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Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF, For many neurodevelopmental disorder (NDD) risk genes, the significance for mutational burden is unestablished. Here, the authors sequence 125 candidate NDD genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations.

Objective. Problematic Social Media Use (PSMU) has an addictive potential for young users. The aim of this study was to show the prevalence of PSMU across Italian regions and its association with health complaints. Materials and methods. Data are gathered from the Italian 2018 Health Behaviour in School-aged Children survey using a representative sample of Italian adolescents aged 11, 13 and 15 years (50.6% males). Participants completed self-administered questionnaires assessing PSMU and health complaints. Results. PSMU affects 8.9% adolescents in Italy and the prevalence is quite consistent across regions. 13-year-olds girls showed the highest percentage of PSMU (13%). Problematic users of social media are more likely to report multiple somatic (OR = 1.84 [95% CI 1.82-1.85]) and psychological (OR = 2.60 [95% CI 2.58-2.63]) symptoms. Conclusions. PSMU represents a widespread problem in Italy. National prevention interventions are needed in order to promote a positive use of social media.

Objective. The aim is to describe dietary habits and their association with socio-demographic characteristics in a large nationally representative sample of Italian adolescents aged 11, 13 and 15 years. Materials and methods. Data from the 2018 Italian Health Behaviour in School-aged Children (HBSC) survey on 58,976 adolescents were analysed to determine eating habits. Logistic regression was used to investigate the association between incorrect dietary habits and potential predictors. Results. 38.3% of boys and 48.1% of girls skipped breakfast and 54.1% did not consume fruit and/or vegetables daily. 15.9% of boys and 11.3% of girls drank carbonated-sugary beverages at least once a day. Incorrect dietary habits were more common among boys, adolescents with lower socio-economic conditions, residents in Southern Italy and those spending more time watching TV. Italian adolescents were more likely to have incorrect dietary habits compared with those from most other countries involved in 2018 HBSC. Conclusions. Action is needed to improve dietary habits among adolescents.

Pancreatic amyloidosis and loss of α and β cells have been shown to occur in cats with diabetes mellitus, although the number of studies currently available is very limited. Furthermore, it is not known whether pancreatic islet inflammation is a common feature. The aims of the present study were to characterize islet lesions and to investigate whether diabetic cats have inflammation of the pancreatic islets. Samples of pancreas were collected postmortem from 37 diabetic and 20 control cats matched for age, sex, breed, and body weight. Histologic sections were stained with hematoxylin and eosin and Congo red; double labeled for insulin/CD3, insulin/CD20, insulin/myeloperoxidase, insulin/proliferating cell nuclear antigen, and glucagon/Ki67; and single labeled for amylin and Iba1. Mean insulin-positive cross-sectional area was approximately 65% lower in diabetic than control cats ( P = .009), while that of amylin and glucagon was similar. Surprisingly, amyloid deposition was similar between groups ( P = .408). Proliferation of insulin- and glucagon-positive cells and the number of neutrophils, macrophages, and T (CD3) and B (CD20) lymphocytes in the islets did not differ. The presence of T and B lymphocytes combined tended to be more frequent in diabetic cats ( n = 8 of 37; 21.6%) than control cats ( n = 1 of 20; 5.0%). The results confirm previous observations that loss of β cells but not α cells occurs in diabetic cats. Islet amyloidosis was present in diabetic cats but was not greater than in controls. A subset of diabetic cats had lymphocytic infiltration of the islets, which might be associated with β-cell loss.

Non-familial small bowel carcinomas are relatively rare and have a poor prognosis. Two small bowel carcinoma subsets may arise in distinct immune-inflammatory diseases (celiac disease and Crohn's disease) and have been recently suggested to differ in prognosis, celiac disease-associated carcinoma cases showing a better outcome, possibly due to their higher DNA microsatellite instability and tumor-infiltrating T lymphocytes. In this study, we investigated the histological structure (glandular vs diffuse/poorly cohesive, mixed or solid), cell phenotype (intestinal vs gastric/pancreatobiliary duct type) and Wnt signaling activation (beta-catenin and/or SOX-9 nuclear expression) in a series of 26 celiac disease-associated small bowel carcinoma, 25 Crohn's disease-associated small bowel carcinoma and 25 sporadic small bowel carcinoma cases, searching for new prognostic parameters. In addition, non-tumor mucosa of celiac and Crohn's disease patients was investigated for epithelial precursor changes (hyperplastic, metaplastic or dysplastic) to help clarify carcinoma histogenesis. When compared with non-glandular structure and non-intestinal phenotype, both glandular structure and intestinal phenotype were associated with a more favorable outcome at univariable or stage-and microsatellite instability/tumor-infiltrating lymphocyte-inclusive multivariable analysis. The prognostic power of histological structure was independent of the clinical groups while the non-intestinal phenotype, associated with poor outcome, was dominant among Crohn's disease-associated carcinoma. Both nuclear beta-catenin and SOX-9 were preferably expressed among celiac disease-associated carcinomas; however, they were devoid, per se, of prognostic value. We obtained findings supporting an origin of celiac disease-associated carcinoma in SOX-9-positive immature hyperplastic crypts, partly through flat beta-catenin-positive dysplasia, and of Crohn's disease-associated carcinoma in a metaplastic (gastric and/or pancreatobiliary-type) mucosa, often through dysplastic polypoid growths of metaplastic phenotype. In conclusion, despite their common origin in a chronically inflamed mucosa, celiac disease-associated and Crohn's disease-associated small bowel carcinomas differ substantially in histological structure, phenotype, microsatellite instability/tumor-infiltrating lymphocyte status, Wnt pathway activation, mucosal precursor lesions and prognosis.

