[Hereditary renal tubule diseases].
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Child↗
Biomedical subjects
D Morin
Publications and source records attributed to D Morin.
Forelimb locomotor generators and quadrupedal locomotion in the neonatal rat.
The spinal localization of the forelimb locomotor generators and their interactions with other spinal segments were investigated on in vitro brainstem-spinal cord preparations of new-born rats. Superfusion of the cervicothoracic cord (C1-T4) with high K+/low Mg2+ artificial cerebrospinal fluid (aCSF) evoked rhythmic motor root activity that was limited to low cervical (C7, C8) and high thoracic (T1) spinal levels. This activity consisted of synchronous, homolateral bursts and a typical alternating bilateral pattern. Rhythmic activity with similar locomotor-like characteristics could be induced with either serotonin (5-HT, 5 microm), N-methyl-d-aspartate (NMDA, 5 microm), kainate (10 microm) or a "cocktail" of 5-HT (5 microm) and NMDA (5 microm). During 5-HT/NMDA perfusion of the cervicothoracic cord, induced bursting was no longer restricted to C7-T1 levels, but also occurred at cervical C3-C5 levels and with C5-C8 homolateral alternation. Spinal transections between C6 and C7 cervical segments did not abolish rhythmic activity in C7-T1, but suppressed locomotor-like rhythmicity at C3-C5 levels. Reduced regions comprising the C7-C8 or C8-T1 segments maintained rhythmicity. Superfusion of the whole cord with 5-HT/NMDA induced ventral root bursting with similar frequencies at all recorded segments (cervical, thoracic and lumbar). After isolation, the T3-T10 cord was unable to sustain any rhythmic activity while cervical and lumbar segmental levels continued to burst, albeit at different frequencies. We also found that the faster caudal and the slower rostral locomotor generators interact to produce coordinated locomotor-like activity in all segments of the intact spinal cord. In conclusion, C7-T1 spinal levels display a strong motor rhythmogenic ability; with the lumbar generators, they contribute to coordinated rhythmic activity along the entire spinal cord of a quadrupedal locomoting mammal.
Action Potentials↗
Is hyperprolinemia type I actually a benign trait? Report of a case with severe neurologic involvement and vigabatrin intolerance.
Hyperprolinemia type I is a deficiency of proline oxidase (McKusick 23950), leading to hyperprolinemia and iminoglycinuria, usually with renal involvement. Hyperprolinemia type I is considered a benign trait. We reported a case of hyperprolinemia type I with a severe neurologic disorder and without renal involvement. The patient had marked psychomotor delay and right hemiparesis. Epilepsy was characterized by status epilepticus or a cluster of seizures. Laboratory findings revealed elevated levels of proline in the serum, urine, and cerebrospinal fluid without delta1-pyrroline 5-carboxylate dehydrogenase in the plasma or urine. Fluorescence in situ hybridization excluded a chromosome 22q11 deletion. Vigabatrin inhibits ornithine transaminase. Thus, vigabatrin could lead to a depletion of the normal pool of pyrroline 5-carboxylate dehydrogenase and could aggravate the clinical condition of the child. In this study, vigabatrin was discontinued. In the following months, the patient had marked psychomotor improvement, without modification of the epilepsy. We suggest that vigabatrin should be avoided in hyperprolinemia type I.
Anticonvulsants↗
Metabolic capabilities of CYP2F2 with various pulmonary toxicants and its relative abundance in mouse lung subcompartments.
The tissue- and species-selective toxicity of a number of pulmonary toxicants has been attributed to the presence and distribution of activating enzymes with high k(cat) in target airways of susceptible species. The mouse is especially sensitive to a variety of metabolically activated lung toxicants. Recombinant CYP2F2 (mouse) was recently shown to effectively metabolize the species-selective pulmonary toxicant naphthalene. Here we show that the pulmonary toxicants 1-nitronaphthalene and 2-methylnaphthalene are metabolized readily with high k(cat) values (17.1 and 67.6 min(-1), respectively) to potentially cytotoxic intermediates at biologically relevant K(m) values (21.5 and 3.7 microM, respectively). Additionally, anthracene and benzo[a]pyrene are both metabolized by CYP2F2 (0.14 +/- 0.04 and 0.04 +/- 0.00 nmol/nmol/min, respectively), albeit at much lower rates. The levels of total CYP in mouse airways are considerably higher than those in parenchyma and trachea, and this is consistent with much higher rates of naphthalene metabolism in microsomal preparations from airways compared with the other subcompartments. The data suggest that CYP2F2 is a prominent cytochrome P450 in mouse lung that metabolizes a number of pulmonary toxicants. The presence of CYP2F2 may be important in the susceptibility of the mouse to metabolically activated pulmonary toxicants.
