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Biomedical subjects

F Silva

Publications and source records attributed to F Silva.

At least 19 recordsLinked to original sources
PubMed2006

Genetic basis of Alzheimer's dementia: role of mtDNA mutations.

Alzheimer's disease (AD) is the most common neurodegenerative disorder associated to dementia in late adulthood. Amyloid precursor protein, presenilin 1 and presenilin 2 genes have been identified as causative genes for familial AD, whereas apolipoprotein E epsilon4 allele has been associated to the risk for late onset AD. However, mutations on these genes do not explain the majority of cases. Mitochondrial respiratory chain (MRC) impairment has been detected in brain, muscle, fibroblasts and platelets of Alzheimer's patients, indicating a possible involvement of mitochondrial DNA (mtDNA) in the aetiology of the disease. Several reports have identified mtDNA mutations in Alzheimer's patients, suggesting the existence of related causal factors probably of mtDNA origin, thus pointing to the involvement of mtDNA in the risk contributing to dementia, but there is no consensual opinion in finding the cause for impairment. However, mtDNA mutations might modify age of onset, contributing to the neurodegenerative process, probably due to an impairment of MRC and/or translation mechanisms.

Alzheimer Disease↗
PubMed2006

Long-term peritoneal dialysis experience in Portugal.

Peritoneal dialysis (PD) penetration varies widely. Since the beginning of this therapy, indications have changed and outcomes have improved. In Portugal, PD still remains clearly underutilized. The results of a 20 year PD programme were evaluated: 312 cumulative patients, 48+/-16 years, 27%>60 years old, 27% diabetic, 59% with prior hemodialysis (HD). The main reason for admission was vascular access failure (48.7%). Admission due to patient preference has increased significantly between first and second decades of the programme (33% vs 47% (P<0.001)); 98 patients (31.4%) were treated with automated PD but this prescription increased to 43% of the active patients.A total of 376 Tenckhoff catheters were surgically implanted, recently by the Popovich-Moncrief technique (77 catheters): the cumulative survival was 82%, 64% and 50% at 1, 3 and 5 years,respectively. A better catheter survival was found in the last decade (85.7%, 69.6%, 54.8% versus 77.3%, 55.5%, 40.2%, at 1, 3 and 5 years, respectively (P=0.007). The patient and technique cumulative survivals were 91, 74, 55% and 85, 67, 41%, at 1, 3, and 5 years, respectively. The main drop-out was to hemodialysis (35.8%), followed by death (23.7%), and transplantation (21.5%). Peritonitis and access-related infections caused 35% of the transfer to HD. Cardiovascular events caused 58% of deaths. The median PD retention was 35.5 months. The rate of peritonitis has decreased to one episode /30 patient months. Hospital admission has also decreased to 4.8 days/patient year. This is a first report on long-term PD experience in Portugal. It has been an effective modality of renal replacement therapy, reflected by the growing patient preference in our PD programme.Experience, knowledge and new technical solutions have improved the outcomes.

Adolescent↗
PubMed2004

Functional activity of eukaryotic signal sequences in Escherichia coli: the ovalbumin family of serine protease inhibitors.

It is widely assumed that the functional activity of signal sequences has been conserved throughout evolution, at least between Gram-negative bacteria and eukaryotes. The ovalbumin family of serine protease inhibitors (serpins) provides a unique tool to test this assumption, since individual members can be secreted (ovalbumin), cytosolic (leukocyte elastase inhibitor, LEI), or targeted to both compartments (plasminogen activator inhibitor 2, PAI-2). The facultative secretion of PAI-2 is mediated by a signal sequence proposed to be inefficient by design. We show here that the same internal domain that promotes an inefficient translocation of murine PAI-2 in mammalian cells is a weak signal sequence in Escherichia coli. In contrast, the ovalbumin signal sequence is much more efficient, whereas the corresponding sequence elements from LEI, maspin and PI-10 are entirely devoid of signal sequence activity in E.coli. Mutations that improve the activity of the PAI-2 signal sequence and that convert the N-terminal regions of maspin and PI-10 into efficient signal sequences have been characterized. Taken together, these results indicate that several structural features contribute to the weak activity of the PAI-2 signal sequence and provide new insights into the plasticity of the "hydrophobic core" of signal sequences. High-level expression of two chimeric proteins containing the PAI-2 signal sequence is toxic, and the reduced viability is accompanied by a rapid decrease in the membrane proton motive force, in ATP levels and in translation. In unc- cells, which lack the F0F1 ATP-synthase, the chimeric proteins retain their toxicity and their expression only affected the proton motive force. Thus, the properties of these toxic signal sequences offer a new tool to dissect the interactions of signal sequences with the protein export machinery.

