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The pathophysiological link between adiposity and blood pressure is not completely understood, and evidence suggests an influence of sex and genetic determinants. We aimed to identify the relationship between adiposity and blood pressure, independent of a robust set of lifestyle and metabolic factors, and to examine the modulating role of sex and Angiotensin-Converting Enzyme (ACE) insertion/deletion (I/D) polymorphisms. In the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) study cohort, 1211 normotensive individuals, aged 30 to 60 years and followed-up after 3.3 years, were characterized for lifestyle and metabolic factors, body composition, and ACE genotype. Body mass index (BMI) and waist circumference (WC) were independently associated with mean arterial pressure, with a stronger relationship in women than men (BMI: r =0.40 versus 0.30; WC: r =0.40 versus 0.30, both P ID and II ACE genotypes in both sexes ( P ACE genotype only in women ( P =0.03). A 5 cm larger WC at baseline increased the risk of developing hypertension at follow-up only in women (odds ratio, 1.56 [95% CI, 1.15–2.10], P =0.004) and in II genotype carriers (odds ratio, 1.87 [95% CI, 1.09–3.20], P =0.023). The hypertensive effect of adiposity is more pronounced in women and in people carrying the II variant of the ACE genotype, a marker of salt sensitivity.

We discuss the project “Per un pugno di libri … scientifici”, aimed at bringing the young generations closer to scientific culture through reading divulgation books about physics. The project, which is addressed to high-school students, is sponsored by INFN and other national and regional research institutions, along with physics departments of some Italian universities.

BackgroundMusculoskeletal ultrasonography (MSUS) is a useful tool for the diagnosis of several Rheumatic and Musculoskeletal Diseases (RMDs) but its role in the diagnostic pathways in clinical practice is still unclear as feasibility issues limit its application as a bed side technique.ObjectivesTo optimize the use of US in clinical practice, the MSUS Study Group of the Italian Society for Rheumatology aimed to develop an algorithm combining US with clinical and laboratory findings to improve the differential diagnosis among patients presenting with joint swelling.MethodsBased on a systematic literature review1 and experts’ opinion, MSUS Study Group Members attempt to identify a set of statements including the main US elementary lesions useful for US scanning in the suspicion of Rheumatoid arthritis (RA), Psoriatic arthritis (PsA), Rheumatic Polymyalgia (PMR), Gout, Calcium Pyrophosphate Deposition Disease (CPPD), Osteoarthritis (OA). Then, the MSUS Study Group defined through a survey and ranked in a 1000minds exercise the most important clinical/laboratory findings for the differential diagnosis of those diseases. Higher-ranked items were fitted in an algorithm driving the differential diagnosis of RMDs to a reduced spectrum of 2 to 4 possible diseases. Finally, the algorithm supported the performance of US according to the established scans for those specific diseases. To assess the algorithm’s performance, a pilot study was conducted on 59 patients, comparing the algorithm-based diagnosis with the final diagnosis based on rheumatologist’s experience and/or on classification criteria.ResultsSets of elementary US lesions and a scanning protocol for each included pathology were created (Table 1), optimized towards high sensibility and specificity. Among the findings evaluated, the age (Table 1.Elementary ultrasound lesions and joints to be scanned for each included pathologyDiseaseSites to scanUS elementary lesionsRAII-IV MCPsSynovial Hypertrophy (SH), Power Doppler (PD), erosionsWristV MTPPsAII-III MCPsPeritendonitisPIPsEnthesitisSoft tissue oedemaFlexor tendons of the handsTenosynovitisSoft tissue oedemaAchille’s tendon enthesisPD, erosionsProximal patellar tendon enthesisCPPDKnees (menisci and Hyaline Cartilage)CPP depositsWrist (triangular fibrocartilage complex)Any involved sitesCPP deposits, SH, PDGoutKneesDouble contour, tophiI MTPInvolved sitesSHPDOAInvolved sitesOsteophytesCartilage changesPMRShouldersBursitisArthritisRotator cuff integrityFigure 1.The final algorithmConclusionThe diagnostic algorithm produced in this pilot study correctly classified patients with the most prevalent RMDs in clinical practice. A longitudinal study on a large sample size is ongoing to evaluate the added value of US when implemented in this algorithm regarding diagnostic certainty, accuracy and early diagnosis.References[1]Sakellariou G, Scirè CA, Adinolfi A, Batticciotto A, Bortoluzzi A, Delle Sedie A, et al. Differential Diagnosis of Inflammatory Arthropathies by Musculoskeletal Ultrasonography: A Systematic Literature Review. Front Med. 7 maggio 2020;7:141.Disclosure of InterestsNone declared

