[Papillary cystadenoma of the epididymis revealing von Hippel-Lindau disease].
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Adult↗
Biomedical subjects
S Richard
Publications and source records attributed to S Richard.
HCaRG, a novel calcium-regulated gene coding for a nuclear protein, is potentially involved in the regulation of cell proliferation.
Since a negative calcium balance is present in spontaneously hypertensive rats, we searched for the gene(s) involved in this dysregulation. A cDNA library was constructed from the spontaneously hypertensive rat parathyroid gland, which is a key regulator of serum-ionized calcium. From seven overlapping DNA fragments, a 1100-base pair novel cDNA containing an open reading frame of 224 codons was reconstituted. This novel gene, named HCaRG (hypertension-related, calcium-regulated gene), was negatively regulated by extracellular calcium concentration, and its basal mRNA levels were higher in hypertensive animals. The deduced protein showed no transmembrane domain, 67% alpha-helix content, a mutated calcium-binding site (EF-hand motif), four putative "leucine zipper" motifs, and a nuclear receptor-binding domain. At the subcellular level, HCaRG had a nuclear localization. We cloned the human homolog of this gene. Sequence comparison revealed 80% homology between rats and humans at the nucleotide and amino acid sequences. Tissue distribution showed a preponderance in the heart, stomach, jejunum, kidney (tubular fraction), liver, and adrenal gland (mainly in the medulla). HCaRG mRNA was significantly more expressed in adult than in fetal organs, and its levels were decreased in tumors and cancerous cell lines. We observed that after 60-min ischemia followed by reperfusion, HCaRG mRNA declined rapidly in contrast with an increase in c-myc mRNA. Its levels then rose steadily to exceed base line at 48 h of reperfusion. HEK293 cells stably transfected with HCaRG exhibited much lower proliferation, as shown by cell count and [(3)H]thymidine incorporation. Taken together, our results suggest that HCaRG is a nuclear protein potentially involved in the control of cell proliferation.
Adaptor Proteins, Signal Transducing↗
Comparison of methyl anthranilate and denatonium benzoate as aversants for learning in chicks.
Methyl anthranilate (MeA) has been widely used as a taste aversant for domestic chicks in the one-trial passive avoidance learning (PAL) task. However, MeA has a strong smell that may be aversive to chicks. Therefore, odourless denatonium benzoate (DB) has been suggested as an alternative taste aversant in PAL. The present study was designed to compare the efficacy of MeA and DB as aversants in the one-trial PAL task. In this task, young chicks peck a visually conspicuous bead coated with a taste aversant and in a single trial learn to avoid a similar, but uncoated bead at subsequent presentation. In Experiment 1, chicks were trained using a silver-coloured bead coated with 100% MeA, 0.5% DB or distilled water. After 3 h, MeA-trained, but not DB-trained chicks, exhibited significantly higher avoidance of the test bead than water-trained chicks. In Experiment 2, three pre-training presentations of an uncoated red bead preceded training with the silver bead. MeA-trained chicks showed significantly higher avoidance of the test bead than water-trained chicks. The numbers of water- and DB-trained chicks that avoided pecking the test bead were low and not significantly different from each other. However, DB-trained chicks exhibited significantly longer latencies to peck the test bead than water-trained chicks, indicating that they had retained some memory of the task. Thus, 0.5% DB is a weaker aversant than MeA and it does not induce high levels of learning in the one-trial PAL task. However, DB may prove useful for investigating weakly reinforced learning.
Animals↗
Overexpression of T-type calcium channels in HEK-293 cells increases intracellular calcium without affecting cellular proliferation.
Increased expression of low voltage-activated, T-type Ca(2+) channels has been correlated with a variety of cellular events including cell proliferation and cell cycle kinetics. The recent cloning of three genes encoding T-type alpha(1) subunits, alpha(1G), alpha(1H) and alpha(1I), now allows direct assessment of their involvement in mediating cellular proliferation. By overexpressing the human alpha(1G) and alpha(1H) subunits in human embryonic kidney (HEK-293) cells, we describe here that, although T-type channels mediate increases in intracellular Ca(2+) concentrations, there is no significant change in bromodeoxyuridine incorporation and flow cytometric analysis. These results demonstrate that expressions of T-type Ca(2+) channels are not sufficient to modulate cellular proliferation of HEK-293 cells.
