Upregulation of inflammasome activity and increased gut permeability are associated with obesity in children and adolescents.

BACKGROUND: Immune activation contributes to the persistent state of inflammation associated with metabolic dysfunction in obesity. The specific immune receptors that sense metabolic stress signals and trigger inflammation are nevertheless largely unknown, and little is known on inflammatory and immune gene regulation in obesity. METHODS: The study includes a cross-sectional and a longitudinal arm. Forty children and adolescents were enrolled: 22 obese subjects and 18 age-matched normal weight controls. Obese subjects participated in an 18-month therapeutic protocol, based on intensive lifestyle modification (dietary regimen, physical activity and behavioral interventions). Expression of genes involved in the inflammasome pathway, plasma concentration of the inflammasome-associated pro-inflammatory cytokines (interleukin (IL)-1ß and IL-18) and indexes of microbial translocation (lipopolysaccharide (LPS), soluble CD14 (sCD14) and intestinal fatty acid-binding protein) were analyzed at baseline in obese subjects compared with controls, and after 18 months in obese subjects. RESULTS: Cross-sectional analyses showed that the LPS-induced expression of genes involved in inflammasome (NLRP3, caspase 5 and NAIP), Nod-like receptors (NLRX1 and NOD1), downstream signaling (P2RX7, RAGE, RIPk2, TIRAP and BIRC2) and effector molecules (IFN-γ, IL-12ß, IL-1ß, CCL2, CCL5, IL-6 and TNFα) was significantly increased in obese subjects at baseline as compared with normal weight controls. The baseline plasma concentration of inflammasome-related cytokines (IL-1ß and IL-18) and of microbial translocation markers (LPS and sCD14) was augmented in obese subjects as compared with controls as well. Longitudinal analyses indicated that intensive lifestyle modification resulted in a normalization of parameters in subjects with a significant reduction of BMI after 18 months. CONCLUSIONS: In children and adolescents, obesity is characterized by the activation of the inflammasome and by an alteration of gut permeability. Successful lifestyle modification is effective in reducing inflammation, suggesting that inhibition of the inflammasome may be a potential therapeutic strategy in obesity.

Adolescents and young adults with type 1 diabetes display a high prevalence of endothelial dysfunction.

AIM: Little is known about endothelial function in adolescents with type 1 diabetes, and we evaluated endothelial dysfunction, using reactive hyperaemia peripheral arterial tonometry (RH-PAT). METHODS: This prospective, observational, 1-year study focused on 73 adolescents with type 1 diabetes, using multiple daily injections or continuous subcutaneous insulin infusion. The subjects were assessed using RH-PAT, body mass index, blood pressure, fasting lipid profile, glycated haemoglobin, insulin requirements and hours of physical exercise per week. RESULTS: Endothelial dysfunction was observed in 56 patients (76.7%), with lower mean RH-PAT scores (1.26 ± 0.22 versus 2.24 ± 0.48, p < 0.0001) and higher glycated haemoglobin values at baseline (8.27 ± 1.24% versus 7.37 ± 0.54%, p = 0.006) and as a mean of the whole period since diagnosis (8.25 ± 1.22% versus 7.72 ± 0.82%, p = 0.034). A higher percentage of patients with endothelial dysfunction showed abnormal cardiac autonomic tests (p = 0.02) and were more sedentary, exercising <4 hours a week, than patients with normal endothelial function. After follow-up in 64/73 patients, we observed endothelial dysfunction in 81.8% of patients, despite a modest improvement in glycated haemoglobin. CONCLUSION: Adolescents with type 1 diabetes displayed evidence of endothelial dysfunction. Good metabolic control (glycated haemoglobin ≤7.5%, 58 mmol/mol) and regular physical activity of at least 4 h a week might be protective.

A simplified indication of metabolic syndrome to recognize subjects with a moderate risk to develop type 2 diabetes mellitus in a large Italian sample.

