The discovery of (1R, 3R)-1-(3-chloro-5-fluorophenyl)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile, a potent and selective agonist of human transient receptor potential cation channel subfamily m member 5 (TRPM5) and evaluation of as a potential gastrointestinal prokinetic agent.

This publication details the discovery of a series of selective transient receptor potential cation channel subfamily M member 5 (TRPM5) agonists culminating with the identification of the lead compound (1R, 3R)-1-(3-chloro-5-fluorophenyl)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile (39). We describe herein our biological rationale for agonism of the target, the examination of the then current literature tool molecules, and finally the process of our discovery starting with a high throughput screening hit through lead development. We also detail the selectivity of the lead compound 39 versus related family members TRPA1, TRPV1, TRPV4, TRPM4 and TRPM8, the drug metabolism and pharmacokinetics (DMPK) profile and in vivo efficacy in a mouse model of gastrointestinal motility.

Glutamine depletion by crisantaspase hinders the growth of human hepatocellular carcinoma xenografts.

BACKGROUND: A subset of human hepatocellular carcinomas (HCC) exhibit mutations of ß-catenin gene CTNNB1 and overexpress Glutamine synthetase (GS). The CTNNB1-mutated HCC cell line HepG2 is sensitive to glutamine starvation induced in vitro with the antileukemic drug Crisantaspase and the GS inhibitor methionine-L-sulfoximine (MSO). METHODS: Immunodeficient mice with subcutaneous xenografts of the CTNNB1-mutated HCC cell lines HepG2 and HC-AFW1 were treated with Crisantaspase and/or MSO, and tumour growth was monitored. At the end of treatment, tumour weight and histology were assessed. Serum and tissue amino acids were determined by HPLC. Gene and protein expression were estimated with RT-PCR and western blot and GS activity with a colorimetric method. mTOR activity was evaluated from the phosphorylation of p70S6K1. RESULTS: Crisantaspase and MSO depleted serum glutamine, lowered glutamine in liver and tumour tissue, and inhibited liver GS activity. HepG2 tumour growth was significantly reduced by either Crisantaspase or MSO, and completely suppressed by the combined treatment. The combined treatment was also effective against xenografts of the HC-AFW1 cell line, which is Crisantaspase resistant in vitro. CONCLUSIONS: The combination of Crisantaspase and MSO reduces glutamine supply to CTNNB1-mutated HCC xenografts and hinders their growth.

Airway barrier dysfunction induced by exposure to carbon nanotubes in vitro: which role for fiber length?

Although carbon nanotubes (CNTs) are increasingly used, their biological effects are only incompletely characterized. However, experimental evidence suggests that the intratracheal instillation of CNTs causes the formation of interstitial granulomas and progressive pulmonary fibrosis in rodents. Using human epithelial Calu-3 cells as a model of airway epithelium in vitro, we have recently reported that the exposure to commercial multi-walled CNTs (MWCNTs) causes a progressive decrease of the transepithelial electrical resistance (TEER), pointing to a CNT-dependent impairment of the epithelial barrier function. To characterize better this behavior, we compared the effects of two types of MWCNTs and single-walled CNTs (SWCNTs) of different lengths on the TEER of Calu-3 monolayers. All the materials were used at a dose of 100 microg/mL corresponding to an exposure of 73 microg/cm(2) of cell monolayer. Only the longer MWCNTs and SWCNTs cause a significant decrease in TEER. To elucidate the mechanism underlying the changes in barrier function, the expression of the junction proteins occludin and ZO-1 has been also assessed. No significant decrease in the mRNA for either protein is detectable after the exposure to any type of CNTs. It is concluded that the impairment of barrier function in Calu-3 monolayers is a peculiar effect of CNTs endowed with clear cut fiber properties and is not referable to marked changes in the expression of junction proteins.

Nature-inspired indolyl-2-azabicyclo[2.2.2]oct-7-ene derivatives as promising agents for the attenuation of withdrawal symptoms: synthesis of 20-desethyl-20-hydroxymethyl-11-demethoxyibogaine.

