Oral and intestinal dysbiosis in Parkinson's disease.

The suspicion of an origin of Parkinson's disease (PD) at the periphery of the body and the involvement of environmental risk factors in the pathogenesis of PD have directed the attention of the scientific community towards the microbiota. The microbiota represents all the microorganisms residing both in and on a host. It plays an essential role in the physiological functioning of the host. In this article, we review the dysbiosis repeatedly demonstrated in PD and how it influences PD symptoms. Dysbiosis is associated with both motor and non-motor PD symptoms. In animal models, dysbiosis only promotes symptoms in individuals genetically susceptible to Parkinson's disease, suggesting that dysbiosis is a risk factor but not a cause of Parkinson's disease. We also review how dysbiosis contributes to the pathophysiology of PD. Dysbiosis induces numerous and complex metabolic changes, resulting in increased intestinal permeability, local and systemic inflammation, production of bacterial amyloid proteins that promote α-synuclein aggregation, as well as a decrease in short-chain fatty acid-producing bacteria that have anti-inflammatory and neuroprotective potential. In addition, we review how dysbiosis decreases the efficacy of dopaminergic treatments. We then discuss the interest of dysbiosis analysis as a biomarker of Parkinson's disease. Finally, we give an overview of how interventions modulating the gut microbiota such as dietary interventions, pro-biotics, intestinal decontamination and fecal microbiota transplantation could influence the course of PD.

Water jet indentation for local elasticity measurements of soft materials.

We present a novel elastography method for soft materials (100Pa-100kPa) based on indentation by a µm-sized water jet. We show that the jet creates a localized deformation ("cavity") of the material that can be easily visualized. We study experimentally how cavity width and depth depend on jet speed, height, incidence angle and sample elasticity. We describe how to calibrate the indenter using gels of known stiffness. We then demonstrate that the indenter yields quantitative elasticity values within 10% of those measured by shear rheometry. We corroborate our experimental findings with fluid-solid finite-element simulations that quantitatively predict the cavity profile and fluid flow lines. The water jet indenter permits in situ local stiffness measurements of 2D or 3D gels used for cell culture in physiological buffer, is able to assess stiffness heterogeneities with a lateral resolution in the range 50-500µm (at the tissue scale) and can be assembled at low cost with standard material from a biology laboratory. We therefore believe it will become a valuable method to measure the stiffness of a wide range of soft, synthetic or biological materials.

A change in boundary conditions induces a discontinuity of tissue flow in chicken embryos and the formation of the cephalic fold.

The morphogenesis of vertebrate body parts remains an open question. It is not clear whether the existence of different structures, such as a head, can be addressed by fundamental laws of tissue movement and deformation, or whether they are only a sequence of stop-and-go genetic instructions. I have filmed by time-lapse microscopy the formation of the presumptive head territory in chicken embryos. I show that the early lateral evagination of the eye cups and of the mesencephalic plate is a consequence of a sudden change in boundary conditions of the initial cell flow occurring in these embryos. Due to tissue flow, and collision of the two halves of the embryo, the tissue sheet movement is first dipolar, and next quadrupolar. In vivo air puff tonometry reveals a simple visco-elastic behaviour of the living material. The jump from a dipolar to a quadrupolar flow changes the topology of the early morphogenetic field which is observed towards a complex vortex winding with a trail (the eye cups and brain folds). The hydrodynamical model accounts for the discontinuity of the vector field at the moment of collision of the left and right halves of the embryo, at a quantitative level. This suggests a possible mechanism for the morphogenesis of the head of amniotes, as compared to cephalochordates and anamniotes.

[Place of molecular imaging in the management of prostate cancer]. / Place de l'imagerie moléculaire dans la prise en charge du cancer de la prostate.