The use of ozone in the treatment of peripheral vascular disease (PVD) is increasing. The purpose of this study was to evaluate the effect of ozone on haemoglobin oxygen affinity in Type-2 diabetic patients with PVD. Twenty diabetic patients presenting with PVD (Clinical stage II-IV according to Fontaine) and 20 non-diabetic healthy matched subjects were studied. In both groups, aliquots of blood were ozonised with mixtures of oxygen-ozone (O2-O3) to reach end-concentrations of 6.5, 13, 26 and 78 micrograms O3 per ml of substrate. At baseline, diabetic patients presented significantly lower haemoglobin oxygen affinity values but higher plasma levels of free haemoglobin and malonyldialdehyde (MDA) than controls. In both diabetic patients and controls, exposure of blood to ozone reduced haemoglobin oxygen affinity in an "all-or-none" fashion, without changing 2-3, diphosphoglycerate concentrations in erythrocytes. Both free haemoglobin and MDA concentrations showed significant, dose-dependent increases after blood ozonisation. Thus, ozone caused a significant increase in oxygen unloading of haemoglobin in both normal subjects and Type-2 diabetic patients with PVD.

For many years, clinical practice has consolidated the use of both hyperbaric oxygen and oxygen-ozone therapy in the treatment of peripheral occlusive arterial disease (POAD). We investigated the influence of these treatments on hemorrheologic parameters that play an important role in the pathogenesis and the clinical course of arteriosclerosis. Two groups of 15 patients suffering from POAD, assigned at random either to a cycle of HBO therapy or O2-O3 therapy, were evaluated for blood viscosity, erythrocyte filterability, hematocrit value, fibrinogen concentration, and thrombin time. The O2-O3 therapy caused a significant increase of erythrocyte filterability and a significant decrease of blood viscosity. By contrast, HBO therapy did not produce any significant change. The increase of lipid peri-oxidation, proved by raised malonyldialdehyde plasma levels, seems a likely mechanism involved in the hemorrheologic effects of O2-O3 therapy.

Blood samples from ten patients with clinically evident manifestations of atherosclerotic disease were used to evaluate in vitro the effects of exogenous glutathione (GSH) on platelet aggregation and on blood filtration and viscosity. In two groups, each of ten atherosclerotic patients, matched for sex, age, prevalent localization, duration and gravity of disease, the effects of GSH infusion (600 mg every day for seven days) on the haemocoagulative pattern, platelet aggregation and blood filtration and viscosity were evaluated in a double-blind, placebo cross-over trial. The GSH in vitro addition resulted in a significant increase in blood filtration and a significant decrease in blood viscosity and platelet aggregation. The venous GSH infusion both significantly decreased blood viscosity and increased blood filtration. Partial thromboplastin time was lengthened after GSH infusion even thought it remained in the normal range.

The increased and irregular post-maximal deflection of the two limbs of thromboelastographic traces has been variably interpreted by the Authors who utilize TEG as a global screening test for haemostasis evaluation. These thromboelastographic patterns have been attributed either to enhanced fibrinolytic activity or to raised clot's rectractility or even to incorrect technique. In our study, 1701 TEG's traces carried out in the last five years have been reviewed in order to evaluate the incidence of such patterns in both healthy subjects and in patients affected by different diseases. The data obtained show that such irregular post-maximal deflection's patterns are quite absence in healthy subjects while reaches a statistically significant incidence only in patients affected by diabetes mellitus, obesity or systemic hypertension. The results seem to suggest that the increased and irregular post-maximal TEG deflection is not a simply product of technique's mistake but may represent an useful index of some haemostatic alterations which need further studies.

The thromboelastographic pattern in chronic obstructive lung disease as compared to normal group during O2 administration was evaluated. The results stressed that the basal hypocoagulability of pathological subjects had become normal after O2 administration. No significant change in the group of normal subjects was observed.

The present study was undertaken to reevaluate the influence of somatostatin on platelet function in insulin-dependent diabetics and in normal subjects. In in vivo studies, nine insulin-requiring diabetics were infused with cyclic somatostatin (250 microgram/hour) for 120 minutes or with saline, in randomized order. This dose of somatostatin, sufficient to depress the basal concentrations of plasma glucose, glucagon and C-peptide, resulted in no significant change of platelet aggregation response to either ADP or collagen. By contrast, a progressive and significant reduction of platelet aggregation response to ADP was found during saline infusion. A similar pattern of response was seen in normal subjects. In all diabetics, but not in normals, somatostatin induced the appearance of circulating platelet aggregates. In in vitro studies, somatostatin augmented the aggregation response to epinephrine in both normals and diabetics. In conclusion, somatostatin counteracts the decrease of platelet aggregation response to ADP seen in saline studies, induces the appearance of platelet aggregates in diabetics and potentiates the aggregation response to epinephrine (in vitro) in both normals and diabetics. These actions of somatostatin suggest some aggregating capacity of the peptide in man.

In 9 subjects with peripheral vascular insufficiencies the AA. have studied the behaviour of the oxyhaemoglobin dissociation curve before and after pentoxyphilline infusion. After this drug no variations were observed as it regards MCHC, 2-3-DPG and so on; however a positive correlation was found between 2-3-DPG and the Hill number. These results suggest that 2-3-DPG may influence the Hill number (which is the expression of the gradient of the oxyhaemoglobin dissociation curve) and therefore may interfere with O2 transport.

