Inflammatory Markers Associated With Subclinical Coronary Artery Disease: The Multicenter AIDS Cohort Study.

BackgroundDespite evidence for higher risk of coronary artery disease among HIV+ individuals, the underlying mechanisms are not well understood. We investigated associations of inflammatory markers with subclinical coronary artery disease in 923 participants of the Multicenter AIDS Cohort Study (575 HIV+ and 348 HIV- men) who underwent noncontrast computed tomography scans for coronary artery calcification, the majority (n=692) also undergoing coronary computed tomography angiography.Methods and resultsOutcomes included presence and extent of coronary artery calcification, plus computed tomography angiography analysis of presence, composition, and extent of coronary plaques and severity of coronary stenosis. HIV+ men had significantly higher levels of interleukin-6 (IL-6), intercellular adhesion molecule-1, C-reactive protein, and soluble-tumor necrosis factor-α receptor (sTNFαR) I and II (all P<0.01) and a higher prevalence of noncalcified plaque (63% versus 54%, P=0.02) on computed tomography angiography. Among HIV+ men, for every SD increase in log-interleukin-6 and log intercellular adhesion molecule-1, there was a 30% and 60% increase, respectively, in the prevalence of coronary stenosis ≥50% (all P<0.05). Similarly, sTNFαR I and II in HIV+ participants were associated with an increase in prevalence of coronary stenosis ≥70% (P<0.05). Higher levels of interleukin-6, sTNFαR I, and sTNFαR II were also associated with greater coronary artery calcification score in HIV+ men (P<0.01).ConclusionsHigher inflammatory marker levels are associated with greater prevalence of coronary stenosis in HIV+ men. Our findings underscore the need for further study to elucidate the relationships of inflammatory pathways with coronary artery disease in HIV+ individuals

An Anisotropic Ballistic Deposition Model with Links to the Ulam Problem and the Tracy-Widom Distribution

We compute exactly the asymptotic distribution of scaled height in a (1+1)--dimensional anisotropic ballistic deposition model by mapping it to the Ulam problem of finding the longest nondecreasing subsequence in a random sequence of integers. Using the known results for the Ulam problem, we show that the scaled height in our model has the Tracy-Widom distribution appearing in the theory of random matrices near the edges of the spectrum. Our result supports the hypothesis that various growth models in $(1+1)$ dimensions that belong to the Kardar-Parisi-Zhang universality class perhaps all share the same universal Tracy-Widom distribution for the suitably scaled height variables.Comment: 5 pages Revtex, 3 .eps figures included, new references adde

Isotopic signature of burial diagenesis and primary lithological contrasts in periplatform carbonates (Miocene, Great Bahama Bank)

The stable isotope geochemistry of Miocene sediments from the leeward margin of the Great Bahama Bank was examined to investigate burial diagenetic processes in periplatform carbonates. Data indicate that, in addition to differences in bulk proportions of neritic and pelagic carbonate along the slope, rhythmic variation in primary carbonate content has controlled patterns of burial diagenesis and associated geochemical signatures throughout much of the succession examined. The present study focuses on Ocean Drilling Program Sites 1006 and 1007, the most distal of five sites drilled from marginal to deep basin environments during Leg 166. These Miocene sections are characterized by their cyclic appearance, manifest as decimeter- to meter-scale alternations between light-colored ooze/chalk/limestone and dark-colored marl/marlstone. The section at Site 1006 contains a high proportion of pelagic carbonate and is unlithified to a subbottom depth of ~675 m. Fluctuations in δ18O and δ13C values at this site are independent of lithological variation and reflect primary conditions. At Site 1007, located at the toe-of-slope and composed of a mixture of bank-derived and pelagic carbonate, limestones are densely cemented, show little evidence of compaction and have δ18O values up to 2‰ higher than coeval sediments at Site 1006. Marlstones at Site 1007 are poorly cemented, exhibit an increase in compaction-related features with depth and have lower and more variable δ18O values that are similar to those of coeval sediments at Site 1006. Isotopic and petrographic characteristics of limestone interbeds result from cement precipitation from cold sea water during the first ~100 m of burial. Higher proportions of insoluble materials and pelagic carbonate seem to have inhibited diagenetic alteration in adjacent marlstones; in spite of significant compaction and pressure solution during burial, original isotopic compositions appear to be best preserved in these intervals at Site 1007. The documented contrasts in petrographic and isotopic patterns illustrate the role of primary sediment composition in controlling lithification processes in periplatform carbonates and stress the importance of considering such factors when interpreting geochemical data from ancient shelf and slope limestones