Adenosine Triphosphatases↗
PubMed2004

Clinicopathological significance and survival influence of p53 protein expression in gastric carcinoma.

AIMS: Mutations in the gene coding for p53 protein are among the most frequent genetic alterations observed in human cancers. The relevance and biological significance of p53 expression in gastric carcinoma are far from being fully established. The aim of our study was to evaluate the influence of p53 detected by immunohistochemistry in the clinicopathological behaviour of a series of gastric carcinoma cases. METHODS AND RESULTS: Samples from 163 patients treated by gastric resection for gastric carcinoma between 1988 and 1995 were used. Surgical specimens were evaluated for the presence of p53 protein detected by immunohistochemistry with a monoclonal antibody. Cases were classified as positive or negative for p53. Several clinicopathological parameters and c-erb B-2 expression were analysed in the same series and compared with the expression of p53. Cumulative survival was evaluated using univariate analysis and Cox model regression. p53 expression was identified in 41 carcinomas (25.2%) and was significantly associated with venous invasion (P = 0.049), lymph node metastases (P = 0.01) and c-erb B-2 expression (P = 0.003). All the parameters except gender, tumour size and Laurén's classification influenced survival on univariate analysis. p53 expression correlated with overall survival (P = 0.006) and survival in the subgroup of patients with intestinal type carcinoma (P = 0.04). In the subgroup of patients with carcinomas not expressing c-erb B-2, p53 expression significantly influenced cumulative survival (P = 0.02). CONCLUSIONS: p53 expression is associated with the aggressive biological behaviour of gastric carcinomas and is related to cumulative survival.

Adult↗
PubMed2001

Development of Zn(II) sensors based on the assisted transfer of metal ions by hydrophobic ligands through gel-supported microinterfaces.

Square-wave voltammetry (SWV) has been used to study the transfer of zinc(II) ion under static conditions, assisted by 5,6-diphenyl-3-(2-pyridyl)-1,2,4-triazine (DPT), through gel-supported microinterfaces. Microhole arrays created by laser photoablation of thin polyester films were used to support an organic gel phase prepared by addition of 1,3:2,4-dibenzylidenesorbitol (DBS) to a solution of o-nitrophenyloctyl ether (o-NPOE) with the appropriate supporting electrolyte. The results show that SWV can be used with the gel-supported microinterfaces if a gelified aqueous reference is used for the organic phase. Under such conditions a preliminary estimate of the detection limit for the determination of Zn2+ is 5 x 10(-8) mol L(-1).

Electrochemistry↗
PubMed2001

MUC1 gene polymorphism in the gastric carcinogenesis pathway.

