Showing papers by "Goethe University Frankfurt published in 2009"
TL;DR: In patients with atrial fibrillation for whom vitamin K-antagonist therapy was unsuitable, the addition of clopidogrel to aspirin reduced the risk of major vascular events, especially stroke, and increased the riskof major hemorrhage.
Abstract: Background Vitamin K antagonists reduce the risk of stroke in patients with atrial fibrillation but are considered unsuitable in many patients, who usually receive aspirin instead. We investigated the hypothesis that the addition of clopidogrel to aspirin would reduce the risk of vascular events in patients with atrial fibrillation. Methods A total of 7554 patients with atrial fibrillation who had an increased risk of stroke and for whom vitamin K–antagonist therapy was unsuitable were randomly assigned to receive clopidogrel (75 mg) or placebo, once daily, in addition to aspirin. The primary outcome was the composite of stroke, myocardial infarction, non–central nervous system systemic embolism, or death from vascular causes. Results At a median of 3.6 years of follow-up, major vascular events had occurred in 832 patients receiving clopidogrel (6.8% per year) and in 924 patients receiving placebo (7.6% per year) (relative risk with clopidogrel, 0.89; 95% confidence interval [CI], 0.81 to 0.98; P = 0.01). The difference was primarily due to a reduction in the rate of stroke with clopidogrel. Stroke occurred in 296 patients receiving clopidogrel (2.4% per year) and 408 patients receiving placebo (3.3% per year) (relative risk, 0.72; 95% CI, 0.62 to 0.83; P<0.001). Myocardial infarction occurred in 90 patients receiving clopidogrel (0.7% per year) and in 115 receiving placebo (0.9% per year) (relative risk, 0.78; 95% CI, 0.59 to 1.03; P = 0.08). Major bleeding occurred in 251 patients receiving clopidogrel (2.0% per year) and in 162 patients receiving placebo (1.3% per year) (relative risk, 1.57; 95% CI, 1.29 to 1.92; P<0.001). Conclusions In patients with atrial fibrillation for whom vitamin K–antagonist therapy was unsuitable, the addition of clopidogrel to aspirin reduced the risk of major vascular events, especially stroke, and increased the risk of major hemorrhage. (ClinicalTrials.gov number, NCT00249873.)
2,075 citations
TL;DR: It is shown that themiR-17~92 cluster is highly expressed in human endothelial cells and that miR-92a, a component of this cluster, controls the growth of new blood vessels (angiogenesis) and may serve as a valuable therapeutic target in the setting of ischemic disease.
Abstract: MicroRNAs (miRs) are small noncoding RNAs that regulate gene expression by binding to target messenger RNAs (mRNAs), leading to translational repression or degradation. Here, we show that the miR-17approximately92 cluster is highly expressed in human endothelial cells and that miR-92a, a component of this cluster, controls the growth of new blood vessels (angiogenesis). Forced overexpression of miR-92a in endothelial cells blocked angiogenesis in vitro and in vivo. In mouse models of limb ischemia and myocardial infarction, systemic administration of an antagomir designed to inhibit miR-92a led to enhanced blood vessel growth and functional recovery of damaged tissue. MiR-92a appears to target mRNAs corresponding to several proangiogenic proteins, including the integrin subunit alpha5. Thus, miR-92a may serve as a valuable therapeutic target in the setting of ischemic disease.
1,188 citations
TL;DR: The hypothesis that ubiquitin represents a selective degradation signal suitable for targeting various types of cargo, ranging from protein aggregates to membrane-bound organelles and microbes, is explored.
1,177 citations
TL;DR: In this paper, the production of mesons containing strange quarks (KS, φ) and both singly and doubly strange baryons (,, and − + +) are measured at mid-rapidity in pp collisions at √ s = 0.9 TeV with the ALICE experiment at the LHC.
1,176 citations
TL;DR: NBR1 (neighbor of BRCA1 gene 1) is an autophagy receptor containing LC3- and ubiquitin (Ub)-binding domains and it is proposed that NBR1 and p62 act as receptors for selective autophagosomal degradation of ubiquitinated targets.
1,049 citations
TL;DR: In this paper, a multicenter trial was conducted to evaluate the use of dronedarone in 4628 patients with atrial fibrillation who had additional risk factors for death.
