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abstract:While the establishment of permanent embassies during the Renaissance has traditionally been regarded as the first step toward the emergence of modern diplomacy, recent scholarship has questioned this grand narrative and suggested framing the history of premodern diplomacy as a much more nuanced and multifaceted process in which many intermediaries and go-betweens coexisted and competed with resident ambassadors. Taking up this thread, this article brings to light the role played in early modern diplomacy by religious refugees, who became influential through their capacity to facilitate cross-confessional exchanges between states that could not officially communicate. Focusing on sixteenth-century Anglo-Venetian diplomacy, the article demonstrates how, after the suspension of diplomatic contact between Venice and England in 1559, religious refugees replaced resident ambassadors and allowed exchanges and the information flow to continue.

In 2013, 42 million children under the age of 5 years were overweight or obese. In the context of obesity, we recently showed that (1) peripheral lymphocytes of obese children/adolescents had an 8-fold increase in double strand breaks (DSBs), expressed as g-H2AX foci, than normal weight adolescents, and (2) 30% of the damage was retained into chromosome mutations. Thus, we investigated DSBs repair efficiency in a group of obese adolescents assessing the kinetic of H2AX phosphorylation in mitomycin C (MMC)-treated lymphocytes harvested 2 h- or 4 h-post mutagen treatment. According to our previous studies, these harvesting times represent the peak of DSBs induction and the time in which an appreciable DSBs reduction was observed. In addition, we evaluated the expression of the high mobility group box-1 protein (HMGB1), a chromatin remodelling protein involved in DSBs repair and obesity. Compared to normal weight adolescents, obese subjects 1) showed higher levels of g-H2AX foci at either 2 h- (0.239±0.041 vs. 0.473±0.048, P=0.0016) or 4 h- (0.150±0.026 vs. 0.255±0.030, P=0.0198) post mutagen treatment, and 2) have repaired a greater amount of the initial lesions (0.088±0.033 vs. 0.218±0.045, P=0.0408). Concordantly, 1) HMGB1 levels of obese individuals increased and decreased at 2h- or 4 h-post mutagen treatment, respectively, and 2) the opposite occurred for the normal weight adolescents where the protein was down-expressed at 2h and over-expressed at 4h. In conclusion, lymphocytes of obese and normal weight adolescents showed a distinct temporal kinetic of repairing MMC-induced DSBs, together with a different expression of HMGB1. The finding that obesity may modulate the repair of DNA damage induced in lymphocytes by genotoxic agents should be confirmed by further experiments.

Circulating levels of cholesterol are derived from either endogenous production or intestinal absorption of dietary and biliary cholesterol. Niemann-Pick C1-Like 1 (NPC1L1) is a transmembrane protein that plays a key role in the intestinal absorption of cholesterol by facilitating its uptake through vesicular endocytosis. NPC1L1 is the molecular target of ezetimibe which binds its extracellular loop and inhibits sterol absorption without affecting the absorption of other molecules. Ezetimibe significantly reduces plasma levels of total and low density lipoprotein cholesterol (LDL-C) as monotherapy or when added to statins, the association with a low dose of statin is of particular interest for patients experiencing statin-related side effects. The recent results of the IMPROVE-IT study, which evaluated the cardiovascular effect of ezetimibe added to simvastatin therapy in subjects who had had an acute coronary syndrome and with LDL-C levels within the recommended range, showed that a further LDL-C lowering reduced the incidence of cardiovascular events. To date, ezetimibe represents the only inhibitor of NPC1L1 available for clinical use, however, novel aminoß- lactam ezetimibe derivatives have been synthesized and their efficacy to inhibit NPC1L1 protein and decrease plasma cholesterol levels is under evaluation.

The adsorption of fully protonated tetracycline (TC) using Na montmorillonite (Na-MMT) as an adsorbent is studied by DFT calculations. Geometric, electronic, and magnetic properties are analyzed. To the best of our knowledge, this is the first theoretical DFT research about Na-MMT as an adsorbent of TC cationic species. Two Na-MMT models are considered: dry and hydrated Na-MMT. The incorporation of four water molecules in the interlayer space results in the expansion of the d001parameter from 10.13 Å (dry) to 12.81 Å (hydrated). Finally, when TC molecule is adsorbed in the basal space of MMT, the increment of the d001parameter is about 10 Å respect to the hydrated model. Dry and hydrated Na-MMT present a nonmagnetic (μ = 0 μB) and semiconductor behavior. Nevertheless, the TC-MMT system becomes conductor, and presents a very important magnetic moment (μ = 10.60 μB). After TC adsorption in MMT a potential valley with a slight depth in the MMT interlayer is generated. For this reason, it is proposed that TC adsorption would provide active sites for the adsorption of new species (like Na ions and water molecules).

