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Airway inflammation is regarded as a central feature of asthma and is mostly sustained by eosinophilic infiltrate. Recent studies have shown that a co-activation of eosinophil- and neutrophil-dependent inflammatory mechanisms might explain why some asthmatics do not respond to conventional asthma therapy. The aim of our study is to determine whether neutrophilic inflammation was involved in 55 allergic children with mild-moderate persistent asthma and the relationship with the response to steroid treatment. Before the sputum analysis, all children underwent spirometry with the reversibility test, and were divided into two groups on the basis of the response (such as >12% of baseline FEV1): group 1 positive and group 2 negative. Eosinophil cationic protein concentrations were measured by radioimmunoassay and neutrophyl myeloperoxidase (MPO) concentrations were measured by an MPO-EIA. Ten healthy children of comparable ages served as control group. Total IgE, FEV1 and FEV/FVC values were similar in both groups. The sputum macrophage count was higher in controls than in allergic asthmatics, but there was no difference between groups 1 and 2 (59.6% vs 18.3% and 17%; p⩽0.005). Sputum neutrophils were significantly higher in group 2 both vs controls (62% vs 34%; p⩽ 0.005) and vs group 1 (62% vs 37%; p⩽0.005). Our data suggest that neutrophils are involved in airway allergic inflammation in mild-moderate persistent childhood asthma and a high neutrophil count in sputum may be related to a lower responsiveness to inhaled corticosteroids. [ABSTRACT FROM AUTHOR]

Background. Measurement of fractional exhaled nitric oxide(FENO) is a noninvasive, simple, well-tolerated, and reproducible marker of airway inflammation. Asthmatic children with normal respiratory function could be affected by airway inflammation. The aim of this study was to assess the correlation between FENO and bronchial hyperesponsiveness(BHR) to methacholine, and between FENO and lung function in atopic children with intermittent asthma. METHODS: Thirty-seven children(21 male), aged 7.2–14.4 years(median: 10.9 years), suffering from mild intermittent atopic asthma with a physician-diagnosed history of wheezing and/or chest tightness were studied. None had taken anti-asthmatic therapy for at least three months before the study. No child had symptoms of respiratory tract infection in the month before the study. All subjects underwent FENO measurement, pulmonary function testing and the methacholine provocation tests. RESULTS: The mean percentages of FEV1 and FEF25–27 were 91.9 ± 10.5 and 88.3 ± 11.8, respectively. The mean FENO was 62.2 ± 39.2 ppb and PC20 methacholine was 0.93 mg/ml ± 0.54. Significant correlations were identified between FENO and FEV1(p < 0.0059, r = 0.468) and between FENO and FEF25–75(p < 0.0098, r = 0.439). There was no correlation between FENO and logPC20(p = 0.14). CONCLUSIONS: A single FENO measurement is probably of scarce prognostic and predictive value and it is not surprising to find discordance with BHR. We suggest that FENO measurement could represent a good marker of airway inflammation also in naïve atopic children with intermittent asthma. Repeated measurements over time are probably necessary to understand better the clinical implications of the data obtained in this study. [ABSTRACT FROM AUTHOR]

In areas of intensive agriculture, wild plant species are confined to field margins, thus they play a role in protecting biodiversity. The aim of the present study was to assess plant diversity in an area of intensive viticulture and to evaluate, for the first time, the impact of field margins on vineyard flora biodiversity. The study was conducted in North-West Italy, were five categories of floristic lists in vineyard-margin pairs were sampled and compared. Five margins were identified: grass-covered (A) and bare (B) headlands, small (C) and wide (D) woodlands, and shrub and herbaceous (E) areas. Two hundred and fifty-two taxa were found, although only 19 were widespread. Differences among categories emerged, highlighting the high floristic complexity of the sites surrounded by wide wooded areas (D). The findings suggest an influence of margin size, in addition to margin type, on the floristic richness of the vineyard. Moreover, an inverse relationship between species richness and both the presence of Poaceae and the degree of soil grass coverage emerged. Enhancing biodiversity, at landscape and field level, by the appropriate management of cover crops and ecological infrastructures, within and around vineyards, could be a strategy in sustainable viticulture. The increase in plant species richness is not an end in itself, but it might help to promote biodiversity at different trophic levels. [ABSTRACT FROM AUTHOR]