Abstract: Background Dronedarone is a new antiarrhythmic drug that is being developed for the treatment of patients with atrial fibrillation. Methods We conducted a multicenter trial to evaluate the use of dronedarone in 4628 patients with atrial fibrillation who had additional risk factors for death. Patients were randomly assigned to receive dronedarone, 400 mg twice a day, or placebo. The primary outcome was the first hospitalization due to cardiovascular events or death. Secondary outcomes were death from any cause, death from cardiovascular causes, and hospitalization due to cardiovascular events. Results The mean follow-up period was 21±5 months, with the study drug discontinued prematurely in 696 of the 2301 patients (30.2%) receiving dronedarone and in 716 of the 2327 patients (30.8%) receiving placebo, mostly because of adverse events. The primary outcome occurred in 734 patients (31.9%) in the dronedarone group and in 917 patients (39.4%) in the placebo group, with a hazard ratio for dronedarone of 0.76 (95% confidence interval [CI], 0.69 to 0.84; P<0.001). There were 116 deaths (5.0%) in the dronedarone group and 139 (6.0%) in the placebo group (hazard ratio, 0.84; 95% CI, 0.66 to 1.08; P = 0.18). There were 63 deaths from cardiovascular causes (2.7%) in the dronedarone group and 90 (3.9%) in the placebo group (hazard ratio, 0.71; 95% CI, 0.51 to 0.98; P = 0.03), largely due to a reduction in the rate of death from arrhythmia with dronedarone. The dronedarone group had higher rates of bradycardia, QT-interval prolongation, nausea, diarrhea, rash, and an increased serum creatinine level than the placebo group. Rates of thyroid- and pulmonary-related adverse events were not significantly different between the two groups. Conclusion Dronedarone reduced the incidence of hospitalization due to cardiovascular events or death in patients with atrial fibrillation. (ClinicalTrials.gov number, NCT00174785.)
918 citations
TL;DR: The recent financial crisis has led to a vigorous debate about the pros and cons of fair value accounting (FVA) as discussed by the authors, and this debate presents a major challenge for FVA going forward and standard setters' push to extend FVA into other areas.
Abstract: The recent financial crisis has led to a vigorous debate about the pros and cons of fair-value accounting (FVA). This debate presents a major challenge for FVA going forward and standard setters’ push to extend FVA into other areas. In this article, we highlight four important issues as an attempt to make sense of the debate. First, much of the controversy results from confusion about what is new and different about FVA. Second, while there are legitimate concerns about marking to market (or pure FVA) in times of financial crisis, it is less clear that these problems apply to FVA as stipulated by the accounting standards, be it IFRS or US GAAP. Third, historical cost accounting (HCA) is unlikely to be the remedy. There are a number of concerns about HCA as well and these problems could be larger than those with FVA. Fourth, although it is difficult to fault the FVA standards per se, implementation issues are a potential concern, especially with respect to litigation. Finally, we identify several avenues for future research.
810 citations
TL;DR: New structure-based insights provide strategies for controlling cellular processes by targeting ubiquitin–UBD interfaces with implications for drug design and cell reprograming.
Abstract: Ubiquitin-binding domains (UBDs) are modular elements that bind non-covalently to the protein modifier ubiquitin. Recent atomic-level resolution structures of ubiquitin-UBD complexes have revealed some of the mechanisms that underlie the versatile functions of ubiquitin in vivo. The preferences of UBDs for ubiquitin chains of specific length and linkage are central to these functions. These preferences originate from multimeric interactions, whereby UBDs synergistically bind multiple ubiquitin molecules, and from contacts with regions that link ubiquitin molecules into a polymer. The sequence context of UBDs and the conformational changes that follow their binding to ubiquitin also contribute to ubiquitin signalling. These new structure-based insights provide strategies for controlling cellular processes by targeting ubiquitin-UBD interfaces.
806 citations
TL;DR: The Dependent Market Economy (DME) model as mentioned in this paper is characterized by the importance of foreign capital for the socioeconomic setup and is located in postsocialist Central Europe, and has comparative advantages in the assembly and production of relatively complex and durable consumer goods.
Abstract: This article enlarges the existing literature on the varieties of capitalism by identifying a third basic variety that does not resemble the liberal market economy or coordinated market economy types. The dependent market economy (DME ) type, as it is named by the authors, is characterized by the importance of foreign capital for the socioeconomic setup and is located in postsocialist Central Europe. Since the collapse of state socialism in the late 1980s, the Czech republic, Hungary, poland, and the slovak republic have introduced a rather successful model of capitalism when compared with other postsocialist states. This article identifies the key elements of the DME model and discusses their interplay. DME s have comparative advantages in the assembly and production of relatively complex and durable consumer goods. These comparative advantages are based on institutional complementarities between skilled, but cheap, labor; the transfer of technological innovations within transnational enterprises; and the provision of capital via foreign direct investment.