Thirty patients who had curative surgery for sigmoid and rectal carcinoma were studied by immunoscintigraphy using a new monoclonal antibody: B72.3 radiolabeled with Iodine-131 (I-131) or Indium-111 (In-111). Results were compared with other conventional diagnostic procedures such as computed tomography, ultrasound, endoscopy, and tumor markers. Seven patients had local recurrences and/or distant metastases. Immunoscintigraphy identified all local recurrences (five cases) that were confirmed by CT and was able to localize three of five liver metastases (two false-negatives). Furthermore, immunoscintigraphy also recorded a false-positive. Preliminary use of B72.3 shows good potential for the evaluation and detection of neoplastic sites.

In an our previous study we studied the influence of O2 therapy administration on the thromboelastographic pattern of patients suffering from chronic obstructive lung disease. We showed that basal hypocoagulability of our patients became normal after O2 administration. In this study we refer the thromboelastographic pattern observed in patients suffering from the same disease before and after hyperventilation. We don't find any changes about total coagulability either in patients or in healthy subjects after hyperventilation. Therefore we suggest that the absence of any changes is due to PCO2 and pH variations that occur at the same time of PO2 modification during hyperventilation; PCO2 and pH variations may influence the haemoglobin oxygen affinity and annul the effect of the increase PO2 on the tissue oxygenation. We suppose that the increase of patients suffering from chronic obstructive lung disease, is due to decreased fibrinolysis or to increased production of prostacycline induced by hyperventilation.

The aim of the present study was to evaluate the role of the strict metabolic control achieved with the aid of an artificial pancreas (Biostator, Miles) on platelet functions in insulin-dependent diabetics (n = 20). Platelet aggregation responses to both ADP and collagen, as well as circulating platelet aggregates according to Wu and Hoak, were determined before and after 24 hours of complete metabolic control; as control group, 18 insulin-dependent diabetics were only monitored without attempts to normalize their blood glucose behaviour. A significant decrease in ADP induced aggregation (p less than 0.01) and circulating platelet aggregates (p less than 0.001) was observed in diabetics during the period of strict metabolic control. No changes were observed in the control group. The present data suggest that the increased platelet activity in diabetes is a consequence of the metabolic derangement of the disease.

Italy has participated in the Health Behaviour in School-aged Children (HBSC) study since 2000. These surveys collect data every four years on the well-being and health behaviour of boys and girls aged 11, 13 and 15. Until 2007, the coordination group of the University of Turin, Siena and Padua directly sent the questionnaires to each sampled school to collect the data. The sample of about 4500 students was nationally representative. In 2008 the HBSC became part of the project "Surveys on behavioral risks in children aged 6-17 years", coordinated by the National Institute of Health (ISS) and promoted by the Ministry of Health, in collaboration with the Ministry of Education, University and Research. For the first time, in 2010, the survey was conducted by health workers in collaboration with teachers in all regions with a representative sample, not just at the national level, but also at regional level. In the 2,504 sampled schools, 77,113 students (25,079 eleven-year-old, 26,048 thirteen-year-old and 25,986 fifteen-year-old) completed an anonymous questionnaire. Knowledge of the health-related behaviour of school-aged adolescents may help monitoring and enable policies for young people to be formulated and implemented.

Objectives: The long term effects of a low protein diet (LPD) on depressive symptoms and the quality of life in elderly Type 2 diabetic are unclear. Methods: 38 elderly Type 2 diabetic patients with CRD (Stage 3 - 4) were enrolled in the study. After 4 weeks on a normal protein diet regimen (NPD) providing 1.0 g/kg per day, all participants were assigned for 30 months, randomly, to a LPD (0.7 g/kg per day), either 7 days a week (LPD 7/7) or 6 days a week (LPD 6/7). Mini mental state examination (MMSE), activities daily living (ADL), cumulative illness severity (CIRS-IS), geriatric depression scale (GDS-15) and short-form healthy survey (SF-36) were evaluated every 3 months. Results: Before the LPD regimen creatinine clearance (CrCl), MMSE, ADL, CIRS-IS, GDS-15 and SF-36 were similar in both LPD 7/7 and LPD 6/7 groups. After 30 months, the mean GDS-15 increased significantly more in LPD 7/7 group than in LPD 6/7 group (p < 0.05). Both mean SF-36 MCS and SF-36 PCS were decreased significantly more in LPD 7/7 group than in LPD 6/7 group (p < 0.05). After 30 months, the decline in CrCl observed was similar in LPD 7/7 and LPD 6/7 groups (2.77 +/- 0.3 and 2.84 +/- 0.3 ml/min/year, respectively). Conclusion: In elderly Type 2 diabetic patients, long term effects of LPD 6/7 regimen in comparison to LPD 7/7 are associated with a similar decline in CrCl, but with decreased depressive symptoms and a better quality of life.

Postprandial hyperglycaemia is an independent predictor of cardiovascular risk. Increased blood viscosity has been considered a major cardiovascular risk factor and may play a role in the vascular complications of diabetes. The present study aimed to verify whether blood viscosity is altered by the increased postprandial hyperglycaemia in aged type 2 diabetic patients. The whole blood viscosity, haematocrit, fibrinogen, glucose, insulin, total cholesterol, and triglyceride plasma levels, heart rate, and systolic and diastolic blood pressures were measured in 15 aged patients affected by type 2 diabetes and 15 healthy age-matched individuals before and 60 and 120 min after a test meal (670 kcal energy intake). In the basal condition, in both healthy control individuals and diabetic patients, the whole blood viscosity at higher shear rate (450/s) was significantly correlated in a negative way with the index of insulin resistance (P < 0.05), and in a positive way with the haematocrit value (P < 0.05) and the platelet count (P < 0.01). After the test meal, the whole blood viscosity significantly decreased (P < 0.01 or less) in aged healthy individuals, whereas it remained unchanged in type 2 diabetic patients. In conclusion, the negative action of postprandial hyperglycaemia in diabetes does not occur via a measurable increase of blood viscosity during that period. The decrease of blood viscosity observed during the postprandial period in normal individuals, however, points to the occurrence of alterations in the regulation of the haemorheological equilibrium in the postprandial period in aged type 2 diabetic patients.

