STW5 (Iberogast®) for constipation in Parkinson's disease.

BACKGROUND: Chronic constipation is one of the most frequent non-motor symptoms in Parkinson's disease (PD), and impairs patients' quality of life. OBJECTIVE: The aim of this pilot study was to assess the efficacy and the tolerability of STW5, a phytotherapeutic agent composed of nine plant extracts, for the treatment of constipation in patients with PD. METHODS: We carried out an open monocentric study of STW5 in the treatment of constipation in parkinsonian patients. Forty-four PD patients with a mean age of 66.4±7.3 years (range, 35-78), a mean disease duration of 12.6±5.4 years (range, 3-27) and with constipation defined by Rome III criteria for functional constipation were included. Following a two-week laxative-free baseline period, all the patients were treated with 20 drops STW5 t.i.d for 28 days, after a seven-day titration period. Treatment efficacy was defined as marked improvement of stool frequency with an increase of three exonerations during the last week of treatment when compared to the week before the initiation of treatment. Responder rate for stool frequency was estimated at 29/45 patients. RESULTS: An increase of stool frequency≥three eliminations/week was observed in only four out of 44 patients (9.0%) at the end of the study. The only significant difference observed before and after treatment was a decrease in stool consistency (P=0.0272). CONCLUSIONS: Our results suggest that STW5 has a safety profile but is not effective as a phytotherapeutic agent in constipation related to Parkinson's disease.

Pathophysiology of Parkinson's disease: Mitochondria, alpha-synuclein and much more .

Parkinson's disease (PD) is a complex, age-related, neurodegenerative disease whose pathogenesis remains incompletely understood. Here, we give an overview of the progress that has been made over the past four decades in our understanding of this disorder. We review the role of mitochondria, environmental toxicants, alpha-synuclein and neuroinflammation in the development of PD. We also discuss more recent data from genetics, which strongly support the endosomal-lysosomal pathways and mitophagy as being central to PD. Finally, we discuss the emerging role of the gut-brain axis as a modulator of PD progression. This article is intended to provide a comprehensive, general and practical review of PD pathogenesis for the general neurologist.

Parkinson disease: the enteric nervous system spills its guts.

Lewy pathology in Parkinson disease (PD) extends well beyond the CNS, also affecting peripheral autonomic neuronal circuits, especially the enteric nervous system (ENS). The ENS is an integrative neuronal network also referred to as "the brain in the gut" because of its similarities to the CNS. We have recently shown that the ENS can be readily analyzed using routine colonic biopsies. This led us to propose that the ENS could represent a unique window to assess the neuropathology in living patients with PD. In this perspective, we discuss current evidence which indicates that the presence of ENS pathology may by exploited to improve our understanding and management of PD and likely other neurodegenerative disorders.

[Treatment of spontaneous intracranial hypotension by epidural saline infusion]. / Traitement de l'hypotension spontanée du liquide cérébrospinal par perfusion épidurale de sérum salé isotonique.

INTRODUCTION: Spontaneous intracranial hypotension (SIH) is an uncommon cause of secondary headache due to a cerebrospinal fluid (CSF) hypotension. Lumbar epidural blood-patch (LEBP) is the most effective treatment and can be repeated in case of relapse. There is no standard therapeutic strategy for patients free of dural tears who fail to respond to several consecutive blood-patches. We report two cases of SIH successfully treated by an epidural saline infusion after two consecutive LEBP. CASE REPORTS: A 35-year-old woman was admitted to hospital for severe orthostatic headache. The diagnosis of SIH was retained. Two LEBP were performed but with no clinical benefit. Headache disappeared totally after an epidural saline infusion. A second woman, aged 75 years, was admitted for chronic orthostatic headaches. The CSF pressure was low. Search for a dural tear was negative. After two unsuccessful LEBPs, the patient was treated with an epidural saline infusion. Her headache resolved completely and definitely. DISCUSSION: It is common procedure to search for a dural tear when patients fail to respond to several consecutive LEPB. Surgical repair is however exceptional. An epidural saline infusion might be an efficient therapeutic alternative despite the small number of cases reported in the literature.