802 citations
TL;DR: Recent data involving purinergic signalling in pathological conditions, including pain, trauma, ischaemia, epilepsy, migraine, psychiatric disorders and drug addiction are highlighted, which are expected to lead to the development of therapeutic strategies for these disorders with novel mechanisms of action.
777 citations
TL;DR: Residues of NEMO involved in binding linear ubiquitin chains are required for NF-kappaB activation by TNF-alpha and other agonists, providing an explanation for the detrimental effect of NemO mutations in patients suffering from X-linked ectodermal dysplasia and immunodeficiency.
TL;DR: Most plasticizers appear to act by interfering with the functioning of various hormone systems, but some phthalates have wider pathways of disruption, and given the sensitivity of some invertebrates, effects assessments are warranted in other invertebrate phyla.
Abstract: This review provides a critical analysis of the biological effects of the most widely used plasticizers, including dibutyl phthalate, diethylhexyl phthalate, dimethyl phthalate, butyl benzyl phthalate and bisphenol A (BPA), on wildlife, with a focus on annelids (both aquatic and terrestrial), molluscs, crustaceans, insects, fish and amphibians. Moreover, the paper provides novel data on the biological effects of some of these plasticizers in invertebrates, fish and amphibians. Phthalates and BPA have been shown to affect reproduction in all studied animal groups, to impair development in crustaceans and amphibians and to induce genetic aberrations. Molluscs, crustaceans and amphibians appear to be especially sensitive to these compounds, and biological effects are observed at environmentally relevant exposures in the low ng l−1 to µg l−1 range. In contrast, most effects in fish (except for disturbance in spermatogenesis) occur at higher concentrations. Most plasticizers appear to act by interfering with the functioning of various hormone systems, but some phthalates have wider pathways of disruption. Effect concentrations of plasticizers in laboratory experiments coincide with measured environmental concentrations, and thus there is a very real potential for effects of these chemicals on some wildlife populations. The most striking gaps in our current knowledge on the impacts of plasticizers on wildlife are the lack of data for long-term exposures to environmentally relevant concentrations and their ecotoxicity when part of complex mixtures. Furthermore, the hazard of plasticizers has been investigated in annelids, molluscs and arthropods only, and given the sensitivity of some invertebrates, effects assessments are warranted in other invertebrate phyla.
Posted Content•
TL;DR: The authors found that the multiplier of government spending multipliers in an alternative empirically-estimated and widely-cited new Keynesian model are much smaller than in these old Keynesian models; the estimated stimulus is extremely small just when needed most, and GDP and employment effects are only one-sixth as large, with private sector employment impacts likely to be even smaller.
Abstract: Renewed interest in fiscal policy has increased the use of quantitative models to evaluate policy. Because of modeling uncertainty, it is essential that policy evaluations be robust to alternative assumptions. We find that models currently being used in practice to evaluate fiscal policy stimulus proposals are not robust. Government spending multipliers in an alternative empirically-estimated and widely-cited new Keynesian model are much smaller than in these old Keynesian models; the estimated stimulus is extremely small just when needed most, and GDP and employment effects are only one-sixth as large, with private sector employment impacts likely to be even smaller.
TL;DR: Continuation of trastuzumab beyond progression was not associated with increased toxicity and showed a significant improvement in overall response and time to progression compared with capecitabine alone in women with HER-2-positive breast cancer who experienced progression during trastzumab treatment.
Abstract: PurposeTrastuzumab shows clinical activity in human epidermal growth factor receptor 2 (HER-2)-positive early and advanced breast cancer. In the German Breast Group 26/Breast International Group 03-05 trial, we investigated if trastuzumab treatment should be continued beyond progression.
Methods
Patients with HER-2-positive breast cancer that progresses during treatment with trastuzumab were randomly assigned to receive capecitabine (2,500 mg/m(2) body-surface area on days 1 through 14 [1,250 mg/m2 semi-daily]) alone or with continuation of trastuzumab (6 mg/kg body weight) in 3-week cycles. The primary end point was time to progression.
