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Biomedical subjects

A Farré

Publications and source records attributed to A Farré.

At least 19 recordsLinked to original sources
PubMed2001

Immortalized bovine pancreatic duct cells become tumorigenic after transfection with mutant k-ras.

Mutation of the K-ras gene is thought to be an early and important event in pancreatic carcinogenesis. In order to study the role of this molecular alteration in the transition from the normal to the neoplastic pancreatic cell, bovine pancreatic duct cells were first immortalized by SV40 large T antigen (Ag) complementary (c)DNA transfection and then transfected with a mutated K-ras gene. As did primary duct cells, the immortalized duct cells (more than 100 passages) expressed cytokeratins, carbonic anhydrase type-II, cystic fibrosis transmembrane conductance regulator (CFTR), and multidrug resistance (mdr). They grew as a single layer after transplantation under plastic domes and formed three-dimensional structures resembling ducts when grown on Matrigel. Cell growth was stimulated by insulin, epidermal growth factor (EGF), transforming growth factor (TGF)-alpha, but cells did not respond to gastrin and CCK-8. They did not form colonies in soft agar nor did they form tumors in nude mice. Immortalized cells transfected with mutated K-ras acquired the ability to form tumors after orthotopic injection into the nude mouse pancreas. It is concluded that SV 40 immortalized bovine pancreatic

Animals↗
PubMed2001

The novel analgesic, cizolirtine, inhibits the spinal release of substance P and CGRP in rats.

Although previous studies have established that cizolirtine (5-([(N,N-dimethylaminoethoxy)phenyl]methyl)-1-methyl-1H-pyrazol citrate) is a potent analgesic in rodents, its mechanism(s) of action remain(s) unclear. In vitro and in vivo approaches were used to assess whether cizolirtine could affect the spinal release of two pain-related neuropeptides, substance P (SP) and calcitonin gene-related peptide (CGRP), in rats. Cizolirtine significantly reduced the K(+)-evoked overflow of both the SP-like material (SPLM; -25% at 0.1 microM--0.1 mM) and CGRPLM (-20% at 0.1--1.0 microM) from slices of the dorsal half of the lumbar enlargement of the spinal cord. Intrathecal perfusion in halothane-anaesthetized rats showed that local application of cizolirtine markedly diminished the spinal outflow of SPLM (up to -50% at 0.1 mM) but only marginally that of CGRPLM. Systemic administration of cizolirtine at an analgesic dose (80 mg/kg i.p.) also reduced spinal SPLM outflow (-50%) but not that of CGRPLM. Under both in vitro and in vivo conditions, idazoxan (10 microM) antagonized the effects of cizolirtine on SPLM and CGRPLM release, suggesting their mediation through alpha(2) adrenoceptors.

Acetic Acid↗
PubMed2001

[The effect of nocturnal oxygen therapy in patients with sleep apnea syndrome and chronic airflow limitation].

Oxygen therapy for patients with sleep apnea-hypopnea syndrome (SAHS) usually causes significant side effects. The aim of this study was to assess the effect of short-term nocturnal oxygen therapy in patients with SAHS and chronic obstructive pulmonary disease. Ten patients with diagnoses of SAHS were enrolled. The patients' mean age was 63 (10) years, mean apnea-hypopnea index (AHI) was 58 +/- 17, mean FVC was 59 +/- 8% of reference and mean FEV1 was 40 +/- 14% of reference. Using a random, single blind design, two polysomnographic studies were performed on two consecutive nights. Oxygen was administered on one night at a mean flow rate of 1.3 +/- 04 l/min and on the other night air was administered at the same rate. Arterial blood gases were analyzed at the end of each study. Oxygen administration improved nocturnal hypoxia and reduced the AHI, which was 40 +/- 20 with oxygen and 58 +/- 17 with air (p < 0.005). Improvement was achieved at the expense of a reduction in the number of hypopneic episodes. No significant differences were observed in apneic episodes and only a slight increase in the duration of hypopneic episodes was observed (21 +/- 7 s with air and 27 +/- 8 s with oxygen [p < 0.01]). Neither quality of sleep nor heart rate changed. Slight respiratory acidosis was observed in 50% of the patients. In conclusion, nocturnal oxygen administration in patients with SAHS and COPD improved nocturnal hypoxia and reduced the total number of respiratory events. However, in these patients oxygen should be administered with care, even when the rate of flow is low, given the tendency for pCO2 and respiratory acidosis to increase.