Animals↗
Development of lumbar rhythmic networks: from embryonic to neonate locomotor-like patterns in the mouse.
Different aspects of spinal locomotor organization have been studied in the mouse during embryonic and neonatal development using in vitro preparations of isolated lumbosacral cords. The first consideration was the embryonic development of an alternating bilateral pattern. From embryonic day (E) 12, perfusion of serotonin could induce relatively synchronous lumbar bursts across the cord. Bilateral activity became progressively alternate at E15 due to the appearance of glycinergic inhibitory interactions (revealed by strychnine application). Strictly alternating patterns were expressed at E18 and were maintained after birth. In a second step, we investigated cellular properties involved in lumbar rhythmogenesis in postnatal day 0-2 preparations which displayed spontaneous locomotor-like activity. Perfusion of receptor antagonists showed the co-operative involvement of N-methyl-D-aspartate (NMDA)- and non-NMDA-receptors for excitatory amino acids-mediated operation of locomotor networks. In a final step we investigated the localization of locomotor networks within the lumbar cord. Data obtained from preparations exhibiting spontaneous or Mg2+-free induced bursts revealed that the networks are present throughout the lumbar cord and that rhythmogenesis is distributed throughout all segmental levels.
Animals↗
S-15176 reduces the hepatic injury in rats subjected to experimental ischemia and reperfusion.
The protective effect of N-[(3, 5-di-tertiobutyl-4-hydroxy-1-thiophenyl)]-3-propyl-N'-(2,3, 4-trimethoxybenzyl)piperazine (S-15176) on liver injury induced by warm ischemia-reperfusion was investigated using a rat model. Animals were subjected to 2 h of ischemia followed by different reperfusion times. Hepatocyte integrity was assessed by measuring plasma alanine and aspartate aminotransferase activities, and by determining reduced and oxidized glutathione in plasma and bile. Hepatocyte function was quantitated by determining bile flow and liver ATP content. Ischemia-reperfusion resulted in severe hepatic injury involving a huge increase in alanine and aspartate aminotransferase activities, a drop in ATP content, and a decrease in bile flow. Plasma and bile reduced (GSH) and oxidized (GSSG) glutathione concentrations were inversely related: plasma levels increased when biliary levels decreased. This was associated with a decrease in animal survival (-34%). S-15176 pretreatment (1.25, 2.5, 5 or 10 mg kg(-1) day(-1)) improved the survival rate and limited tissue damages in a dose-dependent manner. The pretreatment also reduced the aminotransferase leakage from hepatocytes and the increase in plasma glutathione levels. In addition, normalization of the plasma GSSG/GSH ratio, a good index of an oxidative stress, was observed in groups treated with the higher dosage, suggesting that the antioxidant properties demonstrated for the compound in vitro (IC(50)=0.3 microM towards lipid peroxidation) could play a role in its protective effect. S-15176 pretreatment also protected the organ from the drop in ATP levels. At the higher dose, ATP content was maintained at a level almost 86% of the sham-operated group after 60 min of reperfusion. This was associated with a restoration of the biliary flow. These data suggest that S-15176 may be a useful drug in liver surgery to prevent ischemia-reperfusion injury.
Adenosine Triphosphate↗
Evidence for different interactions between beta(1)- and beta(2)-adrenoceptor subtypes with adenylyl cyclase in the rat brain: a concentration-response study using forskolin.
