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Biomedical subjects

A Nadal

Publications and source records attributed to A Nadal.

At least 19 recordsLinked to original sources
PubMed2001

Laparoscopic myotomy vs endoscopic dilation in the treatment of achalasia.

BACKGROUND: The aim of this study was to compare the results obtained in 14 patients with achalasia who underwent laparoscopic Heller's myotomy and Dor's fundoplication with those of 16 patients who had endoscopic dilation. METHODS: The diagnosis of achalasia was confirmed by manometry, endoscopy, and barium swallow. Esophageal symptoms were quantified before and after treatment using a clinical scale. Six patients had had endoscopic dilation prior to surgery. RESULTS: Before treatment, the patients in the surgical group complained of more severe dysphagia (median, 5; range, 0-5 vs median 4; range, 3-5) and chest pain (median, 3; range, 0-5 vs median, 1.5; range, 0-5), but both groups were comparable with respect to regurgitation, heartburn, and manometric results. Both groups achieved significant clinical improvement. The severity score decreased from 5 (range, 0-5) to 1 (range, 0-3) (p < 0.05) for dysphagia to solids in the laparoscopic group and from 4 (range, 3-5) to 1 (range, 0-5) (p < 0.05) in the endoscopic group. Lower esophageal sphincter (LES) basal pressure decreased significantly in both groups (from 29.3 to 11.8 mmHg in the laparoscopic group and from 28.9 to 16.5 mmHg in the endoscopic group). After treatment, there were no significant clinical differences between the two groups. Two patients in the surgical group were converted to open surgery. CONCLUSION: Laparoscopic myotomy is as save and effective as endoscopic dilation in the treatment of achalasia.

Adolescent↗
PubMed2001

Expression of cathepsins B and S in the progression of prostate carcinoma.

Cathepsins B and S (CatB, CatS) are lysosomal cysteine proteases which, among other functions, appear to play a role in cancer progression in different tumor models due to their matrix-degrading properties. To investigate their possible involvement in the development of prostate carcinoma, we immunohistochemically analyzed CatB and CatS in 38 primary human prostatic adenocarcinomas, as well as concomitant high-grade prostatic intra-epithelial neoplasia, nodular hyperplasia and normal tissue. CatB expression was observed in 28 (74%) and CatS in 32 (84%) carcinomas, being concomitant in 24 cases (63%). High-grade intra-epithelial neoplasia expressed CatB in 20/23 cases (87%), and a similar result was obtained for CatS, with expression of both coinciding in 18 cases (78%). In non-neoplastic tissue, strong expression of both proteases was observed in macrophages, inflamed glands and transitional metaplasia, whereas atrophic glands and basal cells of normal glands displayed intense CatB positivity. We conclude that CatB and CatS are often expressed together in neoplastic prostatic cells from pre-invasive to invasive and clinically detectable stages, suggesting a putative role in local invasion, though other functions cannot be ruled out.

Adenocarcinoma↗
PubMed2001

Differential expression of cdc25 cell-cycle-activating phosphatases in human colorectal carcinoma.

cdc25 is a family of cell-cycle phosphatases that activate the cyclin-dependent kinases. cdc25A and B, but not C, have oncogenic potential in vitro. In this study, we analyzed the possible implication of cdc25 genes in the progression of colorectal tumors. RNA and DNA were extracted from 34 paired tumor and normal colorectal tissues and examined by Northern blot, RT-PCR, and Southern blot, respectively. Protein expression was analyzed by Western blot in a subset of normal and tumor samples. The expression levels were correlated with the clinicopathologic characteristics and survival of the patients. cdc25B mRNA was overexpressed in 19 carcinomas (56%). A significant correlation was observed between high cdc25B mRNA levels and the relapse-free, overall, and cancer-related survival of the patients. The cdc25B2 splicing variant was detected in 27 carcinomas (79%) but only in 9 normal samples (26%) and was associated with the grade of the differentiation of the tumors. cdc25A mRNA was overexpressed in four tumors (12%) and cdc25C1 mRNA was overexpressed in nine tumors (26%). A new cdc25C2 splicing variant lacking exon 4 and 5 was identified in all of the tumors and in 56% of the normal samples. No amplifications or gene rearrangements of these genes were detected. In conclusion, these findings indicate that cdc25 isoforms and splicing variants are differentially regulated in colorectal carcinomas and may participate in the development of these tumors. Additionally, the correlation between cdc25B mRNA levels and the survival of the patients also suggest that the cdc25B isoform may be involved in the progression of the disease.