Background: Increased plasma levels of fibrinogen are been associated with an increased risk of cardiovascular accident. We aimed at verifying whether the changes of fibrinogen levels are associated with red blood cell (and/or hemoglobin) concentration. Methods: A group of 381 carefully selected healthy volunteers (219 male and 162 female), aged from 18 to 101 years, were enrolled in this study. Fasting blood samples were taken and all measurements (fibrinogen plasma level, whole blood viscosity, hemoglobin concentration, hematocrit value, red blood cell and white blood cell count, platelet count, glucose, total cholesterol and triglycerides plasma concentration, and C-reactive protein level) were obtained with standardized methodology using appropriate equipment, procedures, and controls. Results and Conclusions: In the male but not in the female group, plasma fibrinogen concentration inversely correlated with hemoglobin (P * 0.0001) and hematocrit value (P * 0.01). In a post hoc analysis, plasma fibrinogen level inversely correlated with hemoglobin in the subgroup of the 93 premenopausal women and directly correlated with age and inversely correlated with platelet count in the subgroup of the 69 postmenopausal women. Results of multiple regression analysis revealed that in all the subjects, except in the postmenopausal women, hemoglobin level is an independent predictor of fibrinogen plasma level. Considering the physiopathologic role of increased plasma fibrinogen concentration and the scarcity of pharmacologic approaches to decrease its level, these findings could be important in designing a preventive therapy of cardiovascular disease

This study aimed at evaluating whether increased availability of the natural precursor of nitric oxide, L-arginine, could influence systemic hemodynamic and rheologic parameters in humans and whether the effects of L-arginine are mediated by endogenous insulin. 10 healthy young subjects participated in the following studies: study I, infusion of L-arginine (1 g/min for 30 min); study II, infusion of L-arginine plus octreotide (25 microg as i.v. bolus + 0.5 microg/min) to block endogenous insulin and glucagon secretion, plus replacement of basal insulin and glucagon; study III, infusion of L-arginine plus octreotide plus basal glucagon plus an insulin infusion designed to mimic the insulin response of study I. L-Arginine infusion significantly reduced systolic (11+/-3, mean+/-SE) and diastolic (8+/-2 mmHg, P < 0.001) blood pressure, platelet aggregation (20+/-4%), and blood viscosity (1.6+/-0.2 centipois, P < 0.01), and increased leg blood flow (97+/-16 ml/min), heart rate, and plasma catecholamine levels (P < 0.01). In study II, plasma insulin levels remained suppressed at baseline; in this condition, the vascular responses to L-arginine were significantly reduced, except for plasma catecholamines which did not change significantly. In study III, the plasma insulin response to L-arginine was reestablished; this was associated with hemodynamic and rheologic changes following L-arginine not significantly different from those recorded in study I. These findings show that systemic infusion of L-arginine in healthy subjects induces vasodilation and inhibits platelet aggregation and blood viscosity. These effects are mediated, in part, by endogenous released insulin.

The purpose of the present study was to determine if opioid agonism (beta-endorphin) and antagonism (Naloxone) exert rheological and cardiovascular effects in normal humans and in patients with essential hypertension. Eight hypertensive patients were matched for age, sex, and body habitus (body mass index, waist to hip ratio) with eight normotensive healthy subjects. In all subjects, heart rate and blood pressure (continuous automatic recording), blood and plasma viscosity, fibrinogen, hematocrit, and platelet aggregation to ADP were evaluated during an infusion of human synthetic beta-endorphin (0.5 mg/h). On a different day and in randomized order, the subjects were submitted to another beta-endorphin infusion preceded by an i.v. naloxone bolus (5 mg in 5 min). beta-Endorphin and naloxone failed to significantly alter heart rate or blood pressure in both normotensive and hypertensive subjects. In hypertensive patients, beta-endorphin significantly increased blood viscosity and ADP-induced platelet aggregation, but only the former effect was naloxone-sensitive. In normotensive subjects, beta-endorphin caused a transient but significant decrease of platelet aggregation that was reversed by naloxone. These data suggest that beta-endorphin may play some role in the inhibitory control of platelet aggregation in normal subjects. An altered responsiveness of some rheological determinants to beta-endorphin seems to be present in human hypertension.

Late-life depression is one of the main health problems among elderly diabetic subjects. In addition, depression is a common psychopathological condition among renal failure patients and most of these patients follow a low protein diet regimen (LPD). However, the effects of LPD on depressive symptoms are unclear.In the present study, the effects of LPD regimen on depressive symptoms in elderly type 2 diabetic subjects with renal failure were investigated.Fifty-two young-old type 2 diabetic patients with renal failure were enrolled in the study. All participants after normal protein diet regimen providing 1.2g/kg per d were instructed to consume either a LPD providing 0.8 g/kg per d, 7 d a wk (LPD 7/7), or a LPD providing 0.8 g/kg per d 6 d a wk (LPD 6/7) randomly.Mean 15-item Geriatric Depression Scale (GDS-15) (2.0±0.6) and Beck Depression Inventory (BDI) (4.1±1.0), during normal protein diet regimen, significantly increased to (6.7±1.6) and (12.2±1.4), respectively, after LPD 7/7 (P0.05 versus normal protein diet). However, after LPD 6/7, mean GDS-15 and BDI significantly decreased to (4.4±1.5) and (6.7±1.6), respectively (P0.05 versus LPD 7/7).LPD 6/7 regimen significantly decreased depressive symptoms in young-old type 2 diabetic patients.