The aim of this study was to investigate beta(1)- and beta(2)-adrenoceptor signalling systems in the rat brain studying the synergistic effects between beta-adrenoceptor agonists and forskolin- induced activation of adenylyl cyclase. Experiments were performed in slices from cerebral cortex and cerebellum because they contain mainly beta(1)- and almost exclusively beta(2)- adrenoceptors, respectively. Five beta-adrenergic agonists were used, clenbuterol, flerobuterol, isoproterenol, salbutamol, and tulobuterol. All agonists stimulated cyclic AMP accumulation in the cerebral cortex but flerobuterol was inactive in the cerebellum. Forskolin amplified the generation of cyclic AMP. Forskolin potentiation was observed in glial cells but not in neurons and was not dependent on the number of beta-adrenoceptors. In return the amplitude of the potentiation was highly dependent on the intrinsic activity of the agonist in the cerebral cortex whereas it was constant whatever the agonist tested in the cerebellum. To analyse this difference we developed a modelling approach using a concentration-response study. Isoproterenol and forskolin stimulations of cyclic AMP production were studied either alone or in combination with increasing concentrations of forskolin and isoproterenol, respectively. In the cerebral cortex isoproterenol and forskolin were both able to potentiate the cyclic AMP accumulation induced by the other compound, whereas, in the cerebellum, isoproterenol was unable to increase the stimulation induced by forskolin. The results support the hypothesis that beta(1)- and beta(2)-adrenoceptors display distinct mechanisms of action in the signalling system by which they stimulate the accumulation of cyclic AMP.
Adenylyl Cyclases↗
[Quality of life of children after organ transplantation].
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Adaptation, Psychological↗
[(3)H]-trimetazidine mitochondrial binding sites: regulation by cations, effect of trimetazidine derivatives and other agents and interaction with an endogenous substance.
Trimetazidine, an antiischaemic drug, has been shown to restore impaired mitochondrial functions. Specific binding sites for [(3)H]-trimetazidine have been previously detected in liver mitochondria. In the present study we confirm this observation and provide additional evidence for the involvement of these sites in the pharmacological effects of the drug. Inhibition experiments using a series of trimetazidine derivatives revealed the presence of three classes of binding sites. An N-benzyl substituted analogue of trimetazidine exhibited a very high affinity (K(i)=7 nM) for one of these classes of sites. Compounds from different pharmacological classes were evaluated for their ability to inhibit [(3)H]-trimetazidine binding. Among the drugs tested pentazocine, ifenprodil, opipramol, perphenazine, haloperidol, and to a lower extent prenylamine, carbetapentane and dextromethorphan competed with high affinity, suggesting a similarity of high affinity [(3)H]-trimetazidine sites with sigma receptors. [(3)H]-Trimetazidine binding was modulated by pH. Neutral trimetazidine had about 10 fold higher affinity than protonated trimetazidine for its mitochondrial binding sites. Various cations also affected [(3)H]-trimetazidine binding. Ca(2+) was the most potent inhibitor and totally suppressed the binding of [(3)H]-trimetazidine to the sites of medium affinity. An endogenous cytosolic ligand was able to displace [(3)H]-trimetazidine from its binding sites. Its activity was not affected by boiling for 15 min, suggesting a non-protein compound. These data suggest that mitochondrial [(3)H]-trimetazidine binding sites could have a physiological relevance and be involved in the antiischaemic effects of the drug.
Algorithms↗
Conserved aromatic residues in the transmembrane region VI of the V1a vasopressin receptor differentiate agonist vs. antagonist ligand binding.
Despite their opposite effects on signal transduction, the nonapeptide hormone arginine-vasopressin (AVP) and its V1a receptor-selective cyclic peptide antagonist d(CH2)5[Tyr(Me)2]AVP display homologous primary structures, differing only at residues 1 and 2. These structural similarities led us to hypothesize that both ligands could interact with the same binding pocket in the V1a receptor. To determine receptor residues responsible for discriminating binding of agonist and antagonist ligands, we performed site-directed mutagenesis of conserved aromatic and hydrophilic residues as well as nonconserved residues, all located in the transmembrane binding pocket of the V1a receptor. Mutation of aromatic residues of transmembrane region VI (W304, F307, F308) reduced affinity for the d(CH2)5[Tyr(Me)2]AVP and markedly decreased affinity for the unrelated strongly hydrophobic V1a-selective nonpeptide antagonist SR 49059. Replacement of these aromatic residues had no effect on AVP binding, but increased AVP-induced coupling efficacy of the receptor for its G protein. Mutating hydrophilic residues Q108, K128 and Q185 in transmembrane regions II, III and IV, respectively, led to a decrease in affinity for both agonists and antagonists. Finally, the nonconserved residues T333 and A334 in transmembrane region VII, controlled the V1a/V2 binding selectivity for both nonpeptide and cyclic peptide antagonists. Thus, because conserved aromatic residues of the V1a receptor binding pocket seem essential for antagonists and do not contribute at all to the binding of agonists, we propose that these residues differentiate agonist vs. antagonist ligand binding.
