A detailed mapping of dopamine D-2 receptors in rat central nervous system by autoradiography with [125I]iodosulpride

The benzamide derivative [125I]iodosulpride was used to generate light microscopic autoradiograms on sections of rat brain and spinal cord. Sites specifically labelled by [125I]iodosulpride over a low background correspond to dopamine D-2 receptors as shown by their pharmacology established by densitometric analysis of 11 typical areas from autoradiograms generated in the presence of five dopamine-competing agents. An atlas of D-2 receptors was established using 1 horizontal, 6 sagittal and 30 frontal sections, the latter serially prepared at 0.5-1 mm intervals. Labelled areas were identified by comparison with corresponding, classically stained sections. When their density, rated according to an arbitrary scale, was then compared to that previously reported for dopamine innervation, evaluated from distributional maps of dopamine histofluorescence or tyrosine hydroxylase immunoreactivity, three situations were found. In areas corresponding to cells of origin and established projection fields of the mesostriatal, mesolimbocortical, diencephalospinal and periglomerular systems the density of D-2 receptors generally paralleled that of dopamine innervation. D-2 receptors in substantia nigra (pars compacta or reticulata) and ventral tegmental area were strongly reduced after injections of the neurotoxin 6-hydroxydopamine into the medial forebrain bundle, suggesting their major localization on dendrites and perikarya of dopamine neurons. Most other described dopamine cell group areas also contained D-2 receptors. In contrast many areas without established dopamine innervation contained D-2 receptors, sometimes in high density. This was the case for large areas of the cerebral cortex (layers I-III and V-VI) outside the established projection fields of the mesocortical system, the cerebellum (moleculare layer and dense patches within lobule 9), the hippocampal formation (lacunosum moleculare layer), several septal, thalamic and hypothalamic nuclei, large tectal areas, numerous brainstem areas (including cranial nerve nuclei), etc. This situation might correspond to areas with minor and still undetected dopamine innervation or to a localization of D-2 receptors on cells (or cell parts) not receiving dopamine inputs. Finally several well-established dopaminergic areas did not reveal any D-2 receptor labelling. This was particularly the case in the hypothalamus (areas of origin or termination of the tuberohypophyseal and incertohypothalamic dopamine systems) but also in the hippocampal formation (alveus, fimbria, hilus dentate gyrus), amygdaloid complex (anterior, basolateral, medial nuclei).(ABSTRACT TRUNCATED AT 400 WORDS)     

The Isolation of Numerals at the Semantic Level

Abstract

In this study, we examine the case of a patient (NM) who could comprehend and produce numerals despite impairment on comprehension tasks and a high degree of anomia for other categories of words. It will be claimed that NM suffered from an impairment to the semantic system affecting all categories except numerals and the series of days and months. The case of a patient presenting with the exact reverse dissociation has been described a few years ago by Cipolotti et al. (Brain 1991; 114: 619–37). We conclude that NM's pattern of performance provides evidence that numerals constitute a relevant and perhaps a distinct category at the semantic level.     

The PROPKD Score: A New Algorithm to Predict Renal Survival in Autosomal Dominant Polycystic Kidney Disease

The course of autosomal dominant polycystic kidney disease (ADPKD) varies among individuals, with some reaching ESRD before 40 years of age and others never requiring RRT. In this study, we developed a prognostic model to predict renal outcomes in patients with ADPKD on the basis of genetic and clinical data. We conducted a cross-sectional study of 1341 patients from the Genkyst cohort and evaluated the influence of clinical and genetic factors on renal survival. Multivariate survival analysis identified four variables that were significantly associated with age at ESRD onset, and a scoring system from 0 to 9 was developed as follows: being male: 1 point; hypertension before 35 years of age: 2 points; first urologic event before 35 years of age: 2 points; PKD2 mutation: 0 points; nontruncating PKD1 mutation: 2 points; and truncating PKD1 mutation: 4 points. Three risk categories were subsequently defined as low risk (0–3 points), intermediate risk (4–6 points), and high risk (7–9 points) of progression to ESRD, with corresponding median ages for ESRD onset of 70.6, 56.9, and 49 years, respectively. Whereas a score ≤3 eliminates evolution to ESRD before 60 years of age with a negative predictive value of 81.4%, a score >6 forecasts ESRD onset before 60 years of age with a positive predictive value of 90.9%. This new prognostic score accurately predicts renal outcomes in patients with ADPKD and may enable the personalization of therapeutic management of ADPKD.     

Preorthographical constraints on visual word recognition: evidence from a case study of developmental surface dyslexia

We investigated the visual word recognition ability of M.T., a young boy with surface dyslexia, by means of a paradigm that measures performance as a function of the eye fixation position within the word, known as the "viewing-position effect" paradigm. In well-achieving readers, the viewing-position effect is mainly determined by factors affecting letter visibility and by lexical constraints on word recognition. We further quantified M.T.'s sensory limitations on letter visibility by computing visual-span profiles - that is, the number of letters recognizable at a glance. Finally, in an ideal-observer's perspective, M.T.'s performance was compared with a parameter-free model combining M.T.'s letter visibility data with a simple lexical matching rule. The results showed that M.T. did not use the whole visual information available on letter identities to recognize words and that preorthographical factors constrained his word recognition performance. The results can be best accounted for by a reduction of the number of letters processed in parallel.     

