Whipple's disease mimicking linitis plastica.
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Diagnosis, Differential↗
Biomedical subjects
M Lorenzo
Publications and source records attributed to M Lorenzo.
[Long-standing skin nodular lesions in a 14-year-old male].
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Adolescent↗
H-ras induces glucose uptake in brown adipocytes in an insulin- and phosphatidylinositol 3-kinase-independent manner.
Fetal brown adipocytes (parental cells) expressed mainly Glut4 mRNA glucose transporter, the expression of Glut1 mRNA being much lower. At physiological doses, insulin stimulation for 15 min increased 3-fold glucose uptake and doubled the amount of Glut4 protein located at the plasma membrane. Moreover, phosphatidylinositol (PI) 3-kinase activity was induced by the presence of insulin in those cells, glucose uptake being precluded by PI 3-kinase inhibitors such as wortmannin or LY294002. H-raslys12-transformed brown adipocytes showed a 10-fold higher expression of Glut1 mRNA and protein than parental cells, Glut4 gene expression being completely down-regulated. Glucose uptake increased by 10-fold in transformed cells compared to parental cells; this uptake was unaltered in the presence of insulin and/or wortmannin. Transient transfection of parental cells with a dominant form of active Ras increased basal glucose uptake by 5-fold, no further effects being observed in the presence of insulin. However, PI 3-kinase activity (immunoprecipitated with anti-alphap85 subunit of PI 3-kinase) remained unaltered in H-ras permanent and transient transfectants. Our results indicate that activated Ras induces brown adipocyte glucose transport in an insulin-independent manner, this induction not involving PI 3-kinase activation.
Adipocytes↗
Insulin/IGF-I rescues immortalized brown adipocytes from apoptosis down-regulating Bcl-xS expression, in a PI 3-kinase- and map kinase-dependent manner.
Serum deprivation of immortalized brown adipocyte cell line resulted in growth arrest in G0/G1 phases of the cell cycle and apoptosis, as detected either by DNA laddering or by increase in the percentage of hypodiploid cells. Furthermore, apoptosis is concurrent with a dramatic increase in the expression of the proapoptotic protein Bcl-xS, the expression of Bcl-xL remaining almost undetectable. Insulin/insulin-like growth factor (IGF-I) rescued serum-deprived brown adipocytes from apoptosis, decreasing the number of hypodiploid cells and increasing the number of cells undergoing cell cycle progression throughout S and G2/M phases of the cell cycle. Moreover, insulin down-regulated Bcl-xS expression without inducing the expression of Bcl-xL. Both phosphatidylinositol (PI) 3-kinase and mitogen-activated protein kinase (MAPK) pathways are necessary for insulin/IGF-I full survival effect, since the use of specific inhibitors of PI 3-kinase activity (wortmannin or LY294002, at the dose that inhibits PI 3-kinase activity induced by insulin) or MAPK kinase activity inhibitor (PD098059, at the dose that inhibits insulin-induced phosphorylation of MAPK) totally blocked the antiapoptotic effect induced by insulin/IGF-I, respectively. In conclusion, insulin survival effect on immortalized brown adipocytes is associated with inhibition of the Bcl-xS content without changing Bcl-xL, in a PI 3-kinase- and MAP kinase-dependent manner.
Adipocytes↗
Inhibition of PI 3-kinase and RAS blocks IGF-I and insulin-induced uncoupling protein 1 gene expression in brown adipocytes.
