and/or a weight-for-height less than 70% of the reference standard, were enrolled in the program. Two senior clinical nurses trained village health aides in each of the five communities. Children visited the health aides biweekly. During the visits, health aides collected demographic and anthropometric information and distributed a 2-week supply of ready-to-use therapeutic food, providing 175 kcal/kg/d. Treatment continued for 8 weeks; children were discharged before 8 weeks if they reached a weight-for-height more than 100% of the reference standard, or required admission to the hospital due to systemic infection or recurrence of edema. Of the 826 children enrolled, 775 (93.7%) recovered, 13 (1.8%) remained malnourished, 30 (3.6%) defaulted, and 8 (0.9%) died. Mean weight gained was 2.7±3.7 g/kg/d, height gained 0.3±0.9 mm/d, and mid-upper arm circumference gained 0.2±0.3 mm/d. Home-based therapy with ready-to-use therapeutic food administered by village health aides is an effective approach to treating malnutrition during food crises in areas lacking health services.

Background The utility of open lung biopsy (OLB) in mechanically ventilated patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) of unknown origin has been questioned because of its potentially low diagnostic yield and possibly related morbidity. To quantify possible benefits and risks, and especially so for bedside lung biopsy, we reviewed retrospectively our 8-year, single unit experience with this procedure. Methods Mechanically ventilated, critically ill patients with acute respiratory failure of unknown origin who underwent OLB were analyzed in a retrospective, single-center, cohort study in a medical intensive care unit in a university medical center. Measurements and Main Results Twenty-seven patients were analyzed (15 female, 12 male, of mean 48 years [standard deviation, 14]), 67% of whom were immunocompromised. All patients underwent bronchoscopy and bronchoalveolar lavage before OLB. Pa o 2 /Fraction of inspired oxygen at the time of biopsy was 188 ± 109 mm Hg. Biopsies were performed in the operating room on 9 patients and at bedside on 18. A specific diagnosis was obtained in 70% of biopsies. Biopsy results led to alteration in treatment in 81% of patients. Minor complications occurred in 52% of patients and major complications in 7%. The rate of complications did not appear to differ with the location of the procedure (bedside vs operating room). No deaths were attributed to the procedure. Conclusions Bedside OLB can be performed safely in selected, mechanically ventilated, critically ill patients with ALI or ARDS. Our results support the concept that lung biopsy often leads to management alterations in patients where a standardized diagnostic workup failed to yield a definitive diagnosis.

Because it leads to a rapid and massive muscle hypertrophy, postnatal blockade of the activin type IIB receptor (ActRIIB) is a promising therapeutic strategy for counteracting muscle wasting. However, the functional consequences remain very poorly documented in vivo. Here, we have investigated the impact of 8-wk ActRIIB blockade with soluble receptor (sActRIIB-Fc) on gastrocnemius muscle anatomy, energy metabolism, and force-generating capacity in wild-type mice, using totally noninvasive magnetic resonance imaging (MRI) and dynamic31P-MRS. Compared with vehicle (PBS) control, sActRIIB-Fc treatment resulted in a dramatic increase in body weight (+29%) and muscle volume (+58%) calculated from hindlimb MR imaging, but did not alter fiber type distribution determined via myosin heavy chain isoform analysis. In resting muscle, sActRIIB-Fc treatment induced acidosis and PCr depletion, thereby suggesting reduced tissue oxygenation. During an in vivo fatiguing exercise (6-min repeated maximal isometric contraction electrically induced at 1.7 Hz), maximal and total absolute forces were larger in sActRIIB-Fc treated animals (+26 and +12%, respectively), whereas specific force and fatigue resistance were lower (−30 and −37%, respectively). Treatment with sActRIIB-Fc further decreased the maximal rate of oxidative ATP synthesis (−42%) and the oxidative capacity (−34%), but did not alter the bioenergetics status in contracting muscle. Our findings demonstrate in vivo that sActRIIB-Fc treatment increases absolute force-generating capacity and reduces mitochondrial function in glycolytic gastrocnemius muscle, but this reduction does not compromise energy status during sustained activity. Overall, these data support the clinical interest of postnatal ActRIIB blockade.

