The recovery of platelet cyclooxygenase activity explains interindividual variability in responsiveness to low-dose aspirin in patients with and without diabetes.

BACKGROUND: Interindividual variability in response to aspirin has been popularized as 'resistance'. We hypothesized that faster recovery of platelet cyclooxygenase-1 activity may explain incomplete thromboxane (TX) inhibition during the 24-h dosing interval. OBJECTIVE: To characterize the kinetics and determinants of platelet cyclooxygenase-1 recovery in aspirin-treated diabetic and non-diabetic patients. PATIENTS/METHODS: One hundred type 2 diabetic and 73 non-diabetic patients on chronic aspirin 100 mg daily were studied. Serum TXB(2) was measured every 3 h, between 12 and 24 h after a witnessed aspirin intake, to characterize the kinetics of platelet cyclooxygenase-1 recovery. Patients with the fastest TXB(2) recovery were randomized to aspirin 100 mg once daily, 200 mg once daily or 100 mg twice daily, for 28 days and TXB(2) recovery was reassessed. RESULTS AND CONCLUSIONS: Platelet TXB(2) production was profoundly suppressed at 12 h in both groups. Serum TXB(2) recovered linearly, with a large interindividual variability in slope. Diabetic patients in the third tertile of recovery slopes (≥ 0.10 ng mL(-1) h(-1) ) showed significantly higher mean platelet volume and body mass index, and younger age. Higher body weight was the only independent predictor of a faster recovery in non-diabetics. Aspirin 100 mg twice daily completely reversed the abnormal TXB(2) recovery in both groups. Interindividual variability in the recovery of platelet cyclooxygenase activity during the dosing interval may limit the duration of the antiplatelet effect of low-dose aspirin in patients with and without diabetes. Inadequate thromboxane inhibition can be easily measured and corrected by a twice daily regimen.

Enhanced soluble CD40 ligand contributes to endothelial cell dysfunction in vitro and monocyte activation in patients with diabetes mellitus: effect of improved metabolic control.

AIMS/HYPOTHESIS: Inflammation plays a pathogenic role in the development of accelerated atherosclerosis in diabetes. Soluble CD40 ligand (sCD40L) is enhanced in diabetes; however, the molecular mechanisms linking sCD40L to accelerated atherosclerosis in diabetes are still unclear. We tested the hypothesis that sCD40L may be involved in the vascular complications in diabetes and exerts its effect by triggering inflammatory reactions on mononuclear and endothelial cells (ECs). METHODS: We studied 70 patients, 40 with type 2 and 30 with type 1 diabetes, with a history or physical examination negative for cardiovascular disease, and 40 non-diabetic and 30 healthy subjects, matched with the type 2 and type 1 diabetic patients, respectively. Plasma and serum sCD40L, and plasma soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, E-selectin and monocyte chemo-attractant protein-1 (MCP-1) were measured. Adhesion molecules and MCP-1 release, the ability to repair an injury in ECs, and O2- generation in monocytes were analysed in vitro after stimulation with serum from patients or controls. RESULTS: Type 2 and type 1 diabetic patients had significantly higher sCD40L levels than controls. Furthermore, high sCD40L was associated with in vitro adhesion molecules and MCP-1 release, impaired migration in ECs and enhanced O2- generation in monocytes. Improved metabolic control was associated with a reduction of plasma sCD40L by 37.5% in 12 type 1 diabetic patients. Furthermore, elevated sCD40L in diabetic patients was significantly correlated with HbA1c levels. CONCLUSIONS/INTERPRETATION: Upregulation of sCD40L as a consequence of persistent hyperglycaemia in diabetic patients results in EC activation and monocyte recruitment to the arterial wall, possibly contributing to accelerated atherosclerosis development in diabetes.

In COPD patients, body weight excess can mask lean tissue depletion: a simple method of estimation.