Humans↗
PubMed2001

p53 and K-ras mutations in pancreatic juice samples from patients with chronic pancreatitis.

BACKGROUND: Mutations in p53 and ras genes are frequent in pancreatic carcinoma. Several ras mutations are consistently detected in the pancreatic juice from patients with chronic pancreatitis. The p53 gene mutations have been detected occasionally in chronic pancreatitis tissue. It was the aim of this study to evaluate the presence and clinical significance of p53 and ras mutations in clinical pancreatic juice samples from patients with chronic pancreatitis. METHODS: Pancreatic juice was obtained from 66 patients with chronic pancreatitis and no evidence of pancreatic carcinoma (51 men, 15 women; age 17-86 years [mean 49.6 +/- 12.9]). Patients were followed prospectively for 26 +/- 3 (4-54) months. Detection of p53 gene mutations was by temperature gradient gel electrophoresis (TGGE) and single strand conformation polymorphism (SSCP) for exons 5-8. Analysis of ras mutations was performed by SSCP/polymerase chain reaction, restriction fragment length polymorphism/polymerase chain reaction. All mutations were confirmed by sequencing. RESULTS: Five of 66 (7.5%) pancreatic juice samples contained p53 mutations, and ras mutations were detected in 6 cases (9%). Cytology was negative in all cases. No pancreatic carcinoma developed during follow-up and neither cancer cells nor preneoplastic lesions could be detected histologically in resected specimens. Although no correlation between p53 mutations and duration of pancreatitis or drinking habits was found, K-ras mutations correlated with both heavy smoking and severity of the disease. CONCLUSION: p53 and ras mutations can be detected in a minority of pancreatic juice samples from patients with chronic pancreatitis in the absence of malignancy.

Adolescent↗
PubMed2001

Clinical usefulness of K-ras gene mutation detection and cytology in pancreatic juice in the diagnosis and screening of pancreatic cancer.

BACKGROUND: The significance of K-ras codon 12 mutation in pancreatic juice is still unclear. Although considerable controversy surrounds this question, the diagnostic utility of K-ras in patients with clinical suspicion of pancreatic cancer (PC) and in PC-risk patients remains unknown. OBJECTIVE: To study prospectively the utility of the K-ras gene mutation and cytology in the diagnosis and screening of PC, and to assess its contribution to clinical decision making. METHODS: Pancreatic juice samples obtained from 90 patients were evaluated prospectively. Group I (n = 40) comprised patients with clinical suspicion of PC; group II (n = 50) comprised 49 patients with chronic pancreatitis and one patient proceeding from a PC family screening. The K-ras mutation was detected by means of artificial restriction fragment length polymorphisms (RFLP) in DNA after polymerase chain reaction (PCR) amplification. RESULTS: In group I, of those patients with a definitive diagnosis of PC, malignant cells were found in 27% and K-ras mutation in 44%. In five cases, molecular analysis contributed to diagnosis (4/11 with negative cytology and 1/2 with insufficient cytological material). K-ras mutation revealed an early tumour in one patient, and was the only sample available for diagnosis in another. In group II, the K-ras gene mutation was detected in 8/49 patients (16%) with chronic pancreatitis, one of whom developed PC (2%). CONCLUSIONS: K-ras mutation analysis of pancreatic juice may complement cytological evaluation in the diagnosis of PC, in spite of its limited contribution to clinical decision making. The presence of K-ras mutation in chronic pancreatitis classifies a subgroup of PC-risk patients who should be evaluated carefully by long-term follow-up.

Adult↗
PubMed2001

Efficacy and tolerability of policosanol in hypercholesterolemic postmenopausal women.