Acetylcholine (ACh) enhances the preferred direction responses of directionally selective ganglion cells (DS GCs; Ariel & Daw, 1982; Ariel & Adolph, 1985) through the activation of nicotinic acetylcholine receptors (nAChRs; Ariel & Daw, 1982; Massey et al., 1997; Kittila & Massey, 1997). DS GCs appear to express at least two types of nAChRs, those that are sensitive to the partially subtype-specific antagonist methyllycaconitine (MLA), and those that are MLA-insensitive (Reed et al., 2002). Our purpose was to confirm the expression of α7 nAChRs by DS GCs and to assess the contributions of other nAChR subtypes to DS GC responses. Using choline as a nAChR partially subtype-specific agonist, we found that the majority of DS GCs demonstrated responses to choline while under synaptic blockade. The blockade or reduction of choline-induced responses by bath application of nanomolar (nM) concentrations of MLA provided direct evidence that the choline responses were mediated by α7 nAChRs. Because choline is a partial agonist for α3β4 nAChRs (Alkondon et al., 1997), the residual choline responses are consistent with mediation by α3β4 nAChRs. Additionally, a subset of DS GCs responded to nicotine but not to choline, indicating the expression of a third nAChR subtype. The pharmacological results were supported by single cell reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry experiments. The expression of α7 and specific non-α7 nAChR subtypes was correlated with the preferred direction. This indicates the possibility of differential responses to ACh depending on the direction of movement. This is the first description of differential expression of multiple nAChR subtypes by DS GCs.

Strychnine is considered a selective competitive antagonist of glycine gated Cl- channels (Saitoh et al., 1994) and studies have used strychnine at low micromolar concentrations to study the role of glycine in rabbit retina (Linn, 1998; Protti et al., 2005). However, other studies have shown that strychnine, in the concentrations commonly used, is also a potent competitive antagonist of alpha7 nicotinic acetylcholine receptors (nAChRs; Matsubayashi et al., 1998). We tested the effects of low micromolar concentrations of strychnine and 3-[2'-phosphonomethyl[1,1'-biphenyl]-3-yl] alanine (PMBA), a specific glycine receptor blocker (Saitoh et al., 1994; Hosie et al., 1999) on the activation of both alpha7 nAChRs on retinal ganglion cells and on ganglion cell responses to a light flash. Extracellular recordings were obtained from ganglion cells in an isolated retina/choroid preparation and 500 microM choline was used as an alpha7 agonist (Alkondon et al., 1997). We recorded from brisk sustained and brisk transient OFF cells, many of which have been previously shown to have alpha7 receptors (Strang et al., 2005). Further, we tested the effect of strychnine, PMBA and alpha-bungarotoxin on the binding of tetramethylrhodamine alpha-bungarotoxin in the inner plexiform layer. Our data indicates that strychnine, at doses as low as 1.0 microM, can inhibit the alpha7 nAChR-mediated response to choline, but PMBA at concentrations as high as 0.4 microM does not. Binding studies show strychnine and alpha-bungarotoxin inhibit binding of labeled alpha-bungarotoxin in the IPL. Thus, the effects of strychnine application may be to inhibit glycine receptors expressed by ganglion cell or to inhibit amacrine cell alpha7 nAChRs, both of which would result in an increase in the ganglion cell responses. Further research will be required to disentangle the effects of strychnine previously believed to be caused by a single mechanism of glycine receptor inhibition.

History A 56-year-old man complain of chronic cough for 6 months without further clinical problems. The patient was otherwise in good health and showed only a moderate bronchial sound at the left ventral paracordial region. Investigations Thorax X-ray revealed an infiltrate in the lingula with segmental borders. The CT scan showed air bronchogramms and bilateral more small infiltrates. DIAGNOSIS, TREATMENT, CLINICAL COURSE: Bronchoscopic transbronchial biopsies revealed a BALT-lymphoma. A seven years old chest X-ray showed the lingual infiltrate in nearly the same extension as the current X-ray. Because of the disseminated manifestation, the slow course and the good performance status we did not start a palliative chemotherapy so far. Conclusion Any pulmonary infiltrate which looks like pneumonia must be given a definite diagnosis if there are no clinical signs of infection.

Radiation-induced pneumonitis is a familiar complication of breast cancer radiotherapy, whereas bronchiolitis obliterans with organizing pneumonia occurs extremely rarely after this treatment. Consequently, testing for BOOP is rarely included in differential diagnosis. This results in delayed diagnosis, so that treatment is ultimately commenced too late. The infiltrations are often located in the unirradiated lung, impeding diagnosis. The radiotherapy-induced BOOP-reaction that can also occur after typical radiation pneumonitis is illustrated by reference to a characteristic case report.