Microwave assisted Diels-Alder cycloaddition of 5-Br-N-benzylpyridinone (2) with methyl acrylate is described to gain an easy access to 7-bromo-2-benzyl-3-oxo-2-aza-5 or 6-carbomethoxy bicyclo[2.2.2]oct-7-enes (3)-(6). The preparation of the ibogaine analogue 20-desethyl-(20-endo)-hydroxymethyl-11-demethoxyibogaine (17) is described by stereoselective hydrogenation of the C(7)-C(8) double bond. Biological evaluation showed an interesting in vitro binding profile toward dopamine transporter, serotonin transporter and opioid receptor systems accompanied by an antiwithdrawal effect in mice for hydroxymethyl 7-indolyl-2-aza-bicyclo[2.2.2]oct-2-ene (14). The simplification of the ibogaine structure appears as a promising approach toward the design of compounds that could reduce the withdrawal symptoms.

Early and subtle abnormalities of left ventricular function in clinically stable coronary artery disease patients with normal ejection fraction.

BACKGROUND: It has been reported that, in the initial phase of ischemic cardiomyopathy, the earliest alterations of left ventricular function are detected during the relaxation phase. The aim of this study was to look for precocious abnormalities in the early stage of ischemic cardiomyopathy in both left ventricular systolic and diastolic phases. METHODS AND RESULTS: Using simultaneous left ventricular catheterization and echo-Doppler techniques, we studied both systolic and diastolic function in 44 (37 males and 7 females, mean age 55.7+/-8) normotensive, clinically stable, coronary artery disease patients with normal left ventricular ejection fraction in comparison to 9 age- and sex-matched normal control subjects (7 males and 2 females, mean age 54.7+/-9). Mean values of E deceleration time, tau, left ventricular end-diastolic volume and pressure, and end-systolic volume and lowest diastolic pressure were significantly higher (from P<.05 to P<.01), whereas mean dP/dt/P values significantly lower (P<.05) in coronary artery disease patients than in controls. A strict relationship (P<.001) between dP/dt/P and tau, left ventricular lowest and end-diastolic pressure was found in all subjects studied. CONCLUSION: Early and subtle abnormalities in parameters of both systolic and diastolic function can be found in the majority of coronary artery disease patients with normal ejection fraction.

Glucagon-like peptide 1 (GLP-1) secretion and plasma dipeptidyl peptidase IV (DPP-IV) activity in morbidly obese patients undergoing biliopancreatic diversion.

BACKGROUND: The physiological inhibitory control of glucagon-like Peptide 1 (GLP-1) on gastric emptying and the contribution of this peptide in the regulation of food intake as a satiety factor suggest that impaired secretion and/or activity of GLP-1 may be involved in the pathogenesis of obesity. We investigated food-mediated GLP-1 secretion as well as plasma activity of dipeptidyl-peptidase IV (DPP-IV), the enzyme responsible for rapid inactivation of the circulating peptide, in morbidly obese patients, before and after weight loss resulting from biliopancreatic diversion. METHODS: Twenty-two morbidly obese non-diabetic patients (BMI = 47.5 +/- 1.8) and 9 age-matched healthy volunteers were studied. A mixed meal (700 kcal) was administered to all subjects and blood samples were collected at 0, 15, 30, 60, 120 min for the determination of circulating glucose, insulin, GLP-1 (7 - 36 amide) concentrations and plasma DPP-IV activity. The patients repeated the test meal after 50 % overweight reduction resulting from surgical treatment (BMI = 33.8 +/- 1.1). RESULTS: While nutrient ingestion significantly increased plasma GLP-1 levels in the control group (30', 60': p < 0.01), the test-meal failed to modify basal peptide values in the obese patients, and an overall reduction in circulating GLP-1 occurred during the observation period (p < 0.001). Plasma DPP-IV activity in the same patients resulted as being significantly higher than controls, both at fasting and in response to the meal (p < 0.05). With respect to preoperative values, an overall increase in circulating GLP-1 levels occurred in all patients following biliopancreatic diversion (p < 0.001). Plasma DPP-IV activity, on the other hand, continued to be abnormally increased, even after considerable weight loss (p < 0.05 vs. controls). CONCLUSIONS: First: In morbid obesity, the accelerated inactivation of circulating GLP-1 could at least partially account for plasma peptide levels lower than normal, the defective availability of such a satiety factor possibly contributing to eating behaviour abnormalities; Second: plasma DPP-IV hyperactivity in the obese did not seem to be affected by the overweight degree, the increase in postoperative GLP-1 levels mainly resulting from hyperstimulation of GLP-1 secretory cells due to surgical manipulation of gastrointestinal tract. If the abnormally accelerated degradation of GLP-1 in obesity is confirmed, selective DPP-IV inhibitors could actually represent an ideal approach to obesity management.

