GABA spectra and remote distractor effect in progressive supranuclear palsy: A pilot study.

Disturbances of the gamma-aminobutyric-acid (GABA) system have been suspected of contributing to the pathophysiology of progressive supranuclear palsy (PSP). The ability to rapidly resolve competitive action decisions, such as shifting the gaze to one particular stimulus rather than another, can be predicted by the concentration of GABA in the region of the frontal cortex relevant to eye movements. For this reason, our study measured GABA levels in seven PSP patients and eight healthy controls, using proton magnetic resonance spectroscopy, and assessed the relationship of these measurements to the remote distractor effect (RDE), an eye-movement paradigm investigating competitive action decisions. No significant differences were found in either frontal-eye-field GABA levels or RDE between PSP patients and controls.

Ictal speech and language dysfunction in adult epilepsy: Clinical study of 95 seizures.

PURPOSE: To analyze the semiological characteristics of the language and speech disorders arising during epileptic seizures, and to describe the patterns of language and speech disorders that can predict laterality of the epileptic focus. METHOD: This study retrospectively analyzed 95 consecutive videos of seizures with language and/or speech disorders in 44 patients admitted for diagnostic video-EEG monitoring. Laterality of the epileptic focus was defined according to electro-clinical correlation studies and structural and functional neuroimaging findings. Language and speech disorders were analyzed by a neurologist and a speech therapist blinded to these data. RESULTS: Language and/or speech disorders were subdivided into eight dynamic patterns: pure anterior aphasia; anterior aphasia and vocal; anterior aphasia and "arthria"; pure posterior aphasia; posterior aphasia and vocal; pure vocal; vocal and arthria; and pure arthria. The epileptic focus was in the left hemisphere in more than 4/5 of seizures presenting with pure anterior aphasia or pure posterior aphasia patterns, while discharges originated in the right hemisphere in almost 2/3 of seizures presenting with a pure vocal pattern. No laterality value was found for the other patterns. CONCLUSION: Classification of the language and speech disorders arising during epileptic seizures into dynamic patterns may be useful for the optimal analysis of anatomo-electro-clinical correlations. In addition, our research has led to the development of standardized tests for analyses of language and speech disorders arising during seizures that can be conducted during video-EEG sessions.

Hypnosis and movement disorders: State of the art and perspectives.

INTRODUCTION: Hypnosis might represent an interesting complementary therapeutic approach to movement disorders, as it takes into account not only symptoms, but also well-being, and empowers patients to take a more active role in their treatment. METHODS: Our review of the literature on the use of hypnosis to treat movement disorders was done by systematically searching the PubMed database for reports published between 1984 and November 2015. The following variables were extracted from each selected paper: study design; sample size; type of movement disorder; hypnotic procedure; treatment duration; and efficacy. RESULTS: Thirteen papers were selected for detailed analysis. Most concerned tremor in Parkinson's disease and tics in Gilles de la Tourette syndrome. Although promising, the data were insufficient to allow conclusions to be drawn on the efficacy of hypnosis in movement disorders or to recommend its use in this setting. CONCLUSION: Well-designed studies taking into account some specific methodological challenges are needed to determine the possible therapeutic utility of hypnosis in movement disorders. In addition to the potential benefits for such patients, hypnosis might also be useful for studying the neuroanatomical and functional underpinnings of normal and abnormal movements.

'The Move', an innovative simulation-based medical education program using roleplay to teach neurological semiology: Students' and teachers' perceptions.

