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Biomedical subjects

R Calle

Publications and source records attributed to R Calle.

At least 19 recordsLinked to original sources
PubMed2006

Paraoxonase 2 (PON2) polymorphisms and development of renal dysfunction in type 2 diabetes: UKPDS 76.

AIMS/HYPOTHESIS: Identification of variants predicting development of renal dysfunction would offer substantial clinical benefits. There is evidence that coding non-synonymous variants in the gene encoding paraoxonase 2 (PON2) are associated with nephropathy in both type 1 and type 2 diabetes. METHODS: We examined the relationship between variation at the C311S and A148G polymorphisms (together with PON2 intronic variant rs12704795) and indices of renal dysfunction (progression to micro- and macroalbuminuria, plasma creatinine increases) in 3,374 newly diagnosed type 2 diabetic subjects from the UK Prospective Diabetes Study followed prospectively (median 14.0 years), using proportional hazards models, adjusted for sex, ethnicity and other known or putative risk factors. RESULTS: rs12704795 genotypes were associated with differing rates of development of microalbuminuria (relative risk [RR] for CC vs AA homozygotes 0.68 [95% CI 0.54-0.87], p=0.002) but not other measures of worsening renal function. Heterozygotes for C311S were more likely to develop microalbuminuria (RR=1.31 [95% CI 1.11-1.54], p=0.001) but less likely to double creatinine levels during follow-up (RR=0.49 [95% CI 0.27-0.89], p=0.02). There was no corroboration of this latter association for related outcomes and no prior evidence supports heterosis effects at this locus. CONCLUSIONS/INTERPRETATION: We conclude that the PON2 variants typed in this study have, at best, a small effect on the risk of renal dysfunction in type 2 diabetes.

Albuminuria↗
PubMed2002

Ecstasy-induced psychotic disorder: six-month follow-up study.

OBJECTIVE: To describe the psychiatric symptoms manifested by persons diagnosed for the first time as having ecstasy-induced psychotic disorder and to explore the evolution of their symptoms over a 6-month period. DESIGN: Observational study with a 6-month follow-up. METHOD: The subjects studied were 32 ecstasy consumers who were treated at two drug-dependency outpatient centers for hallucinatory-delusive manifestations and who were diagnosed as having ecstasy-induced psychotic disorder according to DSM-IV criteria. For the assessment of the intensity of the syndrome and its follow-up, the Brief Psychiatric Rating Scale (BPRS), the Hamilton Depression Rating Scale (HDRS) and the Clinical Global Impression (CGI) were used at the outset and after 1, 3 and 6 months. All subjects received treatment with olanzapine. RESULTS: The treatment program was completed by 96.9% of the patients. At the baseline assessment, a high incidence of symptoms of a severe psychiatric disorder was observed. From the first month the psychotic symptoms (BPRS) were considerably reduced with treatment, with the most severe positive symptoms remitting in the first 3 months. The three assessment indicators (BPRS, HDRS and CGI) showed a statistically significant clinical reduction over the 6 months of the assessment period. Furthermore, no relevant side effects were noted. CONCLUSIONS: In its initial manifestations, a drug-induced psychotic syndrome includes marked symptoms meeting the criteria of a severe psychotic disorder, with the presence of considerable positive and negative symptoms. Olanzapine has been shown to be very effective in these situations and its use is suggested as first-choice therapy.

Adolescent↗
PubMed1998

A randomized trial of adding fluoxetine to a naltrexone treatment programme for heroin addicts.

