Influence of leptin on arterial distensibility - A novel link between obesity and cardiovascular disease?

Background-The mechanisms by which obesity increases the risk of atherosclerotic cardiovascular disease (CVD) are poorly understood. In experimental models, leptin, a hormone produced by adipose tissue, has been shown adversely to affect vascular health. Therefore, we tested the hypothesis that high leptin concentrations are associated with lower arterial distensibility, an index of circulatory function relevant to the atherosclerotic process.Methods and Results-Noninvasive, high-resolution, vascular ultrasound was used to measure brachial artery distensibility in 294 healthy adolescents (aged 13 to 16 years) who had a broad range of body mass indexes. Fat mass was measured by bioelectric impedance analysis; fasting serum leptin concentration by radioimmunoassay; and lipid profile, fasting insulin, glucose, and C-reactive protein concentrations by standard laboratory techniques. Higher leptin concentrations were associated with impaired arterial distensibility (regression coefficient, -1.3% change in arterial distension per 10% increase in leptin; 95% CI, -1.9% to -0.8%; P<0.001). This association was independent of fat mass, blood pressure, and C-reactive protein, fasting insulin, or LDL cholesterol concentrations.Conclusions-Elevation in leptin was associated with impaired vascular function, independent of the metabolic and inflammatory disturbances associated with obesity. Our observations are consistent with data from experimental models and suggest that high leptin concentration is an important mechanism for the adverse influence of body fatness on CVD

Mechanisms of sill and dyke intrusion.

Thesis (M.Sc.)-University of Natal, 1994.Mechanisms of sill and dyke intrusion require an understanding of fracture growth,stress distributions and intensities, dilation,intrusion rates, hydraulic pressure,host-rock effects,en echelon fracture arrays,and flow direction. The methods of previous studies have been applied to natural sill and dyke examples of the Karoo Igneous Province in northern Natal . An en echelon array of Jurassic dolerite sills occurs within Permian Ecca sediments along the Mhlatuze River, west of Empangeni. Dolerite emplacement occurred as two intrusive phases. The first phase resulted in thick, . coarse-grained dolerite sills. The second phase produced relatively thinner, fme-grained sills. The intrusion of fmegrained dolerite into older sills is demonstrated by abrupt variations in the whole-rock and mineral geochemistry profiles across the sills. Syn-crystallisation effects such as crystal settling and fractionation, and post-crystallisation hydrothermal activity is also manifested in the mineralogical and geochemical changes across the sills. The fine grained doleriteis associated with xenolithic dolerite which represents a contaminated magma propagation front of the fine-grained dolerite. The higher viscosity of the xenolithic dolerite hindered propagation, and was thus overtaken and engulfedby the mainmagmapulse. Consistent sinistral off setting of sill segments is interpreted to be the result of a fingered sill periphery intruding an en echelon fracture array. Dilation of individual segments, or fingers, occurred simultaneously. Subsequent interaction of near-tip stresses induced inwardly propagating curvature of adjacent segmentsin the array.Resultant linkage has produced a stepped-sill geometry; sill propagation and flow directions were orthogonal to the plane of linkage. The flow direction is confirmed by shape preferred-orientations of acicular mineral grains within the chilled margins of the sills, indicating the direction of flow to be perpendicular to the plane of the en echelon array, and parallel to strike directions of offset surfaces that link adjacent sill segments. Multiple dyke intrusion is examinedat an outcrop of the Rooi Rand Dyke Swarm, along the Pongola River. Individual intrusive episodes are identifiable on the basis of chill-zone relationships. The pattern along the Pongola River suggests that younger intrusive episodes frequently intrude through the centres of older dykes. A three dimensional analysis of en echelon dyke let segments allows a re-construction of the dilation history,and provides an explanation for the development of blunt-ended intrusion segments. Mineral geochemistry anomalies around dyke tips suggests possible facilitation of incipient fracture via decreases in mineral strengths manifested by geochemical changes. A statistical digital analysis of micro-phenocryst orientations within chilled dyke margins is shown to provide a viable method to ascertain magma flow directions within dykes, and may thus be a useful tool for future investigations

Anti-drug Antibody Responses Impair Prophylaxis Mediated by AAV-Delivered HIV-1 Broadly Neutralizing Antibodies