Although a great number of studies have been carried out on the relationship between chronic obstructive pulmonary disease (COPD) and low body weight, the identification of the most suitable warning signs of this wasting condition is still under debate. It has been indicated in earlier studies that body weight alone is of limited diagnostic value concerning this clinical condition in as far as a great number of COPD patients are usually overweight. For this reason, the aim of the current research was to find parameters that take into consideration the fact that body composition should be taken into account instead of weight only, and to assess whether COPD can be considered a "protein wasting disease", defining sensitive and significant indices of lean tissue depletion in relationship to the severity of the clinical symptoms. One hundred and seventy-five stable COPD outpatients with differing degrees of bronchial obstruction and arterial blood gas abnormalities were consecutively recruited: anthropometric measurements and body composition analysis were carried out; 60 healthy subjects with normal pulmonary function, matched for sex, age and anthropometric parameters, were considered as controls. The data obtained showed a lower prevalence (9%) of underweight COPD patients in comparison with normal weight (37%) and overweight (54%) patients. In COPD patients, the phase angle measured by bioelectrical impedance analysis, whose deterioration is a good indicator of protein mass depletion, was altered by 19%, thus allowing the identification of currently malnourished subjects included in the overweight COPD patients group. In addition, significant correlations (p = 0.000) were found between the same nutritional variable, respiratory function and gas-exchange parameters, thus confirming that the more severe the stage of the pulmonary disease, the higher the degree of protein breakdown, regardless of body weight.

[The hypotriglyceridemic effects of polyunsaturated fatty acids: pathogenetic hypothesis]. / Effetto ipotrigliceridemizzante degli acidi grassi polinsaturi: ipotesi patogenetica.

A large number of experimental and clinical studies focused the attention on the role played by omega-3 polyunsaturated fatty acids on the primary prevention of vascular diseases of atherosclerotic origin, especially influencing plasma triglycerides decrease. Aim of the present work was to investigate whether a relationship between triglyceride synthesis and human energy metabolism could exist, in order to explain the hypotriglyceridemic effect of omega-3 fatty acids that could be due to any thermogenic action. Eight male subjects aged 45 years (from 20 to 62) were studied, selected on the basis of high levels of triglycerides (536.7 +/- 204.3 mg/dl), normal or high levels of total serum cholesterol (219.4 +/- 51.2 mg/dl), normal or low HDL-cholesterol (33.6 +/- 6.3 mg/dl) and moderate obesity (BMI 30.3 +/- 1.7). Anthropometric parameters (body weight, height, waist to hip ratio), body composition measurements (fat free mass, fat mass), biochemical parameters were evaluated before and 10-days after PUFAs supplementation (student t paired test) at the compressive dose of 60 mg/kg BW bis in die. At the end of the observation significant decrease of triglycerides was documented (p < 0.005), while total and HDL-cholesterol did not vary significantly, although improved values were noticed. No change in anthropometric, body composition and energy metabolism parameters was demonstrated, except for respiratory quotient and substrates oxidation: a significant increment of respiratory quotient value (p < 0.05) due both to augmented carbohydrates oxidation (p < 0.05) and correspondent lipid oxidation reduction (p < 0.05) and correspondent lipid oxidation reduction (p < 0.05) without any change in the daily total calorie consumption. In conclusion, from a clinical point of view it is possible to hypothesize, even if in a small number of subjects, that PUFAs hypotriglyceridemic effect could derive from a reduced substrate availability, due to the higher carbohydrate oxidation. In other terms, considering the metabolic cascade of triglyceride synthesis, the augmented drug-induced carbohydrate consumption could provoke a reduced availability of products of intermediate metabolism useful to triglycerides hepatic synthesis.

[Is it possible to obtain a reduction of body weight exclusively via a loss in fat mass? Experience with d-fenfluramine]. / E possibile ottenere la riduzione del peso corporeo esclusivamente attraverso una perdita di massa adiposa? Esperienze con d-fenfluramina.

Aim of the study was to observe if the administration of an anorectic drug, d-fenfluramine, in addition to hypocaloric diet, could influence the body composition and adipose mass distribution during a weight decrease programme in 17 obese women. Drug's effects plus diet on body weight changes were compared with those of a "only-diet programme" in another group of 18 obese subjects, sex and age matched. Both groups were observed for a 6-month period. All subjects were selected on the base of Index Body Weight % within 120-200 and without any therapy for other diseases. Blood samples were drawn before, during (3rd month) and after the period of observation for the measurement of OGTT, serum lipids, liver and kidney function parameters, blood cells count. Body weight and height, body composition, waist-to-hip ratio were also evaluated. Results documented: 1) significant reduction of body weight in the group kept on the combined therapy; 2) significant variation of body composition with increment of fat free mass and adipose mass decrease; 3) significant improvement of glucose tolerance, liver and kidney function parameters. In conclusion, our data show beneficial effects of d-fenfluramine on appetite reduction, influencing the carbohydrates assumption and the consequent fat mass loss with a good tolerability of the drug.