Adult↗
PubMed2000

Nongenomic actions of estrogens and xenoestrogens by binding at a plasma membrane receptor unrelated to estrogen receptor alpha and estrogen receptor beta.

The molecular mechanism used by environmental chemicals to exert their hormone-like actions is still only partially resolved. Although it generally is accepted that xenoestrogens act at the genomic level by binding to intracellular estrogen receptors, we have shown here that they trigger nongenomic effects in pancreatic beta cells. Both xenoestrogens and the circulating hormone, 17beta-estradiol, bind with high affinity to a common membrane binding site unrelated to the intracellular estrogen receptors ERalpha and ERbeta. This binding site is shared by dopamine, epinephrine, and norepinephrine and has the pharmacological profile of the gammaadrenergic receptor. This study provides an outline of the membrane receptor involved in rapid xenoestrogen actions.

Animals↗
PubMed2000

Contribution of steroidogenic factor 1 to the regulation of cholesterol synthesis.

Steroidogenic factor 1 (SF-1) is an orphan member of the nuclear receptor family expressed in steroidogenic tissues, where it has an essential role in the regulation of the steroid hormone biosynthesis, adrenal and gonadal development and endocrine responses fundamental for reproduction. Here we show that SF-1 regulates the transcription of cytosolic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase gene, which is essential for the endogenous synthesis of cholesterol. We have identified an element located 365 bp upstream of the gene for cytosolic HMG-CoA synthase; SF-1 binds as a monomer to this element and confers SF-1 responsiveness to homologous and heterologous promoters. It has been shown that in tissues with a high demand for cholesterol to be used in steroid synthesis, there is a lack of correlation between the cholesterol levels and the activity of the limiting enzymes of the mevalonate pathway. In accord with those results, we observed that cholesterol synthesis from acetate and either cytosolic HMG-CoA mRNA expression or transcriptional activity were not changed in response to 25-hydroxycholesterol in the SF-1-expressing steroidogenic Leydig tumour MA-10 cells. Moreover, the overexpression of SF-1 in non-steroidogenic CV-1 cells renders them less sensitive to the regulatory effects of cholesterol. This observation led to the hypothesis that in steroidogenic tissues the expression of SF-1 permits high levels of endogenous synthesis of cholesterol irrespective of the intracellular levels of this metabolite.

Animals↗
PubMed2000

cdc25a and the splicing variant cdc25b2, but not cdc25B1, -B3 or -C, are over-expressed in aggressive human non-Hodgkin's lymphomas.

cdc25 is a family of phosphatases that activate the cyclin-dependent kinases at different points of the cell cycle. cdc25A and -B, but not -C, have been shown to have oncogenic potential. Three different splicing variants of the cdc25B gene, cdc25B1, -B2 and -B3, have also been identified. Experimental studies suggest that cdc25B2 may be more active in vivo than cdc25B3 and -B1, but the relative expression of these splicing variants in human tumors is not known. In this study, we have analyzed the expression of cdc25A, -B1, -B2, -B3 and -C mRNA in 9 non-neoplastic lymphoid samples, 89 non-Hodgki&ngrave;s lymphomas and 9 hematological cancer cell lines by semi-quantitative RT-PCR. cdc25A, -B and -C protein expression was examined by Western blot. Normal peripheral blood lymphocytes and reactive tissues expressed cdc25B1 and -B3 mRNA and very low or undetectable levels of cdc25A, -B2 and -C. High levels of cdc25A and cdc25B2 were found in 35% and 39% of the tumors, respectively, and they were more frequently observed in aggressive than in indolent lymphomas. cdc25B1 and -B3 splice variants were detected in virtually all tumors, and no significant differences were found between high- and low-grade lymphomas. cdc25A and -B protein expression was also higher in aggressive than in indolent lymphomas. cdc25C expression was relatively low in virtually all cases. In conclusion, these findings suggest that cdc25A and -B2, but not cdc25B1, -B3 and -C, are over-expressed in a relatively large number of malignant lymphomas and may participate in the pathogenesis of aggressive variants.