This randomized, double-blind, multicenter placebo-controlled study was conducted to investigate the efficacy and tolerability of policosanol, a cholesterol-lowering drug purified from sugar cane wax, in women who had experienced menopause and showed elevated serum total cholesterol and low density lipoprotein (LDL)-cholesterol levels despite a 6-week standard lipid-lowering diet. Thus, 56 eligible patients were randomized to receive placebo or policosanol 5 mg/day for 8 weeks and the dose was doubled to 10 mg/day during the next 8 weeks. Policosanol (5 and 10 mg/day) significantly decreased LDL-cholesterol (17.3% and 26.7%, respectively), total cholesterol (12.9% and 19.5%) as well as the ratios of LDL-cholesterol to high-density lipoprotein (HDL)-cholesterol (17.2% and 26.5%) and total cholesterol to HDL-cholesterol (16.3% and 21.0%) compared with baseline and placebo. HDL-cholesterol levels were significantly raised by 7.4% at study completion. No significant changes occurred in the lipid profile of the placebo group. The drug was safe and well tolerated. No drug-related adverse effects were observed. None of the patients administered policosanol but three of those administered placebo withdrew from the trial because of adverse effects: one due to a serious hypertensive status, one because of an allergic reaction (pruritus plus skin rash) and one due to gastrointestinal disturbances (nauseas plus vomiting). Eleven placebo patients reported 24 adverse effects compared with six policosanol patients who reported seven adverse effects (p < 0.05). In addition, five placebo (17.9%) and 13 policosanol patients (46.4%) (p < 0.05) reported improvements in habitual symptoms and health perception during the study. In conclusion, policosanol was effective and well tolerated in hypercholesterolemic postmenopausal women, showing additional benefits in the health perception of the study patients.

Anticholesteremic Agents↗
PubMed2000

A highly sensitive method for K-ras mutation detection is useful in diagnosis of gastrointestinal cancer.

Detection of molecular features such as K-ras mutations has been used to evaluate potential tumour markers in a wide variety of clinical samples. Here we have applied a recently developed highly sensitive method for detection of K-ras codon 12 mutations to colorectal and pancreatic cancer diagnosis. We analysed 67 faecal samples from patients undergoing diagnostic colonoscopy under suspicion of colorectal cancer. PCR products were obtained in 62 of 67 (93%) faecal samples. Mutations were detected in exfoliated cells in 6 of 22 (27%) of the adenomas and in 6 of 11 (55%) of adenocarcinomas. No false positives were observed. Agreement between faecal samples and corresponding tissues was 100% for adenocarcinomas and 65% for adenomas. Mutations were also analysed in 61 pancreatic fine-needle aspirates. Mutations were detected in 36 of 45 (80%) of the pancreatic aspirates diagnosed as pancreatic cancer without false positives. Our findings suggest that, when colorectal cancer is suspected, detection of K-ras codon 12 mutations in faecal samples using this new method is specific for colorectal tumours. Additionally, this technique is a good alternative for evaluation of pancreatic masses.

Adenocarcinoma↗
PubMed2000

Prospective evaluation of the contribution of K-ras mutational analysis and CA 19.9 measurement to cytological diagnosis in patients with clinical suspicion of pancreatic cancer.

The aim of this study was to prospectively evaluate the diagnostic contribution of the detection of K-ras mutation and measurement of serum CA 19.9 concentrations to cytological diagnosis in patients with clinical suspicion of pancreatic cancer. These patients had either the presence or absence of a pancreatic mass as determined by imaging procedures. A total of 156 consecutive patients with clinical suspicion of pancreatic cancer or for confirmation and follow-up of their chronic pancreatitis disease were included: 84 patients presenting a pancreatic mass (group 1) and 72 patients without a pancreatic mass (group 2). K-ras mutations were detected by a restriction fragment length polymorphism/polymerase chain reaction (RFLP/PCR) method and CA 19.9 by an immunoluminometric assay. When a pancreatic mass was present, cytology offered a high sensitivity, but with a significant number of inconclusive results and K-ras mutational analysis offered a highly specific test. In the absence of a pancreatic mass, CA 19.9 (cut-off 100 U/ml) increased the sensitivity of the diagnosis by cytology and K-ras mutational analysis did not add significant information. Thus both tests contribute to the clinical decision process when pancreatic cancer is clinically suspected and the cytological report is not conclusive.

