Vitamin D time profile based on the contribution of non-genetic and genetic factors in HIV-infected individuals of European ancestry

BACKGROUND Vitamin D deficiency is prevalent in HIV-infected individuals and vitamin D supplementation is proposed according to standard care. This study aimed at characterizing the kinetics of 25(OH)D in a cohort of HIV-infected individuals of European ancestry to better define the influence of genetic and non-genetic factors on 25(OH)D levels. These data were used for the optimization of vitamin D supplementation in order to reach therapeutic targets. METHODS 1,397 25(OH)D plasma levels and relevant clinical information were collected in 664 participants during medical routine follow up visits. They were genotyped for 7 SNPs in 4 genes known to be associated with 25(OH)D levels. 25(OH)D concentrations were analyzed using a population pharmacokinetic approach. The percentage of individuals with 25(OH)D concentrations within the recommended range of 20-40ng/ml during 12 months of follow up and several dosage regimens were evaluated by simulation. RESULTS A one-compartment model with linear absorption and elimination was used to describe 25(OH)D pharmacokinetics, while integrating endogenous baseline plasma concentrations. Covariate analyses confirmed the effect of seasonality, body mass index, smoking habits, the analytical method, darunavir/r and the genetic variant in GC (rs2282679) on 25(OH)D concentrations. 11% of the interindividual variability in 25(OH)D levels was explained by seasonality and other non-genetic covariates and 1% by genetics. The optimal supplementation for severe vitamin D deficient patients was 300000 IU two times per year. CONCLUSIONS This analysis allowed identifying factors associated with 25(OH)D plasma levels in HIV-infected individuals. Improvement of dosage regimen and timing of vitamin D supplementation is proposed based on those results.

Normal platelet activation profile in patients with peripheral arterial disease on aspirin.

BACKGROUND Peripheral arterial disease (PAD) is a progressive vascular disease associated with a high risk of cardiovascular morbidity and death. Antithrombotic prevention is usually applied by prescribing the antiplatelet agent aspirin. However, in patients with PAD aspirin fails to provide protection against myocardial infarction and death, only reducing the risk of ischemic stroke. Platelets may play a role in disease development, but this has not been tested by proper mechanistic studies. In the present study, we performed a systematic evaluation of platelet reactivity in whole blood from patients with PAD using two high-throughput assays, i.e. multi-agonist testing of platelet activation by flow cytometry and multi-parameter testing of thrombus formation on spotted microarrays. METHODS Blood was obtained from 40 patients (38 on aspirin) with PAD in majority class IIa/IIb and from 40 age-matched control subjects. Whole-blood flow cytometry and multiparameter thrombus formation under high-shear flow conditions were determined using recently developed and validated assays. RESULTS Flow cytometry of whole blood samples from aspirin-treated patients demonstrated unchanged high platelet responsiveness towards ADP, slightly elevated responsiveness after glycoprotein VI stimulation, and decreased responsiveness after PAR1 thrombin receptor stimulation, compared to the control subjects. Most parameters of thrombus formation under flow were similarly high for the patient and control groups. However, in vitro aspirin treatment caused a marked reduction in thrombus formation, especially on collagen surfaces. When compared per subject, markers of ADP- and collagen-induced integrin activation (flow cytometry) strongly correlated with parameters of collagen-dependent thrombus formation under flow, indicative of a common, subject-dependent regulation of both processes. CONCLUSION Despite of the use of aspirin, most platelet activation properties were in the normal range in whole-blood from class II PAD patients. These data underline the need for more effective antithrombotic pharmacoprotection in PAD.

Clinical usefulness of gene-expression profile to rule out acute rejection after heart transplantation: CARGO II.