[Use of generic anti-epilepsy drugs in France: survey of neurologists and review of the literature]. / Utilisation des médicaments génériques des anti-épileptiques en France: résultats d'une enquête auprès des neurologues et revue de la littérature.

INTRODUCTION: The use of generic substitution for antiepileptic drugs is more and more frequent but remains controversial. PURPOSE AND METHODS: This survey aimed to assess physicians' feelings towards effectiveness, tolerability and clinical impact of generic substitution of antiepileptic drugs on their patients. A questionnaire was sent to all French private neurologists and hospital specialists in epilepsy. Their responses were recorded from December 2005 to March 2006. RESULTS: A total of 312 neurologists responded. A few prescribed generic antiepileptic drugs; but a few as well indicated not to switch their prescription. Most of them felt discomfort by generic substitution. One third reported breakthrough seizures or new adverse events after generic substitution and 70p.cent extra phone consultation. DISCUSSION: Neurologists' reluctance with prescribing generic AEDs may be explained by several different facts: no controlled study about the safety and efficacy of generic AEDs as compared with brand name drugs, substitutions by pharmacists without their agreement, lack of medical information about generic AEDs, symbolic dimension of the treatment, and, most of all, the fear of breakthrough seizures in patients good controlled. CONCLUSION: A prospective controlled evaluation of the safety and efficacy of generic substitution in epilepsy needs to be performed.

Expression of the Na(+)/Ca(2+) exchanger in skeletal muscle.

The expression of the Na(+)/Ca(2+) exchanger was studied in differentiating muscle fibers in rats. NCX1 and NCX3 isoform (Na(+)/Ca(2+) exchanger isoform) expression was found to be developmentally regulated. NCX1 mRNA and protein levels peaked shortly after birth. Conversely, NCX3 isoform expression was very low in muscles of newborn rats but increased dramatically during the first 2 wk of postnatal life. Immunocytochemical analysis showed that NCX1 was uniformly distributed along the sarcolemmal membrane of undifferentiated rat muscle fibers but formed clusters in T-tubular membranes and sarcolemma of adult muscle. NCX3 appeared to be more uniformly distributed along the sarcolemma and inside myoplasm. In the adult, NCX1 was predominantly expressed in oxidative (type 1 and 2A) fibers of both slow- and fast-twitch muscles, whereas NCX3 was highly expressed in fast glycolytic (2B) fibers. NCX2 was expressed in rat brain but not in skeletal muscle. Developmental changes in NCX1 and NCX3 as well as the distribution of these isoforms at the cellular level and in different fiber types suggest that they may have different physiological roles.

Staging of the commitment of murine cardiac cell progenitors.

The staging of murine cardiomyocyte specification and determination was investigated in cultures of tissue explants from pre- and postgastrulated embryos and after transplantation of cardiac or cardiogenic tissues from mouse embryos into 2-day-old chick embryos in different locations. The development of transplanted and cultured cells in cardiomyocytes was evaluated by testing the expression of several cardiac transcription factor genes (Nkx 2.5, eHAND, dHAND, GATA-4), alpha-cardiac actin mRNA, and beta-myosin heavy chain protein. In vitro analyses showed that cells with the potential to form cardiac muscle were present prior to gastrulation in 6.5-day postconception (dpc) epiblasts, as indicated by the expression of Nkx 2.5, eHAND, dHAND, and GATA-4 cardiac transcription factors; desmin transgene; alpha-cardiac actin; and beta-myosin heavy chain. Conversely, epiblasts transplanted into the chicken somitic environment did not exhibit full cardiogenic cell differentiation. It was determined that chick host axial structures did not influence cardiogenesis in transplants. Mesoderm from late streak explants was capable of differentiating into the cardiac phenotype in the avian heterotopic environment, indicating that the specification of cardiac precursors (under way by 6.5 dpc) became irreversible at around the late streak stage in mouse embryo. Although in vitro analyses showed that interaction with endoderm is not required for the specification of murine cardiac cells, the presence of endoderm in explant cultures between mid- and late streak stages stimulated emerging mesodermal cells to adopt a myocardial pathway, whereas ectoderm had no influence on cardiomyogenesis.