To propose a simplified tool to recognize subjects with a moderate risk to develop type 2 diabetes mellitus (Type 2 DM): this method would take into account only variables from metabolic syndrome definitions which are cheaply assessable. A total of 3,003 employees without diabetes in Italy who attended one annual health examination between 2009 and 2012 were enrolled in this cross-sectional study. A questionnaire was administered along with the annual health examination to record personal and familiar anamnesis. To identify Type 2 DM-prone individuals, the diabetes predictive model by Stern MP et al. was used. Then a multiple logistic regression model was developed using the predicted probability 20%+ of developing Type 2 DM as the outcome variable and a panel of easily measurable continuous baseline characteristics as explanatory variables (waist circumference, WC; body mass index, BMI; and systolic blood pressure, SBP). The optimism-adjusted area under the curve of the proposed model receiver-operating characteristic (ROC) is 0.90. The effects of the explanatory variables on the presumed Type 2 DM risk are summarized by the following adjusted odds ratio values: 2.65 for SBP (P < 0.001), 2.01 for WC (P = 0.04) and 4.64 for BMI (P < 0.001). The satisfactory ROC of the proposed model suggests the importance of simple assessments in the prognostic information on Type 2 DM risk. Such ease of use may be particularly relevant in populations facing the transition from traditional to industrial food who do not have a sophisticated health service yet.

Long-lasting immunogenicity and safety of a 2009 pandemic influenza A(H1N1) MF59-adjuvanted vaccine when co-administered with a 2009-2010 seasonal influenza vaccine in young patients with type 1 diabetes mellitus.

AIMS: To evaluate the long-lasting immunogenicity and safety of a pandemic vaccine co-administered with a seasonal influenza vaccine in young subjects with Type 1 diabetes. METHODS: Eighty patients (mean age: 16.7 ± 5.5 years, disease duration: 10.2 ± 4.7 years) were randomly assigned to receive a single or a double dose (1 month apart) of MF59-adjuvanted influenza A(H1N1) vaccine, simultaneously with a single dose of a virosome-adjuvanted trivalent influenza vaccine for the 2009-2010 season. RESULTS: One month after immunization, the rate of seroconversion to 2009 pandemic A(H1N1) was 92.5% with an overall 100% proportion of vaccinees with protective antibody titres (≥ 1:40). No significant differences were observed between vaccinees who received the one-dose or the two-dose schedule. Seasonal vaccine induced a significant increase of both seroprotection rates and antibody levels. Local adverse events at the injection site of pandemic and seasonal vaccines were reported by 66.3% and 50% of subjects, respectively. Solicited systemic adverse events, mainly mild in intensity, were reported by 26.7% of vaccinees. No subjects had an influenza-like illness during the 6-month follow-up. CONCLUSIONS: One injection of 2009 pandemic influenza A(H1N1) MF59-adjuvanted vaccine is immunogenic and safe in young patients with Type 1 diabetes who are at increased risk of influenza morbidities. Pandemic vaccine can be safely co-administered with seasonal influenza vaccine.

The selective inability to draw horizontal lines: a peculiar constructional disorder.

A patient is described who was affected by degenerative dementia and who developed severe constructional apraxia. She showed a dissociation between the construction of horizontal lines (impaired) and oblique or vertical lines (spared) which has never been reported previously. A battery of tests disclosed that this phenomenon was consistent across a range of experimental conditions and that a similar dissociation was evident in perceptual and representational domains. This peculiar clinical finding suggests that mental representations of horizontal and vertical spatial relations in an egocentric coordinate system are functionally dissociated.

Immunological patterns during regular intensive training in athletes: quantification and evaluation of a preventive pharmacological approach.

