Actividad física y factores de riesgo cardiovascular: evidencia de su interrelación a nivel nacional / Physical activity and cardiovascular risk factors: evidence of their interrelation nationwide

RESUMEN Antecedentes: En nuestro país la prevalencia de diabetes tipo 2 (DT2) y de factores de riesgo cardiovascular (FRCV) aumenta continuamente. Aunque el fenómeno se acompaña de adopción de estilos de vida no saludable que facilitan dicho crecimiento, es escasa la implementación de estrategias que puedan modificar la situación. Objetivo: Revisar la evidencia disponible sobre la magnitud del problema de la diabetes y los FRCV en nuestro país, su posible relación con la práctica de actividad física y potencial mecanismo de acción. Metodología: Evaluación de datos de la tercera Encuesta Nacional de Factores de Riesgo (ENFR) e información referida a factores que contribuyen al crecimiento de la prevalencia de DT2. Igualmente estrategias exitosas utilizadas a nivel mundial para su prevención. Resultados: El índice de masa corporal registrado en la población estudiada muestra un aumento del porcentaje de personas con sobrepeso/obesidad inverso a la práctica de actividad física. Igualmente los resultados de las pruebas de tolerancia a la glucosa oral muestran que sus alteraciones (prediabetes/diabetes) son menores entre quienes realizaban actividad física. El porcentaje de personas con valores de presión arterial dentro del rango normal al igual que de colesterol circulante (según valores meta de guías internacionales), es también significativamente menor entre quienes practicaban actividad física. Conclusión: La evidencia presentada demuestra objetivamente la necesidad/ventajas de implementar un programa de prevención primaria de diabetes a gran escala a nivel nacional para disminuir su crecimiento y la pertinencia de incluir la práctica de actividad física como estrategia de prevención tal como propone el PPDBA.

ABSTRACT Background: In our country, the prevalence of type 2 diabetes (DT2) and cardiovascular risk factors (CVRF) increases continuously. Although the phenomenon is accompanied by the adoption of unhealthy lifestyles that facilitate such growth, there is little implementation of strategies that can modify the situation. Objective: To review the available evidence on the magnitude of the problem of diabetes and CVRF in our country, its possible relationship with the practice of physical activity and potential mechanism of action. Methodology: Evaluation of data from the Third National Survey of Risk Factors (ENFR) and information referred to factors that promote the prevalence growth of T2D. Additionally, successful strategies have been used worldwide for its prevention. Results: The body mass index registered in the studied population shows an increase in the percentage of people with overweight/obesity inverse to the practice of physical activity. Likewise, the results of the oral glucose tolerance tests show that their alterations (prediabetes/ diabetes) are lower among those who performed physical activity. The percentage of people with blood pressure values within the normal range as well as circulating cholesterol (according to target values of international guidelines), is also significantly lower among those who practiced physical activity. Conclusion: The presented evidence objectively demonstrates the need/advantages of implementing a large-scale diabetes primary prevention program at the national level to.

Illicit drugs and pharmaceuticals in swimming pool waters.

The occurrence of illicit drugs (cocaine, opioids, amphetamines and cannabis derivatives), some of their metabolites and 48 pharmaceuticals, was investigated in pool and source waters in ten Italian indoor swimming pools. The samples were analyzed by highperformance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), after solid phase extraction (SPE). Cocaine and its metabolites were found in nine swimming pools, at concentrations from 0.3 to 4.2 ng/L for cocaine, 1.1 to 48.7 ng/L for norcocaine, 0.7 to 21.4 ng/L for benzoylecgonine and 0.1 to 7.3 ng/L for norbenzoylecgonine. Opioids, amphetamines and cannabis derivatives were never detected. The most frequent pharmaceuticals were anti-inflammatory drugs: ibuprofen was found in all the pool waters, with a maximum 197 ng/L and ketoprofen was detected in 9/10 samples (maximum 127 ng/L). Among anticonvulsants, carbamazepine and its metabolite, 10,11-dihydro-10,11dihydroxycarbamazepine, were frequent in swimming pool water (8/10 samples) at concentrations up to 62 ng/L. The cardiovascular drug valsartan was also found frequently (8/10 samples), but at lower concentrations (up to 9 ng/L). Other pharmaceuticals were detected occasionally and at lower concentrations (atenolol, enalapril, paracetamol, hydroclorothiazide, irbesartan and dehydro-erythromycin). Carbamazepine, irbesartan and dehydroerythromycin were detected at very low levels (up to 5 ng/L) in only one of the four source water samples. A quantitative risk assessment showed that the health risk for humans to these substance in swimming pool waters was generally negligible, even for vulnerable subpopulations such as children and adolescents.

