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Left ventricular hypertrophy (LVH) is significantly related to adverse clinical outcomes in patients at high risk of cardiovascular events. In patients with atrial fibrillation (AF), data on LVH, that is, prevalence and determinants, are inconsistent mainly because of different definitions and heterogeneity of study populations. We determined echocardiographic-based LVH prevalence and clinical factors independently associated with its development in a prospective cohort of patients with non-valvular (NV) AF. From the "Atrial Fibrillation Registry for Ankle-brachial Index Prevalence Assessment: Collaborative Italian Study" (ARAPACIS) population, 1,184 patients with NVAF (mean age 72 ± 11 years; 56% men) with complete data to define LVH were selected. ARAPACIS is a multicenter, observational, prospective, longitudinal on-going study designed to estimate prevalence of peripheral artery disease in patients with NVAF. We found a high prevalence of LVH (52%) in patients with NVAF. Compared to those without LVH, patients with AF with LVH were older and had a higher prevalence of hypertension, diabetes, and previous myocardial infarction (MI). A higher prevalence of ankle-brachial index ≤0.90 was seen in patients with LVH (22 vs 17%, p = 0.0392). Patients with LVH were at significantly higher thromboembolic risk, with CHA2DS2-VASc ≥2 seen in 93% of LVH and in 73% of patients without LVH (p

OBJECTIVE— Stresshyperglycemiahasbeenassociatedwithincreasedmortalityinpatients with myocardial infarction (MI). We examined the association between plasma glucose levels, circulating inflammatory markers, T-cell activation, and functional cardiac outcome in patients with first MI. RESEARCH DESIGN AND METHODS — Echocardiographic parameters, circulating levels of interleukin-18 (IL-18), C-reactive protein (CPR), and the percent of CD16-CD56, CD4/CD8, CD152, and HLA-DR expression were investigated in 108 patients with acute MI on admission to the emergency ward. RESULTS — Our review found that 31 new hyperglycemic patients (glycemia 7 mmol/l) had higher infarct segment length (P 0.05) and myocardial performance index (P 0.02) and reduced transmitral Doppler flow (P 0.05), pulmonary flow analysis (P 0.02), and ejection fraction (P 0.05) compared with 36 hyperglycemic diabetic patients and 41 normoglycemic patients. Plasma IL-18 and CRP were higher in the hyperglycemic than in the normoglycemic patients (P 0.005), with the highest values in patients with new hyperglycemia (P 0.05). Hyperglycemic patients had a higher percent of CD16/CD56 cells and CD4/CD8 ratio (P 0.01), whereas they had lower CD152 expression (which has a negative regulatory function in T-cell activation) compared with normoglycemic patients (P 0.001). CONCLUSIONS— DuringMI,hyperglycemiaisassociatedwithincreasedlevelsofinflamma- tory markers, enhanced expression of cytotoxic T-cells, and reduced expression of T-cells, which are implicated in limiting the immune process. An increased inflammatory immune process seems a likely mechanism linking acute hyperglycemia to poor cardiac outcome in MI patients.

