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A Casellas

Publications and source records attributed to A Casellas.

11 recordsLinked to original sources
PubMed2000

Transgenic mice overexpressing alpha2A-adrenoceptors in pancreatic beta-cells show altered regulation of glucose homeostasis.

AIMS/HYPOTHESIS: To study the role of the human alpha2A-adrenoceptor in the regulation of insulin secretion and the maintenance of glucose homeostasis in transgenic mice overexpressing this receptor in pancreatic beta cells. METHODS: A human insulin promoter/human alpha2C10-adrenoceptor chimeric gene was microinjected into mouse embryos and transgenic mice were obtained. RESULTS: Analysis by RT-PCR showed that the expression of the transgene was restricted to pancreatic islets. Study of the binding of the alpha2-antagonist [3H]RX821002 to membrane preparations showed that islets from transgenic mice had ninefold higher alpha2-adrenoceptor density than those from controls. Immunohistological analysis showed, however, no change in the number or size of islets between control and transgenic mice. Transgenic animals had normal glycaemia and insulinaemia in basal conditions but greater hyperglycaemic and hypoinsulinaemic responses after injection of the alpha2-agonist, UK14304. The lower blood insulin concentration detected in transgenic mice was a reflection of a stronger inhibitory effect of the alpha2-agonist on glucose-stimulated insulin secretion in transgenic islets than in controls. Furthermore, transgenic mice did not have lower glycaemia to basal values after an intraperitoneal glucose tolerance test. This defect was abolished by treatment with the alpha2-adrenoceptor antagonist, RX821002. CONCLUSION/INTERPRETATION: These results provide evidence in vivo that overexpression of alpha2-adrenoceptors in beta cells can lead to impaired insulin secretion and glucose intolerance.

Adrenergic alpha-Agonists↗
PubMed2000

Anti-inflammatory action of type I interferons deduced from mice expressing interferon beta.

Type I interferons (IFN) are widely used for the therapeutic treatment of viral infections, tumor growth and various chronic diseases such as multiple sclerosis. Antagonism between type I IFNs and IFN-gamma has been described in cells of the immune system, in particular in the activation of macrophages. To study the systemic effects of type I IFNs we used transgenic mice carrying a human IFN-beta (hIFN-beta) gene under the control of the rat insulin I promoter. These animals expressed high levels of hIFN-beta in beta-pancreatic cells, and the ability of the macrophages to respond to pro-inflammatory stimuli was analyzed. Transgenic mice exhibited an increased extravasation of cells to the peritoneal cavity after eliciting with thioglycollate broth. The expression of the inducible form of nitric oxide synthase and cyclooxygenase-2, two enzymes involved in inflammation, was impaired in transgenic animals challenged with lipopolysaccharide and IFN-gamma. Analysis of the mechanisms leading to this attenuated inflammatory response showed a decrease in the serum levels of TNF-alpha and an inhibition of the activation of the transcription factor NF-KB in various tissues. These results indicate that systemic administration of IFN-beta might influence the response to pro-inflammatory stimuli, in particular through the antagonism of IFN-gamma signaling.

Animals↗
PubMed2000

Transgenic mice overexpressing insulin-like growth factor-II in beta cells develop type 2 diabetes.

During embryonic development, insulin-like growth factor-II (IGF-II) participates in the regulation of islet growth and differentiation. We generated transgenic mice (C57BL6/SJL) expressing IGF-II in beta cells under control of the rat Insulin I promoter in order to study the role of islet hyperplasia and hyperinsulinemia in the development of type 2 diabetes. In contrast to islets from control mice, islets from transgenic mice displayed high levels of IGF-II mRNA and protein. Pancreases from transgenic mice showed an increase in beta-cell mass (about 3-fold) and in insulin mRNA levels. However, the organization of cells within transgenic islets was disrupted, with glucagon-producing cells randomly distributed throughout the core. We also observed enhanced glucose-stimulated insulin secretion and glucose utilization in islets from transgenic mice. These mice displayed hyperinsulinemia, mild hyperglycemia, and altered glucose and insulin tolerance tests, and about 30% of these animals developed overt diabetes when fed a high-fat diet. Furthermore, transgenic mice obtained from the N1 backcross to C57KsJ mice showed high islet hyperplasia and insulin resistance, but they also developed fatty liver and obesity. These results indicate that local overexpression of IGF-II in islets might lead to type 2 diabetes and that islet hyperplasia and hypersecretion of insulin might occur early in the pathogenesis of this disease.