AIMS: The purpose of the study was to assess whether fluoxetine would enhance retention in a naltrexone (NTX) treatment programme. DESIGN: Randomized clinical trial. SETTING: The clinical trial was conducted in two Drug Dependence Centres (DCs) of the Basque Country, Spain over a 1-year period. These DCs routinely used naltrexone as part of their treatment. PARTICIPANTS: A total of 112 heroin addicts included in a naltrexone treatment programme were randomly allocated to two groups of 56 patients each. INTERVENTION: One group received 20 mg/24 h of fluoxetine for the first 6 months, while the remaining 56 patients were used as controls. No placebo was used. MEASUREMENTS: Retention rates and hazard functions were estimated. The risk difference and relative risk were also calculated at 6 and 12 months. FINDINGS: The survival functions showed significantly higher retention rates in the fluoxetine group than among the controls. The risk difference at both 6 months (RD6 = 0.23, CI 95% = 0.06-0.42) and 12 months (RD12 = 0.21, CI 95% = 0.09-0.39) favoured the fluoxetine group, with a greater dropout risk at both times among the controls (RR6 = 1.81, CI 95% = 1.11-2.94; RR12 = 1.46, CI 95% = 1.04-2.04). CONCLUSIONS: The study showed that the combination of fluoxetine and naltrexone produced significantly greater retention than in patients given only naltrexone. Placebo-controlled trials are warranted to assess how far this reflects a specific pharmacological effect.

Adult↗
PubMed1996

Diversity of roles of protein kinase C alpha in the proliferation of Swiss 3T3 cells.

We examined the role of protein kinase C alpha (PKC alpha ) in the stimulation of DNA synthesis of Swiss 3T3 cells induced by bombesin, platelet-derived growth factor (PDGF) and phorbol 12-myristate 13-acetate (PMA). We found that cells in which this kinase had been down-regulated showed a partially abrogated mitogenic response to bombesin. The response to PDGF was unaltered; however, the response to PMA was completely suppressed. The mitogenic effect of maximal doses of bombesin and PMA combined was greater than that of either agent alone, suggesting that bombesin does not fully activate the PKC pathway. Accordingly, bombesin-induced PKC alpha translocation from cytosol to membranes was partial, while that observed with PMA was essentially complete. Moreover, exposure to Ro-31-8220, a PKC inhibitor, had significantly greater effects on the response to PMA than on that to bombesin. Our findings point out different roles that PKC alpha may play in diversely activated cells: while, in the case of PMA, stimulation of this kinase may be necessary and sufficient to induce proliferation, it appears to be necessary only for a full response to bombesin, and redundant among the mechanisms triggered by PDGF.

3T3 Cells↗
PubMed1996

Juridical and sociocultural problems on the definition of a law concerning property, usage and access to genetic resources in Colombia.

The property, usage, and access to genetic resources, is today one of the primary topics in international business, as a result of the strategic importance of the resources for the biotechnology industry. Internationally, the sovereignty that each country has over its natural patrimony is recognized. However, the new laws of international marketing have obligated countries in the process of development, such as Colombia, to adopt and copy a concept of intellectual property on living resources that does not have anything to do with the country's sociocultural identity, and sometimes even does not take into account its material enjoyment. The new juridical movement that treats genetic resources as private property produces a cultural conflict between indigenous populations, Afro-Americans and peasants, because for them the genetic resources are an element of community life. In these communities, knowledge is freely transmitted; it is an understanding that they have to conserve their agricultural customs and the relationship that they have with the environment. They do not recognize the term "property' according to patenting laws. These elements have to be considered, respected, and guaranteed in the laws that recognize the genetic resources in the country. On the other hand, not even countries that are pioneers in biotechnological development can adopt a concept about patents that is in agreement with the particularities that the living materials possess. This is obviously the reason for the numerous discussions on the legal interpretation, as well as complicated debates in court. Confronting that situation, there are countries rich in biodiversity, such as Colombia, but which do not have a proper concept and are not economically strong in the international context. These countries have to copy inadequate protection policies that do not take into account all their rights. This paper describes some of the technical, juridical, and sociocultural difficulties which Colombia has to confront, in order to set a guideline on patenting living organisms, and on the access and usage of the genetic resources.

Breeding↗
PubMed1992

Glucose-induced phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) in isolated rat pancreatic islets.

In order to further evaluate the role of protein kinase C activation in glucose-induced insulin secretion, the extent of phosphorylation of the myristoylated alanine-rich C kinase substrate (MARCKS) was examined in freshly isolated rat pancreatic islets prelabeled with [32P]orthophosphate. The islets were incubated with either 2.75 mM glucose alone, 2.75 mM glucose + 1 microM phorbol myristate acetate, 20 mM glucose, or 20 mM glucose + 50 nM staurosporine. After stimulation, the homogenized islets were processed by immunoprecipitation with a specific polyclonal anti-MARCKS antibody, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Densitometric analysis of autoradiograms revealed that phorbol myristate acetate caused a 3.78 +/- 0.97-fold increase in MARCKS phosphorylation over control. In the islets exposed to 20 mM glucose, an increase of 3.43 +/- 0.46-fold over control was observed. In islets exposed to G20 + 50 nM staurosporine, MARCKS phosphorylation was inhibited by 90 +/- 4% compared with control islets exposed to 20 mM glucose alone. Islets similarly treated (but incubated without 32P) were examined by immunocytochemistry using an alpha-PKC-specific monoclonal antibody and visualized by confocal immunofluorescence microscopy. The alpha-PKC redistributed from the cytosol to the plasma membrane in the beta-cells of islets exposed to 20 mM glucose. In separate experiments, unlabeled but similarly treated islets were shown to respond with a 5-7-fold increase in insulin secretion in static incubation. Thus, when freshly isolated rat pancreatic islets are exposed to stimulatory glucose concentrations, they exhibit both a translocation of alpha-PKC and a significant increase in the extent of phosphorylation of MARCKS protein. These data suggest that alpha-PKC is activated during glucose-induced insulin secretion.

Alkaloids↗
PubMed1992

Immunocytochemical localization of alpha-protein kinase C in rat pancreatic beta-cells during glucose-induced insulin secretion.

To investigate the role of protein kinase C (PKC) in the regulation of insulin secretion, we visualized changes in the intracellular localization of alpha-PKC in fixed beta-cells from both isolated rat pancreatic islets and the pancreas of awake unstressed rats during glucose-induced insulin secretion. Isolated, perifused rat islets were fixed in 4% paraformaldehyde, detergent permeabilized, and labeled with a mAb specific for alpha-PKC. The labeling was visualized by confocal immunofluorescent microscopy. In isolated rat pancreatic islets perifused with 2.75 mM glucose, alpha-PKC immunostaining was primarily cytoplasmic in distribution throughout the beta-cells. In islets stimulated with 20 mM glucose, there was a significant redistribution of alpha-PKC to the cell periphery. This glucose-induced redistribution was abolished when either mannoheptulose, an inhibitor of glucose metabolism, or nitrendipine, an inhibitor of calcium influx, were added to the perifusate. We also examined changes in the intracellular distribution of alpha-PKC in the beta-cells of awake, unstressed rats that were given an intravenous infusion of glucose. Immunocytochemical analysis of pancreatic sections from these rats demonstrated a glucose-induced translocation of alpha-PKC to the cell periphery of the beta-cells. These results demonstrate that the metabolism of glucose can induce the redistribution of alpha-PKC to the cell periphery of beta-cells, both in isolated islets and in the intact animal, and suggest that alpha-PKC plays a role in mediating glucose-induced insulin secretion.

Animals↗
PubMed1992

Involvement of protein kinase-C in the mitogenic effect of insulin-like growth factor-I on rat astrocytes.

Insulin-like growth factor-I (IGF-I) stimulates the proliferation of many cell types, including astrocytes. Astrocytes are a population of brain cells highly enriched in IGF-I receptors, which unlike neurons, retain the ability to proliferate in the adult brain. Although astrocyte proliferation in response to IGF-I is well documented, the intracellular mechanisms that mediate this phenomenon are poorly defined. Interestingly, activation of protein kinase-C (PKC) by IGF-I has been observed in several cell types. In this report we first characterized the mitogenic effects of IGF-I on highly purified type I rat astrocyte cultures. Next, we determined whether IGF-I activates PKC in our cultures. Finally, since astrocyte proliferation is stimulated by both IGF-I and the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA), we decided to test the possible involvement of PKC in the mitogenic activity of IGF-I on astrocytes. IGF-I stimulated the DNA synthesis rate in rat astrocytes. Analysis of the time course revealed that IGF-I (10 nM) induces maximal stimulation of [3H]thymidine incorporation (a 4-fold increase) 16-18 h after exposure. TPA also stimulated mitogenesis in our cultures. The dose-response of [3H]thymidine incorporation induced by IGF-I and TPA indicated that 10 nM was the lowest concentration producing a maximal effect for both agents. Analysis of proteins by Western blot revealed that 10 nM IGF-I translocates PKC(alpha), the predominant PKC isoform in astrocyte cultures, from the cytosol to the membrane fraction within 20 min. A similar activation of PKC was achieved with 100 nM TPA. When astrocytes were exposed to IGF-I (10 nM) and TPA (10 nM) in combination, [3H]thymidine uptake was significantly higher than the uptake induced by either IGF-I (10 nM) or TPA (10 nM) alone. However, the effect of IGF-I plus TPA was not fully additive. In a second experiment, the mitogenic effect of IGF-I was partially abolished in cells depleted of PKC by preincubation with high concentrations of TPA (300 nM). Finally, incubation of astrocytes with the PKC inhibitor H-7 at 20 microM, a concentration that completely blocked the mitogenic action of TPA, only reduced the ability of IGF-I to stimulate DNA synthesis by 50%. In summary, our results demonstrate that IGF-I can rapidly activate PKC in astrocytes, and that PKC activation is involved in the mitogenic effect of IGF-I on these cells. However, we conclude that IGF-I also stimulates astrocyte proliferation through PKC-independent pathways.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1992

Ca(2+)-cyclic AMP interactions in sustained cellular responses.

As early as 1970 it was apparent that the cyclic AMP (cAMP) and Ca2+ messenger systems often interact to regulate cellular responses. Work over the past 20 years has greatly expanded our knowledge of these interactions, and has shown that these signalling systems interact in complex ways to regulate sustained cellular responses such as aldosterone secretion, smooth muscle contraction and insulin secretion. The latter system is considered in detail because it illustrates several types of interactions, both positive and negative, which help to determine the normal response of beta-cells to physiological stimuli, and how abnormalities in secretory patterns can develop as a consequence of the prolonged stimulation of a messenger system.

Animals↗
PubMed1991

Influence of staurosporine on glucose-mediated and glucose-conditioned insulin secretion.

The effect of staurosporine, a putative inhibitor of protein kinase C (PKC), on insulin secretion induced by glucose and 4-methyl-2-oxopentanoate (KIC) was examined. In addition, the effects of staurosporine on the actions of other agonists, for which glucose acts as a conditional modifier, were also examined. At 20 nM, staurosporine caused a marked inhibition of second-phase insulin secretion, whether it was stimulated by 10 mM- or 20 mM-glucose, by 15 mM-KIC, or by carbachol or tolbutamide in islets co-perifused with 7.0 mM-glucose. In each case, the second-phase secretory response was inhibited by 70-85%. In contrast, in all cases there was no effect of staurosporine on the magnitude of the first phase of insulin secretion, nor on the time course of first-phase secretion, except when glucose alone was the secretagogue. With either 10 mM- or 20 mM-glucose, the peak of the first phase of insulin secretion was delayed. Staurosporine does not alter glucose metabolism, or the ability of glucose to activate phosphoinositide hydrolysis or to cause the translocation of alpha-PKC to the membrane. These findings support the concept that PKC activation plays an important role in fuel-induced or fuel-conditioned insulin secretion.

Alkaloids↗
PubMed1991

Effects of the phorbol ester phorbol 12-myristate 13-acetate (PMA) on islet-cell responsiveness.