Adeno-associated virus (AAV) delivery of potent and broadly neutralizing antibodies (bNAbs is a promising approach for the prevention of HIV-1 infection. The immunoglobulin G (IgG)1 subtype is usually selected for this application, because it efficiently mediates antibody effector functions and has a somewhat longer half-life. However, the use of IgG1-Fc has been associated with the generation of anti-drug antibodies (ADAs) that correlate with loss of antibody expression. In contrast, we have shown that expression of the antibody-like molecule eCD4-Ig bearing a rhesus IgG2-Fc domain showed reduced immunogenicity and completely protected rhesus macaques from simian-HIV (SHIV)-AD8 challenges. To directly compare the performance of the IgG1-Fc and the IgG2-Fc domains in a prophylactic setting, we compared AAV1 expression of rhesus IgG1 and IgG2 forms of four anti-HIV bNAbs: 3BNC117, NIH45-46, 10-1074, and PGT121. Interestingly, IgG2-isotyped bNAbs elicited significantly lower ADA than their IgG1 counterparts. We also observed significant protection from two SHIV-AD8 challenges in macaques expressing IgG2-isotyped bNAbs, but not from those expressing IgG1. Our data suggest that monoclonal antibodies isotyped with IgG2-Fc domains are less immunogenic than their IgG1 counterparts, and they highlight ADAs as a key barrier to the use of AAV1-expressed bNAbs

Combination of the STING Agonist MIW815 (ADU-S100) and PD-1 Inhibitor Spartalizumab in Advanced/Metastatic Solid Tumors or Lymphomas: An Open-Label, Multicenter, Phase Ib Study

Purpose: The stimulator of IFN genes (STING) is a transmembrane protein that plays a role in the immune response to tumors. Single-agent STING agonist MIW815 (ADU-S100) has demonstrated immune activation but limited antitumor activity. This phase Ib, multicenter, dose-escalation study assessed the safety and tolerability of MIW815 plus spartalizumab (PDR001), a humanized IgG4 antibody against PD-1, in 106 patients with advanced solid tumors or lymphomas. Patients and Methods: Patients were treated with weekly intratumoral injections of MIW815 (50–3,200 μg) on a 3-weeks-on/1-week-off schedule or once every 4 weeks, plus a fixed dose of spartalizumab (400 mg) intravenously every 4 weeks. Results: Common adverse events were pyrexia (n = 23; 22%), injection site pain (n = 21; 20%), and diarrhea (n = 12; 11%). Overall response rate was 10.4%. The MTD was not reached. Pharmacodynamic biomarker analysis demonstrated on-target activity. Conclusions: The combination of MIW815 and spartalizumab was well tolerated in patients with advanced/metastatic cancers, including in patients with anti-PD-1 refractory disease. Minimal antitumor responses were seen

40Ar/39Ar ages of the sill complex of the Karoo large igneous province: implications for the Pliensbachian-Toarcian climate change.

Reliable geochronological results gathered so far (n = 76) have considerably constrained the timing of the emplacement of the Karoo large igneous province (LIP). Yet strikingly missing from this dating effortis the huge southern sill complex cropping out in the >0.6 x 10(6) km2 Main Karoo sedimentary basin. We present 16 new 40Ar/39Ar analyses carried out on fresh plagioclase and biotite separates from 15 sill samples collected along a N-S trend in the eastern part of the basin. The results show a large range of plateau and miniplateau ages (176.2 +- 1.3 to 183.8 +- 2.4 Ma), with most dates suggesting a -3 Ma (181-184 Ma) duration for the main sill events. The available age database allows correlation of the Karoo LIP emplacement with the Pliensbachian-Toarcian second-order biotic extinction, the global warming, and the Toarcian anoxic event (provided that adequate calibration between the 40K and 238U decay constant ismade). The mass extinction and the isotopic excursions recorded at the base of the Toarcian appear to be synchronous with both the increase of magma emission of the Karoo LIP and the emplacement of the sills.The CO2 and SO2 derived from both volcanic emissions as well as carbon-rich sedimentary layers intrudedby sills might be the main culprits of the Pliensbachian-Toarcian climate perturbations. We propose that the relatively low eruption rate of the Karoo LIP is one of the main reasons explaining why its impact on thebiosphere is relatively low contrary to, e.g., the CAMP (Triassic-Jurassic) and Siberia (Permo-Triassic) LIPs