Calcium↗
Arginine methylation inhibits the binding of proline-rich ligands to Src homology 3, but not WW, domains.
Src homology 3 (SH3) and WW domains are known to associate with proline-rich motifs within their respective ligands. Here we demonstrate that the proposed adapter protein for Src kinases, Sam68, is a ligand whose proline-rich motifs interact with the SH3 domains of p59(fyn) and phospholipase Cgamma-1 as well as with the WW domains of FBP30 and FBP21. These proline-rich motifs, in turn, are flanked by RG repeats that represent targets for the type I protein arginine N-methyltransferase. The asymmetrical dimethylation of arginine residues within these RG repeats dramatically reduces the binding of the SH3 domains of p59(fyn) and phospholipase Cgamma-1, but has no effect on their binding to the WW domain of FBP30. These results suggest that protein arginine methylation can selectively modulate certain protein-protein interactions and that mechanisms exist for the irreversible regulation of SH3 domain-mediated interactions.
Amino Acid Sequence↗
Evidence for tetrodotoxin-sensitive sodium currents in primary cultured myocytes from human, pig and rabbit arteries.
Primary cultured human coronary myocytes express a tetrodotoxin-sensitive sodium current (I(Na)). Here, we have investigated whether I(Na) is expressed in vascular smooth muscles cells (VSMCs) isolated from other large arteries, and other mammals. VSMCs were enzymatically dissociated, kept in primary culture, and macroscopic I(Na) was recorded using the whole-cell patch-clamp technique. We found that I(Na) is expressed in VSMCs grown from human aortic (90%; n=50) and pulmonary (44%; n=19) arteries, and in the human aortic myocyte cell line HAVSMC (94%; n=27). I(Na) was also detected in pig coronary (60%; n=33), and rabbit aortic (47%; n=15), but not in rat aortic VSMCs (n=20). These different I(Na) had similar voltage thresholds for activation (approximately equal to -50 mV), and were highly sensitive to extracellularly applied tetrodotoxin. We conclude that I(Na) is expressed in VSMCs grown from various types of large arteries in humans, pig and rabbit.
Animals↗
Central nervous system hemangioblastomas, endolymphatic sac tumors, and von Hippel-Lindau disease.
Von Hippel-Lindau disease (VHL) is a hereditary cancer syndrome caused by germline mutations of the VHL tumor suppressor gene. Major progress has been made in the last decade in both clinical and fundamental aspects of VHL. The VHL gene product, pVHL, has major and multiple functions: pVHL regulates not only first angiogenesis but also extracellular matrix formation and the cell cycle. A molecular diagnosis of VHL is now available, leading to a transformation in clinical management of patients and their families. Diagnosis of VHL has to be suspected in patients with a VHL-related tumor without familial history and especially in case of hemangioblastoma or endolymphatic sac tumors. Such patients should be systematically investigated for clinical and molecular evidence of VHL disease. Treatment of symptomatic hemangioblastomas remains mainly neurosurgical, often in emergency, but stereotactic radiosurgery is emerging as an alternative therapeutic procedure. In the future, antiangiogenic drugs could represent a potential medical treatment of CNS hemangioblastomas in view of their highly vascular structure. Lastly, visceral manifestations of VHL disease are also of critical importance and require early detection for effective treatment.
Central Nervous System Neoplasms↗
Facilitation of L-type calcium currents by diastolic depolarization in cardiac cells: impairment in heart failure.
OBJECTIVE: Decay kinetics of the voltage-gated L-type Ca(2+) current (I(CaL)) control the magnitude of Ca(2+) influx during the cardiac action potential. We investigated the influence of changes in diastolic membrane potential on I(CaL) decay kinetics in cardiac cells. METHODS: Cells were isolated enzymatically from rat ventricles, human right atrial appendages obtained during corrective heart surgery and left ventricles from end-stage failing hearts of transplant recipients. The whole-cell patch-clamp technique was used to evoke I(CaL) by a 100-ms depolarizing test pulse to -10 mV. Conditioning potentials between -80 and 0 mV were applied for 5 s prior to the test pulse. RESULTS: Depolarizing the cells between -80 and -50 mV prior to the test pulse slowed the early inactivation of I(CaL) both in rat ventricular and human atrial cells. This slowing resulted in a significant increase of Ca(2+) influx. This type of facilitation was not observed when the sarcoplasmic reticulum (SR) Ca(2+) content was depleted using ryanodine which reduced the rate of inactivation of I(CaL), or when Ba(2+) replaced Ca(2+) as the permeating ion. Facilitation was favored by intracellular cAMP-promoting agents that, in addition to increasing current peak amplitude, enhanced the fast Ca(2+)-dependent inactivation of I(CaL). Facilitation was impaired in atrial and ventricular human failing hearts. CONCLUSION: Decay kinetics of I(CaL) are regulated by the diastolic membrane potential in rat and human cardiomyocytes. This regulation, which associates slowing of I(CaL) inactivation with reduced SR Ca(2+) release and underlies facilitation of Ca(2+) channels activity, may have profound physiological relevance for catecholamines enhancement of Ca(2+) influx. It is impaired in failing hearts, possibly due to lowered SR Ca(2+) release.
Adrenergic beta-Agonists↗
Facilitation of the L-type calcium current in rabbit sino-atrial cells: effect on cardiac automaticity.
OBJECTIVE: The L-type Ca(2+) current (I(Ca,L)) contributes to the generation and modulation of the pacemaker action potential (AP). We investigated facilitation of I(Ca,L) in sino-atrial cells. METHODS: Facilitation was studied in regularly-beating cells isolated enzymatically from young albino rabbits (0.8-1 kg). We used the whole-cell patch-clamp technique to vary the frequency of the test depolarizations evoked at -10 mV or the conditioning diastolic membrane potential prior to the test pulse. RESULTS: High frequencies (range 0.2-3.5 Hz) slowed the decay kinetics of I(Ca,L) evoked from a holding potential (HP) of -80 mV in 68% of cells resulting in a larger Ca(2+) influx during the test pulse. The amount of facilitation increased progressively between 0.2 and 3.0 Hz. When the frequency was changed from 0.1 to 1 Hz, the averaged increase in the time integral of I(Ca,L) was 27+/-7% (n=22). Application of conditioning voltages between -80 and -50 mV induced similar facilitation of I(Ca,L) in 73% of cells. The maximal increase of Ca(2+) entry occurred between -60 and -50 mV, and was on average 38+/-14% for conditioning prepulses of 5 s in duration (n=15). Numerical simulations of the pacemaker activity showed that facilitation of I(Ca,L) promotes stability of sino-atrial rate by enhancing Ca(2+) entry, thus establishing a negative feedback control against excessive heart rate slowing. CONCLUSION: Facilitation of I(Ca,L) is present in rabbit sino-atrial cells. The underlying mechanism reflects modulation of I(Ca,L) decay kinetics by diastolic membrane potential and frequency of depolarization. This phenomenon may provide an important regulatory mechanism of sino-atrial automaticity.
Animals↗
Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels.
