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Biomedical subjects

A Pujol

Publications and source records attributed to A Pujol.

At least 19 recordsLinked to original sources
PubMed1995

Prediction of carboplatin clearance from standard morphological and biological patient characteristics.

BACKGROUND: Hematologic toxicity of an antineoplastic drug, carboplatin, is largely dependent on its pharmacokinetics. Its therapeutic efficacy may be related to plasma drug exposure. Dosage adjustment based on isotopic determination of glomerular filtration rate has been proposed, but its ambulatory use is not yet conceivable. The dosage adjustment based on a patient's creatinine clearance relies on accurate measurement of urine volume per unit time and can be done with ease. PURPOSE: A population pharmacokinetics study was undertaken to determine a relationship between carboplatin clearance and patient characteristics. A predictive formula was derived that was then prospectively evaluated, and its outcome was compared with that obtained by other methods available to predict carboplatin clearance. METHODS: Plasma carboplatin pharmacokinetics determined as ultrafilterable platinum in 70 patients (age range, 23-84 years) treated with different combination regimens that included carboplatin at doses ranging from 184 mg to 950 mg (1-hour intravenous infusion) for various tumor types. Data were analyzed using the nonlinear mixed effects model (NONMEM). The data from 34 patients (46 cycles) were utilized to derive the most predictive formula. The reliability of the formula was subsequently evaluated by analyzing the data obtained from 36 other patients (49 cycles). RESULTS: Carboplatin clearance (mL/min) was found to be best predicted by the following formula: 0.134.weight + [218.weight.(1-0.00457.age).(1-0.314.sex)]creatinine expressed in micromolar concentration (with weight in kg, age in years, and sex = 0 if male and sex = 1 if female). Prospectively, this formula predicted the carboplatin clearance with good precision (median absolute percent error of 10% [range, 0% to 30%]) and minimal bias (median percent error of 2% [range, -25% to 30%]). This method of prediction was as accurate as the one derived from the measurement of glomerular filtration rate following the injection of 51 chromium-EDTA. CONCLUSION: This formula for the determination of carboplatin clearance can permit individualized determination of carboplatin dosage in adults by simply multiplying the calculated carboplatin clearance by the area under the curve for the desired dosage administration.

Adult↗
PubMed1995

Neonatally administered naltrexone affects several behavioral responses in adult rats of both genders.

The effects of a daily injection of the opioid antagonist naltrexone (NALTX, 1 mg/kg SC), from birth to weaning day, on several behavioral parameters were investigated in adult rats of both genders. This work uses three behavioral tests. The use of the open-field test in addition to the holeboard and plus-maze tests allows the measurement of complementary parameters, and provided further information on diverse components of behavior. The effect of repeated testing (habituation) over 3 consecutive days of open-field testing was also assessed. In accordance with previous reports, female rats showed higher locomotor activity and exploration and a lower level of emotionality than their male counterparts. The response of the animals to repeated testing seemed to be both sex and treatment dependent. In both males and females, NALTX treatment during the preweanling period did not affect locomotor activity, but increased the animals' levels of anxiety and emotionality and decreased exploratory behavior. Our results indicate that neonatal opioids may play an important role in the development of behavioral responses in the adult.

Animals↗
PubMed1995

Evidence from transgenic mice that myc regulates hepatic glycolysis.

The product of the c-myc proto-oncogene (c-Myc) is involved in the control of cell proliferation, differentiation, and apoptosis. It acts as a transcription factor that recognizes the CACGTG motif. This sequence has also been found in the glucose-responsive elements of genes involved in the control of liver glycolysis and lipogenesis. To determine whether c-Myc can regulate hepatic carbohydrate metabolism in vivo, transgenic mice that overexpress c-myc under control of the P-enolpyruvate carboxykinase (PEPCK) gene promoter have been generated. These mice showed a threefold increase in c-Myc protein in liver nuclei. Hepatocytes from transgenic mice were normal and did not acquire the fetal phenotype. However, transgenic mice showed higher levels (threefold) of L-type pyruvate kinase mRNA and enzyme activity than control mice. The increase in pyruvate kinase activity led to a three- to fivefold increase in liver lactate content and a fivefold induction of lactate production by hepatocytes in primary culture. The expression of the 6-phosphofructo-2-kinase gene was also increased in the liver of these transgenic mice. The induction of hepatic glycolysis was related with an increase in the expression (about fourfold) and activity (about threefold) of liver glucokinase, whereas no change was noted in hexokinase-I. This change in glucokinase activity led to an increase in both glucose 6-phosphate and glycogen contents in the liver of transgenic mice. The expression of the liver-specific glucose transporter GLUT2 was also increased in transgenic mice, whereas no change was noted in the mRNA concentration of GLUT1. Furthermore, the changes of liver glucose metabolism led to a marked reduction of blood glucose (25%) and insulin (40%) concentrations in starvation, whereas the fall in both was only 10% in fed mice. Thus, liver glucose metabolism could determine the blood glucose and insulin set points in the transgenic mice. All these results indicated that the increase in c-Myc protein was able to induce liver glucose utilization and accumulation, and suggested that c-Myc transcription factor is involved in the control in vivo of liver carbohydrate metabolism.