Amino Acid Sequence↗
alpha1-adrenergic receptor-induced slow rhythmicity in nonrespiratory cervical motoneurons of neonatal rat spinal cord.
Previous studies have reported that the alpha1-adrenergic system can activate spinal rhythm generators belonging to the central respiratory network. In order to analyse alpha1-adrenergic effects on both cranial and spinal motoneuronal activity, phenylephrine (1-800 microM) was applied to in vitro preparations of neonatal rat brainstem-spinal cord. High concentration of phenylephrine superfusion exerted multiple effects on spinal cervical outputs (C2-C6), consisting of a lengthening of respiratory period and an increase in inspiratory burst duration. Furthermore, in 55% of cases a slow motor rhythm recorded from the same spinal outputs was superimposed on the inspiratory activity. However, this phenylephrine-induced slow motor rhythm generated at the spinal level was observed neither in inspiratory cranial nerves (glossopharyngeal, vagal and hypoglossal outputs) nor in phrenic nerves. Whole-cell patch-clamp recordings were carried out on cervical motoneurons (C4-C5), to determine first which motoneurons were involved in this slow rhythm, and secondly the cellular events underlying direct phenylephrine effects on motoneurons. In all types of motoneurons (inspiratory and nonrespiratory) phenylephrine induced a prolonged depolarization with an increase in neuronal excitability. However, only nonrespiratory motoneurons showed additional rhythmic membrane depolarizations (with spiking) occurring in phase with the slow motor rhythm recorded from the ventral root. Furthermore the tonic depolarization produced in all motoneurons results from an inward current [which persists in the presence of tetrodotoxin (TTX)] associated with a decrease in neuron input conductance, with a reversal potential varying as a Nernstian function of extracellular K+ concentration. Our results indicate that the alpha1-adrenoceptor activation: (i) affects both the central respiratory command (i.e. respiratory period and inspiratory burst duration) and spinal inspiratory outputs; (ii) induces slow spinal motor rhythmicity, which is unlikely to be related to the respiratory system; and (iii), increases motoneuronal excitability, probably through a decrease in postsynaptic leak K+ conductance.
Adrenergic alpha-Agonists↗
Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants.
Over 150 mutations within the coding sequence of the V2 vasopressin receptor (V2R) gene are known to cause nephrogenic diabetes insipidus (NDI). A large number of these mutant receptors fail to fold properly and therefore are not routed to the cell surface. Here we show that selective, nonpeptidic V2R antagonists dramatically increase cell-surface expression and rescue the function of 8 mutant NDI-V2Rs by promoting their proper folding and maturation. A cell-impermeant V2R antagonist could not mimic these effects and was unable to block the rescue mediated by a permeant agent, indicating that the nonpeptidic antagonists act intracellularly, presumably by binding to and stabilizing partially folded mutants. In addition to opening new therapeutic avenues for NDI patients, these data demonstrate that by binding to newly synthesized mutant receptors, small ligands can act as pharmacological chaperones, promoting the proper folding and maturation of receptors and their targeting to the cell surface.
Animals↗
[Lower pole pedicle in a series of 84 pyelo-ureteral junction syndromes surgically treated in children].