[Relationship between eating behavior and distribution of body fat]. / Relazione tra comportamento alimentare e distribuzione del grasso corporeo.

In these recent few years the study of the pathogenesis of obesity include the observation of the difference in eating behaviour between obese and non obese subjects. Therefore, current therapies now take into account, among others, also a program of behavioural therapy. On the other hand, recent studies have revealed the role of different body fat distribution on the obesity prognosis, especially considering cardiovascular risk factors. To this purpose much attention has been focused on the measurement of waist and hips circumferences and their ratio (WHR) considered important predictors of risk associated with obesity. Aim of this study was the observation of some differences in eating habits and psychological status during a 24-hr period in relationship with the android or gynecoid type of obesity. 102 outpatients were divided in two groups: 1) with WHR less than 0.85; 2) with WHR greater than or equal to 0.85. All subjects were given a questionnaire in which by a scale from 0 to 3 they expressed their appetite sensation during different hours of the day. In addition, they indicated their motivation to loose body weight. Our results demonstrated that subjects with WHR greater than or equal to 0.85 showed higher appetite sensation, during the whole day, with a peak at lunch, in comparison with subjects with WHR less than 0.85. Subjects with gynecoid type of obesity seemed to pay much attention to their body image than subjects with android type of obesity and complained less physical disorders than subjects of the second group. These preliminary data seem to suggest a non-secondary role of behavioural pattern in obesity also by affecting the different regional fat distribution.

Changes in plasma DHEAS circadian rhythm in elderly men.

Several reports focused the attention on aging that appears to exert an influence on the temporal structure in the endocrine system of man. Considering that: a) DHEAS blood levels consistently decrease as men age and b) this hormone might be involved in the early development of atherosclerosis, aim of the present work to detect: 1) the possible existence of a circadian rhythm of DHEAS in young and elderly men, 2) eventual change in parameters of other hormonal rhythms. 11 young healthy males (28 +/- 2 yrs) and 12 elderly males (73 +/- 1 yrs) were studied over a 24-hr span during spring. They were submitted to the circadian protocol for the evaluation of DHEAS, PRL and cortisol plasma levels. A significant circadian rhythm of DHEAS plasma levels was observed in the young men (mesor micrograms/dl 273.13 +/- 38.25, amplitude 41.37 +/- 9.29, acrophase at 1351 hr). In the elderly subjects no circadian rhythm was found, but amplitude and mesor appeared statistically reduced in comparison with young people (p less than 0.005 and p less than 0.001, respectively). Confirming previous results the circadian pattern of PRL and cortisol did not change in the two groups. It is suggested that both loss of rhythmicity and low levels of blood DHEAS in elderly may be involved in aging process and considered an aspect of the endocrine temporal structure of old people.

[Circadian and circannual study of the hypophyseal-gonadal axis in healthy young males]. / Studio circadiano e circannuale dell'asse ipofisi-gonadico in giovani maschi sani.

Circadian and circannual variations of Testosterone, FSH and LH secretions, other than Oral Body Temperature (OBT) have been studied in four healthy males. OBT showed a constant circadian rhythm with an acrophase located in the afternoon. Plasma Testosterone exhibited both a circadian (acrophase = hr 09,28) and a circannual rhythm (acrophase = 22 february); plasma FSH also showed a circannual rhythm (acrophase = 13 february). By mean chronogram +/- SEM we documented the highest LH levels in December and the lowest in February. These observations would suggest the hypothesis that the winter could be the period in which the hypophysis-gonadal axis in young males exhibits its maximal activity as previously documented for other hormones.

Long-term treatment with fenfluramine in obese subjects.