Relationship of galectin-3 with obesity, IL-6, and CRP in women.

PURPOSE: To evaluate the association of galectin-3 (Gal3) with obesity and inflammatory status in a cohort of metabolically healthy, predominantly African-American women with varying cardiovascular disease (CVD) risk as determined by CRP levels. METHODS: We assessed the association between BMI and serum levels of Gal3, IL-6, CRP, and adiponectin in metabolically healthy women (N = 97) to determine the overall association between Gal3, obesity, and inflammation in groups at different CVD risk. RESULTS: Obese women had significantly higher serum Gal3 compared to non-obese participants (P = 0.0016), although Gal3 levels were comparable among different classes of obesity. BMI (R 2 = 0.1406, P = 0.0013), IL-6 (R 2 = 0.0689, P = 0.035), and CRP (R 2 = 0.0468, P = 0.0419), but not adiponectin, positively predicted the variance of Gal3 levels in the total study population. However, the predicting effect of BMI (R 2 = 0.2923, P = 0.0125) and inflammation (R 2 = 0.3138, P = 0.038) on Gal3 was only present in women at low/moderate risk of CVD (CRP ≤ 3 µg/mL). CONCLUSIONS: Gal3 is positively correlated with obesity and inflammation in women, while the presence of elevated CVD risk may disturb the strength of Gal3 as a biomarker of inflammation.

Optimal bounds with semidefinite programming: An application to stress-driven shear flows.

We introduce an innovative numerical technique based on convex optimization to solve a range of infinite-dimensional variational problems arising from the application of the background method to fluid flows. In contrast to most existing schemes, we do not consider the Euler-Lagrange equations for the minimizer. Instead, we use series expansions to formulate a finite-dimensional semidefinite program (SDP) whose solution converges to that of the original variational problem. Our formulation accounts for the influence of all modes in the expansion, and the feasible set of the SDP corresponds to a subset of the feasible set of the original problem. Moreover, SDPs can be easily formulated when the fluid is subject to imposed boundary fluxes, which pose a challenge for the traditional methods. We apply this technique to compute rigorous and near-optimal upper bounds on the dissipation coefficient for flows driven by a surface stress. We improve previous analytical bounds by more than 10 times and show that the bounds become independent of the domain aspect ratio in the limit of vanishing viscosity. We also confirm that the dissipation properties of stress-driven flows are similar to those of flows subject to a body force localized in a narrow layer near the surface. Finally, we show that SDP relaxations are an efficient method to investigate the energy stability of laminar flows driven by a surface stress.

[Environmental surveillance of a sample of indoor swimming pools from Emilia Romagna region: microclimate characteristics and chemical parameters, particularly disinfection by products, in pool waters]. / Aspetti igienico-ambientali di un campione di piscine coperte della Regione Emilia Romagna: valutazione delle condizio- ni microclimatiche e dei principali parametri chimici delle acque, con particolare riferimento alla presenza di sottopro- dotti della disinfezione.

The aim of the present study was to investigate the environmental and healthy aspects from a representative sample of indoor swimming pools located in the Emilia Romagna region. During the sampling sessions, the occupational environment was evaluated in terms of microclimate parameters and thermal comfort/discomfort conditions. Moreover the chemical risk was assessed by analyzing from the pool water the presence of disinfection by-products (DBPs), such as: trihalomethanes (THMs), haloacetic acids (HAAs), chlorite, chlorate and bromate. The analytical results are in agreement with the Italian legislation (Accordo Stato-Regioni; 2003) even if in some of the sampled indoor swimming pools, the dosed combined chlorine levels, were greater than the Italian limit. With the regard to the microclimate conditions evaluation, the considered thermal indices, Predicted Mean Vote (PMV) and Predicted Percentage of Dissatisfied (PPD%), described a satisfactory occupational environment. Among DBPs, the THMs mean levels (41.4 +/- 30.0 microg/l) resulted close to the values of the current Italian drinking water legislation, and seem to not represent an health issue. The pool waters chlorate levels (range: 5 - 19537 microg/l) need further investigations as recent epidemiological studies on drinking water hypothesized a potential genotoxicity effect of these compounds which are involved in cellular oxidative processes.