Objective. To evaluate the effect of acute hyperhomocysteinaemia with and without antioxidant vitamins pretreatment on coronary circulation and circulating chemokine levels. Design. Observer-blinded, randomized crossover study. Setting. This study was conducted at a university hospital and at a general hospital in Italy. Subjects. Sixteen healthy hospital staff volunteers (nine men, seven women), aged 26–40 years. Interventions. Subjects were given each three loads in random order at 1-week intervals: oral methionine, 100 mg kg−1 in fruit juice; the same methionine load immediately following ingestion of antioxidant vitamin E, 800 IU, and ascorbic acid, 1000 mg; and methionine-free fruit juice (placebo). Main outcome measures. Coronary flow velocity reserve (CFVR), assessed by noninvasive transthoracic Doppler echocardiography, blood pressure, heart rate, lipid and glucose, monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) parameters evaluated at baseline and 4 h following ingestion of the loads. Results. The oral methionine load increased plasma homocysteine from 12.8 ± 1.8 to 33.3 ± 3.4 μmol L−1 at 4 h (P

Hyperhomocysteinemia increases the risk of death in type 2 diabetic patients (1,2), although the causal relationship with regard to cardiovascular mortality still remains elusive. Acute elevations in circulating homocysteine levels have been shown to impair endothelial function in coronary microcirculation in normal subjects (3). The objective of the present study was to investigate the effect of acute hyperhomocysteinemia on coronary circulation in patients with type 2 diabetes. Coronary flow velocity reserve (CFVR) assessment by transthoracic Doppler echocardiography (TTDE) is a noninvasive method to evaluate coronary flow reserve and provides important information about coronary endothelial function (4). Twenty newly diagnosed (within 6 months of diagnosis) type 2 diabetic patients (14 men and 6 women, age 49 ± 8 years, BMI 26.1 ± 1.8 kg/m2) and 20 healthy control subjects, who were matched for age, sex, and BMI, volunteered for this study after informed written consent was obtained. All subjects (both patients and control subjects) were taking no medication or vitamin supplements, and the protocol was approved by the local ethics committee. The diabetic patients were normotensive, had cholesterol levels within normal ranges, and were free from both micro- and macro- …

In women, iron deficiency anemia-a result of chronic iron loss-is most common during the reproductive years because of physiologic demands such as menstrual blood losses and pregnancy. In other cases, iron deficiency anemia is generally attributed to occult gastrointestinal bleeding. Common causes of chronic gastrointestinal blood loss include erosive esophagitis, gastric and duodenal ulcers, vascular ectasias, colon adenomas, and cancers. Bleeding from the small intestine at sites beyond the duodenal bulb is uncommon. The lesions of the small intestine are responsible for approximately 4% of gastrointestinal bleeding [7]. In this report we describe a case of persistent iron deficiency anemia due to carcinoid tumor of the small intestine.

Twenty-seven subjects suffering from peripheral occlusive arterial disease (POAD, clinical stage II-III according to Fontaine) were enrolled in this study to evaluate the effect of oxygen-ozone therapy upon hemorheological parameters and hemoglobin-oxygen affinity in patients with POAD. All patients underwent a major ozonized autohemotransfusion consisting of the slow reinfusion of 100 ml of autologous blood, previously exposed to a O(2)-O(3) mixture in a glass box for 10 min. Whole blood viscosity, erythrocyte filterability, hematocrit, and fibrinogen levels were assessed at the basal time and 30 min after the reinfusion of ozonized blood. At the same time p50 standard (p50std) values (an indicator of hemoglobin-oxygen affinity) and plasma values of malonyl dialdehyde (MDA, an indicator of lipid peroxidation) were evaluated. At the baseline, patients had significantly higher ( p0.05- p0.001) whole blood viscosity, MDA, and p50std values and significantly lower blood filterability ( p0.01) as compared with 20 matched healthy volunteers (controls). Thirty minutes after the end of a major autohemotransfusion, whole blood viscosity significantly decreased ( p0.01). This was accompanied by a significant fall in plasma fibrinogen level ( p0.01) with no change in hematocrit. Blood filterability, MDA plasma level, and p50std values increased significantly at the same time ( p0.01- p0.005). The 2,3-DPG value did not change significantly. No significant changes occurred when the same patients received a non-ozonized autohemotransfusion (control test). In conclusion, ozonized autohemotransfusion may be useful to improve both the poor rheological properties of the blood and the oxygen delivery to tissues in patients suffering from POAD.

Objectives: Iloprost, an analogue of prostacy- clin, is often utilised in subjects with diabetes mellitus complicated by macroangiopathy. Methods: The eects of iloprost infusion on plasminogen activator inhibitor type-1 (PAI-1), glucometabolic con- trol and cardiovascular equilibrium in patients with type-2 diabetes mellitus and peripheral arterial occlusive disease were investigated. Thirteen (7 men/6 women) normal-weight, normotensive and non-smoker type-2 diabetic patients (63.8 3.4 years, mean SD) with peripheral arterial occlusive disease, stage-II according to Fontaine classi®cation, were enrolled. Eight (four men/four women) patients underwent three study de- signs, each separated by a 1-week interval: study I, in- fusion of iloprost (3 ng kgA1 minA1 for 5 h) for 1 day alone (short-term treatment); study II, infusion of saline (for 5 h) for 1 day (control treatment); study III, infu- sion of iloprost (3 ng kgA1 minA1 for 5 h) over a period of 28 days (long-term treatment). The remaining ®ve (three men/two women) patients underwent study IV only, infusion of saline over a period of 28 days (placebo treatment). Plasma levels of glucose, plasminogen, PAI-1 activity and ®brinogen, blood pressure and heart rate were determined in all studies, while plasma insulin levels, blood HbA1c, walking distance and Winsor index only in studies III and IV. Results: Both short- and long-term treatments with ilo- prost signi®cantly reduced PAI-1 activity (baseline vs end: 17.4 1.9 AU/ml vs 15.0 1.6 AU/ml, P < 0.02; 20.5 7.6 AU/ml vs 7.9 2.1 AU/ml, P < 0.002,respectively). Long-term treatment with iloprost signi®- cantly increased walking distance (baseline vs end: 32541m vs 49652m, P

