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F Bosch

Publications and source records attributed to F Bosch.

At least 91 records · Page 5Linked to original sources
PubMed1996

Evidence from transgenic mice that glucokinase is rate limiting for glucose utilization in the liver.

To study the role of glucokinase (GK) in the control of glucose metabolism in the liver, transgenic mice were generated in which GK was overexpressed under control of the P-enolpyruvate carboxykinase gene promoter. Whereas the expression of the GK gene in starved control mice was blocked, this promoter was able to direct the expression of the enzyme to the liver of starved transgenic mice. Furthermore, starved transgenic mice showed levels of GK activity fourfold higher than those of starved control and similar to those of fed control. This activation of GK led to an increase in the intracellular concentration of glucose 6-phosphate, which was also related to an induction of glycogen accumulation. In addition, L-pyruvate kinase (L-PK) activity increased in transgenic mice, which when starved showed similar levels of activity to control fed mice. The induction of L-PK caused an increase in the hepatic lactate concentration. Furthermore, hepatocytes in primary culture from transgenic mice incubated with 20 mM glucose produced levels of lactate threefold higher than controls, but no difference was noted when the hepatocytes from control and transgenic mice were incubated with 2 mM glucose. These results demonstrated in vivo that the activation of GK is a rate-limiting step in the induction of glycolysis and glycogen synthesis. These changes in liver glucose metabolism led to a marked reduction in blood glucose (30%) and insulin (40%) concentrations. Furthermore, transgenic mice showed lower levels of blood glucose after an intraperitoneal glucose tolerance test, indicating that GK overexpression caused an increase in blood glucose disposal by the liver. All these findings show the key role of liver GK in the control of whole-body glucose homeostasis.-Ferre, T., Riu, E., Bosch, F., Valera, A. Evidence from transgenic mice that glucokinase is rate limiting for glucose utilization in the liver.

Animals↗
PubMed1996

An assessment of the clinicohematological criteria for the accelerated phase of chronic myeloid leukemia.

In order to assess the relative importance of the clinicohematological features most commonly associated with the accelerated phase (AP) of chronic myeloid leukemia (CML) in 175 consecutive patients, 12 variables generally considered as indicating AP were analyzed for their predictive value for blast crisis (BC) appearance in less than 1 yr. At the time of analysis, 118 patients had died and 104 had developed BC. At univariate study, 6 features were associated with a significantly higher BC-probability: poor performance status (ECOG score > or = 2), unexplained fever/sweats, severe bone pain, progressive splenomegaly despite adequate therapy, blood basophils (> or = 20%) and peripheral blasts (6-12%). At logistic regression, only bone pain and blood blasts (6-12%) retained their prognostic importance; the relative risk of unexplained fever/sweats and progressive splenomegaly was also clinically relevant. One-year BC-probability from the appearance of 1 or more of the above features was 77.3% (95% CI: 66-86.6) and 100% since all 4 were observed. Finally, at least 1 of the 4 features was present prior to death in 6 of 7 patients dying from CML-related causes while not in BC. AP can be defined by the appearance along CML evolution of 1 or more of the 4 above-mentioned clinicohematological features.

Adolescent↗
PubMed1996

CNS involvement in mantle-cell lymphoma.

PURPOSE: In non-Hodgkin's lymphomas, CNS involvement is highly dependent on the histology of the lymphoma. Mantle-cell lymphoma (MCL) is a lymphoma type with distinctive histologic, biologic, and clinical features in which CNS involvement has only been rarely described. The purpose of this report is to describe the incidence, clinical characteristics, and outcome of CNS infiltration in patients with MCL seen at a single institution. PATIENTS AND METHODS: Twenty-two patients with MCL, who account for 6% of all patients with nodal lymphomas diagnosed and monitored at a university hospital from 1987 to 1994, were studied. Analysis of the incidence of CNS involvement by the disease was performed. RESULTS: Five of 22 patients (22%; exact 95% confidence interval [CI], 7.8% to 45.4%) with MCL developed CNS involvement at a median of 18 months (range, 6 to 59) from diagnosis. All of these patients presented with poor MCL histologic subtypes and advanced disease. When the CNS infiltration became apparent, all of the patients displayed neurologic signs and had lymphoid cells consistent with the diagnosis of MCL in the CSF. In most of the cases, CNS infiltration was part of resistant disease or generalized relapse and had an ominous significance. CONCLUSION: The incidence of CNS involvement in MCL might be higher than previously recognized. The frequency of CNS infiltration in MCL deserves to be investigated in other series and, if a high incidence is confirmed, the risk factors, mechanisms, and clinical implications of such a complication should be further studied.

