Metabotropic Glutamate Receptors Modulate Exocytotic Tau Release and Propagation.

Using synaptosomes purified from the brains of two transgenic mouse models overexpressing mutated human tau (TgP301S and Tg4510) and brains of patients with sporadic Alzheimer's disease, we showed that aggregated and hyperphosphorylated tau was both present in purified synaptosomes and released in a calcium- and synaptosome-associated protein of 25 kDa (SNAP25)-dependent manner. In all mouse and human synaptosomal preparations, tau release was inhibited by the selective metabotropic glutamate receptor 2/3 (mGluR2/3) agonist LY379268, an effect prevented by the selective mGlu2/3 antagonist LY341495. LY379268 was also able to block pathologic tau propagation between primary neurons in an in vitro microfluidic cellular model. These novel results are transformational for our understanding of the molecular mechanisms mediating tau release and propagation at synaptic terminals in Alzheimer's disease and suggest that these processes could be inhibited therapeutically by the selective activation of presynaptic G protein-coupled receptors. SIGNIFICANCE STATEMENT: Pathological tau release and propagation are key neuropathological events underlying cognitive decline in Alzheimer's disease patients. This paper describes the role of regulated exocytosis, and the soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) protein SNAP25, in mediating tau release from rodent and human synaptosomes. This paper also shows that a selective mGluR2/3 agonist is highly effective in blocking tau release from synaptosomes and tau propagation between neurons, opening the way to the discovery of novel therapeutic approaches to this devastating disease.

Investigation of Variations in the Human Urine Metabolome amongst European Populations: An Exploratory Search for Biomarkers of People at Risk-of-Poverty.

SCOPE: According to Eurostat 2016, approximately 119 million European citizens live at-risk-of-poverty (ROP). This subpopulation is highly diverse by ethnicity, age, and culture in the different EU states, but they all have in common a low income that could represent an increased risk of nutrient deficiencies due to poor nutritional habits. This study aims to investigate the human urine metabolome in the search of common biomarkers representing dietary deficiencies amongst European populations at ROP. METHODS AND RESULTS: 2732 urine samples were collected from 1391 subjects across five different European countries, including the United Kingdom, Finland, Italy, Lithuania, and Serbia, and analyzed using 1 H-NMR spectroscopy. The resulting urine metabolome data were explored according to study design factors including economic status, country, and gender. CONCLUSION: Partitioning of the effects derived from the study design factors using ANOVA-simultaneous component analysis (ASCA) revealed that country and gender effects were responsible for most of the systematic variation. The effect of economic status was, as expected, much weaker than country and gender, but more pronounced in Lithuania than in other countries. Citrate and hippurate were among the most powerful ROP biomarkers. The possible relationship between these markers and nutritional deficiencies amongst the ROP population is discussed.

Identification and pharmacological profile of SPP1, a potent, functionally selective and brain penetrant agonist at muscarinic M1 receptors.

BACKGROUND AND PURPOSE: We aimed to identify and develop novel, selective muscarinic M1 receptor agonists as potential therapeutic agents for the symptomatic treatment of Alzheimer's disease. EXPERIMENTAL APPROACH: We developed and utilized a novel M1 receptor occupancy assay to drive a structure activity relationship in a relevant brain region while simultaneously tracking drug levels in plasma and brain to optimize for central penetration. Functional activity was tracked in relevant native in vitro assays allowing translational (rat-human) benchmarking of structure-activity relationship molecules to clinical comparators. KEY RESULTS: Using this paradigm, we identified a series of M1 receptor selective molecules displaying desirable in vitro and in vivo properties and optimized key features, such as central penetration while maintaining selectivity and a partial agonist profile. From these compounds, we selected spiropiperidine 1 (SPP1). In vitro, SPP1 is a potent, partial agonist of cortical and hippocampal M1 receptors with activity conserved across species. SPP1 displays high functional selectivity for M1 receptors over native M2 and M3 receptor anti-targets and over a panel of other targets. Assessment of central target engagement by receptor occupancy reveals SPP1 significantly and dose-dependently occupies rodent cortical M1 receptors. CONCLUSIONS AND IMPLICATIONS: We report the discovery of SPP1, a novel, functionally selective, brain penetrant partial orthosteric agonist at M1 receptors, identified by a novel receptor occupancy assay. SPP1 is amenable to in vitro and in vivo study and provides a valuable research tool to further probe the role of M1 receptors in physiology and disease.

