Dynamics of vessel wall changes following the implantation of the Absorb everolimus-eluting bioresorbable vascular scaffold: a multi-imaging modality study at 6, 12, 24 and 36 months

Aims: To assess observations with multimodality imaging of the Absorb bioresorbable everolimus-eluting vascular scaffold performed in two consecutive cohorts of patients who were serially investigated either at 6 and 24 months or at 12 and 36 months. Methods and results: In the ABSORB multicentre single-arm trial, 45 patients (cohort B1) and 56 patients (cohort B2) underwent serial invasive imaging, specifically quantitative coronary angiography (QCA), intravascular ultrasound (IVUS), radiofrequency backscattering (IVUS-VH) and optical coherence tomography (OCT). Between one and three years, late luminal loss remained unchanged (6 months: 0.19 mm, 1 year: 0.27 mm, 2 years: 0.27 mm, 3 years: 0.29 mm) and the in-segment angiographic restenosis rate for the entire cohort B (n=101) at three years was 6%. On IVUS, mean lumen, scaffold, plaque and vessel area showed enlargement up to two years. Mean lumen and scaffold area remained stable between two and three years whereas significant reduction in plaque behind the struts occurred with a trend toward adaptive restrictive remodelling of EEM. Hyperechogenicity of the vessel wall, a surrogate of the bioresorption process, decreased from 23.1% to 10.4% with a reduction of radiofrequency backscattering for dense calcium and necrotic core. At three years, the count of strut cores detected on OCT increased significantly, probably reflecting the dismantling of the scaffold; 98% of struts were covered. In the entire cohort B (n=101), the three-year major adverse cardiac event rate was 10.0% without any scaffold thrombosis. Conclusions: The current investigation demonstrated the dynamics of vessel wall changes after implantation of a bioresorbable scaffold, resulting at three years in stable luminal dimensions, a low restenosis rate and a low clinical major adverse cardiac events rate.

Altered transmission of HOX and apoptotic SNPs identify a potential common pathway for clubfoot.

Clubfoot is a common birth defect that affects 135,000 newborns each year worldwide. It is characterized by equinus deformity of one or both feet and hypoplastic calf muscles. Despite numerous study approaches, the cause(s) remains poorly understood although a multifactorial etiology is generally accepted. We considered the HOXA and HOXD gene clusters and insulin-like growth factor binding protein 3 (IGFBP3) as candidate genes because of their important roles in limb and muscle morphogenesis. Twenty SNPs from the HOXA and HOXD gene clusters and 12 SNPs in IGFBP3 were genotyped in a sample composed of non-Hispanic white and Hispanic multiplex and simplex families (discovery samples) and a second sample of non-Hispanic white simplex trios (validation sample). Four SNPs (rs6668, rs2428431, rs3801776, and rs3779456) in the HOXA cluster demonstrated altered transmission in the discovery sample, but only rs3801776, located in the HOXA basal promoter region, showed altered transmission in both the discovery and validation samples (P = 0.004 and 0.028). Interestingly, HOXA9 is expressed in muscle during development. An SNP in IGFBP3, rs13223993, also showed altered transmission (P = 0.003) in the discovery sample. Gene-gene interactions were identified between variants in HOXA, HOXD, and IGFBP3 and with previously associated SNPs in mitochondrial-mediated apoptotic genes. The most significant interactions were found between CASP3 SNPS and variants in HOXA, HOXD, and IGFBP3. These results suggest a biologic model for clubfoot in which perturbation of HOX and apoptotic genes together affect muscle and limb development, which may cause the downstream failure of limb rotation into a plantar grade position.

Genomic screening identifies novel linkages and provides further evidence for a role of MYH9 in nonsyndromic cleft lip and palate.

