Antigen-positive platelet transfusion in neonatal alloimmune thrombocytopenia (NAIT)

Neonatal alloimmune thrombocytopenia (NAIT) is a fetomaternal incompatibility most commonly induced by maternal anti-HPA-1a, IgG alloantibodies against a polymorphic epitope of the glycoprotein IIb/IIIa complex in approximately 97.5% of white patients. Current guidelines recommend transfusion of immunologically compatible platelets to prevent cerebral hemorrhage, the most severe complication in affected newborns. Such platelet concentrates, however, are often not readily available. In a retrospective analysis in German and Canadian centers, 27 newborns with NAIT were identified who received platelets from random donors. Unexpectedly, 24 of 27 newborns showed an increase above a threshold of 40 x 10(9) platelets per liter, with moderate (n = 8) or significant (n = 16) platelet count increments (more than 80 x 10(9)/L). We conclude that transfusion of platelet concentrates from random donors is an appropriate strategy in the management of unexpected, severe NAIT predominantly in first pregnancies, pending the availability of compatible platelets.     

MRP8 and MRP14 control microtubule reorganization during transendothelial migration of phagocytes

MRP14 (S100A9) is the major calcium-binding protein of neutrophils and monocytes. Targeted gene disruption reveals an essential role of this S100 protein for transendothelial migration of phagocytes. The underlying molecular mechanism comprises major alterations of cytoskeletal metabolism. MRP14, in complex with its binding partner MRP8 (S100A8), promotes polymerization of microtubules. MRP14 is specifically phosphorylated by p38 mitogen-activated protein kinase (MAPK). This phosphorylation inhibits MRP8/MRP14-induced tubulin polymerization. Phosphorylation of MRP14 is antagonistically regulated by binding of MRP8 and calcium. The biologic relevance of these findings is confirmed by the fact that MAPK p38 fails to stimulate migration of MRP14(-/-) granulocytes in vitro and MRP14(-/-) mice show a diminished recruitment of granulocytes into the granulation tissue during wound healing in vivo. MRP14(-/-) granulocytes contain significantly less polymerized tubulin, which subsequently results in minor activation of Rac1 and Cdc42 after stimulation of p38 MAPK. Thus, the complex of MRP8/MRP14 is the first characterized molecular target integrating MAPK- and calcium-dependent signals during migration of phagocytes.     

Source apportionment of methane escaping the subsea permafrost system in the outer Eurasian Arctic Shelf

The East Siberian Arctic Shelf holds large amounts of inundated carbon and methane (CH₄). Holocene warming by overlying seawater, recently fortified by anthropogenic warming, has caused thawing of the underlying subsea permafrost. Despite extensive observations of elevated seawater CH₄ in the past decades, relative contributions from different subsea compartments such as early diagenesis, subsea permafrost, methane hydrates, and underlying thermogenic/ free gas to these methane releases remain elusive. Dissolved methane concentrations observed in the Laptev Sea ranged from 3 to 1,500 nM (median 151 nM; oversaturation by ∼3,800%). Methane stable isotopic composition showed strong vertical and horizontal gradients with source signatures for two seepage areas of δ¹³C-CH₄ = (−42.6 ± 0.5)/(−55.0 ± 0.5) ‰ and δD-CH₄ = (−136.8 ± 8.0)/(−158.1 ± 5.5) ‰, suggesting a thermogenic/natural gas source. Increasingly enriched δ¹³C-CH₄ and δD-CH₄ at distance from the seeps indicated methane oxidation. The Δ¹⁴C-CH₄ signal was strongly depleted (i.e., old) near the seeps (−993 ± 19/−1050 ± 89‰). Hence, all three isotope systems are consistent with methane release from an old, deep, and likely thermogenic pool to the outer Laptev Sea. This knowledge of what subsea sources are contributing to the observed methane release is a prerequisite to predictions on how these emissions will increase over coming decades and centuries.