Animals↗
PubMed1995

Isolation of a fully infectious variant of parvovirus H-1 supplanting the standard strain in human cells.

A variant H-1 virus, designated H-1 dr virus, was isolated from stock of the standard H-1 virus strain propagated in the newborn human kidney cell line NB-E. Molecular cloning and sequence analysis revealed an in-frame deletion at map positions 39 to 41. This deletion affects the open reading frames encoding the nonstructural proteins NS-1 and NS-2 and the untranslated leader sequence of the R3 transcripts encoding the capsid proteins. In addition, H-1 dr virus harbors a 58-nucleotide duplication inboard from the right-hand terminal palindrome. Internal deletions and terminal reiterations are hallmarks of H-1 virus type I variants that typically are defective interfering particles. Indeed, H-1 dr virus was found to progressively supplant the standard strain in serially coinfected NB-E cell cultures. However, H-1 dr virus differed from previously described type I variants in its full infectivity, as was apparent from its ability to give yields of replication and progeny virus production that were similar to those of the standard virus strain in NB-E cells. Hence, the interference of H-1 dr virus in the propagation of standard H-1 virus in coinfected cells was not accompanied by a drop in the titer of infectious virus. Moreover, H-1 dr virus proved to induce the same pathogenic effects in newborn hamsters as the standard virus strain did.

Base Sequence↗
PubMed1995

[The temporomandibular joint meniscus in MRI].

The continuing improvement of the MRI's equipment and software led us to a continuous adaptation of the exam technique. We use today a bilateral coil technique, 3 inches in diameter. Four slices are performed for each articulation (4 mm thick) in the true sagittal plane. A fast spin echo, balanced in proton density, for one minute, allows the study of 15 steps inside a full open/close cycle. Oblique coronal cuts are also performed parallel to the long axis of the condyle in a T1-weighted spin echo sequence in close and half-open positions. The analysis of 350 subjects allows to detail more precisely the meniscal displacement. Beside the classic anterior luxation, the meniscus slips medially, laterally and may rotate. These different situations may be isolated or combined. The dynamic study is specifically useful in the displacement with reduction exams. It enables permits to point out the timing of the disk disturbance: this information may be of great help in therapeutic decisions.

Adolescent↗
PubMed1995

[Myxoid liposarcoma. MRI imaging].

PURPOSE: Myxoid liposarcoma is the most common type of liposarcoma (approximately 40 to 50% of all liposarcomas). The main tissue component is a myxoid matrix present primarily in extracellular compartments; proliferating lipoblasts account for less 10% of the tumor: MRI appearances are not typical for lipomatous tumor. Nevertheless histological features may permit understanding MRI findings and identifying patients with myxoid liposarcoma. MATERIALS AND METHODS: Clinical history and radiologic images of 7 patients with histologically verified myxoid liposarcoma were retrospectively studied. In all patients the tumor presented in a lower extremity as a painless, slowly growing mass. MR images were available for review in all cases (T1- and T2-weighted images); in addition fat-suppression before and after gadolinium enhancement were assessed with T1-weighted sequences. RESULTS: MRI examination revealed an "encapsulated" tumor, non infiltrating and septated. On T1-weighted sequences all the lesions show lacy, amorphous and linear foci of high signal within a low signal of the tumor due to the predominance of a myxoid matrix. The high sensitivity of MRI demonstrates the presence of small areas of high signal and fat-suppression technique is valuable for characterizing soft-tissue tumors: suppression of high signal intensity on fat-saturated T1-weighted images indicates the presence of fatty tissue components. CONCLUSION: Clinical correlation with MRI appearances on T1-weighted sequences (in addition to fat-suppression technique) may suggest the possibility of myxoid liposarcoma.

