Artificial Pancreas: In Silico Study Shows No Need of Meal Announcement and Improved Time in Range of Glucose with Intraperitoneal vs. Subcutaneous Insulin Delivery

Contemporary Artificial Pancreas (AP) consists of a subcutaneous (SC) glucose sensor, a SC insulin pump and a control algorithm. Even the most advanced systems are far from optimal, in particular due to the non-physiologic nature of SC route. While SC insulin delivery is convenient and minimally invasive, it introduces delays to insulin action that make tight control difficult, particularly during meals. In addition frequent patient interventions are needed, e.g., at mealtime. The intraperitoneal (IP) insulin delivery could address this major challenge since it exhibits a faster pharmacokinetics/pharmacodynamics, hence making easier to quickly respond to glycemic disturbances. A 1-day hospital closed-loop study has shown significant improvements of IP glucose control vs SC AP, and that meal announcement is not necessary. However, the IP AP has not been tested in more realistic everyday life conditions. In this work we have performed an in silico study of 14 days of an IP AP by using the UVA/Padova simulator which includes intra- and inter-day variability of insulin sensitivity and several real life scenarios. We show superiority of IP AP vs SC AP in terms of quality of glucose control (time in range 87% IP vs 80% SC) without the need of a meal announcement

A nonparametric approach for model individualization in an artificial pancreas

The identification of patient-tailored linear time invariant glucose-insulin models is investigated for type 1 diabetic patients, that are characterized by a substantial inter-subject variability. The individualized linear models are identified by considering a novel kernel-based nonparametric approach and are compared with a linear time invariant average model in terms of prediction performance by means of the coefficient of determination, fit, positive and negative max errors, and root mean squared error. Model identification and validation are based on in-silico data collected from the adult virtual population of the UVA/Padova simulator. The data generation involves a protocol designed to produce a sufficient input excitation without compromising patient safety, compatible also with real life scenarios. The identified models are exploited to synthesize an individualized Model Predictive Controller (MPC) for each patient, which is used in an Artificial Pancreas to maintain the blood glucose concentration within an euglycemic range. The MPC used in several clinical studies, synthesized on the basis of a non-individualized average linear time invariant model, is also considered as reference. The closed-loop control performance is evaluated in an in-silico study on the adult virtual population of the UVA/Padova simulator in a perturbed scenario, in which the MPC is blind to random variations of insulin sensitivity in each virtual patient. © 2015, IFAC (International Federation of Automatic Control) Hosting by Elsevier Ltd. All rights reserved

Towards a Model-Based Field-Frequency Lock for NMR

Peer reviewedPublisher PD

The Association between serum cytokines and damage to large and small nerve fibers in diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is a frequent complication of type 2 diabetes mellitus (DM) and may involve small and large peripheral nerve fibers. Recent evidence suggests a role of cytokines in DPN. The paper is aimed at exploring whether the serum concentration of cytokines is associated with small and large nerve fiber function and with neuropathic pain (NP). We recruited a group of 32 type 2 DM patients who underwent serum cytokines (TNF-α, IL-2, IL-4, IL-6, and IL-10) dosage as well as electrodiagnostic and quantitative sensory testing (QST) assessment to explore damage to large and small nerve fibers. Raised serum levels of IL-6 and IL-10 correlated with markers of large nerve fiber sensory and motor axonal damage. Raised IL-10 serum level was associated with signs of motor nerve demyelination. No differences were found in pain characteristics and electrodiagnostic and QST markers of small nerve fiber function in relation to cytokines serum levels. IL-6 and IL-10 serum levels were associated with large nerve fiber damage but not to small fibers function or NP. IL-6 and IL-10 cytokines might play a role in the pathogenesis of nerve fiber damage or represent a compensatory or neuroprotective mechanism