INTRODUCTION: Neurological disorders are frequently being managed by general practitioners. It is therefore critical that future physicians become comfortable with neurological examination and physical diagnosis. Graduating medical students often consider neurological examination as one of the clinical skills they are least comfortable with, and they even tend to be neurophobic. One way to improve the learning of neurological semiology is to design innovative learner-friendly educational methods, including simulation training. METHODS: The feasibility of mime-based roleplaying was tested by a simulation training program in neurological semiology called 'The Move'. The program was proposed to third-year medical students at Pierre and Marie Curie University in Paris during their neurology rotation. Students were trained to roleplay patients by miming various neurological syndromes (pyramidal, vestibular, cerebellar, parkinsonian) as well as distal axonopathy, chorea and tonic-clonic seizures. Using an anonymous self-administered questionnaire, the students' and teachers' emotional experience and views on the impact of the program were then investigated. RESULTS: A total of 223/365 students (61%) chose to participate in the study. Both students and teachers felt their participation was pleasant. Students stated that The Move increased their motivation to learn neurological semiology (78%), and improved both their understanding of the subject (77%) and their long-term memorization of the teaching content (86%). Although only a minority thought The Move was likely to improve their performance on their final medical examination (32%), a clear majority (77%) thought it would be useful for their future clinical practice. Both students (87%) and teachers (95%) thought The Move should be included in the medical curriculum. CONCLUSION: Mime-based roleplaying simulation may be a valuable tool for training medical students in neurological semiology, and may also help them to overcome neurophobia.

Thrombolysis in Stroke Patients with Isolated Aphasia.

BACKGROUND: Data about evolution of aphasia following stroke are rare and controversial especially following fibrinolysis. The aim of this study was to describe the early clinical patterns of isolated aphasia in consecutive stroke patients with or without thrombolysis. METHODS: Clinical and radiological data of consecutive stroke patients were routinely entered in prospective registry. Patients were considered aphasic when NIHSS (National Institutes of Health Stroke Scale) item 9 >0. 'Isolated aphasia' was defined by aphasic patients without motor limb deficit. We created a 'composite language score' obtained by summing the NIHSS items 1b, 1c and 9, which reflects language-processing ability. Recovery of functions was evaluated as measured by global NIHSS, composite language score and language screening test (LAST) at baseline, H24 and day 7 (D7). 'Mild deficit' was defined as global NIHSS <5. RESULTS: A total of 100 consecutive patients met study criteria for isolated aphasia. Twenty-five underwent thrombolysis and 75 did not. There was no difference between the 2 groups concerning demographic characteristics, involved territories and presence of arterial occlusion, initial median NIHSS, composite language and LAST scores at entrance. Evolution was significantly better in thrombolysed patient for the 3 testings: NIHSS, composite language score and LAST at D7 (respective p = 0.0002; p = 0.01 and p = 0.004). Similar results were found when we focused on the subgroups of patients with initial 'mild' deficits (p = 0.01; p = 0.0003 and p = 0.007). No symptomatic hemorrhagic transformation occurred following thrombolysis. CONCLUSION: These data strongly suggest that thrombolysis is safe and effective in patients with 'isolated aphasia,' even if the global NIHSS score is <5.

[LAST-Q: Adaptation and normalisation in Quebec of the Language Screening Test]. / LAST-Q: adaptation et normalisation franco-québécoises du Language Screening Test.

The goal of the present study was to adapt and to establish normative data for the recently developed Language Screening Test (LAST; Flamand-Roze et al., 2011) in the French-Canadian population according to age and level of education. After an adaptation process, 100 French-Canadian speakers were evaluated with the LAST-Q. As expected, a perfect score of 15/15 was obtained for all high level education participants, and a score of 14/15 was obtained for all participants with a lowest level of education or aged 80 years or more. Thanks to this adaptation, LAST-Q can be used in acute patients in stroke unit in Quebec.

[Language and swallowing disorders in acute stroke patients: tools and early management]. / Troubles du langage et de la déglutition à la phase aiguë des accidents vasculaires cérébraux : outils d'évaluation et intérêt d'une prise en charge précoce.

INTRODUCTION: The contribution of stroke units to improve morbidity, mortality and recovery in stroke victims is clearly demonstrated. However, acute management of language disorders in these specialized units is controversial and little standardization is seen for the management of swallowing disorders. STATE OF THE ART: The recently validated French scale for rapid screening for language disorders (LAST) in acute stroke patients should enable optimal detection and early management. A standardized protocol should be used to screen for and manage swallowing disorders. This protocol should include daily evaluations, individually tailored rehabilitation sessions, adaptation of food textures, patient education for adequate eating position, team training, and information for families. PERSPECTIVES AND CONCLUSIONS: These protocols imply co-operation and coordination between the medical and allied profession teams and the daily presence of a speech and language therapist. This presence is crucial for patients in stroke units to achieve the full benefits of the management scheme proposed in this paper.