Adult↗
PubMed1996

Fludarabine in resistant or relapsing B-cell chronic lymphocytic leukemia: the Spanish Group experience.

Fludarabine produces high response rates in patients with B-cell chronic lymphocytic leukemia (CLL). Nevertheless, response to fludarabine of patients with previously treated CLL varies from 17% to 74% (0% to 38% CR). In 68 patients with heavily pretreated and advanced CLL, an overall response rate to fludarabine of 28% (4% CR) was observed. Response correlated with sensitivity of the disease to previous treatments (relapsing vs. refractory disease) (62% vs. 20%; p = 0.005) and, albeit not significantly, with the number of cycles of fludarabine (>3 vs. < or = 3) that patients could receive (36% vs. 15%; p = NS). Responding patients had a longer survival (median, not reached) than those not responding (median, 11 months) (p = 0.03). Severe toxicity was observed in some cases. It is concluded that fludarabine is a highly useful agent in CLL. However, in order to improve its effectiveness and decrease its toxicity, fludarabine should be given as soon as a lack of response to front-line therapy is observed and before the disease becomes completely resistant to therapy.

Anemia, Hemolytic, Autoimmune↗
PubMed1996

Expression of retinoblastoma gene product (pRb) in mantle cell lymphomas. Correlation with cyclin D1 (PRAD1/CCND1) mRNA levels and proliferative activity.

Mantle cell lymphomas (MCLs) are molecularly characterized by bcl-1 rearrangement and constant cyclin D1 (PRAD-1/CCND1) gene overexpression. Cyclin D1 is a G1 cyclin that participates in the control of the cell cycle progression by interacting with the retinoblastoma gene product (pRb). Inactivation of the Rb tumor suppressor gene has been implicated in the development of different types of human tumors including some high grade non-Hodgkin's lymphomas. To determine the role of the retinoblastoma gene in the pathogenesis of MCLs and its possible interaction with cyclin D1, pRb expression was examined in 23 MCLs including 17 typical and 6 blastic variants by immunohistochemistry and Western blot. Rb gene structure was studied in 13 cases by Southern blot. Cytogenetic analysis was performed in 5 cases. The results were compared with the cyclin D1 mRNA levels examined by Northern analysis, and the proliferative activity of the tumors was measured by Ki-67 growth fraction and flow cytometry. pRb was expressed in all MCLs. The expression varied from case to case (mean, 14.1% of positive cells; range, 1.3 to 42%) with a significant correlation with the proliferative activity of the tumors (mitotic index r = 0.85; Ki-67 r = 0.7; S phase = 0.73). Blastic variants showed higher numbers of pRb-positive cells (mean, 29%) than the typical cases (10%; P < 0.005) by immunohistochemistry and, concordantly, higher levels of expression by Western blot. In addition, the blastic cases also had an increased expression of the phosphorylated protein. No alterations in Rb gene structure were observed by Southern blot analysis. Cyclin D1 mRNA levels were independent of pRb expression and the proliferative activity of the tumors. These findings suggest that pRb in MCLs is normally regulated in relation to the proliferative activity of the tumors. Cyclin D1 overexpression may play a role in the maintenance of cell proliferation by overcoming the suppressive growth control of pRb.