The East Siberian Arctic Shelf (ESAS) is the world’s largest and shallowest shelf sea system, formed through inundation of northeast Siberia during sea level transgression in the early Holocene. The ESAS holds substantial but poorly constrained amounts of organic carbon and methane (CH₄). These carbon/methane stores are contained in unknown partitions as gas hydrates, unfrozen sediment, subsea permafrost, gas pockets within and below the subsea permafrost, and as underlying thermogenic gas (1–3). Methane release to the atmosphere from these compartments could potentially have significant effects on the global climate (4, 5), yet there are large uncertainties regarding the size and the vulnerability toward remobilization of these inaccessible and elusive subsea carbon/methane pools. Conceptual development and modeling have predicted that warming of the ESAS system by a combination of geothermal heat and climate-driven Holocene heat flux from overlying seawater, recently further enhanced by Anthropocene warming, may lead to thawing of subsea permafrost (6, 7). Subsea permafrost drilling in the Laptev Sea, in part at the same sites as 30 y ago, has recently confirmed that the subsea permafrost has indeed come near the point of thawing (8). In addition to mobilization of the carbon/methane stored within the subsea permafrost, its degradation can also lead to the formation of pathways for gaseous methane from underlying reservoirs, allowing further methane release to the overlying water column (3, 9).Near-annual ship-based expeditions to the ESAS over the past two decades have documented widespread seep locations with extensive methane releases to the water column (3, 10). Methane levels are often found to be 10 to 100 times higher than the atmospheric equilibrium and are particularly elevated in areas of strong ebullition from subsea gas seeps (“methane hotspots”). Similarly, elevated dissolved methane concentrations in bottom waters appear to be spatially related to the thermal state of subsea permafrost as deduced from modeling results and/or geophysical surveys (7, 9). Currently, we lack critical knowledge on the quantitative or even relative contributions of the different subsea pools to the observed methane release, a prerequisite for robust predictions on how these releases will develop. An important distinction needs to be made between pools that release methane gradually, such as methane produced microbially in shallow sediments during early diagenesis or in thawing subsea permafrost, versus pools with preformed methane that may release more abruptly once pathways are available, such as from disintegrating methane hydrates and pools of thermogenic (natural) gas below the subsea permafrost. Multidimensional isotope analysis offers a useful means to disentangle the relative importance of these different subsea sources of methane to the ESAS: Stable isotope data (δ¹³C-CH₄ and δD-CH₄) provide useful information on methane formation and removal pathways, and the radiocarbon content of methane (Δ¹⁴C-CH₄) helps to determine the age and methane source reservoir (see SI Appendix, text S1 for details on these isotope systematics and typical isotopic signatures for the ESAS subsea system).Here, we present triple-isotope–based source apportionment of methane conducted as part of the Swedish–Russian–US investigation of carbon–climate–cryosphere interactions in the East Siberian Arctic Ocean (SWERUS-C3) program. To this end, the distribution of dissolved methane, its stable carbon and hydrogen isotope composition, as well as natural radiocarbon abundance signature, were investigated with a focus on the isotopic fingerprint of methane escaping the seabed to pinpoint the subsea sources of elevated methane in the outer Laptev Sea.     

Mild heat treatments induce long-term changes in metabolites associated with energy metabolism in <Emphasis Type="Italic">Drosophila melanogaster</Emphasis>

Heat-induced hormesis, the beneficial effect of mild heat-induced stress, increases the average lifespan of many organisms. Yet little is known about the mechanisms underlying this effect. We used nuclear magnetic resonance spectroscopy to investigate the long-term effects of repeated mild heat treatments on the metabolome of male Drosophila melanogaster. 10 days after the heat treatment, metabolic aging appears to be slowed down, and a treatment response with 40 % higher levels of alanine and lactate and lower levels of aspartate and glutamate were measured. All treatment effects had disappeared 16 days later. Metabolic reprogramming has been associated with the life extending effects of dietary restriction. The metabolite changes induced by the hormetic treatment suggest that the positive effects might not be limited to the repair pathways induced, but that there also is a change in energy metabolism. A possible direct link between changes in energy metabolism and heat induced increase in Hsp70 expression is discussed.     

Lifespan extension of Drosophila melanogaster through hormesis by repeated mild heat stress

We assessed the impact of repeated episodes of a mild heat stress on lifespan, fecundity, heat stress resistance and Hsp70 expression in Drosophila melanogaster. There was a significant increase in lifespan of females repeatedly exposed to a mild heat stress when measured in both a pair and a group situation. There was no effect on fecundity when the flies were first exposed to the mild heat stress at an age later than 3 days old, but when it did occur on day 3, there was a significant effect on cumulative fecundity levels over 18 days. The negative fitness effect appears to be the result of a direct cessation or reduction of oviposition during the first bout of stress exposure, and is influenced by the age at which this first exposure occurs. The mild heat stress had no impacton egg viability. The mild heat stress exposures increased resistance to potentially lethal heat stress and levels of Hsp70 expression in heat-exposed flies were higher than those in controls. This revised version was published online in July 2006 with corrections to the Cover Date.     

