Search

Based on our earlier work, a 2.5-fold increase in insulin secretion should completely inhibit hepatic glucose production through the hormone's direct effect on hepatic glycogen metabolism. The aim of the present study was to test the accuracy of this prediction and to confirm that gluconeogenic flux, as measured by three independent techniques, was unaffected by the increase in insulin. A 40-min basal period was followed by a 180-min experimental period in which an increase in insulin was induced, with euglycemia maintained by peripheral glucose infusion. Arterial and hepatic sinusoidal insulin levels increased from 10 +/- 2 to 19 +/- 3 and 20 +/- 4 to 45 +/- 5 microU/ml, respectively. Net hepatic glucose output decreased rapidly from 1.90 +/- 0.13 to 0.23 +/- 0.16 mg. kg(-1). min(-1). Three methods of measuring gluconeogenesis and glycogenolysis were used: 1) the hepatic arteriovenous difference technique (n = 8), 2) the [(14)C]phosphoenolpyruvate technique (n = 4), and 3) the (2)H(2)O technique (n = 4). The net hepatic glycogenolytic rate decreased from 1.72 +/- 0.20 to -0.28 +/- 0.15 mg. kg(-1). min(-1) (P0.05), whereas none of the above methods showed a significant change in hepatic gluconeogenic flux (rate of conversion of phosphoenolpyruvate to glucose-6-phosphate). These results indicate that liver glycogenolysis is acutely sensitive to small changes in plasma insulin, whereas gluconeogenic flux is not.

Colchicine has been traditionally used for the treatment of gout. At present there is no generally accepted alternative to colchicine for the treatment of acute attacks or for the prevention of further attacks. The complex actions of this substance, which are mainly attributable to its stabilising action on the cytoskeleton and cell membranes, and its special pattern of distribution form the basis for the results presented here regarding the prophylactic or therapeutic actions of colchicine in a whole range of other diseases. This is all the more significant in that in several instances it concerns diseases that have so far been unsatisfactorily controlled by other treatments. Because of its astonishing absence of side effects, some authors consider that low dose colchicine may be considered as an alternative to previous therapies or even a means of first choice. It is therefore incorrect to think that medical research has shown little interest in this long-known potential and has not sought to confirm promising options by means of controlled studies. Fibrotic and inflammatory systemic diseases and those in which leucocytic chemotaxis play a role seem to be particularly predestined for this.

Contributions of gluconeogenesis to glucose production were determined between 14 to 22 hours into a fast in type 2 diabetics (n = 9) and age-weight-matched controls (n = 7); ages, 60.4 +/- 2.3 versus 55.6 +/- 1.2 years and body mass indices (BMI) 28.6 +/- 2.3 versus 26.6 +/- 0.8 kg/m2. Production was measured using a primed-continuous [6,6-2H2]glucose infusion and gluconeogenesis from 2H enrichment at carbons 2 and 5 of blood glucose on 2H2O ingestion. Plasma glucose concentration declined from 9.6 +/- 0.6 at 14 hours to 7.3 +/- 0.6 at 22 hours in the diabetics (P = .001) and from 5.4 +/- 0.1 to 5.0 +/- 0.1 in the controls (P < .05). Production from the 17th to 22nd hour declined 27.1% +/- 0.6% in the diabetics versus 18.5% +/- 0.8% in the controls (P = .001); from 10.4 +/- 0.3 to 7.6 +/- 0.2 versus 10.0 +/- 0.4 to 8.2 +/- 0.4 micromol/kg/min. Percent contributions of gluconeogenesis to production measured at 1 1/2 to 2-hour intervals beginning the 15th hour were 6.8% +/- 1.0% more in the diabetics than controls. The quantity of glucose contributed by gluconeogenesis declined 19.8% +/- 3.8% (P < .001) in the diabetics and 6.9% +/- 2.3% in the controls (P = .05); 7.21 +/- 0.32 to 5.74 +/- 0.26 versus 6.20 +/- 0.28 to 5.75 +/- 0.24 micromol/kg/min. The contribution of glycogenolysis to production, estimated from the difference between production and gluconeogenesis, declined to the same extent in diabetic and control subjects, 40.7% +/- 6.6% and 37.7% +/- 4.1%; from 3.23 +/- 0.35 to 1.86 +/- 0.26 versus 3.81 +/- 0.22 to 2.42 +/- 0.28 micromol/kg/min. Thus, gluconeogenesis contributed more to glucose production in the diabetic than control subjects. Production and the contribution of gluconeogenesis declined more in the diabetic subjects during the fast. The factors regulating these changes remain uncertain.