Since its introduction in 1987, dual-energy X-ray absorptiometry (DXA) has revolutionized bone assessment, becoming the gold standard for measuring bone mineral density (BMD). Its low radiation exposure and high accuracy have made it indispensable in diagnosing osteoporosis, aligning with World Health Organization criteria. However, DXA evolution extends beyond BMD measurement, with emerging tools like the Trabecular Bone Score (TBS) and the DXA-based Bone Strain Index (BSI). TBS provides insights into trabecular bone architecture, enhancing the prediction of fracture risk. Despite limitations like body mass index correlation, TBS aids in evaluating patients with conditions such as diabetes and glucocorticoid exposure. BSI, introduced in 2019, evaluates bone strength using finite element analysis, complementing BMD and TBS by assessing bone fatigue.Advancements in DXA-based tools extend to Hip Structural Analysis and three-dimensional DXA software, offering valuable insights into hip fracture risk. Moreover, DXA serves beyond bone assessment, aiding in abdominal aortic calcification assessment, enhancing cardiovascular risk stratification. In summary, the expanding capabilities of DXA promise comprehensive skeletal and cardiovascular health evaluation, contributing significantly to clinical management and prevention strategies., Competing Interests: None declared., (Thieme. All rights reserved.)

Antimicrobial resistance (AMR) is recognized as a global threat. AMR bacteria accumulate in sewage sludge however, knowledge on the persistence of human pathogens and AMR in the sludge line of the wastewater treatment is limited. Sludge can be used, with or without additional treatment, as fertilizer in agricultural fields. The aim of this study is to obtain knowledge about presence of human pathogens and AMR in the sewage sludge, before and after the anaerobic digestion (AD) applying innovative combinations of methods. Fifty sludge samples were collected. Cultivation methods combined with matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and Antibiotic Susceptibility Test (AST) were used obtaining knowledge about the microbial community, pathogens, and antibiotic resistant bacteria while the droplet digital Polymerase Chain Reaction (ddPCR) was performed to detect most common AMR genes. In total, 231 different bacterial species were identified in the samples. The most abundant species were spore-forming facultative anaerobic bacteria belonging to Bacillus and Clostridium genera. The AD causes a shift in the microbial composition of the sludge (p = 0.04). Seven pathogenic bacterial species constituting 188 colonies were isolated and tested for susceptibility to Clindamycin, Meropenem, Norfloxacin, Penicillin G, and Tigecycline. Of the Clostridium perfringens and Bacillus cereus isolates 67 and 50 %, respectively, were resistant to Clindamycin. Two B. cereus and two C. perfringens isolates were also resistant to other antibiotics showing multidrug resistance. ARGs (bla OXA , bla TEM , ermB, qnrB, tet(A)-(W), sulI-II) were present at 7-8 Log gene copies/kg of sludge. AD is the main driver of a reduction of some ARGs (1 Log) but resistant bacteria were still present. The results showed the usefulness of the integration of the proposed analytical methods and suggest a decrease in the risk of presence of cultivable pathogens including resistant isolates after AD but a persistent risk of ARGs' horizontal transmission., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in pediatric obesity. Our study aims to identify a predictive anthropometrical measure for NAFLD in obese children., Methods: We retrospectively enrolled children and adolescents with obesity. Physical, biochemical, and ultrasound assessments were available. ROC curve tests were performed to identify the best predictor of NAFLD among waist-to-height ratio (WHR), BMI z-score, and triponderal mass index (TMI, an anthropometric index recently associated with increased adiposity in children). Subsequently, a cut-off value was identified., Results: In total, 1900 children and adolescents (1011 with NAFLD) were included. WHR (AUC 0.62, 95% CI 0.59-0.64) was the best predictor of NAFLD compared to BMI z-score (AUC 0.58, 95% CI 0.55-0.60) and TMI (AUC 0.58, 95% CI 0.55-0.61). WHR ≥ 0.53 in boys and 0.63 in girls displayed the best sensitivity and specificity for NAFLD presence. In addition, children with high WHR showed a significantly higher risk of NAFLD (boys: OR 2.43, 95% CI 1.61-3.68, p < 0.0001; girls: OR 1.92, 95% CI 1.58-2.34, p < 0.0001) and elevated ALT (OR 5.71, 95% CI 2.09-15.56, p = 0.0007; girls: OR 2.16, 95% CI 1.70-2.74, p < 0.0001) independent of covariates., Conclusions: WHR might represent a good anthropometric tool to candidate children and adolescents to NAFLD screening. WHR cut-off differs according to sex, being lower in boys than girls., Impact: Waist-to-height ratio is a better predictor of non-alcoholic fatty liver disease risk compared to other anthropometric measures in obese children and adolescents. The predictive cut-off of waist-to-height ratio differs between boys and girls, being lower in boys than girls. The use of waist-to-height ratio measurement and its cut-off in clinical practice might help clinician in identifying obese children and adolescents at risk of non-alcoholic fatty liver disease., (© 2020. International Pediatric Research Foundation, Inc.)