The voltage gated calcium channel family is a major target for a range of therapeutic drugs. Mibefradil (Ro 40-5967) belongs to a new chemical class of these molecules which differs from other Ca2+ antagonists by its ability to potently block T-type Ca2+ channels. However, this molecule has also been shown to inhibit other Ca2+ channel subtypes. To further analyze the mechanism governing the Ca2+ channel-Mibefradil interaction, we examined the effect of Mibefradil on various recombinant Ca2+ channels expressed in mammalian cells from their cloned cDNAs, using Ca2+ as the permeant ion at physiological concentration. Expression of alpha1A, alpha1C, and alpha1E in tsA 201 cells resulted in Ca2+ currents with functional characteristics closely related to those of their native counterparts. Mibefradil blocked alpha1A and alpha1E with a Kd comparable to that reported for T-type channels, but had a lower affinity (approximately 30-fold) for alpha1C. For each channel, inhibition by Mibefradil was consistent with high-affinity binding to the inactivated state. Modulation of the voltage-dependent inactivation properties by the nature of the coexpressed beta subunit or the alpha1 splice variant altered block at the Mibefradil receptor site. Therefore, we conclude that the tissue and sub-cellular localization of calcium channel subunits as well as their specific associations are essential parameters to understand the in vivo effects of Mibefradil.
Alternative Splicing↗
The organization of the striatal output system: a single-cell juxtacellular labeling study in the rat.
The aim of the present study was to provide a detailed account of the axonal branching pattern of striatal projection neurons in the rat. Seventy-seven striatofugal neurons were singly labeled following juxtacellular injection of biotin dextran amine. Their axons were entirely reconstructed along the sagittal plane with the help of a light microscope equipped with a camera lucida. The major findings of this study can be summarized as follows, (1) the striatofugal system originates from medium-sized spiny neurons that project only to globus pallidus (GP, type I, 36.4%), to both GP and substantia nigra pars reticulata (SNr, type II, 26%), or to globus pallidus, entopeduncular nucleus (EP) and SNr (type III, 37.6%); (2) the striatofugal system displays a high degree of axonal collateralization; about two-thirds of its axons arborize into two or three striatal target structures; (3) virtually all striatofugal axons send collaterals to the GP and none project exclusively to the EP and or SNr; (4) the three types of striatal projection neurons share similar somatodendritic morphology and have no preferential distribution in the dorsal striatum. These data, together with those of previous investigations, indicate that the striatofugal system can no longer be considered to be a simple dual (direct indirect) projection system. Instead, it stands out as a complex and widely distributed neuronal network whose elements are endowed with a highly patterned set of axon collaterals, which allows them to control in an exquisitely precise manner the flow of information along the main axis of the basal ganglia.
Animals↗
Isolation and characterization of a dehydrin gene from white spruce induced upon wounding, drought and cold stresses.
A cDNA clone encoding a dehydrin gene was isolated from a cDNA library prepared from white spruce (Picea glauca) needle mRNAs. The cDNA, designated PgDhn1, is 1159 nucleotides long and has an open reading frame of 735 bp with a deduced amino acid sequence of 245 residues. The PgDhn1 amino acid sequence is highly hydrophilic and possesses four conserved repeats of the characterized lysine-rich K-segment (EKKGIMD-KIKEKLPG), and an 8-serine residue stretch prior to the first lysine-rich repeat that is common to many dehydrins. The DEYGNP conserved motif is, however, absent in the PgDhn1 sequence. In unstressed plants, the highest level of transcripts was detected in stem tissue and not fully expanded vegetative buds. PgDhn1 expression was also clearly detected in reproductive buds, at various stages of development. The mRNAs corresponding to PgDhn1 cDNA were induced upon wounding and by jasmonic acid (JA) and methyl jasmonate (MeJa) treatments. Upon drought stress, increased transcript accumulation was observed in needle tissue reaching a maximum level 48 h after treatment. Treatments of seedlings with abscisic acid or ethephon also resulted in high levels of transcript accumulation in needle tissue. Finally, cold induction of PgDhn1 transcripts was also detected as early as 8 h after treatment.
Abscisic Acid↗
An immunological syndrome featuring transverse myelitis, Evans syndrome and pulmonary infiltrates after unrelated bone marrow transplant in a patient with severe aplastic anemia.