We use a selection of wood-based and coconut-based activated carbons to investigate the factors controlling the removal of the hepatotoxin microcystin-LR (m-LR) from aqueous solutions. The wood carbons contain both micropores and mesopores. The coconut carbons contain micropores only. Confirming previously published observations, we also find that the wood-based carbons adsorb more microcystin than the coconut-based carbons. From a combination of a judicious modification of a wood-based carbon's surface chemistry and of the solution chemistry, we demonstrate that both surface and solution chemistry play minor roles in the adsorption process, with the adsorbent surface chemistry exhibiting less influence than the solution chemistry. Conformational changes at low solution pH probably contribute to the observed increase in adsorption by both classes of adsorbent. At the solution pH of 2.5, the coconut-based carbons exhibit a 400% increased affinity for m-LR compared with 100% increases for the wood-based carbons. In an analysis of the thermodynamics of adsorption, using multiple temperature adsorption chromatography methods, we indicate that m-LR adsorption is an entropy-driven process for each of the carbons, except the most hydrophilic and mesoporous carbon, B1. In this case, exothermic enthalpy contributions to adsorption also exist. From our overall observations, since m-LR contains molecular dimensions in the secondary micropore width range, we demonstrate that it is important to consider both the secondary micropore and the mesopore volumes for the adsorption of m-LR from aqueous solutions. Copyright 2001 Academic Press.

An activated carbon with a relatively high oxygen content was heated at various temperatures in an argon atmosphere to produce a series of carbons with decreasing oxygen content. A second activated carbon with a relatively low oxygen content was treated with an ozone–oxygen mixture to produce a series of carbons with increasing oxygen content. In both cases, the pore size distribution and pore volume were unaffected by the treatment conditions. Adsorption isotherm and enthalpy of water displacement measurements were made for adsorption of 2-methylisoborneol (MIB) by these carbons in water. Both measurements show the importance of the oxygen content on the adsorption of MIB from aqueous solution. Increasing surface oxygen content at a constant pore volume leads to a decrease in both the amount adsorbed and the enthalpy of adsorption. To test the role of the solvent in this adsorption process, a relatively non-polar solvent, dichloromethane (DCM), was used to make adsorption measurements. Adsorption isotherms show that the amount of MIB adsorbed from DCM solution is independent of the oxygen content. These results indicate that the solvent plays an important role in the control of the adsorption from solution of a sparingly soluble solute.

To examine the mechanism by which metformin lowers endogenous glucose production in type 2 diabetic patients, we studied seven type 2 diabetic subjects, with fasting hyperglycemia (15.5 +/- 1.3 mmol/l), before and after 3 months of metformin treatment. Seven healthy subjects, matched for sex, age, and BMI, served as control subjects. Rates of net hepatic glycogenolysis, estimated by 13C nuclear magnetic resonance spectroscopy, were combined with estimates of contributions to glucose production of gluconeogenesis and glycogenolysis, measured by labeling of blood glucose by 2H from ingested 2H2O. Glucose production was measured using [6,6-2H2]glucose. The rate of glucose production was twice as high in the diabetic subjects as in control subjects (0.70 +/- 0.05 vs. 0.36 +/- 0.03 mmol x m(-2) min(-1), P < 0.0001). Metformin reduced that rate by 24% (to 0.53 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0009) and fasting plasma glucose concentration by 30% (to 10.8 +/- 0.9 mmol/l, P = 0.0002). The rate of gluconeogenesis was three times higher in the diabetic subjects than in the control subjects (0.59 +/- 0.03 vs. 0.18 +/- 0.03 mmol x m(-2) min(-1) and metformin reduced that rate by 36% (to 0.38 +/- 0.03 mmol x m(-2) x min(-1), P = 0.01). By the 2H2O method, there was a twofold increase in rates of gluconeogenesis in diabetic subjects (0.42 +/- 0.04 mmol m(-2) x min(-1), which decreased by 33% after metformin treatment (0.28 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0002). There was no glycogen cycling in the control subjects, but in the diabetic subjects, glycogen cycling contributed to 25% of glucose production and explains the differences between the two methods used. In conclusion, patients with poorly controlled type 2 diabetes have increased rates of endogenous glucose production, which can be attributed to increased rates of gluconeogenesis. Metformin lowered the rate of glucose production in these patients through a reduction in gluconeogenesis.

Phenylacetate ingestion has been used to probe Krebs cycle metabolism and to augment waste nitrogen excretion in urea cycle disorders. Phenylalkanoic acids, including phenylacetate, have been proposed as potential therapeutic agents in the treatment of diabetes. They inhibit gluconeogenesis in the liver in vitro and reduce the blood glucose concentration in diabetic rats. The effect of sodium phenylacetate ingestion on blood glucose and the contribution of gluconeogenesis to glucose production have now been studied in 7 type 2 diabetic patients. The study was not designed to test whether the changes in glucose metabolism observed in the rat could be reproduced in humans. After an overnight fast, over a period of 1 hour, 4.8 g phenylacetate was ingested, which is the highest dose used to probe Krebs cycle metabolism. Glucose production was measured by tracer kinetics using [6,6-2H2]glucose and gluconeogenesis by the labeling of the hydrogens of blood glucose on 2H2O ingestion. The concentration of phenylacetate in plasma peaked by 2 hours after its ingestion, and about 40% of the dose was excreted in 5 hours. The plasma glucose concentration and production, and the contribution of gluconeogenesis to glucose production, were unaffected by phenylacetate ingestion at the highest dose used to probe Krebs cycle metabolism.

Effects of free fatty acids (FFAs) on endogenous glucose production (EGP) and gluconeogenesis (GNG) were examined in healthy subjects (n = 6) during stepwise increased Intralipid/heparin infusion (plasma FFAs 0.8+/-0.1, 1.8+/-0.2, and 2.8+/-0.3 mmol/l) and during glycerol infusion (plasma FFAs approximately 0.5 mmol/l). Rates of EGP were determined with D-[6,6-2H2]glucose and contributions of GNG from 2H enrichments in carbons 2 and 5 of blood glucose after 2H2O ingestion. Plasma glucose concentrations decreased by approximately 10% (P < 0.01), whereas plasma insulin increased by approximately 47% (P = 0.02) after 9 h of lipid infusion. EGP declined from 9.3+/-0.5 (lipid) and 9.0+/-0.8 pmol x kg(-1) x min(-1) (glycerol) to 8.4+/-0.5 and 8.2+/-0.7 micromol x kg(-1) x min(-1), respectively (P < 0.01). Contribution of GNG similarly rose (P < 0.01) from 46+/-4 and 52+/-3% to 65+/-8 and 78+/-7%. To exclude interaction of FFAs with insulin secretion, the study was repeated at fasting plasma insulin (approximately 35 pmol/l) and glucagon (approximately 90 ng/ml) concentrations using somatostatin-insulin-glucagon clamps. Plasma glucose increased by approximately 50% (P < 0.005) during lipid but decreased by approximately 12% during glycerol infusion (P < 0.005). EGP remained unchanged over the 9-h period (9.9+/-1.2 vs. 9.0+/-1.1 micromol x kg(-1) x min(-1)). GNG accounted for 62+/-5 (lipid) and 60+/-6% (glycerol) of EGP at time 0 and rose to 74+/-3% during lipid infusion only (P < 0.05 vs. glycerol: 64+/-4%). In conclusion, high plasma FFA concentrations increase the percent contribution of GNG to EGP and may contribute to increased rates of GNG in patients with type 2 diabetes.

Corticotropin-releasing hormone (CRH) and proenkephalin (PENK) are hypothalamic peptides involved in the stress response and hypothalamic-pituitary axis regulation. Previous research has implicated these peptides in the pathogenesis of affective disorders. In this study we investigated two polymorphisms located in the genes that code for CRH and PENK by means of association and linkage analyses. A total of 138 bipolar patients and 108 controls were included in the association study. In addition, 24 families were available for linkage analysis, including six families of probands with documented periodic positivity of dexamethasone suppression tests (DST) during remission. We found no association of bipolar disorder with either gene. Similarly, we did not find any evidence of linkage (P = 0.56 for CRH and 0.52 for PENK) in the entire sample or in the subsample of families of DST positive probands. In conclusion, our study does not support the hypothesis that genes coding for CRH or PENK contribute to the genetic susceptibility to bipolar disorder. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:178-181, 2000.

Different types of dipeptide building units containing N- or C-terminal arginine were prepared for synthesis of the backbone cyclic analogues of the peptide hormone bradykinin (BK: Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg). For cyclization in the N-terminal sequence N-carboxyalkyl and N-aminoalkyl functionalized dipeptide building units were synthesized. In order to avoid lactam formation during the condensation of the N-terminal arginine to the N-alkylated amino acids at position 2, the guanidino function has to be deprotected. The best results were obtained by coupling Z-Arg(Z)2-OH with TFFH/collidine in DCM. Another dipeptide building unit with an acylated reduced peptide bond containing C-terminal arginine was prepared to synthesize BK-analogues with backbone cyclization in the C-terminus. To achieve complete condensation to the resin and to avoid side reactions during activation of the arginine residue, this dipeptide unit was formed on a hydroxycrotonic acid linker. HYCRAM technology was applied using the Boc-Arg(Alloc)2-OH derivative and the Fmoc group to protect the aminoalkyl function. The reduced peptide bond was prepared by reductive alkylation of the arginine derivative with the Boc-protected amino aldehyde, derived from Boc-Phe-OH. The best results for condensation of the branching chain to the reduced peptide bond were obtained using mixed anhydrides. Both types of dipeptide building units can be used in solid-phase synthesis in the same manner as amino acid derivatives.

The National Heart, Lung, and Blood Institute Growth and Health Study (NGHS) is an epidemiologic study of 1,213 Black and 1,166 White girls (ages 9-10) of risk factors for obesity. NGHS used Harter's Self-Perception Profile for Children (SPPC) to measure domain-specific competence and overall self-worth. This report reviews the psychometric properties of the SPPC in this biracial cohort at baseline and Year 3 visits (ages 11-12). Simple structure yielding unique components for each of the SPPC domains was obtained for White but not Black girls, whether analyzed overall or by parental education level. Internal consistency was higher for White girls in both years. The lack of simple structure was reflected in the higher correlations among the subscales for Black girls. The structure and internal consistency improved in Year 3 for Black girls, indicating that the physical appearance and athletic competence domains were not yet fully differentiated at baseline. Readers should be cautious, however, when interpreting the SPPC in young Black girls.

Impaired glucose effectiveness (i.e., a diminished ability of glucose per se to facilitate its own metabolism), increased gluconeogenesis, and endogenous glucose release are, together with insulin resistance and beta-cell abnormalities, established features of type 2 diabetes. To explore aspects of the pathophysiology behind type 2 diabetes, we assessed in a group of healthy people prone to develop type 2 diabetes (n = 23), namely first-degree relatives of type 2 diabetic patients (FDR), 1) endogenous glucose release and fasting gluconeogenesis measured using the 2H2O technique and 2) glucose effectiveness. The FDR group was insulin resistant when compared with an age-, sex-, and BMI-matched control group without a family history of type 2 diabetes (n = 14) (M value, clamp: 6.07 +/- 0.48 vs. 8.06 +/- 0.69 mg x kg(-1) lean body weight (lbw) x min(-1); P = 0.02). Fasting rates of gluconeogenesis (1.28 +/- 0.06 vs. 1.41 +/- 0.07 mg x kg(-1) lbw x min(-1); FDR vs. control subjects, P = 0.18) did not differ in the two groups and accounted for 53 +/- 2 and 60 +/- 3% of total endogenous glucose release. Glucose effectiveness was examined using a combined somatostatin and insulin infusion (0.17 vs. 0.14 mU x kg(-1) x min(-1), FDR vs. control subjects), the latter replacing serum insulin at near baseline levels. In addition, a 360-min labeled glucose infusion was given to simulate a prandial glucose profile. After glucose infusion, the integrated plasma glucose response above baseline (1,817 +/- 94 vs. 1,789 +/- 141 mmol/l per 6 h), the ability of glucose to simulate its own uptake (1.50 +/- 0.13 vs. 1.32 +/- 0.16 ml x kg(-1) lbw x min(-1)), and the ability of glucose per se to suppress endogenous glucose release did not differ between the FDR and control group. In conclusion, in contrast to overt type 2 diabetic patients, healthy people at high risk of developing type 2 diabetes are characterized by normal glucose effectiveness at near-basal insulinemia and normal fasting rates of gluconeogenesis.

A number of association studies have investigated the role of the monoamine oxidase A (MAOA) gene in the susceptibility to bipolar disorder. Although some studies have reported positive findings, there remains some controversy, because results from different studies have not been consistent. A common explanation for inconsistencies between studies is genetic heterogeneity. We have focused on lithium responsive bipolar disorder as a way to reduce heterogeneity. In this study, we investigated the role of MAOA in lithium responsive bipolar patients using association and linkage study designs. The investigation used 138 patients and 108 normal controls. In addition, 25 families were also studied. Our results were not supportive of a major role of MAOA in the predisposition to bipolar disorder.

Emotion-induced eating has been implicated as a risk factor for the development of obesity, yet no research has been done on emotion-induced eating in children. The National Heart, Lung, and Blood Institute Growth and Health Study (NGHS), a multicenter collaborative study of risk factors for obesity, developed an instrument for measuring emotion-induced eating in children and tested hypotheses regarding the association of emotion-induced eating with food intake and adiposity in preadolescent children.Subjects were 1,213 black girls and 1,166 white girls who were 9 and 10 at study entry. Baseline data were utilized in this report. Girls were assessed by trained female health examiners who recorded height, weight, and indices of sexual maturation. Girls kept a 3-day food diary. Dietary data were coded and analyzed for total caloric and macro nutrient intake. A measure of emotion-induced eating was derived from seven questions about eating in response to emotions (Cronbach's alpha = .78).Black girls had significantly higher emotion-induced eating scores than white girls (10.8 vs. 9.7, p.0001). For white girls, but not for black girls, emotion-induced eating was associated with increased intake of sucrose. In both races, a modest inverse association was found between body mass index and emotion-induced eating.Prospective studies are needed to explore further the role of emotion-induced eating and food intake and the role of emotion-induced eating in the development of obesity.

Fruit allergy is frequently associated with birch pollinosis. The aim of this study was to investigate which kiwi allergens were involved in subjects allergic to fruit alone and in patients allergic to both fruit and birch pollen. Sera of nine patients (five with both kiwi and birch pollen allergy and four with isolated kiwi allergy) were studied by immunoblot of kiwi extract. Eight of the nine sera reacted with the 30 kDa protein. Furthermore, IgE-binding proteins were seen at approximately 23 kDa (detected by five sera), 43 kDa and 80 kDa (four sera), and80 kDa (two sera). One serum showed no IgE binding to any kiwi allergen. The 30 kDa is the major allergen in kiwi and was purified by anion-exchange chromatography and characterized by isoelectrofocusing and amino acid sequencing. The comparison of its partial amino acid sequence with data from the Swiss Protein Bank revealed that this protein is actinidine. The carbohydrate structures in kiwi and birch pollen extracts were investigated with seven lectins. On kiwi blot, Aleuria aurantia agglutinin showed strong reactivity (indicating fucose residues) to the components of 35 to 92 kDa, while concanavalin A (indicating mannose, glucose or N-acetylglucosamine residues) showed weak binding at 67 kDa. In contrast, strong binding of Galanthus nivalis agglutinin (indicating mannose residues) and concanavalin A was found on birch pollen blots. The presence of IgE against carbohydrate structures was determined by means of enzyme-linked immunosorbent assay (ELISA) after periodate treatment of kiwi extract. The IgE binding was reduced by periodate treatment of kiwi coated microtiter plates, but not by sera reacting exclusively with the 30 kDa protein. Furthermore, selected sera were treated with proteinase K-digested kiwi and birch pollen extracts as the sources of crossreactive carbohydrate determinants. In accordance with the results of sodium periodate treatment, significant levels of anti-cross-reactive carbohydrate determinant IgE were found in sera from patients allergic to both kiwi and birch pollen. Our results show that the major allergen for kiwi allergy is the 30 kDa protein and additionally that the cross-reaction between kiwi and birch pollen allergy is mainly due to carbohydrate moieties.