OBJECTIVE: To evaluate the involvement and consequences of the lower pole pedicle (LPP) associated with ureteropelvic junction syndrome. MATERIAL AND METHOD: Retrospective study in 81 children presenting a total of 84 ureteropelvic junction syndromes operated consecutively between 1994 and 1998. Urinary tract ultrasound and cystography were systematically performed. Renal scintigraphy (DTPA or MAG 3) was performed in 80 children. Preoperative intravenous urography was performed in 60 children. LPP was considered to be present when its participation in the obstruction was confirmed intraoperatively (Anderson Hynes technique with uncrossing of the vascular pedicle). RESULTS: Group I: a LPP was revealed in 24 kidneys (28.5% of cases), 17 left kidneys and 7 right kidneys, in 14 boys and 10 girls, with a mean age of 4 years (range: 2 months-14 years). Group II: 60 kidneys without LPP (71.5% of cases), 32 left kidneys and 28 right kidneys, in 40 boys and 17 girls, with a mean age of 2 years (range: 1 month-15 years). The most frequent presenting complaint was recurrent low back pain in 58% of cases in group I (14/24) and 5% of cases in group II (3/60). The mean age at diagnosis was 6 years. Hydronephrosis was detected by antenatal ultrasound in 33% of cases in group I (8/24) and in 72% of cases in group II (43/60). Kidney function in group I was greater than 40% in 19 patients, between 20 and 39% in 2 patients and less than 20% in 2 patients. These results were not influenced by age at diagnosis and were not significantly different from those observed in group II. Renal malrotation was observed in 2 cases in group I and in 12 cases in group II. Histology of the junction revealed nonspecific fibrosis in the same percentage of cases (91%) in the two groups. The mean follow-up was 15 months (range: 2 months-5 years). No surgical failure was observed. CONCLUSION: Ureteropelvic junction syndrome associated with a LPP appears to present later with recurrent low back pain in older children. It does not worsen the functional prognosis of the affected kidney. LPP can be visualized by duplex ultrasound. It may act as an inducer of obstruction by aggravating a pre-existing abnormality of the ureteropelvic junction. When LPP is associated with isolated dilatation of the pyelocaliceal cavities, the risk of subsequent decompensation requires closer ultrasound surveillance, until puberty.
Adolescent↗
Trimetazidine ameliorates the hepatic injury associated with ischaemia-reperfusion in rats.
Ischaemia-reperfusion induces structural and functional damage to hepatocytes. The purpose of this study was to evaluate the protective effect of trimetazidine, an anti- ischaemic drug, in a rat liver model of ischaemia-reperfusion. Male Wistar rats were divided into groups pretreated with different doses of trimetazidine (1, 5, 10 or 20 mg kg-1 day-1) or saline for 7 days. Liver ischaemia was induced for 120 min and blood reflow was subsequently restored for 30, 60, 90 or 120 min. The activities of alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) as well as the bile flow and the liver ATP content were determined. Ischaemia-reperfusion induced major alterations of hepatic functions involving increases of ASAT and ALAT activities, a drop of ATP content and a sharp decrease in bile flow. Trimetazidine pretreatment reduced the liver injury. Indeed, it lowered the increase in ALAT and ASAT activities observed immediately after reperfusion and maintained higher concentrations of hepatic ATP. Simultaneously, bile flow was increased. These effects were dose-dependent and 5 mg kg-1 day-1 seemed to be the lowest effective dose. In this experimental model trimetazidine pretreatment reduced the liver damage induced by ischaemia-reperfusion. Our data suggest that trimetazidine may be a useful drug in liver surgery to prevent ischaemia-reperfusion injury.
Animals↗
Comparison of ultrasound and dimercaptosuccinic acid scintigraphy changes in acute pyelonephritis.
The strategy for morphological investigations in children with acute pyelonephritis (APN) remains debatable. We studied 70 children (median age 2.0 years) admitted with a first episode of pyelonephritis using a high-resolution ultrasound technique (RUS) and compared the results with 99m technetium-dimercaptosuccinic acid (DMSA) renal scintigraphy. The DMSA scan was abnormal in 62 children (89%). However, using a high-frequency transducer we found abnormal sonogram changes in 61 children (87%), consisting of an increased kidney volume in 42, and/or a thickening of the wall of the renal pelvis in 42, and/or a focal hyper- or hypoechogenicity in 36, and/or a diffuse hyperechogenicity in 31 children. Micturating cystourethrography was performed in all children, revealing vesicoureteral reflux (VUR) in 22 (31%). Among those children with VUR, 4 had a normal DMSA scan, 2 an abnormal RUS, and 2 a normal DMSA scan and RUS. Our data suggest that B-mode RUS performed with a high-frequency transducer by a trained radiologist is nearly as sensitive as the DMSA scan in diagnosing renal involvement in children with unobstructed APN and in predicting VUR.