Blotting, Western↗
PubMed2000

Engineering pancreatic islets.

Pancreatic islets are neuroendocrine organs that control blood glucose homeostasis. The precise interplay of a heterogeneous group of cell populations (beta, alpha, delta and PP cells) results in the fine-tuned release of counterbalanced hormones (insulin, glucagon, somatostatin and pancreatic polypeptide respectively). Under the premises of detailed knowledge of the physiological basis underlying this behaviour, two lines of investigation might be inferred: generating computational and operational models to explain and predict this behaviour and engineering islet cells to reconstruct pancreatic endocrine function. Whilst the former is being fuelled by new computational strategies, giving biophysicists the possibility of modelling a system in which new "emergent" properties appear, the latter is benefiting from the useful tools and strategic knowledge achieved by molecular, cell and developmental biologists. This includes using tumour cell lines, engineering islet cell precursors, knowledge of the mechanisms of differentiation, regeneration and growth and, finally, therapeutic cloning of human tissues. Gaining deep physiological understanding of the basis governing these processes is instrumental for engineering new pancreatic islets.

Animals↗
PubMed2000

INK4a/ARF locus alterations in human non-Hodgkin's lymphomas mainly occur in tumors with wild-type p53 gene.

INK4a/ARF locus codes for two different proteins, p16(INK4a) and p14(ARF), involved in cell cycle regulation. p14(ARF) is considered an upstream regulator of p53 function. To determine the role of these genes in the pathogenesis of human non-Hodgkin's lymphomas we have analyzed exon 1beta, 1alpha, and 2 of the INK4a/ARF locus and p53 gene aberrations in 97 tumors previously characterized for p16(INK4a) alterations. p53 alterations were detected in four of 51 (8%) indolent lymphomas but in 15 of 46 (33%) aggressive tumors. Inactivation of p14(ARF) was always associated with p16(INK4a) alterations. Exon 1beta was concomitantly deleted with exon 1alpha and 2 in eight tumors. One additional lymphoblastic lymphoma showed deletion of exon 1alpha and 2 but retained exon 1beta. No mutations were detected in exon 1alpha and 1beta in any case. Two of the three mutations detected in exon 2 caused a nonsense mutation in the p16(INK4a) reading frame and a missense mutation in the ARF reading frame involving the nucleolar transport domain of the protein. The third mutation was a missense mutation in the p16(INK4a) reading frame, but it was outside the coding region of p14(ARF). Aggressive lymphomas with p14(ARF) inactivation and p53 wild type showed a significantly lower p53 protein expression than tumors with no alteration in any of these genes. In this series of tumors, inactivation of the INK4a/ARF locus mainly occurred in tumors with a wild-type p53 gene because only two lymphomas showed simultaneous aberrations in these genes. Tumors with concomitant alterations of p16(INK4a) and p14(ARF)/p53 genes seem to exhibit a worse clinical behavior than lymphomas with no alterations or isolated inactivation of any of these genes. These findings indicate that p14(ARF) genetic alterations occur in a subset of aggressive NHLs, but they are always associated with p16(INK4a) aberrations. Concomitant disruption of p16(INK4a) and p14(ARF)/p53 regulatory pathways may have a cooperative effect in the progression of these tumors.

Carrier Proteins↗
PubMed2000

Junctional communication of pancreatic beta cells contributes to the control of insulin secretion and glucose tolerance.