[Diet and gut microbiota: two sides of the same coin?] / Dieta e microbiota intestinale: due facce di una stessa medaglia?

Gut microbiota is a complex ecosystem, resident in the digestive tract, exerting multiple functions that can have a significant impact on the pathophysiology of the host organism. The composition and functions of this "superorganism" are influenced by many factors, and among them, the host's dietary habits seem to have a significant effect. Dietary changes in the evolution of human history and in the different stages of life of the human subjects are responsible for qualitative and functional modification of gut microbiota. At the same time, the different dietary models adopted in worldwide geographic areas take into account the inter-individual differences concerning composition and microbial function. This close relationship between diet, gut microbiota and host seems, in fact, to be responsible for the protection or predisposition to develop several metabolic, immunological, neoplastic and functional diseases. Thus, several studies have evaluated the impact of diet and lifestyle modification strategies on gut microbiota composition and functions which, in turn, seems to affect the effectiveness of such therapeutic measures. Gut microbiota manipulation strategies, as complementary to dietary modifications, represent a fascinating field of research, even if consolidated data are still lacking.

In vitro pharmacological and rat pharmacokinetic characterization of LY3020371, a potent and selective mGlu2/3 receptor antagonist.

Metabotropic glutamate 2/3 (mGlu2/3) receptors are of considerable interest owing to their role in modulating glutamate transmission via presynaptic, postsynaptic and glial mechanisms. As part of our ongoing efforts to identify novel ligands for these receptors, we have discovered (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid; (LY3020371), a potent and selective orthosteric mGlu2/3 receptor antagonist. In this account, we characterize the effects of LY3020371 in membranes and cells expressing human recombinant mGlu receptor subtypes as well as in native rodent and human brain tissue preparations, providing important translational information for this molecule. In membranes from cells expressing recombinant human mGlu2 and mGlu3 receptor subtypes, LY3020371.HCl competitively displaced binding of the mGlu2/3 agonist ligand [3H]-459477 with high affinity (hmGlu2 Ki = 5.26 nM; hmGlu3 Ki = 2.50 nM). In cells expressing hmGlu2 receptors, LY3020371.HCl potently blocked mGlu2/3 agonist (DCG-IV)-inhibited, forskolin-stimulated cAMP formation (IC50 = 16.2 nM), an effect that was similarly observed in hmGlu3-expressing cells (IC50 = 6.21 nM). Evaluation of LY3020371 in cells expressing the other human mGlu receptor subtypes revealed high mGlu2/3 receptor selectivity. In rat native tissue assays, LY3020371 demonstrated effective displacement of [3H]-459477 from frontal cortical membranes (Ki = 33 nM), and functional antagonist activity in cortical synaptosomes measuring both the reversal of agonist-suppressed second messenger production (IC50 = 29 nM) and agonist-inhibited, K+-evoked glutamate release (IC50 = 86 nM). Antagonism was fully recapitulated in both primary cultured cortical neurons where LY3020371 blocked agonist-suppressed spontaneous Ca2+ oscillations (IC50 = 34 nM) and in an intact hippocampal slice preparation (IC50 = 46 nM). Functional antagonist activity was similarly demonstrated in synaptosomes prepared from epileptic human cortical or hippocampal tissues, suggesting a translation of the mGlu2/3 antagonist pharmacology from rat to human. Intravenous dosing of LY3020371 in rats led to cerebrospinal fluid drug levels that are expected to effectively block mGlu2/3 receptors in vivo. Taken together, these results establish LY3020371 as an important new pharmacological tool for studying mGlu2/3 receptors in vitro and in vivo. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.