Genetics of Human Hypertension

BACKGROUND: Hypertension is a multifactorial disease involving interactions among genetic, environmental, demographic, vascular and neuroendocrine factors. Essential hypertension is the most frequent diagnosis in this syndrome, indicating that a monocausal etiology has not been identified. However, a number of risk factors underlying essential hypertension have also been identified including age, sex, genetics, demographic factors, and others. Remarkable progress in molecular biological research has been achieved in clarifying the molecular basis of Mendelian hypertensive disorders. Causative genes and chromosomal fragments harboring disease susceptibility genes have been identified, e. g., for glucocorticoid-remediable aldosteronism, Liddle's syndrome, mineralocorticoid excess. MOLECULAR GENETIC STUDIES: Molecular genetic studies have now identified mutations in eight genes that cause Mendelian forms of hypertension and nine genes that cause Mendelian forms of hypotension in humans. No single genetic variant has emerged from linkage or association analyses as consistently related to blood pressure level in every sample and in all populations. However, a number of polymorphisms in candidate genes have been associated with differences in blood pressure. Most prominent have been the polymorphisms in the renin-angiotensin-aldosterone system. CONCLUSION: Essential hypertension is likely to be a polygenic disorder that results from the inheritance of a number of susceptibility genes and involves multiple environmental determinants. These determinants complicate the study of blood pressure variations in the general population. The complex nature of the hypertension phenotype makes large-scale studies indispensable, when screening of familial and genetic factors is intended.     

Spatial heterogeneity of myocardial perfusion predicts local potassium channel expression and action potential duration

AIMS: In the heart, there is not only a transmural gradient of left ventricular perfusion and action potential duration (APD), but also spatial heterogeneity within each myocardial layer, where local blood flow and energy turnover vary more than three-fold between individual regions. We analysed at high spatial resolution whether a corresponding heterogeneity also extends to ion channel gene expression and APD. METHODS AND RESULTS: In the open-chest beagle dog, left ventricular 300 microL samples of very low or high flow were identified by radioactive microspheres and expression levels determined by quantitative PCR. The distribution of epicardial APD was assessed by mapping local activation repolarization intervals (ARIs) and QT interval (QT). ERG, the potassium channel mediating IKr, and KChIP2, the interacting protein modulating Ito, were increased in Low flow (3.3- and 2.5-fold, P < 0.001 and <0.05, respectively; n = 6 hearts, 30-31 samples each) as compared with High flow areas. This suggested enhanced repolarizing currents in Low flow areas, and in consequence, mathematical model analysis predicted a shorter local APD upon enhanced ERG and IKr. Epicardial mapping revealed a patchy, temporally stable APD pattern (n = 11), a small apico-basal gradient and an APD prolongation induced by the ERG blocker dofetilide predominantly in areas of short basal ARI or QT, respectively (n = 9). In addition, in Short QT areas, ERG expression was three-fold increased (P < 0.05, n = 4). CONCLUSION: The spatial pattern of perfusion is matched by the novel patterns of K+ channel expression and APD. Whenever this newly recognized intramural dispersion of APD increases, it may contribute to arrhythmogenesis.     

The MPO Study: just a European HEMO Study or something very different?

Although results from observational and epidemiological studies suggested a survival benefit associated with high-flux hemodialysis, conclusive evidence from prospective randomized clinical trials has been lacking. Both the HEMO Study in the USA and the Membrane Permeability Outcome Study (MPO Study) in Europe are randomized studies investigating the effect of high- and low-flux hemodialysis on patient outcomes, even though there were some significant differences in the design of the two studies. An earlier randomized clinical trial could not show differences on patient survival between patient groups being treated with membranes of different material and permeability, but this trial was not designed specifically to examine this particular endpoint. Based on these previous experiences, the MPO Study addressed a hemodialysis patient population which was considered to be more susceptible to the intervention with high-flux dialysis. To identify these patients with an elevated risk, low serum albumin levels were chosen as an indicator; low serum albumin is associated with malnutrition, inflammation, atherosclerosis, and with increased risk of morbidity and mortality. Together with low serum albumin, patients had to be new to dialysis to be selected for the MPO Study. These particular considerations on patient selection, together with additional methodological refinements in the study design allow the conclusion that the MPO Study is valid on its own rather than being a European version of the HEMO Study.     

