Political Regimes and Sovereign Credit Risk in Europe, 1750-1913

This article uses a new panel data set to perform a statistical analysis of political regimes and sovereign credit risk in Europe from 1750 to 1913. Old Regime polities typically suffered from fiscal fragmentation and absolutist rule. By the start of World War I, however, many such countries had centralized institutions and limited government. Panel regressions indicate that centralized and?or limited regimes were associated with significant improvements in credit risk relative to fragmented and absolutist ones. Structural break tests also reveal close relationships between major turning points in yield series and political transformations

Discovery of Dual-Action Membrane-Anchored Modulators of Incretin Receptors

The glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide-1 (GLP-1) receptors are considered complementary therapeutic targets for type 2 diabetes. Using recombinant membrane-tethered ligand (MTL) technology, the present study focused on defining optimized modulators of these receptors, as well as exploring how local anchoring influences soluble peptide function.Serial substitution of residue 7 in membrane-tethered GIP (tGIP) led to a wide range of activities at the GIP receptor, with [G(7)]tGIP showing enhanced efficacy compared to the wild type construct. In contrast, introduction of G(7) into the related ligands, tGLP-1 and tethered exendin-4 (tEXE4), did not affect signaling at the cognate GLP-1 receptor. Both soluble and tethered GIP and GLP-1 were selective activators of their respective receptors. Although soluble EXE4 is highly selective for the GLP-1 receptor, unexpectedly, tethered EXE4 was found to be a potent activator of both the GLP-1 and GIP receptors. Diverging from the pharmacological properties of soluble and tethered GIP, the newly identified GIP-R agonists, (i.e. [G(7)]tGIP and tEXE4) failed to trigger cognate receptor endocytosis. In an attempt to recapitulate the dual agonism observed with tEXE4, we conjugated soluble EXE4 to a lipid moiety. Not only did this soluble peptide activate both the GLP-1 and GIP receptors but, when added to receptor expressing cells, the activity persists despite serial washes.These findings suggest that conversion of a recombinant MTL to a soluble membrane anchored equivalent offers a means to prolong ligand function, as well as to design agonists that can simultaneously act on more than one therapeutic target

Neurocognition and quality of life after reinitiating antiretroviral therapy in children randomized to planned treatment interruption

Objective: Understanding the effects of antiretroviral treatment (ART) interruption on neurocognition and quality of life (QoL) are important for managing unplanned interruptions and planned interruptions in HIV cure research. Design: Children previously randomized to continuous (continuous ART, n=41) vs. planned treatment interruption (PTI, n=47) in the Pediatric European Network for Treatment of AIDS (PENTA) 11 study were enrolled. At study end, PTI children resumed ART. At 1 and 2 years following study end, children were assessed by the coding, symbol search and digit span subtests of Wechsler Intelligence Scale for Children (6-16 years old) or Wechsler Adult Intelligence Scale ( 6517 years old) and by Pediatrics QoL questionnaires for physical and psychological QoL. Transformed scaled scores for neurocognition and mean standardized scores for QoL were compared between arms by t-test and Mann-Whitney U test, respectively. Scores indicating clinical concern were compared (<7 for neurocognition and <70 for QoL tests). Results: Characteristics were similar between arms with a median age of 12.6 years, CD4 + of 830 cells/\u3bcl and HIV RNA of 1.7 log 10 copies/ml. The median cumulative ART exposure was 9.6 in continuous ART vs. 7.7 years in PTI (P=0.02). PTI children had a median of 12 months off ART and had resumed ART for 25.2 months at time of first assessment. Neurocognitive scores were similar between arms for all tests. Physical and psychological QoL scores were no different. About 40% had low neurocognitive and QoL scores indicating clinical concern. Conclusion: No differences in information processing speed, sustained attention, short-term memory and QoL functioning were observed between children previously randomized to continuous ART vs. PTI in the PENTA 11 trial

Odd Chain Fatty Acids; New Insights of the Relationship Between the Gut Microbiota, Dietary Intake, Biosynthesis and Glucose Intolerance

