Mutations in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31 in Spanish families with autosomal dominant retinitis pigmentosa

PURPOSE: Mutations in the systemically expressed pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31 have recently been associated with autosomal dominant retinitis pigmentosa (adRP). This study was intended to identify mutations in PRPF3, PRPF8, and PRPF31 in 150 Spanish families affected by adRP, to measure the contribution of mutations in these genes to adRP in that population, and to correlate RP phenotype expression with mutations in pre-mRNA splicing-factor genes. METHODS: Denaturing gradient gel electrophoresis (DGGE) and direct genomic sequencing were used to evaluate the complete coding region and flanking intronic sequences of the PRPF31 gene, exon 42 of PRPF8, and exon 11 of PRPF3 for mutations in 150 unrelated index patients with adRP. Ophthalmic and electrophysiological examination of patients with RP and their relatives was performed according to preexisting protocols. RESULTS: Three nonsense mutations caused by insertion and deletion sequences and two missense mutations (Arg2310Gly) and within the stop codon of the PRPF8 gene (TGA-->TTG), were detected in five unrelated heterozygous patients. Three patients were heterozygous carriers of different nonsense mutations in exon 8 of the PRPF31, gene and one Thr494Met mutation was found in exon 11 of the PRPF3 gene. Cosegregation of the mutation in PRPF8 and PRPF3 with adRP was observed. However, two nonsense mutations in PRPF31 causing adRP detected in two families showed asymptomatic carriers. CONCLUSIONS: Nine mutations, six of which are novel, in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31, causing adRP have been identified in the Spanish population. Their contribution to adRP is approximately 5% after correction in relation to mutations found in other genes causing adRP. The patients carrying a mutation in the pre-mRNA splicing-factor PRPF8 gene showed a type 1 diffuse RP. The existence of asymptomatic carriers of the nonsense mutation in the PRPF31 gene suggests incomplete penetrance for these mutations in the families.     

Internal carotid stenosis and giant cell arteritis

We report on the case of a 69-year-old man admitted with a transient ischemic attack preceded by a two months history of severe headache. Giant cell arteritis was diagnosed by means of temporal artery biopsy. Angiography showed an intra- and extracranial stenosis of the left internal carotid artery. The possible relationship between this stenosis and vasculitis is discussed and stroke as a clinical manifestation of the giant cell arteritis is reviewed.     

Disruption of the Cys5-Cys7 disulfide bridge in the platelet glycoprotein Ibbeta prevents the normal maturation and surface exposure of GPIb-IX complexes

This work aimed at elucidating the molecular genetic defect in two related patients with Bernard-Soulier syndrome (BSS) phenotype. Flow cytometric analysis revealed undetectable levels of platelet glycoproteins (GP), Ibalpha and IX, although plasma glycocalicin was detectable in both cases. The complete sequencing of GPIbalpha, GPIbbeta, and GPIX revealed the presence of a single point mutation, a G to A substitution, in codon 30 of GPIbbeta, that changes Cys5 to Tyr. The parents and sibling of the patients, heterozygotes for this mutation, were asymptomatic and they all showed a reduced platelet content of GPIbalpha and GPIX. Transient transfection of the mutant GPIbalpha subunit failed to render surface expression of GPIbalpha and exerted a dominant-negative effect on the surface exposure of the GPIb-IX complex. Metabolic labelling and immunoprecipitation analysis of transfected cells indicated that [5Tyr]GPIbbeta may associate with GPIX and GPIbalpha, but the maturation of the GPIb-IX complex is impaired. Substitution of either Cys5 or Cys7 by Ala failed to show surface expression of GPIb-IX, suggesting that the Cys5- Cys7 disulfide loop in GPIbbeta is essential for the efficient processing and trafficking of GPIb-IX complexes toward the plasma membrane. Our findings indicate that the identified novel GPIbbeta mutation is responsible for the BSS phenotype of the patients and provide an explanation for the molecular mechanism underlying the reduced platelet content of GPIb-IX complex in the heterozygous individuals.     