Adult↗
PubMed1994

Expression of GLUT-2 antisense RNA in beta cells of transgenic mice leads to diabetes.

An insulin response to glucose is required to correct hyperglycemia. Two proteins, the glucose transporter GLUT-2 and the glucose-phosphorylating enzyme glucokinase, have been implicated in the control of glucose metabolism in beta cells. To study the role of glucose transporter GLUT-2 in the regulation of insulin secretion and in the development of diabetes mellitus, we have obtained transgenic mice expressing high levels of GLUT-2 antisense RNA in beta cells. Western blot analysis showed an 80% reduction in GLUT-2 protein in the beta cells of these animals. Islets from transgenic mice showed impaired glucose-stimulated insulin secretion. In addition, much higher levels of blood glucose were detected in transgenic mice than in controls when glucose tolerance tests were performed. These results suggest that the reduction of GLUT-2 in the pancreas could be a crucial step in the development of diabetes mellitus.

Animals↗
PubMed1994

Transgenic mice overexpressing phosphoenolpyruvate carboxykinase develop non-insulin-dependent diabetes mellitus.

An increase in hepatic gluconeogenesis is believed to be an important factor responsible for the fasting hyperglycemia detected in patients with non-insulin-dependent diabetes mellitus (NIDDM). Phosphoenolpyruvate carboxykinase (GTP) (PEPCK; EC 4.1.1.32) is a regulatory enzyme of gluconeogenesis. To study the role of the expression of PEPCK gene in the development of NIDDM, we have produced lines of transgenic mice expressing a PEPCK minigene under control of its own promoter. Transgenic mice were hyperglycemic and had higher serum insulin concentrations. In addition, alterations in liver glycogen content and muscle glucose transporter GLUT-4 gene expression were detected. The overexpression of the PEPCK gene led to an increase in glucose production from pyruvate in hepatocytes in primary culture. When intraperitoneal glucose tolerance tests were performed, blood glucose levels were higher than those detected in normal mice. This animal model shows that primary alterations in the rate of liver glucose production may induce insulin resistance and NIDDM.

Animals↗
PubMed1994

Regulated expression of human insulin in the liver of transgenic mice corrects diabetic alterations.

Transgenic mice expressing the P-enolpyruvate carboxykinase (PEPCK)/human insulin chimeric gene have been obtained as a model to study the feasibility of gene therapy for diabetes. These transgenic animals were healthy and normoglycemic and expressed human insulin in a physiologically regulated manner, mainly in the liver. Streptozotocin-treated transgenic mice had high levels of human insulin immunoreactivity in serum and showed a significant decrease (up to 40%) in glycemia compared with streptozotocin-treated control mice. The expression of genes involved in liver glucose metabolism, such as glucokinase, pyruvate kinase, and PEPCK, which is markedly altered by diabetes, was significantly recovered in transgenic mice treated with streptozotocin. In addition, the activity of both glucokinase and glycogen synthase, and the content of glucose 6-phosphate and glycogen, were normal in the liver, even when transgenic animals were treated with diabetogenic doses of streptozotocin. These results constitute an indication in vivo that diabetes gene therapy is possible, by means of the production of insulin in extrapancreatic tissues.

Animals↗
PubMed1994

Overexpression of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in transgenic mice causes hepatic hyperketogenesis.

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMG-CoA synthase) is a key enzyme in the ketone body pathway. To determine its role in the regulation of liver ketogenesis, transgenic mice expressing a P-enolpyruvate carboxykinase/HMG-CoA synthase chimeric gene have been obtained. An increase in the concentration of mitochondrial HMG-CoA synthase mRNA was detected in these mice, which was associated with a 3-fold increase in HMG-CoA synthase activity in liver mitochondrial extracts. Transgenic mice were normoglycemic and had normal levels of plasma triglycerides and lower free fatty acids. However, the plasma concentration of ketone bodies was about three times higher in transgenic mice than in control animals. Hepatocytes in primary culture from transgenic mice expressed the chimeric gene in a regulated manner and showed a 3-fold increase in beta-hydroxybutyrate and acetoacetate concentrations in the medium. This animal model thus shows that the overexpression of mitochondrial HMG-CoA synthase causes ketone body overproduction, suggesting that this enzyme may be a regulatory step in liver ketogenesis.