To the Editor: Nonvalvular atrial fibrillation (NVAF) is the most common sustained arrhythmia encountered in clinical practice and is associated with a 5-fold increased risk for stroke (1). Moreover, patients with NVAF often suffer from atherosclerotic complications such as acute myocardial infarction (AMI) (2). Peripheral artery disease (PAD) is an established marker of systemic atherosclerosis but its prevalence in NVAF is still unclear. We reasoned that inclusion of ankle-brachial index (ABI), which is an established tool for diagnosis of PAD (3), in the CHA2DS2-VASc (4) score would better define the prevalence of vascular disease. To address this issue, the Italian Society of Internal Medicine (SIMI) established an Italian registry documenting ABI in NVAF patients. The Atrial Fibrillation Registry for the ARAPACIS (Ankle-brachial Index Prevalence Assessment: Collaborative Italian Study) study is an independent research project involving all Regional Councils of SIMI. The first objective of the study was to estimate the prevalence of ABI ≤0.90 in NVAF patients. Consecutive patients with NVAF referred to internal medicine wards were eligible for the enrollment. Enrollment started in October 2010 and continued until October 30, 2012. Patients were enrolled if they were 18 years or older and had a diagnosis of NVAF, recording during the qualifying admission/consultation or in the preceding 12 months, and if it was possible to obtain the ABI measurement. Exclusion criteria included the following: acquired or congenital valvular AF, active cancer, disease with life expectancy 0.90 (93% vs. 82%; p < 0.0001). Logistic regression analysis demonstrated that ABI ≤0.90 was significantly associated with a smoking habit (odds ratio [OR]: 1.99; 95% confidence interval [CI]: 1.48 to 2.66; p < 0.0001), diabetes (OR: 1.93; 95% CI: 1.51 to 2.46; p < 0.0001), age class 65 to 74 years (OR: 2.05; 95% CI: 1.40 to 3.07; p < 0.0001), age class ≥75 years (OR: 3.12; 95% CI: 2.16 to 4.61; p < 0.0001), and history of previous transient ischemic attack/stroke (OR: 1.64; 95% CI: 1.20 to 2.24; p = 0.002). Vascular disease, as assessed by the history elements of CHA2DS2VASc score, was recorded in 17.3% of patients; inclusion of ABI ≤0.90 in the definition of vascular disease yielded a total prevalence of 33%. A higher prevalence of vascular disease was detected if ABI ≤0.90 was included in the CHA2DS2VASc score (Fig. 1). CHA2DS2VASc including ABI ≤0.90 was more associated with previous stroke (43%; OR: 1.85; 95% CI: 1.41 to 2.44; p < 0.0001) compared to CHA2DS2VASc with ABI 0.91 to 1.39 (23%; OR: 1.52; 95% CI: 1.10 to 2.11; p = 0.0117). To the best of our knowledge, there is no large-scale study that specifically examined the prevalence of ABI ≤0.90 in NVAF. In our population, 21% had ABI ≤0.90 indicating that NVAF is often associated with systemic atherosclerosis. The CHADS2 has been recently refined with the CHA2DS2-VASc score, which includes vascular disease as documented by a history of AMI, symptomatic PAD, or detection of atherosclerotic plaque in the aortic arch (4). Comparison of vascular prevalence as assessed by CHA2DS2-VASc score and/or ABI ≤0.90 is of interest to define the potentially positive impact of measuring ABI in the management of NVAF patients. Inclusion of ABI ≤0.90 in the definition of vascular disease greatly increased the prevalence of vascular disease, which increased from 17.3% (based on history alone) to 33% (based on ABI) in the entire population. If ABI ≤0.90 was encompassed in the definition of vascular disease of CHA2DS2-VASc score the prevalence of vascular disease increased in every risk class. Inclusion of ABI ≤0.90 in the CHA2DS2-VASc score allowed us to better define the risk profile of NVAF patients with an up-grading of the risk score in each CHA2DS2-VASc score category. This may have important therapeutic implications if the new score could be tested prospectively, as a higher number of NVAF patients would potentially be candidates for an anticoagulant treatment by measuring ABI. A prospective study is, therefore, necessary to validate the risk score of this new definition of vascular disease. In conclusion, this study provides the first evidence that one-fifth of NVAF patients had an ABI ≤0.90, indicating that it may represent a simple and cheap method to better define the prevalence of vascular disease in NVAF.

Pfeifer-Weber-Christian's panniculitis is a rare syndrome characterized by fever, arthralgias, fatigue and recurrent nodular panniculitis. It has been associated with pancreatic diseases, trauma, connective tissue diseases, alpha-1-antitrypsin deficiency, systemic lupus erythematosus, infections, lymphoproliferative diseases and neoplasias. We report the case of a 43-year-old obese male patient who presented with asthenia, arthralgias, intermittent fever, skin erythema and a large hard-elastic tumor of the right calf. Laboratory analysis revealed increased values of the immunophlogosis parameters and positivity for serum antinuclear antibodies. Surgical drainage of the abscess-like tumor mass, revealed leakage of a sterile, subflavious, oily and thick liquid; a skin biopsy showed intra and perivascular infiltration by neutrophils, diagnostic for leukocytoclastic vasculitis. Treatment with prednisone induced clinical improvement and normalization of the laboratory data. The clinical picture, laboratory data and efficacy of prednisone therapy confirmed that the patient developed Pfeifer-Weber-Christian's panniculitis in the clinical setting of an antinuclear antibody-positive leukocytoclastic vasculitis.