Animals↗
PubMed1997

Pruritus in chronic hepatitis C: association with high serum bile acids, advanced pathology, and bile duct abnormalities.

Pruritus is a common symptom of chronic cholestatic liver diseases but is considered rare in chronic hepatitis. We observed pruritus to be an unusually common complaint in patients with advanced chronic hepatitis C. We reviewed the records of 175 chronic hepatitis C patients to identify patients with severe, diffuse, unexplained pruritus; 12 consecutive prospective patients undergoing liver biopsy for chronic hepatitis C served as controls. Assessment included laboratory biochemical tests and assessment of liver pathology by stage, grade, hepatic activity index, and a bile duct score. Pruritus was present in nine (5.1%) patients. Serum AST, ALT, alkaline phosphatase, GGTP, total bilirubin, and ferritin were similar in pruritics and controls. Pruritics had higher serum bile acids (2028.4 +/- 223.1 mmol/liter vs 423.1 +/- 194.3, P < 0.001), higher transferrin saturation (57.5 +/- 6.8% vs 33.2 +/- 3.3, P < 0.01), and lower HCV RNA by bDNA (24.5 +/- 12.7 x 10(5) vs 172.7 +/- 54.1 x 10(5), P < 0.05). Pathology revealed cirrhosis in 6/9 (66.6%) pruritics vs 1/12 (8.3%) controls (P < 0.01). Pruritics had higher pathologic stage (3.7 +/- 0.2 vs 2.2 +/- 0.4, P < 0.01), grade (4.4 +/- 0.2 vs 2.1 +/- 0.2, P < 0.001), activity index (14.3 +/- 1.9 vs 8.6 +/- 1.9, P < 0.025), and bile duct score (7.6 +/- 0.6 vs 4.7 +/- 0.4, P < 0.01). Of eight pruritics treated with IFN-alpha2b, two had complete ALT response and one relapsed. Pruritus followed a relapsing course and only three patients partially responded despite a variety of interventions. In conclusion, pruritus is a common complication of advanced CHC. Its presence is associated with high serum bile acids, advanced pathology and bile duct abnormalities. The clinical course of pruritus is relapsing and response to therapy is inconsistent. These features suggest that pruritus in CHC has a pathogenesis that may vary from that of chronic cholestatic diseases.

Antiviral Agents↗
PubMed1995

The breakthrough phenomenon during alpha-interferon therapy of chronic hepatitis C: incidence, management, and outcome.

OBJECTIVES: Some patients treated with alpha-interferon (alpha-IFN) for chronic hepatitis C (CHC) initially respond with normalization of ALT only to encounter a rise in ALT while still on the drug. This phenomenon is called breakthrough (BT). We reviewed our experience with BT to clarify its incidence, pathogenesis, management, and outcome. METHODS: Charts from 71 consecutive patients with CHC treated with alpha-IFN were reviewed. Forty of these patients were part of a study of 1-yr escalating dose alpha-IFN, initiated at 2 million units (MU) 3 times per week. Endpoints that were evaluated were: reachievement of normal ALT, complete response (CR) (defined as normal ALT at the end of therapy), and sustained CR maintained for 6 months after therapy. RESULTS: Twenty-one (29.5%) patients sustained 28 BT events. Thirteen (46.4%) BT events occurred during the first 6 months of a course of alpha-IFN therapy, and 15 (53.6%) occurred during months 7 through 12. Of patients experiencing BT, six (28.6%) completed their course of therapy with a CR, of which two (9.5%) were sustained. By comparison, of 22 patients who normalized ALT without BT, all completed their course with a CR by definition (p < 0.0001), and nine (40.9%, p < 0.05) had a sustained CR. Of 28 BT events, 13 (46.4%) were followed by reattainment of normal ALT. Of 16 BT events managed with continuation of the same dose of alpha-IFN, normal ALT was reachieved in seven (43.8%). Of 12 BT events managed with an escalation in alpha-IFN dose, six (50%) reachieved normal ALT. A full sequential series of hepatitis C virus RNA PCR from periods of elevated, normal, and again elevated ALT was available for 12 BT events. The pattern was +/+/+ in six, +/-/+ in five, and +/-/- in one. In one additional patient, an apparent BT was attributable to alpha-IFN-induced autoimmune hepatitis. CONCLUSIONS: BT is a common event that may occur at any point during alpha-IFN therapy of CHC. This may limit the benefits of maintenance strategies. After a BT event, normal ALT can be reestablished in about 50% of cases, although the chance of a sustained CR falls to less than 10%. No advantage was demonstrated for escalating the alpha-IFN dose after a BT event. Therefore, we recommend continuation of the same dose as the initial approach. We suspect that BT relates to nonspecific ALT fluctuation in some patients and to emergence of resistant hepatitis C virus strains in others. Other causes of ALT elevation must also be considered in patients with apparent BT.