In the management of prostate cancer in recent years, innovative therapies have appeared requiring precise and reliable disease detection. In 2021, new generation imaging (PET/CT, multiparametric MRI, PET/MRI) have their place at all stages of the prostate cancer natural history to help target the lesion(s) and guide therapy and improve the results obtained. PSMA PET/CT is currently the leader in this type of imaging with a complete offer during the disease: both from diagnosis, to recurrence or in the oligo-metastatic and metastatic stage resistant to castration with a pivotal role in the PSMA theranostic approach. However, multiparametric MRI also has many detection advantages when the prostate is left in place, which suggests the potential major benefit of hybrid PSMA PET/MRI imaging.

[Behavioral disorders in Parkinson's disease: from pathophysiology to the mastery of dopaminergic treatment]. / Maladie de Parkinson: de la physiopathologie des troubles psychiques à la maîtrise du traitement dopaminergique.

INTRODUCTION: Behavioral changes in Parkinson's disease are complex and their pathophysiology is not yet fully understood. The dopaminergic system seems to play a major role and most of the behavioral disorders in Parkinson's disease can be classified into either hypodopaminergic if related to the disease itself or hyperdopaminergic if related to dopaminergic treatment. STATE OF THE ART: Subthalamic stimulation, which enables withdrawal of dopaminergic medication at an advanced stage in the disease, provides a model for the study of certain nonmotor, dopamine-sensitive symptoms. Such a study has shown that apathy, which is the most frequent behavioral problem in Parkinson's disease, is part of a much broader hypodopaminergic behavioral syndrome which also includes anxiety and depression. Nonmotor fluctuations--essential fluctuations in the patient's psychological state--are an expression of mesolimbic denervation, as shown in positron emission tomography. Drug-induced sensitization of the denervated mesolimbic system accounts for hyperdopaminergic behavioral problems that encompass impulse control disorders that can be alternatively classified as behavioral addictions. The association of impulse control disorders and addiction to the dopaminergic medication has been called dopamine dysregulation syndrome. While L-dopa is the most effective treatment for motor symptoms, dopamine agonists are more effective in improving the nonmotor levodopa-sensitive symptoms. On the other hand, L-dopa induces more motor complications and dopamine agonist more behavioral side effects. There is increasing data and awareness that patients' quality of life appears to be dictated by hypo- and hyperdopaminergic psychological symptoms stemming from mesolimbic denervation and dopaminergic treatment rather than by motor symptoms and motor complications related to nigrostriatal denervation and dopaminergic treatment. PERSPECTIVES: Better management requires knowledge of the clinical syndromes of hyper- and hypodopaminergic behaviors and nonmotor fluctuations, a better understanding of their underlying mechanisms and the development of new evaluation tools for these nonmotor symptoms. CONCLUSIONS: The neurologist who strives to gain mastery of dopaminergic treatment needs to fine tune the dosage of levodopa and dopamine agonists on an individual basis, depending on the presence of motor and nonmotor signs respectively.

Topiramate-induced delusional parasitosis.

A 48-year-old woman with temporal lobe epilepsy and no prior history of psychiatric illness was started on topiramate (TPM). The dose was titrated up to 150 mg twice daily over 14 weeks and led to a significant reduction in seizure frequency. Upon reaching this dose, she developed intense pruritus and the firm belief that her skin was infected by parasites. She was diagnosed with delusional parasitosis (DP). Consequently, her TPM was weaned off and her DP settled completely without the use of antipsychotic medication. DP is characterized by the unshakeable conviction that small organisms infest the body despite the absence of confirmatory medical evidence. DP can occur in a wide variety of organic and psychiatric disorders or as an isolated delusional disorder. Rarely DP can be drug-induced. While psychiatric symptoms are a well recognized side-effect of TPM, this is, to our knowledge, the first reported case of TPM-induced DP.

Emergence and development of gut motility in the chicken embryo.