Recording of Pacing Stimulus Artifacts by Endovascular Defibrillation Lead Systems: Comparison of True and Integrated Bipolar Circuits

Background: The occurrence ICD undersensing of ventricular fibrillation due to the presence of a pacing stimulus artifact (PSA) is in part related to the amplitude of the artifact recorded on the ICD rate sensing circuit. There is little comparative data regarding PSA amplitude recorded by commercial ICD rate-sensing circuits.Purpose: To compare PSA amplitude recorded by commercial endovascular defibrillation leads utilizing integrated or true bipolar sensing circuits.Methods: Nineteen large (60–120 kg) pigs were utilized. Two different commercial endovascular defibrillation leads were evaluated, each with its distal tip located at the right ventricular apex: (1) Medtronic Transvene; and (2) CPI Endotak. Three different rate-sensing circuits were evaluated: (1) Transvene true bipolar (tip-ring); (2) Transvene integrated bipolar (tip-coil); and (3) Endotak integrated bipolar (tip-coil). Using a separate pacing lead located at the left ventricular apex (n = 19 animals) or right ventricular outflow tract (n = 10 animals), pacing was performed at a pulse width of 0.5 milliseconds at outputs of 1.5, 5 and 10 volts. PSA amplitude was recorded at each output by each circuit.Results: During pacing from the left ventricular apex, at each pacing output voltage the PSA amplitude recorded by the true bipolar circuit (0.6 ± 0.1 mV at 1.5 volts, 2.0 ± 0.5 mV at 5 volts, 3.7 ± 0.8 mV at 10 volts) was significantly smaller than recorded by the Transvene integrated circuit (1.4 ± 0.3 mV at 1.5 volts, 3.8 ± 0.7 mV at 5 volts, 4.1 ± 0.8 mV at 10 volts) or the Endotak integrated circuit (1.8 ± 0.4 mV at 1.5 volts, 4.2 ± 1.0 mV at 5 volts, 6.3 ± 1.8 mV at 10 volts). During pacing from the right ventricular outflow tract, at each pacing output voltage the PSA amplitude recorded by the true bipolar circuit (0.7 ± 0.1 mV at 1.5 volts, 1.7 ± 0.4 mV at 5 volts, 4.0 ± 0.7 mV at 10 volts) was significantly smaller than recorded by the Transvene integrated circuit (1.1 ± 0.4 mV at 1.5 volts, 3.9 ± 1.2 mV at 5 volts, 7.5 ± 1.8 mV at 10 volts) or the Endotak integrated circuit (1.6 ± 0.7 mV at 1.5 volts, 4.3 ± 1.7 mV at 5 volts, 7.5 ± 2.6 mV at 10 volts). For both pacing sites, the PSA amplitude recorded by the two integrated circuits was not significantly different.Conclusions: For a given pacing output voltage, PSA amplitude recorded by commercial endovascular rate sensing/defibrillation leads is greater when the sensing circuit is integrated than when it is true bipolar. These data may be helpful in planning ICD implantation in patients with previously implanted permanent pacemakers.     

Relation between body mass index and radiological progression in patients with rheumatoid arthritis

OBJECTIVE: To determine if there is an influence of body mass index (BMI) on the radiological progression in early and longer duration rheumatoid arthritis (RA). METHODS: Fifty-four patients with RA were observed in a progressive 2 year followup for radiological progression of joint damage. At the beginning of study, 27 (50%) patients had a duration of complaints less than 6 months, grouped as early RA. BMI at the beginning and end of the study were monitored, together with HLA-DRB1 alleles, initial joint erosions, duration of disease, age, sex, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Outcome was defined as radiographic damage according to yearly increase of Larsen score. RESULTS: Increased radiographic joint damage of patients was significantly correlated with lower BMI at the beginning of the study (r = 0.363, p < 0.05), the presence of initial joint erosions (r = 0.341, p < 0.01), ESR (r = 0.315, p < 0.05), and CRP at study entry (r = 0.427, p < 0.01). Patients with an increase of Larsen score > or = 5.8/year were found to have a lower weight at the beginning of their complaints (BMI 24.8 +/- 4.7 vs 27.8 +/- 3.8; p < 0.05) as well as after the time of observation (BMI 24.6 +/- 3.7 vs 27.6 +/- 4.9; p < 0.05). Stepwise logistic regression analysis revealed a BMI < 27 at the beginning of disease (beta = 2.04, p = 0.003, odds ratio = 7.69), the presence of HLA-DR4 shared epitope (beta = 1.76, p = 0.015, OR 5.82), and joint erosions at study entry (beta = 1.56, p = 0.044, OR 4.78) as significant predictors for rapid joint damage. CONCLUSION: Together with the presence of HLA-DR4 shared epitope and erosive disease at study entry, a low BMI at the beginning of RA was found in association with higher radiographic progression in RA. Accordingly, BMI could be of interest as a sensitive and inflammation-independent predictor for radiological outcome of RA.