A patient with severe aplastic anemia underwent a matched unrelated bone marrow transplant, following which he developed a complex autoimmune syndrome. This featured transverse myelitis, immune mediated Coombs positive hemolytic anemia and immune thrombocytopenia (Evans syndrome), pulmonary infiltrates, eosinophilia, muscle pains and cramps and lichenoid dermatitis all of which may represent manifestations of graft-versus-host disease as they showed response to immunosuppression. Thus, although immune-mediated cytopenias after an allogeneic bone marrow transplant are rare, they should be considered as a possible cause of cytopenia in post-transplant patients.
Adult↗
Renal lesions in von Hippel-Lindau disease: immunohistochemical expression of nephron differentiation molecules, adhesion molecules and apoptosis proteins.
AIMS: Renal lesions in von Hippel-Lindau disease comprise clear cell simple cysts, atypical cysts and carcinomas. Although histological and molecular studies suggest that cystic lesions may represent precursors of carcinomas, there is no detailed phenotypic evidence of their relationship. METHODS AND RESULTS: To investigate such a possible relationship between cystic lesions and solid carcinomas, we studied the pathological and immunohistochemical features of 328 lesions of 33 kidneys originating from 23 patients with von Hippel-Lindau disease, using a panel of antibodies directed against cytoskeleton proteins, cell surface proteins, integrin subunits, adhesion molecules, lectins, and apoptosis and proliferation markers. Solid carcinomas (n = 175) were all of clear cell type and mostly nuclear grade 1. Cystic lesions (n = 138) consisted of cystic clear cell carcinomas (n = 15), atypical cysts (n = 20) and simple cysts (n = 103). Clear cells of the simple cysts, atypical cysts and solid carcinomas coexpressed cytokeratins (CK8, CK19) and vimentin, and expressed a similar pattern of tubular markers (CD24, tetraglonolobus), integrin subunits (alpha3, alpha5, alpha6, alphav, beta1) and cell adhesion molecules (ICAM 1, VCAM 1). In all lesions studied, proliferation rate (MIB1 index) was low, and apoptosis marker expression (fragmented DNA, p53, bcl-2) inconspicuous. CONCLUSIONS: Phenotypic alterations found in solid renal cell carcinomas are already present in simple and atypical renal cysts of von Hippel-Lindau disease.
Adenocarcinoma, Clear Cell↗
Pancreatic involvement in von Hippel-Lindau disease. The Groupe Francophone d'Etude de la Maladie de von Hippel-Lindau.
BACKGROUND & AIMS: Pancreatic involvement in von Hippel-Lindau (VHL) disease, a genetic disorder with a dominant mode of inheritance affecting various organs, has rarely been studied. We assessed the prevalence, type of lesions, natural history, and impact of pancreatic involvement in patients with VHL. METHODS: A total of 158 consecutive patients from 94 families with VHL disease were studied in a prospective French collaborative study. All patients underwent systematic screening for VHL lesions, including computerized tomography (CT) scanning of the pancreas reviewed by an experienced radiologist. Clinical data, investigations, and treatments performed were also reviewed. RESULTS: Pancreatic involvement was observed in 122 patients (77.2%) and included true cysts (91.1%), serous cystadenomas (12.3%), neuroendocrine tumors (12.3%), or combined lesions (11.5%). The pancreas was the only organ affected in 7.6% of patients. Patients with pancreatic lesions had fewer pheochromocytomas than those without (14/122 vs. 16/36; P<0.0001), and patients with neuroendocrine pancreatic tumors had renal involvement less often than those without (8/99 vs. 6/20; P = 0.013). None of the patients with neuroendocrine tumors had symptoms of hormonal hypersecretion. Pancreatic lesions evolved in half of patients but required specific treatment in only 10 (8.2%) when they were symptomatic or for the resection of large neuroendocrine tumors. CONCLUSIONS: Pancreatic involvement is seen in most patients with VHL disease. Although symptoms are rare, specific treatment of pancreatic lesions is required in selected patients, mainly those with neuroendocrine tumors.