Fetal brown adipocytes expressed uncoupling protein 1 (UCP1) mRNA, this expression being blunted throughout culture for 24 h in a serum-free medium. At physiological doses, either insulin-like growth factor I (IGF-I) or insulin turned out to be as potent as dibutyryl cAMP (dbcAMP) in increasing UCP1 gene transcription rate (1 h) and also UCP1 mRNA accumulation (3 h), their maximal effect (15-fold increase) reached upon treatment for 24 h. Upon treatment with either IGF-I or insulin for 48 h, a 7-fold increase in the UCP1 protein content relative to levels in the control cells was found, this induction being abolished in the presence of cycloheximide. Moreover, either IGF-I or insulin transactivates the UCP1-chloramphenicol acetyl transferase (CAT) fusion gene after transient transfection of primary brown adipocytes, these effects being tissue-specific. Transient transfection of dominant-negative form of phosphatidylinositol (PI) 3-kinase completely blocked the transactivation of the fusion gene UCP1-CAT induced by either IGF-I or insulin, although inhibition of p70S6kinase with rapamycin does not preclude transactivation of the UCP1 promoter by insulin. Furthermore, transient transfection of dominant-negative form of p21-ras or treatment of cells with a mitogen-activated protein kinase kinase (MEK-1) inhibitor (PD098059) completely abolished insulin-induced UCP1-CAT transactivation. Cotransfection with dominant-negative p85 or with dominant-negative Ras also produced down-regulation of the insulin or IGF-I-induced 12-O-tetradecanoylphorbol-13-acetate response element (TRE)-CAT (five AP-1, activating protein-1, binding sites arranged in tandem) transactivation. In addition, insulin induced AP-1 DNA binding activity, this effect being totally prevented in the presence of MEK-1 inhibitor. These results strongly suggest that either IGF-I or insulin induced thermogenic-differentiation through AP-1 activity in a PI 3-kinase and Ras/MAPK dependent manner in brown adipocytes.
Adipocytes↗
Can Ringer's lactate be used safely with blood transfusions?
BACKGROUND: Blood bank recommendations specify that Ringer's lactate solution (LR) should be avoided while transfusing blood. However, there are few studies either evaluating or quantifying increased coagulation during rapid infusion of LR and blood. DESIGN AND METHODS: Whole blood (WB, n = 25) and packed red blood cells (PRBC, n = 26) were rapidly admixed with normal saline (NS), Lactate solution and LR with 1 g (LR-1), 2 g (LR-2), and 5 g (LR-5) CaCl2/L solutions for assessment of infusion time, filter weight, and clot formation. RESULTS: No significant differences in infusion time or filter weight using WB or PRBC with NS or LR were seen. No significant difference in clot formation between NS and LR with WB or PRBC was found, but the presence of visible clot was increased in the LR-5 group (P = 0.013, WB, and P = 0.002, PRBC). CONCLUSION: A comparison of LR and NS with rapid infusion rates of blood showed no significant difference between infusion time, filter weight and clot formation. Blood bank guidelines should be revised to allow the use of LR in the rapid transfusion of PRBC.
Blood Coagulation↗
Losartan versus ramipril in the treatment of postrenal transplant erythrocytosis.
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Angiotensin-Converting Enzyme Inhibitors↗
Tumor necrosis factor-alpha causes insulin receptor substrate-2-mediated insulin resistance and inhibits insulin-induced adipogenesis in fetal brown adipocytes.
Treatment of fetal brown adipocytes with 0.6 nM tumor necrosis factor (TNF)-alpha for 24 h resulted in a partial impairment in the expression of fatty acid synthase, glycerol-3-phosphate dehydrogenase, and glucose transporter (GLUT)-4 messenger RNAs (mRNAs), as well as in the enhancement in the cytoplasmic lipid content in response to insulin. However, the expression of the tissue-specific gene, uncoupling protein 1, is increased by the presence of TNF-alpha. The antiadipogenic effect of TNF-alpha was accompanied by a down-regulation of CCAAT/enhancer-binding protein-alpha and beta mRNAs and up-regulation of CCAAT/enhancer-binding protein-delta, with the expression of peroxisome proliferator-activated receptor-gamma remaining essentially unmodified. Moreover, TNF-alpha caused an insulin resistance on the insulin-induced glucose uptake in brown adipocytes. Pretreatment with TNF-alpha resulted in hypophosphorylation of the insulin receptor in response to insulin, without affecting the number of insulin receptors per cell or its molecular mass. However, insulin receptor substrate (IRS)-1 and IRS-2 signaling in response to insulin showed functional differences. Thus, TNF-alpha pretreatment induced a hypophosphorylation of IRS-2 but not of IRS-1. This effect leads to an impairment in the IRS-2-associated phosphatidylinositol (PI) 3-kinase activation due to a decreased association of alpha-p85 regulatory subunit of PI 3-kinase with IRS-2 but not in the IRS-1-associated PI 3-kinase activation in response to insulin. Our results indicate that TNF-alpha induced an IRS-2- but not IRS-1-mediated insulin resistance on glucose transport and lipid synthesis in fetal brown adipocytes.
