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Biomedical subjects

A Rosa

Publications and source records attributed to A Rosa.

At least 19 recordsLinked to original sources
PubMed1999

A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32.

Autosomal dominant hypercholesterolemia (ADH), one of the most frequent hereditary disorders, is characterized by an isolated elevation of LDL particles that leads to premature mortality from cardiovascular complications. It is generally assumed that mutations in the LDLR and APOB genes account for ADH. We identified one large French pedigree (HC2) and 12 additional white families with ADH in which we excluded linkage to the LDLR and APOB, implicating a new locus we named "FH3." A LOD score of 3.13 at a recombination fraction of 0 was obtained at markers D1S2892 and D1S2722. We localized the FH3 locus to a 9-cM interval at 1p34.1-p32. We tested four regional markers in another set of 12 ADH families. Positive LOD scores were obtained in three pedigrees, whereas linkage was excluded in the others. Heterogeneity tests indicated linkage to FH3 in approximately 27% of these non-LDLR/non-APOB ADH families and implied a fourth locus. Radiation hybrid mapping located four candidate genes at 1p34.1-p32, outside the critical region, showing no identity with FH3. Our results show that ADH is genetically more heterogeneous than conventionally accepted.

Adult↗
PubMed1999

Ticlopidine-induced prolonged cholestasis: a case report.

We report a case of ticlopidine-induced prolonged cholestasis in a 60-year-old man with no previous hepatobiliary disease who presented with sudden right upper abdominal pain, jaundice and pruritus three months after starting ticlopidine therapy. Other drugs taken by the patient were not considered probable causes. The diagnostic evaluation showed no biliary obstruction and other possible causes of intra-hepatic cholestasis were excluded. The liver biopsy showed a cholestatic hepatitis with bile duct damage. The disease ran a severe and protracted course, but symptoms and jaundice eventually subsided five months after drug withdrawal. More than a year later, relevant abnormalities of liver function tests consistent with anicteric cholestasis still persist, fulfilling criteria for a minor form of drug-induced prolonged cholestasis. This syndrome has been reported infrequently in relation to several drugs, mainly chlorpromazine, and only once with ticlopidine.

Cholestasis↗
PubMed1999

[Could angiotensin II type I receptor antagonists have a superior beneficial effect than that of angiotensin II converting enzyme inhibitors with respect to the risk of cerebrovascular accident?].

In contrast with the expected results, the Captopril Prevention Project study has found that the relative risk of stroke was greater by 25% in patients treated with ACEI than in patients receiving the conventional diuretics +/- betablockers regimen (Hanson et al. ISH Amsterdam, June 98). This difference persisted after adjustment for the initial differences of blood pressure levels between the groups after randomisation. This does not mean that ACEI would worsen the risk of stroke when compared to a placebo, since a potent protective effect of diuretics and betablockers on the relative risk of stroke has long been demonstrated. Nonetheless, these results suggest that for a similar blood pressure lowering effect, conventional therapy is more effective than ACEI to prevent stroke. This finding, in discrepancy with the current prevailing opinion that ACEI have emerged as the most effective preventive treatment to reduce cardiovascular morbidity, is regarded as surprising by the investigators. However, a number of animal experimental data may help to envisage the complete inhibition of angiotensin II formation as a two-edged sword, because of the multiplicity of its receptors mediating different, and even opposite effects. In a series of experimental studies in mammals, the group of Fernandez has provided a bundle of observations suggesting that angiotensin II contributes to early reperfusion following acute ischemia by enabling the recruitment of pre-existing collateral vascularisation, an effect mediated via the stimulation of non-AT1 receptors (possibly AT2). Indeed, the worsening of stroke in the gerbil after incomplete ligation of the carotid by pre-treatment with ACEI had been demonstrated by these authors (J Cerebral Blood Flow Metab, 1988; 24:937), and they further show that pre-administration of losartan significantly reduced the ischemic brain damage and the mortality induced by the abrupt ligation of one carotid, but that this preventive effect of losartan was abolished if enalapril was co-administrated (J Cardiovasc Pharmacol 1994; 24:937). The first available clinical data on stroke risk with ACEI reported in the CPP study, showing a less effective prevention of stroke with ACEI than diuretics supports the hypothesis that similar mechanism may also prevail in humans, and lead us to propose to discuss the rationale for a large multicentric trial aiming to compare the protective effect of ARAT1 and ACEI on the risk of recurrence of stroke.