Background: The transmembrane 6 superfamily member 2 (TM6SF2) E167K polymorphism influences estimated glomerular filtration rate (eGFR) in adults without diabetes and without obesity. We aimed exploring the impact of this polymorphism on eGFR in children with obesity with and without non-alcoholic fatty liver disease (NAFLD)., Methods: We genotyped 531 children with obesity for TM6SF2 E167K polymorphism. NAFLD was defined by ultrasound detected liver steatosis and/or ALT > 40 IU/L., Results: Patients carrying the TM6SF2 167K allele showed higher eGFR levels compared with E167 homozygous patients both among subjects with and without NAFLD. A general linear model confirmed a direct and significant association of eGFR values with TM6SF2 genotype both in patients with and without NAFLD. This association, however, was stronger in patients with NAFLD., Conclusions: Children with obesity carrying the TM6SF2 167K allele show higher eGFR levels compared with E167 allele homozygous subjects, independently of NAFLD. A major effect of this polymorphism in the presence of NAFLD was captured.

We first investigated in obese children the protective role of the hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) rs72613567:TA variant in liver damage. Six hundred eighty-five obese children were genotyped for HSD17B13, patatin-like phospholipase domain containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), and membrane bound O-acyltransferase domain containing 7 (MBOAT7) polymorphisms and underwent anthropometrical, ultrasonographic, and biochemical evaluation. Indirect measurement of liver fibrosis (Pediatric NAFLD Fibrosis Index [PNFI]) was calculated. The population was clustered in 2 genetic risk groups based on the numbers of steatogenic alleles (low: carriers up to 3 risk alleles, high: 4-6 risk alleles). Carriers of the HSD17B13 rare A allele showed lower percentage of hepatic steatosis and both lower serum transaminase and PNFI levels than noncarriers, even after adjustments for confounders. These findings were also confirmed in both risk groups. We demonstrated the protective effect of the rs72613567:TA HSD17B13 variant in reducing liver damage in obese children regardless of genetic predisposition.

Background: PNPLA3 I148M polymorphism has an effect on modulation of estimated glomerular filtration rate (eGFR) in nonobese nondiabetic adults and in children with histologically confirmed nonalcoholic fatty liver disease (NAFLD)., Objectives: The objective of the study is to explore the impact of PNPLA3 I148M polymorphism on eGFR in children with obesity with and without NAFLD., Methods: We genotyped 591 patients with obesity for PNPLA3 I148M polymorphism. Anthropometrical, biochemical, and instrumental data were collected. NAFLD was defined by the presence of ultrasound-detected liver steatosis and/or ALT levels greater than 40 IU/L., Results: Patients with NAFLD showed significantly lower eGFR levels compared with subjects without NAFLD. Children with PNPLA3 MM genotype showed lower eGFR levels compared with those with either PNPLA3 IM or II genotypes both in the presence and absence of NAFLD. A general linear model for eGFR variance, including gender, duration of obesity, PNPLA3 genotypes, HOMA, BMI-SDS, LDL-C, and triglycerides as covariates, confirmed an inverse association between eGFR and PNPLA3 genotype only in the presence of NAFLD., Conclusions: Children with obesity and PNPLA3 MM genotype show lower eGFR levels compared with other genotypes, with a major effect of this polymorphism in the presence of NAFLD., (© 2019 World Obesity Federation.)