MUC1 like most mucin genes shows extensive length polymorphism in the central core region. In a previous study it was shown that individuals with small MUC1 alleles/genotypes have an increased risk for development of gastric carcinoma. Our aim was to see if MUC1 gene polymorphism was involved in susceptibility for the development of conditions that precede gastric carcinoma: chronic atrophic gastritis (CAG) and intestinal metaplasia (IM). We evaluated MUC1 polymorphism in a population of 174 individuals with chronic gastritis (CG) displaying (CAG) and/or intestinal metaplasia (IM). The population of patients with CG shows MUC1 allele frequencies significantly different from the gastric carcinoma patients and blood donors population. A significantly lower frequency of CAG and IM was observed in MUC1 VNTR heterozygotic patients. Within the group of patients with IM, MUC1 large VNTR homozygotes show a significantly higher frequency of complete IM while small VNTR homozygotes show a significantly higher frequency of incomplete IM. These findings show that MUC1 polymorphism may define different susceptibility backgrounds for the development of conditions that precede gastric carcinoma: chronic atrophic gastritis (CAG) and intestinal metaplasia (IM).

Adult↗
PubMed2001

[Mammary carcinoma ine ectopic breast tissue. A case report].

Ectopic breast tissue, that includes supernumerary breasts and aberrant breast tissue, develops along the mammary line. Malignancies rarely develop in this tissue. We report a 44 years old female subjected to a resection of a 3 cm Ø tumor located 2 cm below the right lower mammary sulcus. The pathological study reported an infiltrating ductal carcinoma. The patient was operated again and a metastatic carcinoma was detected in three resected axillary lymph nodes. Adjuvant chemotherapy and radiotherapy was indicated.

Adult↗
PubMed2000

Extended structural variation of a pentanucleotide repeat in the GSTP1 gene: characterisation in a normal population and in thyroid and gastric tumours.

The promoter region of the human GSTP1 gene contains a polymorphic short tandem repeat (STR) locus consisting of pentanucleotide repeat units (ATAAA). In this work we report the existence of a total of 26 alleles in a Caucasian population. While differences in size (ranging from one to five base pairs) were responsible for the major variation, in five size-defined classes, two alternative sequences were found. Automatic fragment sizing and sequencing analysis revealed that this polymorphism is of a highly complex nature in contrast with previous reports. A genetic population study was carried out on a random sample from Portugal showing no deviation from Hardy-Weinberg equilibrium. Somatic instability studies were also performed on gastric and thyroid tumours using this STR: no instability was detected in thyroid tumour tissues when compared with their normal counterpart but in gastric tumour tissues microsatellite instability (MSI) was detected in 9.6% of the cases and loss of heterozygosity (LOH) also in 9.6% of the cases studied. The results obtained with GSTP1 in gastric cancer were compared with previously reported data on MSI using BAT-26 and several dinucleotide repeat markers.

Alleles↗
PubMed2000

Both transmembrane domains of SecG contribute to signal sequence recognition by the Escherichia coli protein export machinery.

A chimeric protein containing the uncleaved signal sequence of plasminogen activators inhibitor-2 (PAI2) fused to alkaline phosphatase (AP) interferes with Escherichia coli protein export and arrests growth. Suppressors of this toxicity include secG mutations that define the Thr-41-Leu-42-Phe-43 (TLF) domain of SecG. These mutations slow down the export of PAI2-AP. Another construct encoding a truncated PAI2 signal sequence (hB-AP) is also toxic. Most suppressors exert their effect on both chimeric proteins. We describe here five secG suppressors that only suppress the toxicity of hB-AP and selectively slow down its export. These mutations do not alter the TLF domain: three encode truncated SecG, whereas two introduce Arg residues in the transmembrane domains of SecG. The shortest truncated protein only contains 13 residues of SecG, suggesting that the mutation is equivalent to a null allele. Indeed, a secG disruption selectively suppresses the toxicity of hB-AP. However, the missense mutations are not null alleles. They allow SecG binding to SecYE, although with reduced affinity. Furthermore, these mutated SecG are functional, as they facilitate the export of endogenous proteins. Thus, SecG participates in signal sequence recognition, and both transmembrane domains of SecG contribute to ensure normal signal sequence recognition by the translocase.

Alkaline Phosphatase↗
PubMed2000

Vertebral hemangioma mimicking a metastatic bone lesion in well-differentiated thyroid carcinoma.