Aphasia in border-zone infarcts has a specific initial pattern and good long-term prognosis.

BACKGROUND: While border-zone infarcts (BZI) account for about 10% of strokes, studies on related aphasia are infrequent. The aim of this work was to redefine specifically their early clinical pattern and evolution. METHODS: We prospectively studied consecutive patients referred to our stroke unit within a 2-year period. Cases of aphasia in right-handed patients associated with a MRI confirmed left-sided hemispheric BZI were included. These patients had a standardized language examination in the first 48 h, at discharge from stroke unit and between 6 and 18 months later. RESULTS: Eight patients were included. Three had anterior (MCA/ACA), two posterior (MCA/PCA), two both anterior and posterior, and one bilateral BZI. All our patients initially presented transcortical mixed aphasia, characterized by comprehension and naming difficulties associated with preserved repetition. In all patients, aphasia rapidly improved. It fully recovered within a few days in three patients. Initial improvement was marked, although incomplete in the five remaining patients: their aphasias specifically evolved according to the stroke location toward transcortical motor aphasia for the three patients with anterior BZI and transcortical sensory aphasia for the two patients with posterior BZI. All patients made a full language recovery within 18 months after stroke. CONCLUSIONS: We report a specific aphasic pattern associated with hemispheric BZI, including an excellent long-term outcome. These findings appear relevant to (i) clinically suspect BZI and (ii) plan rehabilitation and inform the patient and his family of likelihood of full language recovery.

[Congenital hypogonadotropic hypogonadism]. / Hypogonadisme hypogonadotrope congénital.

Congenital hypogonadotropic hypogonadism is defined by reduced steroid hormone synthesis and secretion due to low LH and FSH secretion. It is a rare disease with an unknown prevalence (about 1/5000). It results from a fetal defect in GnRH neuron migration, a defect of pituitary development or from a functional defect of the hypothalamopituitary axis between GnRH neurons and gonadotropic cells. The diagnosis should be considered at birth in males with micropenis, during adolescence in case of delayed puberty or absent puberty, and during adulthood in case of infertility. It may be restricted to the gonadotropic axis, combined with other endocrine system defects or be part of a complex syndrome. Several gene defects have now been described. Molecular studies should be performed to confirm the diagnosis and to help provide appropriate genetic counseling. Treatment to induce puberty should be provided at adolescence, followed by hormonal substitution treatment during adulthood. Specific infertility treatment may also be proposed but patients with the dominant form of gonadotropic deficiency should be informed of the risk of transmission.

PepT1-mediated epithelial transport of dipeptides and cephalexin is enhanced by luminal leptin in the small intestine.

Dietary proteins are mostly absorbed as di- and tripeptides by the intestinal proton-dependent transporter PepT1. We have examined the effects of leptin on PepT1 function in rat jejunum and in monolayers of the human enterocyte-like 2 cell Caco-2. Leptin is produced by the stomach and secreted in the gut lumen. We show here that PepT1 and leptin receptors are expressed in Caco-2 and rat intestinal mucosal cells. Apical (but not basolateral) leptin increased Caco-2 cell transport of cephalexin (CFX) and glycylsarcosine (Gly-Sar), an effect that was associated with increased Gly-Sar uptake, increased membrane PepT1 protein, decreased intracellular PepT1 content, and no change in PepT1 mRNA levels. The maximal velocity (Vmax) for Gly-Sar transport was significantly increased by leptin, whereas the apparent Michaelis-Menten constant (Km) did not change. Furthermore, leptin-stimulated Gly-Sar transport was completely suppressed by colchicine, which disrupts cellular translocation of proteins to plasma membranes. Intrajejunal leptin also induced a rapid twofold increase in plasma CFX after jejunal perfusion with CFX in the rat, indicating enhanced intestinal absorption of CFX. These data revealed an unexpected action of gastric leptin in controlling ingestion of dietary proteins.

Role of nonesterified fatty acids in necrotizing pancreatitis: an in vivo experimental study in rats.