Aged↗
PubMed1996

[Comparative study of the treatment of postoperative pain in function of the surgical service].

HYPOTHESIS AND OBJECTIVES: A high level of pain has been observed among surgical patients and it has been suggested that surgical specialty may be an important factor in pain, although no relation has been conclusively demonstrated. In this study we compared the characteristics of postoperative pain and pain treatment given in several surgical services. PATIENTS AND METHODS: We studied 249 patients in orthopedic surgery and traumatology (OST, n = 95), general surgery (GS, n = 66), gynecology and obstetrics (GO, n = 51), urology (URO, n = 16), vascular surgery (VS, n = 9), ophthalmology (OPH, n = 7), otorhinolaryngology (ORL, n = 5). The characteristics of analgesic treatment (type of prescription, drug, route, dose and compliance) were recorded, as were degree of pain expressed on a visual analog scale and a verbal assessment scale 24 h after surgery, and level of patient satisfaction with the analgesic treatment. RESULTS: Thirty percent of the patients reported moderate to unbearable pain the day after surgery. Severe pain was most common in OST patients. Analgesics, mainly diclofenac (52%) and pethidine (36%), were prescribed by protocol for 93% of patients. Although there were differences among the various services, compliance with diclofenac prescription was better; compliance was high among GO patients for both drugs. Over half the patients reported having had severe or unbearable pain during the hours following surgery. Most said relief was sufficient or high (55%) with treatment and described themselves as satisfied or very satisfied (62%) with the analgesic received. Surgery on extremities was the most painful and generated the greatest dissatisfaction. CONCLUSIONS: This study suggests that type of surgery may condition the prevalence of and severity of postoperative pain. Although type of surgery and location are important factors, there are sufficient differences and deficiencies in treatment to explain, at least partly, the variation observed.

Adolescent↗
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

Increased expression of the PRAD-1/CCND1 gene in hairy cell leukaemia.

The PRAD-1/CCND1 gene encodes Cyclin D1, a cyclin involved in cell cycle regulation at the G1-S transition. Over-expression of this gene is a highly specific molecular marker of mantle cell lymphomas (MCLs), but it may also be up-regulated in some chronic lymphoproliferative disorders, mainly chronic lymphocytic leukaemia. We have examined PRAD-1/CCND1 gene expression by Northern blot and Western blot analysis in a series of 18 hairy cell leukaemias (HCLs), nine other splenic malignant lymphoproliferative disorders, and three normal/reactive spleens. Over-expression of the mRNA PRAD-1/CCND1 gene was observed in 16/18 HCLs, including one case of hairy cell leukaemia variant, whereas this molecular alteration was not found in other cases examined. mRNA levels varied from case to case, but they were lower than those observed in MCLs. At the protein level, Western blotting analysis showed Cyclin D1 protein expression in the 11 HCLs analysed. No bcl-1 rearrangements were seen with the MTC, p94PS and PRAD-1 (lambda-P1-4) probes used, and no PRAD-1/CCND1 gene amplification was detected in any case. These findings indicate that PRAD-1/CCND1 is over-expressed at mRNA and protein levels in a high number of HCLs. However, the levels of expression are much lower than in MCLs, and this expression is not associated with bcl-1 rearrangements or PRAD-1/CCND1 gene amplification.

Blotting, Northern↗
PubMed1995

Mucosal mantle cell (centrocytic) lymphomas.