BackgroundSarcoidosis (S) is a granulomatous disease with multi-organ involvement displaying a mixed immune-mediated pathophysiology. Raynaud’s phenomenon (RP) has been occasionally reported in S patients [1] and serum positivity for autoantibodies has been detected in S patients but their significance is debated [2].ObjectivesWe described nailfold videocapillaroscopy (NVC) findings and estimated the prevalence of serum anti-nuclear (ANA) and extractable nuclear antigen autoantibodies (ENA-Abs) in S patients, comparing them with age- and sex- matched healthy controls (HCs) and patients with primary Raynaud’s phenomenon (PRP). Secondarily, we analysed potential correlations between NVC findings with the occurrence of autoantibodies, immunomodulatory treatment, laboratory parameters, variables of pulmonary function and whole-body imaging.MethodsTwenty-seven (27) S patients, classified according to WASOG criteria[3], were assessed through NVC examination, laboratory parameters (including serum concentrations of angiotensin-converting enzyme [ACE], C-reactive protein [CRP], calcium, phosphorus, albumin, 25-hydroxyvitamin D, parathormone, ANA and ENA), pulmonary function tests (PFTs), chest-X ray and positron emission tomography/computerized tomography (PET/CT).Among NVC parameters, we analysed capillary dilations, giant capillaries, haemorrhages, nonspecific abnormalities, and capillary absolute number for mm [4].Pulmonary involvement was classified by X-ray Scadding staging system (SSS) scoring S patients in 4 grades [5]. From PET data, the maximum standard uptake value (SUVmax) was quantified as a variable of tissue 18-fluorodeoxyglucose hyper-uptake: consequently, S patients were defined PET-positive when SUV value ≥ 2.5. NVC parameters and ANA/ENA dosage were recorded also in 30 PRPs and 30 HCs.ResultsWe excluded, among the cohort of S patient, one participant having a systemic sclerosis in overlap with S. The remaining 26 S patients (mean age 56.5 ± 12.5 years, 53.8 % of females, disease duration 28.4 ± 55.1 months, 27% glucocorticoid-naïve) showed a significant higher rate of dilations and nonspecific abnormalities and a lower mean capillary absolute number than PRPs and HCs (p < 0.01 for all comparisons). (Figure 1)The prevalence of ANA positivity was significantly higher in S patients compared with PRPs and HCs (p < 0.02 for both). Among the whole cohort of patients only one S patient displayed a positive ENA-Ab (Ro52).In the analysis of S patients’ subgroup, a significant negative correlation was detected between serum ACE levels with the presence of capillary dilations (rho = -0.45, p = 0.04), between CRP and mean capillary absolute number (rho = -0.49, p = 0.02) and a positive correlation was also detected between the mean capillary absolute number and the forced vital capacity percentage (FVC%) (rho = 0.40, p = 0.04).ConclusionOur findings suggest a microvascular involvement in sarcoidosis whose investigation by NVC could be useful for the detection of an overlapping connective tissue disease and for the monitoring of the phenotypes of S patients displaying RP.The positivity for autoantibodies in S patients is in line with literature data suggesting, at least partially, autoimmune features of the disease or the production of autoantibodies reactive to tissue damage.The correlations between NVC findings with ACE levels and lung function variables generate hypotheses of a potential partial vascular impairment in sarcoidosis disease activity and lung involvement.References[1]Nigro A et al. Reumatismo 2004; 56: 278-81.[2]Kobak S et al. Autoimmune Diseases 2014[3]Judson M.A et al. Clin Rev Allergy Immunol 2015; 49: 63-78.[4]Smith V et al. Autoimmun Rev 2020; 19: 102458.[5]Scadding J.G. Br Med J 1961; 2: 1165-72.Disclosure of InterestsNone declared

BackgroundDuring pregnancy profound physiologic changes are required to ensure fetal development and meet maternal needs. Microvascular remodelling is one major responsible for pregnancy haemodynamic adaptation, still it is not routinely evaluated in the obstetric field [1–2].ObjectivesTo investigate the role of nailfold capillaroscopy (NCV) as a gold-standard and safe technique in detecting microvascular changes during normal pregnancy and to explore its possible application in clinical obstetric setting.MethodsA population of 30 healthy pregnant women was longitudinally followed performing clinical assessment and NVC evaluation at each trimester and post-partum. Thirty non-pregnant age-matched healthy women having received at least two NVCs with a minimum 9 to 12-month interval were selected as controls. All NVC images were evaluated by a qualitative and semi-quantitative assessment using current standardised approach [3]. Statistical analyses were conducted to explore NVC parameters trend throughout gestation and its possible association with pregnancy course and clinical macrovascular parameters (i.e., systemic blood pressure, umbilical artery Doppler ultrasound).ResultsA progressive significant increase of capillary neoangiogenesis and a specular reduction in capillary dilations was observed during pregnancy (ppConclusionThis first comprehensive longitudinal NVC evaluation during normal pregnancy reports significant physiological microvascular variations throughout gestation, suggesting NVC as a safe and promising technique for further investigate and define patterns of microvascular changes in pregnant patients with rheumatic diseases.References[1]Thevissen et al. Expert Rev Med Devices. 2017;14(12):961–7.[2]Abdo et al. Physiol Res 2014;63:395–408.[3]Smith et al. Autoimmun Rev 2020; 19(3):102458.Disclosure of InterestsNone declared