[Exposure to organic halogen compounds in drinking water of 9 Italian regions: exposure to chlorites, chlorates, thrihalomethanes, trichloroethylene and tetrachloroethylene]. / Valutazione dell'esposizione a composti organoalogenati nelle acque potabili di 9 Province Italiane: indagine sulla presenza di cloriti, clorati, trialometani, trielina e tetracloroetilene.

This study investigated the exposure to organohalogens compounds in drinking water from 9 Italian towns (Udine, Genova, Parma, Modena, Siena, Roma, L'Aquila, Napoli and Catania). Overall, 1199 samples collected from 72 waterworks were analyzed. THMs, trichloroethylene and tetrachloroethylene were evaluated using the head-space gas chromatographic technique (detection limit of 0.01 microg/l; chlorite and chlorate analysis was performed by ion chromatography (detection limit of 20 microg/l). THMs were evidenced in 925 samples (77%) (median value: 1.12 micro/l; range: 0.01-54 mciro/l) and 7 were higher than the THMs Italian limit of 30 microg/l. Chlorite and chlorate levels were higher than the detection limit in 45% for chlorite and in 34% for chlorate samples; median values were 221 microg/l and 76 microg/l, respectively. Chlorite values were higher than the chlorite Italian limit (700 microg/l) in 35 samples (8.7%). Trichloroethylene and tetrachloroethylene were measured in 29% and 44% of the investigated samples and showed values lower than the Italian limit (highest levels of 6 microg/l and 9 microg/l, respectively). The low levels detected of THMs, trichloroethylene and tetrachloroethylene have no potentials effects on human health, whereas, the levels of chlorite and chlorates should be further evaluated and their potential effects for the populations using these drinking waters, better understood.

Adipokines in cord blood and risk of wheezing disorders within the first two years of life.

BACKGROUND: Adipokines are involved in the regulation of many inflammatory processes and are present at very high concentrations in cord blood of term infants. OBJECTIVE: We analysed data of a large prospective birth cohort study to examine whether adiponectin and leptin concentration in cord blood are determinants of wheezing disorders in children within the first 2 years of life. METHODS: Seven hundred and forty mothers and their newborns were included in this analysis. Adiponectin and leptin concentrations were measured in cord blood. The cumulative incidence of physician-reported asthma or obstructive bronchitis was recorded during a 2-year follow-up. RESULTS: During the first 2 years of life, asthma or obstructive bronchitis was reported by the caring paediatricians for 157 (19.6%) of the children. We found a strong interaction of cord blood adiponectin and history of atopic disease in the mother with respect to the risk of physician-reported asthma or obstructive bronchitis (P=0.006). Compared with children with cord blood levels in the middle quintile (reference category), the odds ratios for physician-reported asthma or obstructive bronchitis in the bottom quintile and top quintile were 0.14 [95% confidence interval (CI) 0.02-0.90] and 2.12 (95% CI 0.67-6.66), respectively (P for trend=0.0003), among children of mothers with a history of atopy. This association was independent of other established risk factors. Leptin levels in cord blood were not associated with risk of asthma or obstructive bronchitis. CONCLUSIONS: In children of mothers with a history of atopy, concentrations of adiponectin in cord blood could play an important role in determining risk of wheezing disorders in early childhood.

Defining the role of T cell-derived leptin in the modulation of hepatic or intestinal inflammation in mice.