Results
We randomly assigned 78 patients to capecitabine and 78 patients to capecitabine plus trastuzumab. Sixty-five events and 38 deaths in the capecitabine group and 62 events and 33 deaths in the capecitabine-plus-trastuzumab group occurred during 15.6 months of follow-up. Median times to progression were 5.6 months in the capecitabine group and 8.2 months in the capecitabine-plus-trastuzumab group with an unadjusted hazard ratio of 0.69 (95% CI, 0.48 to 0.97; two-sided log-rank P = .0338). Overall survival rates were 20.4 months (95% CI, 17.8 to 24.7) in the capecitabine group and 25.5 months (95% CI, 19.0 to 30.7) in the capecitabine-plus-trastuzumab group (P = .257). Overall response rates were 27.0% with capecitabine and 48.1% with capecitabine plus trastuzumab (odds ratio, 2.50; P = .0115). Continuation of trastuzumab beyond progression was not associated with increased toxicity.
Conclusion
Continuation of trastuzumab plus capecitabine showed a significant improvement in overall response and time to progression compared with capecitabine alone in women with HER-2-positive breast cancer who experienced progression during trastuzumab treatment. J Clin Oncol 27: 1999-2006. (C) 2009 by American Society of Clinical Oncology
TL;DR: ARFI imaging is a promising US-based method for assessing liver fibrosis in chronic viral hepatitis, with diagnostic accuracy comparable to that of TE in this preliminary study.
Abstract: In our pilot study, the results of US-based acoustic radiation force impulse imaging were comparable to those of transient elastography and FibroTest scoring for the noninvasive measurement of liver fibrosis.
TL;DR: A molecular link between Aβ and tau protein in AD pathology in vivo is established, illustrating the potential of quantitative proteomics and establishing synergistic, age-associated effects of A β and t Tau in perishing mitochondria.
Abstract: Alzheimer's disease (AD) is characterized by amyloid-beta (Abeta)-containing plaques, neurofibrillary tangles, and neuron and synapse loss. Tangle formation has been reproduced in P301L tau transgenic pR5 mice, whereas APP(sw)PS2(N141I) double-transgenic APP152 mice develop Abeta plaques. Cross-breeding generates triple transgenic ((triple)AD) mice that combine both pathologies in one model. To determine functional consequences of the combined Abeta and tau pathologies, we performed a proteomic analysis followed by functional validation. Specifically, we obtained vesicular preparations from (triple)AD mice, the parental strains, and nontransgenic mice, followed by the quantitative mass-tag labeling proteomic technique iTRAQ and mass spectrometry. Within 1,275 quantified proteins, we found a massive deregulation of 24 proteins, of which one-third were mitochondrial proteins mainly related to complexes I and IV of the oxidative phosphorylation system (OXPHOS). Notably, deregulation of complex I was tau dependent, whereas deregulation of complex IV was Abeta dependent, both at the protein and activity levels. Synergistic effects of Abeta and tau were evident in 8-month-old (triple)AD mice as only they showed a reduction of the mitochondrial membrane potential at this early age. At the age of 12 months, the strongest defects on OXPHOS, synthesis of ATP, and reactive oxygen species were exhibited in the (triple)AD mice, again emphasizing synergistic, age-associated effects of Abeta and tau in perishing mitochondria. Our study establishes a molecular link between Abeta and tau protein in AD pathology in vivo, illustrating the potential of quantitative proteomics.
TL;DR: A linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms in a common set of 1,031 multiplex autism families, implicating SEMA5A as an autism susceptibility gene.
Abstract: Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 x 10(-7)). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.
TL;DR: The role of microglial cells in the pathogenesis of Alzheimer's disease (AD) neurodegeneration is unknown as discussed by the authors, and the role of neuroglial activation occurs in the human brain at sites of neurofibrillary degeneration, however, anti-inflammatory drugs do not prevent or reverse neuronal tau pathology.