INTRODUCTION: In acute pancreatitis, nonesterified fatty acids (NEFA) might be released by lipase and cause tissue necrosis by their detergent properties, but this has not been established in vivo. AIMS: To measure the release of NEFA in the blood stream, pancreatic tissue, and peritoneal cavity during taurocholate-induced acute necrotizing pancreatitis in rats. METHODOLOGY: Ascites and blood were repeatedly sampled; after 24 hours, pancreatic lesions were scored, and NEFA were measured in the pancreas. The effects of a specific lipase inhibitor (Tetrahydrolipstatin [THL]) were also studied. RESULTS: A slight transient increase (22%) of NEFA concentration was observed in systemic circulation but did not parallel the time course of lipase activity, arguing against an intravascular production of NEFA by circulating lipase. Pancreatic NEFA did not differ between rats with pancreatitis and control rats. NEFA in ascites increased to threefold the basal value immediately after taurocholate and decreased rapidly thereafter, whereas lipase increased later in ascites and remained elevated during the 24-hour duration of the experiment. Lipase inhibition by THL neither modified the early increase of NEFA in ascites, nor altered the macroscopic, enzymatic, and histologic evolution of pancreatitis. CONCLUSION: This in vivo study does not confirm the hypothetical role of NEFA produced by pancreatic lipase in the necrotic process and its systemic complications, up to now mainly suggested on the basis of ex vivo experiments.

The peptide YY-preferring receptor mediating inhibition of small intestinal secretion is a peripheral Y(2) receptor: pharmacological evidence and molecular cloning.

A peptide YY (PYY)-preferring receptor [PYY > neuropeptide Y (NPY)] was previously characterized in rat small intestinal crypt cells, where it mediates inhibition of fluid secretion. Here, we investigated the possible status of this receptor as a peripheral Y(2) receptor in rats. Typical Y(2) agonists (PYY(3-36), NPY(3-36), NPY(13-36), C2-NPY) and very short PYY analogs (N-alpha-Ac-PYY(22-36) and N-alpha-Ac-PYY(25-36)) acting at the intestinal PYY receptor were tested for their ability to inhibit the binding of (125)I-PYY to membranes of rat intestinal crypt cells and of CHO cells stably transfected with the rat hippocampal Y(2) receptor cDNA. Similar PYY preference was observed and all analogs exhibited comparable high affinity in both binding assays. The same held true for the specific Y(2) antagonist BIIE0246 with a K(i) value of 6.5 and 9.0 nM, respectively. BIIE0246 completely abolished the inhibition of cAMP production by PYY in crypt cells and transfected CHO cells. Moreover, the antagonist 1) considerably reversed the PYY-induced reduction of short-circuit current in rat jejunum mucosa in Ussing chamber and 2) completely abolished the antisecretory action of PYY on vasoactive intestinal peptide (VIP)-induced fluid secretion in rat jejunum in vivo. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) experiments showed that Y(2) receptor transcripts were present in intestinal crypt cells (3 x 10(2) molecules/100 ng RNA(T)) with no expression in villus cells, in complete agreement with the exclusive binding of PYY in crypt cells. Finally, a full-length Y(2) receptor was cloned by RT-PCR from rat intestinal crypt cells and also from human small intestine. We conclude that the so-called PYY-preferring receptor mediating inhibition of intestinal secretion is a peripheral Y(2) receptor.

Differential upregulation of cellular adhesion molecules at the sites of oxidative stress in experimental acute pancreatitis.