Macrophages enhance muscle satellite cell proliferation and delay their differentiation.

This study investigated the effect of macrophages on in vitro satellite cell myogenesis in the turkey and mouse. Macrophages are considered to act as scavengers of tissue debris during the muscle degeneration-regeneration process. The number of dividing cells and of myoblasts expressing the myogenic regulatory factor MyoD indicated that macrophages enhanced satellite cell proliferation in both species. This was confirmed by observations with cultures treated for bromodeoxyuridine (BrdU) incorporation. In mouse and turkey macrophage-satellite cell cocultures, the number of differentiated myoblasts, the frequency of myogenin-positive cells, and the expression of developmental myosin isoforms were reduced as compared with control cultures, indicating that macrophages delayed satellite cell differentiation. The possibility that macrophages facilitate muscle fiber reconstitution by enhancing satellite cell proliferation should be taken into consideration in designing future strategies of satellite cell transplantation as a treatment for muscular dystrophies.

The homeobox gene Msx1 is expressed in a subset of somites, and in muscle progenitor cells migrating into the forelimb.

In myoblast cell cultures, the Msx1 protein is able to repress myogenesis and maintain cells in an undifferentiated and proliferative state. However, there has been no evidence that Msx1 is expressed in muscle or its precursors in vivo. Using mice with the nlacZ gene integrated into the Msx1 locus, we show that the reporter gene is expressed in the lateral dermomyotome of brachial and thoracic somites. Cells from this region will subsequently contribute to forelimb and intercostal muscles. Using Pax3 gene transcripts as a marker of limb muscle progenitor cells as they migrate from the somites, we have defined precisely the somitic origin and timing of cell migration from somites to limb buds in the mouse. Differences in the timing of migration between chick and mouse are discussed. Somites that label for Msx1(nlacZ )transgene expression in the forelimb region partially overlap with those that contribute Pax3-expressing cells to the forelimb. In order to see whether Msx1 is expressed in this migrating population, we have grafted somites from the forelimb level of Msx1(nlacZ )mouse embryos into a chick host embryo. We show that most cells migrating into the wing field express the Msx1(nlacZ )transgene, together with Pax3. In these experiments, Msx1 expression in the somite depends on the axial position of the graft. Wing mesenchyme is capable of inducing Msx1 transcription in somites that normally would not express the gene; chick hindlimb mesenchyme, while permissive for this expression, does not induce it. In the mouse limb bud, the Msx1(nlacZ )transgene is downregulated prior to the activation of the Myf5 gene, an early marker of myogenic differentiation. These observations are consistent with the proposal that Msx1 is involved in the repression of muscle differentiation in the lateral half of the somite and in limb muscle progenitor cells during their migration.

BEN/SC1/DM-GRASP expression during neuromuscular development: a cell adhesion molecule regulated by innervation.

BEN/SC1/DM-GRASP is a cell adhesion molecule belonging to the Ig superfamily that is transiently expressed during avian embryogenesis in a variety of cell types, including the motoneurons of the spinal cord. We have investigated the pattern of BEN expression during neuromuscular development of the chick. We show that both motoneurons and their target myoblasts express BEN during early embryonic development and that the protein becomes restricted at neuromuscular contacts as soon as postsynaptic acetylcholine receptor clusters are observed in muscle fibers. Muscle cells grown in vitro express and maintain BEN expression even when they fuse and give rise to mature myotubes. When embryos are deprived of innervation by neural tube ablation, BEN expression is observed in muscle fibers, whereas, in control, the protein is already restricted at neuromuscular synaptic sites. These results demonstrate that all myogenic cells intrinsically express BEN and maintain the protein in the absence of innervation. Conversely, when neurons are added to myogenic cultures, BEN is rapidly downregulated in muscle cells, demonstrating that innervation controls the restricted pattern of BEN expression seen in innervated muscles. After nerve section in postnatal muscles, BEN protein becomes again widely spread over muscle fibers. When denervated muscles are allowed to be reinnervated, the protein is reexpressed in regenerating motor axons, and reinnervation of synaptic sites leads to the concentration of BEN at neuromuscular junctions. Our results suggest that BEN cell adhesion molecule acts both in the formation of neuromuscular contacts during development and in the events leading to muscle reinnervation.