We evaluated, both in toilet-trained and not-toilet-trained children, the impact of cleaning the genital area with plain water on the false positive rate at urine dipstick, and evaluated which factors could be associated to falsely positive findings. We prospectively enrolled 612 patients consecutively attending our nephro-urological outpatient clinic. Firstly, we performed urine dipsticks on urine samples collected from patients whose genital area had not been cleaned before. Then we collected a second sample from the patients with positive urine dipstick, after their genital area had been cleaned with plain water. The urine dipstick was considered falsely positive if we documented its normalization at urine dipstick made on the urine sample collected after cleaning the genital area. We found a falsely positive urine dipstick in 25.5% of the patients, and more in detail in 22.9% of the not-toilet-trained children, and in 26.6% of the toilet-trained children (p = 0.37). The only factors leading to a significant increased RR to have a false positive were non-retractable foreskin (RR = 4.38; 95% CI, 2.15-8.9; p = 0.0001) and female gender (RR = 2.47; 95% CI, 1.77-3.44; p < 0.0001)., Conclusion: Cleaning the genital area with plain water should always be performed before collecting urine samples, even if only a urine dipstick without culture is needed. What is Known: • Cleaning the genital area reduces the urine bacterial contamination rate in populations of toilet-trained pediatric patients. • There are no studies assessing the impact of cleaning the genital area on the quality of the urine dipstick, nor on which factors could affect the urine dipstick findings. What is New: • Falsely positive urine dipstick was found in 25.5% of the 612 prospectively enrolled toilet-trained and not-toilet-trained children. • Non-retractable foreskin and female gender significantly increases the relative risk of falsely positive urine dipsticks.

Background: Increased thyroid stimulating hormone (TSH) serum concentration can be a marker of subclinical hypothyroidism (SCH) or transient hyperthyrotropinemia. The aim of our study was to evaluate whether high serum TSH concentrations in allergic children could represent true SCH or isolated and transient hyperthyrotropinemia., Methods: We enrolled 620 allergic children (1.11-12.8 years) consecutively attending to our department. They were classified as atopics and non-atopics on the basis of the atopy work-up and, at baseline, they were investigated for thyroid function and low-grade inflammation state. Further, TSH was evaluated after 6 (T1) and 12 (T2) months., Results: Both atopics and non-atopics showed higher SCH prevalence compared to controls (p=0.0055 and p=0.02, respectively), and a significant association between atopy and SCH (OR 10.11, 95% CI 1.36-75.12) was found. Both at T1 and T2, atopics had a significant risk of developing severe SCH compared to non-atopics (RR 1.8, 95% CI 1.39-2.34 and 1.61, 95% CI 1.21-2.14; respectively)., Conclusions: Our data may suggest that hyperthyrotropinemia in atopic children could be used as a marker of true SCH.

Aim: To verify the prevalence of thyroid autoimmunity (TA) and the possible association between atopy and TA in children affected by skin disease., Methods: Three hundred and twenty-four children consecutively referred due to skin disease symptoms to our Pediatric Department were enrolled. One hundred and eighty-seven were diagnosed with atopic dermatitis (AD), 95 with acute urticaria, 40 with chronic urticaria (CU), and 2 with alopecia areata (AA). According to the work-up for atopy, the children were divided into two groups: Atopics and non-atopics. TA was diagnosed by serum thyroid peroxidase autoantibodies and/or thyroglobulin autoantibodies levels more than twice normal values over a period of two months by immunoassay., Results: In all children with skin disease, a significant prevalence of TA in atopics compared with non-atopics (13.67% vs 2.67%, P = 0.0016) and a significant association between TA and atopy (OR = 5.76, 95%CI: 1.71-19.35) were observed. These findings were confirmed as significant in children with AD: TA in atopics was 11.5%, while TA in non-atopics was 2.7% (P = 0.03, OR = 4.68, 95%CI: 1.02-21.38). In addition, atopics with CU showed a significantly higher prevalence of TA (26.9%), but none of the non-atopics showed CU (P = 0.0326). On the other hand, atopics with AA showed a 100% (2 out of 2) prevalence of TA, compared with none of the non-atopics., Conclusion: In children with skin disease, atopy seems to be associated with an increased risk of TA.