Acute Disease↗
[Hematuria revealing primary hyperparathyroidism in a child].
BACKGROUND: Hematuria rarely reveals primary hyperparathyroidism in the child. CASE REPORT: A 10-year-old boy presented with gross hematuria and urolithiasis. Biological findings showed hypercalcemia and hypercalciuria. Initially, parathormone plasma levels remained within normal range, but raised after a few months and at that time, ultrasound scan examination showed a parathyroid adenoma. Nevertheless, two surgical explorations were necessary to cure hypercalcemia and hyperparathyroidism. Histological aspects of parathyroid adenoma were not found on pathological examination. CONCLUSION: Symptomatic hypercalciuria may be the first symptom revealing primary hyperparathyroidism in children. Surgical treatment remains difficult in such a case.
Calcium↗
The pH-partition profile of the anti-ischemic drug trimetazidine may explain its reduction of intracellular acidosis.
PURPOSE: The anti-ischemic drug trimetazidine (TMZ) acts by a combination of molecular mechanisms which begin to be understood. Thus, it acts in the micromolar range to significantly reduce intracellular acidification during ischemia. To search for a possible physicochemical explanation of this phenomenon, we investigated the transfer mechanisms of the various electrical forms of this dibasic drug. METHODS: The transfer characteristics of TMZ were studied by electrochemistry at the water/1,2-dichloroethane interface. Cyclic voltammetry was used to measure the formal transfer potentials of singly and doubly protonated forms of TMZ (noted TH+ and TH(2)2+, respectively) as a function of aqueous pH, and the partition coefficient of neutral TMZ (log P(T)) was measured by two-phase titration. RESULTS: log P(T) was measured to be 1.04 +/- 0.06, and the acid-base dissociation constants in water were deduced to be pK(w)a1 = 4.54 +/- .02 and pK(w)a2 = 9.14 +/- 0.02. The partition coefficients of TH+ and TH(2)2+ were found to be respectively log P0'TH+ = -3.78 +/- 0.16 and log P0'TH(2)2+ = -9.84 +/- 0.30, which agrees well with the charge being delocalized on two nitrogen atoms in TH+. The pH-partition profile of TMZ was then established in the form of its ionic partition diagram, which showed that the affinity of the ions for the organic phase is pH-dependent and strongly increased by the interfacial potential. CONCLUSIONS: This behavior suggests a physicochemical mechanism whereby efflux of protonated TMZ out of an acidified cell is facilitated, in effect exporting protons to extracellular space.
Acid-Base Equilibrium↗
Proprioceptive control of wrist extensor motor units in humans: dependence on handedness.
The effectiveness of the monosynaptic proprioceptive assistance to the wrist extensor motoneurone activity was investigated during voluntary contraction in relation to the subjects' handedness. The reflex responses of 411 single motor units to homonymous tendon taps were recorded in the wrist extensor carpi radialis muscles in both arms of five right-handed and five left-handed subjects. In the right-handed subjects, the motor unit reflex responses were clearly lateralized in favour of their right arm, whereas no side-related differences were observed in the left-handed subjects, whatever the motor units' mechanical properties and firing rates. When the muscle spindle sensitivity was by-passed by electrically stimulating the primary afferents in both arms of three right-handed and three left-handed subjects, no side-related differences were observed in the Hoffmann reflex (H-reflex) amplitude in either of the two lateralization groups. The effectiveness of the primary afferent synapses on to the motoneurones therefore does not seem to depend on the subject's handedness. Without excluding the possibility of structural changes being involved at the periphery, the comparisons carried out on the data obtained using electrical vs mechanical stimulation suggest that the asymmetrical effectiveness of the proprioceptive assistance observed in favour of the right arm in the right-handed subjects might result from either the gamma or beta drive being more efficient. This asymmetry might result from the preferential use of the right hand in skilled movements. In a predominantly right-handed world, however, left-handed people might tend to develop the ability to use their right arm almost as skillfully as their preferred left arm, which could explain the symmetrical effectiveness of the proprioceptive assistance observed here in the left-handers' wrist extensor muscles.
Action Potentials↗