Proper insulin secretion requires the coordinated functioning of the numerous beta cells that form pancreatic islets. This coordination depends on a network of communication mechanisms whereby beta cells interact with extracellular signals and adjacent cells via connexin channels. To assess whether connexin-dependent communication plays a role in vivo, we have developed transgenic mice in which connexin 32 (Cx32), one of the vertebrate connexins found in the pancreas, is expressed in beta cells. We show that the altered beta-cell coupling that results from this expression causes reduced insulin secretion in response to physiologically relevant concentrations of glucose and abnormal tolerance to the sugar. These alterations were observed in spite of normal numbers of islets, increased insulin content, and preserved secretory response to glucose by individual beta cells. Moreover, glucose-stimulated islets showed improved electrical synchronization of these cells and increased cytosolic levels of Ca(2+). The results show that connexins contribute to the control of beta cells in vivo and that their excess is detrimental for insulin secretion.

Animals↗
PubMed2000

[Sinonasal intestinal-type adenocarcinoma: report of 7 cases].

The intestinal-type adenocarcinoma of the nasal cavity and paranasal sinuses are uncommon tumors, with less than 4% of the total of malignancies of this region. They have histological similitudes with the glandular estructure of the intestinal mucosa. In some aspects they are similar to others tumors of this area, symptoms, an etiological relation with the exposure to wood dust ... but they have differences in the local aggressivity, this is important for the tractament, evolution and survival. The authors present a revision about clinic characteristics, diagnostic and tractament of seven cases of nasosinusal intestinal type adenocarcinoma.

Adenocarcinoma↗
PubMed1999

Non-genomic actions of 17beta-oestradiol in mouse pancreatic beta-cells are mediated by a cGMP-dependent protein kinase.

1. Intracellular calcium concentration ([Ca2+]i) was measured in mouse whole islets of Langerhans using the calcium-sensitive fluorescent dye Indo-1. 2. Application of physiological concentrations of 17beta-oestradiol in the presence of a stimulatory glucose concentration (8 mM) potentiated the [Ca2+]i signal in 83 % of islets tested. Potentiation was manifested as either an increase in the frequency or duration of [Ca2+]i oscillations. 3. The effects caused by 17beta-oestradiol were mimicked by the cyclic nucleotide analogues 8-bromoguanosine-3',5'-cyclic monophosphate (8-Br-cGMP) and 8-bromoadenosine-3',5'-cyclic monophosphate (8-Br-cAMP). 4. Direct measurements of both cyclic nucleotides demonstrated that nanomolar concentrations of 17beta-oestradiol in the presence of 8 mM glucose increased cGMP levels, yet cAMP levels were unchanged. The increment in cGMP was similar to that induced by 11 mM glucose. 5. Patch-clamp recording in intact cells showed that 8-Br-cGMP reproduced the inhibitory action of 17beta-oestradiol on ATP-sensitive K+ (KATP) channel activity. This was not a membrane-bound effect since it could not be observed in excised patches. 6. The action of 17beta-oestradiol on KATP channel activity was not modified by the specific inhibitor of soluble guanylate cyclase (sGC) LY 83583. This result indicates a likely involvement of a membrane guanylate cyclase (mGC). 7. The rapid decrease in KATP channel activity elicited by 17beta-oestradiol was greatly reduced using Rp-8-pCPT-cGMPS, a specific blocker of cGMP-dependent protein kinase (PKG). Conversely, Rp-cAMPS, which inhibits cAMP-dependent protein kinase (PKA), had little effect. 8. The results presented here indicate that rapid, non-genomic effects of 17beta-oestradiol after interaction with its binding site at the plasma membrane of pancreatic beta-cells is a cGMP-dependent phosphorylation process.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1999

Disregulation of p16MTS1/CDK4I protein and mRNA expression is associated with gene alterations in squamous-cell carcinoma of the larynx.