Diabetes is an independent risk factor for the development of coronary heart disease and has a tremendous impact on mortality. In patients with noninsulin-dependent diabetes mellitus, coronary heart disease is the leading cause of death. Both hyperinsulinemia and hyperglycemia have been suggested as risk factors for accelerated atherogenesis in diabetes. Whichever mechanism is implicated, a beneficial effect of therapy in preventing cardiovascular disease is a major requirement. Until now, it is not clear whether stringent control of blood glucose levels reduces the risk of development of coronary heart disease in patients with noninsulin-dependent diabetes mellitus. This review emphasizes the relative roles of insulin and glucose on coronary heart disease development in noninsulin-dependent diabetes mellitus. The different therapeutic options of pharmacological treatment in hyperglycemia in noninsulin-dependent diabetes mellitus are discussed, as well as their impact on coronary heart disease risk.

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 Authors have examined the PO2 and PCO2 of peripheral arterial blood in 10 hypertensive subjects before and after 20 mg of nifedipine administered by sublingual route. A PaO2 decrease and a light increase of PaCO2 were observed; this pattern, if considered together with the increase of CO2 and the decrease of pulmonary resistance, may be attributed to a greater perfusion of those districts having a low V/Q ratio.

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.

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 haemodynamic effects of salbutamol were studied in 14 patients with chronic obstructive lung disease with a single dose of 100 and 200 gamma, administered by i.v. injection. The results of study revealed salbutamol intravenous injection significantly increases heart rate, cardiac index and decreases vascular systemic resistance. There was no significant change in blood gas tensions. This study indicates that salbutamol produces variation in preload and afterload by a direct action on vascular smooth muscle.

Background —We assessed the role of glucose and insulin in the regulation of circulating levels of soluble intercellular adhesion molecule-1 (sICAM-1) and vascular adhesion molecule-1 (sVCAM-1) in normal subjects and in patients with type 2 diabetes. Methods and Results —Plasma glucose concentrations were acutely raised in 10 normal subjects and 10 newly diagnosed, complication-free type 2 diabetic patients and maintained at 15 mmol/L for 2 hours. In normal subjects, plasma sICAM-1, but not sVCAM-1, levels rose significantly ( P P P Conclusions —Acute hyperglycemia increases circulating sICAM-1 levels in normal subjects, whereas the correction of hyperglycemia with insulin or l-arginine supplementation restored to normal levels the increased plasma sICAM-1 levels of type 2 diabetic patients.

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.

CD4+CD25+Foxp3+ regulatory T cells (Treg) specialize in suppressing immune responses. In this study, 47 consecutive colon cancer patients were subjected to circulating Treg frequency assessment by flow cytometry before and after cancer resection. Thirty-two healthy subjects served as controls. Circulating Treg frequencies were significantly higher in colon cancer patients with respect to healthy controls. When patients were subgrouped according to Dukes stages, a linear relationship was observed between Dukes stages and Treg frequencies. In radically resected patients, Treg frequencies were shown to have significantly dropped down. Patients with advanced colon cancer were more likely to have significantly higher proportions of circulating Treg frequencies than Dukes A and B patients when compared to healthy subjects. Of note, nonradically resected patients were found to display reductions in—but not normalization of—Treg frequencies. These results suggest that cancer itself may be able to drive Treg recruitment as a strategy of immunoevasion.

Yellow nail syndrome is a rare cause of edema due to a disordered lymphatic drainage. We recently observed two cases of long-standing, chronic edema, whose nature could not be understood despite innumerable diagnostic procedures. The diagnosis was suspected based on an attentive clinical exam and confirmed by radionuclide lymph scan. Yellow nail syndrome has to be considered in the differential diagnosis in cases of systemic edema, as well as long standing pleural effusions, particularly in patients with bronchiectasis or sinusitis. Clues to diagnosis are the presence of dystrophic, yellowish nails, peripheral lymphedema and relapsing pleural effusions and/or ascites. Long-term control of symptoms is difficult to achieve and may benefit from the judicious use of diuretics and intravenous albumin and by topical alpha-tocopherol. Pleurodesis may be needed. Other pathologic conditions are often associated to yellow nail syndrome and should be ruled out. Yellow nail syndrome is a rare cause of edema due to a disordered lymphatic drainage. We recently observed two cases of long-standing, chronic edema, whose nature could not be understood despite innumerable diagnostic procedures. The diagnosis was suspected based on an attentive clinical exam and confirmed by radionuclide lymph scan. Yellow nail syndrome has to be considered in the differential diagnosis in cases of systemic edema, as well as long standing pleural effusions, particularly in patients with bronchiectasis or sinusitis. Clues to diagnosis are the presence of dystrophic, yellowish nails, peripheral lymphedema and relapsing pleural effusions and/or ascites. Long-term control of symptoms is difficult to achieve and may benefit from the judicious use of diuretics and intravenous albumin and by topical alpha-tocopherol. Pleurodesis may be needed. Other pathologic conditions are often associated to yellow nail syndrome and should be ruled out.

Profound immune dysfunction is a constant feature in B-cell chronic lymphocytic leukemia (B-CLL) patients. Immunological abnormalities include hypogammaglobulinemia, impaired immunoglobulin class switching and diminished germinal center formation. This state of immune suppression renders B-CLL patients highly susceptible to infections, which contribute greatly to morbidity and mortality in this disease. Impaired T cell function in B-CLL is well-documented and has been suggested to result from inhibitory effects exerted by malignant B lymphocytes. Because the presence of leukemic cells may represent a major obstacle to efficient T cell activation, T lymphocytes were separated from CLL B cells, stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin for 4h, and then cocultured with autologous leukemic B cells both at a 1:1 ratio or at the same ratio as in vivo for 24-40 h. CLL B cell expression of CD86 and CD95 was markedly upregulated using this approach, whereas CD80 expression was augmented only in a minority of patients; these effects were partially preserved even when preactivated T cells were rechallenged with CLL B cells at the same low T/B cell ratio as that observed in vivo. Finally, CD80 upregulation on CLL B cells appeared to be mainly dependent on CD40L-mediated stimulation, whereas CD86 and CD95 expression was efficiently augmented by soluble factors released by preactivated T lymphocytes. In conclusion, efficient activation of T lymphocytes in B-CLL may be achieved which, in turn, may result in enhanced antigen-presenting capacity and susceptibility to apoptosis of leukemic cells via CD86 and CD95 upregulation, respectively.

The case of a 43-year-old male with non-Hodgkin's lymphoma (stage IV B), and hypo-IgG and IgM, who developed acute colonic pseudo-obstruction or Ogilvie's syndrome during chemotherapy, is presented. The simultaneous occurrence of a unilateral segmental vesicular rash indicative of herpes zoster infection suggests an etiopathogenetic relationship between the colonic pseudo-obstruction and herpetic involvement of the motor celiac sympathetic ganglia. The rapid resolution of the abdominal dilation and the functional recovery from the colonic pseudo-obstruction after anti-viral therapy is also consistent with the diagnostic hypothesis.

The Authors report the clinical case of a patient with a deficit of humoral immunity who developed infections since puberty. The serum levels of IgG and IgA decreased progressively in the fourth decade of life, while serum IgM increased. Moreover, the patient developed a marked CD4+ T lymphocytopenia and a meager B lymphocytopenia, vitiligo, positivity for anti-SSA/Ro autoantibodies and granulomatous phlogosis of the knee. The heterogeneity of the clinical and laboratory data suggests that this patient might present an overlap immunodeficiency syndrome with some of the clinical and immunological features typical of the hyper-IgM syndrome (in the X-linked or autosomal forms) and others that can be referred to a nosologically distinct humoral immunodeficiency such as the common variable immunodeficiency.

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.

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.

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.