Angiotensin Receptor Antagonists↗
PubMed1998

Chimeric purine transporters of Aspergillus nidulans define a domain critical for function and specificity conserved in bacterial, plant and metazoan homologues.

In Aspergillus nidulans, purine uptake is mediated by three transporter proteins: UapA, UapC and AzgA. UapA and UapC have partially overlapping functions, are 62% identical and have nearly identical predicted topologies. Their structural similarity is associated with overlapping substrate specificities; UapA is a high-affinity, high-capacity specific xanthine/uric acid transporter. UapC is a low/moderate-capacity general purine transporter. We constructed and characterized UapA/UapC, UapC/UapA and UapA/UapC/UapA chimeric proteins and UapA point mutations. The region including residues 378-446 in UapA (336-404 in UapC) has been shown to be critical for purine recognition and transport. Within this region, we identified: (i) one amino acid residue (A404) important for transporter function but probably not for specificity and two residues (E412 and R414) important for UapA function and specificity; and (ii) a sequence, (F/Y/S)X(Q/E/P) NXGXXXXT(K/R/G), which is highly conserved in all homologues of nucleobase transporters from bacteria to man. The UapC/UapA series of chimeras behaves in a linear pattern and leads to an univocal assignment of functional domains while the analysis of the reciprocal and 'sandwich' chimeras revealed unexpected inter-domain interactions. cDNAs coding for transporters including the specificity region defined by these studies have been identified for the first time in the human and Caenorhabditis elegans databases.

Amino Acid Sequence↗
PubMed1998

Anencephaly and faciocranioschisis: evidence of complete failure of closure 3 of the neural tube in humans.

We report on a patient with median cleft of face and anencephaly as apparent consequence of delayed closure of the most rostral end of the neural tube. No other structural anomalies were found. To our knowledge, this child represents the first description of an isolated and complete failure of closure 3 of the neural tube and supports the hypothesis of a multi-site model of neural tube closure in humans.

Anencephaly↗
PubMed1998

Variability in the serotonin transporter gene and increased risk for major depression with melancholia.

The serotonin transporter (SERT) gene is a particularly interesting candidate for genetic involvement in affective disorders owing to its role in both the regulation of serotonergic neurotransmission and the mechanism of action of many antidepressant drugs. In this study, variability in the SERT gene was analyzed for the first time in a sample of patients with major depression with melancholia (MDDM) in the context of a genetic association study. Two different polymorphisms of the SERT gene (17q11.1-17q12) were analyzed: a variable number of tandem repeats (VNTR) polymorphism in intron 2, and a deletion/insertion polymorphism (5-HTTLPR) in the promoter region of the gene, the short variant of which (allele 484) reduces the transcriptional efficiency of the SERT gene. Our sample consisted of 74 unrelated subjects who strictly met DSM-IV criteria for MDDM and 84 healthy controls, all of Spanish origin. The analysis of haplotype distribution for both polymorphisms showed significant differences between cases and controls (log-likelihood ratio chi2=11.15, df=4, P=0.025). Moreover, when the frequencies of the 484-STin2.10 haplotype were considered in comparison with any other haplotype combination, a significant increase in this haplotype was found in patients with MDDM [z=2.53 (95% CI, 1.21-5.34), P=0.007]. According to these results, variability in the SERT gene has a small effect on liability to MDDM. Our findings are compatible with an additive effect of both the 484 low-activity allele and a mutation elsewhere within the transporter gene or a susceptibility locus nearby in linkage disequilibrium with the VNTR marker.

Carrier Proteins↗
PubMed1998

[Congenital afibrinogenemia].

The authors present a case of congenital afibrinogenemia. A review of the literature is made, and some aspects of this rare inherited coagulation disorder are suggested and commented on.

Afibrinogenemia↗
PubMed1997

Suppression of KIF2 in PC12 cells alters the distribution of a growth cone nonsynaptic membrane receptor and inhibits neurite extension.