To determine the relationship between p16MTS1/CDK4I expression, gene inactivation and 9p21 loss of heterozygosity (LOH) in the development of laryngeal carcinomas, we have examined p16MTS1/CDK4I protein and mRNA expression in a series of 7 normal and 36 tumoral tissues, and the presence of gene alterations and 9p21 LOH. Fifteen tumors (42%) showed low levels of pl6MTS1/CDK4I protein expression (similar to normal samples), 7 carcinomas (19%) expressed higher levels, and no protein expression was seen in 14 tumors (39%). No gene alterations were detected in 11 of the 15 tumors (73%) with protein levels similar to normal tissues. Most of the cases with absence of protein expression (86%) had gene alterations. Of the 7 tumors with protein over-expression, 4 showed frameshift or point mutations (2 cases each). mRNA analysis showed pl6MTS1/CDK4I -gene expression in 12 of 17 carcinomas examined. Gene alterations were detected in 9 of the 12 mRNA-positive tumors and in 2 of the 5 negative carcinomas. Concordant expression of p16alpha and p16beta transcripts was observed in all tumors. 9p21 LOH was detected in 23 carcinomas, 18 of which (78%) showed associated p16MTS1/CDK4I -gene alterations. These results indicate that disregulation of p16MTS1/CDK4I protein and mRNA expression is a frequent phenomenon in laryngeal carcinomas commonly associated with gene alterations and 9p21 LOH. The relative number of discrepancies between protein and mRNA expression and the presence of genetic alterations indicate that a comprehensive study of the gene including all these parameters may be necessary to assess the role of this gene in the pathogenesis of such tumors.

Amino Acid Substitution↗
PubMed1999

Homologous and heterologous asynchronicity between identified alpha-, beta- and delta-cells within intact islets of Langerhans in the mouse.

1. Using laser scanning confocal microscopy to image [Ca2+]i within intact murine islets of Langerhans, we analysed the [Ca2+]i signals generated by glucose in immunocytochemically identified alpha-, beta- and delta-cells. 2. Glucagon-containing alpha-cells exhibited [Ca2+]i oscillations in the absence of glucose, which petered out when islets were exposed to high glucose concentrations. 3. Somatostatin-containing delta-cells were silent in the absence of glucose but concentrations of glucose as low as 3 mM elicited oscillations. 4. In pancreatic beta-cells, a characteristic oscillatory calcium pattern was evoked when glucose levels were raised from 3 to 11 mM and this was synchronized throughout the beta-cell population. Remarkably, [Ca2+]i oscillations in non-beta-cells were completely asynchronous, both with respect to each other and to beta-cells. 5. These results demonstrate that the islet of Langerhans behaves as a functional syncytium only in terms of beta-cells, implying a pulsatile secretion of insulin. However, the lack of a co-ordinated calcium signal in alpha- and delta-cells implies that each cell acts as an independent functional unit and the concerted activity of these units results in a smoothly graded secretion of glucagon and somatostatin. Understanding the calcium signals underlying glucagon and somatostatin secretion may be of importance in the treatment of non-insulin-dependent diabetes mellitus since both glucagon and somatostatin appear to regulate insulin release in a paracrine fashion.

Animals↗
PubMed1999

Expression of p27/Kip1 is down-regulated in human prostate carcinoma progression.

p27(Kip1) is a cyclin-dependent kinase inhibitor whose down-regulation has been observed in several tumour models, including breast, colorectal, and gastric carcinomas. The purpose of this study was to assess p27(Kip1) protein expression in normal and benign prostatic epithelia as well as the possible existence of abnormalities in prostate carcinoma progression. p27(Kip1) expression was immunohistochemically analysed in 51 normal tissue samples, 11 nodular hyperplasias (NH), 22 high-grade prostatic intraepithelial neoplasias (PIN), 56 localized prostate adenocarcinomas, and 19 metastases. Immunoblotting was performed in ten cases. Normal prostate epithelium and NH showed diffuse and intense p27(Kip1) nuclear expression in most cases. A significant p27(Kip1) down-regulation was observed in many carcinomas when compared with benign epithelium. Forty-seven cases (84 per cent) were low p27(Kip1) expressors (<50 per cent positive cells) and nine cases (16 per cent) were high p27(Kip1) expressors. p27(Kip1) down-regulation was also consistently seen in PIN. Fourteen out of 19 metastases (74 per cent) were low p27(Kip1) expressors. Six metastatic samples had their corresponding primary tumour analysed and three cases showed decreased expression in the metastasis. It is concluded that p27(Kip1) is constitutively expressed in normal and benign prostatic tissue. This expression is clearly down-regulated in neoplastic progression from the preinvasive lesions through invasive carcinoma and metastases and this therefore occurs in early stages of neoplastic transformation.

Adenocarcinoma↗