Alcohol addiction: evaluation of alcohol abstinence after a year of psycho-medical-social treatment.

The aim of this study was to evaluate alcohol abstinence in alcoholics and their family relationships after a year of treatment. The 100 alcoholics recruited were divided into two groups: ALC, where treatment consisted of clinical control and meetings of with the family consulting together with their relatives at the Centre for Study and Treatment of Alcoholism and CAT, where treatment consisted of clinical control and weekly attendance together with their relatives at Alcoholics-in-Treatment-Clubs (CAT). The clinical condition of the sample was assessed by laboratory data. The subjects were given an MQ-Quant questionnaire, based on an artificial neural network (ANN) model, which analyses the communicative fatigue of their interactions. The same examination was applied after 1 year excluding patients relapsed and their relatives. Psycho-medical-social treatment by the attendance of alcoholics and their families into a Multifamily Community induces alcohol abstinence of about 79%. This percentage is greater than psycho-medical treatment carried out in the Centre of Alcoholism for ALC group (50%). We observed a significant difference between the communicative fatigue of the ALC group compared to the CAT group.

Evidence for early impairment of glucagon-like peptide 1-induced insulin secretion in human type 2 (non insulin-dependent) diabetes.

UNLABELLED: To investigate a possible role of an enteroinsular axis involvement in the pathogenesis of type 2 diabetes, plasma glucagon-like peptide 1 (GLP-1) 7-36 amide response to nutrient ingestion was evaluated in type 2 diabetics affected by different degrees of beta-cell dysfunction. METHODS: 14 patients on oral hypoglycaemic treatment (group A: HbA1C = 8.1 +/- 1.8 %) and 11 age-matched diabetic patients on diet only (group B: HbA1C = 6.4 +/- 0.9) participated in the study. 10 healthy volunteers were studied as controls. In the postabsorptive state, a mixed meal (700 kCal) was administered to all subjects, and blood samples were regularly collected up to 180' for plasma glucose, insulin, glucagon, and GLP-1 determination. RESULTS: In the control group, the test meal induced a significant increase in plasma GLP-1 at 30' and 60' (p < 0.01); the peptide concentrations then returning toward basal levels. beta-cell function estimation by HOMA score confirmed a more advanced involvement in group A than in group B (p < 0.01). In contrast, the insulin resistance degree showed a similar result in the two groups (HOMA-R). In group A, first-phase postprandial insulin secretion (0 - 60') resulted, as expected, in being significantly reduced compared to healthy subjects (p < 0.001). In the same patients the mean fasting GLP-1 value was similar to controls, but the meal failed to increase plasma peptide levels, which even tended to decrease during the test (p < 0.01). In group B, food-mediated early insulin secretion was higher than in group A (p < 0.001), although significantly reduced when compared to controls (p < 0.01). Like group A, no GLP-1 response to food ingestion occurred in group B patients in spite of maintained basal peptide secretion. Whereas the test-meal did not significantly modify plasma glucagon levels in the control group, glucagon concentrations increased at 30' and 60' in both diabetic groups (p < 0.01). CONCLUSIONS: 1) The functional integrity of GLP-1 cells results as being seriously impaired even in the condition of mild diabetes; 2) the early peptide failure could contribute to the development of beta-cell deterioration which characterizes overt type 2 diabetes.

Urinary excretion of glucagon-like peptide 1 (GLP-1) 7-36 amide in human type 2 (non-insulin-dependent) diabetes mellitus.