BACKGROUND: Severe acute pancreatitis (AP)(2) is associated with exaggerated leukocyte adherence and activation. Endothelial cellular adhesion molecules (CAMs) can be induced by cytokines, but also directly by oxygen free radicals (OFRs), mediated by nuclear factor kappa-B (NF-kappa B). We investigated the behavior of inducible CAMs in relation to pancreatic oxidative stress. Our novel modification of cerium capture histochemistry (reaction of OFRs with cerium produces laser reflective Ce perhydroxide precipitates) combined with reflectance confocal laser scanning microscopy (CLSM) allows the histological codemonstration of in vivo OFR production and immunolabeled CAMs, or NF-kappa B. METHODS: Taurocholate AP was induced in rats; sham operated and normal animals served as controls. To achieve in situ, in vivo reaction of cerium with OFRs, animals were perfused with CeCl(3) solution at different time points (1, 2, 8, 24 h) and then sacrificed. E-selectin, P-selectin, ICAM-1, VCAM, and NF-kappa B p65 were labeled by immunofluorescence (IF) on frozen sections of cerium perfused pancreata. IF and Ce perhydroxide reflectance were simultaneously detected by CLSM. Pancreatic gene expression of the same CAMs was quantified by competitive RT-PCR (MIMIC internal control). RESULTS: Control pancreata showed negligible reflectance and minimal CAM expression. Early (1, 2 h) AP samples were characterized by intense, heterogeneous acinar OFR production, strong P-selectin, and increasing ICAM expression, with nuclear translocation of p65, histologically all colocalizing with the areas of acinar oxidative stress. Adherent polymorphonuclear leukocytes (PMNs) displayed weak OFR formation. Later (8, 24 h), a slowly declining P-selectin, but persisting ICAM-1 expression, was paralleled by widespread adherence of PMNs producing surprisingly large amounts of OFRs. VCAM and E-selectin showed a mild increase at 24 h. CAM gene activation was in good correlation with the protein expression. CONCLUSIONS: The early acinar oxidative stress is colocalized with NF-kappa B activation, preferential P-selectin, and ICAM upregulation in this AP model. Subsequently, adherent, activated PMNs become the major source of OFRs, thereby contributing to tissue damage.

Vasoactive intestinal peptide is involved in the inhibitory effect of interleukin-1 beta on the jejunal contractile response induced by acetylcholine.

UNLABELLED: Although previous studies have shown that interleukin-1 beta (IL-1 beta) decreases acetylcholine (ACh)-induced intestinal contraction by an action on the enteric nervous system, the neuromediator(s) involved are still unknown. AIM: To determine the role of nitric oxide (NO), vasoactive intestinal peptide (VIP) and/or adenosine triphosphate (ATP) in mediating this inhibitory effect. METHODS: The effects of NO synthase inhibitors, VIP and ATP antagonists on motor response to the ACh were investigated before and after 90-min exposure of a rat preparation of jejunal longitudinal muscle-myenteric plexus to IL-1 beta. NG-nitro-L-arginine methyl ester, NG-nitro-L-arginine and NG-monomethyl-L-arginine were used to inhibit NO synthase, VIP (10-28) and [D-p-Cl-Phe6, Leu17] VIP to block VIP receptors, and suramin to block ATP receptors. RESULTS: NO synthase inhibitors failed to block the inhibitory effect of IL-1 beta on ACh-contracted jejunum smooth muscle. Suramin also failed to affect IL-1 beta-induced inhibition, whereas VIP antagonists abolished it. Moreover, the action of IL-1 beta was partly reproduced by VIP. CONCLUSIONS: While neither NO nor ATP accounts for the inhibitory effect of IL-1 beta on ACh-contracted jejunum, VIP seems to be a key-mediator of this effect.

Four-flux model for a multilayer, plane absorbing and scattering medium: application to the optical degradation of white paint in a space environment.

We generalize the four-flux radiative transfer model to the case of a multilayer medium. A concrete application, that of the study of the optical degradation of white paint in a simulated space environment, is presented. The degraded material is decomposed in a damaged layer and in an unaffected layer, and we assume that the degradation is due to a variation Dkappa of the imaginary part of the refractive index in the damaged layer. Then we find an empirical law for variation Dkappa with dose, taking into account possible saturation.

Caseinomacropeptide specifically stimulates exocrine pancreatic secretion in the anesthetized rat.

The effect of caseinomacropeptide (CMP) (the [106-169] fragment of kappa-casein produced during digestion of milk protein), was studied in anesthetized rats using bile diversion for a pure pancreatic juice collection system. Intraduodenal administration of CMP induced a dose-related specific stimulation of pancreatic secretion which was nearly abolished by devazepide, atropine, hexamethonium, vagotomy or perivagal capsaicin pretreatment. Moreover, CMP did not inhibit in vitro trypsin activity. These results demonstrate that CMP is more likely to stimulate pancreatic secretion specifically through cholecystokinin release and activation of a vago-vagal cholinergic reflex loop than by inhibition of luminal trypsin, in anesthetized rats.