Aim: To verify if subclinical hypothyroidism (SCH) could be associated to atopy in children., Methods: Seven hundred and thirty-two Caucasian children from South Italy presenting symptoms of allergic disease were enrolled and submitted to atopy, obesity, chronic low grade inflammation, and SCH work up., Results: Four hundred and forty-five out of 705 (63.12%) children affected by allergic disease were diagnosed as atopic and 260 (36.88%) as not atopic. The SCH prevalence was 6.3%. Significant higher prevalence of SCH among atopic children with average (group 2) and high (group 3) low grade chronic inflammation compared to atopic children with mild (group 1) low grade chronic inflammation was present. Moreover, group 1 and group 2 presented an OR to show SCH of 2.57 (95%CI: 1.55-6.26) and 2.96 (95%CI: 1.01-8.65), respectively. Both in atopic and not atopic children we found C3 serum levels significantly higher in group 3 respect to group 2 and group 1. Noteworthy, among atopic patients, also total immunoglobulin E (IgE) serum levels, were significantly higher in group 3 compared to group 2 and group 1 children. In atopic children, C3 and total IgE serum values increased in parallel with the increase of C-reactive protein values, while in not atopic children this phenomenon was not evident., Conclusion: The possibility exists that an increasing atopic inflammation contributes to SCH occurrence. So far this is the first report in literature showing an association between SCH and atopy but further studies are needed to confirm our data.

Background: The epidemiological decrease of Helicobacter pylori (Hp) infection has been recently associated to the increase of several extra-intestinal allergic disorders., Objective: We investigated the role of specific Hp IgG production in the development of IgE or not IgE mediated food allergy (FA) in children affected by atopic dermatitis (AD)., Methods: From January 2010 to July 2013, 290 South Italian children, aged between 26 and 142 months, were consecutively referred to the Pediatric Clinic of the Pediatric Department at Second University of Naples and were diagnosed as affected by AD. The patients were classified in two groups on the basis of diagnosis of food allergy (88 FA affected and 202 not FA affected) and further divided on the basis of the diagnosis of atopy (63 IgE mediated and 23 not IgE mediated). Hp serum IgG was detected using an enzyme linked immunosorbent assay (ELISA) kit (Wampole® Helicobactor pylori IgG ELISA II, Wampole Laboratories, Cranbury, NJ) and Hp stool antigens using enzyme immunoassay (Premier Platinum HpSa plus, Cincinnati OH)., Results: We found a statistically significant higher prevalence of Hp serology positivity in not FA vs. FA AD-affected children (p = 0.032) and a significant inverse association between FA and Hp immunization (1/OR 0.32 95% CI 0.11-0.95). Further, we identified an absolute prevalence Hp serology positivity in not-IgE-mediated rather than in IgE-mediated FA AD-affected patients (p = 0.0006)., Conclusion: We hypothesize that specific Hp IgG production could protect against the development of both FA and atopy in AD-affected children.

A potential role of Helicobater Pylori (HP) infection in several extra-intestinal pathologies has been recently suggested. The aim of our study was to assess the role of serology positive for HP in atopic and non atopic infants and children affected by atopic dermatitis, urticaria, rhinitis and asthma. We included 615 children affected by atopic diseases. According to prick test positivity and age, we divided the patients into two groups: atopic or non-atopic patients and infants (0-2 years) or children (2-12 years). The serum levels of antibodies for H. pylori immunoglobulin G were measured by using an ELISA test. We found a not significant difference between group 1 and group 2 about atopy. There was a significant higher frequency of HP positive serology in older children. As for infants, a higher significant prevalence of HP positive serology was found in non-atopic patients. HP positive serology was significantly higher only in non-atopic infants affected by atopic dermatitis and urticaria than in atopic. In group 2, non atopic children shown a significant increase in the prevalence of HP serum positivity than atopic children. As for asthma, there was an higher prevalence of HP serology positive in non atopic asthmatic children group than in atopic asthmatics. On the contrary, the prevalence of positive HP serology was not significantly different between atopic and non atopic children affected by dermatitis, urticaria, and rhinitis. The present data confirm an inverse association between HP positive serology and atopy in both groups. However, the higher prevalence of positive HP serology was observed in non atopic asthmatics children than in atopic asthmatics. We could speculate that HP infection can favour non-atopic asthma onset.