Comparative analysis of satellite cell properties in heavy- and lightweight strains of turkey.

The growth of muscle during postnatal development results partly from the proliferation of satellite cells and their fusion with muscle fibres. We analysed the properties of satellite cells in a heavyweight (HW) turkey strain characterized by high body weight and a fast growth rate, and in a lightweight farm strain (LW) characterized by low body weight and a slow growth rate. Satellite cell activation was then examined in stretched-overloaded anterior latissimus dorsi (ALD) muscle by weighting one wing in young turkeys from both strains. As early as day 1 of stretching for HW and day 2 for LW, small embryonic-like fibres expressing ventricular cardiac myosin heavy chain (MHC) isoform were observed. Following four days of stretching, the number of nascent fibres had increased in both strains but was significantly greater in HW than LW ALD muscle. The proliferation and differentiation capacities of satellite cells from HW and LW strains were investigated in culture. As judged by in vitro measurements of 3H-thymidine incorporation and DNA content, satellite cells of HW turkey exhibited a greater proliferative capability than those of LW turkey. No differences in the temporal appearance of muscle markers (desmin, MHC isoforms) were noted in vitro between the two strains. These data confirm our in vivo observations indicating that selection based on growth rate does not modify muscle fibre maturation. Our in vivo and in vitro observations suggest that variations in the postnatal muscle growth pattern between HW and LW strains may be related to a difference in the capacity of their satellite cells to proliferate.

Mouse-chick chimera: a developmental model of murine neurogenic cells.

Chimeras were prepared by transplanting fragments of neural primordium from 8- to 8.5- and 9-day postcoital mouse embryos into 1.5- and 2-day-old chick embryos at different axial levels. Mouse neuroepithelial cells differentiated in ovo and organized to form the different cellular compartments normally constituting the central nervous system. The graft also entered into the development of the peripheral nervous system through migration of neural crest cells associated with mouse neuroepithelium. Depending on the graft level, mouse crest cells participated in the formation of various derivatives such as head components, sensory ganglia, orthosympathetic ganglionic chain, nerves and neuroendocrine glands. Tenascin knockout mice, which express lacZ instead of tenascin and show no tenascin production (Saga, Y., Yagi, J., Ikawa, Y., Sakakura, T. and Aizawa, S. (1992) Genes and Development 6, 1821-1838), were specifically used to label Schwann cells lining nerves derived from the implant. Although our experiments do not consider how mouse neural tube can participate in the mechanism required to maintain myogenesis in the host somites, they show that the grafted neural tube behaves in the same manner as the chick host neural tube. Together with our previous results on somite development (Fontaine-Pérus, J., Jarno, V., Fournier Le Ray, C., Li, Z. and Paulin, D. (1995) Development 121, 1705-1718), this study shows that chick embryo constitutes a privileged environment, facilitating access to the developmental potentials of normal or defective mammalian cells. It allows the study of the histogenesis and precise timing of a known structure, as well as the implication of a given gene at all equivalent mammalian embryonic stages.

Seasonal variation in the phenotype of adult ferret (Mustela putorius furo) cremaster muscle.

Using immunocytochemistry, electrophoresis and immunoblotting, we studied the expression of fast and slow myosin heavy chain isoforms in adult ferret muscles during quiescent and breeding periods. Adult cremaster muscle expressed slow and fast myosin heavy chain in relatively similar amounts during the quiescent period. During the breeding period, the expression of slow myosin heavy chain, I, significantly decreased, and fast myosin heavy chain II, was predominant. No alteration of the MHC pattern in EDL and soleus muscles was detected between the quiescent and breeding periods. The possible involvement of androgens and mechanical factors in the regulation of myosin heavy chain expression in adult cremaster muscle is discussed.