The effect of fenfluramine, an anorectical drug, given for nine months to a group of 156 obese subjects, on body-weight and adipose mass reduction as well as on glucose tolerance, has been studied. Subjects were divided in four different groups according to various protocols of therapy: the first group took the drug once a day in a single 60 mg dose in the morning; the second group received the drug once a day in a single 40 mg dose in the morning; the third group took the drug divided in three equal daily doses and the last group was treated with diet alone. During the first three months of treatment, fenfluramine 60 mg, given both in a single dose in the morning and divided in three equal daily doses, combined with diet, produces a significant body-weight reduction in comparison with the group of obese subjects treated with diet alone. In the following three months, it was possible to document a further body weight loss in all subjects, whatever the group to which they were assigned. At the end of the sixth month of observation, only slight differences could be demonstrated among the groups as regards the body-weight and adipose mass decrease. In addition the results failed to demonstrate a statistically different weight loss when the drug as administered in a single dose in the morning, compared with the conventional treatment of three times a day. No significant improvement of glucose tolerance was documented. In conclusion, in long-term treatment with fenfluramine, in contrast with short-term studies, no direct effect of this drug on body-weight and adipose mass decrease was demonstrated.

[Circadian and circumannual variations in the level of plasma TSH and prolactin in healthy adult males]. / Variazioni circadiane e circannuali dei livelli del TDH e della prolattina plasmatici in adulti sani di sesso maschile.

4 healthy young volunteers were submitted to the study of circadian and circannual oscillations of plasma TSH and Prolactin. Our data demonstrated the existence of a circadian rhythm for TSH with acrophase at 04,39 and a circannual rhythm of the same hormone with acrophase in January. While for Prolactin it was possible to detect a circadian rhythm with acrophase at 04,29. We failed to demonstrate any circannual variation of plasma hormonal levels.

[Modifications in the oscillation of substrates in obese subjects subjected to variations in the pattern of meal-timing]. / Modificazioni dell'oscillazione dei substrati in obesi sottoposti a variazione del ritmo di assunzione dei pasti.

In a group of obese subjects kept on hypocaloric diet during a period of 18 days, an eventual different behaviour of carbohydrates and lipids oxidation following to meal-timing manipulation (a single meal given only at 10.00 hr or at 18.00 hr of each day) has been studied by indirect calorimetry. No significant difference of body weight reduction was noticed in both dietetic regimens. In the group of obese subjects who consumed the single meal at 10.00, a slight increase of carbohydrates oxidation was noticed, without a statistical significance, whereas in the group with single meal at 18.00 h a significant increase of lipids oxidation resulted.

Circannual rhythm of insulin release and hypoglycemic effect of tolbutamide stimulus in healthy man.

Four healthy non obese young volunteers were observed for a 24-hr period, every other month, over the course of one year. Tolbutamide was injected i.v. each day of the experiment every four hours. Tolbutamide-induced insulin secretion (T.I.I.S.) was evaluated by planimetrically measuring insulin areas above basal levels. Tolbutamide-induced hypoglycemic effect was evaluated by measuring the blood glucose difference between the 5th and 25th minute after the drug injection (delta G5'-25'). The macroscopic evaluation of T.I.I.S. and delta G5'-25' (mean chronograms) permitted the detection of the existence of a circannual variation of both variables. In particular the maximum level of the blood glucose drop (delta G5'-25') was registered in February. Subsequently the quantification of the rhythm of T.I.I.S. was obtained by fitting a sine curve, according to the Cosinor method. The highest insulin release was confirmed in winter. As previously documented, the existence of a statistically significant circadian rhythm of T.I.I.S. was confirmed in the morning, i.e. the same period of the day in which insulin-induced hypoglycemia occurs.

Time-related behaviour of endocrine secretion: circannual variations of FT3, cortisol, HGH and serum basal insulin in healthy subjects.

Four healthy young male volunteers were submitted to the study of circadian and circannual bioperiodicities of several hormones: FT3, FT4, cortisol, HGH, prolactin, PTh and plasma insulin levels. They were observed for a whole year and their blood samples were collected six times a day, every other month. The results were analyzed by two-way ANOVA macroscopic analysis and Student t-test. Our data registered a circannual variation in the mean circadian plasma levels of the following hormones: cortisol (peak in December), HGH (peak in April), FT3 (peak in April), insulin (peak in February). FT4, prolactin and PTH showed no cyclic variation during the period of observation.