3-Hydroxybutyric Acid↗
PubMed1994

Naltrexone administration effects on regional brain monoamines in developing rats.

The effects of the opioid antagonist naltrexone (NALTX) daily administration (1 mg/kg SC) from birth on the levels of dopamine (DA), serotonin (5-HT), and their respective major metabolites, in the striatum, midbrain, and hypothalamus of 7-, 14-, and 22-day-old rats were investigated. Naltrexone treatment increased the striatal HVA/DA ratio on postnatal day 7. At day 14, two subpopulations (A and B) were found among the treated animals. The subpopulation A showed decreased HVA/DA and increased DOPAC/DA ratios, whereas the subpopulation B presented a higher DA concentration. No significant effect appeared on the striatal dopaminergic system in 22-day-old pups. The serotonergic system was affected by exposure to naltrexone only from day 14. The subpopulation A showed a reduction in all the parameters measured in the three regions studied, although in the subpopulation B, lower 5-HIAA/5-HT ratios appeared in the midbrain and hypothalamus. At 22 days of age NALTX treatment elevated striatal 5-HT and 5-HIAA and the ratio of 5-HIAA/5-HT in the midbrain and hypothalamus. These data suggest an endogenous opioid modulation on the central aminergic systems during the neonatal period and point out the consequences of opioid plasticity on related neurotransmitter systems.

Aging↗
PubMed1994

Predictive factors of the long term outcome in gastro-oesophageal reflux disease: six year follow up of 107 patients.

There is little information concerning the long term outcome of patients with gastro-oesophageal reflux disease (GORD). Thus 109 patients with reflux symptoms (33 with erosive oesophagitis) with a diagnosis of GORD after clinical evaluation and oesophageal testing were studied. All patients were treated with a stepwise approach: (a) lifestyle changes were suggested aimed at reducing reflux and antacids and the prokinetic agent domperidone were prescribed; (b) H2 blockers were added after two months when symptoms persisted; (c) anti-reflux surgery was indicated when there was no response to (b). Treatment was adjusted to maintain clinical remission during follow up. Long term treatment need was defined as minor when conservative measures sufficed for proper control, and as major if daily H2 blockers or surgery were required. The results showed that one third of the patients each had initial therapeutic need (a), (b), and (c). Of 103 patients available for follow up at three years and 89 at six years, respective therapeutic needs were minor in 52% and 55% and major in 48% and 45%. Eighty per cent of patients in (a), 67% in (b), and 17% in (c) required only conservative measures at six years. A decreasing lower oesophageal sphincter pressure (p < 0.001), radiological reflux (p = 0.028), and erosive oesophagitis (p = 0.031), but not initial clinical scores, were independent predictors of major therapeutic need as shown by multivariate analysis. The long term outcome of GORD is better than previously perceived.

Adult↗
PubMed1994

Predictive factors of in-hospital CNS complications following liver transplantation.

We prospectively evaluated 84 consecutive adult patients with chronic liver disease before and after liver transplantation to define the type and frequency of post-transplant neurologic complications, and to assess possible pretransplant and operative variables associated with in-hospital CNS complications. There were 25 patients (30%) who presented 23 neurologic complications of the central and six of the peripheral nervous system. Seventy-five percent of the complications occurred in the first month post-transplant. The most frequent CNS complications included anoxic (six patients) and septic (five) encephalopathy, as well as brain hemorrhage (five). Patients who presented CNS complications had a higher mortality rate than those who did not (55% versus 17%, p = 0.002). Multiple logistic regression analysis showed abnormal pretransplant neurologic examination suggestive of chronic hepatic encephalopathy (p = 0.007) and noncholestatic liver disease (p = 0.012) to be independently associated with in-hospital CNS complications. These data indicate that CNS neurologic complications following liver transplant are common in patients with noncholestatic liver disease and are associated with increased mortality. The pretransplant neurologic examination is an important predictor of CNS complications that occur in the immediate post-transplant period.

Adult↗
PubMed1993

A developmental study on stress-induced antinociception measured by the tail electric stimulation test.