The authors report a case of abnormal accumulation of I-131 in a thoracic vertebra in a patient with a well-differentiated thyroid carcinoma. The presumptive diagnosis was metastatic bone disease. Further diagnostic work-up confirmed a benign bone lesion. Bone metastasis, when shown on I-131 whole-body scintigraphy, usually supports a change in the staging and therapeutic approach to a patient with thyroid carcinoma. The authors believe that, although an infrequent lesion, the differential diagnosis of abnormal accumulation of I-131 in the body of a vertebra in patients with well-differentiated thyroid carcinoma should raise the possibility of a benign hemangioma. Complete work-up of the suggested bone metastatic lesion should be performed before tumor restaging and I-131 therapy is recommended.

Carcinoma, Papillary↗
PubMed1999

Segregation analysis of tetra- and pentanucleotide short tandem repeat polymorphisms: deviation from Mendelian expectations.

Short tandem repeat (STR) polymorphisms are powerful tools for linkage studies, chromosome mapping and population analysis. The instability of these microsatellite regions is a prevailing event in several tumors and human genetic diseases and, despite various reports associating instability-related genes and meiosis control, the dynamics of these STR regions in normal cells/individuals has frequently been disregarded. Having previously assayed somatic instability in gastric cancer for some tetra- and pentanucleotide STRs and given the increased application of this type of marker for routine forensic expertise, we report the results of an extensive analysis of segregation in nuclear families of a normal population for the same loci. No mutations were detected in 2374 parent/offspring allelic transfers at TH01, TPO, VWA31/A, MBPB, and CD4 STR loci. Nonsignificant differences were found between gene frequencies of parental and offspring generations. However, the segregation analysis revealed significant deviation from Mendelian expectations for: VWA31/A locus - alleles 19, 17 and 14 and TH01 locus - allele 6. In particular, parental meiosis strongly favored specific allele transmission, depending upon the sex of the offspring. Specific mating types are apparently responsible for most of these abnormal segregations. These results suggest selective factors working either at the gametic or zygotic levels.

Female↗
PubMed1999

Acute sporadic non-A, non-B hepatitis in Northeastern Brazil: etiology and natural history.

In a 4-year follow-up study, patients with acute sporadic non-A, non-B (NANB) hepatitis were evaluated to determine the etiology and natural history of the disease. Acute hepatitis C virus (HCV) was detected in 13 of 43 (30%) of patients, anti-hepatitis E virus (HEV) IgG in 5 (12%), and 25 (58%) were considered non-A-E. The HCV RNA was detected in all HCV patients but none of the non-A-E cases. The initial clinical and biochemical presentation of the HCV and non-A-E cases was quite similar, although 2 of the non-A-E patients had severe disease. The 5 patients who were found to be anti-HEV IgG-reactive recovered within 6 months of follow-up. Of the 13 HCV cases, alanine transaminase (ALT) levels returned to normal in 7 (53. 8%), while 6 (46.2%) continued to show abnormal ALT after 6 months of follow-up. However, 9 (69.2%) of them remained HCV-RNA-positive, denoting virological/biochemical dissociation. Long-term follow-up showed a reappearance of HCV RNA in 2 of the 4 patients who were in virological remission performing 84% of chronicity rate. Acute non-A-E hepatitis patients were less likely to evolve toward chronicity, as compared with acute HCV cases (16% vs. 84%; P =.0001). Only 4 (16%) of the non-A-E patients were hepatitis G virus (HGV)-RNA-positive. Concerning risk factors for acquiring parenterally transmitted viruses, tattooing was the only one that could be associated with HCV transmission (P =.002). No risk factors could be identified for putative non-A-E virus transmission. Liver biopsies performed for chronic HCV patients showed a variable degree of inflammation, while the non-A-E patients presented less severe histological disease.

Acute Disease↗
PubMed1999

Plasma lycopene concentrations in humans are determined by lycopene intake, plasma cholesterol concentrations and selected demographic factors.