Adipocytes↗
Insulin receptor substrate (IRS) proteins IRS-1 and IRS-2 differential signaling in the insulin/insulin-like growth factor-I pathways in fetal brown adipocytes.
In the present study we have investigated the contribution of the insulin receptor substrate proteins (IRS-1 and IRS-2) to the insulin/insulin like growth factor I (IGF-I)-signaling pathways in fetal rat brown adipocytes, a model that expresses both insulin and IGF-I receptors. Insulin/IGF-I rapidly stimulated IRS-1 and IRS-2 tyrosine phosphorylation, their association with p85alpha, and IRS-1- and IRS-2-associated phosphatidylinositol (PI) 3-kinase activation to the same extent, the effect of insulin being stronger than the effect of IGF-I at the same physiological dose (10 nM). Furthermore, insulin/IGF-I stimulated IRS-1-associated Grb-2 phosphorylation. However, IRS-2-associated Grb-2 phosphorylation was barely detected. Pull-down experiments with glutathione-S-transferase-fusion proteins containing SH2-domains of p85alpha revealed a strong association between IRS-1 and IRS-2 with p85alpha in response to insulin/IGF-I, the insulin effect being stronger than IGF-I. However, the Grb-2-SH2 domain showed functional differences. While a strong association between IRS-1/Grb-2 was found, IRS-2/Grb-2 association was virtually absent in response to insulin/IGF-I, as also demonstrated in competition studies with a phosphopeptide containing the phosphotyrosine 895 residue within the putative Grb-2-binding domain. Finally, insulin/IGF-I stimulated tyrosine phosphorylation of the three SHC proteins (46, 52, and 66 kDa). Moreover, insulin/IGF-I markedly increased the amount of Grb-2-associated SHC proteins by the same extent. Our results suggest that both IRS-1 and IRS-2 are required for phosphatidylinositol 3-kinase activation that leads to adipogenic and thermogenic differentiation of fetal brown adipose tissue; meanwhile, IRS-1 and SHC, but not IRS-2, associate with Grb-2 leading to the ras-mitogen-activated protein kinase-signaling pathway required for fetal brown adipocyte proliferation.
Adaptor Proteins, Signal Transducing↗
Spinal cord injury. A preventable public burden.
BACKGROUND: Spinal cord injury (SCI) is a devastating occurrence with important consequences for the individual and society. Previous studies have documented the epidemiology and costs of SCI and the rehabilitation needs after SCI; however, data about the preventability of SCI are lacking. OBJECTIVE: To test the hypotheses that most SCIs are preventable and that much of the cost of SCI is borne by the public. DESIGN: Retrospective review of medical records and trauma registry data. SETTING: A 417-bed county hospital with a level I trauma center. METHODS: To evaluate the preventability of SCI, the records of trauma patients sustaining SCI from July 1, 1990, through June 30, 1995, were reviewed. The criteria for preventability of blunt injuries included the following: failure to use restraint devices; intoxication of drivers, motorcyclists, or pedestrians; and falls or diving accidents involving the use of drugs or alcohol. The criteria for preventability of penetrating injuries included the following: illegal possession of a firearm, accidental discharge of a weapon, and suicide attempts. Statistics were performed with the paired Student t test and chi 2 with significance attributed to a P value less than .05. RESULTS: Spinal cord injury occurred in 150 patients; 71% of the injuries were the result of blunt trauma. Injury was potentially preventable in 74% of the blunt injuries and 66% of the penetrating injuries (P = .15). Patients with a penetrating SCI were younger (P < .001) and relied more on public funding than did those with a blunt SCI (65% vs 81%; P = .05). CONCLUSIONS: Most SCIs are preventable with strict enforcement of existing statutes. Furthermore, the financial burden of these preventable injuries is largely borne by the public.