The urinary excretion of insulinotropic glucagon-like peptide 1 (GLP-1) was investigated as an indicator of renal tubular integrity in 10 healthy subjects and in 3 groups of type 2 diabetic patients with different degrees of urinary albumin excretion rate. No significant difference emerged between the groups with respect to age of the patients, known duration of diabetes, metabolic control, BMI, or residual beta-cell pancreatic function. Endogenous creatinine clearance was significantly reduced under conditions of overt diabetic nephropathy, compared with normo and microalbuminuric patients (p < 0.01). Urinary excretion of GLP-1 was significantly higher in normoalbuminuric patients compared to controls (490.4 +/- 211.5 vs. 275.5 +/- 132.1 pg/min; p < 0.05), with further increase under incipient diabetic nephropathy conditions (648.6 +/- 305 pg/min; p < 0.01). No significant difference resulted, in contrast, between macroproteinuric patients and non-diabetic subjects. Taking all patients examined into account, a significant positive relationship emerged between urinary GLP-1 and creatinine clearance (p = 0.004). In conclusion, an early tubular impairment in type 2 diabetes would occur before the onset of glomerular permeability alterations. The tubular dysfunction seems to evolve with the development of persistent microalbuminuria. Finally, the advanced tubular involvement, in terms of urinary GLP1 excretion, under overt diabetic nephropathy conditions would be masked by severe concomitant glomerular damage with the coexistence of both alterations resulting in a peptide excretion similar to control subjects.

Detection of early abnormalities of left ventricular function by hemodynamic, echo-tissue Doppler imaging, and mitral Doppler flow techniques in patients with coronary artery disease and normal ejection fraction.

We have investigated the possibility of detecting early abnormalities of left ventricular function at the initial phase of ischemic cardiomyopathy. Sixteen normotensive patients with coronary artery disease and normal left ventricular ejection fraction and 6 control patients were studied by invasive hemodynamic techniques in combination with transmitral Doppler flow or with echo-tissue Doppler imaging. The extent of the percentage of left ventricular longitudinal shortening and the systolic peak velocity at echo-tissue Doppler were significantly higher in the control patients than in patients with ischemic cardiomyopathy (P <.01). Left ventricular end-diastolic pressure was higher (P <.05), whereas mean values of isovolumic contraction and relaxation indexes (dP/dt/P: P <.05; +dP/dt: P <.05; -dP/dt: P <.01) were lower in patients with ischemic cardiomyopathy. Tau was significantly longer in ischemic patients (42.7 +/- 8.8 versus 34.5 +/- 3.7 ms, P <.05). In the control patients, the aortic valve closure to peak E interval by transmitral Doppler flow was significantly longer than that measured by echo-tissue Doppler (P <.001), whereas in patients with ischemic cardiomyopathy, this interval difference was still present and significantly shorter (P <.05). In patients with coronary artery disease and normal ejection fraction, minor and early abnormalities of left ventricular function related to isovolumic contraction and relaxation as well as to longitudinal shortening could be detected. In addition, a suction-like effect, detected during early filling evaluation with echo-tissue Doppler, is significantly decreased but not abolished during the early stages of coronary artery disease.

Effect of nutrient ingestion on glucagon-like peptide 1 (7-36 amide) secretion in human type 1 and type 2 diabetes.

Exogenous glucagon-like peptide 1(GLP-1) bioactivity is preserved in type 2 diabetic patients, resulting the peptide administration in a near-normalization of plasma glucose mainly through its insulinotropic effect. GLP-1 also reduces meal-related insulin requirement in type 1 diabetic patients, suggesting an impairment of the entero-insular axis in both diabetic conditions. To investigate this metabolic dysfunction, we evaluated endogenous GLP-1 concentrations, both at fasting and in response to nutrient ingestion, in 16 type 1 diabetic patients (age = 40.5 +/- 14yr, HbA1C = 7.8 +/- 1.5%), 14 type 2 diabetics (age = 56.5 +/- 13yr, HbA1C = 8.1 +/- 1.8%), and 10 matched controls. In postabsorptive state, a mixed breakfast (230 KCal) was administered to all subjects and blood samples were collected for plasma glucose, insulin, C-peptide and GLP-1 determination during the following 3 hours. In normal subjects, the test meal induced a significant increase of GLP-1 (30', 60': p < 0.01), returning the peptide values towards basal concentrations. In type 2 diabetic patients, fasting plasma GLP-1 was similar to controls (102.1 +/- 1.9 vs. 97.3 +/- 4.01 pg/ml), but nutrient ingestion failed to increase plasma peptide levels, which even decreased during the test (p < 0.01). Similarly, no increase in postprandial GLP-1 occurred in type 1 diabetics, in spite of maintained basal peptide secretion (106.5 +/- 1.5 pg/ml). With respect to controls, the test meal induced in both diabetic groups a significant increase in plasma glucagon levels at 60' (p < 0.01). In conclusion, either in condition of insulin resistance or insulin deficiency chronic hyperglycemia, which is a common feature of both metabolic disorders, could induce a progressive desensitization of intestinal L-cells with consequent peptide failure response to specific stimulation.