The gastrointestinal tract transports the food bolus by peristalsis. Gut motility starts at an early age in the developing embryo, well before it is required for nutrition of the organism. We present a comprehensive kinematic study of the emergence and physiological development of gut motility in all regions of the lower digestive tract of the chicken embryo from embryonic days E5 through E9. We characterized motility emergence time, propagation patterns, speed, frequency and amplitude of peristalsis waves. We found that the emergence of an uninterrupted circular ring of smooth muscle correlated with the appearance of propagative contractile waves, at E6 in the hindgut and midgut, and at E9 in the caecal appendix. We show that peristalsis at these stages is critically dependent on calcium and is not mediated by neurons as gut motility is insensitive to tetrodotoxin and takes place in the hindgut in the absence of neurons. We further demonstrate that motility also matures in ex-vivo organ culture. We compare our results to existing literature on zebrafish, mouse and human motility development, and discuss their chronological relationship with other major developmental events occurring in the chicken embryonic gut at these stages. Our work sets a baseline for further investigations of motility development in this important animal model.

Control of arterial branching morphogenesis in embryogenesis: go with the flow.

Formation of a properly branched vascular system during embryogenesis is crucial for embryo survival. Here we review the regulation of the morphogenesis of the arterial and venous system during embryogenesis. We show that in addition to deterministic patterning mechanisms and plasticity of endothelial cells, arterial-venous differentiation and branching morphogenesis involves a prominent role for blood flow. Based on in vivo observations of developing arteries, we identified a novel morphological event crucial for the morphogenesis of the arterial tree, disconnection of small side branches. This disconnection of side branches occurs exactly at the point of bifurcation. The rate of disconnection of side branches depends on flow velocity and branching angle. The balance between disconnection and maintenance of arterial side branches determines the number of side branches connected to a large artery. Based on these observations, we postulate that the number of pre-existing collaterals connected to a large artery is a function of the disconnection process and can be regulated by hemodynamics. We furthermore show that embryonic arteries already adapt their lumen diameter to the amount of flow carried. Taken together, we suggest that hemodynamics plays a pivotal role in shaping the arterial system. We suggest that flow-evoked remodeling processes determine the number of preexisting collaterals during critical periods of embryo-fetal development. Insight into these basic principles of arterial growth and branching during embryogenesis may aid to understanding the observed variability in the capacity to establish a collateral circulation in patients with ischemic diseases and finding new strategies for therapeutic arteriogenesis.

How Tissue Mechanical Properties Affect Enteric Neural Crest Cell Migration.

Neural crest cells (NCCs) are a population of multipotent cells that migrate extensively during vertebrate development. Alterations to neural crest ontogenesis cause several diseases, including cancers and congenital defects, such as Hirschprung disease, which results from incomplete colonization of the colon by enteric NCCs (ENCCs). We investigated the influence of the stiffness and structure of the environment on ENCC migration in vitro and during colonization of the gastrointestinal tract in chicken and mouse embryos. We showed using tensile stretching and atomic force microscopy (AFM) that the mesenchyme of the gut was initially soft but gradually stiffened during the period of ENCC colonization. Second-harmonic generation (SHG) microscopy revealed that this stiffening was associated with a gradual organization and enrichment of collagen fibers in the developing gut. Ex-vivo 2D cell migration assays showed that ENCCs migrated on substrates with very low levels of stiffness. In 3D collagen gels, the speed of the ENCC migratory front decreased with increasing gel stiffness, whereas no correlation was found between porosity and ENCC migration behavior. Metalloprotease inhibition experiments showed that ENCCs actively degraded collagen in order to progress. These results shed light on the role of the mechanical properties of tissues in ENCC migration during development.

Betaine use by rhizosphere bacteria: genes essential for trigonelline, stachydrine, and carnitine catabolism in Rhizobium meliloti are located on pSym in the symbiotic region.

Rhizobium meliloti is known to use betaines synthesized by its host, Medicago sativa, as osmoprotectants and sources of energy. It is shown in the present report that the symbiotic megaplasmid (pSym) of R. meliloti RCR2011 encodes functions essential to the catabolism of three betaines, trigonelline (nicotinic acid N-methylbetaine), stachydrine (proline betaine or dimethylproline), and carnitine (gamma-trimethyl-beta-hydroxybutyrobetaine). Preliminary evidence is presented showing that functions on pSym also influence the catabolism of choline and its oxidative product, glycine betaine. Genes implicated in betaine catabolism are found in the symbiotic region of pSym. Trigonelline catabolism functions lie between two clusters of symbiotic genes, nifKDH and nok/fixVI'. Stachydrine and carnitine functions lie to the right of trigonelline catabolism functions, immediately to the right of fixVI'. Information necessary to choline and glycine betaine catabolism is probably encoded to the right of stachydrine catabolism functions.