Forebrain-selective AMPA-receptor antagonism guided by TARP γ-8 as an antiepileptic mechanism.

Pharmacological manipulation of specific neural circuits to optimize therapeutic index is an unrealized goal in neurology and psychiatry. AMPA receptors are important for excitatory synaptic transmission, and their antagonists are antiepileptic. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment. We hypothesized that blockade of forebrain AMPA receptors without blocking cerebellar AMPA receptors would be antiepileptic and devoid of motor impairment. Taking advantage of an AMPA receptor auxiliary protein, TARP γ-8, which is selectively expressed in the forebrain and modulates the pharmacological properties of AMPA receptors, we discovered that LY3130481 selectively antagonized recombinant and native AMPA receptors containing γ-8, but not γ-2 (cerebellum) or other TARP members. Two amino acid residues unique to γ-8 determined this selectivity. We also observed antagonism of AMPA receptors expressed in hippocampal, but not cerebellar, tissue from an patient with epilepsy. Corresponding to this selective activity, LY3130481 prevented multiple seizure types in rats and mice and without motor side effects. These findings demonstrate the first rationally discovered molecule targeting specific neural circuitries for therapeutic advantage.

Activation of Muscarinic M1 Acetylcholine Receptors Induces Long-Term Potentiation in the Hippocampus.

Muscarinic M1 acetylcholine receptors (M1Rs) are highly expressed in the hippocampus, and their inhibition or ablation disrupts the encoding of spatial memory. It has been hypothesized that the principal mechanism by which M1Rs influence spatial memory is by the regulation of hippocampal synaptic plasticity. Here, we use a combination of recently developed, well characterized, selective M1R agonists and M1R knock-out mice to define the roles of M1Rs in the regulation of hippocampal neuronal and synaptic function. We confirm that M1R activation increases input resistance and depolarizes hippocampal CA1 pyramidal neurons and show that this profoundly increases excitatory postsynaptic potential-spike coupling. Consistent with a critical role for M1Rs in synaptic plasticity, we now show that M1R activation produces a robust potentiation of glutamatergic synaptic transmission onto CA1 pyramidal neurons that has all the hallmarks of long-term potentiation (LTP): The potentiation requires NMDA receptor activity and bi-directionally occludes with synaptically induced LTP. Thus, we describe synergistic mechanisms by which acetylcholine acting through M1Rs excites CA1 pyramidal neurons and induces LTP, to profoundly increase activation of CA1 pyramidal neurons. These features are predicted to make a major contribution to the pro-cognitive effects of cholinergic transmission in rodents and humans.

Adverse Food Reaction and Functional Gastrointestinal Disorders: Role of the Dietetic Approach.

Bloating, abdominal discomfort or pain, disturbed bowel habits are very common symptoms, frequently reported by the patients soon after food ingestion. These symptoms may occur in different clinical conditions, such as functional bowel disorders, food adverse reactions, gluten-related syndromes, which frequently are interrelated. Consequently, in clinical practice, it is necessary to perform a correct diagnosis in order to identify, for the single patient, the most appropriate therapeutic strategy, which may include not only specific drugs, but also, and mainly, life style changes (healthy nutritional behavior and constant physical activity). The aim of this review is to provide to the general physician, according to the available evidence, the most appropriate diagnostic work-ups for recognizing the different clinical scenarios (i.e. food allergy and intolerance, functional bowel diseases, gluten-related syndromes), to identify their clinical interrelationships and to suggest the most appropriate management. In fact, as far as food intolerances are concerned, it is well known that the number of patients who believe that their symptoms are related to food intolerance is increasing and consequently they restrict their diet, possibly causing nutritional deficiencies. Furthermore, there is an increasing use of unconventional diagnostic tests for food intolerance which lack accurate scientific evidence; the application of their results may induce misdiagnosis and unhealthy therapeutic choices. Consequently the recognition of food intolerance has to be performed on the basis of reliable tests within an agreed diagnostic workup.