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth anomaly that requires prolonged multidisciplinary rehabilitation. Although variation in several genes has been identified as contributing to NSCLP, most of the genetic susceptibility loci have yet to be defined. To identify additional contributory genes, a high-throughput genomic scan was performed using the Illumina Linkage IVb Panel platform. We genotyped 6008 SNPs in nine non-Hispanic white NSCLP multiplex families and a single large African-American NSCLP multiplex family. Fourteen chromosomal regions were identified with LOD>1.5, including six regions not previously reported. Analysis of the data from the African-American and non-Hispanic white families revealed two likely chromosomal regions: 8q21.3-24.12 and 22q12.2-12.3 with LOD scores of 2.98 and 2.66, respectively. On the basis of biological function, syndecan 2 (SDC2) and growth differentiation factor 6 (GDF6) in 8q21.3-24.12 and myosin heavy-chain 9, non-muscle (MYH9) in 22q12.2-12.3 were selected as candidate genes. Association analyses from these genes yielded marginally significant P-values for SNPs in SDC2 and GDF6 (0.01

Uptake And Metabolism Of 5’-AMP In The Erythrocyte Play Key Roles In The 5’-AMP Induced Model Of Deep Hypometabolism

UPTAKE AND METABOLISM OF 5’-AMP IN THE ERYTHROCYTE PLAY KEY ROLES IN THE 5’-AMP INDUCED MODEL OF DEEP HYPOMETABOLISM Publication No. ________ Isadora Susan Daniels, B.A. Supervisory Professor: Cheng Chi Lee, Ph.D. Mechanisms that initiate and control the natural hypometabolic states of mammals are poorly understood. The laboratory developed a model of deep hypometabolism (DH) initiated by uptake of 5’-adenosine monophosphate (5’-AMP) into erythrocytes. Mice enter DH when given a high dose of 5’-AMP and the body cools readily. Influx of 5’-AMP appears to inhibit thermoregulatory control. In a 15°C environment, mice injected with 5’-AMP (0.5 mg/gw) enter a Phase I response in which oxygen consumption (VO2) drops rapidly to 1/3rd of euthermic levels. The Phase I response appears independent of body temperature (Tb). This is followed by gradual body temperature decline that correlates with VO2 decline, called Phase II response. Within 90 minutes, mouse Tb approaches 15°C, and VO2 is 1/10th of normal. Mice can remain several hours in this state, before gradually and safely recovering. The DH state translates to other mammalian species. Our studies show uptake and metabolism of 5’-AMP in erythrocytes causes biochemical changes that initiate DH. Increased AMP shifts the adenylate equilibrium toward ADP formation, consequently decreasing intracellular ATP. In turn, glycolysis slows, indicated by increased glucose and decreased lactate. 2,3-bisphosphoglycerate levels rise, allosterically reducing oxygen affinity for hemoglobin, and deoxyhemoglobin rises. Less oxygen transport to tissues likely triggers the DH model. The major intracellular pathway for AMP catabolism is catalyzed by AMP deaminase (AMPD). Multiple AMPD isozymes are expressed in various tissues, but erythrocytes only have AMPD3. Mice lacking AMPD3 were created to study control of the DH model, specifically in erythrocytes. Telemetric measurements demonstrate lower Tb and difficulty maintaining Tb under moderate metabolic stress. A more dramatic response to lower dose of 5’-AMP suggests AMPD activity in the erythrocyte plays an important role in control of the DH model. Analysis of adenylates in erythrocyte lysate shows 3-fold higher levels of ATP and ADP but similar AMP levels to wild-type. Taken together, results indicate alterations in energy status of erythrocytes can induce a hypometabolic state. AMPD3 control of AMP catabolism is important in controlling the DH model. Genetically reducing AMP catabolism in erythrocytes causes a phenotype of lower Tb and compromised ability to maintain temperature homeostasis.