Several studies have indicated that patients with bipolar disorder (BD) who respond well to lithium prophylaxis constitute a biologically distinct subgroup. Lithium is thought to stabilize mood by acting at the phosphoinositide cycle. We have investigated a polymorphism located in the gene (PLCG1) that codes for a gamma-1 isozyme of phospholipase (PLC), an enzyme that plays an important role in the phosphoinositide second messenger system. A population-based association study and a family-based linkage study were carried out on patients who were considered excellent responders to lithium prophylaxis. Response to lithium was evaluated prospectively with an average follow-up of 14.4 +/- 6.8 years. The PLCG1 polymorphism was investigated in 136 excellent lithium responders and 163 controls. In addition, the segregation of this marker was studied in 32 families ascertained through lithium-responsive bipolar probands. The allele distributions between lithium-responsive bipolar patients and controls were different, with a higher frequency of one of the PLCG1 polymorphisms in patients (chi2 = 8.09; empirical P = 0.033). This polymorphism, however, confers only a small risk (OR = 1.88, CI 1.19-3.00). Linkage studies with the same marker yielded modest support for the involvement of this gene in the pathogenesis of BD when unilineal families were considered (Max LOD = 1.45; empirical P = 0.004), but not in the whole sample. Our results provide preliminary evidence that a PLC isozyme may confer susceptibility to bipolar disorder, probably accounting for a fraction of the total genetic variance. Whether this polymorphism is implicated in the pathogenesis of BD or in the mechanism of lithium response remains to be determined.

The effect of implantable cardioverter/defibrillator (ICD) lead placement in the right ventricle (RV) on defibrillation efficacy has not been thoroughly investigated. Therefore, the goal of this combined experimental and clinical study was to evaluate the effect of a septal and a non-septal position of the right ventricular endocardial spring lead on defibrillation energy.In 12 isoflurane-anaesthetized swine and subsequently in 8 patients who underwent ICD implantation, two different positions of the distal spring lead in the RV were investigated in randomized order: non-septal position (free wall of the RV) and septal position (interventricular septum). For each position, separate 50% probability determinations of energy (E50), peak voltage (V50) and peak current (A50) were calculated using the three reversal up/down defibrillation procedure. The E50, V50, A50 and impedance (I) were averaged and compared using the two-sided t-test for paired samples.Both the experimental study and the clinical study demonstrated that placing the distal defibrillation lead near to the septum rather than near to the ventricular free wall resulted both in the swine and in the patients in significantly lower E50-31.6%/ - 37.1%, V50-16.1%/-20.9% and A50 -10.0%/ - 24.2%, respectively. Defibrillation impedances were significantly reduced only in the experimental study.Defibrillation efficacy depends on the position of the distal spring electrode in the RV. A septal position significantly reduces the energy requirements compared to a non-septal position. The decrease in energy requirements might be explained by an increase in current flow through the septum and the posterolateral wall of the left ventricle. reserved

We report a case of a 64-year-old woman with increasing shortness of breath due to massive pericardial effusion. Cardiac magnetic resonance imaging (CMRI) identified typical findings for pericarditis. Pericardectomy was needed due to suspicion of pericardial abscess formation. Histological examination of the resected tissue revealed an undifferentiated primary pericardial synovial sarcoma. The present case illustrates that pericardial tumours could be an important differential diagnosis to pericarditis, even if typical findings of pericarditis were present in CMRI.

Lactulose is therapeutically used in hepatic encephalopathy, constipation, and salmonellosis. This semisynthetic disaccharide is neither metabolized nor absorbed in the normal small intestines. Comparable to plant-polysaccharides lactulose is bacterially fermented in the colon to short chain fatty acids and gases. Major consequences are a drop in pH and a change in composition and metabolic activity of the colonic flora. These and other potential effects suggest complex mechanisms of action of lactulose, with the potential for additional indications in diagnosis and therapy. The use of lactulose as substrate for the H2-breath-test is well known as a means for the measurement of oroeceal transit time and as test for small intestinal bacterial overgrowth. An extension of the diagnostic potential is given by the assessment of the permeability in diffuse intestinal disease with combined disaccharide/monosaccharide test solutions, especially in Crohn's disease. Explanations for positive effects in the prophylaxis of cholesterol-gallstones, in the therapy of hypercholesterolemia and in the prevention of colorectal adenoma and carcinoma can be found in changes in lipid- and bile acid metabolism found after lactulose ingestion. Lactulose may lead to an improved glucose-tolerance in parallel to fibre and acarbose effects which involve several mechanisms of carbohydrate metabolism. Lactulose presumably reduces pathogenic bacteria in favor of the health promoting bifidusflora; also, production and absorption of endotoxines may be reduced; this suggests that lactulose may have therapeutic effects on both infectious and idiopathic inflammatory bowel diseases. Numerous studies with interesting but not as yet convincingly documented clinical relevance suggest that the many effects of lactulose may be interesting subjects for future research.

