NPY Levels In Type 1 Diabetic Men of Different Duration.

Background: The aim of the present study was to evaluate whether the different duration of type 1 diabetes mellitus influences basal NPY secretion. Design: The NPY concentrations were measured in sixty-eight men with insulin-dependent diabetes mellitus (IDDM) (duration: group 1 (n.21) <5 years (range 2-4 years); group 2 (n.24) >5 years and <10 years (range: 6-9 years); group 3 (n.29) >10 years (range: 11-14 years)) and in age matched normal control subjects (n. 30). Results: The NPY levels were significantly lower in group 3 than in group 2 and 1 and in the control group, in group 2 than in group 1 and in the control group and in group 1 than control group. Conclusion: These results support the view that the duration of diabetes may have a modulatory role in the decreased basal NPY secretion observed in diabetics

Defining a meta-design framework for knitting the emergent city elements

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A regional-scale conceptual and numerical groundwater flow model in fluvio-glacial sediments for the Milan Metropolitan area (Northern Italy)

Study region: The Milan metropolitan area lies on one of the most important aquifer in Italy, heavily exploited for public and industrial water supply. The area, covering 3135 km2 in the Po Plain (Northern Italy) with a continental climate, is bounded by the Po, the Adda and the Ticino rivers and by the prealpine foothills. Regional hydrology is characterised by a network of natural and man-made elements, and lowland springs. The sedimentary sequence, from bottom to top, is formed by meandering river plain deposits, the distal fringe of the glacial outwash plains and proximal braid-plain deposits. Study focus: This study proposes a general approach for aquifer geometry reconstruction and hydrodynamic parametrization of hydrofacies in fluvio-glacial deposits, and their implementation into a 3D regional groundwater flow model. This approach is based on sedimentologically-defined lithofacies/hydrofacies and their correlation in space to obtain nearly homogeneous subunits starting from available data (i.e. 8628 borehole logs, grain size distributions, well tests) and sedimentological knowledge. New hydrological insights for the region: The calibrated 3D FEM groundwater model allows quantifying the main components of the hydrogeological budget at the regional scale, and the fluxes among the different hydro-stratigraphic units. A sensitivity analysis of groundwater levels to the main recharge components suggests importance of anthropogenic disturbances with respect to natural recharge, and that land-use change may impact water resources more than climate change

Inhibition of Larval Development of Marine Copepods Acartia tonsa by Neonocotinoids

Neonicotinoids (NEOs) are neurotoxic pesticides widely used in agriculture due to their high effectiveness against pest insects. Despite their widespread use, very little is known about their toxicity towards marine organisms, including sensitive and ecologically relevant taxa such as copepods. Thus, we investigated the toxicity of five widely used NEOs, including acetamiprid (ACE), clothianidin (CLO), imidacloprid (IMI), thiacloprid (THI), and thiamethoxam (TMX), to assess their ability to inhibit the larval development of the copepod Acartia tonsa. The more toxic NEOs were ACE (EC50 = 0.73 μg L−1), TMX (EC50 = 1.71 μg L−1) and CLO (EC50 = 1.90 μg L−1), while the less toxic compound was IMI (EC50 = 8.84 μg L−1). Early life-stage mortality was unaffected by NEOs at all of the tested concentrations. The calculated toxicity data indicated that significant effects due to ACE (EC20 = 0.12 μg L−1), THI (EC20 = 0.88 μg L−1) and TMX (EC20 = 0.18 μg L−1) are observed at concentrations lower than established chronic aquatic life benchmarks reported by USEPA for freshwater invertebrates. Nevertheless, since environmental concentrations of NEOs are generally lower than the threshold concentrations we calculated for A. tonsa, the effects may be currently of concern only in estuaries receiving wastewater discharges or experiencing intense runoff from agricultur

Interactions between Natural Health Products and Oral Anticoagulants: Spontaneous Reports in the Italian Surveillance System of Natural Health Products