Sodium sensitivity of blood pressure in long-term detoxified alcoholics.

To investigate whether sodium sensitivity of blood pressure participates in the relationship of arterial hypertension to chronic alcohol consumption, 30 alcoholics detoxified from 6 to 12 months and 30 teetotaler controls underwent a dietary sodium manipulation study. They received a daily 55 mmol sodium diet for 7 days, followed by a 260 mmol sodium diet for 7 days. Changes in 24-hour urinary sodium excretion between the end of each period were similar in alcoholics and controls (202+/-16 SEM mmol and 227+/-11, respectively). Plasma renin activity in alcoholics was lower than in controls at both low (2.4+/-0.4 ng angiotensin I/mLxh(-1) versus 3. 7+/-0.2, P<0.003) and high sodium intake (0.47+/-0.10 versus 0. 82+/-0.10, P<0.05), with smaller variations in alcoholics (-1.9+/-0. 3 versus -2.9+/-0.2, P<0.009). In alcoholics, alteration in sodium intake was followed by greater changes in both systolic and mean blood pressure (ambulatory blood pressure monitoring), which rose by 10.6+/-2.2 mm Hg and 7.3+/-1.5 versus 4.7+/-1.4 and 3.9+/-1.0 in controls, respectively (P<0.03 for systolic and P<0.05 for mean blood pressure). The ratio of changes in mean blood pressure to those in 24-hour urinary sodium excretion was higher in alcoholics (0.044+/- 0.011 mm Hgxmmol(-1) versus 0.018+/-0.0041, P<0.005). Our data show that in detoxified alcoholics, there is an abnormal response of both blood pressure and plasma renin activity to variations in salt intake similar to that in sodium-sensitive arterial hypertension. The precise relationship between the sodium sensitivity of blood pressure in detoxified alcoholics and the long-term influence of alcohol on blood pressure remains to be elucidated.

Comparison of fasting plasma leptin concentrations in healthy subjects with high and low plasma insulin.

This study was initiated to evaluate the role of hyperinsulinemia in the regulation of fasting plasma leptin. We measured plasma leptin and insulin concentrations in 404 healthy nondiabetic subjects. For analytical purposes, the population was divided into quartiles on the basis of the lowest (quartile 1) and highest (quartile 4) plasma insulin response to oral glucose, and fasting plasma leptin values in these 2 dichotomous groups were compared. The total plasma integrated insulin response was 4-fold greater in quartile 4, associated with significantly higher (P < .001) fasting plasma leptin (12.60+/-0.85 v8.53+/-0.56 ng/mL). Fasting plasma leptin concentrations remained significantly higher in the hyperinsulinemic quartile when comparisons were made after subdividing the population on the basis of gender, body mass index (BMI), or waist to hip ratio (WHR). These results demonstrate that fasting plasma leptin concentrations are significantly higher in hyperinsulinemic individuals, and this difference is independent of either overall or central obesity.

Comparison of the results of immunocytochemical assays for biologic variables on preoperative fine-needle aspirates and on surgical specimens of primary breast carcinomas.