Current Resources

Reviews of: Treating the Tough Adolescent: A Family-Based Step-by-St Guide. (1998) Scott P. Sells. New York: The Guilford Press. Reviewed by John P. Nasuti Essential Skills in Family Therapy: From the First Interview to Termination. (1998) JoEllen Patterson, Lee Williams, Claudia Grauf-Grounds, and Larry Chamow. New York: The Guilford Press. Reviewed by Rowena Fong Putting Families First America's Family Support Movement and the Challenge of Change. (1994) Sharon L. Kagan and Bernice Weissbound, Editors. San Francisco: Jossey-Bass Publishers. Reviewed by Anthony N. Maluccio The Work-Family Challenge Rethinking Employment. Edited by Susan Lewis and Jeremy Lewis. 1996. Thousand Oaks, California: SAGE Publications, Ltd. Reviewed by Harry J. Macy

Stable-Isotope and Trace Element Time Series from Fedchenko Glacier (Pamirs) Snow/Firn Cores

In summer 2005, two pilot snow/firn cores were obtained at 5365 and 5206 m a.s.l. on Fedchenko glacier, Pamirs, Tajikistan, the world's longest and deepest alpine glacier. The well-defined seasonal layering appearing in stable-isotope and trace element distribution identified the physical links controlling the climate and aerosol concentration signals. Air temperature and humidity/precipitation were the primary determinants of stable-isotope ratios. Most precipitation over the Pamirs originated in the Atlantic. In summer, water vapor was re-evaporated from semi-arid regions in central Eurasia. The semi-arid regions contribute to non-soluble aerosol loading in snow accumulated on Fedchenko glacier. In the Pamir core, concentrations of rare earth elements, major and other elements were less than those in the Tien Shan but greater than those in Antarctica, Greenland, the Alps and the Altai. The content of heavy metals in the Fedchenko cores is 2-14 times lower than in the Altai glaciers. Loess from Afghan-Tajik deposits is the predominant lithogenic material transported to the Pamirs. Trace elements generally showed that aerosol concentration tended to increase on the windward slopes during dust storms but tended to decrease with altitude under clear conditions. The trace element profile documented one of the most severe droughts in the 20th century.

Recent Increases in Atmospheric Concentrations of Bi, U, Cs, S and Ca from a 350-Year Mount Everest Ice Core Record

High-resolution major and trace elements (Sr, Cs, Ba, La, Ce, Pr, Nd, Sm, Eu, Tb, Dy, Ho, Er, Tm, Yb, Lu, Bi, U, Tl, Al, S, Ca, Ti, V, Cr, Mn, Fe, and Co) quantified in a Mount Everest ice core ( 6518 m above sea level) spanning the period 1650-2002 AD provides the first Asian record of trace element concentrations from the pre-industrial era, and the first continuous high-resolution Asian record from which natural baseline concentrations and subsequent changes due to anthropogenic activities can be examined. Modern concentrations of most elements remain within the pre-industrial range; however, Bi, U, and Cs concentrations and their enrichment factors (EF) have increased since the similar to 1950s, and S and Ca concentrations and their EFs have increased since the late 1980s. A comparison of the Bi, U, Cs, S, and Ca data with other ice core records and production data indicates that the increase in atmospheric concentrations of trace elements is widespread, but that enrichment varies regionally. Likely sources for the recent enrichment of these elements include mining, metal smelting, oil and coal combustion, and end uses for Bi, and mining and refinement for U and Cs. The source of the synchronous enrichment of Ca and S is less certain, but may be related to land use and environmental change.

High-Resolution Ice Cores from US ITASE (West Antarctica): Development and Validation of Chronologies and Determination of Precision and Accuracy

Shallow ice cores were obtained from widely distributed sites across the West Antarctic ice sheet, as part of the United States portion of the International Trans-Antarctic Scientific Expedition (US ITASE) program. The US ITASE cores have been dated by annual-layer counting, primarily through the identification of summer peaks in non-sea-salt sulfate (nssSO(4)(2-)) concentration. Absolute dating accuracy of better than 2 years and relative dating accuracy better than 1 year is demonstrated by the identification of multiple volcanic marker horizons in each of the cores, Tambora, Indonesia (1815), being the most prominent. Independent validation is provided by the tracing of isochronal layers from site to site using high-frequency ice-penetrating radar observations, and by the timing of mid-winter warming events in stable-isotope ratios, which demonstrate significantly better than 1 year accuracy in the last 20 years. Dating precision to 1 month is demonstrated by the occurrence of summer nitrate peaks and stable-isotope ratios in phase with nssSO(4)(2-), and winter-time sea-salt peaks out of phase, with phase variation of < 1 month. Dating precision and accuracy are uniform with depth, for at least the last 100 years.