Recently, there has been considerable interest in the relationship between allergic and autoimmune diseases. We evaluated the prevalence of thyroid autoimmunity in 566 children affected by atopic dermatitis (AD), urticaria, rhinitis, chronic cough, and asthma. Our results suggest that allergy and autoimmunity can be two potential outcomes of dysregulated immunity. It is tempting to speculate that NK Th2 cells can favour asthma onset and at the same time improve thyroid autoimmunity.

Pancreatic islets are commonly isolated for research and transplantation without taking into consideration that they undergo mechanical or chemical stress during this process. In order to counteract both types of injuries, the compound AEOL10150, a novel MnSOD mimic, was added during isolation of islet at concentrations ranging from 18 to 100 microM. Mechanical or chemical stress-related pro-apoptotic signals were then studied. We demonstrate that this MnSOD mimic diminishes the negative effects of mechanical stress by blocking insulin impairment, production of non-specific islet beta-cell proteins, transcription of iNOS and FAS, activation of caspase-3 and -9 and, ultimately, apoptosis. Moreover, the effects of the MnSOD mimic on isolated islets were greatly influenced by dosage: the best dose able to fully counteract mechanical stress was found to be 100 microM; doses > or =150 microM were themselves highly toxic for islet cells. On the other hand, rIL-1beta-induced chemical stress is rather complex, and there was no protection in this scenario. Therefore, contrarily to what has been previously reported, MnSOD mimic administration is only capable of counteracting mechanical stress, and not cytokine-induced cytotoxicity, and that this drug acts within a limited concentration range.

Non-hypercalcemic analogs of vitamin D(3) modulate the immune response through antigen-presenting cells (APCs) and activated T-cells. A large population-base case-control showed that vitamin D(3) intake significantly decreases the risk of type 1 diabetes development. The aim of this study was, therefore, to observe the in vivo effects of a vitamin D(3) analog administered to Bio Breeding (BB) rats. 1,25-Dihydroxy-16,23Z-diene-26,27-hexafluoro-19-nor vitamin D(3) (BXL-219, formerly Ro 26-2198) (BioXell, Milan, Italy) was administered in vivo to BB rats from days 42 to 110 of life at 0.2 microg/Kg BW. Control animals received only vehicle (olive oil, 4.8 microl/100 g BW). The animals of these two groups were subjected to insulin treatment as they became diabetic. Insulin (Humulin, 28.6 UI/day) was administered irrespective of diabetes occurrence to another group of rats for comparison. Blood glucose, insulin levels, glycosuria, degree of islet infiltration, and the expression of some antigens were observed. Results showed that the vitamin D(3) analog reduced diabetes incidence, although limitedly, in BB rats while administration of oral insulin increased diabetes incidence. In addition, the vitamin D(3) analog did not stimulate an enhancement in the expression of CD4 and CD25 in BB rats as it does in NOD mice, which may explain the failure of this as well as other antidiabetic treatments in the BB animal model of type 1 diabetes.

The Bio Breeding (BB) rat is a useful animal model of type 1 autoimmune diabetes. The aim of this study was to observe and follow the cytokine and antigenic expressions within the islets of Langerhans in young non-diabetic, in pre-diabetic hyperglycemic, and in overtly diabetic animals. BB rats were therefore checked at day 21 up to day 90 of life for blood glucose, insulin levels, degree of islet infiltration, expression of proinflammatory and protective cytokines and antibodies including CD4, CD8, CD25, LFA-1, and ICAM-1. Animals were treated with insulin as they became diabetic. We found that islets of non-diabetic BB rats became positive to both IL-1beta and IL-4 very early on, confirming a local but intense production of both cytokines within the islets during the initial non-diabetic period. In addition, we observed that the production of these interleukins together with the expression levels of CD4 and CD25 are events predictive for type 1 diabetes onset in non-diabetic BB rats, as for non-obese diabetic (NOD) mice. In particular, the production of IL-1beta and IL-4 during the non-diabetic period together with the lack of enhancement of CD4 and CD25, indicating selective recruitment of activated T cells, may explain the failure of anti-diabetic treatments in this animal model of type 1 diabetes., ((c) 2006 Wiley-Liss, Inc.)