Adult↗
What some effects might not be: the time to verify membership in "well-defined" categories.
Armstrong, Gleitman, and Gleitman (1983) reported shorter categorization times for members of well-defined categories judged more typical. They concluded that these effects could not originate in a graded, similarity-based category representation and consequently that the typicality effects obtained with natural categories might not be indicative of such a structure either. In this article, we re-examine this conclusion, focusing first on the performance obtained with well-defined categories of different sizes. Only the larger categories used showed variations in typicality ratings and produced typicality effects on categorization times. However, multiple regression analyses showed the effects on categorization times to be better explained by a measure of associative strength, called category dominance. The range of various predictor variables was equated in a follow-up experiment involving large, natural, and well-defined categories. Results obtained with well-defined categories showed pronounced dominance effects when typicality was controlled, but no reliable typicality effect when category dominance and instance familiarity were controlled. Results were opposite for natural categories. By showing that well-defined categories fail to produce unbiased typicality effects, our results bring added support to the hypothesis that the effects obtained with natural categories originate in a graded, similarity-based category structure.
Concept Formation↗
Induction of chalcone synthase expression in white spruce by wounding and jasmonate.
The phenylpropanoid pathway has important functions in angiospermous plants following exposure to environmental stresses, such as wounding and pathogen attack, that lead to production of compounds including lignin, flavonoids and phytoalexins. Chalcone synthase (CHS) is a key enzyme in this pathway, catalyzing the first step in flavonoid biosynthesis, whose expression can be induced in response to environmental stress. To explore the response of conifers to environmental stress, expression of spruce CHS and its inducibility were investigated. A partial spruce CHS cDNA clone was isolated using PCR. Examination of the expression patterns of the CHS gene family in white spruce revealed accumulation of CHS mRNA in needle tissue following mechanical wounding, or application of signal molecules like jasmonic acid or methyl jasmonate. Repeated mechanical wounding or jasmonate applications had an enhancing effect on transcript accumulation in needles. A systemic accumulation of CHS mRNAs following wounding was also observed. Conifers thus appear to possess a general wound response similar to that found for angiosperms, which includes CHS induction as well as its inducibility by jasmonic acid and airborne methyl jasmonate.
Acyltransferases↗
Hepatic fibrosis in rheumatoid arthritis patients treated with methotrexate: application of a new semi-quantitative scoring system.
OBJECTIVE: Evaluation of hepatic lesions in patients treated with methotrexate (MTX) generally used the Roenigk histological score. However, the sensitivity of the method for hepatic fibrosis assessment has been discussed. The semi-quantitative histological scoring system (SSS) offers a sensitive and specific evaluation of liver fibrosis. Both scores have been evaluated in liver biopsies of patients with rheumatoid arthritis. METHODS: Seventy-four liver biopsies were obtained in 57 rheumatoid arthritis patients before initiation of MTX (group 1, 38 cases), in cases of a persistently high level of transaminases during 1 yr of treatment (group 2, 10 cases) and after a MTX total dose of 2 g (group 3, 26 cases). Eleven biopsies of groups 1 and 3 originated from the same patient in 11 cases. Specimens were examined blindly by two anatomopathologists. The three groups were compared with an ANOVA. Sequential biopsies performed in 11 patients were compared with the Wilcoxon paired test. RESULTS: The Roenigk score and the SSS were significantly correlated (P<0.0001). Only a mild fibrosis was found in 33.8% (25/74) of the biopsies with the Roenigk score. Liver fibrosis, graded as mild (48.6%), moderate (41.8%) or severe (4%), was demonstrated in 94.6% (70/74) of the biopsies with the SSS. The Roenigk score and the SSS of the three patient groups were not statistically significantly different. The scores did not progress in the 11 patients who had serial biopsies. CONCLUSION: SSS is much more sensitive than the Roenigk score for the evaluation of hepatic fibrosis. However, SSS did not show progression of hepatic fibrosis in patients with rheumatoid arthritis treated with MTX.
Adult↗