Objective. Staff at public New York City sexually transmitted disease (STD) clinics screen patients for acute HIV infection (AHI) using pooled nucleic acid amplification tests. AHI screening is expensive but important for populations at high risk of acquiring HIV. We analyzed if targeting AHI screening in STD clinics could reduce program costs while maintaining AHI case detection.Methods. From January 2009 through May 2010, we screened all patients with negative rapid HIV tests for AHI. Using risk information on cases detected during this universal screening period, we developed criteria for targeted AHI screening and compared case yields and testing costs during 12 months of universal screening (June 2009 through May 2010) vs. 12 months of targeted screening (June 2010 through May 2011).Results. During the defined period of universal screening, we identified 40 AHI cases, and during targeted screening, we identified 35 AHI cases. Because of targeting efforts, the number needed to test to find one AHI case dropped from 1,631 to 254. With targeted screening, it cost an average of $4,535 per case detected and 39.3 cases were detected per 10,000 specimens; using universal screening, $29,088 was spent per case detected and 6.1 cases were detected per 10,000 specimens processed.Conclusion. Targeted screening identified similar numbers of AHI cases as when screening all clinic patients seeking HIV testing, but at one-seventh the cost.

Background:Acylcarnitines are biomarkers of fatty acid metabolism, and examining their patterns in preterm newborn may reveal metabolic changes associated with particular conditions related to prematurity. Isomeric acylcarnitines in dried blood spots (DBS) and plasma have never been assessed in preterm infants.Methods:We studied 157 newborn divided into four groups by weeks of gestational age (GA), as follows: 22–27?wk in group 1; 28–31?wk in group 2; 32–36?wk in group 3; and 37–42?wk in group 4. Samples were collected on the third day of life. Acylcarnitines were separated and quantified using ultra-performance liquid chromatography tandem mass spectrometry.Results:Acylcarnitine concentrations correlated significantly with GA and birth weight in both DBS and plasma samples. Concentrations were lower in preterm newborn, except for acylcarnitines derived from branched-chain amino acids, which were higher and correlated with enteral feeding. On day 3 of life, no correlations emerged with gender, respiratory distress syndrome, bronchopulmonary dysplasia, surfactant administration, or mechanical ventilation.Conclusion:We established GA-based reference ranges for isomeric acylcarnitine concentrations in preterm newborn, which could be used to assess nutritional status and the putative neuroprotective role of acylcarnitines.

La guía para el manejo y el tratamiento de las dislipemias del American College of Cardiology/American Heart Associationestadounidense y la del National Institute for Health and Clinical Excellencebritánico recomiendan cambios importantes, como la supresión de los objetivos terapéuticos o la utilización de unas tablas de riesgo nuevas. Este estudio pretende evaluar el impacto de utilizar estas nuevas guías en comparación con lo que supone la aplicación de la guía europea.

There is no consensus on darunavir (DRV) target levels in plasma for clinical use, and information about variability in plasma concentrations is limited.

Low density lipoproteins (LDL) and high density lipoproteins (HDL) are independent risk factors for coronary heart disease (CHD); decreasing LDL-cholesterol (LDL-C) levels with statin therapy represents the primary goal in the management of cardiovascular disease. However, despite the efficacy of statins in reducing cardiovascular morbidity and mortality, a significant residual risk has been observed even after reaching the LDL-C target, suggesting that other risk factors beyond LDL-C should be addressed, including low levels of HDL-cholesterol (HDL-C). Several clinical trials have shown an inverse relationship between HDL-C levels and cardiovascular risk, and 1 mg/dl increment in HDL-C is associated in epidemiological studies with a 2-3 decrease in cardiovascular risk, suggesting that raising HDL-C levels might have beneficial effects to reduce cardiovascular disease. However, several lines of evidence indicate that the functional properties of HDL may be relevant as well. In patient with CAD and normal HDL-C levels, HDL exhibit significantly reduced protective functions, and rather appear to be pro-atherogenic; on the other hand some genetic mutations causing low levels of HDL-C are not associated with increased atherosclerosis. Furthermore, although niacin significantly increased HDL-C levels, no further clinical benefit was observed from the addition of niacin to statin therapy, suggesting that increasing HDL-C levels is not sufficient and perhaps functional properties of HDL must be considered when choosing a therapeutic strategy to reduce the residual cardiovascular risk.