Human microvascular islet endothelial cells (IEC) exhibit specific morphological and functional characteristics that differ from endothelia derived from other organs. One of these characteristics is the expression of alpha-1 proteinase inhibitor (Api). In this study, we observed its expression in nonobese diabetic (NOD) mouse IEC, in relation to the occurrence of type 1 diabetes and in response to cytokines, namely IL-1 beta and IL-10. In addition, IL-10-deficient NOD mice as well as IL-10 transgenic NODs were studied. Results have demonstrated that Api expression is: (i) highly specific for IEC in NOD mouse islets, as for humans; (ii) linked to the occurrence of early type 1 diabetes, and iii) strongly modulated by Th1 and Th2 cytokines. In fact, Api mRNA found in pre-diabetic NOD animals is significantly reduced when they become hyperglycemic and disappears by 25 weeks of age, when mice are diabetic. Moreover, Api mRNAs are never seen in nondiabetic controls. Furthermore, in cultured NOD IEC, Api expression is downregulated by the addition of IL-1 beta and is upregulated by IL-10; it is always absent in IL-10-deficient NOD mice and overexpressed in IL-10 transgenic NODs, thus further supporting that this cytokine upregulates Api expression.

We studied the alterations of cytokines and ICAM-1 expression in the NOD mouse pancreas produced by the administration of Cyclosporine A (CY) and Tacrolimus (TA), two widely used immunosuppressive drugs. Results evidenced differences in the effects of these two drugs. In fact, during treatment and after withdrawal, CY-treated animals remained euglycemic, showed good islet cell preservation and had low levels of Th1 and Th2 cytokines; ICAM-1 positivity within the islets was also found to be relatively low. On the other hand, TA-treated animals had infiltrated islets containing numerous dendritic cells, adhesion molecule overexpression, increased IFN-gamma and ICAM-1 mRNA transcripts, and interestingly, high levels of circulating ICAM-1. However, even these animals remained euglycemic. These findings lead to the thought that these drugs may exert their effects in very different ways. Moreover, in TA-treated animals, the presence of an islet infiltrate containing numerous dendritic cells coupled with maintenance of euglycemia is suggestive for the involvement of immunosurveillance mechanisms. J. Cell. Biochem. Suppl. 36: 107-116, 2001., (Copyright 2001 Wiley-Liss, Inc.)

The objective of this study was to determine whether abnormal microstructure of sleep in non-dipper hypertensive patients was present in their offspring. Subjects included 11 normotensive offspring of non-dipper hypertensive parents (FH + ND), 6 of dipper hypertensive parents (FH + D) and 5 of normotensive parents (Controls). We measured blood pressure beat-to-beat by Finapres and all stages of sleep by polysomnographically recording simultaneously during spontaneous nocturnal sleep. We analysed blood pressure pattern for 4-min long random periods while the subjects were awake and during all stages of sleep; sleep efficiency (SE), sleep latency (SL), delta-sleep latency (delta-SL), REM sleep latency (REM-SL), Stage 1, Stage 2, Stage 3, Stage 4 and REM duration and percentage values, and microstructural aspects of sleep (arousal and microarousal temporization and features). FH + D and controls showed a fall in blood pressure greater than 10% in all stages of NREM sleep and in the FH + ND blood pressure fall in less than 10% of waking values in all NREM stages. REM sleep and heart rate were similar in the three groups during all stages of sleep. FH + ND showed the same number of arousals but more microarousals than FH + D and controls (p < 0.0001). Microarousals induced several stage shifts through lighter sleep. For this reason, FH + ND spent more time in stage 2 than FH + D and controls. In conclusion, offspring of non-dipper hypertension parents showed a greater number of microarousals than the other two groups.