Higher plasma lycopene concentrations have been associated with a reduced risk of several chronic diseases. Determinants of lycopene concentrations in humans have received limited attention. We had blood lycopene concentrations and lycopene consumption data available from 111 participants in a two-center cancer prevention trial involving beta-carotene and examined determinants of plasma lycopene levels cross-sectionally. The median plasma lycopene level was 0.59 micromol/L (range 0.07-1.79). Low plasma concentrations of lycopene were associated with the following variables in univariate analyses: study site (Florida lower than Connecticut, P = 0.001), being nonmarried (P = 0.02), having lower income (P = 0.003), being nonwhite race/ethnicity (P = 0.03), having lower dietary lycopene intake (r = 0.29, P = 0.002), having lower plasma cholesterol (r = 0. 43, P = 0.0001) and triglyceride levels (r = 0.26, P = 0.005), and consuming less vitamin C (r = 0.20, P = 0.03). Women had slightly higher plasma lycopene levels than men (0.65 vs. 0.58 micromol/L; P = 0.31), despite lower dietary intake of lycopene (1,040 vs. 1,320 microg/d; P = 0.50). Plasma lycopene levels did not differ in smokers and nonsmokers. In stepwise regression analyses, the determinants of plasma lycopene were plasma cholesterol, dietary lycopene, and marital status; these three variables explained 26% of the variance in plasma lycopene. Relatively few lifestyle and demographic factors were important determinants of plasma lycopene levels, with plasma cholesterol, marital status, and lycopene intake being of greatest importance.

Adult↗
PubMed1999

Recurrent ectopic adrenocorticotropic hormone producing thymic carcinoid detected with octreotide imaging.

Primary thymic carcinoids are rare tumors in which the tumor cells retain functional somatostatin receptors. In-111-labeled octreotide imaging has been used to diagnose abdominal carcinoids with a sensitivity rate of approximately 87%. The authors describe a case of a recurrent, ectopic cortisol-releasing hormone that produced thymic carcinoid localized as a focal area of increased activity in the upper mediastinum when planar and tomographic octreotide scintigraphy was used. Chest CT and MRI failed to localize the tumor. This may be the first reported case of In-111-labeled octreotide used to identify Cushing's syndrome caused by a cortisol-releasing hormone that produced thymic carcinoid.

Adult↗
PubMed1999

Transcriptional activation of ydeA, which encodes a member of the major facilitator superfamily, interferes with arabinose accumulation and induction of the Escherichia coli arabinose PBAD promoter.

Induction of genes expressed from the arabinose PBAD promoter is very rapid and maximal at low arabinose concentrations. We describe here two mutations that interfere with the expression of genes cloned under arabinose control. Both mutations map to the ydeA promoter and stimulate ydeA transcription; overexpression of YdeA from a multicopy plasmid confers the same phenotype. One mutation is a large deletion that creates a more efficient -35 region (ATCACA changed to TTCACA), whereas the other affects the initiation site (TTTT changed to TGTT). The ydeA gene is expressed at extremely low levels in exponentially growing wild-type cells and is not induced by arabinose. Disruption of ydeA has no detectable effect on cell growth. Thus, ydeA appears to be nonessential under usual laboratory growth conditions. The ydeA gene encodes a membrane protein with 12 putative transmembrane segments. YdeA belongs to the largest family of bacterial secondary active transporters, the major facilitator superfamily, which includes antibiotic resistance exporters, Lac permease, and the nonessential AraJ protein. Intracellular accumulation of arabinose is strongly decreased in mutant strains overexpressing YdeA, suggesting that YdeA facilitates arabinose export. Consistent with this interpretation, very high arabinose concentrations can compensate for the negative effect of ydeA transcriptional activation. Our studies (i) indicate that YdeA, when transcriptionally activated, contributes to the control of the arabinose regulon and (ii) demonstrate a new way to modulate the kinetics of induction of cloned genes.

Arabinose↗