Non-invasive diagnostic approach to non-alcoholic fatty liver disease: current evidence and future perspectives.

Non-alcoholic fatty liver disease is a new epidemic liver disease, thus, its early diagnosis and the identification of those patients with the worst prognosis is mandatory. Liver biopsy is still the diagnostic gold standard, even if it is associated to a significant rate of complications; moreover, the interpretation of histological samples is not always univocal. Several non-invasive alternative scores have been proposed for the diagnostic approach to non-alcoholic fatty liver disease. This article evaluates the performance of the currently available non-invasive diagnostic strategies. The authors also suggest a potential diagnostic algorithm, with two or more non-invasive techniques, to increase the overall accuracy for identifying patients with worst prognosis, and to minimize the recourse to liver biopsy.

Dietary habits and their relationship with hormones and metabolism in overweight and obese women with polycystic ovary syndrome.

OBJECTIVE: This study investigates energy intake, macronutrient composition and habitual food choices in overweight/obese women with polycystic ovary syndrome (PCOS) and controls similar for age and body mass index (BMI), and their relationship with hormonal and metabolic parameters. DESIGN: Case-control study carried out in an academic hospital in Bologna, Italy. PATIENTS: One-hundred obese or overweight (BMI >25 kg/m(2) ) women with PCOS, diagnosed according to Rotterdam criteria, and 100 age- and BMI-matched controls. MEASUREMENTS: Dietary habits were investigated by means of the 7 days food diary. Fasting hormones and metabolic parameters were investigated in all subjects. RESULTS: We showed that diet does not differ between the two groups as regards energy, macronutrient and advanced glycosylated end product intake, except for a lower percentage of energy from lipids and a higher intake of fibres by PCOS women. PCOS women were characterized by a higher consumption of cheese and high-glycaemic index starchy sweets and a preference for raw oil rather than other cooked fats, compared to controls. The PCOS or control status influenced some of the relationships between dietary components, food choices and metabolic parameters, particularly insulin(AUC) and HDL-cholesterol. CONCLUSIONS: This study did not find major differences in dietary habits between PCOS and normoandrogenic control women. Our findings support the hypothesis that specific foods may influence metabolic and hormonal pattern and that this relationship may be differently regulated in PCOS and normoandrogenic women; however, they give little support to the hypothesis of a strong dependence of PCOS status on nutritional factors.

Plasma antioxidant enzymes and clastogenic factors as possible biomarkers of colorectal cancer risk.

Oxidative damage plays an important role in the pathogenesis of colorectal (CR) cancer. This study investigated the activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and glutathione-S-transferase (GST) in plasma of 82 participants of a screening program for CR cancer prevention (30 females and 52 males; age 50-70 years). All subjects resulted positive to fecal occult blood test and were subsequently classified, according to the colonoscopy and histological findings, in patients with CR cancer, patients with colorectal polyps or controls. Furthermore, the activity of clastogenic factors (CFs) in plasma from study population was measured as the ability of inducing micronuclei (MN) in vitro in peripheral of a healthy donor. CAT and GR activities were significantly lower in CR cancer patients compared to controls (P<0.05) and polyps groups (P<0.05). SOD activity was significantly higher in patients with CR cancer than in polyp (P<0.05) and control (P<0.05) groups. GST activity was not significantly different in plasma of the three groups. An increase of CFs induction was observed in plasma of CR cancer patients (MN: 8.89±3.42) with respect to control (MN: 6.37±0.96 P<0.05). These results can contribute to define plasma biomarkers associated to oxidative stress damage that could predictive of CR cancer risk.

Cortisol, energy intake, and food frequency in overweight/obese women.