Critical Care↗
Malic enzyme and glucose 6-phosphate dehydrogenase gene expression increases in rat liver cirrhogenesis.
The cirrhogenic ability of thioacetamide has been used to induce a model of chronic generalized liver disease that resembles the preneoplastic state of human fibrosis. Malic enzyme (ME) and glucose-6-phosphate dehydrogenase (G6PDH) are two cytosolic NADPH-generating enzymes; their activities significantly increased in liver when macronodular cirrhosis was induced by long-term thioacetamide administration to rats. The progressive increase in G6PDH and ME activities during the cirrhogenic process is parallel to the induction in gene expression of both enzymes detected by the increase in their mRNAs. These data indicate that NADPH-consuming mechanisms such as the microsomal oxidizing system and the maintenance of the cell redox state could be involved. A relationship between the extent of G6PD and ME gene expression and oxidative stress generated by the oxidative metabolism of thioacetamide is proposed as the hepatic concentration of malondialdehyde, a metabolite derived from lipid peroxidation, underwent a progressive and significant enhancement during thioacetamide-induced cirrhogenesis. These results led us to suggest that the enhanced activities of G6PDH and ME might be related to microsomal mechanisms of detoxification as well as to the maintenance of the cellular redox state. Furthermore, the noticeable increase in the hepatocyte population involved in DNA replication parallel to G6PDH activity suggests that G6PDH, through ribose-5-phosphate, might also be involved in the processes of DNA synthesis and repair.
Animals↗
Gallstones in cirrhotics revisited by a laparoscopic view.
Surgical literature around 1980 has emphasized the technical challenge and the risks of cholecystectomy in cirrhotic patients reporting discouraging results. The aim of this study is the retrospective analysis of laparoscopic cholecystectomy in cirrhotics. The collected laparoscopic experience of 3 surgical groups for the last 5 years is reported. Cirrhotics were classified according to Child-Pugh criteria. Postoperative complications were classified using Clavien's rules. Forty patients were recruited; 31 received successful laparoscopic cholecystectomy. Liver cirrhosis was preoperatively diagnosed in all Child-Pugh B (n = 11) and in 11/20 Child-Pugh A patients. Compared with 989 noncirrhotics undergoing laparoscopic cholecystectomy, cirrhotics were similar in terms of age (59.9+/-10.3 vs. 58.1+/-10.9) and sex (male: 51.6% vs. 50.1%). Acute cholecystitis has a similar frequence in cirrhotics and noncirrhotics (3.2% vs. 4.1%, respectively). Bile duct stones and acute pancreatitis were significantly more frequent in cirrhotic patients (6.4% vs. 3.7%, p < 0.001; and 6.4% vs. 0.3%, p < 0.001, respectively). Endoscopic papillotomy and stone extraction combined with laparoscopic cholecystectomy was performed in 2 patients. Intraoperatively, technical problems occurred in 5 (16.1%) patients: liver bed bleeding (n = 4) was significatively more frequent in cirrhotics vs. noncirrhotics (p < 0.001). Mean operative time was 90 min, range 50-180, and it was not significantly longer than in noncirrhotics (85 min, range 30-200). Conversion rate was also similar (3%). Seven patients presented 8 postoperative complications (Class II): right side lung effusion (n = 2), ascites (n = 2), temporary worsening of Child-Pugh status (n = 2), hyperosmotic coma (n = 1), and umbilical hernia (n = 1). Mean hospital stay in noncomplicated cases was the same for noncirrhotics (3+/-1). The authors suggest a more liberal use of laparoscopic cholecystectomy for symptomatic gallstones in selected Child-Pugh A and B patients.