BackgroundUltrasound (US) demonstrated to be reliable and accurate for the diagnosis of crystal induced arthropathies, especially gout and calcium pyrophosphate deposition disease (CPPD) and validated definitions for uric acid and calcium pyrophosphate deposition in joints were released by the Outcome Measures in Rheumatology (OMERACT) US group. Less is known regarding hydroxyapatite (HA) deposition disease (HAAD) and the role of US in the assessment of HA crystal deposition.It is general belief that HA crystals create posterior acoustic shadowing, monosodium urate could create or not US beam attenuation while CPP crystals generally do not attenuate the US beam.ObjectivesAim of this proof-of-concept study was to investigate the US appearance in terms of beam attenuation due to increasing concentrations of MSU, CPP and HA crystals.MethodsSixteen synthetic crystal suspensions with known concentrations of CPP (26-109 mg/mL), HA (31-153 mg/mL) and MSU (90-500 mg/mL) were prepared. These specific concentrations were selected to replicate the X-ray attenuation characteristics of those crystals when imaged by conventional radiography, computed tomography (CT) and dual-energy CT (DECT) in vivo[1]. The density of the agar-based lipogel background was intentionally increased to mimic the X-ray attenuation of hyaline cartilage (i.e., 100-120 HU at 120 kVp). Each crystal suspension was placed in a plastic container filled with US gel, next to the control (i.e., crystal-free background) calibration phantom. We acquired all US images using a Samsung RS80A system equipped with a high-frequency linear array transducer (4-18 MHz) set at the maximum frequency, by applying the same settings. US scans were performed by a single experienced sonographer, blinded to the crystal type and concentration. For each of the 16 crystal suspensions, at least two images were recorded both in the long- and short-axis views, the latter including the control phantom in the field of view. Interpretation of US images for the extent of US beam attenuation and the presence of acoustic shadowing was performed in consensus with a second experienced sonographer.ResultsNone of the five CPP phantoms generated posterior acoustic shadowing or US beam attenuation regardless of CPP concentration. HA 31mg/mL did not generate US beam attenuation, while HA 62, 92 and 123 mg/mL generated a progressively increasing US beam attenuation with posterior acoustic shadow clearly generated by HA 153 mg/mL. Similarly, MSU 90 mg/mL did not generate US beam attenuation. MSU 195 mg/mL generated only a very faint US beam attenuation that became progressively more visible at 270 and 345 mg/mL even if a clear posterior acoustic shadow was detectable only with MSU 420 and 500 mg/mL (Figure 1).Figure 1.Short-axis views comparing the US attenuation characteristics, including acoustic shadowing, of increasing concentrations (in mg/mL) of CPP, HA and MSU crystals. The left column shows the US attenuation of the crystal-free (0 mg/mL) agar-based lipogel background for referenceConclusionThis proof-of-concept study confirmed that in the concentrations of crystals encountered in vivo, CPP do not generate posterior shadowing, while MSU and HA determine US beam attenuation proportionally to the concentration of the crystals. Being this a proof-of-concept study, attenuation of the US beam was assessed empirically and not in a quantitative or semi-quantitative way. However, this study highlights the potential of US to differentiate between CPP, MSU and HA crystals based on their appearance on gray scale imaging. Future studies should be carried out with different crystal concentrations, different US equipment and settings, in order to create a scoring system for US beam attenuation that is actually lacking.References[1]Pascart T et al. Dual-energy computed tomography in calcium pyrophosphate deposition: initial clinical experience. Osteoarthritis Cartilage 2019;27:1309–14. doi:10.1016/j.joca.2019.05.007Disclosure of InterestsNone declared

Movement competence (MC) is defined as the development of sufficient skill to assure successful performance in different physical activities. Monitoring children MC during maturation is fundamental to detect early minor delays and define effective intervention. To this purpose, several MC assessment batteries are available. When evaluating movement strategies, with the aim of identifying specific skill components that may need improving, widespread MC assessment is limited by high time consumption for scoring and the need for trained operators to ensure reliability. This work aims to facilitate and support the assessment by designing, implementing and validating an instrumented version of the TGMD-2 locomotor subtest based on Inertial Measurement Units (IMUs) to quantify MC in children rapidly and objectively. 45 typically developing children, aged 6–10, performed the TGMD-2 locomotor subtest (six skills). During the tests, children wore five IMUs mounted on lower back, on ankles and on wrists. Sensor and video recordings of the tests were collected. Three expert evaluators performed the standard assessment of TGMD-2. Using theoretical and modelling approaches, algorithms were implemented to automatically score children tests based on IMUs’ data. The automatic assessment, compared to the standard one, showed an agreement higher than 87% on average on the entire group for each skill and a reduction of time for scoring from 15 to 2 min per participant. Results support the use of IMUs for MC assessment: this approach will allow improving the usability of MC assessment, supporting objectively evaluator decisions and reducing time requirement for the evaluation of large groups.

The development of new therapies for the treatment of type 2 diabetes requires robust, reproducible and well validatedin vivoexperimental systems. Mice provide the most ideal animal model for studies of potential therapies. Unlike larger animals, mice have a short gestational period, are genetically similar, often give birth to many offspring at once and can be housed as multiple groups in a single cage. The mouse model has been extensively metabolically characterized using different tests. This report summarizes how these tests can be executed and how arising data are analyzed to confidently determine changes in insulin resistance and insulin secretion with high reproducibility. The main tests for metabolic assessment in the mouse reviewed here are the glucose clamp, the intravenous and the oral glucose tolerance tests. For all these experiments, including some commonly adopted variants, we describe: (i) their performance; (ii) their advantages and limitations; (iii) the empirical formulas and mathematical models implemented for the analysis of the data arising from the experimental procedures to obtain reliable measurements of peripheral insulin sensitivity and beta cell function. Finally, a list of previous applications of these methods and analytical techniques is provided to better comprehend their use and the evidences that these studies yielded.