The role of leptin in the immune system has been well established. While adipocytes represent the major source, leptin production by lymphocytes, infiltrating at the site of inflammation, was recently demonstrated. However, the significance of this locally released leptin remains unresolved. In the present study, two models in which absence of leptin-signalling is associated with protection were employed: the model of ConA-induced hepatitis and the CD4(+)CD45Rb(high) transfer model of colitis. For the ConA model, scid mice were reconstituted with either WT or leptin-deficient (ob/ob) CD4(+) T cells. Eight weeks post transfer, ConA was injected and serum ALT, TNFalpha, leptin as well as liver mononuclear cell activation and histological signs of inflammation were evaluated. No difference between recipients of WT or ob/ob cells was observed for any of the parameters evaluated. In the second model, either WT or ob/ob CD4(+)CD45Rb(high) cells were transferred into scid mice. No histological differences were detected, although recipients of ob/ob cells showed higher weight loss compared to recipients of WT cells. Spontaneous production of IL-6 from colon cultures obtained from recipients of ob/ob cells was reduced compared to recipients of WT cells, whereas stimulation of lamina propria lymphocytes with leptin resulted in a higher IFNgamma release in recipients of ob/ob cells compared to recipients of WT cells. In conclusion, the present study provides evidence that T cell-derived leptin does not play a major role in the regulation of the inflammatory process, indicating that the adipose tissue is the critical player in the immune-modulating effects of leptin.

Leptin receptor expression on T lymphocytes modulates chronic intestinal inflammation in mice.

BACKGROUND: Leptin regulates appetite through the long isoform of its receptor in the hypothalamus. Although leptin regulates immune responses, it is still unknown whether a direct effect of leptin on lymphocytes is required. AIMS: To clarify whether expression of leptin receptors on T lymphocytes modulates intestinal inflammation in mice. METHODS: The model of colitis induced by transfer of CD4(+)CD45RB(high) (RB(high)) cells into scid mice was used. Wild-type (WT) or leptin receptor deficient (db/db) RB(high) cells were transferred into scid mice and development of colitis evaluated. RESULTS: Leptin receptors were expressed on both RB(high) and RB(low) cells. Intestinal lymphocytes of mice with colitis expressed high leptin levels compared with healthy controls whereas the opposite was true for serum leptin levels. Transfer of RB(high) cells from db/db mice induced delayed disease compared with transfer of WT cells. A high rate of apoptosis in lamina propria lymphocytes and reduced cytokine production were observed early on in scid mice receiving db/db RB(high) cells. These effects were not due to the high levels of glucocorticoids present in db/db mice as administration of corticosterone to WT mice failed to reproduce this phenomenon. High expression of peroxisome proliferator activated receptor gamma was observed in the colon of recipients of db/db compared with WT cells. Freshly isolated db/db RB(high) cells produced low levels of interferon gamma. Despite delayed onset of colitis, as disease progressed differences between mice receiving WT or db/db cells were no longer apparent. CONCLUSIONS: These results suggest that leptin affects the immune response, partly by acting on the long isoform of its receptor expressed on T lymphocytes.

[Halogenated volatile organic compounds in bottled mineral water and soft drinks]. / Composti Alogenati Organici Volatili (AOV) nelle acque minerali naturali e in altre bevande di largo consumo.

74 mineral natural water samples and 56 samples of different commercial drinks have been analysed by head-space chromatography in order to evidence the presence of volatile halogenated organic compounds (VHO). Trihalomethanes (THM) as drinking water chlorination by-products and trichloroethane, carbon tetrachloride, trichloroethylene and tetrachloroethylene as ubiquitarious substances have been investigated. The presence of VHO has been evidenced in 20,3% of mineral natural water samples and in the 58,9% of the commercial soft drinks: this latest group has usually shown higher levels of the investigated compounds. The results of the present study has been compared with a similar study performed in 1991 in the same area: the VHO values observed in the present study appear to be lower than those obtained in the previous study.

[Microbiological characterization of solid wastes and aerosol in a municipal solid waste landfill site]. / Caratterizzazione microbiologica dei rifiuti solidi e degli aerosol che si generano nelle discariche controllate di rifiuti solidi urbani.

Authors report data about microbiological characterization of solid wastes and aerosol in the municipal solid waste landfill site in Poiatica (RE). In solid waste samples high values of total coliform and fecal coliform were observed (10(5)-10(6) CFU/g): total bacterial counts at 22 degrees, at 36 degrees and at 44 degrees ranged from 10(7) to 10(9) CFU/g. Aerosol samples collected during waste movement in the landfill site showed values of total and fecal bacterial ranging from 10(3)-10(4) CFU/m3. Staphylococci and fungi reported the same values while streptococci, total and fecal coliform and spore evidenced lower values. Municipal solid wastes and aerosol have to be considered as an infective substrate: it is necessary to adopt protective barriers in occupationally exposed subjects.