Adult↗
PubMed1991

Upper gastrointestinal bleeding following open heart surgery. Predominant finding of aggressive duodenal ulcer disease.

We reviewed our experience with endoscopically evaluated severe upper gastrointestinal hemorrhage following open heart surgery. Of 4892 patients undergoing open heart surgery, 18 (0.4%) sustained upper gastrointestinal hemorrhage requiring endoscopic evaluation. Endoscopy identified the source of bleeding in all cases. No significant complications of endoscopy were observed. Duodenal ulcers (DUs) were found in 16 (89%) of cases and were felt to be the source of bleeding in 15 (83%). Aggressive features, such as multiplicity, large size, or distal location were associated with 13 (81%) of the DU cases. Complications necessitated endoscopic or surgical therapy in eight (44%) patients with DUs. We conclude that aggressive DU disease accounts for the majority of severe upper gastrointestinal bleeding following open heart surgery.

Aged↗
PubMed1989

[Neutrophil-dependent inflammatory reactions in systemic lupus erythematosus].

We studied the possible role of polymorphonuclear neutrophil (PMN) aggregation in Systemic Lupus Erythematosus (SLE) by the capacity of sera from 32 lupus patients to induce in vitro normal PMN aggregation. Neutrophil aggregating activity (NAA) in this group was significantly greater than that found in 8 inactive SLE patients and in 8 controls. In patients with SLE, there was a positive correlation between disease severity and the quantitative measure of NAA. High levels of NAA were particularly characteristic of central nervous system SLE. These data suggest that the formation of intravascular leukoaggregates may contribute to morbidity in SLE. Normal PMN increase their spontaneous superoxide anion production (0.21 nmol/min 10(7) PMN) when stimulated with sera from SLE patients. Lupus PMN also show an enhancement of 100% in superoxide production in vitro when stimulated with lupus sera. When N formyl methionine leucyl phenylalanine (FMLP) was used, lupus PMN showed an O2-production of 2.1 nmol/min 10(7) which is 5-fold the response of normal PMN stimulated by FMLP. Our results show the existence of seric factors in SLE patients that can stimulate O2-production by PMN. Lupus neutrophils show an increased response to membrane stimuli such as FMLP, capable of triggering the respiratory burst. Lupus neutrophils appear more responsive membrane stimuli such as FMLP, capable of triggering the respiratory burst. Lupus neutrophils appear more responsive to membrane stimuli. The seric and the cellular factors seem to indicate an increased rate of superoxide production by PMN in SLE patients, which can be relevant to vasculitis and tissue damage.

Adult↗
PubMed1978

Concealed atrial electrical activity.

In the following paragraphs we describe a case diagnosed clinically and haemodynamically as a cardiomyopathy. Atrial flutter which was not in evidence in the standard ECG was diagnosed by the use of a new technique of amplification and filtering of special surface leads (T.A.F.). The diagnosis was later confirmed by means of special internal techniques (intra-atrial ECG and His bundle recording). The existence of a subpraventricular rhythm, probably sinusal, and also unapparent in the standard ECG, was observed by using the same method after electrical defibrillation. We comment on the extreme rareness of discovering concealed atrial rhythms and their possible explanation, and we emphasize the usefulness of the T.A.F. technique in their diagnosis.

Adult↗