Introduction: Hydrotherapy is used as a treatment in arthrosis conditions, backache, coronary disease, etc. [1]. Movements performed in water have different characteristics when compared to the same movements out of water, and these differences change depending on the water temperature and depth. Subjects’ characteristics, such as proprioception, sensory feedback, vestibular apparatus responses are influenced by the presence of water, which has proprieties, like friction, viscosity, reaction forces, different from those of air [2]. Walking in water could be used in aquatic therapy. In literature several methods were proposed to quantify the stability during walking out of water: the related synthetic indices can be grouped as stability indices and variability indices [3]. The aim of this work is to understand how these indices (describing elements such as complexity, stability, variability, smoothness in walking and postural control) change among tests conducted in or out of the water, in order to provide objective indications on the motor control response in relation to the different characteristics of the walking in the water. Methods: Eleven (6 male and 5 female) healthy subjects participated in the study (age 27.0 ± 3.4, height 174.2 ± 8.2, mass 70.2 ± 11.8). The participants were asked to walk barefoot at self-selected speed for 10 meters, repeating the task for three times, first out then in the water. Measures were collected using 3 tri-axial wireless inertial sensor (OPALS, Apdm, USA, sampling frequency 128 Hz), inserted in waterproofed boxes and fixed to the body segments (shanks, pelvis) [2]. 30 strides for participant were considered. The following parameters for quantifying gait stability and variability were applied: Harmonic Ratio (HR), Poincaré plots (SD1, SD2), maximum Floquet multipliers (FM), Multiscale Entropy (MSE), recurrence qualification analysis (RQA), Lyapunov exponents (sLE) [4]. Results: Most significant results are shown in Table 1. HR and sLE on the three axis and RQA on the vertical (V) axis showed higher values out of the water, while RQA on the mediolateral (ML) and anteriorposterior (AP) axis, MSE on the three axis, SD1 and SD2 showed higher values in the water. Table 1. Mean values and standard deviation of the most significant indices, in and out of the water. sLE HR SD2 V ML AP V ML AP In 0.5 ± 0.2 0.6 ± 0.3 0.7 ± 0.3 1.2 ± 0.2 1.6 ± 0.4 1.0 ± 0.2 0.2 ± 0.2 Out 1.1 ± 0.2 1.0 ± 0.2 1.1 ± 0.2 3.6 ± 0.7 3.3 ± 1.0 3.5 ± 0.5 0.5 ± 0.2 MSE τ = 6 Recurrence SD1 V ML AP V ML AP In 1.4 ± 0.1 1.3 ± 0.2 0.8 ± 0.2 13 ± 3 26 ± 3 28 ± 6 0.20 ± 0.10 Out 1.0 ± 0.1 1.1 ± 0.3 1.1 ± 0.1 22 ± 2 15 ± 3 25 ± 2 0.03 ± 0.01 Discussion: Preliminary variability and stability results suggested that walking in water is more stable (lower values sLE), less fluid (lower values HR) and more variable (higher values SD1 e SD2) compared to walking out of the water. The RQA in the water shows a greater postural control along the AP and ML axes, while along the V axis a greater postural control is observed out of water. MSE along the three axes is higher in water: this could suggest that walking in water is conducted in a less automatic way [4]. Future research will be focused on the interpretation of the physiological meaning of these indices, in relation to the different characteristics of walking in the water environment and to the effects that water has on walking performance.

The aim of this study was to evaluate the contribution of insulin processing to the improved meal-related B-cell function previously shown with the DPP-4 inhibitor vildagliptin. Fifty-five patients with type 2 diabetes (56.5+/-1.5 years; BMI=29.6+/-0.5 kg/m(2); FPG=9.9+/-0.2 mmol/l; HbA1c=7.7+/-0.1 %) were studied: 29 patients were treated with vildagliptin and 26 patients with placebo, both added to an ongoing metformin regimen (1.5-3.0 g/day). A standardized breakfast was given at baseline and after 52 weeks of treatment, and proinsulin related to insulin secretion was measured with C-peptide in the fasting and postprandial (over 4 h post-meal) states to evaluate B-cell function. The between-treatment difference (vildagliptin-placebo) in mean change from baseline in fasting proinsulin to C-peptide ratio (fastP/C) was -0.007+/-0.009 (p=0.052). Following the standard breakfast, 52 weeks of treatment with vildagliptin significantly decreased the dynamic proinsulin to C-peptide ratio (dynP/C) relative to placebo by 0.010+/-0.008 (p=0.037). Importantly, when the P/C was expressed in relation to the glucose stimulus (i.e., the fasting glucose and glucose AUC(0-240 min), respectively), the P/C relative to glucose was significantly reduced with vildagliptin vs. placebo, both in the fasting state (p=0.023) and postprandially (p=0.004). In conclusion, a more efficient B-cell insulin processing provides further evidence that vildagliptin treatment ameliorates abnormal B-cell function in patients with type 2 diabetes.

Glucagon-like peptide-1 (GLP-1) plays a significant role in glucose homeostasis through its incretin effect on insulin secretion. However, GLP-1 also exhibits extrapancreatic actions, and in particular its possible influences on insulin sensitivity are controversial. To study the dynamic action of GLP-1 on insulin sensitivity, we applied advanced statistical modeling methods to study glucose disappearance in mice that underwent intravenous glucose tolerance test with administration of GLP-1 at various dose levels. In particular, the minimal model of glucose disappearance was exploited within a population estimation framework for accurate detection of relationships between glucose disappearance parameters and GLP-1. Minimal model parameters were estimated from glucose and insulin data collected in 209 anesthetized normal mice after intravenous injection of glucose (1 g/kg) alone or with GLP-1 (0.03–100 nmol/kg). Insulin secretion markedly increased, as expected, with increasing GLP-1 dose. However, minimal model-derived indexes, i.e., insulin sensitivity and glucose effectiveness, did not significantly change with GLP-1 dose. Instead, fractional turnover rate of insulin action [P2 = 0.0207 ± 24.3% (min) at zero GLP-1 dose] increased steadily with administered GLP-1 dose, with significant differences at 10.4 nmol/kg (P2 = 0.040 ± 15.5%, P = 0.0046) and 31.2 nmol/kg (P2 = 0.050 ± 29.2%, P = 0.01). These results show that GLP-1 influences the dynamics of insulin action by accelerating insulin action following glucose challenge. This is a novel mechanism contributing to the glucose-lowering action of GLP-1.

We studied islet function in mice with β-cell-targeted expression of a dominant-negative mutant of hepatocyte nuclear factor (HNF)-1α. At age 2–3 months, anesthetized transgenic and wild-type male mice underwent an intravenous glucose (1 g/kg) tolerance test (IVGTT). It was found that transgenic mice had an abolished insulin response in association with severe glucose intolerance. In other tests, the 5-min insulin response to intravenous arginine was impaired by 79% (P = 0.032) and the 15-min insulin response to gastric glucose was suppressed by 97% (P = 0.006). In islets incubated for 60 min, the insulin response to glucose (3.3–22.2 mmol/l) was impaired by >80% in transgenic mice. In contrast, insulin responses to nonglucose secretagogues were only partially suppressed (to GLP-1 [100 nmol/l] by 40%, to carbachol [1 μmol/l] by 20%, and to palmitate [0.5 mmol/l] by 15%), whereas the response to depolarization by KCl (50 mmol/l) was not reduced. Finally, the IVGTT data insulin sensitivity in transgenic mice was not significantly different from that of wild-type mice. Thus, mice with targeted suppression of β-cell HNF-1α represent a good diabetes model exhibiting severely impaired insulin secretion after glucose with marked glucose intolerance. In contrast, the insulin responses to nonglucose stimuli are not suppressed when the islet insulin content is taken into account.