Developmental modulation of myosin expression by thyroid hormone in avian skeletal muscle.

It is well established that a rise in circulating thyroid hormone during the second half of chick embryo development significantly influences muscle weight gain and bone growth. We studied thyroid influence on differentiation in slow anterior latissimus dorsi (ALD) and fast posterior latissimus dorsi (PLD) muscles of embryos rendered hypothyroid by hypophysectomy or administration of an anti-thyroid drug. The expression of native myosins and myosin light chains (MLCs) was studied by electrophoretic analysis, and the myosin heavy chain (MHC) was characterized by immunohistochemistry. The first effects of hypothyroid status were observed at day 21 of embryonic development (stage 46 according to Hamburger and Hamilton). Analysis of myosin isoform expression in PLD muscles of hypothyroid embryos showed persistence of slow migrating native myosins and slow MLCs as well as inhibition of neonatal fast MHC expression, indicating retarded differentiation of this muscle. In ALD muscle, hypothyroidism maintained fast embryonic MHC and induced noticeable amounts of fast MLCs, thus delaying slow muscle differentiation. Our results suggest that thyroid hormones play a role in modulating the appearance of neonatal fast MHC and the disappearance of isomyosins transiently present during embryogenesis. However, T3 supplemental treatment would seem to compensate in part for the effects of hypothyroidism induced by hypophysectomy, suggesting that thyroid hormone might interfere with other factors also accounting for the observed effects.

Role of nerve and tension in maturation of posthatching slow-tonic muscle in chicken.

The role of motor innervation and muscle tension in the posthatching maturation of the slow-tonic anterior latissimus dorsi (ALD) muscle of the chicken has been investigated. Modification of the muscle tension was obtained either by maintaining ALD in a shortened state or by stretching, after or without denervation. In denervated as well as in innervated ALD, shortening resulted in atrophy and inhibition of developmental change in muscle fiber population. In contrast, stretch causes hypertrophy, transformation of all 3B fibers, increase in SM2 isomyosin expression, and decrease in Ca2+-activated myosin ATPase in innervated or denervated ALD. On the other hand oxidative activity in ALD fibers was strikingly reduced after denervation even in presence of stretch-induced hypertrophy. This study suggests that a passive stretch can be involved in some, but not all, changes in ALD characteristics occurring after denervation and may be also involved in normal posthatching development of the slow-tonic muscle. Possible clinical implications of these results in relation to treatments for preventing muscle atrophy resulting from immobilization or disuse are suggested.

Developmental changes in myosin isoforms from slow and fast latissimus dorsi muscles in the chicken.

In the course of muscle differentiation, changes in fibre-type population and in myosin composition occur. In this work, the expression of native myosin isoforms in developing fast-twitch (posterior latissimus dorsi; PLD) and slow-tonic (anterior latissimus dorsi; ALD) muscles of the chick was examined using electrophoresis under nondissociating conditions. The major isomyosin of 11-day-old embryonic PLD comigrated with the adult fast myosin FM3. Two additional components indistinguishable from adult fast FM2 and FM1 isomyosins appeared successively during the embryonic development. The relative proportion of these latter isoforms increased with age, and the adult pattern was established by the end of the 1st month after hatching. Between day 11 and day 16 of embryonic development, PLD muscle fibres also contained small amounts of slow isomyosins SM1 and SM2. This synthesis of slow isoforms may be related to the presence of slow fibres within the muscle. At all embryonic and posthatch stages, ALD was composed essentially of slow isomyosins that comigrated with the two slow components SM1 and SM2 identified in adult. Several studies have reported that the SM1:SM2 ratio decreases progressively throughout embryonic and posthatching development, SM2 being predominant in the adult. In contrast, we observed a transient increase in SM1:SM2 ratio at the end of embryonic life. This could reflect a transitional neonatal stage in myosin expression. In addition, the presence in trace amounts of fast isomyosins in developing ALD muscle could be related to the presence of a population of fast fibres within this muscle.