In the present study, we present evidence about the cellular functions of KIF2, a kinesin-like superfamily member having a unique structure in that its motor domain is localized at the center of the molecule (Noda Y., Y. Sato-Yoshitake, S. Kondo, M. Nangaku, and N. Hirokawa. 1995. J. Cell Biol. 129:157-167.). Using subcellular fractionation techniques, isopicnic sucrose density centrifugation of microsomal fractions from developing rat cerebral cortex, and immunoisolation with KIF2 antibodies, we have now identified a type of nonsynaptic vesicle that associates with KIF2. This type of organelle lacks synaptic vesicle markers (synapsin, synaptophysin), amyloid precursor protein, GAP-43, or N-cadherin. On the other hand, it contains betagc, which is a novel variant of the beta subunit of the IGF-1 receptor, which is highly enriched in growth cone membranes. Both betagc and KIF2 are upregulated by NGF in PC12 cells and highly concentrated in growth cones of developing neurons. We have also analyzed the consequences of KIF2 suppression by antisense oligonucleotide treatment on nerve cell morphogenesis and the distribution of synaptic and nonsynaptic vesicle markers. KIF2 suppression results in a dramatic accumulation of betagc within the cell body and in its complete disappearance from growth cones; no alterations in the distribution of synapsin, synaptophysin, GAP-43, or amyloid percursor protein are detected in KIF2-suppressed neurons. Instead, all of them remained highly enriched at nerve terminals. KIF2 suppression also produces a dramatic inhibition of neurite outgrowth; this phenomenon occurs after betagc has disappeared from growth cones. Taken collectively, our results suggest an important role for KIF2 in neurite extension, a phenomenon that may be related with the anterograde transport of a type of nonsynaptic vesicle that contains as one of its components a growth cone membrane receptor for IGF-1, a growth factor implicated in nerve cell development.

Amyloid beta-Protein Precursor↗
PubMed1996

[Does general paralysis still exist in non-AIDS patients?].

A 33 year-old man was twice admitted in psychiatry for a non typical depression. He was later hospitalized for a convulsive seizure. Then, the discovery of dementia, neurologic trouble, positivity of syphilitic reaction in blood and in cerebro-spinal fluid allowed to diagnose general paralysis. General paralysis is a late complication of syphilis and it has become exceptional because of efficacy of detection and treatment of early state of syphilis. Now, most of cases affects AIDS patients. Nevertheless, this case shows that realisation of syphilitic reaction is always justified by any dementia or any non typical depression.

Adult↗
PubMed1996

Erythromycin biosynthesis: exploiting the catalytic versatility of the modular polyketide synthase.

DEBS 1 + TE is a recombinant modular polyketide synthase (PKS) in which the first two biosynthetic modules of the 6-deoxyerythronolide B synthase are linked to the thioesterase domain normally found at the C-terminus of DEBS 3. Incubation of DEBS 1 + TE with propionyl-CoA, methylamalonyl-CoA, and NADPH gives the triketide lactone (2R,3S,4S,5R)-2,4-dimethyl-3, 5-dihydroxy-n-heptanoic acid delta-lactone (2), the cyclized form of the normal triketide chain elongation product of DEBS 1. In order to probe the molecular recognition features of the PKS and to explore its synthetic versatility, [2,3-13C2]-(2S,3R)-2-methyl-3-hydroxypentanoyl-NAC thioester (3), an analogue of the normal diketide chain elongation intermediate, and (2RS)-methyl-malonyl-CoA were incubated with DEBS 1 + TE, leading to the formation of the predicted labeled triketide ketolactone [4,5-13C2]-8, as established by 13C NMR analysis and comparison with spectra of synthetic 8. This stereoselective conversion illustrates the potential of using modular PKSs as multifunctional catalysts for the enzymatic synthesis of novel polyketides.

Erythromycin↗
PubMed1996

Mesenteric arteriovenous fistula causing portal hypertension and bleeding duodenal varices.