Introduction. The safety of vitamin K antagonists (VKA) use can be compromised by many popular herbal supplements taken by individuals. The literature reports that 30% of warfarin-treated patients self-medicates with herbs. Possible interactions represent an health risk. We aimed to identify all herbs-oral anticoagulants interactions collected in the Italian database of suspected adverse reactions to “natural health” products. Methods. The Italian database of spontaneous reports of suspected adverse reactions to natural products was analyzed to address herb-VKAs interactions. Results. From 2002 to 2009, we identified 12 reports with 7 cases of INR reduction in patients treated with warfarin (n = 3) and acenocoumarol (n = 4), and 5 cases of INR increase (all warfarin associated). It was reported 8 different herbal products as possibly interacting. Discussion. Our study confirms the risk of interactions, highlighting the difficulty to characterize them and their mechanisms and, finally, prevent their onset. The reported data underline the urgent need of healthcare providers being aware of the possible interaction between natural products and VKA, also because of the critical clinical conditions affecting patients. This is the first step to have the best approach to understand possible INR alterations linked to herb-VKA interaction and to rightly educate patients in treatment with VKA

Rheumatic heart disease with triple valve involvement

Acute rheumatic fever (ARF) is a postinfectious, nonsuppurative sequela of pharyngeal infection caused by Streptococcus pyogenes, or Group A β hemolytic Streptococcus (GABHS). Of the associated symptoms, only damage to the heart’s valvular tissue, or rheumatic heart disease (RHD), can become a chronic condition leading to congestive heart failure, stroke, endocarditis, and death. ARF is the most common cause of cardiac disease in children in developing countries. A joint meeting of the World Health Organization and the International Society estimated that 12 million people in developing countries were affected by acute rheumatic fever and rheumatic heart disease, with the majority of these being children. This level of morbidity is comparable to developed countries’ in the last century, before an increase in the standard of living and the introduction of penicillin. Significant trivalvular disease, involving the mitral, aortic and tricuspid valves, is uncommon. Although rare, trivalvular disease has been described in the literature. Clinical and hemodynamic manifestations depend on the severity of each lesion. We reported this case because of the rare presentation of an uncommon disorder and to highlight the fact that the presence of trivalvular disease can be difficult to diagnose, even for a trained physician

High doses of CpG oligodeoxynucleotides stimulate a tolerogenic TLR9–TRIF pathway

CpG-rich oligodeoxynucleotides activate the immune system, leading to innate and acquired immune responses. The immune-stimulatory effects of CpG-rich oligodeoxynucleotides are being exploited as a therapeutic approach. Here we show that at high doses, CpG-rich oligodeoxynucleotides promote an opposite, tolerogenic response in mouse plasmacytoid dendritic cells in vivo and in a human in vitro model. Unveiling a previously undescribed role for TRIF and TRAF6 proteins in Toll-like receptor 9 (TLR9) signalling, we demonstrate that physical association of TLR9, TRIF and TRAF6 leads to activation of noncanonical NF-κB signalling and the induction of IRF3- and TGF-β-dependent immune-suppressive tryptophan catabolism. In vivo, the TLR9-TRIF circuit--but not MyD88 signalling--was required for CpG protection against allergic inflammation. Our findings may be relevant to an increased understanding of the complexity of Toll-like receptor signalling and optimal exploitation of CpG-rich oligodeoxynucleotides as immune modulators

Does whole-body electrical muscle stimulation combined with strength training promote morphofunctional alterations?

OBJECTIVES: The aim of this study was to evaluate the effects of 8 weeks of strength training (ST) combined with whole-body electrical stimulation (EMS) on morphofunctional adaptations in active individuals. METHODS: Fifty-eight volunteers were randomly distributed into the following groups: an untrained control (UN) group (n=16), an ST group (n=21) or an ST combined with EMS (ST+EMS) group (n=21). Both intervention groups (the ST and ST+EMS groups) performed 3 exercises (biceps curl, back squats and high-pulley tricep extensions) twice a week for 8 weeks. The subjects performed 3 sets of 8 to 12 maximum repetitions (MRs) with a 90-second rest duration between sets. The ST+EMS group performed the resistance training exercises wearing a whole-body suit that provided electrical stimulation at frequencies between 80-85 Hz, with a continuously bipolar impulse duration and pulse breadth of 350 ms. The intensity for each muscle group was controlled by Borg’s category ratio (CR)-10 scale; the intensity started at 5-6 and eventually reached 7-8. One-repetition maximum strength (1RM) and muscle thickness (MT) were measured before and after the training intervention. MT was evaluated in the biceps brachii (BB), triceps brachii (TB), and vastus lateralis (VL). RESULTS: No differences (p40.05) were found between the ST and ST+EMS groups. Improvements (po0.05) in the absolute values of the morphofunctional parameters after the training protocol were observed. Significant differences were found between both the intervention groups and the UN group (po0.05). The ST+EMS group presented high percentage changes (po0.05) in muscular strength for the 1RMsquat (43.2%, ES=1.64) and the MT of the BB (21.6%, ES=1.21) compared to the ST (20.5%, ES=1.43, 11.9%, ES=0.77) group. CONCLUSIONS: Our data suggest that the combination of ST+EMS may promote alterations in muscle strength and MT in healthy active subjects