Tianeptine and paroxetine in major depressive disorder,with a special focus on the anxious component in depression: an international, 6-week double-blind study dagger

Tianeptine (37.5 mg/day) and paroxetine (20 mg/day) were compared in a population of depressive patients without past or current history of co-morbid anxiety and/or important anxiolytic treatment. In a 6-week, double blind trial, the special focus was on anxious symptoms.Both drugs showed good efficacy on depressive symptomatology, assessed with MADRS and HDRS, but no difference was detected between tianeptine and paroxetine, for any assessment criterion. Despite the choice of selected depressive patients, without any co-morbid anxious disorder, anxiety scale scores at inclusion (HAMA and BAS) were appreciable but correlated poorly with depressive scores. Both tianeptine and paroxetine improved the apparent anxious component in depression. Tolerability of both drugs was good, although significantly better with tianeptine.Thus tianeptine and paroxetine are effective and safe treatments for major depression and may also act directly on the anxious component of the psychopathology. Copyright 2001 John Wiley & Sons, Ltd.     

Rupture of splenic artery aneurysm during pregnancy and posterior evolution of gestation

We present a case of splenic artery aneurysm rupture in a 26 weeks pregnant patient. Facing to the maternal collapse and after the ultrasonographical diagnosis of massive hemoperitoneum, the rapid intervention proved to be crucial in controlling the hemorrhage and allowed for the continuation of gestation and successful delivery.     

Imported histoplasmosis in Spain

Histoplasma capsulatum is a dimorphic fungus endemic in the American continent but not in Europe, where cases are usually imported. Its favorite habitat is in warm humid soils. Guano from birds and bats enhance the sporulation of the mycelial phase.1 Man acquires H. capsulatum through inhalation of spores. Most people infected by this fungi remain asymptomatic, but around 10-50% can start an illness ranging from acute pulmonary histoplasmosis to chronic histoplasmosis. In both, there is close clinical resemblance to pulmonary tuberculosis. Immunodepressed patients undergo a more severe form of the disease, usually presenting in the acute disseminated form. We present seven immunocompetent patients with histoplasmosis acquired after traveling to several American countries.     

Identification of IgE binding polypeptides cross-reactive with the Parietaria judaica main allergenic polypeptide

The major allergen of the pollen of Parietaria judaica was characterized using an anti-allergen MAb AC/15.1. The antibody was able to immunoadsorb four different polypeptides (10,000, 20,000, 30,000 and 40,000 mol. wt) from the pollen proteins radioiodinated by the Bolton-Hunter's reagent. The four polypeptides have been shown not to be covalently linked, except for the 10,000 mol. wt polypeptide (Pj10), which appeared to form Pj10 dimers under non-reducing conditions. All of them contained the antigenic epitope defined by the monoclonal antibody and demonstrated human IgE binding ability. The structural relationship of these polypeptides in the native allergen is discussed.     

Conservative management of bleeding duodenal ulcer without a visible vessel: prospective randomized trial

Between January 1983 and December 1985, 305 patients were admitted to our hospital because of bleeding duodenal ulcer. A subgroup of 69 patients aged 50 or above in whom emergency endoscopy showed non-arterial bleeding or signs of recent haemorrhage without a visible vessel entered a prospective therapeutic trial. The patients were randomized to receive either (1) early surgery, implying immediate operation, or (2) expectant management, with surgery reserved only for patients with further haemorrhage. The two groups were homogeneous with respect to age, sex, prior ingestion of ulcerogenic drugs, mode of bleeding, admission haematocrit, number with hypovolaemic shock and number with active bleeding on initial endoscopy. Overall mortality was 8.6 per cent. Mortality in patients submitted to early surgery was five times higher than that in those allocated to expectant therapy (14.7 per cent versus 2.9 per cent; risk ratio 5.07). The results suggest that expectant management is advisable in patients with bleeding duodenal ulcer not bleeding massively and in whom endoscopy does not disclose spurting arterial bleeding or a visible vessel.