We report a case of portal hypertension associated with a non-traumatic arteriovenous fistula, presenting with bleeding duodenal varices. The patient was admitted for melaena. Emergency endoscopy showed oesophageal varices with no signs of recent bleeding and with no blood in the upper gastrointestinal tract. Arteriography of the coeliac axis and superior mesenteric artery failed to detect any bleeding source. Endoscopy was repeated because of persistent bleeding and revealed active bleeding from varices in the distal duodenum. The patient underwent surgery and a large paraduodenal varicose vein associated with an arteriovenous fistula was found. Resection of the paramural varix and surgical occlusion of the arteriovenous fistula were effective in the control of bleeding. Liver biopsy revealed mild portal fibrosis without cirrhosis. Three years after surgery the patient still has oesophageal varices but has not had recurrent bleeding. There was regression of intraduodenal varices.

Aged↗
PubMed1996

[Neurologic complications in a case of Werner syndrome].

A 39 year old caucasian man was admitted in 1994 to the neurological department with a left pure motor hemiplegia that appeared suddenly. This patient showed typical features of Werner's syndrome. He had a hoarse voice, a diffuse muscle weakness and atrophy in the upper and lower limbs with chronic ulcers on the legs. His scalp and public hair were sparse. Cranial MRI revealed several lesions in the white matter, low signal intensity on T1 weighted images and high signal on T2 weighted images. Cerebrospinal fluid (CSF was inflammatory with hypercytosis and proteinorachia was 0.50 g/l with synthesis of IgG. Sural nerve biopsy revealed muscle atrophy and the loss of myelinated fibers. Thus, central and peripheral nervous systems were affected in this case.

Adult↗
PubMed1996

[Primary and secondary prevention of ischemic cerebrovascular accidents of arteriosclerosis by platelet inhibitors].

Cohort studies currently available suggest that the most effective platelet inhibitors for the secondary prevention of ischaemic cerebrovascular accidents are acetylsalicylic acid and ticlopidine. Aspirin reduces the risk by 20%. It seems that moderate doses (100-300 mg/day) are sufficient and better tolerated. Ticlopidine would seem to be more effective than aspirin as it reduces the risk by more than 20% with respect to aspirin therapy. Only aspirin has been evaluated in the setting of primary prevention and it seems to be ineffective in preventing cerebral infarction. Nowadays, other anti-platelet molecules are under evaluation, one of which is Clopidogrel.

Arteriosclerosis↗
PubMed1994

Evidence by a voltage clamp study of an electrically mediated block to polyspermy in the egg of the ascidian Phallusia mammillata.

Eggs of the ascidian Phallusia mammillata were voltage clamped (from -100 to +60 mV) and inseminated with a low or heavy sperm concentration. From inseminations with low sperm concentration (1 x 10(6) sp/ml), we found that fertilization currents occurred between -100 and +40 mV: they were always inward and displayed an analogous pattern whatever the clamped voltage. We established that the percentages of inseminated eggs that produced a fertilization current varied as a function of the clamped voltage. These percentages were not statistically different from 100% at clamped voltages between -100 and -30 mV, they decreased to 68 and 56% at clamped Vm of -10 and 0 mV, respectively, but were not statistically different from 0% at clamped Vm between +10 and +40 mV. We never obtained any egg electrical response at a clamped voltage of +50 mV. Almost all eggs (96%) which responded electrically were penetrated by one or several spermatozoa. These eggs were resuming meiosis (81 to 50%) at values of clamped Vm between -100 and 0 mV, respectively. At clamped Vm between +10 and +50 mV, the percentages of eggs resuming meiosis were not statistically different from 0. These results indicate that in P. mammillata eggs, the occurrence of an electrical response is voltage dependent and consequently that the initial depolarizing shift of the fertilization potential constitutes a fast block to polyspermy. However, in this species, the sperm penetration is not voltage dependent, since it occurred at clamped Vm from -100 to +40 mV. On the other hand, when eggs were clamped from -100 to +60 mV and inseminated with a heavy sperm concentration (2 x 10(7) sp/ml), the curves expressing, respectively, the percentages of eggs which responded electrically, the percentages of eggs which were penetrated by one or several spermatozoa, and the percentages of eggs resuming meiosis, as functions of the clamped Vm, were shifted by approximately 35 mV toward more positive voltages, compared to the corresponding curves obtained from eggs inseminated with a low sperm concentration. This last result means that the critical value of the membrane potential which characterizes the electrical block to polyspermy is dependent on the sperm concentrations used for inseminations.

Animals↗