Adult↗
PubMed2000

Survival of cancer of the pancreas. Bases for new strategies in diagnosis and therapy.

OBJECTIVE: The ominous prognosis of pancreatic carcinoma (PC) has led to a nihilistic attitude among physicians, and to the need to develop better tools for diagnosis, staging and treatment. The aim of this study was to analyze a series of patients with PC in order to determine stage-related survival, and to try to improve diagnostic and therapeutic strategies. METHODS: This was a retrospective study of 167 patients diagnosed from 1987 to 1993. The diagnosis was based on cytological pathology findings or on a clinical course compatible with PC. TNM stage and survival were calculated. We also analyzed age, sex, time elapsed until diagnosis, diagnostic tests, size and location, cytologic pathology confirmation, number of patients undergoing surgery, and procedures used. RESULTS: Age: 67 +/- 12 years, 82 men and 85 women. Time elapsed until diagnosis: 3 +/- 15.7 months. Pathologic diagnosis: 74.8%. LOCATION: head 75%, body 13.9%, tail 7.2%, diffuse 2.4%, not reported 1.2%. Size: 4.6 +/- 2 cm. TNM staging: stage I 13%; stage II 25%; stage III 20%; stage IV 42%. Stage-related survival: stage I 14 months; stage II 6 months; stage III 4 months; stage IV 1 month. Total survival: 3 months. Surgery was done in 66.5% and resection in 10%; curative surgery in 6.5%; bypass in 81% and diagnostic laparotomy in 9%. In 55% of the patients surgery revealed a higher stage of disease than had been diagnosed preoperatively. Postoperative mortality was 18%. Survival at 1 and 5 years after curative surgery was 80% and 20%, respectively. CONCLUSIONS: Diagnosis was made at a late stage in many patients. Few patients were candidates for radical surgery. Early diagnosis, preoperative staging and postoperative management should be improved in these patients, and surgery should be associated with complementary chemotherapy and/or radiotherapy.

Adult↗
PubMed1999

K-ras mutations in DNA extracted from the plasma of patients with pancreatic carcinoma: diagnostic utility and prognostic significance.

PURPOSE: Previous studies have demonstrated the presence of K-ras mutations in the plasma of patients with pancreatic carcinoma. However, the diagnostic utility and the prognostic significance of this finding have never been addressed. PATIENTS AND METHODS: Forty-four consecutive patients with histologically confirmed primary pancreatic ductal adenocarcinoma were included. A control group of 37 patients with chronic pancreatitis, 10 patients with other tumors of the pancreatic area, nine patients with acute pancreatitis, and four healthy volunteers was also included. Plasma DNA was isolated and K-ras codon-12 mutations were analyzed by means of restriction fragment length polymorphism-polymerase chain reaction and single-strand conformation polymorphism techniques. Patients were followed up to establish their clinical outcome. RESULTS: The mutant-type K-ras gene was found in plasma DNA samples of 12 (27%) of 44 patients with pancreatic ductal adenocarcinoma; this finding was related to the tumor stage (P = .05), mainly in the presence of distant metastases (P = .02). In addition, K-ras mutations were detected in the plasma DNA of two (5%) of 37 patients with chronic pancreatitis. In the subset of patients with pancreatic masses, the sensitivity and specificity of plasma K-ras analysis for pancreatic adenocarcinoma were 27% and 100%, respectively. Finally, pancreatic carcinoma patients with the mutant-type K-ras gene in plasma DNA exhibited a shorter survival time than patients with the wild-type gene (P<.005), and plasma K-ras mutations were identified as the only independent prognostic factor (odds ratio, 1.51; 95% confidence interval, 1.02 to 2.23). CONCLUSION: Plasma K-ras analysis is a highly specific, low-sensitivity approach that has diagnostic and prognostic clinical implications in patients with pancreatic carcinoma.