Sedimentology and geochemistry of an urban coastal lake system: Coombabah Lake Nature Reserve, Gold Coast, Queensland

A study was initiated to address environmental concerns associated with changes in land use in the catchment area of Coombabah Lake, a brackish coastal lake system located in southeast Queensland. Sedimentological and geochemical data derived from a series of cores that penetrate the ca. 0–6000 year-old lacustrine sequence indicate that throughout much of its history, Coombabah Lake has remained a quiet, shallow, water body fed by fine-grained sediment dropped from suspension. Discrete and laterally continuous, shelly horizons form the basis for the stratigraphy developed for the lake sequence. A lithological transition in the upper 50 cm of the sediment column, from mud to shell-rich, sandy mud, suggests that the depositional regime changed ~500 years ago as accommodation space was filled. At this time, the dominant sedimentary processes changed to include reworking, partial bypass of sediment, the intermittent concentration of shell debris by winnowing, and the development of a flood-tidal delta complex in the lower reaches of the lake. Sharp increases in total organic carbon, total nitrogen, and total phosphorus concentrations below the lithological transition at 50 cm depth suggest that the capacity of the system to preserve organic matter and trap nutrients decreased significantly after the transition in depositional regime. Results indicate that current conditions in Lake Coombabah are governed by natural processes associated with the long-term evolution of coastal lake systems, and reveal little to suggest that there were any adverse affects resulting from recent human activities in the surrounding catchment

Sedimentology and geochemistry of an urban coastal lake system: Coombabah Lake Nature Reserve, Gold Coast, Queensland

A study was initiated to address environmental concerns associated with changes in land use in the catchment area of Coombabah Lake, a brackish coastal lake system located in southeast Queensland. Sedimentological and geochemical data derived from a series of cores that penetrate the ca. 0–6000 year-old lacustrine sequence indicate that throughout much of its history, Coombabah Lake has remained a quiet, shallow, water body fed by fine-grained sediment dropped from suspension. Discrete and laterally continuous, shelly horizons form the basis for the stratigraphy developed for the lake sequence. A lithological transition in the upper 50 cm of the sediment column, from mud to shell-rich, sandy mud, suggests that the depositional regime changed ~500 years ago as accommodation space was filled. At this time, the dominant sedimentary processes changed to include reworking, partial bypass of sediment, the intermittent concentration of shell debris by winnowing, and the development of a flood-tidal delta complex in the lower reaches of the lake. Sharp increases in total organic carbon, total nitrogen, and total phosphorus concentrations below the lithological transition at 50 cm depth suggest that the capacity of the system to preserve organic matter and trap nutrients decreased significantly after the transition in depositional regime. Results indicate that current conditions in Lake Coombabah are governed by natural processes associated with the long-term evolution of coastal lake systems, and reveal little to suggest that there were any adverse affects resulting from recent human activities in the surrounding catchment

Antibiotic and Antiinflammatory Therapy Transiently Reduces Inflammation and Hypercoagulation in Acutely SIV-Infected Pigtailed Macaques

Increased chronic immune activation and inflammation are hallmarks of HIV/SIV infection and are highly correlated with progression to AIDS and development of non-AIDS comorbidities, such as hypercoagulability and cardiovascular disease. Intestinal dysfunction resulting in microbial translocation has been proposed as a lead cause of systemic immune activation and hypercoagulability in HIV/SIV infection. Our goal was to assess the biological and clinical impact of a therapeutic strategy designed to reduce microbial translocation through reduction of the microbial content of the intestine (Rifaximin-RFX) and of gut inflammation (Sulfasalazine-SFZ). RFX is an intraluminal antibiotic that was successfully used in patients with hepatic encephalopathy. SFZ is an antiinflammatory drug successfully used in patients with mild to moderate inflammatory bowel disease. Both these clinical conditions are associated with increased microbial translocation, similar to HIV-infected patients. Treatment was administered for 90 days to five acutely SIV-infected pigtailed macaques (PTMs) starting at the time of infection; seven untreated SIVsab-infected PTMs were used as controls. RFX+SFZ were also administered for 90 days to three chronically SIVsab-infected PTMs. RFX+SFZ administration during acute SIVsab infection of PTMs resulted in: significantly lower microbial translocation, lower systemic immune activation, lower viral replication, better preservation of mucosal CD4+ T cells and significantly lower levels of hypercoagulation biomarkers. This effect was clear during the first 40 days of treatment and was lost during the last stages of treatment. Administration of RFX+SFZ to chronically SIVsab–infected PTMs had no discernible effect on infection. Our data thus indicate that early RFX+SFZ administration transiently improves the natural history of acute and postacute SIV infection, but has no effect during chronic infection

IDOL regulates systemic energy balance through control of neuronal VLDLR expression.