[Toxoplasmosis among pregnant women in France : Seroprevalence, seroconversion and knowledge levels. Trends 1965-1995.]. / La toxoplasmose chez la femme enceinte en France : séroprévalence, taux de séroconversion et niveau de connaissance des mesures préventives. Tendances 1965-1995.

The main trends and the significant points concerning the evolution of seroprevalence, seroconversion's rate and knowledge's level of preventive measures against toxoplasmosis in pregnant women in France are : a progressive decrease of immunisation's ratio with regional variation (national mean is estimated at 54 % in 1995); diversity of factors having a potential influence on the contamination, the trends of most of them tend to decrease the contamination but the exact impact is difficult to appreciate; stability of seroconversion's rate since 15 years 4 to 5 p.1000 of the whole pregnancy for nine months exposition period; ways of contamination are still the same; few informations about knowledge's level concerning preventives measures and performances of educative action.

Can physics help to explain embryonic development? An overview.

Recent technical advances including digital imaging and particle image velocimetry can be used to extract the full range of embryonic movements that constitute the instantaneous 'morphogenetic fields' of a developing animal. The final shape of the animal results from the sum over time (integral) of the movements that make up the velocity fields of all the tissue constituents. In vivo microscopy can be used to capture the details of vertebrate development at the earliest embryonic stages. The movements thus observed can be quantitatively compared to physical models that provide velocity fields based on simple hypotheses about the nature of living matter (a visco-elastic gel). This approach has cast new light on the interpretation of embryonic movement, folding, and organisation. It has established that several major discontinuities in development are simple physical changes in boundary conditions. In other words, with no change in biology, the physical consequences of collisions between folds largely explain the morphogenesis of the major structures (such as the head). Other discontinuities result from changes in physical conditions, such as bifurcations (changes in physical behaviour beyond specific yield points). For instance, beyond a certain level of stress, a tissue folds, without any new gene being involved. An understanding of the physical features of movement provides insights into the levers that drive evolution; the origin of animals is seen more clearly when viewed under the light of the fundamental physical laws (Newton's principle, action-reaction law, changes in symmetry breaking scale). This article describes the genesis of a vertebrate embryo from the shapeless stage (round mass of tissue) to the development of a small, elongated, bilaterally symmetric structure containing vertebral precursors, hip and shoulder enlarges, and a head.

Acute bilateral mydriasis associated with anti-GQ1b antibody.

Miller Fisher syndrome (MFS) is an autoimmune neuropathy characterized by external ophthalmoplegia, ataxia and areflexia. Mydriasis is present in 35% of typical MFS. We report five patients with acute bilateral mydriasis, either isolated or associated with external ophthalmoplegia for which the presumed diagnosis of "atypical MFS" was confirmed by the positivity of anti-GQ1b antibodies. Acute bilateral mydriasis raises important differential diagnoses in clinical practice. This report demonstrates that acute mydriasis can be autoimmune mediated and that anti-GQ1b antibodies are useful to confirm the diagnosis in unexplained cases.

[A fundamental symmetry between morphogenesis and function of branched organs]. / Sur une symétrie fondamentale entre la morphogenèse et le fonctionnement des organes arborisés.

It is generally difficult to find any relationship between the morphogenesis of an organ and its final function. A priori, such a relationship has no reason to exist, since organs do not actually function during their formation. I will show in this article that, for a very large class of organs--the branched organs--there exists a hidden relationship between their morphogenesis and their function. This class of organs comprises: the lungs, the salivary mammary and lacrymal glands, the kidneys, the pancreas, and possibly other organs, such as testes. For all these organs, a fundamental fact that comes from recent developments in physics explains at the same time how they form, and why they work. This suggests, first, that complex organs are not the result of gradual and long selection processes, and, second, that this specific structure for the organs is imposed by the laws of physics. The growth process, as described here, is possibly the only one that allows both to build a fluid-secreting organ, and make it work.