Background Limited information is available on anti-retroviral concentrations in women/infant pairs receiving prophylaxis for breastfeeding transmission of HIV and on the relationship between drug levels and the virological and haematochemistry parameters.Methods Patient population included HIV-positive pregnant women receiving antiretroviral prophylaxis from gestational week 25 until 6 months after delivery and their breastfed infants. Blood and breast milk samples were collected at delivery, and at months 1, 3 and 6 postpartum. Drug concentrations were measured by liquid chromatography–mass spectrometry.Results Overall, 66 women were studied: 29 received zidovudine (ZDV), lamivudine (3TC) and nevirapine (NVP), 28 stavudine (d4T), 3TC and NVP, and 9 ZDV, 3TC and lopinavir/ritonavir (LPV/r). Women who received >9 weeks of pre-partum prophylaxis were significantly more likely to have an undetectable viral load both in plasma and in breast milk at delivery. No emergence of resistance mutations was observed in breast milk. Breast milk/plasma concentration ratios were 0.6 for ZDV, 3TC and NVP, 1.0 for d4T and 0.4 for LPV/r. Only NVP reached significant levels in the infants. No correlation with any adverse events, including infant anaemia, was observed with drug concentrations. Two infants who acquired HIV infection had non-nucleoside reverse transcriptase inhibitor mutations at month 6.Conclusions Maternal administration of these three regimens up to 6 months postpartum was effective and safe for both mothers and infants. No significant correlation was found between drug concentrations and infant haematological parameters, supporting the hypothesis that other factors may contribute to the development of anaemia in these settings.

HDLs possess several physiological activities that may explain their antiatherosclerotic properties. Among them, the most relevant is the ability of HDL to promote the efflux of excess cholesterol from peripheral tissues to the liver for excretion.

To cite this article:Banfi C, Brioschi M, Lento S, Pirillo A, Galli S, Cosentino S, Tremoli E, Mussoni L. Statins prevent tissue factor induction by protease‐activated receptors 1 and 2 in human umbilical vein endothelial cells in vitro. J Thromb Haemost2011; 9: 1608–19.

The aim of this study was to assess whether the Burnout Syndrome is clearly expressed in orthodontic practice and to identify its impact in both general dentistry and orthodontics.

We first prove an extremal property of the infinite Fibonacci*word f: the family of the palindromic prefixes {hn| n ≥ 6}of fis not only a circular code but “almost” a comma-free one (see Prop. 12 in Sect. 4). We also extend to a more general situation the notion of a necklace introduced for the study of trinucleotides codes on the genetic alphabet, and we present a hierarchy relating two important classes of codes, the comma-free codes and the circular ones.

The objective of this study was to evaluate the plasma drug concentrations in human immunodeficiency virus (HIV)-infected pregnant women receiving highly active antiretroviral therapy (HAART) and to define the rate of occurrence of subtherapeutic concentrations for some commonly used antiretroviral drugs during pregnancy. We evaluated HIV-infected women (n = 68) in the third trimester of pregnancy in steady-state treatment with an HAART regimen administrated on a twice a day basis, which included 2 nucleoside reverse transcriptase inhibitors plus nelfinavir (NFV), lopinavir/ritonavir (LPV/r), or nevirapine (NVP). Blood samples were collected at predose (Ctrough). The following thresholds were used to define therapeutic drug concentrations-NFV: 0.8 μg/mL; LPV: 4.0 μg/mL/1.0 μg/mL (experienced/naive); and NVP: 3.1 μg/mL. At predose sampling, adequate drug concentrations were found in a higher proportion of women receiving NFV (70.8%) and LPV (75.0%) than NVP (55.6%). Median Ctroughplasma concentrations were 1.2 μg/mL for NFV, 5.5 μg/mL for LPV, and 3.1 μg/mL for NVP. Women receiving lopinavir/ritonavir had the lowest rates of detectable (>50 copies/mL) HIV RNA (15.4%) compared with rates of 22.2% and 41.7% among women receiving NVP and NFV, respectively. Genotypic resistance was detected in 50% of women with detectable HIV RNA for whom samples were available for testing. Subtherapeutic predose concentrations among HIV-infected pregnant women were more commonly found with NVP than with protease inhibitors. LPV administration was associated with the best viral load suppression.