Liver X receptors limit cellular lipid uptake by stimulating the transcription of Inducible Degrader of the LDL Receptor (IDOL), an E3 ubiquitin ligase that targets lipoprotein receptors for degradation. The function of IDOL in systemic metabolism is incompletely understood. Here we show that loss of IDOL in mice protects against the development of diet-induced obesity and metabolic dysfunction by altering food intake and thermogenesis. Unexpectedly, analysis of tissue-specific knockout mice revealed that IDOL affects energy balance, not through its actions in peripheral metabolic tissues (liver, adipose, endothelium, intestine, skeletal muscle), but by controlling lipoprotein receptor abundance in neurons. Single-cell RNA sequencing of the hypothalamus demonstrated that IDOL deletion altered gene expression linked to control of metabolism. Finally, we identify VLDLR rather than LDLR as the primary mediator of IDOL effects on energy balance. These studies identify a role for the neuronal IDOL-VLDLR pathway in metabolic homeostasis and diet-induced obesity

Diagenesis of Lower Cretaceous Pelagic Carbonates, North Atlantic: Paleoceanographic Signals Obscured

The stable isotope and minor element geochemistry of Neocomian (Lower Cretaceous) pelagic carbonates of the North Atlantic Basin (Deep Sea Drilling Project Sites 105, 367, 387, 391, and 603) was examined to develop a diagenetic model for pelagic limestones. In particular, we hoped to test the fidelity of whole-rock geochemical records as paleoceanographic indicators for pelagic deposits of pre-Aptian age, in which individual microfossils are not available for analysis. Data indicate that in addition to depth of burial, rhythmic variations in primary carbonate content have strongly controlled diagenetic patterns and associated geochemical signatures in these Neocomian sequences. Samples become increasingly depleted in Sr and 18O with increasing CaCO3 content. Within individual sedimentary sections, substantial decreases in Sr/Ca ratios and δ18O values are evident over a range of 4 to 98% CaCO3. However, even over a relatively narrow range of 50 to 98% CaCO3 a 2.5‰ variation in δ18O values and a change of a factor of 1.7 in Sr/Ca ratios are observed. Carbon isotope compositions do not vary as extensively with CaCO3 content, but carbonate- rich intervals tend to be relatively depleted in 13C. Petrographic analysis reveals that these geochemical patterns are related to the transfer of CaCO3 from carbonate- poor intervals (calcareous shales and marlstones) to adjacent carbonate-rich intervals (limestones) during burial compaction and pressure solution. This process results in the addition of diagenetic cement to carbonaterich intervals to produce a bulk composition that is relatively depleted in Sr and 18O and, at the same time, enables the retention of more-or-less primary carbonate that is relatively enriched in Sr and 18O in adjacent carbonate- poor intervals. Thus, although cyclic variations in CaCO3 content are primary in the Neocomian sequences examined, measured variations in Sr/Ca ratios and δ18O values are not and, as such, do not provide reliable proxies for past variations in climate, oceanographic conditions, or global ice volume

Associations between birth size and later height from infancy through adulthood : an individual based pooled analysis of 28 twin cohorts participating in the CODATwins project

Background: There is evidence that birth size is positively associated with height in later life, but it remains unclear whether this is explained by genetic factors or the intrauterine environment. Aim: To analyze the associations of birth weight, length and ponderal index with height from infancy through adulthood within mono- and dizygotic twin pairs, which provides insights into the role of genetic and environmental individual-specific factors. Methods: This study is based on the data from 28 twin cohorts in 17 countries. The pooled data included 41,852 complete twin pairs (55% monozygotic and 45% same-sex dizygotic) with information on birth weight and a total of 112,409 paired height measurements at ages ranging from 1 to 69 years. Birth length was available for 19,881 complete twin pairs, with a total of 72,692 paired height measurements. The association between birth size and later height was analyzed at both the individual and within-pair level by linear regression analyses. Results: Within twin pairs, regression coefficients showed that a 1-kg increase in birth weight and a 1-cm increase in birth length were associated with 1.14-4.25 cm and 0.18-0.90 cm taller height, respectively. The magnitude of the associations was generally greater within dizygotic than within monozygotic twin pairs, and this difference between zygosities was more pronounced for birth length. Conclusion: Both genetic and individual-specific environmental factors play a role in the association between birth size and later height from infancy to adulthood, with a larger role for genetics in the association with birth length than with birth weight

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci