Long-term plasma levels of leptin and adiponectin in Rett syndrome.

OBJECTIVE: Rett syndrome is a progressive neurological disorder affecting almost exclusively females after age 6 months and characterised by acquired microcephaly, psychomotor retardation, growth failure, purposeless hand movements, autistic-like behaviour and wide-based and stiff legged gait. Leptin and adiponectin, peptides secreted by adipose tissue, are involved in the regulation of body weight and energy expenditure. DESIGN AND PATIENTS: We investigated in patients with Rett syndrome the variations of plasma leptin and adiponectin and their relation over a 2-year period. Sixteen female patients, mean age at the basal time 9.4 +/- 4.3 years, with classical Rett syndrome were enrolled. Controls were 16 healthy female subjects, mean age at the basal time 9.9 +/- 3.4 years. MEASUREMENTS: Blood samples were withdrawn in the morning at the baseline, 12 months after and 24 months after; plasma leptin and adiponectin concentrations were detected by ELISA. RESULTS: In patients, leptin concentrations significantly increased, while adiponectin concentrations significantly decreased. Both leptin and adiponectin values were significantly higher than those found in controls at each time. Leptin significantly correlated with adiponectin in patients, while there was not a significant correlation in controls. CONCLUSION: Since all patients were not obese, we might hypothesize that in Rett syndrome leptin and adiponectin might participate to clinical manifestations other than weight balance.

Rett syndrome and plasma leptin levels.

OBJECTIVE: To describe in patients with Rett syndrome (classic and preserved-speech variant) plasma leptin levels and their relationship to BMI (body mass index) and age. STUDY DESIGN: Female patients (n = 48; age range 3-20 years) affected by classic Rett syndrome were enrolled into the study. Eleven female patients, age range 3 to 20 years, with preserved-speech variant Rett syndrome were included in the study. Controls were 24 healthy female subjects, age range 3 to 20 years. Blood samples (3 mL) were withdrawn from an antecubital vein in the morning; plasma leptin concentrations were detected by enzyme-linked immunosorbent assay method. RESULTS: Patients with classic Rett syndrome and preserved-speech variant had leptin values significantly higher than controls. Leptin concentrations did not significantly differ between patients with classic Rett and preserved-speech variant. Leptin values positively correlated with age and BMI. CONCLUSIONS: Because in all patients the increased leptin concentrations were not associated to obesity, we hypothesize that in patients with Rett syndrome leptin might participate to clinical manifestations other than weight balance.

Variations of peripheral markers of serotoninergic system in selected vascular patients.

BACKGROUND AND AIM: Serotonin (5-HT), a decarboxylated derivative of tryptophan, is synthesized in the enterochromaffin cells and released into blood stream to be incorporated into platelets. At the site of endothelial lesions, platelets aggregate and secrete 5-HT that presents several vascular actions involved in thrombosis and atherogenesis. In fact, 5-HT may induce vasoconstriction in the presence of endothelial injury, aggregation of platelets, and mitogenesis of arterial smooth muscle cells and endothelial cells. It may also contribute to the vascular inflammation associated with atherogenesis by increasing the synthesis of Interleukin-6 in vascular smooth muscle cells. We evaluated serotonin levels in plasma and platelets of patients with unstable angina and ischemic stroke, to identify an association between serotonin and atherosclerosis of coronary and cerebral arteries. METHODS AND RESULTS: Twenty patients (14 men, 6 women, mean age 69 +/- 10 years) with unstable angina and 15 patients (7 men, 8 women, mean age 81 +/- 10 years) with ischemic stroke were included in the study. Twenty-four healthy subjects matched for age and sex constituted the control group. Blood samples were drawn in the morning to determine plasma and platelet concentrations of serotonin. In patients with unstable angina serotonin levels in platelets were significantly lower (p < 0.001) than those observed in controls, while serotonin concentrations in plasma did not significantly differ from those found in controls. In patients affected by stroke serotonin levels in plasma and in platelets did not significantly differ from those found in normal subjects. CONCLUSIONS: Our findings may contribute to the knowledge to different mechanisms involved in the pathogenesis of cardiac and cerebral ischemia.

Cardiac dysautonomia and serotonin plasma levels in Rett syndrome.

BACKGROUND: In Rett syndrome the autonomic nervous system is abnormal at various levels, from the central to the peripheral nervous system. A role for serotoninergic dysfunction has been suggested. OBJECTIVES: The aim of our study was to evaluate the relation between cardiac dysautonomia (expressed by means of heart rate variability) and plasma serotonin levels in girls affected with Rett syndrome. Heart rate variability and plasma serotonin levels were evaluated in 28 Rett girls aged 1-14 years. A Pearson correlation was used to determine whether there was a relationship between plasma serotonin levels and each heart rate variability parameter. RESULTS: In untreated Rett girls the plasma serotonin levels correlated with the sympathovagal balance, as expressed by the low frequency (LF) to high frequency (HF) ratio (p<0.05). CONCLUSIONS: Our results suggest that cardiac dysautonomia could be linked to serotoninergic dysfunction and that treatment with a serotonin analogue could be useful in improving the sympathovagal balance.

Stimulation of endogenous adenosine release by oral administration of quercetin and resveratrol in man.

Epidemiological evidence indicates that moderate alcohol consumption is associated with a significant decrease in the incidence of certain cardiovascular disorders, which can lead to impaired quality of life and to death. However, there are no objective data suggesting a cause-effect relationship and detailed research based on definitive working hypotheses is needed. We tested two flavonoids in man and found that these substances can belong, at least in part, to a wine-dependent mechanism, which leads to increased adenosine plasma levels. If these results could be confirmed by analyzing all the possible influences leading to blood nucleoside increase, a hypothesis of diet-dependent cellular preconditioning could be discussed.

[Meta-analysis of antiaggregant therapy trials. Proposal of an additional reading key]. / La metanalisi dei trial di terapia antiaggregante. Proposta di una chiave aggiuntiva di lettura.

The efficacy of drug treatment is conventionally assessed by clinical trials. In these studies, experimental design, data analysis and interpretation of results are based on statistical methods. It is difficult to relate to a specific patient the data obtained from statistically analysed studies of population. In our opinion the statistical parameter NNT (Number of patients Needed to Treat) indicates the effectiveness of a treatment taking into consideration the basal risk as well as the risk reduction after therapy. We applied the NNT parameter to data taken from the metaanalysis Antiplatelet Trialists' Collaboration concerning secondary prevention of adverse vascular events with antiplatelet drugs. We focused on the long-term effect of antiplatelet therapy on the adverse events reduction; in the first year of treatment we observed a NNT value of 37, in the second year a NNT value of 59 and in the third year a NNT value of 200; in the fourth year we found absence of effect. The NNT parameter allows us to evaluate immediately the economic consequences of therapeutic strategies and the clinical impact of a long-term treatment.

Experimental model of short-time exercise-induced preconditioning in POAD patients.

Regular physical exercise improves walking performance in patients affected with peripheral obliterative arterial disease (POAD). The mechanisms underlying the phenomenon are still controversial. In order to verify the hypothesis that physical conditioning of lower limbs on a treadmill and ischemic preconditioning of the heart could share some biological aspects, 14 POAD subjects underwent a training program on the treadmill consisting of five repeated submaximal exercises at five-minute and two-hour intervals preceding the maximal tolerance test. Moreover, a protocol with two daily submaximal walking exercises over one week was also performed. Pain-free and total walking distance were measured before and after they performed the program. Moreover, plasma levels of adenosine and adenosine triphosphate (ATP) were measured and polymorphonuclear (PMN) leukocyte activity was studied together with rheologic parameters. Pain-free distance was prolonged by 15.4% and 14.3%, and total distance was prolonged by 23.1% and 26.9%, in the exercises with five-minute and two-hour intervals, respectively. After one week of daily exercises, the onset of pain and the end of the test were delayed by 24% and 43.7%, respectively. An improvement in blood rheology and a reduced PMN reactivity were also observed with the three protocols, associated with an increase in plasma levels of adenosine and ATP. Similarly to ischemic preconditioning in the heart, the possibility is suggested that an adenosine-mediated mechanism may contribute to the development of physical conditioning in treadmill-trained POAD patients.

Pharmacological preconditioning of ischaemia.

Five repeated submaximal treadmill exercises at 2 h intervals following a maximal test prolong walking distance and reduce haemorheological derangement in a second maximal test in patients affected with peripheral obliterative arterial disease (POAD). An increase in adenosine plasma levels is observed during maximal tests, thus suggesting the possibility of an ischaemic preconditioning of lower limbs. The intravenous infusion of 50-100-200 mg buflomedil, and the oral administration of 300-600-900 mg of the drug in POAD patients, also produce an increase in plasma levels of adenosine. Finally, 600 mg buflomedil orally at 12 h intervals produced pulse increase in adenosine plasma levels without any accumulation of the drug or adenosine for at least one week. The possibility of a pharmacological preconditioning of ischaemia is suggested.

Pharmacokinetics and pharmacodynamics of neutrophil-associated ciprofloxacin in humans.

OBJECTIVE: To study the possibility that the penetration of the antibiotic ciprofloxacin into polymorphonuclear leukocytes (PMN) may be associated with some changes in cell reactivity. DESIGN: Superoxide anion and chemiluminescence generation induced by formyl-methionyl-leucyl-phenylalanine (fMLP) and platelet-activating factor (PAF) were studied ex vivo in 12 healthy volunteers (mean age, 53.15 +/- 16.3 years; mean body weight, 71.23 +/- 6.9 kg) at fixed intervals up to 72 hours from the administration of a single oral dose of 250 mg ciprofloxacin. Cytosolic free calcium levels ([Ca2+]i) in resting and stimulated cells were also evaluated. The dynamic parameters of the effects on PMNs were compared with the kinetic profile of the drug in plasma and in PMNs. RESULTS: Superoxide generation induced by the stimulating agents increased significantly, reaching a peak after 12 hours (+116% [p < 0.001] for fMLP and +66% [p < 0.05] for PAF). Similarly, chemiluminescence production showed a threefold increase in the response to the stimulating agents 12 hours after drug administration (p < 0.001). The increase in [Ca2+]i in stimulated PMNs was significantly potentiated (p < 0.001). The mathematic analysis of the effects of ciprofloxacin showed that time to maximal activity was between 10.4 hours (PAF-dependent [Ca2+]i increase), and 15 hours (fMLP-induced superoxide anion and chemiluminescence production). The ratio of PMNs to plasma ciprofloxacin concentration increased progressively, from 0.5 at 30 minutes to 10.4 after 24 hours. In addition, time to maximal activity and half-life differed in PMNs and in plasma (4.66 versus 1.90 hours and 13.03 versus 7.28 hours, respectively). CONCLUSIONS: Ciprofloxacin administration induced a long-lasting enhancement of PMN reactivity to fMLP and PAF. The levels of the drug in the cells were greater and more sustained in the time than those in plasma.

Increase in plasma levels of adenosine and adenine nucleotides after intravenous infusion of buflomedil in humans.

To clarify the mode of action of the vasoactive agent buflomedil, we evaluated plasma levels of adenosine and adenine nucleotides after intravenous (i.v.) infusion in humans of 50, 100, and 200 mg of the drug in 20 min. Buflomedil induced an increase of the same order of magnitude in plasma levels of adenosine and adenine nucleotides. Maximal adenosine increase (84%) was observed at the end of the infusion period, whereas peak plasma levels of ATP and ADP (69 and 55%, respectively) and of AMP (61%) were detected 10 and 5 min after discontinuation of infusion, respectively. Although the exact mode of action of buflomedil at the molecular level remains unclear, some indirect findings suggest that the increase in adenosine may be due to enhanced release rather than to inhibition of cell uptake. Because such activity of buflomedil consists of enhancement of physiologic mechanisms of vasodilation and tissue protection occurring in the course of ischemic events, new pharmacologic perspectives for the drug may arise.