Objective To review the evidence on the effects of disinfection of environmental surfaces in hospitals (as compared with cleaning without use of disinfectants) on the occurrence of nosocomial infections. Methods Systematic review of experimental and nonexperimental intervention studies dealing with environmental disinfection or cleaning in different health care settings. Results A total of 236 scientific articles were identified. None described a meta-analysis, systematic review, or randomized controlled trial. Only 4 articles described completed cohort studies matching the inclusion criteria. None of these studies showed lower infection rates associated with routine disinfection of surfaces (mainly floors) versus cleaning with detergent only. Conclusions Disinfectants may pose a danger to staff, patients, and the environment and require special safety precautions. However, targeted disinfection of certain environmental surfaces is in certain instances an established component of hospital infection control. Given the complex, multifactorial nature of nosocomial infections, well-designed studies that systematically investigate the role of surface disinfection are required.

Myostatin is a potent inhibitor of muscle growth. Genetic deletion of Myostatin leads to massive hyperplasia and hypertrophy of skeletal muscle. However, the overall muscle pattern is preserved. We show that, during chick embryonic development, Myostatin is expressed at stages and positions unlikely to influence qualitative muscle development. In the somites, Myostatin is predominantly expressed in a central domain of the dermomyotome but not at the dorsomedial and ventrolateral lips, where most cells for myotomal elongation are recruited. During limb bud development, Myostatin is transiently expressed at early stages in both myogenic and nonmyogenic regions. Myostatin is reexpressed during limb bud development at a time when splitting of muscle is underway. Heterotopically developed wing buds that fail to form muscle still express Myostatin. This demonstrates that, in the limb, not all Myostatin-expressing cells are of myogenic origin. Ectoderm and Sonic hedgehog have different effects on the expression of Myostatin dependent on stages at which the operation was performed and the length of the postoperative period. Finally, we show that application of Myostatin protein into the developing limb bud results in a down-regulation of Pax-3 and Myf-5, both genes associated with proliferation of myogenic cells; and, furthermore, Myostatin also prevents the expression of MyoD, a gene associated with muscle differentiation. The long-term effect of Myostatin treatment leads to a deficiency of limb muscle. Therefore, Myostatin negatively affects gene expression of transcription factors, which are necessary for establishing myogenic cell identity.

The responses of many ganglion cells in the rabbit retina are mediated, at least in part, by acetylcholine (ACh) acting on neuronal nicotinic acetylcholine receptors (nAChRs). nAChRs are comprised of α and β subunits; three β subunits and nine α subunits of nAChRs have been identified and these subunits can combine to form a large number of functionally distinct nAChR subtypes. We examined the effects of cholinergic agents on the light-evoked responses of ganglion cells to determine which nAChR subtypes mediate the effects of ACh. Extracellular recordings of retinal ganglion cells were made in intact everted eyecup preparations and nicotinic agonists and antagonists were added to the superfusate. While several ganglion cell classes exhibited methyllycaconitine (MLA) sensitivity, the directionally selective (DS) ganglion cells were most sensitive; exposure to 30 nanomolar MLA, a concentration reportedly too low to affect αBgt-insensitive nAChRs, suppressed the stimulus-evoked responses of DS cells without eliminating directional selectivity. Epibatidine, which at low concentrations is an agonist selective for αBgt-insensitive nAChRs, stimulated firing of various cell types including DS ganglion cells at low nanomolar concentrations. The effects of the various agents tested persisted under cobalt-induced synaptic blockade. The low nanomolar MLA and epibatidine sensitivity of DS cells suggests that DS ganglion cells express both αBgt-sensitive and αBgt-insensitive nAChRs. Other ganglion cell types appear to express only αBgt-sensitive nAChRs but not αBgt-insensitive nAChRs.

Bone morphogenetic proteins (BMPs) can either promote growth of embryonic muscle by expanding the Pax-3-expressing muscle precursor population or restrict its development by inducing apoptosis. Follistatin, a proposed BMP antagonist, is expressed in embryonic muscle. Deficiency in Follistatin results in muscle defects and postnatal asphyxia. Here, we report that during chick limb development Follistatin enhances BMP-7 action to induce muscle growth but prevents the ability of BMP-7 to induce apoptosis and muscle loss. Follistatin, unlike another BMP-binding protein, Noggin, promotes Pax-3 expression and transiently delays muscle differentiation and thus exerts proliferative signalling during muscle development. We provide data which show that Follistatin binds BMP-7 and BMP-2 at low affinities and that the binding is reversible. These data suggest that Follistatin acts to present BMPs to myogenic cells at a concentration that permits stimulation of embryonic muscle growth.