Phase II study of liposomal doxorubicin, docetaxel and trastuzumab in combination with metformin as neoadjuvant therapy for HER2-positive breast cancer

Background:The aim of this study was to improve activity over single human epidermal growth factor receptor 2 (HER2)-blockade sequential neaodjuvant regimens for HER2-positive breast cancer, by exploiting the concomitant administration of trastuzumab, taxane and anthracycline, while restraining cardiac toxicity with use of liposomal doxorubicin, and by adding metformin, based on preliminary evidence of antitumor activity.Patients and methods:This multi-center, single-arm, two-stage phase II trial, assessed the safety and the activity of a new treatment regimen for HER2-positive, early or locally advanced breast cancer. Patients received six 21-day cycles of non-pegylated liposomal doxorubicin, 50 mg/m(2) intravenously (i.v.) on day 1, docetaxel, 30 mg/m(2) i.v. on days 2 and 9, trastuzumab, 2 mg/kg/week i.v. on days 2, 9, and 16 (with 4 mg/kg loading dose), in association with metformin 1000 mg orally twice daily. The primary endpoint was the rate of pathological complete response (pCR) in the breast and axilla (ypT0/is ypN0). A subgroup of patients performed a 3-deoxy-3-18F-fluorothymidine positron emission tomography (FLT-PET) at baseline and after one cycle.Results:Among 47 evaluable patients, there were 18 pCR [38.3%, 95% confidence interval (CI) 24.5-53.6%]. A negative estrogen-receptor status, high Ki67, and histological grade 3 were related with pCR, although only grade reached statistical significance. FLT-PET maximum standardized uptake value after one cycle was inversely related to pCR in the breast (odds ratio 0.29, 95% CI 0.06-1.30, p = 0.11). Toxicity included grade 3-4 neutropenia in 70% and febrile neutropenia in 4% of patients, grade 1-2 nausea/vomiting in 60%/38%, and grade 3 in 4%/2%, respectively, grade 1-2 diarrhea in 72%, and grade 3 in 6%. There were two cases of reversible grade 2 left-ventricular ejection-fraction decrease, and one case of sharp troponin-T increase.Conclusions:The concomitant administration of trastuzumab, liposomal doxorubicin, docetaxel, and metformin is safe and shows good activity, but does not appear to improve activity over conventional sequential regimens

Allosteric modulation of metabotropic glutamate receptor 4 activates IDO1-dependent, immunoregulatory signaling in dendritic cells

Metabotropic glutamate receptor 4 (mGluR4) possesses immune modulatory properties in vivo, such that a positive allosteric modulator (PAM) of the receptor confers protection on mice with relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE). ADX88178 is a newly-developed, one such mGluR4 modulator with high selectivity, potency, and optimized pharmacokinetics. Here we found that application of ADX88178 in the RR-EAE model system converted disease into a form of mild-yet chronic-neuroinflammation that remained stable for over two months after discontinuing drug treatment. In vitro, ADX88178 modulated the cytokine secretion profile of dendritic cells (DCs), increasing production of tolerogenic IL-10 and TGF-β. The in vitro effects required activation of a Gi-independent, alternative signaling pathway that involved phosphatidylinositol-3-kinase (PI3K), Src kinase, and the signaling activity of indoleamine 2,3-dioxygenase 1 (IDO1). A PI3K inhibitor as well as small interfering RNA targeting Ido1-but not pertussis toxin, which affects Gi protein-dependent responses-abrogated the tolerogenic effects of ADX88178-conditioned DCs in vivo. Thus our data indicate that, in DCs, highly selective and potent mGluR4 PAMs such as ADX88178 may activate a Gi-independent, long-lived regulatory pathway that could be therapeutically exploited in chronic autoimmune diseases such as multiple sclerosis