Climate Variability in West Antarctica Derived from Annual Accumulation-Rate Records from ITASE Firn/Ice Cores

Thirteen annually resolved accumulation-rate records covering the last similar to 200 years from the Pine Island-Thwaites and Ross drainage systems and the South Pole are used to examine climate variability over West Antarctica. Accumulation is controlled spatially by the topography of the ice sheet, and temporally by changes in moisture transport and cyclonic activity. A comparison of mean accumulation since 1970 at each site to the long-term mean indicates an increase in accumulation for sites located in the western sector of the Pine Island-Thwaites drainage system. Accumulation is negatively associated with the Southern Oscillation Index (Sol) for sites near the ice divide, and periods of sustained negative Sol (1940-42, 1991-95) correspond to above-mean accumulation at most sites. Correlations of the accumulation-rate records with sea-level pressure (SLP) and the SOI suggest that accumulation near the ice divide and in the Ross drainage system may be associated with the midlatitudes. The post-1970 increase in accumulation coupled with strong SLP-accumulation-rate correlations near the coast suggests recent intensification of cyclonic activity in the Pine Island-Thwaites drainage system.

Solar Forcing of the Polar Atmosphere

We present highly resolved, annually dated, calibrated proxies for atmospheric circulation from several Antarctic ice cores (ITASE (International Trans-Antarctic Scientific Expedition), Siple Dome, Law Dome) that reveal decadal-scale associations with a South Pole ice-core Be-10 proxy for solar variability over the last 600 years and annual-scale associations with solar variability since AD 1720. We show that increased (decreased) solar irradiance is associated with increased (decreased) zonal wind strength near the edge of the Antarctic polar vortex. The association is particularly strong in the Indian and Pacific Oceans and as such may contribute to understanding climate forcing that controls drought in Australia and other Southern Hemisphere climate events. We also include evidence suggestive of solar forcing of atmospheric circulation near the edge of the Arctic polar vortex based on ice-core records from Mount Logan, Yukon Territory, Canada, and both central and south Greenland as enticement for future investigations. Our identification of solar forcing of the polar atmosphere and its impact on lower latitudes offers a mechanism for better understanding modern climate variability and potentially the initiation of abrupt climate-change events that operate on decadal and faster scales.

Reduction in Northward Incursions of the South Asian Monsoon Since ~1400 AD Inferred from a Mt. Everest Ice Core

A highly resolved Mt. Everest ice core reveals a decrease in marine and increase in continental air masses related to relatively high summer surface pressure over Mongolia, and reduction in northward incursions of the summer South Asian monsoon since similar to 1400 AD. Previously published proxy records from lower sites south of the Himalayas indicate strengthening of the monsoon since this time. These regional differences are consistent with a south north seesaw in convective activity in the Asian monsoon region, and reflect a southward shift in the mean summer position of the monsoon trough since similar to 1400 AD. The change in monsoonal circulation at 1400 AD is synchronous with a reduction in solar irradiance and the onset of the LIA. This demonstrates a hemispheric scale circulation reorganization at this time, and the potential for future large shifts in monsoonal circulation.

Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese

OBJECTIVES This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk. BACKGROUND AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored. METHODS We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases). RESULTS We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements. CONCLUSIONS The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

Judentum und Christentum : Vortr. geh. in d. Montefiore-Loge U.O.B.B.

von Maximilian Stein

Cerf Berr et son époque : Conférence faite à Strasbourg le 17 janiver 1906

par M. Ginsburger. Trad. en français par e. Ginsburger