Olfactory neuroepithelium alterations and cognitive correlates in schizophrenia

BACKGROUND: Few studies have investigated alterations of olfactory neuroepithelium (ONE) as a biomarker of schizophrenia, and none its association with cognitive functioning. METHOD: Fresh ONE cells from twelve patients with schizophrenia and thirteen healthy controls were collected by nasal brushing, cultured in proper media and passed twelve times. Markers of cell proliferation (BrdU incorporation, Cyclin-D1 and p21 protein level) were quantified.Cognitive function was measured using Brief Neuropsychological Examination-2. PRIMARY OUTCOME: proliferation of ONE cells from schizophrenic patients at passage 3. Secondary outcome: association between alteration of cell proliferation and cognitive function. RESULTS: Fresh ONE cells from patients showed a faster cell proliferation than those from healthy controls at passage 3. An opposite trend was observed at passage 9, ONE cells of patients with schizophrenia showing slower cell proliferation as compared to healthy controls. In schizophrenia, overall cognitive function (Spearman's rho -0.657, p\u202f<\u202f0.01), verbal memory - immediate recall, with interference at 10\u202fs and 30\u202fs (Spearman's rho from -0.676 to 0.697, all p\u202f<\u202f0.01) were inversely associated with cell proliferation at passage 3. CONCLUSION: Fresh ONE cells collected by nasal brushing might eventually represent a tool for diagnosing schizophrenia based upon markers of cell proliferation, which can be easily implemented as single-layer culture. Cell proliferation at passage 3 can be regarded as a promising proxy of cognitive functioning in schizophrenia. Future studies should replicate these findings, and may assess whether ONE alterations are there before onset of psychosis, serving as an early sign in patients with at risk mental state

Oenological characterisation of indigenous strains of S. cerevisiae isolated in a biodynamic winery in the Cortona DOC area

Genotypic and technological characterisation of the S. cerevisiae population isolated in a biodynamic winery in the Cortona DOC area was performed to gain better knowledge of the variables that influence winemaking. The oenological performance of 11 S. cerevisiae strains was evaluated with physiological tests; strain typing was performed through analysis of interdelta sequences and 26S rDNA sequencing. The analysis revealed a remarkable variability in terms of S. cerevisiae strains, despite the homogeneity of wine features, underlining the high levels of biodiversity characterising biodynamic agriculture. Some strains were found in wines of different vintages, suggesting the presence of an established microbiota in the winery. Oenological tests demonstrated that while some yeasts provided reliable oenological performance, other strains were not able to accomplish prompt and effective alcoholic fermentation, or were characterised by spoilage characteristics, such as excessive production of volatile phenols or acetic acid. Indigenous strains of S. cerevisiae could be a useful instrument for reliable winemaking without altering the native microbiota of each oenological environment. However, characterisation of their oenological suitability, and the application of practices able to drive the evolution of microbiota, must be employed to reduce the risk of wine spoilage

S-Glutathionylation at Cys328 and Cys542 Impairs STAT3 Phosphorylation.

STAT3 is a latent transcription factor that promotes cell survival and proliferation and is often constitutively active in cancers. Although many reports provide evidence that STAT3 is a direct target of oxidative stress, its redox regulation is poorly understood. Under oxidative conditions STAT3 activity can be modulated by S-glutathionylation, a reversible redox modification of cysteine residues. This suggests the possible cross-talk between phosphorylation and glutathionylation and points out that STAT3 is susceptible to redox regulation. Recently, we reported that decreasing the GSH content in different cell lines induces inhibition of STAT3 activity through the reversible oxidation of thiol groups. In the present work, we demonstrate that GSH/diamide treatment induces S-glutathionylation of STAT3 in the recombinant purified form. This effect was completely reversed by treatment with the reducing agent dithiothreitol, indicating that S-glutathionylation of STAT3 was related to formation of protein-mixed disulfides. Moreover, addition of the bulky negatively charged GSH moiety impairs JAK2-mediated STAT3 phosphorylation, very likely interfering with tyrosine accessibility and thus affecting protein structure and function. Mass mapping analysis identifies two glutathionylated cysteine residues, Cys328 and Cys542, within the DNA-binding domain and the linker domain, respectively. Site direct mutagenesis and in vitro kinase assay confirm the importance of both cysteine residues in the complex redox regulatory mechanism of STAT3. Cells expressing mutant were resistant in this regard. The data presented herein confirmed the occurrence of a redox-dependent regulation of STAT3, identified the more redox-sensitive cysteines within STAT3 structure, and may have important implications for development of new drugs

Meniscal T1rho and T2 measured with 3.0T MRI increases directly after running a marathon