BACKGROUND: Fine-needle aspiration biopsy (FNAB) is a well-documented procedure for the diagnosis and biologic characterization of breast carcinoma. In order to compare the immunocytochemical expression of biologic parameters on cytology and on histology, estrogen receptor (ER) and progesterone receptor (PgR) status, p53 protein expression, and Ki67 growth fraction were evaluated on presurgical fine-needle aspirates (FNAs) from breast carcinoma patients and on the corresponding surgical samples prior to any systemic therapy. METHODS: FNAs were performed on 104 patients with primary breast carcinoma at the time of diagnosis and subjected to immunocytochemical evaluation of ER, PgR, p53, and Ki67. The same parameters were immunohistochemically evaluated on the corresponding paraffin embedded sections. RESULTS: ER, PgR, p53, and Ki67 were evaluable on FNAs and on paired tissue sections in 100, 97, 68, and 84 cases, respectively. Concordance between cytology and histology was 89% for ER, 78% for PgR, 79% for p53, and 70% for Ki67. CONCLUSIONS: The concordance between the results of immunocytochemical evaluation of ER, PgR, p53, and Ki67, on both cytology and histology, underscores the reliability of the biologic characterization of breast carcinoma by FNAB. This approach could be particularly useful in predicting prognosis and response to treatment in patients who are candidates for neoadjuvant chemotherapy and/or endocrine therapy.

Hyperinsulinemia in a normal population as a predictor of non-insulin-dependent diabetes mellitus, hypertension, and coronary heart disease: the Barilla factory revisited.

The study was initiated to evaluate the ability of hyperinsulinemia (as a surrogate measure of insulin resistance) to predict the development in a previously healthy population of three putative outcomes of this abnormality--glucose intolerance, hypertension, and coronary heart disease (CHD). The study involved defining the incidence at which these changes occurred between 1981 and 1993 to 1996 in 647 individuals who were free of any disease when initially studied. The study population consisted of approximately 90% of the subjects evaluated in 1981, divided into quartiles on the basis of the plasma insulin response to a glucose challenge as determined in 1981. The results indicated that the 25% of the population with the highest insulin response in 1981 had significant (P < .001) increases in the incidence of impaired glucose tolerance (IGT) or type 2 diabetes (eightfold), hypertension (twofold), or CHD (threefold). Furthermore, the ability of hyperinsulinemia to predict the three clinical endpoints was independent of differences in age, gender, or body mass index (BMI). Finally, if CHD is considered the clinical endpoint, multiple logistic regression analysis indicates that the values for plasma triglyceride (TG) and mean arterial blood pressure ([MAP] as measured in 1981) also predict the development of CHD. These results indicate that the untoward clinical effects of insulin resistance and/or compensatory hyperinsulinemia, glucose intolerance, hypertension, and CHD clearly can develop in less than 15 years.

Patients' opinions, feelings, and attitudes after a campaign to promote the Di Bella therapy.

BACKGROUND: An emotional campaign promoting the Di Bella cancer therapy was launched by the Italian media in 1997. Its effects on patients' hopes, feelings, and decision-making processes were largely unknown. We undertook an investigation of this issue. METHODS: Between Feb 25 and March 31, 1998, a ten-item questionnaire was distributed to 1300 unselected adult patients attending 13 cancer centres throughout Italy. Four expert psycho-oncologists reviewed the design and validity of the contents of the questionnaire. Sociodemographic information was also collected. FINDINGS: 1120 (86%) questionnaires were returned and analysed. The main sources of information were television/radio (62%) and newspapers (26%); only 5% cited doctors. The campaign induced optimism in the patients about the efficacy of the method (ineffective 1%, effective 42%, uncertain 57%), and 53% said their hope of cure was increased. However, 48% felt more confused. 24% do not discuss new treatments with their oncologists, and 20% would like to but cannot. When choosing a treatment, the advice of a trusted doctor was judged more important than scientific progress (53% vs 32%) and 63% would try even unproven treatments in the hope of a cure. Replies to many of the questions were influenced by patients' educational attainment and by the degree of communication with their oncologists. INTERPRETATION: Science cannot prevent the harm caused by such campaigns and their psychological consequences, particularly for less educated patients. When making decisions, patients are looking for hope from the treatment and trust in their doctor, both of which depend on effective doctor-patient communications that therefore need to be improved.

Can weight gain in healthy, nonobese volunteers be predicted by differences in baseline plasma insulin concentration?