METHODS: Autonomic nervous function was evaluated by means of power spectral analysis of heart rate and blood pressure variability in dipper (n = 10) and non-dipper (n = 9) essential hypertensive subjects during sleep. The non-dipper subjects were defined as those in whom the nocturnal decrease in blood pressure was < 10% of the daytime blood pressure. We measured beat-to-beat blood pressure by using a Finapres device and all stages of sleep by simultaneous polysomnographic recording during spontaneous nocturnal sleep. We analysed the pattern of changes in blood pressure for random periods of 4 min duration while the patient was awake and during all stages of sleep. For each period (waking, stages 2, 3 and 4 of sleep) a segment of 256 stationary data points was analysed. In the frequency domain, the spectral characteristics of the stationary segments were estimatred by fast Fourier transformation over three frequency bands: low frequency (0.025-0.07 Hz), mid-frequency (0.07-0.14 Hz) and high frequency (0.14-0.35 Hz). RESULTS: Pulse-interval power spectral analysis did not reveal any difference between dippers and non-dippers during waking. In dipper patients, the low-frequency pulse interval (LFPI) decreased during sleep whereas the high-frequency pulse interval increased; the mid-frequency systolic blood pressure and diastolic blood pressure (DBP) decreased significantly and the high-frequency DBP increased during sleep. In non-dipper patients, the LFPI increased from wakefulness to stages 2 and 3 of sleep and the high-frequency pulse interval decreased during sleep; the mid-frequency systolic blood pressure and DBP increased in stage 4 sleep and the high-frequency DBP decreased during sleep. CONCLUSIONS: These findings indicate that non-dipper hypertensive subjects are characterized by increased LFPI and mid-frequency blood pressure during sleep compared with dipper subjects. This alteration in the autonomic nervous function may explain the non-dipper phenomenon in essential hypertension.

To study a possible hypercoagulability in vascular disease, in 22 patients with essential hypertension and in 13 patients with obliterative arteriopathies of the lower limbs we measured the levels of plasma thrombomodulin (TM), plasma and urine beta-thromboglobulin (beta-TG), plasma D-dimer (DD) and plasminogen activator-inhibitor (PAI-1) and compared to the values obtained from 10 healthy volunteers. The values observed in hypertensive patients show only PAI-1 levels significantly higher. All the parameters were found to be significantly increased in vasculopathic patients. These data confirm that in vasculopathic patients endothelium damage, platelet activation, impaired fibrinolytic potential and increase of fibrin turnover, occur. On the other hand, in the hypertensive patients, at first stages of the disease, we have found only an increase of PAI-1 plasma levels documenting impaired fibrinolytic potential.

The objective of this study was to determine whether the macrostructure and microstructure of sleep were altered in non-dipper essential hypertensive patients. Patients included 9 non-dipper essential hypertensive patients and 10 dippers. We measured blood pressure beat-to-beat by Finapres and all stages of sleep by polysomnografically recording simultaneously during spontaneous nocturnal sleep. We analysed blood pressure pattern for 4-min long random periods while the patients were awake and during all stages of sleep; sleep-efficiency (SE), sleep-latency (SL), delta sleep-latency (delta-SL), REM sleep-latency (REM-SL), St. 1, St.2, St.3, St.4 and REM duration and percentage (%) values, and microstructural aspects of sleep (arousal and microarousal temporisation and features). Dipper patients showed a fall in blood pressure (BP) greater than 10% in all stages of NREM sleep; in the non-dipper patients BP fell by less than 10% of waking values in all NREM stages. REM sleep as well as HR were similar in both groups during all stages of sleep. Non-dippers showed the same number of arousals but more microarousals than dippers (p < 0.001). During and after microarousals BP and HR increased in non-dippers, but showed light variation in dippers. Microarousals induced several stage shifts towards lighter sleep. For this reason non-dippers spent less time in stage 4 than dippers (p < 0.001). In conclusion, non-dipper essential hypertensive patients are a subset of patients with central sympathetic hyperactivity responsible for quantitative and qualitative alteration of sleep.