In order to examine metabolic zonation in human liver, [2-14C]glycerol, which labels carbons 2 and 5 of glucose-6-P, and [1-14C]lactate, which labels carbons 3 and 4 of glucose-6-P, in the process of gluconeogenesis, were infused intravenously into healthy subjects who ingested acetaminophen and had fasted 36 h. Distributions of 14C were determined in glucose in blood and in the glucuronic acid moiety of acetaminophen glucuronide excreted in urine. Ratios of 14C in carbons 2 and 5 to 14C in carbons 3 and 4 were significantly higher in blood glucose than in glucuronide. Since glucose and glucuronic acid are formed from glucose-6-P in liver without randomization of carbon, the differences in the ratios indicate that the pool of glucose-6-P in liver is not homogeneous. The glucuronide sampled glucose-6-P with more label from lactate than glycerol compared to the glucose-6-P sampled by the glucose. The apparent explanation is the greater decrease in glycerol compared with lactate concentration as blood streams from the periportal to the perivenous zones of the liver lobule. Glucuronidation is then expressed in humans relatively more in the perivenous than periportal zones and gluconeogenesis from glycerol more in the periportal than perivenous zones.

A case of dysphagia and hoarseness due to external compression by anterior hyperostosis between the third and fourth cervical vertebra is reported. Immediate relief of the symptoms was accomplished by surgical excision of the hyperostosis through an antero-lateral approach. The pathogenesis of the symptoms with reference to literature is discussed.

This study was undertaken to demonstrate how psychoanalysis can shed new light on a much studied life history. Clara's emotional life knew a sequence of losses and "prohibited" intimate relationships that created grave loyalty, identity, and identificatory conflicts for her. Since her early childhood, when her father forced her to give up her mother, she had been forced into a choice between the love objects most dear to her and the one on whom she depended for her emotional survival. This resulted in her later repetition compulsion to maneuver herself into the same conflict of loyalty and in her hesitation to decide when choosing one object meant losing the other. Clara had never known a normal separation, only loss and abandonment. She strove to combine the incompatible and succeeded in remaining loyal not only to her mother and father, but also to Robert Schumann, and eventually to Johannes Brahms. Clara Schumann's ideals were conflicted not only because she was educated by two men who were fighting each other, but also because her father, as well as Robert, had internally inconsistent and ambiguous ideas about women. Clara not only had to be obedient and creative, but self-sufficient at the same time. She was partially able to satisfy her own and her partner's needs and solve her deficiencies by projective identification, choosing taciturn men, more maternal than she.

TPS7109 Background: This is an ongoing phase III multicenter randomized trial comparing adjuvant pharmacogenomic-driven chemotherapy, based on thymidilate synthase (TS) and excision-repair cross-complementing -1 (ERCC1) gene expression versus standard adjuvant chemotherapy in completely resected stage II-IIIA non-small cell lung cancer (EudraCT #: 2008-001764-36). Methods: In all registered patients, before randomization, expression of ERCC1 and TS is assessed by qRT-PCR on paraffin-embedded tumor specimens in a central laboratory. Randomization is stratified by stage and smoking status. Trial was emended on Feb, 2011 with the 7th staging system. Primary end point is overall survival; secondary end points include recurrence-free survival, therapeutic compliance, toxicity profile and comparative evaluation of ERCC1 and TS mRNA versus protein. It is assumed that the 5-year survival in the control arm is 45% and the hazard reduction associated to the experimental treatment is 30%. With a power of 90% to detect the estimated effect with log-rank test, a significant level of 5% (2 tails), 336 events have to be observed; the expected total number of patients is 700. The final statistical analysis will group together all control arms and all tailored chemotherapies groups. Efficacy analysis will be done on an intent-to-treat basis. Cox proportional hazard model will be used for estimating hazard ratios after adjusting for relevant variables. Within 45 days post-surgery, patients in each genetic profile are randomized to receive either a standard chemotherapy selected by the investigator (cisplatin/vinorelbine, cisplatin/docetaxel or cisplatin/gemcitabine) or an experimental treatment (tailored arms) selected as follows: 1) high ERCC1 and high TS 4 cycles of single agent paclitaxel 2) high ERCC1 and low TS 4 cycles of single agent pemetrexed 3) low ERCC1 and high TS 4 cycles of cisplatin/gemcitabine 4) low ERCC1 and low TS) 4 cycles of cisplatin/pemetrexed. All chemotherapy regimens are administered for a total of 4 cycles on a 3-weekly basis. Currently, 312 patients have been randomized from 26 institutions mainly located in Italy and Germany (average enrolment: 13 patients/month).