OBJECTIVE: This retrospective study investigated the relation between daily urinary free cortisol excretion rate, as a marker of cortisol production rate, to daily caloric intake, food choice, body mass index (BMI), and waist circumference. METHODS: One hundred twenty-seven overweight/obese women and 21 normal-weight subjects were enrolled in the study. Fasting blood samples for metabolic parameters were taken from each subject, followed by an oral glucose tolerance test. Cortisol excretion rate was assessed on 24-h urine collection (UFC/24 h). In obese patients, the daily caloric intake was calculated, and a weekly food-frequency questionnaire was assessed. Analysis of variance was used to assess the differences between groups. The relations between parameters were investigated by simple and multiple regressions. RESULTS: Obese women had significantly higher UFC/24 h than the normal-weight women (P < 0.001). The obese subjects had an unbalanced diet, particularly rich in saturated lipids, and weekly food choice showed a preference for highly caloric foods. UFC/24 h values and waist circumference were significantly correlated (P < 0.001), regardless of BMI. In the obese group, after adjustment for BMI, the UFC/24 h values were also significantly and positively correlated to daily carbohydrate and lipid intake and to weekly starchy food consumption. CONCLUSION: We demonstrated a significant association between higher UFC/24 h and energy intake, fats, and consumption of starchy foods, and that these relations were independent of BMI.

Body weight, lifestyle, dietary habits and gastroesophageal reflux disease.

While lifestyle modifications are currently used as first-line treatment for subjects with gastroesophageal reflux disease (GERD), the pathogenetic role of lifestyle factors and consequently, the efficacy of lifestyle measures is controversial. Our aim was to systematically review the pathogenetic link between overweight/obesity, dietary habits, physical activity and GERD, and the beneficial effect of specific recommended changes, by means of the available literature from the 1999 to the present. Obesity, in particular, abdominal obesity, plays a key role in determining GERD symptoms and complications through mechanical and metabolic effects. Controlled weight loss (by diet or surgery) is effective in improving GERD symptoms. No definitive data exist regarding the role of diet and, in particular, of specific foods or drinks, in influencing GERD clinical manifestations. Moderate physical activity seems to be beneficial for GERD, while vigorous activity may be dangerous in predisposed individuals. In conclusion, being obese/overweight and GERD-specific symptoms and endoscopic features are related, and weight loss significantly improves GERD clinical-endoscopic manifestations. The role of dietary behavior, mainly in terms of specific dietary components, remains controversial. Mild routine physical activity in association with diet modifications, i.e. a diet rich in fiber and low in fat, is advisable in preventing reflux symptoms.

Stress-related development of obesity and cortisol in women.

Chronic exposure to environmental stress may play a role in the development of obesity, through hyperactivation of the hypothalamic-pituitary-adrenocortical (HPA) axis. This study investigated the dynamics of weight gain and the activity of the HPA axis in women who developed weight gain after a stressful event. This is a case-control retrospective study. Two groups of age-matched premenopausal women were selected. One (n = 14) included women characterized by a rapid weight gain following a stressful event, defined as the "stress-related obesity " (SRO) group, and the other (n = 21) women with nonstress-related development of obesity, defined as the "nonstress-related obesity " (NSRO) group. Twenty-one healthy premenopausal women served as normal-weight controls. Baseline hormonal and metabolic parameters, and 24-h urinary free cortisol (UFC/24 h) excretion rate (as a measure of HPA-axis activity) were measured in all women. Anthropometry, diet, and physical activity were similar in both obese groups. Both obese groups showed similar metabolic and hormonal profiles, but the SRO group had UFC/24 h values (41.1 +/- 14.3 microg) significantly higher (P < 0.001) with respect to the NSRO (26.6 +/- 17.6 microg) or the normal-weight control groups (21.1 +/- 9.8 microg). Moreover, time (years) to achieve maximum Deltaweight gain (kg) and the Deltaweight gain/time ratio were significantly shorter (P < 0.001) and higher (P < 0.001) in the SRO group with respect to the NSRO group, respectively. In the SRO group, there was a tendency to a significant correlation between UFC/24 h and the Deltaweight gain/time ratio. These findings support the concept that SRO has distinct pathophysiological mechanisms, including hyperactivity of the HPA axis.

Is the Mediterranean lifestyle still a reality? Evaluation of food consumption and energy expenditure in Italian and Spanish university students.