The effects of regular intensive exercise training on immune system homeostasis and the potential value of treatment with an immunostimulating agent were assessed in this randomized, double-blind, placebo-controlled, parallel-group study. A total of 60 athletes were studied over a 3-month period of regular intensive physical activity. After 1 and 3 months there were significant decreases in the immunoglobulin levels in the whole athlete population compared with baseline values. Specifically there were significant decreases in immunoglobulin M and immunoglobulin G (G1 and G2 subclasses). There was also a significant decrease in natural killer cells and a slight but significant increase in B and T lymphocytes. In the thymomodulin-treated group, unlike the placebo group, there was no significant decrease in the immunoglobulin G2 subclass and there was a significant increase in the T-helper cell subpopulation. The clinical relevance of these immunological findings should be evaluated in larger clinical and epidemiological studies.

Use of telethermography in the management of sports injuries.

Telethermography can contribute to the diagnostic process in the management of sports injuries by clearly demonstrating thermal alterations in the tissues involved. Although there are no typical images, in general hyperthermic images are found when inflammatory reactions prevail, and hypothermic pictures when compression or degenerative processes are present. Telethermography is not only an aid to diagnosis, it also appears to be an ideal tool in controlling the injury evolution and treatment efficacy. In fact this objective method of evaluation is noninvasive, innocuous and repeatable, and well-related to the clinical and functional status.

Pirprofen in the treatment of sports injuries.

Patients with sports injuries were treated with pirprofen, a non-steroidal anti-inflammatory drug, in two separate studies. In the single centre study, 39 athletes were treated with 1000 mg/day pirprofen for 2 weeks. In the multicentre study, a further 80 athletes were treated with a variable dosage (600-1200 mg/day) until the disappearance of symptoms, but for no longer than 2 weeks. Efficacy was considered excellent or good in 99/119 (83%) of the patients treated. The clinical variables of pain and mobility significantly (P less than 0.05) improved after 1 week of treatment. Tolerability was satisfactory, the main side-effects involving the gastro-intestinal tract.

Telethermographic evaluation of NSAIDs in the treatment of sports injuries.

In a multicenter double-blind clinical trial, forty-five athletes, 39 males and 6 females, mean age 20.87 yr (SD 4.48), affected by sports injuries were treated with diclofenac, suprofen, or placebo, orally administered for a period of 1 wk. An objective examination like telethermography was performed with the clinical evaluations (pain on movement or at pressure, motility, and swelling) before and after the treatment period, in all patients. Moreover, at the end of the trial both investigator and patient gave their global judgement of efficacy. The statistical analysis showed a significant superiority of diclofenac sodium versus suprofen and placebo both in patients' and in investigators' global evaluations (P less than 0.05--Kruskal-Wallis tests). This superiority appeared particularly clear in the telethermographic evaluation (P less than 0.05), which is more objective than the clinical one, attesting to the usefulness of the early administration of anti-inflammatory drugs in management of sports injuries. Furthermore, a correlation analysis showed that telethermography is a good technique in controlling the recovery process.

A receptor-antibody sandwich assay for teicoplanin.

We have developed a new method for quantifying teicoplanin in complex matrixes, a receptor-antibody sandwich assay (RASA). The method is based on bioselective adsorption of teicoplanin onto microtiter plates coated with albumin-epsilon-aminocaproyl-D-alanyl-D-alanine, a synthetic analog of its biological target, and reaction with anti-teicoplanin antibodies. The sandwich complexes are detected by incubation with peroxidase-labeled goat antibodies to rabbit IgGs and chromogenic reaction with o-phenylenediamine. The dose-response curve was linear for teicoplanin concentrations in the range from 0 to 0.15 mg/L. We used the assay to measure teicoplanin concentrations in various biological matrixes. Analytical recovery from serum was 99.5%, the interassay CV was 5.1%, and the detection limit was 30 micrograms/L (P less than 0.01). Mean analytical recoveries from other biological specimens were 98% from ascitic fluid, 100% from pleuric liquid, 104.8% from prostate homogenate, and 98.5% from bronchial expectorate.

Effects of CDP-choline on platelet aggregation and the antiaggregatory activity of arterial wall in the rat.