e18010 Background: CTX has been registered for head and neck and colorectal cancer. Our randomized phase II/III trial is to assess the efficacy and safety of CTX in combination with two different chemotherapy (CT) regimens. Methods: Chemonaive pts with histologically confirmed stage IIIB or IV NSCLC and PS 0–2 received CTX 400 mg/m2 (loading dose) and then 250 mg/m2 weekly either combined with G 1,000 mg/m2 days 1 + 8 for 2 cycles (3qw) followed by D 75 mg/m2 day 1 for 2 cycles (q3w) (arm A) or CP AUC5 day 1 and G 1,200 mg/m2 days 1 + 8 for 4 cycles (q3w) (arm B). If pts did not progress single agent CTX was continued (“maintenance”) until tumor progression or unacceptable toxicity. Results: 340 pts received 2,826 infusions of CTX combined with CT and 2,015 infusions without CT. Toxicities requiring clinical intervention are shown below (Table). 142 pts on single-agent CTX received up to 33 cycles without significant toxicity (arm A: 64 pts, range 1-33 cycles, median 3, mean 5.6, and 11 pts ≥10 cycles; ar...

8048 Background: The EGFR-targeting antibody cetuximab is undergoing broad clinical investigation in NSCLC. Our randomized trial assesses the safety of cetuximab combined with 2 different chemotherapy (CT) regimens in pts with advanced NSCLC. Phase II results are reported. Methods: Pts with histologically confirmed stage IIIB or IV NSCLC, WHO PS 0–2, and no prior CT received cetuximab 400 mg/m2 loading dose followed by 250 mg/m2 weekly either combined with G 1000 mg/m2 days 1 + 8 for 2 cycles (3qw) followed by D 75 mg/m2 day 1 for 2 cycles (q3w) (arm A) or CP AUC5 day 1 and G 1200 mg/m2 days 1 + 8 for 4 cycles (q3w) (arm B). Maintenance cetuximab was administered until disease progression or unacceptable toxicity. Results: 229 pts evaluable for safety received 1810 infusions of cetuximab combined with CT and 1216 infusions of maintenance cetuximab. 35 pts in arm A received 1–26 cycles (median 4) of maintenance cetuximab and 6 pts received ≥10 cycles; 50 pts in arm B received 1–22 cycles (median 3) and 7 pts ≥10 cycles. Grade 1 or 2 skin reactions related to study medication occurred in 84% of pts in arm A and 77% in arm B. In general, toxicity was more common in pts receiving CP (leukopenia and neutropenia 10%; pneumonia and fever 10%). In arm B, thrombopenia developed in 14% of pts and allergic reactions in 8%. Toxicities requiring clinical intervention are shown below. Updated results will be presented for 320 pts. Conclusions: Cetuximab does not significantly increase CT toxicity in the induction phase and is well tolerated in the maintenance phase. Notably, ∼75% of pts developed skin rash (grade 3/4 in ∼5% of pts). [Table: see text] [Table: see text]

To examine the fate of the carbons of acetate and to evaluate the usefulness of labeled acetate in assessing intrahepatic metabolic processes during gluconeogenesis, [2-14C]acetate, [2-14C]ethanol, and [1-14C]ethanol were infused into normal subjects fasted 60 h and given phenyl acetate. Distributions of 14C in the carbons of blood glucose and glutamate from urinary phenylacetylglutamine were determined. With [2-14C]acetate and [2-14C]ethanol, carbon 1 of glucose had about twice as much 14C as carbon 3. Carbon 2 of glutamate had about twice as much 14C as carbon 1 and one-half to one-third as much as carbon 4. There was only a small amount in carbon 5. These distributions are incompatible with the metabolism of [2-14C]acetate being primarily in liver. Therefore, [2-14C]acetate cannot be used to study Krebs cycle metabolism in liver and in relationship to gluconeogenesis, as has been done. The distributions can be explained by: (a) fixation of 14CO2 from [2-14C]acetate in the formation of the 14C-labeled glucose and glutamate in liver and (b) the formation of 14C-labeled glutamate in a second site, proposed to be muscle. [1,3-14C]Acetone formation from the [2-14C]acetate does not contribute to the distributions, as evidenced by the absence of 14C in carbons 2-4 of glutamate after [1-14C]ethanol administration.

To quantify intrahepatic Krebs cycle metabolism, phenyl acetate, excreted in urine as a glutamine conjugate, was given to healthy subjects infused with [3-14C]lactate. They were studied after 60 h of fasting and when given glucose after an overnight fast. Distributions of 14C in glutamate from urinary phenylacetylglutamine and blood glucose were determined. Corrections to the distributions because of the fixation of 14CO2 formed from the [3-14C]lactate were determined by administering [14C]bicarbonate. Comparisons of distributions in glucose and glutamate support the assumption that the glutamate distributions reflect those in hepatic alpha-ketoglutarate. From the distributions in glutamate, the extent of exchange of labeled with unlabeled carbons and relative flow rates in the cycle in liver were estimated. Dilution of 14C by 12C in the cycle was found in the fasted but not the fed state. In the fasted state, pyruvate carboxylation was estimated to be at least twice the rate of Krebs cycle flux and the rate of pyruvate's decarboxylation less than 1/25 the rate of its carboxylation. In the fed state, the rate of decarboxylation was estimated to be between one-sixth and one-half the rate of carboxylation. The rate of conversion of oxalacetate to fumarate in both states appeared to be greater than 6 times the rate of Krebs cycle flux.