OBJECTIVE To compare the effects of the ACE inhibitor perindopril and the β-blocker carvedilol on blood pressure and endothelial functions in N1DDM patients with hypertension. RESEARCH DESIGN AND METHODS We conducted a double-blind randomized trial in 26 patients with NIDDM and mild hypertension. A 4-week run-in placebo period preceded the active 12-week treatment with perindopril (4–8 mg daily) or carvedilol (25–50 mg daily). Endothelial functions were assessed by evaluating the hemodynamic (mean blood pressure, leg blood flow) and rheological (platelet aggregation, blood viscosity, and blood filterability) responses to an intravenous bolus of 3 g L-arginine, the natural precursor of nitric oxide. RESULTS Both perindopril and carvedilol significantly reduced mean blood pressure (P < 0.001) and increased leg blood flow (P < 0.05) to the same extent; blood filterability remained unchanged in both perindopril- and carvedilol-treated groups. Carvedilol reduced platelet aggregation and blood viscosity significantly (P < 0.05) but perindopril did not. Before treatment, the hemodynamic and rheologic responses to L-arginine were significantly lower in patients (P < 0.05–0.01) than in 20 nondiabetic nonhypertensive control subjects. After 12 weeks of treatment, both drugs normalized the hemodynamic responses to L-arginine. Platelet aggregation response to L-arginine was ameliorated by carvedilol and remained unchanged in the perindopril group. CONCLUSIONS At the doses used, both drugs effectively reduce blood pressure and normalize the hemodynamic responses to L-arginine. The implications of the ameliorated endothelial function for the poor cardiovascular outlook of the NIDDM hypertensive patient need further assessment.

We evaluated the effect of insulin on platelet function, blood viscosity, and filterability in healthy subjects and in patients with Type 2 (non-insulin-dependent) diabetes mellitus. Fifteen diabetic patients were free from cardiovascular complications (group A), while the other 15 patients had both clinical and measured evidence of coronary or peripheral vascular disease (group B); 15 non-diabetic subjects served as controls. On blood samples taken without stasis, maximal platelet aggregation to 1.25 micromol l(-1) ADP, blood and plasma viscosity, and blood filterability were measured in basal conditions, and after incubation of blood, plasma or platelet-rich plasma with insulin at two physiological concentrations (120 and 480 pmol l(-1)). Compared with healthy subjects, the diabetic patients of group B had higher values of blood (p < 0.01) and plasma (p < 0.05) viscosity, and platelet aggregation response to ADP (p < 0.01), as well as lower values of blood filterability (p < 0.01). The diabetic patients of group A had values intermediate between normal subjects and the patients of group B. In non-diabetic subjects, insulin significantly decreased platelet aggregation and blood viscosity at low shear rates (22.5 s(-1)) (p < 0.01 for both), and had no significant effects on other parameters. In the diabetic patients of group A, insulin decreased blood viscosity at high (225 s(-1)) rates of shear (p < 0.01) and increased blood filterability (p < 0.01). The effects of insulin were not dose-related. In the diabetic patients of group B, none of the parameters evaluated was significantly influenced by insulin. Type 2 diabetic patients present many abnormalities of the rheologic properties of blood. The beneficial effects of insulin on platelet aggregation and blood viscosity are not evident in Type 2 diabetic patients, especially those with vascular complications and this may be relevant to the development of those complications.

Background Acute hyperglycemia may increase vascular tone in normal humans via a glutathione-sensitive, presumably free radical–mediated pathway. The objective of this study was to investigate whether or not the vascular effects of hyperglycemia are related to reduced availability of nitric oxide. Methods and Results Acute hyperglycemia (15 mmol/L, 270 mg/dL) was induced in 12 healthy subjects with an artificial pancreas. Systolic and diastolic blood pressures, heart rate, and plasma catecholamines showed significant increases ( P P P l -arginine (n=7, 1 g/min) but not d -arginine (n=5, 1 g/min) or l -lysine (n=5, 1 g/min) in the last 30 minutes of the hyperglycemic clamp completely reversed all hemodynamic and rheological changes brought about by hyperglycemia. Infusion of N G -monomethyl- l -arginine (L-NMMA; 2 mg/min) to inhibit endogenous nitric oxide synthesis in 8 normal subjects produced vascular effects qualitatively similar to those of hyperglycemia but quantitatively higher ( P Conclusions The results show that acute hyperglycemia in normal subjects causes significant hemodynamic and rheological changes that are reversed by l -arginine. Moreover, the effects of hyperglycemia are mimicked to a large extent, but not entirely, by infusion of L-NMMA. This suggests that hyperglycemia may reduce nitric oxide availability in humans.