Subjects with impaired glucose tolerance (IGT) are usually overweight and exhibit insulin resistance with a defective compensation of insulin secretion. In this study, we sought to establish the interrelation between insulin secretion and insulin sensitivity after oral glucose in non-obese subjects with IGT and we also examined this interrelation in relation to the 2 main incretins, glucagon-like peptide (GLP-1) and gastric inhibitory polypeptide (GIP). To that end, 13 women with IGT and 17 women with normal glucose tolerance (NGT) underwent an oral glucose tolerance test (OGTT) with measurements of glucose, insulin, C-peptide, GLP-1, and GIP. Insulin secretion (TIS) and insulin sensitivity (OGIS) were assessed using models describing the relationship between glucose, insulin and C-peptide data. These models allowed estimation also of the hepatic extraction of insulin. The age (54.2 +/- 9.7 [mean +/- SD] years) and body mass index (BMI; 26.0 +/- 4.0 kg/m(2)) did not differ between the groups. Subjects with IGT displayed lower TIS during the initial 30 minutes after oral glucose (0.97 +/- 0.17 [mean +/- SEM] v 1.75 +/- 0.23 nmol/L in NGT; P =.018) and lower OGIS (397 +/- 21 v 463 +/- 12 mL/min/m(2); P =.005). The incremental 30-minute TIS times OGIS (reflecting insulin secretion in relation to insulin sensitivity) was significantly reduced in IGT (359 +/- 51 v 774 +/- 91 nmol/min/m(2), P =.001). This measure correlated inversely to the 2-hour glucose level (r = -0.71; P

Insulin sensitivity and secretion are related in a curvilinear inverse asymptotic function. However, the signaling factors mediating this relation are not known. In this study, we explored whether circulating glucose, lipids or two adipocyte-derived hormones, leptin and adiponectin, are related to the curvilinear function between insulin sensitivity and secretion in subjects with normal glucose tolerance. Thereby, insulin secretion (2-5-min insulin response to intravenous arginine) and insulin sensitivity (euglycemic, hyperinsulinemic clamp) were established in 68 healthy women, aged 61 years. We confirmed the curvilinear relation between insulin sensitivity and insulin secretion (r = -0.71, P < 0.001). To quantify the ability of the beta cells to secrete insulin for balancing a change in insulin sensitivity, we introduce the beta cell compensation index (BCI) by dividing insulin secretion by insulin sensitivity. This index correlated significantly with circulating triglycerides, leptin and adiponectin as well as BMI, but not fasting or 2-h glucose. A multivariate stepwise regression analysis using these variables as independent variables and lg BCI as the dependent variable revealed that leptin (r = 0.54, P < 0.001) and adiponectin (r = -0.33, P = 0.008) independently contributed to lg BCI (R-2 of the model = 0.19m, P = 0.038). The study, therefore, suggests that adipocyte-derived hormones contribute to the beta cell compensation to insulin resistance. (C) 2002 Elsevier Science B.V. All rights reserved. (Less)

Water quality two-dimensional models are often partitioned into separate modules with separate hydraulic and biological units. In most cases this approach results in poor flexibility whenever the biological dynamics has to be adapted to a specific situation. Conversely, an integrated approach is pursued in this article, producing a two-dimensional hydraulic-water quality model, named Shallow Water Analysis and Modeling Program (SWAMP) designed for shallow water bodies. The major objective of the work is to create a comprehensive two-dimensional water quality assessment tool, based on an open framework and combining easy programming of additional procedures with a user-friendly interface. The model is based on the numerical solution of the partial differential equations describing advection-diffusion and biological processes on a two-dimensional rectangular finite elements mesh. The hydraulics and advection-diffusion modules model were validated both with experimental tracer data collected at a constructed wetland site and a comparison with a commercial hydrodynamic software, showing good agreement in both cases. Moreover, the model was tested in critical conditions for mass conservation, such as time-varying wet boundary, showing a considerable numerical robustness. In the last part of the article water quality simulations are presented, though validation data are not yet available. Nevertheless, the observed model response demonstrates general consistency with expected results and the advantages of integrating the hydraulic and quality modules. The interactive graphical user interface (GUI) is also shown to represent a simple and effective connective tool to the integrated package. © 2002 Wiley Periodicals, Inc. Numer Methods Partial Differential Eq 18: 663–687, 2002; DOI 10.1002/num.10014

Loop checking mechanisms are used to detect and prune infinite SLD derivations, through run time checks which are introduced in logic program interpreters. Simple loop checks, i.e. checks which do not depend on the specific logic program, have been widely studied in literature. Since no sound and complete loop check exists even in the case of function-free programs, several subclasses have been characterized for which sound and complete loop checks can be determined. In this paper a theoretical framework for analysing properties of loop check mechanisms for logic programs is proposed, which exploits general mathematical results about well-quasi-ordered ( wqo ) sets. In a way, the method can be viewed as a counterpart of well known techniques based on well-founded partial-ordering, used in termination proofs for rewriting systems and for logic programs. The main results are obtained on the basis of a combinatorial analysis of properties of wqo sets of goals. As shown in the paper, subclasses of programs, for which sound and complete simple loop checks exist, can be easily framed in the wqo approach. Reasons for the different behaviours of subsumption loop checks based on list and multiset goal comparisons are also plainly highlighted.