Collagenase-isolated rat islets were labelled for 2 h in myo-[2-3H]inositol solution supplemented with 2.75 mM-glucose. The phorbol ester phorbol 12-myristate 13-acetate (PMA; 0.1 or 1 microM) was also present in some experiments. After labelling, islets were washed and then perifused in 2.75 mM-glucose to establish basal [3H]inositol-efflux and insulin-secretory rates. Subsequently, the responses of these islets to stimulation with various agonists were assessed. Inositol phosphate accumulation was measured at the termination of the perifusion. In separate experiments, the cellular location of protein kinase C (PKC) after PMA pretreatment was measured by quantitative immunoblotting of membrane and cytosolic fractions. The following observations were made. (1) Labelling in 0.1-1 microM-PMA had no deleterious effect on total [3H]inositol incorporation during the 2 h labelling period. However, islets labelled for 2 h in 1 microM-PMA were unable to respond, in terms of increases in insulin release, to a 1 microM-PMA stimulus during the subsequent perifusion. (2) As compared with the responses of control islets labelled in 2.75 mM-glucose alone, islets labelled in the additional presence of 1 microM-PMA displayed a significant impairment in phosphoinositide (PI) hydrolysis, but an enhancement of both first-and second-phase insulin secretion, in response to subsequent 20 mM-glucose stimulation. (3) Decreasing extracellular Ca2+ level to 0.1 mM and including the Ca(2+)-channel antagonist nitrendipine (0.5 microM) along with 1 microM-PMA during the [3H]inositol-labelling period did not alter the response of the islets to the subsequent addition of 20 mM-glucose. Glucose-induced PI hydrolysis was still inhibited and 20 mM-glucose-induced insulin release was still enhanced. (4) A markedly amplified and sustained insulin-secretory response to 200 microM-tolbutamide in the presence of 2.75 mM-glucose was also obtained from 1 microM-PMA-pretreated islets. This contrasts sharply with the small and transient response to tolbutamide noted in control islets. (5) When present only during the perifusion phase of the experiments, nitrendipine (0.5 microM) abolished the amplified insulin-secretory responses to both 20 mM-glucose and 200 microM-tolbutamide noted in PMA-pretreated islets. (6) Prior labelling in 1 microM-PMA dramatically amplified the insulinotropic effect of 25 mM-K+ or 5 microM-A23187 stimulation. The amplified insulin-secretory response to K+, but not to A23187, was abolished by inclusion of nitrendipine during the perifusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Glucose-induced translocation of protein kinase C in rat pancreatic islets.

The role of protein kinase C (PKC) as a mediator of glucose-induced insulin secretion has been a subject of controversy. Glucose-induced translocation of PKC has not been reported, and the relevant PKC isoenzymes in islets have not been identified. To address these issues, we developed specific antibodies to the alpha, beta, and gamma isoenzymes of PKC. Western blots of homogenates of freshly isolated rat islets probed with these antibodies revealed that the major isoenzyme present is alpha-PKC. Islets were perifused for 15 min with either 2.75 mM glucose, 20 mM glucose, 20 mM glucose plus 30 mM mannoheptulose, 15 mM alpha-ketoisocaproate, or alpha-ketoisocaproate plus mannoheptulose. Quantitative immunoblotting of membrane and cytosol fractions showed that alpha-PKC translocated from the cytosol to the membrane in freshly isolated rat islets stimulated with either 20 mM glucose or 15 mM alpha-ketoisocaproate. Both the secretory response and the translocation of alpha-PKC were blocked by the addition of mannoheptulose, an inhibitor of glucose metabolism, in islets stimulated with glucose but not in islets stimulated with alpha-ketoisocaproate. These results support a role for alpha-PKC in mediating glucose-induced insulin secretion in pancreatic islets.

Amino Acid Sequence↗
PubMed1990

Physiology and pathophysiology of insulin secretion.