OBJECTIVE: To evaluate the correspondence of diet and lifestyle to the Mediterranean model in two groups of Italian and Spanish university students. DESIGN: A cross-sectional nutritional survey to determine BMI, dietary habits (FFQ), energy daily expenditure and lifestyle (SenseWear Armband; BodyMedia Inc.), and to define the Mediterranean diet quality index (MDQI) in the different student groups. SETTING: Bologna (Italy) and León (Spain). SUBJECTS: The survey was carried out on 210 (105 Italian; 105 Spanish) university students (mean age 27.0 (sd 3.8) years) of two different Mediterranean areas, Bologna (Italy) and León (Spain). RESULTS: The frequency of consumption of some food groups showed differences related to nationality and gender. Some classic Mediterranean foods such as cereals and vegetables were generally consumed more frequently by Italian students; others such as fish and pulses by Spanish students. Percentage of overweight was higher among Spanish students in spite of their higher physical activity level. CONCLUSION: Young generations seem to give up the traditional Mediterranean dietary pattern, adopting new dietary trends. Overweight appears to be related not only to physical activity level, but also to the poor MDQI.

Dietary Selenium for the counteraction of oxidative damage: fortified foods or supplements?

Since any significant modification in the Se status, leading to changes in the activity of the seleno-enzymes, may have important consequences on the susceptibility of tissues to oxidative stress, considerable efforts have been made upon increasing Se dietary intake. In this respect, an important debate is still open about the bioavailability and the effectiveness of Se, and more generally nutrients, in supplements compared with foods. Using male Wistar rats, we have compared the effectiveness of two different diets in which an adequate Se content (0.1 mg/kg) was achieved by adding the element as sodium selenite or as component of a lyophilized Se-enriched food, in the counteraction of an oxidative stress induced by intraperitoneal administration of adriamycin. Both Se-enriched diets were able to reduce the consequences of the oxidative stress in liver, mainly by increasing glutathione peroxidase activity. This increase was more evident in rats fed on the diet enriched with the lyophilized food, probably due to the different chemical forms of Se, or to other components of the food itself. Although further studies are needed, data herein presented may contribute to the characterization of the effectiveness of Se from different sources, foods or supplements, in the light of dietary advice to the population concerning improvement of Se intake.

Circulating obestatin levels and the ghrelin/obestatin ratio in obese women.

OBJECTIVE: We measured blood levels of obestatin, total ghrelin, and the ghrelin/obestatin ratio and their relationship with anthropometric and metabolic parameters, adiponectin and insulin resistance, in overweight/obese and normal-weight women. DESIGN: Outpatients Unit of Endocrinology of the S Orsola-Malpighi Hospital of Bologna, Italy. METHODS: Fasting obestatin, ghrelin, adiponectin and lipid levels, fasting and glucose-stimulated oral glucose tolerance test insulin, and glucose levels were measured in 20 overweight/obese and 12 controls. The fasting ghrelin/obestatin ratio was calculated; the homeostasis model assessment-IR (HOMA-IR) and insulin sensitivity index (ISI(composite)) were calculated as indices of insulin resistance. RESULTS: Obese women had higher obestatin and lower ghrelin blood levels, and a lower ghrelin/obestatin ratio compared with controls. In all subjects, obestatin was significantly and positively correlated with total cholesterol and triglycerides, but not with ghrelin, anthropometric, and metabolic parameters. In the obese women, however, obestatin and ghrelin concentrations were positively correlated. By contrast, the ghrelin/obestatin ratio was significantly and negatively correlated with body mass index, waist, waist-to-hip ratio, fasting insulin, and HOMA-IR, and positively with ISI(composite) but not with adiponectin. None of these parameters were correlated with the ghrelin/obestatin ratio in the obese. CONCLUSIONS: Increased obestatin, decreased ghrelin levels, and a decreased ghrelin/obestatin ratio characterize obesity in women. This supports the hypothesis that the imbalance of ghrelin and obestatin may have a role in the pathophysiology of obesity. On the other hand, some relevant differences between our data on circulating levels of obestatin and the ghrelin/obestatin ratio in obese subjects and those reported in the few studies published so far imply that further research is needed.