PURPOSE: To prospectively evaluate changes in T1rho and T2 relaxation time in the meniscus using 3.0 T MRI in asymptomatic knees of marathon runners and to compare these findings with those of age-matched healthy subjects. MATERIAL AND METHODS: Thirteen marathon runners underwent 3.0 T MRI including T1rho and T2 mapping sequences before, 48-72 h after, and 3 months after competition. Ten controls were examined at baseline and after 3 months. All images were analyzed by two musculoskeletal radiologists identifying and grading cartilage, meniscal, ligamentous. and other knee abnormalities with WORMS scores. Meniscal segmentation was performed to generate T1rho and T2 maps in six compartments. RESULTS: No differences in morphological knee abnormalities were found before and after the marathon. However, all marathon runners showed a significant increase in T1rho and T2 values after competition in all meniscus compartments (p &lt; 0.0001), which may indicate changes in the biochemical composition of meniscal tissue. While T2 values decreased after 3 months T1rho values remained at a high level, indicating persisting changes in the meniscal matrix composition after a marathon. CONCLUSION: T2 values in menisci have the potential to be used as biomarkers for identifying reversible meniscus matrix changes indicating potential tissue damage. T1rho values need further study, but may be a valuable marker for diagnosing early, degenerative changes in the menisci following exercise

The nonlinear effect of somatic cell count on milk composition, coagulation properties, curd firmness modeling, cheese yield, and curd nutrient recovery

The aim of this study was to investigate the relationships between somatic cell count (SCC) in milk and several milk technological traits at the individual cow level. In particular, we determined the effects of very low to very high SCC on traits related to (1) milk yield and composition; (2) coagulation properties, including the traditional milk coagulation properties (MCP) and the new curd firming model parameters; and (3) cheese yield and recovery of milk nutrients in the curd (or loss in the whey). Milk samples from 1,271 Brown Swiss cows from 85 herds were used. Nine coagulation traits were measured: 3 traditional MCP [rennet coagulation time (RCT, min), curd firming rate (k20, min), and curd firmness after 30 min (a30, mm)] and 6 new curd firming and syneresis traits [potential asymptotic curd firmness at infinite time (CFP, mm), curd firming instant rate constant (kCF, % 7 min-1), syneresis instant rate constant (kSR, % 7 min-1), rennet coagulation time estimated using the equation (RCTeq, min), maximum curd firmness achieved within 45 min (CFmax, mm), and time at achievement of CFmax (tmax, min)]. The observed cheese-making traits included 3 cheese yield traits (%CYCURD, %CYSOLIDS, and %CYWATER, which represented the weights of curd, total solids, and water, respectively, as a percentage of the weight of the processed milk) and 4 nutrient recoveries in the curd (RECFAT, RECPROTEIN, RECSOLIDS, and RECENERGY, which each represented the percentage ratio between the nutrient in the curd and milk). Data were analyzed using a linear mixed model with the fixed effects of days in milk, parity, and somatic cell score (SCS), and the random effect of herd-date. Somatic cell score had strong influences on casein number and lactose, and also affected pH; these were traits characterized by a quadratic pattern of the data. The results also showed a negative linear relationship between SCS and milk yield. Somatic cell score influenced almost all of the tested coagulation traits (both traditional and modeled), with the exceptions of k20, CFP, and kSR. Gelation was delayed when the SCS decreased (slightly) and when it increased (strongly) with respect to a value of 2, as confirmed by the quadratic patterns observed for both RCT and RCTeq. The SCS effect on a30 showed a quadratic pattern almost opposite to that observed for RCT. With respect to the CFt parameters, kCF decreased linearly as SCS increased, resulting in a linear decrease of CFmax and a quadratic pattern for tmax. Milk SCS attained significance for %CYCURD, %CYWATER, and RECPROTEIN. As the SCS increased beyond 3, we observed a progressive quadratic decrease of the water retained in the curd (%CYWATER), which caused a parallel decrease in %CYCURD. With respect to RECPROTEIN, the negative effect of SCS was almost linear. Recovery of fat and (consequently) RECENERGY was characterized by a more evident quadratic trend, with the most favorable values associated with an intermediate SCS. Together, our results confirmed that high SCS has a negative effect on milk composition and technological traits, highlighting the nonlinear trends of some traits across the different classes of SCS. Moreover, we report that a very low SCS has a negative effect on some technological traits of mil