The literature offers several examples of executable specification languages, ranging from mathematically based notation to visual formalisms. In this paper, an analysis environment for executable system specifications based on the language RSF (Requirement Specification Formalism) is presented. The analysis environment also contains two other linguistic tools — RSQ (Requirement Specification Querying), and SEF (Specification Execution Filtering). Using RSQ, classes of execution paths with certain properties can be exercised, so that selected behavioral aspects can be observed. Using SEF, the amount of information and the times at which it is output can be controlled, making the behavior analysis more effective. The paper shows how the notation of RSF, with its few basic concepts, is naturally exploited as a nucleus for the other tools, which are easily integrated to produce the final analysis environment. The combination of RSQ and SEF allows the planning of testing and analysis activities. A working session is shown for a specification describing a telephone switch call handler.

No effective interventions to reduce risk for new-onset diabetes after transplantation (NODAT), a condition associated with postoperative hyperglycemia and reduced patient and graft survival, have been established. In this 1-year, proof-of-concept clinical trial, we randomly assigned 50 renal transplant recipients to immediate-postoperative isophane insulin for evening blood glucose ≥140 mg/dl (treatment group) or short-acting insulin and/or oral antidiabetic agents for blood glucose ≥180-250 mg/dl (standard-of-care control group). We included only patients without a history of diabetes who received tacrolimus. By the third postoperative evening, all patients in the treatment group had blood glucose ≥140 mg/dl and were subsequently treated with basal insulin; during the first 3 weeks after transplantation, the mean ± SD daily insulin dosage was 17±11 IU/d. Among controls, 23 (92%) of 25 had blood glucose ≥200 mg/dl and 18 (72%) of 25 received standard-of-care antihyperglycemic treatment. Asymptomatic hypoglycemia occurred five times in the treatment group and once in the control group. Throughout follow-up, the treatment group had 73% lower odds of NODAT (odds ratio, 0.27) than the control group, and hemoglobin A1c was on average 0.38% lower in the treatment group than the control group. Twelve months after transplantation, all patients in the treatment group were insulin-independent, whereas 7 (28%) of 25 controls required antidiabetic agents. The groups did not differ for insulin sensitivity, but the treatment group showed better β-cell function throughout the 1-year follow-up. In conclusion, this study suggests regimens that include basal insulin significantly reduce the odds for NODAT after renal transplantation, presumably via insulin-mediated protection of β cells.

Apart from glucose, proteins and lipids also stimulate incretin and islet hormone secretion. However, the glucoregulatory effect of macronutrients in combination is poorly understood. We therefore developed an oral mixed meal model in mice to 1) explore the glucagon-like peptide-1 (GLP-1) and islet hormone responses to mixed meal versus isocaloric glucose, and 2) characterize the relative contribution of individual macronutrients to these responses. Anesthetized C57BL/6J female mice were orally gavaged with 1) a mixed meal (0.285 kcal; glucose, whey protein and peanut oil; 60/20/20% kcal) versus an isocaloric glucose load (0.285 kcal), and 2) a mixed meal (0.285 kcal) versus glucose, whey protein or peanut oil administered individually in their mixed meal caloric quantity, i.e., 0.171, 0.055 and 0.055 kcal, respectively. Plasma was analyzed for glucose, insulin and intact GLP-1 before and during oral challenges. Plasma glucose was lower after mixed meal versus after isocaloric glucose ingestion. In spite of this, the peak insulin response (P = 0.02), the peak intact GLP-1 levels (P = 0.006) and the estimated ?-cell function (P = 0.005) were higher. Furthermore, the peak insulin (P = 0.004) and intact GLP-1 (P = 0.006) levels were higher after mixed meal ingestion than the sum of responses to individual macronutrients. Compared to glucose alone, we conclude that there is a marked early insulin response to mixed meal ingestion, which emanates from a synergistic, rather than an additive, effect of the individual macronutrients in the mixed meal and is in part likely caused by increased levels of GLP-1.

Women with former gestational diabetes are at increased risk of Type 2 diabetes, which likely relates to hyperlipidaemia and ectopic lipid storage, mainly in the liver. Here, we examined the response of non-esterified fatty acid dynamics to oral glucose loading (oral glucose tolerance test).We studied women with former gestational diabetes with normal glucose tolerance (n = 60) or impaired glucose metabolism (n = 12) and compared them with healthy women after normal pregnancy (control subjects, n = 15). During a 3-h oral glucose tolerance test, glucose, insulin and non-esterified fatty acid were frequently measured to compute the area under the non-esterified fatty acid curve and parameters of β-cell function and insulin sensitivity. Through mathematical modelling, we assessed insulin sensitivity of lipolysis inhibition and the fractional non-esterified fatty acid turnover rate. We also measured some serum liver enzymes.Women with former gestational diabetes were slightly older and had greater body mass than control subjects. Subjects with impaired glucose metabolism had lower oral glucose insulin sensitivity, but higher fasting insulin and area under the non-esterified fatty acid curve, which inversely related to oral glucose insulin sensitivity and independently determined mean glycaemia. Model-derived non-esterified fatty acid parameters were lower in subjects with impaired glucose metabolism than in control subjects, particularly sensitivity of non-esterified fatty acid inhibition to insulin (2.50 ± 0.52 vs. 1.06 ± 0.20 · 10(-2) ml/μU). Also, subjects with impaired glucose metabolism had higher liver transaminases. However, all non-esterified fatty acid parameters showed only modest inverse correlation with liver transaminases.Despite greater insulinaemia, circulating non-esterified fatty acids are higher in women with former gestational diabetes than in control subjects, which likely results from reduced sensitivity of lipolysis inhibition to insulin. This parameter may serve as indicator of an early metabolic derangement in this population at risk for diabetes.