Mechanisms by which various classes of extracellular signals regulate insulin secretion are discussed regarding their cellular and molecular actions. Under physiological circumstances, the small postprandial changes in plasma glucose concentrations (approximately 4.4-6.6 mM) primarily serve as a conditioned modifier of insulin secretion and dramatically alter the responsiveness of islets to a combination of neurohormonal agonists. These agonists have two functions. Cholecystokinin (CCK) and acetylcholine activate the hydrolysis of polyphosphoinositides, and gastric inhibitory polypeptide (GIP) and glucagonlike peptide 1 activate adenylate cyclase. These two functional classes of neurohumoral agonists act synergistically to enhance insulin secretion when plasma glucose is greater than 6.0 mM but not when it is less than or equal to 4 mM. On the other hand, an increase in plasma glucose concentration to 8-10 mM induces an increase in insulin secretory rate in the absence of any of the neurohormonal agonists. Remarkably, high glucose leads to an increase in the same intracellular signals, as does a combination of acetylcholine and GIP. On the basis of these data, a model of how insulin secretion is regulated under physiological circumstances is proposed. This model emphasizes that the regulation of insulin secretion occurs in three stages: cephalic, early enteric, and later enteric. In this view, the crucial event occurring during the first two phases is the agonist-induced, translocation of protein kinase C (PKC) to the plasma membrane under conditions in which an increase in Ca2+ influx does not occur. PKC is now in a cellular location and a Ca2(+)-sensitive conformation such that an increase in Ca2+ influx rate occurring during the third phase leads to its immediate activation and an enhanced rate of insulin secretion. Furthermore, under physiological circumstances, an optimal insulin secretory response is dependent on a correct temporal pattern of signals arising from neural and enteric sources. If this pattern is deranged, an abnormal pattern of insulin secretion is observed. An important new insight is provided by the observation that agonists (e.g., CCK or acetylcholine) that act to stimulate the hydrolysis of phosphatidylinositides, when acting for a short period (10-20 min), induce an enhanced responsiveness of islets to glucose, i.e., proemial sensitization. However, when acting unopposed for several hours, these agonists will induce a time-dependent suppression of responsiveness to glucose and other agonists. The latter observation implies that optimal insulin secretion is dependent on periodic rather than a continuous exposure to the correct pattern of extracellular signals.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Four-day continuous infusion of cisplatin and 5-fluorouracil in head and neck cancer.

A combination of cisplatin and 5-fluorouracil, both administered 4 days continuously as infusion, was assessed in advanced head and neck cancer. Of the 37 patients studied, there were 15 complete and 17 partial responses (40.5% and 45.9%, respectively). Survival is 79.1% at 22 months. None of the patients in complete response has relapsed. In general toxic effects were moderate. Given as initial treatment, the regimen is effective and of considerable use in this type of patient.

Adult↗
PubMed1987

[Value of drill-biopsy in breast cancer].

This study reports the results of 649 drill biopsies performed on breast tumors before any treatment. Diagnostic of malignancy was achieved with a drill biopsy in 89% cases (579/649 procedures). Pathological subtypes, i.e. common infiltrating types, special pathological types, were determined in 98% cases (566/579), while histo-prognostic grading, according to Scarff, Bloom and Richardson, was performed in 98% of the common infiltrating type carcinomas (498/507). Reliability of the technique was related to the tumor size 57%, 87.5%, 93.5% and 98.5% in T1, T2, T3 and T4 tumors (TNM classification), respectively. Comparative reliability of the three different operators was 86.5%, 88.5% and 92%, and was related to their technical experience. This study has demonstrated the diagnostic value of a "malignant" drill biopsy, which is independent of the results of the initial radiological and clinical work-up: suspicious or malignant (group A: 635 cases, or non-suspicious group B: 14 cases). However, "non malignant" drill biopsy has no value and should not be conclusive.

Biopsy, Needle↗
PubMed1986

Conservative management of intraductal breast carcinoma with tumorectomy and radiation therapy.

Between 1967 and 1983, 54 patients with strictly noninvasive intraductal breast carcinoma were treated with tumorectomy and radiation therapy. Median follow-up was 55 months. Three patients had a recurrence in the treated breast; two were noninvasive, and one was invasive. One patient died of disease. Actuarial 5-year disease-free survival rate was 95.2%. No axillary node recurrences occurred in patients treated with irradiation to the breast and regional nodes (34 patients), or in patients treated with breast irradiation alone (20 patients). These preliminary results suggest that combined tumorectomy and radiation therapy could be a valuable conservative alternative to mastectomy in the treatment of noninvasive intraductal breast carcinoma.

Adult↗