Low levels of plasma viremia (below 50 copies/ml of HIV-1 RNA) can be detected in the majority of HIV subjects successfully treated with HAART. Aim of our study was to evaluate the impact of different antiretroviral regimens on this residual viremia and on proviral HIV-1 DNA in HAART-treated subjects with plasma HIV RNA <400 cp/ml and no history of virological failure. To this purpose, a cross-sectional analysis of 319 HIV-positive patients on HAART with plasma HIV RNA <400 cp/ml was performed. Subjects had been on HAART for a median of 3.6 years: the current regimen included two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor (PI) in 104 (32.6) cases, of which 73 treated with a boosted PI; two NRTIs plus a non-NRTI (NNRTI) were prescribed in 166 (52.2) cases, and NRTIs-only in 49 cases (15.4). Patients treated with PI had the lowest nadir CD4 cell count (237191 cells/l) compared to patients treated with NNRTI (384192 cells/l) or NRTIs-only (387222 cells/l). Cell-associated HIV-1 DNA was measured in 231 subjects. Residual viremia was measured in 238 subjects with plasma HIV-1 RNA levels < 50 copies/ml. Multivariate analysis showed that the use of NNRTI was independently associated to low levels of residual viremia and high levels of HIV-1DNA, whereas the use of PI was independently associated to low levels of HIV-1 DNA. The better virological performance of NNRTI in terms of low residual viremia is consistent with specific literature data, whereas the greater impact of PI on the viral reservoirs is noteworthy and needs further investigations.

Low levels of plasma viremia (below 50 copies/ml of HIV-1 RNA) can be detected in the majority of HIV+ subjects successfully treated with HAART. Aim of our study was to evaluate the impact of different antiretroviral regimens on this residual viremia and on proviral HIV-1 DNA in HAART-treated subjects with plasma HIV RNA < 400 cp/ml and no history of virological failure. To this purpose, a cross-sectional analysis of 319 HIV-positive patients on HAART with plasma HIV RNA < 400 cp/ml was performed. Subjects had been on HAART for a median of 3.6 years: the current regimen included two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor (PI) in 104 (32.6%) cases, of which 73 treated with a boosted PI; two NRTIs plus a non-NRTI (NNRTI) were prescribed in 166 (52.2%) cases, and NRTIs-only in 49 cases (15.4%). Patients treated with PI had the lowest nadir CD4 cell count (237+191 cells/μl) compared to patients treated with NNRTI (384+192 cells/μl) or NRTIs-only (387+222 cells/μl). Cell-associated HIV-1 DNA was measured in 231 subjects. Residual viremia was measured in 238 subjects with plasma HIV-1 RNA levels < 50 copies/ml. Multivariate analysis showed that the use of NNRTI was independently associated to low levels of residual viremia and high levels of HIV-1DNA, whereas the use of PI was independently associated to low levels of HIV-1 DNA. The better virological performance of NNRTI in terms of low residual viremia is consistent with specific literature data, whereas the greater impact of PI on the viral reservoirs is noteworthy and needs further investigations.

Abruzzese: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Galimberti:Incyte: Honoraria; Novartis: Speakers Bureau. Castagnetti:Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Pregno:Incyte-Italy,: Membership on an entity's Board of Directors or advisory committees, Other: conference reports; Novartis-Italy: Membership on an entity's Board of Directors or advisory committees, Other: conference reports; Pfizer-Italy: Membership on an entity's Board of Directors or advisory committees, Other: conference reports. Bocchia:CELGENE: Honoraria; Incyte: Honoraria. Gugliotta:Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Foà:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees.

Oxidised lowdensity lipoprotein LDL is believed to be the most atherogenic form of LDL. However, while a number of experimental data support this concept, the protective role of antioxidants that may prevent LDL oxidation in atherosclerosis is only partially confirmed by studies in man. Observational and epidemiological data as well as randomised trials failed to provide clearcut indications, because of mixed results on the protective role of antioxidants against cardiovascular diseases. In spite of the lack of a general consensus, recent data reinforce the concept that a regular intake of antioxidants present in food blocks the progression of atherosclerosis and that the reduced ability of LDL to oxidise may represent a good marker to follow the action of antioxidants. Among their properties statins also possess antioxidant activities and the aim of this paper is to review the scientific evidence for such an effect and its possible clinical relevance.