OBJECTIVE The endothelium plays a pivotal role in the regulation of vascular tone by releasing nitric oxide (NO). Increased availability of L-arginine, the natural precursor of NO, induces vasodilatation and inhibits platelet activity. We studied the effect of metformin on hemodynamic and rheological responses to L-arginine in patients with NIDDM. RESEARCH DESIGN AND METHODS Ten newly diagnosed NIDDM patients with mild fasting hyperglycemia (7.5 ± 0.3 mmol/l) and without evidence of both micro- and macrovascular complications were investigated. They received an intravenous infusion of L-arginine (1 g/min for 30 min) with evaluation of plasma glucose and insulin, systolic (sBP) and diastolic (dBP) blood pressure, heart rate and plasma catecholamines, platelet aggregation, and blood viscosity and filterability. The L-arginine test was repeated after an 8-week treatment with metformin (850 mg b.i.d.). RESULTS Metformin treatment significantly reduced basal fasting plasma glucose, HbA1c, and platelet aggregation to ADP (P < 0.05); the other parameters did not change. During pretreatment test, L-arginine infusion decreased sBP (from 137 ± 4.1 to 129 ± 4.5 mmHg, P < 0.01) and dBP (from 79 ± 1.9 to 75 ± 1.2 mmHg, P < 0.01) without affecting heart rate or plasma catecholamines. Both platelet aggregation and blood viscosity showed significant decrements after L-arginine, while blood filterability did not change. After metformin treatment, the decrease in blood pressure after L-arginine infusion was significantly enhanced, with a maximal decrease of sBP of 12 ± 3.4 mmHg (8 ± 2.5 mmHg pretreatment, P < 0.05) and dBP of 9.5 ± 2.4 mmHg (4.5 ± 1.9 mmHg pretreatment, P < 0.01). Heart rate, plasma norepinephrine levels, and blood filterability also rose significantly (P < 0.05–0.01). The decrease in both platelet aggregation and blood viscosity after L-arginine was significantly amplified after metformin. CONCLUSIONS We conclude that L-arginine infusion in newly diagnosed NIDDM patients without vascular complications produces relevant hemodynamic and theological changes, which are amplified by an 8-week treatment with metformin. Whether these vascular effects of metformin will improve the poor cardiovascular outlook of the diabetic patient is still unknown.

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.

Ten non-obese type 2 diabetic patients with secondary failure to sulfonylureas received an intensive insulin therapy (four doses schedule) for 90 days. The glycaemic control was poor at entry (HbA1c = 11.7 +/- 1.2%) and ameliorated significantly after insulin (HbA1c = 7.1 +/- 0.7%, p less than 0.01). The reintroduction of the sulfonylurea after insulin withdrawal resulted in a persistent satisfactory long-term control (300 days) in all, but two diabetics responded no more after about 3 and 4 months of clinical remission (good control on sulfonylurea). Both basal and stimulated (iv glucagon and mixed meal) beta-cell secretory activity increased significantly at 3 months and declined thereafter without falling below baseline values. Three months of strict metabolic control seem to restore the sensitivity to sulfonylurea by enhancing beta-cell secretory activity in non-obese type 2 diabetic patients.

The present study aimed at investigating the respective effects of continuous and pulsatile intravenous delivery of glucagon in insulin-dependent diabetic subjects. The study was performed in seven insulin-dependent diabetic subjects proven to have no residual insulin secretion. In random order and in different days each subject was submitted to glucagon delivery given continuously (58 ng/min) and in a pulsatile (377 ng/min during 2 min followed by 11 min during which no glucagon was infused) manner. In this conditions plasma glucose levels were significantly higher during pulsatile glucagon delivery. In particular in the last 65 min plasma glucose levels reached 10.8 +/- 0.3 vs 12.9 +/- 0.4 mmol/l (p less than 0.05) during continuous and pulsatile glucagon delivery respectively. Similarly plasma lipid changes also evidenced a greater effects of pulsatile rather than continuous hormone administration in producing the metabolic derangements classically encountered in insulin-dependent diabetic subjects. In conclusion, pulsatile glucagon delivery seem to produce greater metabolic effects than continuous hormone delivery.

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.

Air pollution induced by automobile exhaust fumes seems to be involved in increased cardiovascular and respiratory morbidity. The effects of inhalation of such pollutant gases on platelet function and blood viscosity have not been sufficiently investigated, even if these parameters seem to be in strict correlation with cardiovascular function. Twelve healthy non-smoking volunteers were exposed for 30 minutes in a closed room to air polluted by automobile fumes. Platelet aggregation, blood viscosity, HbCO levels and P50 STD were determined before and after exposure. Cardiovascular parameters (blood pressure, heart rate and ECG) were also measured. At the end of the test, HbCO levels were significantly increased, but P50 STD was significantly reduced; an impairment of both platelet function and blood viscosity was observed. No significant changes in cardiovascular parameters were recorded. The decreases in platelet aggregation and blood viscosity were not directly correlated with either the increase in carbon monoxide levels or with the reduced P50 STD levels. It can be reasonably concluded that gasoline exhaust fumes could have been responsible for the observed alterations.