[Innervation, activity rhythm and accumulation of myosin light chains in a fast muscle of chickens]. / Innervation, rythme d'activité et accumulation des chaînes légères de myosine d'un muscle rapide de poulet.

The fast posterior latissimus dorsi muscle (PLD) of the chick ceases to accumulate slow myosin light chains (MLC) during neonatal development. On day 18 of embryonic life slow MLC represented only 2% of total MLC, and LC3F was first detected. In chick embryo, spinal cord stimulation at a slow rhythm modifies PLD differentiation toward the slow type: LC3F did not accumulate and slow MLC increased. In contrast, stimulation at a fast rhythm accelerated LC3F accumulation. PLD denervation on day 2 after hatching inhibited the synthesis of LC3F. Direct stimulation at a fast rhythm led to post-hatching development into normal fast type while a slow rhythm influenced the development of denervated PLD towards the slow type. In innervated PLD, the effect of stimulation at a slow rhythm was less important than in denervated PLD. These results suggest that the rhythm of the neural and/or contractile activity plays an important role in the MLC expression during embryonic and post-natal development of the chicken fast muscle.

Effects of low and high frequency patterns of stimulation on contractile properties, enzyme activities and myosin light chain accumulation in slow and fast denervated muscles of the chicken.

The effects of denervation and direct stimulation in fast and slow latissimus dorsii muscles were investigated in chicken. In slow ALD muscle, denervation resulted in an incompleteness of the relaxation, a decrease in MDH and CPK activities and an increase in fast myosin light chains (MLC) accumulation. Direct stimulation at either fast or slow rhythm prevented the effects of denervation on relaxation and CPK activity but was ineffective on MDH activity and fast MLC accumulation. Moreover, direct stimulation of denervated ALD caused rhythm-dependent change in tetanic contraction. In fast PLD muscle, the main changes in muscle properties following denervation were a slowing down of the time course of the twitch and an incompleteness of the relaxation, a decrease in LDH and CPK activities and in LC3F accumulation. Stimulation at a high frequency partly prevented the effects of denervation and resulted in a large accumulation of LC3F, while a low frequency stimulation did not restore the twitch time to peak, increased MDH activity and induced synthesis of slow MLC. This study emphasizes the role of muscle activity and its pattern in some properties of slow and fast chicken muscles following denervation.

Influence of spinal cord stimulation upon myosin light chain and tropomyosin subunit expression in a fast muscle (posterior latissimus dorsi) of the chick embryo.

Latissimus dorsi muscles of the chick consist of a slow (ALD) and a fast (PLD) muscle. The influence of chronic spinal cord stimulation in the chick embryo upon the expression of myosin light chains and tropomyosin subunits was investigated. Early in development the two muscles exhibited the same ratio of alpha- and beta-tropomyosin subunits. Later, in the slow muscle the ratio beta:alpha decreased and in chicken the amounts of the two components were about the same. In the fast muscle, the alpha-subunit increased and reached 66% in young chicken. In the fast muscle, the alpha-subunit increased and reached 66% in young chicken. In the In the early stages of embryonic development, both muscles accumulated slow and fast light chains. However, in ALD the amount of slow light chains was greater than that of fast light chains and the reverse was observed in PLD muscle. Later during development, the slow components decreased in PLD while the fast components increased; the reverse was observed in ALD muscle. The fast myosin LC3f has been detected in 18-day-old embryonic PLD. Chronic spinal cord stimulation at a low rhythm was performed from day 10 of embryonic development to day 15 or 16. In both muscles from spinal cord-stimulated embryos, the beta-tropomyosin subunit was lower than in control embryos. In ALD, the pattern of light chains was unaffected by chronic stimulation while in PLD muscle the slow and fast components were modified. In particular the ratio LCs:LCf was increased in spinal cord-stimulated embryos with regard to controls.