Adenocarcinoma↗
PubMed1998

Endogenous cholecystokinin enhances postprandial gastroesophageal reflux in humans through extrasphincteric receptors.

BACKGROUND & AIMS: Exogenous cholecystokinin (CCK) decreases lower esophageal sphincter (LES) pressure and increases transient LES relaxations (TLESRs) in humans. The aims of this study were to determine whether endogenous CCK increases gastroesophageal reflux in humans and whether this is a direct effect on the LES. METHODS: Esophageal pH, LES pressure, and gallbladder volume were measured in 8 healthy volunteers after ingestion of a 181-kcal meal alone or adding 12 g cholestyramine to increase endogenous CCK release. In 7 additional volunteers, the effect of cholestyramine was studied during intravenous perfusion of saline or the CCK-A receptor antagonist loxiglumide. In circular LES strips from 9 transplant donors, we measured the effect of CCK-8 (10(-11) to 3 x 10(-8) mol/L) on basal tension and on electrical field-induced relaxation. RESULTS: Cholestyramine increased gallbladder emptying, reflux episodes, TLESRs, and time of esophageal pH of <4. Loxiglumide inhibited postprandial gallbladder emptying, reflux episodes, TLESRs, and time of pH of <4 and prevented the decrease in LES pressure induced by cholestyramine. In vitro, CCK-8 contracted LES strips through a tetrodotoxin-insensitive pathway but did not modify electrical field-induced LES relaxations. CONCLUSIONS: Endogenous CCK enhances postprandial gastroesophageal reflux in humans by increasing the rate of TLESRs and reduces postprandial LES pressure. These actions seem mediated by extrasphincteric CCK-A receptors that override a direct contractile effect of CCK on the LES muscle.

Adult↗
PubMed1998

K-ras gene mutations in the diagnosis of fine-needle aspirates of pancreatic masses: prospective study using two techniques with different detection limits.

Detection of K-ras mutations may be useful in the evaluation of pancreatic cancer. The aim of this study was to assess, in a prospective design, the diagnostic utility of K-ras mutation analysis in 62 consecutive fine-needle aspirates of pancreatic masses, using two PCR-based techniques-standard and enriched-with detection limits of a mutant allele in the presence of 10(2) or 10(3) wild-type alleles, respectively. Cytology alone offered a diagnostic sensitivity of 75%. The enriched higher sensitivity detection technique, in combination with cytology, offered a diagnostic sensitivity of 91% without false positives. The molecular analysis would have contributed to diagnosis in an additional 14 cases of pancreatic cancer. The standard technique contributed to diagnosis in an additional 9 cases. These results strongly support the use of the enriched method of detecting K-ras mutations as a complement to cytology in the evaluation of pancreatic masses.

Aged↗
PubMed1997

Chloroquine stabilizes pancreatic lysosomes and improves survival of mice with diet-induced acute pancreatitis.

Activation of digestive zymogens by lysosomal enzymes has been suggested as a triggering event in acute pancreatitis (AP). chloroquine (CQ), a weak base that accumulates in the lysosomes and increases their pH, can inhibit the activity of lysosomal enzymes. In the present study, we examined the effect of CQ on choline-deficient, ethionine-supplemented (CDE) diet-induced AP. CQ-diphosphate (15-50 mg.kg-1) or vehicle was given intraperitoneally at 0, 24, and 48 h to female CD1 mice that were fed with either normal diet or CDE diet. For mortality studies, animals were observed for 168 h. Serum and pancreas samples were collected from animals sacrificed 56 h after the start of the CDE diet. Treatment with CQ at 50 mg.kg-1 significantly (p < 0.05) improved the survival of mice with CDE diet-induced AP. In the normal pancreas, CQ decreased the specific activity of lysosomal enzymes cathepsin B1, beta-hexosaminidase, beta-glucuronidase, and acid phosphatase. In the pancreas with AP, CQ did not modify the activity of cathepsin B1, whereas it increased the latency of all enzymes. In conclusion, our results confirm the beneficial effect of CQ on survival of mice with CDE diet-induced AP and suggest that this effect of CQ may be due to its stabilizing action on lysosomes.