The present study was aimed at characterizing the effects of beta-endorphin on plasma glucose, insulin and glucagon plasma levels in subjects with type-2 diabetes mellitus. Infusion of 0.5 mg/h human beta-endorphin produced significant and simultaneous increments in both insulin and glucagon concentrations and decreased plasma glucose levels (-18 +/- 4 mg/dl, 60 min level, p less than 0.01). When the same diabetics were rendered euglycemic by an insulin infusion (1 mU/kg/min), beta-endorphin did not produce the expected decrease in plasma glucose concentrations nor raise plasma insulin levels; only the response of glucagon was preserved. Normal subjects were rendered hyperglycemic by an intravenous glucose infusion to match the plasma glucose levels of diabetic subjects. In this condition, beta-endorphin produced a significant increase of insulin concentrations, whereas glucagon remained suppressed. The intravenous administration of the long-acting met-enkephalin analogue DAMME (0.25 mg) blunted the hormonal responses to the subsequent beta-endorphin infusion in diabetic patients, although the inhibition was short-lived (30-40 min). Naloxone (5 mg), an opiate antagonist, did not produce any significant change in the insulin and glucagon responses to beta-endorphin, while somatostatin (0.25 mg/h) completely abolished the hormonal responses to the opioid.(ABSTRACT TRUNCATED AT 250 WORDS)

Summary The effect of nicergoline, an alpha-adrenergic blocking drug, upon insulin response to glucose has been investigated in 8 subjects with Type II (adult-onset) diabetes mellitus with fasting hyperglycemia. All subjects had no acute insulin response to intravenous glucose (20 g) pulse (AIR=Acute Insulin Response=1±5%, mean±SEM, mean change 3–10 min, % basal). Nicergoline infusion (0.1 mg/min) resulted in both a partial restoration of AIR (43±12 %, p

Changes in the main parameters of left ventricular function by comparison with the baselines were examined echocardiography in 11 patients after a single i.v. dose of salbutamol. The results suggest that salbutamol certainly has peripheral vascular effects leading to changes in ventricular volumes. The drug also appears to exert a positive intropic action, as shown by the changes it induced in EF and, more particularly VCF values.

This study was undertaken to assess the mechanism by which prostaglandins of the E series inhibit glucose-induced insulin secretion in man. Acute insulin response (mean change 3–10 min) to iv glucose (0.33 g/kg) was decreased by 40% during the infusion of prostaglandin E2 (10 μg/min) and glucose disappearance rates were reduced (P < 0.05). Insulin response to arginine (5 g iv) and tolbutamide (1 g iv) were not affected by the same rate of prostaglandin E2 infusion. The inhibitory effect of prostaglandin E2 on glucoseinduced insulin secretion was prevented by theophylline (100 mg as a loading dose followed by a 5 mg/min infusion), a drug that increases the intracellular cAMP concentrations by inhibiting phosphodiesterase activity. Our data suggest the involvement of the adenylate cyclase system in the inhibitory action of prostaglandin E2 on glucose-induced insulin secretion in man.

Oxygen-release capacity of the red blood cells was investigated in non-acidotic insulin-dependent diabetics before and after the achievement of strict metabolic control with the aid of the artificial pancreas. P50std (oxygen tension at 50% oxygen saturation) values were low in basal condition and returned to normal after the 24-h treatment period. No significant changes were observed in the content of red cell 2,3-diphosphoglycerate nor in the acid-base balance. Only the labile form of glycosylated hemoglobin showed significant decreases after treatment. These results suggest that insulin-dependent diabetics may have a state of relative tissue hypoxia which can be easily overcome by the achievement of strict metabolic control.