The possible influence of weaning on the development of different neural mechanisms involved in stress-induced antinociception (SIA) was studied. Male Wistar albino rats were used for studies on adult and pre- and postweanling rats of 20 and 25 days of age, respectively. Animals were stressed by warm-water (20C) swimming for 3-min periods. Antinociception was assessed by the tail electric stimulation test. The thresholds for the motor response (tail withdrawal) (TW), vocalization during stimulus (V), and vocalization after discharge (VAD) were recorded. These responses are considered to be integrated at spinal, medulla oblongata, and diencephalon-rhinencephalon levels, respectively. In 20-day-old neonates, swimming stress only induced significant increases in the VAD thresholds that were not significantly reversed by naloxone (NAL) (1 mg/kg). Twenty-five-day-old rats showed increased threshold for the three nociceptive responses after stress, the effects on TW and V being antagonized by NAL. Adult rats subjected to stress showed increased threshold for the three responses, an effect that was antagonized by NAL in all cases. These results suggest that the weaning period might be critical for the development of the mechanisms mediating SIA. Besides, a different involvement of opioid systems throughout development, particularly in relation to the affective/emotional component of pain, is also suggested.

Aging↗
PubMed1993

Fiber type composition and enzyme activities of muscles in two models of obese rats.

1. In oxidative (soleus) and glycolytic (extensor digitorum longus) muscles of obese Zucker rats, a significant decrease in the percentage of relative area occupied by glycolytic fibers was observed. 2. The activity of citrate synthase and beta-hydroxy-acyl-CoA-dehydrogenase was significantly higher in muscles of obese than of lean Zucker rats. 3. In rats, 6 weeks after lesion of the ventromedial hypothalamus, no changes were observed. 4. This indicates that neither the proportion of oxidative fibers, nor the oxidative capacities are decreased in skeletal muscles of obese rats suggesting that insulin resistance cannot be ascribed to a higher glycolytic-oxidative fiber ratio.

Animals↗
PubMed1992

Controlled trial of intravenous corticosteroids in severe acute asthma.

BACKGROUND: The value of corticosteroids in severe acute asthma continues to be debated. METHODS: Ninety consecutive patients admitted to the emergency room with severe acute asthma were studied in a randomised, double blind, controlled trial to determine the efficacy of corticosteroids. Eighty two patients completed the study. All received oxygen therapy and intensive bronchodilator treatment. The patients were divided into three groups for steroid treatment, receiving intravenous methylprednisolone 10 mg/kg every four hours for 48 hours (29 patients, group A); intravenous methylprednisolone 2 mg/kg every 4 hours for 48 hours (27 patients, group B); or no intravenous corticosteroids (26 patients, group C). RESULTS: There were no differences on admission among the three groups in forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF), or arterial oxygen or carbon dioxide tension; and the rates of recovery in FEV1, FVC, and PEF were similar. CONCLUSIONS: Corticosteroids given with bronchodilators have not shown a beneficial effect in the first 48 hours of recovery of severe acute asthma. Only in those patients who failed to respond by the third hour of treatment, and in those who were previously taking oral corticosteroids, does a favourable, though not statistically significant, effect appear to occur.

Acute Disease↗
PubMed1992

Insulin receptor kinase activity in muscles and white adipose tissue during course of VMH obesity.

Early after lesion of the ventromedial hypothalamus nuclei (VMH), insulin-induced glucose utilization is increased in white adipose tissue (WAT), whereas oxidative and glycolytic muscles are, respectively, normoresponsive or resistant to insulin. Five weeks later, all of the muscles are resistant, whereas WAT returns to normal responsiveness. The aim of this study was to characterize the insulin receptor kinase activity in WAT and muscles 1 and 6 wk after lesion. The number and affinity of insulin receptors were not modified in any of the tissues studied. Autophosphorylation and phosphorylation of an exogenous substrate were similar in oxidative and glycolytic muscles of VMH and control rats both 1 and 6 wk after the lesion. Insulin receptors from WAT of 1-wk VMH rats exhibited a 2.5-fold increase in insulin-stimulated autophosphorylation and phosphorylation. Six weeks after the lesion, both autophosphorylation and phosphorylation returned to normal values. This suggests that insulin receptor tyrosine kinase activity does not play a significant role in the insulin resistance of skeletal muscles but has a crucial role in mediating the variations of insulin action on WAT observed during the development of VMH obesity.

Adipose Tissue↗