Peripheral hyperinsulinism is said to be associated and perhaps implicated in the pathogenesis of hypertension. There is however some inconsistency in the evidence of the relationship between insulin and blood pressure. We prospectively investigated glucose metabolism, insulin and C-peptide values and serum lipids in a large sample of hypertensive as compared with age and body habitus-matched normotensive subjects. As a group, the 145 hypertensives (blood pressure: 160/99±8.5/6.5 mmHg, mean±SD) had significantly elevated fasting plasma insulin (p

The aim of the present study was to further evaluate the significance of circulating platelet aggregates induced by somatostatin in insulin-dependent diabetic subjects. Eight insulin-dependent diabetics and eight normals were infused with somatostatin at increasing doses (250, 500, and 750 microgram/h), each dose for 30 min. In diabetics, somatostatin induced the appearance in blood of platelet aggregates in a dose-dependent fashion, the highest level being observed with the highest dose (750 microgram/h), p less than 0.005). In normals, circulating platelet aggregates were detected only with the infusion of the highest rate of somatostatin (p less than 0.025). This effect of somatostatin was reversible, since it tended to disappear 30 min after the infusion was stopped. In six additional insulin-dependent diabetics, a previous infusion of phentolamine (0.5 mg/min) completely prevented the appearance of platelet aggregates by somatostatin. No significant variation of the aggregation response to both ADP and collagen and the platelet count was seen in both experiments. Somatostatin, as expected, reduced the basal concentration of plasma glucose, glucagon, and C-peptide in both diabetics and normals. On the basis of these results, we suggest that somatostatin has some proaggregating capacity in vivo, probably by interacting with adrenergic mechanisms.

Although it has been demonstrated that diabetes mellitus may enhance apoptosis in myocardial (4) and endothelial cells (5), still, no evidence exists in humans about the potential role of diabetes in the evolution of diabetic atherosclerotic plaques toward instability by enhancing VSMC apoptosis. We hypothesize that by enhancing the proinflammatory cytokines, diabetes may exert proapoptotic effects on VSMCs of atherosclerotic plaque. To address these issues, cell death by apoptosis and expression and localization of TNF-9 and IL-1b was evaluated in carotid plaques of asymptomatic diabetic and nondiabetic patients. The study group consisted of 26 type 2 diabetic and 30 nondiabetic patients enlisted to undergo carotid endarterectomy for asymptomatic extracranial high-grade (.70%) internal carotid artery stenosis

This study examines the effect of baclofen, a specific gamma-aminobutyric acid analog which crosses the blood-brain barrier freely, upon insulin, glucagon, and GH responses to iv glucose in normal man. Normal subjects received two consecutive iv glucose tolerance tests (0.33 g/kg) before and after the acute oral administration of 5, or 10 or 20 mg baclofen, respectively, (10 subjects for each group). The dose of baclofen was divided and given 8 and 1 h before the performance of the posttreatment test. A fourth group of normal subjects served as placebo group (8 subjects). The highest dose of baclofen significantly increased insulin responses to glucose and raised basal glucagon levels (P less than 0.01). No significant change occurred with the other doses. Baclofen produced a dose-related increase in basal GH levels; a 10-fold increase was observed with the 20-mg dose. However, glucose-induced glucagon and GH suppression were not affected by baclofen. Despite the increased hormonal secretions, glucose tolerance did not change after baclofen. These results seem to indicate that gamma-aminobutyric acid may play a role in the neuroendocrine control of the pancreatic islets.

Several studies in animals suggest a link between haemocoagulative patterns and blood gas changes. Furthermore platelet functions seem to be affected by O2 concentrations. In the present study we have evaluated "in vitro" the effect of low PO2 concentrations on platelet aggregation in man. In 15 normal subjects (mean age 32 +/- 5) platelet aggregation ADP (end conc. 1,25 microM) and collagen induced 2 micrograms/Ml) was determined before and after exposition to low PO2 concentrations (O2 conc. 5,04%). The results show that low PO2 concentrations determine a significant increase (P less than 0,001) of platelet aggregation as compared to controls. Although the mechanism of the direct influence of PO2 concentrations upon human platelet is unclear, this finding suggest new therapeutic approaches in chronic lung obstructive diseases.

Human diabetes mellitus is characterized by impaired insulin response to intravenous glucose. In search of possible endogenous factors which impair insulin release, we have investigated the effect of lysine acetylsalicylate (LAS), an inhibitor of endogenous prostaglandin (PGs) synthesis, upon insulin responses to glucose and arginine in subjects with type II (adult-on-set) diabetes mellitus. Acute insulin response to glucose (20 g) was significantly increased by LAS (response before LAS=26 +/- 10%; during LAS=77+15%, mean+/-SEM, mean change 3-10 min insulin, % basal, n=8, p 0.01), as well as second phase insulin secretion (before LAS=1437+/-316%; during LAS=3960+/-550%, change 10-60 min, uU/ml-min, % basal, p less than 0.01). This effect was associated with an increase in glucose disappearance rates (p less than 0.01). Acute insulin response to arginine (5 g iv) was also increased by LAS infusion. These results suggest that endogenous PGs may be one of the factors which impair insulin secretion in human diabetes.

Mean corpuscular volume and Red Blood Cell 2-3, diphosphoglycerate in insulin dependent diabetics and in non insulin dependent diabetics were evaluated. Only in insulin dependent diabetics an increased mean corpuscular volume was found while in non insulin dependent diabetics red blood cell 2-3, DPG level appears to be reduced. These findings were not correlated with the metabolic parameters neither they seemed to be dependent upon sex, age or vascular disease. The Authors suggest that the increase of mean corpuscular volume might be indicative of a tendency to macromegaloblastosis in insulin dependent diabetics; with regard to RBC 2-3, DPG level it seems to be extremely variable in dependence on oxygen request at the tissue level.