Refining a specification S1 means to provide another specification S2 which contains all the information given in S1 but with more detail. In this paper, we use logical implication from lower to higher levels of logic specifications to give a definition of refinement between these levels. This guarantees that any property of the higher level is also verified at the lower one. The definition of the relation "is refinement of" is given for specifications which are general first-order theories and it is proved to be transitive. A relevant aspect is that the different levels of logic specifications are in general not immediately comparable, because they can use different vocabularies. For this reason, the concept of transcription is introduced formally in our definition. Then the particular case of Horn specifications is considered. Horn specification semantics can be given by the methodology of least models. This may suggest definitions of the concept of refinement different from the one based on logical implication from lower to higher levels. However, conceptual problems can arise depending on the kind of the refinement definition chosen. Perhaps the most interesting effect is that the property of refinement transitivity may be lost. A possible way to restore the transitivity is provided.

Minimal model analysis for insulin sensitivity has been validated against the glucose clamp and is an accepted method for estimating insulin sensitivity from IVGTT. However minimal model analysis requires a 3 h test and relevant expertise to run the mathematical model. The aim of this study was to suggest a simple predictor of minimal model analysis index using only 1 h IVGTT. We studied participants with different clinical characteristics who underwent 3 h regular (n = 336) or insulin-modified (n = 160) IVGTT, or 1 h IVGTT and euglycaemic–hyperinsulinaemic clamp (n = 247). Measures of insulin sensitivity were insulin sensitivity index estimated by minimal model analysis (SI) and the mean glucose infusion rate (clamp) (M). A calculated SI (CSI) predictor, $${\text{CS}}_{{\text{I}}} = {\text{ $ \alpha $ }} \times {K_{\text G} } \mathord{\left/ {\vphantom {{K_{G} } {{\left( {{\Delta {\text{AUC}}_{{{\text{INS}}}} } \mathord{\left/ {\vphantom {{\Delta {\text{AUC}}_{{{\text{INS}}}} } T}} \right. \kern-\nulldelimiterspace} T} \right)}}}} \right. \kern-\nulldelimiterspace} {{\left( {{\Delta {\text{AUC}}_{{{\text{INS}}}} } \mathord{\left/ {\vphantom {{\Delta {\text{AUC}}_{{{\text{INS}}}} } T}} \right. \kern-\nulldelimiterspace} T} \right)}}$$ , was suggested, based on the calculation of the rate of glucose disappearance K G and the suprabasal AUC of insulin concentration ΔAUCINS over T = 40 min. For all the participants, α was assumed equal to the regression line slope between K G/(ΔAUCINS/T) and SI in control participants. CSI and SI showed high correlation (R 2 = 0.68–0.96) and regression line slopes of approximately one in the majority of groups. CSI tended to overestimate SI in type 2 diabetic participants, but results were more reliable when CSI was computed with insulin-modified rather than regular IVGTT. CSI showed behaviours similar to SI as regards relationships with BMI, acute insulin response and sex. CSI showed good correlation with M (R 2 = 0.82). A short test can achieve a good approximation of minimal model analysis and clamp insulin sensitivity. The importance of a method such as CSI is that it allows analysis of IVGTT datasets with samples limited to 1 h.

In the last years there has been a growing interest of researchers for themes dealing with chronic illness and issues related to that condition. Several authors have studied the difficulties caregivers have to cope with, especially when the patient's partner has this role. That condition would have both physical and psychological consequences, but its real effects seem to depend on a complex set of interacting elements. On the basis of these researches, in the current study we aimed to explore the influence of adult attachment and marital satisfaction on the impact that chronic illness can have on patient's partner and on his/her health-related quality of life. The sample is composed of 40 chronic renal failure patients' partner-caregivers. Each caregiver filled in a battery of tests for finding out the characteristics of adult attachment and marital satisfaction, health-related quality of life and the association between these variables and the impact of chronic illness on partners. Descriptive statistics, correlations and one-sample t test analysis have been performed. Results show a significant correlation between attachment style and caregiving burden; there are no gender differences in disease impact on caregiver. Moreover caregivers seem to have a worse quality of life in comparison to general population. Understanding caregiving can lead, at a future time, to planning specific interventions for both patients and partners, using a global and integrated approach that respects individuals and couples in their biologic, psychological and relational dimensions.

Relation grammars are introduced as a powerful formalism for specifying the syntax of visual languages and, more generally, of multi-dimensional languages. Textual languages use only the implicit relation of sequential concatenation of symbols. The proposed extension relax this limitation and allows the introduction of any number of relations. By analogy with textual grammars, relation grammars make it easier to recognize the purpose of the lexical analysis phase and that of the syntactic one for parsing multi-dimensional structures.

Dietary addition of either conjugated linoleic acid (CLA) or n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) has been shown to alter adiposity and circulating lipids, risk markers of cardiovascular diseases. However, CLA may decrease insulin sensitivity, an effect that may be reversed by n-3 LC-PUFA. Thus, the potential of CLA plus n-3 LC-PUFA to affect insulin secretion and sensitivity in non-diabetic young and old, lean and obese subjects was tested.CLA (3 g daily) plus n-3 LC-PUFA (3 g daily) or control oil (6 g daily) was given to lean (n=12; BMI 20-26 kg/m(2)) or obese (n=10; BMI 29-35 kg/m(2)) young (20-37 years old) or lean (n=16) or obese (n=11) older men (50-65 years) for 12 weeks. The study had a double-blind, placebo-controlled randomized crossover design, and primary end points were insulin secretion and sensitivity during a standardized meal test, evaluated by modeling glucose, insulin and C-peptide data.The combination was well tolerated. There was no significant difference in fasting levels of glucose, insulin or C-peptide after CLA/n-3 LC-PUFA treatment compared with control oil. Neither insulin secretion nor estimated sensitivity was affected by CLA/n-3 LC-PUFA in lean or obese young subjects or in older lean subjects. However, in older obese subjects, estimated insulin sensitivity was reduced with CLA/n-3 LC-PUFA compared with control (P=0.024).The results do not support beneficial effects of CLA/n-3 LC-PUFA for beta-cell dysfunction or insulin resistance in humans but suggest that insulin sensitivity in older obese subjects is reduced.