[The educational offer of masters in middle manager for the health professions]. / L'offerta formativa dei master in funzioni di coordinamento per le frofessioni sanitarie.

BACKGROUND: In Italy recent legislation has been introduced regarding middle and top management roles in the health professions. Although universities have begun educational courses and health organizational models for coordination and management roles, unfortunately, there is still a lack of homogeneous and coordinated planning for putting the principles of legislation into practice correctly. MATERIALS AND METHODS: Investigation of these words in the main national searching motors: Masters, coordination, health professions. Statistic elaboration with the calculation of average and standard deviation. Graphs with histograms and maps. S.W.O.T. analysis. OUTCOMES: General and specific data, averages and standard deviations, concerning the principal Masters activated in the academic year 2005/2006, in terms of participants, territorial distribution, profits and expenses , as well as the general number of the students in each classroom. DISCUSSION: Comparative considerations were made between the data concerning the activation of Masters' courses and Specialist Degrees in the Health Professions and the question of how to develop a correct synergy between the managerial health professionals (Specialist Degree) and middle management professionals (Master). CONCLUSIONS: The S.W.O.T. analysis underlines the important innovations in development of an organizational culture within the National Health Service, the great variability in the distribution of Masters' Schools throughout Italy, the need to apply rational and organizational models that combine effectiveness and efficiency without disorientating the professionals and managers holding organizational roles.

Efficacy of long term cyclic administration of the poorly absorbed antibiotic Rifaximin in symptomatic, uncomplicated colonic diverticular disease.

AIM: To comparatively evaluate the long term efficacy of Rifaximin and dietary fibers in reducing symptoms and/or complication frequency in symptomatic, uncomplicated diverticular disease. METHODS: 307 patients (118 males, 189 females, age range: 40-80 years) were enrolled in the study and randomly assigned to: Rifaximin (400 mg bid for 7 d every month) plus dietary fiber supplementation (at least 20 gr/d) or dietary fiber supplementation alone. The study duration was 24 mo; both clinical examination and symptoms' questionnaire were performed every two months. RESULTS: Both treatments reduced symptom frequency, but Rifaximin at a greater extent, when compared to basal values. Symptomatic score declined during both treatments, but a greater reduction was evident in the Rifaximin group (6.4 +/- 2.8 and 6.2 +/- 2.6 at enrollment, P = NS, 1.0 +/- 0.7 and 2.4 +/- 1.7 after 24 mo, P < 0.001, respectively). Probability of symptom reduction was higher and complication frequency lower (Kaplan-Meyer method) in the Rifaximin group (P < 0.0001 and 0.028, respectively). CONCLUSION: In patients with symptomatic, uncomplicated diverticular disease, cyclic administration of Rifaximin plus dietary fiber supplementation is more effective in reducing both symptom and complication frequency than simple dietary fiber supplementation. Long term administration of the poorly absorbed antibiotic Rifaximin is safe and well tolerated by the patients, confirming the usefulness of this therapeutic strategy in the overall management of diverticular disease.

Dietary habits and related psychological and social factors: influence on the body weight of elementary school children.

This article studies the alimentary habits of children in relation to their body mass index (BMI) and food preferences, and to underline the influences of cultural and social aspects. The investigation tested 198 children (90 male and 108 female) from Cento (Ferrara), using food frequency questionnaires that were completed by the children. Subjects were subdivided into three groups based on their BMI--normal weight, overweight and underweight--taking into consideration their food frequency and preferences. The correlations between the BMI of children, mother's geographic origin and cultural level revealed differences between boys and girls. The variability of results does not allow precise correlations to be made between food frequency and children's weight, psychological and social aspects. Some incorrect dietary habits were revealed in the overweight and underweight groups. These could be controlled for and corrected by an alimentary education programme.