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by a sustained accumulation of long-lived and well-differentiated B lymphocytes in lymphoid tissues, peripheral blood and bone marrow. Although the pathogenesis of this disease is not entirely understood, altered apoptosis is believed to play a relevant role in B-CLL. In this study, we compared the expression of CD95, the best characterized surface molecule involved in triggering the apoptotic machinery, on normal and CLL B cells before and after in vitro activation with polyclonal stimulators. Cell activation was monitored by verifying the induced expression of the early activation antigen CD69. Freshly analyzed CLL B cells showed significantly lower levels of CD95 than normal B cells. Moreover, following in vitro culture with phorbol 12-myristate 13-acetate (PMA) + ionomycin, phytohemagglutinin, or pokeweed mitogen, CLL B cells failed to upregulate CD95 expression as efficiently as normal B cells. Impairment of CD95 upregulation was mainly observed following PMA + ionomycin treatment. In contrast, CLL B cells were shown to express CD69 as well as normal B cells, regardless of the activator used, indicating that CLL B cells retain the ability to respond to activating stimuli but are unable to efficiently implement the CD95-mediated activation-induced cell death (AICD) program. In conclusion, these results suggest that prolonged survival of CLL B cells may be contributed to by alterations in AICD mechanisms.

The present study aimed at evaluating whether acute elevations of plasma glucose concentrations could influence systemic hemodynamic parameters and baroreflex activity in humans. Plasma glucose concentrations were acutely raised to 15 mmol/l in 12 healthy male volunteers. During hyperglycemia, there were significant increments of systolic [from 118 +/- 9 to 138 +/- 12 (SD) mmHg, P < 0.01] and diastolic (from 71 +/- 5 to 85 +/- 6 mmHg, P < 0.001) blood pressure, as well as heart rate (from 76 +/- 7 to 85 +/- 10 beats/min, P < 0.01) and plasma catecholamine levels. Both maximal and steady-state mean arterial pressure after squatting were higher during hyperglycemia (27 +/- 8 and 16 +/- 6 mmHg, respectively) compared with levels obtained during euglycemia (18 +/- 5 and 2 +/- 0.6 mmHg, respectively, P < 0.001). The infusion of the somatostatin analogue octreotide (25 micrograms as i.v. bolus followed by a 0.5 microgram/min infusion), to avoid the possible confounding vascular actions of insulin, did not influence the hemodynamic effects of hyperglycemia except for a lesser increase of both heart rate and plasma catecholamines. Glutathione (600 mg as an iv bolus followed by a 5 mg/min infusion) completely prevented the vascular effects of hyperglycemia. This study shows that acute hyperglycemia, similar to that observed in poorly controlled diabetic patients, produces relevant systemic hemodynamic changes and also alters baroreflex activity via a glutathione-sensitive presumably free radical-mediated pathway.

Hypomagnesemia and low erythrocyte magnesium content are both common findings in non-insulin-dependent diabetic subjects. Moreover, intracellular magnesium may play a crucial role in modulating B-cell response to glucose by interfering with potassium permeability. Eight elderly, moderately obese, non-insulin-dependent diabetic subjects were treated with either magnesium supplementation (3 g/day) to the diet or placebo. Both treatment schemes lasted 4 weeks and were separated by a 'wash-out' of 3 weeks. At the end of each treatment period, an iv glucose tolerance test (0.33 g/kg for 3 min) and an iv arginine (5 g) test were performed to determine the B- and A-cell responses. Dietary magnesium supplementation vs placebo produced a slight but significant decrease in basal plasma glucose (8.6 ± 0.3 vs 8.0 ± 0.1 mmol/l, p < 0.05) and an increase in acute insulin response after iv glucose (37.1 ± 2.3 vs −14.7 ±0.9 pmol · 1−1 · (10 min)−1, p < 0.01) and after iv arginine (151 ± 22 vs 81 ± 15 pmol · 1−1 · (10 min)−1, p < 0.01), respectively. Plasma glucagon levels were unaffected by chronic dietary magnesium supplementation as well under basal conditions as in response to arginine. Net increase in acute insulin response after iv glucose and after iv arginine was significantly correlated to the net increase in erythrocyte magnesium content after dietary magnesium supplementation. We conclude that magnesium administration may be a useful adjuvant to the classic hypoglycemic agents in the treatment of non-insulin-dependent diabetic subjects.