Myostatin (Mstn) participates in the regulation of skeletal muscle size and has emerged as a regulator of muscle metabolism. Here, we hypothesized that lack of myostatin profoundly depresses oxidative phosphorylation-dependent muscle function. Toward this end, we explored Mstn −/− mice as a model for the constitutive absence of myostatin and AAV-mediated overexpression of myostatin propeptide as a model of myostatin blockade in adult wild-type mice. We show that muscles from Mstn −/− mice, although larger and stronger, fatigue extremely rapidly. Myostatin deficiency shifts muscle from aerobic toward anaerobic energy metabolism, as evidenced by decreased mitochondrial respiration, reduced expression of PPAR transcriptional regulators, increased enolase activity, and exercise-induced lactic acidosis. As a consequence, constitutively reduced myostatin signaling diminishes exercise capacity, while the hypermuscular state of Mstn−/− mice increases oxygen consumption and the energy cost of running. We wondered whether these results are the mere consequence of the congenital fiber-type switch toward a glycolytic phenotype of constitutive Mstn −/− mice. Hence, we overexpressed myostatin propeptide in adult mice, which did not affect fiber-type distribution, while nonetheless causing increased muscle fatigability, diminished exercise capacity, and decreased Pparb/d and Pgc1a expression. In conclusion, our results suggest that myostatin endows skeletal muscle with high oxidative capacity and low fatigability, thus regulating the delicate balance between muscle mass, muscle force, energy metabolism, and endurance capacity.

Background Hashimoto's encephalopathy, also called steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), is a rare syndrome with an unknown pathogenesis. Clinical onset is insidious or acute with variable neurological symptoms. Spinal protein is elevated in most cases, but findings are non-specific in routine blood tests and on cerebral CT and EEG. The most important diagnostic clue is elevated levels of thyroid antibodies, especially anti-thyroid peroxidase antibody (anti-TPO). Administration of corticosteroids is the treatment of choice and usually results in complete recovery. Case report A 66-year-old woman had experienced episodic neurological symptoms over a few weeks. On admission she demonstrated moderate aphasia, tremor and myoclonus, but no other focal neurological signs. A cerebral CT scan and routine blood tests did not provide diagnostic clues. The cerebrospinal fluid protein level was markedly elevated, and treatment with antibiotic and antiviral agents against possible encephalitis was started. However, the clinical condition did not improve. Further testing showed elevated levels of anti thyroxine peroxidase (aTPO) antibodies. Based on this finding, and after exclusion of other causes, the patient was diagnosed with Hashimoto's encephalitis. On treatment with systemic steroids, the clinical condition improved over a few days. Conclusion Hashimoto's encephalitis is a rare syndrome. Still, it is important to diagnose patients correctly. Treatment with steroids induces marked clinical improvement and usually confers a good prognosis.

Background: Intestinal bleeding of unknown origin can lead to a difficult workup. Abdominal colic, melena/hematemesis, and jaundice represent the pathognomonic triad for hemobilia, but clinical presentation and etiology of this entity are varying. Seldom all of these symptoms are present, and rarely does hemobilia cause melena or hematemesis. Often the correct diagnosis is missed. Patients frequently have a long history of complaints and inadequate therapy. Case Report: We report on a patient who complained of repeated, severe epigastric pain and massive melena induced by exercise activity. After 2 years of complaints and an unnecessary operation, ultrasound detected a liver hemangioma. It was supposed that the hemangioma was causing hemobilia during strenuous physical activity. The patient underwent a partial liver resection to eliminate the hemangioma. All complaints resolved, and the patient remained asymptomatic postoperatively. Conclusions: Physicians should be aware of hemobilia as a rare cause of upper gastrointestinal bleeding, especially if esophagogastroduodenoscopy cannot demonstrate any bleeding source. Ultrasound is able to visualize many diseases leading to hemobilia and should be integrated into the early workup of unclear intestinal bleedings.

This one day workshop was organized by Helge Amthor and Thomas Voit and brought together 17 researchers from 4 different countries (Germany, France, UK, USA) with complimentary backgrounds and a particular expertise associated with myostatin. The aim of this workshop was to evaluate the prospective therapies based on myostatin blockade and to strengthen the collaboration between these different laboratories. Such a collective effort seemed particularly timely since many laboratories developed an increasing number of different strategies for myostatin blockade as well as an increasing number of different animal models. Some groups are using a recombinant protein to block the circulating myostatin, some viral gene delivery, while others are using nonviral gene delivery based strategies (for review see [1]). Most of the studies on the effect of myostatin blockade focused on wild type mice and on dystrophic mdx mice, however, a number of other mouse models for neuromuscular disorders have been explored. Several studies have used other species such as rats [2] and also dogs [3]. In addition, a number of different application routes were used and different outcome measures studied, therefore, comparison of data from different laboratories remains difficult. Helge Amthor pointed out that myostatin is highly conserved across species and is functional in healthy individuals. Thus, the hypothesis that deleting or blocking myostatin is beneficial for skeletal muscle can be misleading and may result in a negligence to explore its proper physiological function in skeletal muscle, such as the way it modifies the oxidative metabolism. He reminded us to be cautious about a possible experimentation and publication bias resulting from such hypothesis and the loss of scientific independence due to industrial partnership.