The morphology, phenotype, genotype and clinical behaviour of four cases of mantle cell lymphoma (centrocytic lymphoma) presenting primarily in mucosa (two gastric, one in large bowel and one tonsillar) are reviewed. Their relationship with the broader group of mantle cell and mucosa-associated lymphoid tissue (MALT) lymphomas is also discussed. All four tumours showed a monomorphic picture of mantle cells (centrocytes) arranged in a diffuse, or vaguely nodular, pattern. Scattered non-neoplastic germinal centres were entrapped within the tumour cells, although there was no follicular colonization. In two cases distinct epithelial infiltration by tumour cells was observed. All four tumours had a CD19, CD20, CD5, IgD, Leu8 immunophenotype, whereas KiM1P and CD10 expression were absent. DRC antibody showed loose aggregates of dendritic cells in three of four cases. Three cases showed PRAD-1/Cyclin D1 overexpression by Northern blot analysis. Although we were not able to detect bcl-1 rearrangement in the major translocation cluster (MTC) breakpoint, the possibility of bcl-1 rearrangement involving other cluster breakpoints cannot be ruled out. The four cases evolved as a disseminated disease, involving either peripheral lymph nodes, spleen or bone marrow. The biological behaviour of mantle cell lymphoma presenting in mucosa appears, irrespective of localization or macroscopic presentation, similar to that of nodal mantle cell lymphoma. Their tendency to dissemination contrasts with MALT lymphomas, which tend to remain localized, and from which mucosa mantle cell lymphoma must be distinguished. The presence of lymphoepithelial lesions does not seem to be a useful differential feature, since occasional epithelial infiltration was seen in two cases. Reactivity with CD5 appears to be especially useful in distinguishing these, since all four cases were clearly positive, in contrast with what is usually found in MALT lymphomas.

Aged↗
PubMed1995

Presenting features, natural history, and prognostic factors in localized non-Hodgkin's lymphomas: analysis of 117 cases from a single institution.

Clinical features and prognostic factors were analyzed in a series of 117 patients with localized non-Hodgkin's lymphoma (stage I-II). Median age of the patients was 53 years and 52% were men; 22% had a lymphoma of low-grade histology and one-third presented with extranodal involvement. Eighty percent of the patients achieved a complete response (CR); stage of disease and histology were revealed as the most important factors for response. When analysis was restricted to intermediate/high-grade cases, stage showed a predictive value for response. With a median follow-up of 4.5 years, median overall survival was 12.0 years, with 73% and 62.5% of patients being alive at 5 and 10 years, respectively. Main initial parameters significantly related to a shorter survival were intermediate/high-grade histology, stage II, poor performance status, bulky disease, high serum LDH levels, increased ESR, and advanced International Index. In the multivariate analysis, stage, histology and performance status (PS) were statistically significant. Among intermediate/high-grade lymphoma patients, stage and PS provided prognostic value for survival. Twenty-six patients relapsed after CR; median survival after relapse was 2.7 years. Stage (I vs II) was the only predictive variable for relapse in both the whole series and the intermediate/high-grade subset.

Actuarial Analysis↗
PubMed1995

Insulin inhibits liver expression of the CCAAT/enhancer-binding protein beta.

The CCAAT/enhancer-binding protein beta (C/EBP beta) is a transcription factor that is abundant in the liver. The concentration of C/EBP beta mRNA in the liver of mice and rats fed a high-carbohydrate diet, which causes a rise in blood insulin levels, was lower (80 and 65%, respectively) than that detected in animals fed a standard diet. Similarly, the expression of the human insulin gene in the liver of transgenic mice led to a decrease in the concentration of C/EBP beta mRNA. However, no change was detected in the mRNA levels of C/EBP alpha or cAMP regulatory element-binding protein transcription factors in the livers of these mice. Furthermore, the expression of the C/EBP beta gene increased in the liver of diabetic rats and decreased in the liver of diabetic animals treated with vanadate, an insulin mimetic agent. In addition, a decrease in C/EBP beta protein was observed in liver nuclei from mice after insulin injections, in mice fed a high-carbohydrate diet, and in transgenic mice expressing the insulin gene in the liver. These results suggest that insulin might control gene expression in vivo, at least in part, by a mechanism involving a decrease in the transcription factor C/EBP beta.

Animals↗
PubMed1995

[Characteristics of patients with low grade malignant lymphoma and long survival].