The effects of the acute (250 mg/kg) and chronic (250 mg/kg for two weeks) treatments with CDP-choline on platelet aggregation and thromboxane formation and on the platelet antiaggregatory activity of thoracic aorta, have been studied in the rat. The acute administration resulted mainly in reduced platelet reactivity to aggregating agents, with no change of platelet thromboxane formation. The antiaggregatory activity of aortic walls was also concomitantly reduced. After chronic treatment, the major effect was a greater antiaggregatory activity of the vessel wall in respect of the control values, whereas platelet function was not affected. CDP-choline treatment, thus exerts favourable effects especially in the acute treatment, by reducing platelet reactivity.

Diets rich in saturated, monounsaturated and polyunsaturated fatty acids differently affect plasma lipids, platelet and arterial wall eicosanoids in rabbits.

New Zealand male rabbits, on a moderate dietary fat intake (10.2% w/w) received, as the major dietary lipid, butter, olive oil and corn oil, respectively, for a period of 8 weeks. At the end of the dietary treatment, plasma total cholesterol was significantly decreased in the corn oil group, compared to butter, whereas the olive-oil-consuming rabbits had an intermediate cholesterolemia; the corn oil and olive oil groups had significantly elevated high-density lipoprotein (HDL) cholesterolemia, compared to the butter group. Maximal platelet aggregability, with collagen and arachidonic acid, did not appear to differ in the three treatment groups. Thromboxane B2 release in the sera of treated rabbits was slightly higher after corn oil administration. The arterial release of prostacyclin (PGI2), tested by perfusing platelet-rich plasma through the aorta of donor rabbits, was lowest in the corn oil group. Corn oil is the most effective dietary fat in reducing cholesterolemia, but it may also reduce PGI2 release from arteries. Butter has the most unfavorable effect on lipidemia and HDL-cholesterol, whereas dietary olive oil shows an intermediate lipid-lowering activity but preserves arterial PGI2 production.

Platelets from aged rats aggregate more, but are more sensitive to prostacyclin.

The balance between vascular eicosanoids has been explored in young (1 month of age) and aged (11 month of age) rats. PRP from mature rats was more reactive to collagen (lower threshold, greater amplitude of aggregation curve and higher TxB2 formation) than PRP from young animals. Release of 6-keto-PGF1 alpha from PRP-perfused isolated aortas (pg@ul) was higher and the inhibition of PRP aggregation after perfusion correspondingly greater, in mature rats. Platelets from aged rats were more sensitive to exogenous prostacyclin (higher inhibition of aggregation and greater accumulation of cAMP). The fatty acid compositions of plasma and platelet lipids were not different in the two age groups. Compensatory mechanisms were operating in the aged rats, counteracting the greater platelet aggregability with higher vascular prostacyclin production and greater sensitivity of platelets to this eicosanoid.

Arachidonic acid metabolites induce beta-adrenoceptor desensitization in rat lung in vitro.

The possible involvement of arachidonic acid (AA) or its metabolites in beta-adrenoceptor desensitization has been studied in rat lung parenchyma both from a functional and a biochemical point of view. In vitro perfusion of rat lungs with AA (3 X 10(-5)M for 20 min) reduced the relaxant effect of isoproterenol (ISO) on lung parenchymal strips, shown by a shift to the right of ISO dose-response curve, similar to that obtained using desensitizing concentration of specific beta-agonist. Moreover, AA treatment reduced the capacity of ISO to stimulate adenylate-cyclase activity, whereas the number of beta-receptor binding sites was not significantly modified. Inhibition of cyclo-oxygenase pathway by indomethacin (INDO) (1.5 X 10(-5)M) prevented both the loss of ISO-relaxing capacity and the decrease of adenylate-cyclase activity induced by AA treatment. In order to support the role of eicosanoids in beta-adrenoceptor desensitization, changes of endogenous free AA levels have also been studied in lung homogenates. Perfusion of rat lung with ISO (10(-6)M for 20 min) decreased by about 50% the levels of free AA and the pretreatment with BW755C (9 X 10(-5)M), a lipo- and cyclo-oxygenase inhibitor, prevented this phenomenon. On the basis of these results, we suggest that the activation of AA cascade is actually involved in beta-adrenoceptor desensitization in lung tissues with a possible interference at the site beyond the drug-receptor interaction.