Recent findings have shown an inverse association between circulating C15:0/C17:0 fatty acids with disease risk, therefore, their origin needs to be determined to understanding their role in these pathologies. Through combinations of both animal and human intervention studies, we comprehensively investigated all possible contributions of these fatty acids from the gut-microbiota, the diet, and novel endogenous biosynthesis. Investigations included an intestinal germ-free study and a C15:0/C17:0 diet dose response study. Endogenous production was assessed through: a stearic acid infusion, phytol supplementation, and a Hacl1$^{−/−}$ mouse model. Two human dietary intervention studies were used to translate the results. Finally, a study comparing baseline C15:0/C17:0 with the prognosis of glucose intolerance. We found that circulating C15:0/C17:0 levels were not influenced by the gut-microbiota. The dose response study showed C15:0 had a linear response, however C17:0 was not directly correlated. The phytol supplementation only decreased C17:0. Stearic acid infusion only increased C17:0. Hacl1$^{−/−}$ only decreased C17:0. The glucose intolerance study showed only C17:0 correlated with prognosis. To summarise, circulating C15:0 and C17:0 are independently derived; C15:0 correlates directly with dietary intake, while C17:0 is substantially biosynthesized, therefore, they are not homologous in the aetiology of metabolic disease. Our findings emphasize the importance of the biosynthesis of C17:0 and recognizing its link with metabolic disease.The authors are grateful to the Medical Research Council for core funding (Lipid Profiling and Signalling programme grant; number UD99999906, Cambridge Lipidomics Biomarker Research Initiative; grant G0800783, MRC Human Nutrition Research PhD programme). Grant GAČR: GA15–09518S and grant Czech Science Foundation GACR: 16-06326S funded part of the gut microbiota investigation. The authors would like to acknowledge the USDA (ACNC-USDA-CRIS 6251-51000-005-03S) for funding of the dose response animal study within this manuscript. The Human study “Dairy Fat supplementation” was supported by research grants from the Hospices Civils de Lyon (Actions Incitatives); from the Programme Hospitalier de Recherche Clinique Interregional; from the Agence Nationale de la Recherche (Programme de Recherche en Nutrition Humaine and the Programme National de Recherche en Alimentation); and from the Innovation Stratégique Industrielle program of the Agence pour l’Innovation OSEO (Innovation Thérapeutique – Diabète project). K. Seyssel and M. Alligier were recipients of a doctoral fellowship from the Ministère de l’Enseignement Supérieur et de la Recherche (France). The phytol supplementation animal study was supported by grants from the Academy of Finland (138690), the Sigrid Juselius Foundation and NordForsk under the Nordic Centres of Excellence Programme in Food, Nutrition and Health, project “Mitohealth” (070010). The NIH Grant R01-DK-18243 for funding of the canine study. HACL1 knockout mouse model was supported by grants from the Flemish “Fonds Wetenschappelijk Onderzoek” (G.0721.10N) and KU Leuven (OT/14/100)

Acute mountain sickness.

Acute mountain sickness (AMS) is a clinical syndrome occurring in otherwise healthy normal individuals who ascend rapidly to high altitude. Symptoms develop over a period ofa few hours or days. The usual symptoms include headache, anorexia, nausea, vomiting, lethargy, unsteadiness of gait, undue dyspnoea on moderate exertion and interrupted sleep. AMS is unrelated to physical fitness, sex or age except that young children over two years of age are unduly susceptible. One of the striking features ofAMS is the wide variation in individual susceptibility which is to some extent consistent. Some subjects never experience symptoms at any altitude while others have repeated attacks on ascending to quite modest altitudes. Rapid ascent to altitudes of 2500 to 3000m will produce symptoms in some subjects while after ascent over 23 days to 5000m most subjects will be affected, some to a marked degree. In general, the more rapid the ascent, the higher the altitude reached and the greater the physical exertion involved, the more severe AMS will be. Ifthe subjects stay at the altitude reached there is a tendency for acclimatization to occur and symptoms to remit over 1-7 days

Was it Uruguay or Coffee? The causes of the beef jerky industry’s decline in southern Brazil (1850 – 1889)

What caused the decline of the beef jerky’s production in Brazil? The main sustenance for slaves, beef jerky was the most important industry in southern Brazil. Nevertheless, by 1850, producers were already worried that they could not compete with Uruguayan industry. Traditional interpretations impute the decline to labor markets differences in productivity, since Brazil used slaves while Uruguay had abolished slavery in 1842. Recent research also raises the possibility of a Brazilian “Dutch Disease”, resulting from the coffee exports boom. We test both hypothesis and argue that Brazilian production’s decline was associated with structural changes in demand for low quality meat. Trade protection policies created disincentives for Brazilian producers to increase productivity and diversify its cattle industry