Chronic nifedipine dosing enhances cephalexin bioavailability and intestinal absorption in conscious rats.

Cephalexin, a beta-lactam antibiotic, is rapidly absorbed via the di-and tripeptide intestinal transporters, as for many peptidomimetic drugs. Acute nifedipine has been shown to increase intestinal absorption of several beta-lactams: amoxicillin and cefixime in humans, and cephalexin in the rat. We showed previously that the nervous system was involved in the increasing effect of nifedipine on cephalexin intestinal absorption in anesthetized rats. The aim of the present study was 2-fold: 1) to investigate whether the effect of nifedipine is maintained in conscious rats, and 2) to determine whether the nifedipine effect will persist during chronic nifedipine administration. Acute and chronic oral administration of nifedipine significantly increased oral cephalexin area under the plasma concentration-time curve (34 and 25%, respectively) and maximum concentration in plasma (57 and 51%, respectively), while the distribution and elimination parameters of intra-arterial cephalexin were not affected by acute or chronic nifedipine administration. In conclusion, acute nifedipine effect on intestinal absorption of cephalexin is independent of anesthesia in rats. Since nifedipine could still enhance cephalexin intestinal absorption after a 7-day b.i.d. treatment, it can be envisaged to apply this effect to increase bioavailability of poorly absorbed peptidomimetic drugs in man.

Structure-activity studies including a Psi(CH(2)-NH) scan of peptide YY (PYY) active site, PYY(22-36), for interaction with rat intestinal PYY receptors: development of analogues with potent in vivo activity in the intestine.

Peptide YY (PYY) is a gut hormone that inhibits secretion and promotes absorption and growth in the intestinal epithelium. We have performed structure-activity studies with the active site, N-alpha-Ac-PYY(22-36)-NH(2), for interaction with intestinal PYY receptors. Investigation of aromatic substitutions at position 27 resulted in analogues that exhibited potent in vitro antisecretory potencies with N-alpha-Ac-[Trp(27)]PYY(22-36)-NH(2) exhibiting even greater potency than intact PYY. In vivo studies in dogs revealed that this analogue also promoted intestinal absorption of water and electrolytes during continuous intravenous and intraluminal infusion. Investigations carried out to identify features that would enhance stability revealed that incorporation of Trp(30) increased affinity for PYY receptors. A "CH(2)-NH" scan revealed that incorporation of reduced bonds at position 28-29 or 35-36 imparted greater receptor affinity. In general, disubstituted analogues designed based on the results of single substitutions exhibited good receptor affinity with N-alpha-Ac-[Trp(27),CH(2)-NH(35-36)]PYY(22-36)-NH(2) having the greatest affinity (IC(50) = 0.28 nM). Conservative multiple substitutions with Nle-->Leu and Nva-->Val also imparted good affinity. An analogue designed to encompass most of the favored substitutions, N-alpha-Ac-[Nle(24,28),Trp(30),Nva(31), CH(2)-NH(35-36)]PYY(22-36)-NH(2), exhibited a proabsorptive effect in dogs comparable to, but longer lasting than, that of intact hormone. Selected analogues also exhibited good antisecretory potencies in rats with N-alpha-Ac-[Trp(30)]PYY(22-36)-NH(2) being even more potent than PYY. However, the potencies did not correlate well with the PYY receptor affinity or the proabsorptive potencies in dogs. These differences could be due to species effects and/or the involvement of multiple receptors and neuronal elements in controlling the in vivo activity of PYY compounds. PYY(22-36) analogues exhibited good affinity for neuronal Y2 receptors but poor affinity for Y1 receptors. Also, crucial analogues in this series hardly bound to Y4 and Y5 receptors. In summary, we have developed PYY(22-36) analogues which, via interacting with intestinal PYY receptors, promoted potent and long-lasting proabsorptive and antisecretory effects in in vivo models. These compounds or analogues based on them may have useful clinical application in treating malabsorptive disorders observed under a variety of conditions.