[Exposure to water disinfection by-products and adverse pregnancy outcomes: results of a case-control study carried out in Modena (Italy)]. / Esposizione a sottoprodotti della disinfezione delle acque potabili ed effetti sul neonato: studio caso-controllo presso l'azienda ospedaliera Policlinico di Modena.

Chlorination By Products (CBPs) in drinking water have been associated with an increased risk of adverse pregnancy outcomes, such as small term birth (STB) and preterm delivery. Up to date epidemiological evidence is weakened by a generally inaccurate exposure assessment, often at an ecological level: in this study the exposure is evaluated at the individual level. A case control study with incident cases was performed in Modena between October 1999-September 2000. 332 subjects were enrolled: 93 preterm births (26th-37th week of pregnancy), 73 STB (from 38th week, and weight less than the lowest 10th percentile) and 166 controls. Exposure was assessed both by applying a questionnaire on personal habits and by personal water sampling directly at subjects' home. THMs were analysed in all samples, chlorite and chlorate in water samples treated with chlorine dioxide. Subjects usually drinking tap water were few (5.2%): most of them were living in areas supplied by water treated with chlorine dioxide (87%). Levels of THMs were low (mean: 0.73 microgram/l), while chlorite and chlorate concentrations were relatively high (mean: 217.8 microgram/l for chlorites and 95.2 microgram/l for chlorates). Preterm birth did not show any significant association with CBPs, while STB appeared significantly associated, after adjusting for many potential confounders, with CBPs induced by chlorine dioxide treatment, especially with levels of chlorate higher than 200 microgram/l (OR: 4.7; 95%CI: 1.15-19.72). The association between STB and chlorate must be investigated further as the number of water utilities applying chlorine dioxide as disinfection treatment is increasing.

[Presence of disinfection by-products (DBPs) and other halogenated compounds in drinking water samples collected in the areas of Modena and Parma]. / Indagine sulla presenza di sottoprodotti della clorazione (Disinfection By-Products: DBPs) ed altri composti alogenati nelle acque potabili di Modena e Parma.

The Authors report data about the presence of Disinfection By-Products (DBPs) and other halogenated compounds in drinking water samples collected in the areas of Modena and Parma (20 water supplies). Trihalomethanes, chlorite and chlorate (only in water samples treated with chlorine dioxide), and halogenated compounds were investigated. On the whole, trihalomethanes were evidenced in the 85% of the samples (n. 285) at low levels, while chlorite and chlorate were present in the 67% and 63% of the treated samples with chlorine dioxide (257 samples). Chlorite mean and median values were 225.70 microg/l and 136.75 microg/l respectively, ranging from 20 to 2000 microg/l. Chlorate concentrations were lower than chlorite: the mean value was 102.93 mg/l, while median level was 50 microg/l (range: 20-1500 microg/l). The high concentrations of chlorite and the wide range of values within each municipality plant in Modena and Parma suggest to investigate further in order to evaluate the human exposure in drinking water thoroughly.

[Epidemiology of work related injuries in young people: results of a survey carried out in Modena (Italy) between January and June 2000]. / Epidemiologia degli infortuni lavorativi in minori: risultatidi una indagine condotta nella città di Modena nel periodo gennaio-giugno 2000.

Work related injuries, above all those involving young people, are an important health and social issue, even though up to now small attention has been deserved in spite of the presence of about 68 workers per 1000 young people and the occurrence of 27400 injures in young people in 2000 in Italy. This study was aimed at improving the knowledge on work related injures occurring in Modena in 14-17 year old subjects in the period January-June 2000. A descriptive epidemiological study was carried out. Information was collected at the two emergency departments operating in Modena by checking hospital and INAIL records. Injures were defined as events caused by a violent external cause producing one or more lesions. Injuries were defined as work related when occurring during working activities or "in itinere". Work related injures and other injures were compared using the different statistical methods. Work related injuries occurring in young people during January-June 2000 in Modena were 76 (6-month incidence: 1.5 per 100 subjects of the same age) and represent 8.5% of all injuries. The most involved subjects were 17 year old males working in the industrial field, and in most cases prognoses were lasting less than 8 days. A Cluster Analysis identified two types of injures: the "in itinere" ones which resulted similar to the road accidents, both for body sites involved and for the way of occurrence and the injuries occurring at the working place characterised by a high frequency of lesions concerning hand, head, above all eyes. The study showed a remarkable incidence of work related injuries among 14-17 year old subjects in Modena in the first 6 months of 2000. Nevertheless many difficulties in finding information raised during the survey: a higher accuracy and completeness in collecting and recording of the data is needed to better define the epidemiological aspects of this issue.