In this study, we have evaluated the effect, over approximately 14 yr, of differences in baseline degree of hyperinsulinemia on weight gain in 647 healthy, nonobese factory workers. The subjects were divided into 4 quartiles, on the basis of their plasma insulin response to an oral glucose challenge, in 1981. At that time, the mean (+/-SD) plasma insulin concentration, 2 h after the glucose challenge, varied from 18+/-5 to 106+/-42 microU/mL. Despite this approximate 6-fold difference in plasma insulin response at baseline, the weight gain over the period of observation was similar in all quartiles, with mean (+/-SD) increments (kg) of 1.8+/-5.1, 1.6+/-5.3, 2.3+/-5.2, and 2.3+/-5.7, going from the lowest quartile to the highest quartile, in terms of insulin concentration. Furthermore, when the population was considered as a whole, there was no correlation between baseline degree of hyperinsulinemia and change in either absolute (r = 0.004) or percent (r = 0.003) weight gain. Finally, there was no difference in the number of individuals who gained more than 4.5 kg, as a function of their baseline insulin response. Consequently, we conclude that 6-fold differences in plasma insulin responses to glucose do not predict weight gain in a healthy, nonobese population.

[Lipids in enteral nutrition: does an optimal ratio between omega-6 and omega-3 exist?]. / I lipidi in nutrizione enterale: esiste un rapporto ottimale omega-6/omega-3?

The ratio between PUFA omega-6 and omega-3 is 3:1 in the unweaned, 5:1 in the young man, 5-10:1 in the adult. The PUFA omega-6 prevail over omega-3 because of elongation and desaturation processes. Linoleic acid is the beginning of the omega-6 series, a-linolenic acid of the omega-3 series. Both acids give rise to PUFA which must be introduced with diet because the human race is not able to synthetize. They represent the 2-6% of total daily caloric intake and correspond about to 10 g every day according to LARN 1986-1987. During some diseases (after surgery, trauma, sepsis, etc.) their need increases until 25-50 g every day, so it is necessary a proper enteral nutrition (EN). For this reason the bromatological composition of diets for EN must respect the physiological ratio between omega-6 and omega-3 PUFA. The composition of 37 diets for EN was examined and it was found that 7 (18%) have a proper ratio between the two series of PUFA. Twenty-three (62%) do not signal any ratio, two have 6:1, two 4.5:1, in three the ratio is in favour of omega-3. Then the concentration of linoleic and alfa-linolenic acid was examined and it was found that 24 (64%) diets signal the concentration of linoleic acid, 10 (27%) of both acids, two have no data about and only one diet reports the concentration of alfa-linolenic acid. A more exact formulation of PUFA into the composition of EN diets is suggested because PUFA are now recognized to play an important role in the fields of inflammation and immunity.

Dipyridamole-induced ischemia as a prognostic marker of future adverse cardiac events in adult patients with hypertrophic cardiomyopathy. Echo Persantine Italian Cooperative (EPIC) Study Group, Subproject Hypertrophic Cardiomyopathy.

BACKGROUND: Myocardial ischemia may play a role in the natural history of hypertrophic cardiomyopathy (HCM). To assess the relative prevalence and the prognostic value of dipyridamole-induced ischemia, 79 patients with HCM and without concomitant coronary artery disease (53 men; mean age, 46+/-15 years) underwent a high-dose (up to 0.84 mg/kg over 10 minutes) dipyridamole test with 12-lead ECG and two-dimensional echo monitoring and were followed up for a mean of 6 years. METHODS AND RESULTS: Twenty-nine patients (37%) showed ECG (ie, ST depression > or = 2 mV) signs of myocardial ischemia during dipyridamole test (group 1), whereas 50 (63%) had a negative test (group 2). No patient had transient wall motion abnormalities during the dipyridamole test. During the follow-up, 16 events (ie, left ventricular or atrial enlargement, unstable angina, syncope, atrial fibrillation, and bundle-branch block) occurred in 29 patients in group 1 and 5 in 50 patients in group 2 (55% versus 10%, P<.001). Patients with a positive dipyridamole test showed worse 72-month event-free survival rates compared with patients with a negative test (36.2% versus 84.2%, P<.001). A forward stepwise event-free survival analysis identified dipyridamole test positivity by ECG criteria (chi2=19.7, P=.0001), rest gradient (chi2=11.3, P=.0008), and age (chi2=4.1; P=.0413) as independent and additive predictors of subsequent events. CONCLUSIONS: ECG signs of myocardial ischemia elicited by dipyridamole are frequent in patients with HCM and identify patients at higher risk of cardiac events, suggesting a potentially important pathogenetic role of inducible myocardial ischemia in determining adverse cardiac events in these patients.