PURPOSE: To analyse the initial and evolutive characteristics of the patients with low-grade lymphoma and long survival (> or = 12 years). MATERIAL AND METHODS: The initial data (clinical, laboratory, histologic type, stage) and the clinical course (response to therapy, response duration) of 52 patients with low-grade lymphoma diagnosed before 1980 were analysed. The statistical study was carried out by means of the chi-square test with Yates' correction and Student's t; the actuarial survival was estimated, and the duration of remission was assessed by the Kaplan and Meier method. Curves were compared by the log rank method. RESULTS: The 12-year survival as a whole was 32% (CI: 95%: 18.5%-45.5%). Of the 52 patients, 13 (25%) survived over 12 years. Nine were men and 4 women, with median age of 41 years (range: 22-68 years). Three cases had lymphocytic lymphoma and 10 had follicular lymphoma; 2 were in stage I-II and 11 in stage III-IV. Those patients who would become long-survivors had at diagnosis lesser frequency of spread lymph-node regional involvement (> or = 3 sites): 46% vs 81.8%, p = 0.04, as well as lesser percentage of bone-marrow involvement (38.4% vs 78.1%, p = 0.023). They were also better responders to treatment (CR+PR = 100% vs 71%, p = 0.013) and with longer duration (actuarial median duration of response 8 years vs 1.5 years, p = 0.005). CONCLUSIONS: According to the present analysis, low-grade lymphoma patients who have at diagnosis low tumoral involvement (not too extensive lymph-node involvement, disease-free bone-marrow) and show good response to treatment have a better prognosis and may hope for a longer survival.

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

Refractory anemia with excess of blasts and isochromosome 12p in a patient with primary mediastinal germ-cell tumor.

Isochromosome(12p), a cytogenetic abnormality characteristic of germ-cell tumors, is exceedingly rare in hematologic disorders. The cytogenetic analysis of a patient diagnosed as refractory anemia with excess of blasts with an associated i(12p), who previously had a teratocarcinoma of the mediastinum, is presented. The cytogenetic analysis was performed at diagnosis of the hematologic malignancy, with all 30 metaphases in the bone marrow culture showing a 47,X, -Y, +8, +i(12)(p10) karyotype. The cytogenetic findings in this patient are compared with those published concerning the association of mediastinal germ-cell tumors and malignant hematologic disorders.

Adolescent↗
PubMed1994

PRAD-1/cyclin D1 gene overexpression in chronic lymphoproliferative disorders: a highly specific marker of mantle cell lymphoma.

The t(11;14)(q13;q32) translocation and its molecular counterpart bcl-1 rearrangement are frequently associated with mantle cell lymphomas (MCLs) and only occasionally with other variants of B-cell lymphoid malignancies. This translocation seems to activate the expression of PRAD-1/cyclin D1 gene located downstream from the major breakpoint cluster region of this rearrangement. However, the possible overexpression of this gene in other lymphoproliferative disorders independently of bcl-1 rearrangement is unknown. We have examined the overexpression of PRAD-1 gene in a large series of 142 lymphoproliferative disorders including 20 MCLs by Northern blot analysis. Cytogenetic and/or bcl-1 rearrangement analysis with 2 probes (MTC, p94PS) were performed in 28 cases. Strong PRAD-1 overexpression was observed in 19 of the 20 MCLs including 3 gastrointestinal forms and 4 blastic variants. t(11;14) and/or bcl-1 rearrangement was detected in 6 of the 12 MCLs examined. No correlation was found between the different levels of mRNA expression and the pathologic characteristics of the lymphoma. Among chronic lymphoproliferative disorders other than MCL, only 1 atypical chronic lymphocytic leukemia (CLL) with a t(11;14) translocation and bcl-1 rearrangement and the 2 hairy cell leukemias (HCLs) analyzed showed upregulation of PRAD-1 gene. The expression in the 2 HCLs was lower than in MCL, and no bcl-1 rearrangement was observed. These findings indicate that PRAD-1 overexpression is a highly sensitive and specific molecular marker of MCL but it may also be upregulated in some B-CLLs and in HCL.

Biomarkers, Tumor↗
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↗