Air quality and well-being perception in subjects attending university libraries in Modena (Italy).

We studied four libraries in the University of Modena and Reggio Emilia (Northern Italy) to determine the presence of polluting agents such as total dusts, formaldehyde and other volatile organic compounds (VOCs) including benzene, toluene and xylenes and to assess the sense of well-being perceived by library users. This investigation was suggested by an increase in reported symptoms related to Sick Building Syndrome (SBS) observed in recent decades among people spending most of their time in various indoor environments, including libraries. The microclimatic conditions and the concentrations of pollutants indicated an acceptable situation on the whole, even though a wide range of total dust values (40-350 microg/m3) and total VOCs (203-749 microg/m3) was observed. However, the perception of the different environmental parameters by the 130 library users that were interviewed identified the existence of some discomfort mainly caused by the feeling of poor ventilation. Moreover, 78.5% of the subjects stated they had at least one of the 16 investigated symptoms potentially related to a SBS. The place of occurrence of the self-reported symptoms was also investigated, the symptoms arising during library attendance more frequently than elsewhere were only four, and in particular feeling hot, sore eyes, dry throat and breathing difficulties. Overall, our study has shown the existence of an association between microclimatic perceptions as reported by library users and subjective symptoms related to SBS, considering the four libraries separately, the highest prevalence of self-reported symptoms was found in the library where environmental discomfort as perceived by users was greatest. Nevertheless, an association between subjective self-reported symptoms and both microclimatic conditions as resulted by instrumental measurements and/or pollutants concentrations was not apparent.

IL-1 beta -converting enzyme (caspase-1) in intestinal inflammation.

IL-1 beta-converting enzyme (ICE; caspase-1) is the intracellular protease that cleaves the precursors of IL-1 beta and IL-18 into active cytokines. In the present study, the effect of ICE deficiency was evaluated during experimental colitis in mice. In acute dextran sulfate sodium-induced colitis, ICE-deficient (ICE KO) mice exhibited a greater than 50% decrease of the clinical scores weight loss, diarrhea, rectal bleeding, and colon length, whereas daily treatment with IL-1 receptor antagonist revealed a modest reduction in colitis severity. To further characterize the function of ICE and its role in intestinal inflammation, chronic colitis was induced over a 30-day time period. During this chronic time course, ICE KO mice exhibited a near complete protection, as reflected by significantly reduced clinical scores and almost absent histological signs of colitis. Consistently, colon shortening occurred only in dextran sulfate sodium-exposed wild-type mice but not in ICE KO mice. Protection was accompanied by reduced spontaneous release of the proinflammatory cytokines IL-18, IL-1 beta, and IFN-gamma from total colon cultures. In addition, flow cytometric analysis of isolated mesenteric lymph node cells revealed evidence of reduced cell activation in ICE KO mice as evaluated by surface expression of CD3 CD69 and CD4 CD25. We conclude that inhibition of ICE represents a novel anti-inflammatory strategy for intestinal inflammation.

Lessons from interleukin-deficient mice: the interleukin-1 system.

The study of cytokine-deficient mice has provided important information for a better understanding of inflammatory processes. In this report, the characterization of mice deficient for various components of the interleukin (IL)-1 system is reviewed. Results obtained by studying mice deficient for IL-1alpha, IL-1beta, IL-1 receptor antagonist, IL-1 receptor type I, IL-1 receptor accessory protein, IL-1 receptor-associated kinase, and the IL-1beta-converting enzyme caspase-1 are summarized. Because some of the components of the IL-1 system are shared with IL-18, similarities between IL-1beta and IL-18 are also discussed.

Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-gamma and TNF-alpha production.

Interleukin (IL)-18, initially described as interferon (IFN)-gamma-inducing factor, is expressed in the inflamed mucosa of patients with Crohn's disease. To investigate the role of IL-18 in intestinal inflammation, the effect of neutralizing antimurine IL-18 antiserum in dextran sulfate sodium (DSS)-induced colitis in BALB/c and C57BL/6 mice was examined. During a dose response of DSS, levels of colonic IL-18 increased parallel with clinical worsening. With the use of confocal laser microscopy, the increased IL-18 was localized to the intestinal epithelial layer. Anti-IL-18 treatment resulted in a dose-dependent reduction of the severity of colitis in both BALB/c and C57BL/6 mice. Colon shortening following DSS-induced colitis was partially prevented in the treatment groups. In the colon tissue homogenates, IFN-gamma concentrations were lower in the anti-IL-18-treated DSS-fed mice compared with untreated DSS-fed mice. This suppressive effect of anti-IL-18 administered in vivo was also observed on spontaneous tumor necrosis factor-alpha, IL-18, and IFN-gamma production from ex vivo colon organ cultures. The stimulation of lamina propria mononuclear cells by IL-18 and IL-12 resulted in a synergistic increase in IFN-gamma synthesis. These findings suggest that IL-18 is a pivotal mediator in experimental colitis.

A novel IL-18BP ELISA shows elevated serum IL-18BP in sepsis and extensive decrease of free IL-18.

IL-18 binding protein (IL-18BP) is a circulating antagonist of the proinflammatory Th1 cytokine IL-18. It effectively blocks IL-18 by forming a 1:1 high affinity (Kd=400 pM) complex, exhibiting a very low dissociation rate. We have developed a sandwich ELISA for IL-18BPa and determined its limit of detection (62 pg/ml). Interference by IL-18 and related cytokines, as well as cross reactivity with other IL-18BP isoforms (b, c, and d) were determined. Using this ELISA, we measured serum IL-18BPa in large cohorts of healthy individuals and in septic patients. Serum IL-18BPa in healthy individuals was 2.15+/-0.15 ng/ml (range 0.5-7 ng/ml). In sepsis, the level rose to 21.9+/-1.44 ng/ml (range 4-132 ng/ml). Total IL-18 was measured in the same sera by an electrochemiluminescence assay and free IL-18 was calculated based on the mass action law. Total IL-18 was low in healthy individuals (64+/-17 pg/ml) and most of it ( approximately 85%) was in its free form. Total IL-18 and IL-18BPa were both elevated in sepsis patients upon admission (1.5+/-0.4 ng/ml and 28.6+/-4.5 ng/ml, respectively). At these levels, most of the IL-18 is bound to IL-18BPa, however the remaining free IL-18 is still higher than in healthy individuals. We conclude that IL-18BPa considerably inhibits circulating IL-18 in sepsis. Yet, exogenous administration of IL-18BPa may further reduce circulating IL-18 activity.

Regulation of free and bound leptin and soluble leptin receptors during inflammation in mice.

Leptin, an appetite-regulating hormone/cytokine, circulates both free and bound to soluble leptin receptors (s-leptin R). An electrochemiluminescence (ECL) assay for the quantitative measurement of murine s-leptin R was developed. The absence of s-leptin R immunoreactivity in the serum of db(pas)/db(pas)mice demonstrated the specificity of the assay, which detected s-leptin R both in the free form and complexed with leptin. The distribution of free vs bound leptin and the regulation of s-leptin R were evaluated in mice following administration of the pro-inflammatory stimuli endotoxin (100 microg/mouse) and turpentine (100 microl/mouse). Both endotoxin and turpentine significantly increased serum leptin and s-leptin R levels compared to control mice. The distribution of free vs bound leptin was not altered by administration of endotoxin or turpentine. In fact, approximately 50% of total leptin was present in the free form in either control, endotoxin- or turpentine-injected mice. On the contrary, during the hyperleptinemia of pregnancy, only 10% of total leptin was present in the free form. We conclude that inflammation leads to the increase of both bound and free leptin. Therefore, the total amount of bioactive leptin is increased during acute inflammation, suggesting that leptin participates in the host response to inflammation.