[Time structure of endocrine secretion. II. Circannual variations in the free fractions of tri- and tetraiodothyronine, cortisol, human growth hormone and plasma insulin in healthy subjects]. / La struttura temporale della secrezione endocrina: II. Variazioni circannuali delle frazioni libere della tri-tetraiodio tironina, del cortisolo, dell'human growth hormone e dell'insulina plasmatica in soggetti sani.

Circadian and circannual variations of several endocrine activities and their biological implications in health and diseases were described in men. Aim of our work was to perform a further observation on circannual bioperiodicities of some hormone: free fractions of T3 and T4, cortisol, HGH, PTH and serum insulin. Four healthy young males volunteered to be submitted to the study from June and their blood-samples collected six times a day, every other month, in the course of one year. Our data were analysed by macroscopic (mean chronogram) and microscopic (Cosinor test) methods. First we could document a circadian phase-shift of the highest peak of secretion, occurring in the course of the year, for FT3, FT4, Cortisol, HGH and serum basal insulin. Then we could detect a circannual oscillation of the highest diurnal secretion for FT3 (October), cortisol (December) HGH (April) and serum basal insulin (February). FT4 showed the lowest secretion in October. Almost the same cyclic variations were demonstrated when Mesors and Amplitudes of the same values were examined except for slight shiftings. PTH showed no cyclic variation during the period of observation.

[1) Temporal structure of endocrine secretion: circannual changes in insulin responsiveness to tolbutamide in man]. / 1) Struttura temporale della secrezione endocrina: variazione circannuale della responsività insulinica alla tolbutamide nell'uomo.

In our previous observations we could detect the existence of circadian rhythms of either tolbutamide-induced insulin release with the acrophase early in the morning (at 04.20) or an insulin-induced hypoglycemia with the acrophase at 10.30 a.m. Aim of our work was to extend the observation to circannual rhythms of the same parameters. Four healthy young volunteers were submitted to the study in the early months of the year and observed in a 24 hrs-period, every other month, in the course of one year. 250 mg tolbutamide were injected i.v. in each day of the experiment every four hours with starting points at a random sequence. The data were analyzed by microscopic analysis: Halberg's Cosinor method. The highest insulin release occurred in winter (Acrophase: Jan. 19 with 95% confidence limits: Oct. 31 - April 1).

[Measurement of energy expenditure through heart rate monitoring]. / Misura del costo energetico con il monitoraggio della frequenza cardiaca.

In studies of energy balance it is of utmost importance to measure with a certain degree of accuracy the energy expenditure. So far the energy cost has been measured by taking accurate diaries of various activities performed during a day. This study tries to find the possibility to measure the energy cost through heart rate, since it is correlated with oxygen consumption. In 17 obese and non obese healthy subjects the relation between oxygen consumption and heart rate has been studied minute by minute during various physical activities. Data show the existence of a very close relationship between the two variables demonstrating that continuous heart rate monitoring (dynamic ECG) may be considered as a valid tool for energy expenditure measurements. Since each subject shows his own linear equation, it is necessary to assess it before the measurement.

[Effect of scheduling of meal times on the circadian rhythm of energy expenditure]. / Influenza dell'ora di somministrazione dei pasti sul ritmo circadiano della spesa energetica.

15 obese subjects were studied under different meal-timing schedules in order to see if meal-timing could affect the circadian pattern of energy expenditure. 4 subjects were given one meal (700 Kcal.) a day at h 10 in the morning (for 3 days) or at h 18 in the afternoon (for another 3 days). 4 subjects were given 3 meals (240 Kcal. each) at h 10, h14, h 18 for 3 days. 7 subjects were kept absolutely fasting for 36 hours. O2 consumption and CO2 production were measured minute by minute for 30' every 4 hours by means of a gas-analyser Mijnardht Oxicon II. Urine Samples were taken every 4 hours for urinary nitrogen determination. Energy expenditure was calculated according to Consolation's formula. Cosinor test was used to detect circadian rhythms. A statistically significative circadian rhythm of energy expenditure could be detected in all the protocols. The observed small differences among acrophases and the overlapping of confidence's ellipses allow to conclude that meal-timing doesn't affect the circadian rhythm of energy expenditure and suggest that this rhythm can be considered endogenous.