Pulmonary drug reactions are a relative common factor causing interstitial pulmonary diseases. The correct diagnosis is important since a causal therapy is possible by stopping the administration. A stringent correlation between dose/time of administration and the type of the reaction exists for only a few drugs. Possible hints for an increased risk to develop a drug reaction are known reactions to that specific drug, the patient's history, the type of the underlying disease, genetic poly-morphisms, occupational factors and interactions with other drugs. Still however, the tracing of a certain drug as cause of a pulmonary reaction can be difficult in the individual case and may require great efforts rarely even a biopsy. The pathologist then has to describe the patterns of reactions, exclude other causes and correlate his findings with the clinical data. In most cases however the diagnosis of a drug reaction will be by exclusion. A list of typical drug reactions is included.

Pulmonary fibroses are terminal stages of exposure to a whole series of very diverse noxae. Both occupational and nonoccupational causes must be distinguished. Finally, there is the large collective category "idiopathic" fibroses. In terms of their systematics, fibroses can be classified in five largegroups. The classification criteria are etiological when the causes are known, and morphological-descriptive in cases of idiopathic fibrosis. Occupational and "idiopathic" fibroses often cannot be distinguished in biopsy material because of their great histomorphological similarity. In such circumstances, the result of further analyses is crucial. For this reason, the possibility that an occupational pulmonary fibrosis is present must also be considered even in "idiopathic" pulmonary fibroses in order to arrange for further analyses such as BAL, ashing and energy-dispersive X-ray analysis to be performed.

Following a notice in the journal Deutsches Arzteblatt from July 2007 on the case of a 61 -year-old woman, who suffered fatal respiratory failure following intake of nitrofurantoin we report a case from the Zusamklinik. A 73-year-old woman had been suffering from coughing and dyspnea for six months. Due to a chronic infection of the bladder she had taken 100 mg of nitrofurantoin daily for one year. Fine endinspiratory crackles on both sides of her lungs could be heard, the lung function showed a restrictive lung disorder and a serious respiratory insufficiency. Transaminases and ANA were increased. On the conventional chest X-ray and the CT-thorax infiltrates on both sides and also small pleural effusions appeared. In a transbronchial lung biopsy a BOOP-reaction was histologically confirmed, the BAL showed 37% lymphocytes. Under treatment with steroids the patient's condition, the respiratory insufficiency, the X-ray findings and the transaminases improved. After administration of steroids for ten months, a complete reconstitution was achieved. Twelve months later, even without steroids, no symptoms occurred. Because of the history and the other findings a hypersensitive pneumonitis in combination with a drug-induced hepatitis is the most likely diagnosis, a drug-induced lupus erythematosus, however, is also possible.

Embryonic muscle growth requires a fine balance between proliferation and differentiation. In this study we have investigated how this balance is achieved during chick development. Removal of ectoderm from trunk somites results in the down-regulation of Pax-3 expression and cell division of myogenic precursors is halted. This initially leads to an up-regulation of MyoD expression and to a burst in terminal differentiation but further muscle growth is arrested. Locally applied bone morphogenetic protein-4 (BMP-4) to somites mimics the effect of the ectoderm and stimulates Pax-3 expression which eventually results in excessive muscle growth in somites. Surprisingly, BMP-4 upregulates expression of noggin which encodes a BMP-4 antagonist. This suggests that the proliferation enhancing activity of BMP-4 can be limited via up-regulation of noggin and that myogenic cells differentiate, as an intrinsic property, when deprived of BMP-4 influence. In contrast to BMP-4, Sonic hedgehog (Shh) locally applied to somites arrests muscle growth by down-regulation of Pax-3 and immediate up-regulation of MyoD expression. Such premature muscle differentiation in somites at tongue and limb levels prevents myogenic migration and thus tongue and limb muscle are not formed. Therefore, precise limitation of differentiation, executed by proliferative and Pax-3 promoting signals, is indispensable for continuous embryonic muscle growth.