Context.—C1 inhibitor (C1-INH) is an α2-globulin that blocks esterolytic activity of the first component of the classic complement cascade. The α-granules of normal human platelets also contain C1-INH, which is expressed on the platelet surface during platelet secretion in healthy patients, but it is clearly reduced in patients with hereditary angioedema (HAE).Objective.—To evaluate the effects of in vivo C1-INH concentrate infusion on platelet responsiveness and coagulation system activity in patients with HAE.Design.—Assessment of the platelet activity and plasma levels of C1-INH, activated factor XII (XIIa), and prothrombin fragment F1.2 (F1.2) before and after infusion of 15 U/kg of C1-INH concentrate.Patients.—In 6 patients (4 men and 2 women), HAE was diagnosed according to the accepted clinical and laboratory criteria.Measurements.—Platelet aggregation (final concentrations: adenosine diphosphate, 0.5, 1.25, and 2.5μM; collagen, 5 μg/mL), C1-INH antigen (radial immunodiffusion), C1-INH activity (chromogenic substrates), and XIIa and F1.2 (enzyme-linked immunosorbent assay).Results.—After C1-INH infusion, we observed a prompt increase of C1-INH level and a slow return toward its plasma preinfusion values within 4 to 7 days, a significant decrease of both adenosine diphosphate– and collagen-induced platelet aggregation versus preinfusion values (maximum after 1–2 days; P < .001), and a rapid decrease of high basal values of XIIa and F1.2 in 30 and 120 minutes, respectively.Conclusions.—These data show a role of C1-INH in the control of platelet activity and that its deficiency increases platelet aggregability and plasma levels of XIIa and F1.2 in patients with HAE.

Background & Aims: Some patients with serum hepatitis C virus (HCV) have persistently normal aminotransferase (ALT) levels and are affected by cirrhosis. This study prospectively evaluated progression of the disease in a group of anti-HCV–positive patients with persistently normal ALT levels. Methods: Thirty-seven subjects were studied. Each subject underwent liver biopsy at baseline and after 5 years of follow-up. At baseline, serum samples were tested for genotypes and HCV RNA load. ALT levels and serum HCV RNA were tested every other month and every 6 months, respectively. Patients with increased ALT were discharged from the study and treated with IFN. Five years after the end of IFN therapy, a liver biopsy was performed. Results: Liver biopsy at baseline showed chronic hepatitis in 34 patients and normal histology in 3 patients, 2 of whom were negative for HCV RNA and 1 positive. HCV genotypes were distributed as follows: 2a, 56%; 1b, 41%; and 1a, 3%. At the end of 7-year follow-up, 73% of the patients still had normal ALT values. Liver histology after 5 years was comparable to that observed at entry to study. Conclusions: Most patients with persistently normal ALT serum levels have very mild chronic hepatitis. However, healthy anti-HCV–positive subjects exist. In patients with HCV-related chronic hepatitis associated with persistently normal ALT levels, the grade of disease activity does not increase over years and progression to cirrhosis is slow or absent. GASTROENTEROLOGY 2000;118:760-764

Objective: In Type 2 diabetes, it is not clear if renal size is constantly related to the glomerular filtration rate. In addition, it is not known ifkidney volume (KV) is associated with an increased urinary albumin and IgG excretion. Methods: The relationship between kidney volume, creatinine clearance (CrCI), urinary albumin and IgG excretion in 95 Type 2 diabetic patients with different stages of nephropathy (1 ― 4 Stage sec NKDF-QD) was elevated and compared to 85 non-diabetic subjects with similar degree of kidney function. Results: In Type 2 diabetic patients the KV/CrCl ratio was increased, in comparison with the control subjects, from about 15% in Stage 1 to 53% in Stage 4. In T2D subjects, significant correlations were found between KV and urinary albumin excretion (r = 0.665, p < 0.05), and between KV and urinary IgG excretion (r = 0.800, p < 0.001). Conclusion: The present study finds that Type 2 diabetic subjects, are characterized by an increased ratio between KV/CrCl, throughout the different progressive stages of nephropathy. In Type 2 diabetes relationships between KV and urinary albumin and between KV and IgG excretion also were found to be significant, suggesting a role for the impaired size selectivity of proteinuria as a possible determinant of KV.

The objective of this study was to assess the role of L-arginine, the natural precursor of nitric oxide, for testing endothelial function in physiological and pathophysiological conditions. In an initial study of 20 healthy subjects, mean blood pressure decreases in response to increasing doses of L-arginine (1, 2, 3, and 5 g) were 1.1 +/- 1.3, 2.6 +/- 1.5, 7.6 +/- 1.3, and 7.7 +/- 2 mmHg, respectively, P < 0.01. The enantiomer D-arginine (3 g) did not produce any change in mean blood pressure and platelet aggregation (n = 10), whereas the infusion of the L-arginine analog NG-monomethyl-L-arginine (6 mg/min) reduced by 70% the vascular effects of L-arginine. In the whole population of 52 healthy subjects, there was an inverse correlation between age and blood pressure or platelet aggregation changes after L-arginine. Compared with matched controls (n = 20), the changes in mean blood pressure and platelet aggregation after L-arginine were significantly lower in non-insulin-dependent diabetic (n = 20) and hypercholesterolemic (n = 16), but not in hypertensive (n = 20), subjects. Changes in blood viscosity were significantly lower only in hypercholesterolemic subjects. Our findings suggest that an intravenous bolus of 3 g L-arginine may be a simple and useful tool to assess the endothelial control of blood pressure and platelet activity in health and disease.