19005 Background: The novel therapeutic agent cetuximab, a monoclonal antibody that specifically targets the epidermal growth factor receptor, is currently registered for colorectal and head and neck cancer and is undergoing broad clinical investigations in advanced NSCLC. This randomized trial assesses the feasibility of cetuximab in combination with two common chemotherapeutic regimens in patients with locally advanced or metastatic NSCLC. Early phase II results are reported. Methods: Patients with histologically confirmed stage IIIB or IV NSCLC, WHO performance status 0–2, and no prior chemotherapy received cetuximab 400 mg/m2 as initial dose then 250 mg/m2 weekly either in combination with gemcitabine 1,000 mg/m2 days 1 and 8 for two 3-weekly cycles followed by docetaxel 75 mg/m2 day 1 for 2 cycles (q3w) or gemcitabine 1200 mg/m2 days 1 and 8 and carboplatin AUC5 day 1 for a maximum of 4 cycles (q3w). Cetuximab was administered until disease progression or unacceptable toxicity. Results: 142 patients ...

The effect of fasting vs. refeeding on hepatic glycogen repletion by the direct pathway, i.e., glucose----glucose 6-phosphate (G-6-P)----glycogen, was determined. Acetaminophen was administered during an infusion of glucose labeled with [1-13C]- and [6-14C]glucose into four healthy volunteers after an overnight fast and into the same subjects 4 h after breakfast. 13C enrichments in C-1 and C-6 of glucose formed from urinary acetaminophen glucuronide compared with enrichments in C-1 and C-6 of plasma glucose provided an estimate of glycogen formation by the direct pathway. The specific activity of glucose from the glucuronide compared with the specific activity of the plasma glucose, along with the percentages of 14C in C-1 and C-6 of the glucose from the glucuronide, also provided an estimate of the amount of glycogen formed by the direct pathway. The estimates were similar. Those from [6-14C]glucose would have been higher than from [1-13C]glucose if the pentose cycle contribution to overall glucose utilization had been significant. After an overnight fast, during the last hour of infusion, 49 +/- 3% of the glycogen formed was formed via the direct pathway. After breakfast, at similar plasma glucose and insulin concentrations, the percentage increased to 69 +/- 7% (P less than 0.02). Thus the contributions of the pathways to hepatic glycogen formation depend on the dietary state of the individual. For a dietary regimen in which individuals consume multiple meals per day containing at least a moderate amount of carbohydrates most glycogen synthesis occurs by the direct pathway.

Hepatic fructose-6-phosphate (fructose-6-P) cycling and pentose cycle activity were quantified in hyperthyroid patients. A measure of the fructose-6-P cycle was the incorporation of 14C, on administering [3-3H,6-14C]galactose, into carbon 1 of blood glucose and the 3H/14C ratio in blood glucose. The measure of the pentose cycle was the randomization of 14C to carbon 1 of blood glucose on administering [2-14C]galactose. [2-3H]Galactose was also administered, so the 3H/14C ratio in blood glucose measured the extent of equilibration of glucose-6-P with fructose-6-P. Patients given [3-3H,6-14C]galactose were restudied when euthyroid. Of the 14C from [3-3H,6-14C]galactose, 7.7-9.5% was in carbon 1 of glucose in both states. 3H/14C ratios were also the same in both states. Fructose-6-P cycling was estimated to be 13 +/- 1% the rate of glucose turnover in the euthyroid and 15 +/- 1% that in the hyperthyroid state. The pentose cycle contributed about 2% to glucose utilization, similar to previous estimates in healthy humans. As in healthy individuals, about 25% of 3H was retained in the conversion of [2-3H]glucose-6-P to glucose. Thus, the fractions of glucose turnover participating in hepatic fructose-6-P and pentose cycling are similar in hyperthyroid and healthy subjects. As a result, augmented fructose-6-P cycling does not substantially contribute to increased hepatic oxygen consumption in hyperthyroidism.

Quantification of gluconeogenesis (GNG) with carbon labeled tracers results in underestimation due to exchange and loss of tracer C in TCA cycle. We have reported the use of deuterium labeling of body water pool in order to label the glucogenic precursor phosphoenol pyruvate (JCI 95:172, 1995). The appearance of 2H on C-6 of glucose quantifies GNG from pyruvate, if correctred for incomplete equilibration of label at the pyruvate level, but does not include glycerol. Since 2H from water labels C-5 of glucose via pyruvate, and also labels C-2 of the triose phosphate pool, appearance of2 H on C-5 of glucose gives an estimate of total GNG, eliminating the uncertainty of incomplete equilibration and including glycerol.