Branching morphogenesis in a reaction-diffusion model

I show that a class of reaction-diffusion models of vasculature growth developed in the mid 1970s is in fact a class of dendritic growth models. I then comment on the relevance of these models.

Characterization of the binding of plasminogen to fibrin surfaces: the role of carboxy-terminal lysines.

In the present study we have quantitatively characterized the interaction of purified human Glu- and Lys-plasminogen with intact and degraded fibrin by ligand-binding experiments using a radioisotopic dilution method and antibodies against human plasminogen. A fibrinogen monolayer was covalently linked to a solid support with polyglutaraldehyde and was treated with thrombin or with thrombin and then plasmin to respectively obtain intact and degraded fibrin surfaces. Under these conditions, a well-defined surface of fibrin is obtained (410 +/- 4 fmol/cm2) and, except for a 39-kDa fragment, most of the fibrin degradation products remain bound to the support. New binding sites for plasminogen were detected on the degraded surface of fibrin. These sites were identified as carboxy-terminal lysine residues both by inhibition of the binding by the lysine analogue 6-aminohexanoic acid and by carboxy-terminal end-group digestion with carboxypeptidase B. The binding curves exhibited a characteristic Langmuir adsorption isotherm saturation profile. The data were therefore analyzed accordingly, assuming a single-site binding model to simplify the analysis. Equilibrium dissociation constants (Kd) and the maximum number of binding sites (Bmax) were derived from linearized expression of the Langmuir isotherm equation. The Kd for the binding of Glu-plasminogen to intact fibrin was 0.99 +/- 0.17 microM and for degraded fibrin was 0.66 +/- 0.22 microM. The Kd for the binding of Lys-plasminogen to intact fibrin was 0.41 +/- 0.22 microM and for degraded fibrin was 0.51 +/- 0.12 microM.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of the enhanced intrinsic activity of single-chain urokinase-type plasminogen activator during ongoing fibrinolysis.

The activation of plasminogen at the surface of fibrin by single-chain urokinase-type plasminogen activator (scu-PA) was investigated using recombinant forms of a plasmin-resistant mutant of scu-PA, rscu-PA-Glu158, and an inactive catalytic site mutant of human plasminogen, rPg-Ala741. Conversion of cleavable 125I-labeled single-chain proteins to their two-chain forms, was quantitated by radioisotope counting of protein bands on reduced SDS-polyacrylamide gels. The efficiency of the activation (moles of plasmin generated per mol of plasminogen activator) of native Glu-plasminogen bound to degraded fibrin was comparable for scu-PA and its two-chain form (tcu-PA) and approximately 4-fold lower for rscu-PA-Glu158. The corresponding values with rPg-Ala741 were 4-fold or 9-fold lower for scu-PA or rscu-PA-Glu158, as compared to tcu-PA. In contrast, in solution in the absence of fibrin, the efficiency of scu-PA for activation of rPg-Ala741 was 100-fold lower than that of tcu-PA. Initial activation rates of rPg-Ala741 (32.7 fmol/well containing 50 microliters of solution) with 4 nM tcu-PA were comparable in solution and bound to degraded fibrin (v(o) = 1.01 and 1.16 fmol/min, respectively). In contrast, with 4 nM scu-PA the corresponding values when rPg-Ala741 was bound to degraded fibrin were 20-fold higher as compared to the soluble phase (v(o) = 0.23 and 0.012 fmol/min, respectively). Comparable results were obtained when using Glu- or Lys-forms of rPg-Ala741. Furthermore, in the presence of normal human plasma, activation of Glu-plasminogen bound to degraded fibrin was found to be about 2.5-fold more efficient with scu-PA than with tcu-PA. These findings indicate that the fibrin specificity of scu-PA does not require its conversion to tcu-PA, nor conversion of Glu- to Lys-plasminogen, but appears to be due to the additional binding of plasminogen to partially digested fibrin; scu-PA may thus represent a physiological functional form of u-PA in plasma.