Acid Phosphatase↗
PubMed1996

Diagnostic utility of K-ras mutations in fine-needle aspirates of pancreatic masses.

BACKGROUND & AIMS: Mutations at codon 12 of the K-ras gene are present in 65%-100% of carcinomas of human exocrine pancreas and could be used as a potential tumor marker at the tissue level. The purpose of this study was to assess, in large series of patients, the utility of K-ras mutation analysis to evaluate fine-needle aspirates of pancreatic masses. METHODS: One hundred fifteen fine-needle aspirates obtained from 93 patients were evaluated retrospectively. Cytological analysis was based on the review of cell blocks. Mutations were detected by using artificial restriction fragment length polymorphisms using the Hphl and BstNl approaches. RESULTS: The sensitivity and specificity of cell block cytology was 64% and 100%, respectively, for the diagnosis of pancreatic carcinoma. K-ras mutations were detected in 41 pancreatic carcinomas (sensitivity, 59%) and in one mucinous cystic tumor; specificity of ras analysis alone was 100%. The sensitivity of cytology combined with K-ras mutations were 77.6% and 100%, respectively. CONCLUSIONS: The detection of K-ras mutations would have suggested the diagnosis of pancreatic cancer in 14 cases otherwise not detected by cytology alone. K-ras mutation analysis should be restricted to cell blocks containing suspicious, normal-appearing duct cells, or insufficient material in the cytological examination.

Aged↗
PubMed1996

K-ras and p53 mutations in hamster pancreatic ductal adenocarcinomas and cell lines.

K-ras and p53 gene alterations are frequently found in human pancreatic carcinomas and cell lines. The aim of this study was to analyze for the presence of K-ras and p53 gene mutations in hamster pancreatic tumors and cell lines. Mutations at the first coding exon of the K-ras gene and in exons V to VIII of the hamster p53 gene were analyzed in six cell lines (H2T, PC1, PC1.2, PC1.0, WD, and PD) and in N-nitroso-bis(2-oxopropyl)amine-induced pancreatic (n = 9) and extra-pancreatic (n = 4) tumors. K-ras mutations were present in seven of the nine pancreatic tumors and in all extra-pancreatic tumors. No p53 mutations were detected in the tumors. All cell lines analyzed contained K-ras mutations. Moreover, four of the six cell lines contained single amino acid substitutions in the p53 gene. Cell lines derived from nitrosamine-induced pancreatic tumors in the hamster contained K-ras and p53 alterations similar to those found in cell lines derived from human pancreatic carcinomas.

Animals↗
PubMed1996

[Activity and subcellular distribution of lysosomal enzymes in acute pancreatitis induced by CDE diet in mice].

The aim of the present study was to analyze the activity and subcellular distribution of the lisosomal enzymes and the stability of the lisosomes in acute pancreatitis induced by CDE diet in mice. The activity and the latency of the catepsin-B1 enzymes, acid phosphatase, beta-hexosaminidase and beta-glucuronidase in normal pancreas and in pancreatitis induced by CDE diet were determined. The distribution of the acid phosphatase lisosomal marker was determined in subcellular fractions obtained by differential centrifugation. The activity of the catepsin-B1 enzyme increased 47% in the pancreas of mice with pancreatitis induced by CDE diet. The acid phosphatase activity was not modified and the beta-hexosaminidase and beta-glucuronidase was decreased. The specific activity of the acid phosphatase lisosomal marker also increased in the subcellular fraction containing the zimogene granules and decreased the latency (parameter indicative of lisosome stability) of all the lisosomal enzymes analyzed in the pancreatic homogenate. These results suggest that the lisosomal enzymes, specially the catepsin-B1, and the decrease in the stability of the lisosomes may play a role in the pathogenesis of acute pancreatitis.

Acid Phosphatase↗