Differential systemic and regional hemodynamic profiles of four angiotensin-I converting-enzyme inhibitors in the rat

Summary Angiotensin-converting enzyme (ACE) inhibitors decrease blood pressure by reducing systemic vascular resistance. That the peripheral vasodilating properties of ACE inhibitors might not be homogeneously distributed in all vascular beds and might differ from one drug to another has been investigated in the normotensive rat by the pulsed Doppler technique using the active components of four different ACE inhibitors: captopril, enalapril, perindopril, and ramipril.Systemic (cardiac output and blood pressure) and regional (kidney, mesentery, hindquarter) hemodynamic responses to saline or to cumulative bolus injections (0.01–1 mg/kg) of captopril, enalaprilat, perindoprilat, or ramiprilat were continuously monitored. The effects of successive bolus injections (0.3–300 ng/kg) of angiotensinII were also investigated. The four ACE inhibitors produced an almost complete blockade of plasma angiotensin-II converting-enzyme activity (83%, 100%, 100%, and 100%, respectively), induced dose-dependent decreases in mean blood pressure, did not significantly affect cardiac output, and reduced total peripheral and mesenteric vascular resistances to the same extent. Hindlimb vascular resistance was identically decreased, but to a lower extent than total peripheral resistance by enalaprilat, perindoprilat, and ramiprilat, whereas it was increased by captopril at low doses only. Renal resistance was markedly decreased by the four drugs, and éspecially by captopril. The decreasing rank order for ACE-inhibitor-induced vasodilation is exactly the same (renal>total peripheral=mesenteric >hindlimb vascular resistances) as that of angiotensin-II-induced regional vasoconstriction, indicating that the vasodilator properties of ACE inhibitors are mainly due to angiotensin-II vasomotor tone suppression. None of the investigated compounds significantly affected mesenteric and hindlimb blood flows, except captopril, which lowered the latter significantly. Finally, the four drugs increased renal blood flow markedly.Thus, the four drugs exhibited different regional vasodilating patterns, those of enalaprilat, perindoprilat, and ramiprilat being almost similar, while that of captopril was different.     

Assessment of antioxidative activity of lipid- and water-soluble vitamins in human whole blood. Comparative analysis between a biological test and chemical methods

Assessment of the antioxidant activity of vitamins and other compounds is of interest in the understanding of their in vivo effects. In this study, we have investigated the activity of several lipid and water-soluble vitamins in human whole blood. Measurements were carried out using a biological test that enables the evaluation of both red blood cells and plasma resistance against free radical activity induced by 2,2'-azobis (2-amidinopropane)hydrochloride (AAPH). Antioxidant activity of vitamins has been determined by using the biological test versus chemical methods (chemiluminescence, DMPD radical). We have observed strong anti-oxidant potentials for vitamins B6 and B9 with biological tests, but not with chemical methods. At 10 microM, the vitamin B9 efficiency in inhibiting radical-induced red blood cell hemolysis was almost three times higher than vitamin C efficiency and two times higher than alpha-tocopherol efficiency. Antioxidant activity was not observed for vitamins B1 or B2, nor for retinol. The weak activity of beta-carotene still remains to be investigated particularly in relation to oxygen pressure. Our study demonstrated that the biological test is more useful than the chemical methods employed in this instance, for the evaluation of antioxidant capacity of lipophilic and putatively biologically active compounds.     

Arabic number reading deficit: A single case study or when 236 is read (2306) and judged superior to 1258

Abstract

This paper presents a single-case study of a patient (NR) showing a very specific (though not isolated) disorder in Arabic number reading. The type of reading errors and the pattern of the results observed in tasks tapping different components of the number processing system support the hypothesis of a deficit in the syntactic module of the Arabic comprehension system (in McCloskey, Sokol, & Goodman's [1986] model). NR's deficit is also examined in the light of two other number reading models: Seron and Deloche (1984) and Cohen and Dehaene (1991). In addition, the opposition beween semantic and asemantic transcoding models is discussed. In tasks based on a representation of the quantity, NR's errors with Arabic forms seem to result from correct semantic processing based on the expected verbal transcoded forms; this is easily interpretable in the semantic transcoding model (e.g. McCloskey et al., 1986), whereas in asemantic perspectives (e.g. Seron & Deloche, 1984; Cohen & Dehaene, 1991) no direct explanation is proposed. In this respect, a “preferred entry code” hypothesis is developed.     

Severe Serotonin Depletion after Conditional Deletion of the Vesicular Monoamine Transporter 2 Gene in Serotonin Neurons: Neural and Behavioral Consequences

The vesicular monoamine transporter type 2 gene (VMAT2) has a crucial role in the storage and synaptic release of all monoamines, including serotonin (5-HT). To evaluate the specific role of VMAT2 in 5-HT neurons, we produced a conditional ablation of VMAT2 under control of the serotonin transporter (slc6a4) promoter. VMAT2^sert−cre mice showed a major (−95%) depletion of 5-HT levels in the brain with no major alterations in other monoamines. Raphe neurons contained no 5-HT immunoreactivity in VMAT2^sert−cre mice but developed normal innervations, as assessed by both tryptophan hydroxylase 2 and 5-HT transporter labeling. Increased 5-HT_1A autoreceptor coupling to G protein, as assessed with agonist-stimulated [³⁵S]GTP-γ-S binding, was observed in the raphe area, indicating an adaptive change to reduced 5-HT transmission. Behavioral evaluation in adult VMAT2^sert−cre mice showed an increase in escape-like reactions in response to tail suspension and anxiolytic-like response in the novelty-suppressed feeding test. In an aversive ultrasound-induced defense paradigm, VMAT2^sert−cre mice displayed a major increase in escape-like behaviors. Wild-type-like defense phenotype could be rescued by replenishing intracellular 5-HT stores with chronic pargyline (a monoamine oxidase inhibitor) treatment. Pargyline also allowed some form of 5-HT release, although in reduced amounts, in synaptosomes from VMAT2^sert−cre mouse brain. These findings are coherent with the notion that 5-HT has an important role in anxiety, and provide new insights into the role of endogenous 5-HT in defense behaviors.