Case-Control Studies↗
Effectiveness of immunomodulating treatment (thymostimulin) in chronic obstructive pulmonary disease.
We conducted a prospective randomized study to assess the effect of thymostimulin in patients with long-standing chronic obstructive pulmonary disease (COPD) during a 1-year follow-up. A total of 38 patients in the intervention group and 40 in the control group received standard treatment for COPD. Patients in the intervention group were also given thymostimulin intramuscularly (1 mg/kg day for the 1st week followed by once a week for 6 months). At the end of the study period, patients treated with thymostimulin showed a statistically significant lower number of exacerbations and hospital admissions as compared with controls. However, there were no changes in the number of patients with severe or moderate impairment of respiratory function throughout the study period. No significant differences were found by Multitest or in serum concentrations of immunoglobulins and T-cell subsets before and after thymostimulin treatment. We conclude that treatment with thymostimulin is effective in the prevention of COPD exacerbations acting on the cellular immune response involved in bronchopulmonary defense.
Adjuvants, Immunologic↗
Alterations in the insulin signaling pathway induced by immortalization and H-ras transformation of brown adipocytes.
In fetal brown adipocyte primary cultures, insulin rapidly (at 5 min) induced tyrosine phosphorylation of the insulin receptor beta-subunit; this effect was maximal at physiological concentrations (1 nM). Insulin also stimulated insulin receptor substrate-1 tyrosine phosphorylation and subsequently activated phosphatidylinositol 3-kinase. Moreover, a 3-fold increase in the Ras.GTP active form and a 6-fold increase in Raf-1 kinase activity were induced after insulin stimulation. An immortalized brown adipocyte cell line (by permanent simian virus 40 large T antigen and pMEXneo cotransfection) showed a reduced maximal responsiveness to insulin in the same range of insulin concentrations studied (1-100 nM). Transformed brown adipocyte cell line (by permanent simian virus 40 large T antigen and pMEXneo H-ras(lys12) cotransfection) developed insulin resistance upstream from Ras, showing an impairment in the insulin receptor autophosphorylation, and in insulin receptor substrate-1 tyrosine phosphorylation and its association with phosphatidylinositol 3-kinase upon treatment with 1 nM insulin, although insulin receptor number and affinity (Kd) remained unaltered. This lack of effect was ameliorated upon treatment with higher insulin concentrations, in a dose-dependent manner. However, downstream from Ras, events such as formation of the Ras.GTP active form, and Raf-1 kinase and 12-O-tetradecanoylphorbol-13-acetate response element-chloramphenicol transferase (transiently transfected) activities were overstimulated, compared with those in primary and immortalized cells, in an insulin-independent manner. Wheat-germ lectin-purified receptors from H-ras(lys12)-transformed brown adipocytes showed a marked phosphorylation in the basal state, which was suppressed by serine-threonine phosphatase pretreatment. Moreover, alkaline phosphatase pretreatment restored the tyrosine kinase activity of the receptor in response to insulin. We conclude that the decreased tyrosine autophosphorylation rate of the insulin receptor from H-ras(lys12)-transformed brown adipocytes is a consequence of its basal serine/threonine phosphorylation, resulting in severe insulin resistance.
Adipocytes↗
Phosphatidylinositol 3-kinase is a requirement for insulin-like growth factor I-induced differentiation, but not for mitogenesis, in fetal brown adipocytes.
In the present study we have examined the role of phosphatidylinositol 3-kinase (PI 3-kinase) in the insulin-like growth factor I (IGF-I)-signaling pathways involved in differentiation and in mitogenesis in fetal rat brown adipocytes. Activation of PI 3-kinase in response to IGF-I was markedly inhibited by two PI 3-kinase inhibitors (wortmannin and LY294002) in a dose-dependent manner. IGF-I-stimulated glucose uptake was also inhibited by both compounds. The expression of adipogenic-related genes such as fatty acid synthase, malic enzyme, glycerol 3-phosphate dehydrogenase, and acetylcoenzyme A carboxylase induced by IGF-I was totally prevented in the presence of IGF-I and any of those inhibitors, resulting in a marked decrease of the cytoplasmic lipid content. Moreover, the expression of the thermogenic marker uncoupling protein induced by IGF-I was also down-regulated in the presence of wortmannin/LY294002. IGF-I-induced adipogenic- and thermogenic-related gene expression was only partly inhibited by the p70S6k inhibitor rapamycin. In addition, pretreatment of brown adipocytes with either wortmannin or LY294002, but not with rapamycin, blocked protein kinase C zeta activation by IGF-I. In contrast, IGF-I-induced fetal brown adipocyte proliferation was PI 3-kinase-independent. Our results show for the first time an essential requirement of PI 3-kinase in the IGF-I-signaling pathways leading to fetal brown adipocyte differentiation, but not leading to mitogenesis. In addition, protein kinase C zeta seems to be a signaling molecule also involved in the IGF-I differentiation pathways downstream from PI 3-kinase.
Adipocytes↗
The prevalence of serological markers for syphilis amongst a sample of Spanish prostitutes.
The results of a multicentre study of 1668 Spanish prostitutes are described with regard to syphilis infection. For those women who permitted serological tests (n = 1095), 30.59% (confidence interval (CI): 30.55%-30.63%) were positive for markers indicating current or prior infection. After adjustment was made for other variables, a significant association with syphilis infection was observed for periods of exposure (i.e. age and years working as a prostitute). No significant associations were detected for either intravenous drug use, or educational attainment. The results of this study are similar to those of some other investigations into the prevalence of syphilis amongst prostitutes.
Adolescent↗
Laparoscopic adjustable silicone gastric banding: preliminary results of the University of Naples experience.
BACKGROUND: Laparoscopic adjustable silicone gastric banding (LASGB) is a minimally invasive surgical procedure indicated for the treatment of patients with morbid obesity. METHODS: From January 1996, eight patients successfully underwent the video-laparoscopic procedure. RESULTS: Preoperative body mass index was 44.4 +/- 4.7 (range 37.9-53.3). Mean operative time was 255 +/- 73 minutes (range 150-360). Mean hospital stay was 3 +/- 1 days. Intraoperative complications were absent. CONCLUSION: Preliminary results have been satisfactory, and encourage us to continue with LASGB.
Adult↗
Insulin-like growth factor I and insulin induce adipogenic-related gene expression in fetal brown adipocyte primary cultures.
Fetal rat brown adipocytes show high-affinity binding sites for both insulin-like growth factor I (IGF-I) and insulin. Cell culture for 24 h in the presence of IGF-I or insulin, independently, up-regulated the mRNA expression of adipogenic-related genes, such as fatty acid synthase (FAS), glycerol-3-phosphate de-hydrogenase and insulin-regulated glucose transporter Glut4, and down-regulated the expression of phosphoenolpyruvate carboxykinase mRNA in a dose-dependent manner. Moreover, both IGF-I and insulin increased the FAS gene transcription rate at 2 h, producing a time-dependent accumulation of FAS mRNA. Furthermore IGF-I or insulin increased glucose uptake and lipid content throughout the 24 h culture period. Our results suggest that both IGF-I and insulin are major signals involved in initiating and/or maintaining the expression of adipogenic-related genes in fetal rat brown adipocytes.
Adipose Tissue, Brown↗