A grammatical inference technique tailored for the definition of the syntax of visual languages is presented. The technique employs a functional similarity measure between icons, the primitives of visual languages. An algorithm based on this technique has been implemented and utilized for the development of the inference module of a system for the automatic generation and use of user-defined visual languages. Experimental results comparing the behaviour of the algorithm with that of Levine [18] are shown. The results suggest the efficacy of the algorithm for the generation of application-specific visual languages.

A system to generate and interpret customized visual languages in given application areas is presented. The generation is highly automated. The user presents a set of sample visual sentences to the generator. The generator uses inference grammar techniques to produce a grammar that generalizes the initial set of sample sentences, and exploits general semantic information about the application area to determine the meaning of the visual sentences in the inferred language. The interpreter is modeled on an attribute grammar. A knowledge base, constructed during the generation of the system, is then consulted to construct the meaning of the visual sentence. The architecture of the system and its use in the application environment of visual text editing (inspired by the Heidelberg icon set) enhanced with file management features are reported. >

Most commercial blood warmers are unable to warm blood components to greater than 35 degrees C at rapid flow rates (greater than 100 mL/min) because of problems with inefficient heat transfer and resistance to the flow of blood through the instrument's tubing. A new blood warmer, using a closed-flow 40 degrees C counter-current water bath and large- bore tubing, is able to warm cold (10 degrees C) packed red cells to temperatures greater than 35 degrees C even at flow rates of 500 mL per minute. To evaluate the effects on red cells of prolonged exposure to the 40 degrees C heat exchanger, blood from five volunteers stored for 42 days in AS-1 was run through the blood warmer using flow rates equivalent to the transfusion of a unit of blood over 4 hours. Compared with unwarmed blood, these blood units showed no significant changes in plasma hemoglobin, mean corpuscular hemoglobin concentration, potassium, ATP, pH, and osmotic fragility. In vivo survivals of chromium-51-labeled warmed autologous red cells were greater than 75 percent in four volunteers and 49.5 percent in the fifth volunteer, whose abnormally low unwarmed red cell ATP level suggested a storage problem. Thus, this blood warmer, which warms blood efficiently at high flow rates, causes no red cell damage, even with prolonged exposure of old red cells to the 40 degrees C heat exchanger.

RSF is a formalism for specifying and prototyping systems with time constraints. Specifications are given via a set of transition rules. The application of a transition rule is dependent upon certain events. The occurrence times of the events and the data associated with them must satisfy given properties. As a consequence of the application of a rule, some events are generated and others are scheduled to occur in the future, after given intervals of time. Specifications can be queried, and the computation of answers to queries provides a generalized form of rapid prototyping. Executability is obtained by mapping the RSF rules into logic programming. The rationale, a definition of the formalism, the execution techniques which support the general notion of rapid prototyping and a few examples of its use are presented. >

The liver plays an essential role in maintaining glucose homeostasis, which includes insulin-mediated processes such as hepatic glucose output (HGO) and uptake, as well as in clearance of insulin itself. In type 2 diabetes, the onset of hyperglycaemia [itself a potent inhibitor of hepatic glucose output (HGO)], alongside hyperinsulinaemia, indicates the presence of hepatic insulin insensitivity. Increased HGO is central to the onset of hyperglycaemia and highlights the need to target hepatic insulin insensitivity as a central component of glucose-lowering therapy. The mechanisms underlying the development of hepatic insulin insensitivity are not well understood, but may be influenced by factors such as fatty acid oversupply and altered adipocytokine release from dysfunctional adipose tissue and increased liver fat content. Furthermore, although the impact of insulin insensitivity as a marker of cardiovascular disease is well known, the specific role of hepatic insulin insensitivity is less clear. The pharmacological tools available to improve insulin sensitivity include the biguanides (metformin) and thiazolidinediones (rosiglitazone and pioglitazone). Data from a number of sources indicate that thiazolidinediones, in particular, can improve multiple aspects of hepatic dysfunction, including reducing HGO, insulin insensitivity and liver fat content, as well as improving other markers of liver function and the levels of mediators with potential involvement in hepatic function, including fatty acids and adipocytokines. The current review addresses this topic from the perspective of the role of the liver in maintaining glucose homeostasis, its key involvement in the pathogenesis of type 2 diabetes and the tools currently available to reduce hepatic insulin insensitivity.

Aims/hypothesis: Glucagon-like peptide-1 (GLP-1) is known to be a potent stimulator of insulin secretion. How- ever, whether GLP-1 also affects insulin clearance is not known. To explore this, we developed a technique to determine prehepatic insulin secretion in mice, based on deconvolution of plasma C-peptide concentrations. The estimated beta cell se- cretion was then related to plasma insulin levels to allow de- termination of clearance rate of endogenously produced insulin. Materials and methods: Kinetic parameters of C-peptide were estimated after i.v. injection of human C-peptide (0.8 or 3 nmol/ kg) or glucose (1 g/kg), either alone or together with GLP-1 (10 nmol/kg), in anaesthetised NMRI mice. Results: C-peptide was distributed in two compartments (distribution volume 11.4±0.4 ml, 42±2% of which was in the accessible com- partment). Fractional C-peptide clearance was 8.2±0.6% of the total distribution volume per minute. GLP-1 mark- edly enhanced prehepatic insulin secretion; more than 80% of prehepatic secretion occurred during the first minute after injection. Fractional clearance of endogenously re- leased insulin after glucose was 0.66±0.11 min-1 and this was reduced to 0.36±0.10 min-1 by GLP-1 (p=0.04). Conclusions/interpretation: It is possible to perform C-pep- tide deconvolution for estimating prehepatic insulin secre- tion in mice. GLP-1 reduces the clearance of endogenously released insulin; therefore, it may affect insulin levels by increasing prehepatic insulin secretion and by reducing in- sulin clearance.