AIMS A non-invasive gene-expression profiling (GEP) test for rejection surveillance of heart transplant recipients originated in the USA. A European-based study, Cardiac Allograft Rejection Gene Expression Observational II Study (CARGO II), was conducted to further clinically validate the GEP test performance. METHODS AND RESULTS Blood samples for GEP testing (AlloMap(®), CareDx, Brisbane, CA, USA) were collected during post-transplant surveillance. The reference standard for rejection status was based on histopathology grading of tissue from endomyocardial biopsy. The area under the receiver operating characteristic curve (AUC-ROC), negative (NPVs), and positive predictive values (PPVs) for the GEP scores (range 0-39) were computed. Considering the GEP score of 34 as a cut-off (>6 months post-transplantation), 95.5% (381/399) of GEP tests were true negatives, 4.5% (18/399) were false negatives, 10.2% (6/59) were true positives, and 89.8% (53/59) were false positives. Based on 938 paired biopsies, the GEP test score AUC-ROC for distinguishing ≥3A rejection was 0.70 and 0.69 for ≥2-6 and >6 months post-transplantation, respectively. Depending on the chosen threshold score, the NPV and PPV range from 98.1 to 100% and 2.0 to 4.7%, respectively. CONCLUSION For ≥2-6 and >6 months post-transplantation, CARGO II GEP score performance (AUC-ROC = 0.70 and 0.69) is similar to the CARGO study results (AUC-ROC = 0.71 and 0.67). The low prevalence of ACR contributes to the high NPV and limited PPV of GEP testing. The choice of threshold score for practical use of GEP testing should consider overall clinical assessment of the patient's baseline risk for rejection.

Calcareous dinocysts and grain size distribution along profile Stevns-Klint

The distribution patterns of calcareous dinoflagellate cysts were studied in the classic Cretaceous Tertiary (K-T) boundary section of Stevns Klint, Denmark, focusing mainly on the response of the cyst association to an abrupt environmental catastrophe. A major part of the Fish Clay, which covers the K-T boundary at its base and is exposed in the investigated section, contains fallout produced by an asteroid impact. Calcareous dinoflagenate cysts are the best preserved remains of carbonate-producing phytoplankton in this layer. The potential of this group of microfossils for the analysis of survival strategies and extinction patterns has been underestimated. The cyst species of the investigated section can be grouped into four assemblages that represent victims, survivors, opportunists, and specially adapted forms. The victims (Pithonelloideae) were an extremely successful group throughout the Upper Cretaceous, but were restricted to the narrow outer shelf. This restriction minimized their spatial distribution, which generally should be large to facilitate escape from unfavorable conditions. Spatial restriction optimized the population decrease by mass mortality, disabling a successful recovery. In contrast, the survivors that became the dominating group in the Danian had a wide spatial range from the shelf environment to the oceanic realm. A unique calcareous dinocyst assemblage in the Fish Clay shows that even under the stressed conditions immediately following the impact event, some species flourished due to special adaptation or high ecological tolerance. The ability of these dinoflagellate species to form calcareous resting cysts in combination with their generally wide spatial distribution in a variety of environments appears to be the main reason for a low extinction rate at the K-T boundary as opposed to the high extinction rate of other phytoplankton groups, such as the coccolithophorids.

Paleocoenographic investigations on sediment profile GeoB6008

Near-shore waters along the northwest African margin are characterized by coastal upwelling and represent one of the world's major upwelling regions. Sea surface temperature (SST) records from Moroccan sediment cores, extending back 2500 years, reveal anomalous and unprecedented cooling during the 20th century, which is consistent with increased upwelling. Upwelling-driven SSTs also vary out of phase with millennial-scale changes in Northern Hemisphere temperature anomalies (NHTAs) and show relatively warm conditions during the Little Ice Age and relatively cool conditions during the Medieval Warm Period. Together, these results suggest that coastal upwelling varies with NHTAs and that upwelling off northwest Africa may continue to intensify as global warming and atmospheric CO2 levels increase.

Age determination and pollen profile of sediment core Voulkaria 1966, Greece

Lake Voulkaria is situated in northwestern Greece in the Prefecture of Etoloakarnania, 6 km SW of the city of Vonitsa and 10 km east of the northern tip of the island of Levkás (Leukás, Lefkada). The lake is separated from the Ionian Sea on the West by a narrow limestone ridge ca 10 m high and has a size of 940 ha. An almost continuous fringe of Phragmites surrounds the open water. This reed bank is up to 500 m wide along the southern shore of the lake. Water depth is low, predominantly less than 2 m. In the south-eastern part of the lake a maximum depth of 3.1 m was measured in September 1997.