Oral polyunsaturated phosphatidylcholine reduces platelet lipid and cholesterol contents in healthy volunteers.

The effects of orally administered polyunsaturated phosphatidylcholine (PPC) on plasma lipids, lipoproteins and platelet function and composition were studied in seven healthy male volunteers. PPC (Nattermann & Cie, GmbH, Cologne, Federal Republic of Germany), 10 g/day, was given for a 6-week period after a 4-week wash out; laboratory tests were repeated after a further 4-week period after the end of treatment. PPC did not appear, during treatment, to modify the levels of plasma total cholesterol and triglycerides. High density lipoprotein (HDL) cholesterol levels were, however, increased after six weeks of PPC. The most dramatic changes occurred in platelet membrane composition: the total lipid/total protein and the cholesterol/protein ratios were reduced significantly, whereas increases of the phospholipid/total lipid ratio and of the linoleic acid membrane content were observed. Platelet function tests, both in whole blood and in platelet rich plasma, were not modified. Similarly, the thromboxane B2 formation after standard stimuli and the sensitivity to exogenous prostaglandin I2 also were unchanged. During the final wash out period following treatment, a reduction of plasma total and low density lipoprotein (LDL) cholesterol levels also was recorded. PPC appears to be capable of modulating lipid exchanges between cell membranes and the plasma compartment.

Heated fat, vitamin E and vascular eicosanoids.

A semisynthetic diet containing adequate amounts of vitamin E and 10% (w/w) of a mixture of polyunsaturated oils subjected to heating and characterized by elevated indexes of thermal alteration (polar component, dimer triglyceride, altered triglyceride contents and reduced alpha-tocopherol levels) was fed to growing male rats for a period of eight weeks. It resulted in a selective alteration of the production of vascular eicosanoids (elevation of platelet thromboxane formation and decrease of vascular prostacyclin release) compared to the values found in rats fed a diet containing a fresh mixture of polyunsaturated oils. Major nutritional parameters, plasma lipids and the fatty acid profiles of plasma, liver and heart lipids were not different in the two groups of animals. Supplementation of an excess vitamin E (300 mg/kg) to the diet containing heated fat neutralized the adverse effects of heated fat on vascular eicosanoid production.

Sex differences in platelet thromboxane and arterial prostacyclin production in control and n-6 fatty acid supplemented rats.

Sex differences in eicosanoid production in platelets and vessel walls have been studied in control and n-6 fatty acid supplemented rats. In platelet rich plasma (PRP) of control female rats, arachidonic acid (AA) levels in phospholipids (PL), thromboxane B2 (TxB2) formation following collagen stimulation and aggregatory responses to collagen were higher than in PRP of male rats. 6 keto PGF1 alpha release from PRP-perfused isolated aortas were the same for both sexes, but the antiaggregatory activity of the wall was higher in males than in females, in association with a greater sensitivity of male platelets to prostacyclin. The administration of n-6 fatty acid supplements increased AA level in PL, TxB2 production and aggregation only in male platelets. Production of 6 keto PGF1 alpha and the antiaggregatory activity of aortic walls were reduced after dietary treatment in males, but biochemical and functional parameters were not correlated in females. The results indicate complex sex-related differences in fatty acid metabolism and eicosanoid production, and in responses to n-6 dietary fatty acids in platelets and the vascular system in the rat.

[Preventive medicine in secondary spondyloarthrosis caused by chronic microtraumatism in helicopter personnel]. / Aspetti di medicina preventiva nella spondiloartrosi secondaria a microtraumatismo cronico nel personale elicotterista.

After an examination of the three operational stages in the modern concept of preventive medicine, the main pathogenetic cofactors in secondary arthrosis following chronic microtraumatisation are identified, described and evaluated in order to establish the correct preventive approach to the condition in helicopter pilots.