Abstract: The role of microglial cells in the pathogenesis of Alzheimer’s disease (AD) neurodegeneration is unknown. Although several works suggest that chronic neuroinflammation caused by activated microglia contributes to neurofibrillary degeneration, anti-inflammatory drugs do not prevent or reverse neuronal tau pathology. This raises the question if indeed microglial activation occurs in the human brain at sites of neurofibrillary degeneration. In view of the recent work demonstrating presence of dystrophic (senescent) microglia in aged human brain, the purpose of this study was to investigate microglial cells in situ and at high resolution in the immediate vicinity of tau-positive structures in order to determine conclusively whether degenerating neuronal structures are associated with activated or with dystrophic microglia. We used a newly optimized immunohistochemical method for visualizing microglial cells in human archival brain together with Braak staging of neurofibrillary pathology to ascertain the morphology of microglia in the vicinity of tau-positive structures. We now report histopathological findings from 19 humans covering the spectrum from none to severe AD pathology, including patients with Down’s syndrome, showing that degenerating neuronal structures positive for tau (neuropil threads, neurofibrillary tangles, neuritic plaques) are invariably colocalized with severely dystrophic (fragmented) rather than with activated microglial cells. Using Braak staging of Alzheimer neuropathology we demonstrate that microglial dystrophy precedes the spread of tau pathology. Deposits of amyloid-beta protein (Aβ) devoid of tau-positive structures were found to be colocalized with non-activated, ramified microglia, suggesting that Aβ does not trigger microglial activation. Our findings also indicate that when microglial activation does occur in the absence of an identifiable acute central nervous system insult, it is likely to be the result of systemic infectious disease. The findings reported here strongly argue against the hypothesis that neuroinflammatory changes contribute to AD dementia. Instead, they offer an alternative hypothesis of AD pathogenesis that takes into consideration: (1) the notion that microglia are neuron-supporting cells and neuroprotective; (2) the fact that development of non-familial, sporadic AD is inextricably linked to aging. They support the idea that progressive, aging-related microglial degeneration and loss of microglial neuroprotection rather than induction of microglial activation contributes to the onset of sporadic Alzheimer’s disease. The results have far-reaching implications in terms of reevaluating current treatment approaches towards AD.
TL;DR: This study confirms the modest CNS antitumor activity of lapatinib and adds that further studies of Lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.
Abstract: Purpose: Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine. Experimental Design: Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as ≥50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease. Results: Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patients experienced a ≥20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a ≥20% volumetric reduction in their CNS lesions. Conclusions: This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.
TL;DR: Alterations in the ubiquitin system that occur during the initiation and progression of cancer are now being uncovered, and this knowledge is starting to be exploited for both molecular diagnostics and the development of novel strategies to combat cancer.
Abstract: The ubiquitin system is a network of proteins dedicated to the ubiquitylation of cellular targets and the subsequent control of numerous cellular functions. The deregulation of components of this elaborate network leads to human pathogenesis, including the development of many types of tumour. Alterations in the ubiquitin system that occur during the initiation and progression of cancer are now being uncovered, and this knowledge is starting to be exploited for both molecular diagnostics and the development of novel strategies to combat cancer.
TL;DR: Loperamide-loaded HSA nanoparticles with covalently bound transferrin or the OX26 or R17217 antibodies induced significant anti-nociceptive effects in the tail-flick test in ICR (CD-1) mice after intravenous injection, demonstrating thatTransferrin or these antibodies covalent coupled to HSA particle are able to transport loperamide and possibly other drugs across the blood-brain barrier (BBB).
TL;DR: This review aims at exposing the experience of the authors working in the FASE subsection of IALM (International Academy of Legal Medicine) in the field of age estimation both on the dead and the living, at highlighting advantages and limits of each method, and suggesting practical solutions concerning the age estimation process for adults and subadults, dead and living, and pedopornographic material.
TL;DR: In this paper, a major revision of the SCIAMACHY retrievals was reported, which improved the consistency between observed and assimilated column average mixing ratios and the agreement with independent validation data.
Abstract: Methane retrievals from the Scanning Imaging Absorption Spectrometer for Atmospheric Chartography (SCIAMACHY) instrument onboard ENVISAT provide important information on atmospheric CH_4 sources, particularly in tropical regions which are poorly monitored by in situ surface observations Recently, Frankenberg et al (2008a, 2008b) reported a major revision of SCIAMACHY retrievals due to an update of spectroscopic parameters of water vapor and CH_4 Here, we analyze the impact of this revision on global and regional CH_4 emissions estimates in 2004, using the TM5-4DVAR inverse modeling system Inversions based on the revised SCIAMACHY retrievals yield ∼20% lower tropical emissions compared to the previous retrievals The new retrievals improve significantly the consistency between observed and assimilated column average mixing ratios and the agreement with independent validation data Furthermore, the considerable latitudinal and seasonal bias correction of the previous SCIAMACHY retrievals, derived in the TM5-4DVAR system by simultaneously assimilating high-accuracy surface measurements, is reduced by a factor of ∼3 The inversions result in significant changes in the spatial patterns of emissions and their seasonality compared to the bottom-up inventories Sensitivity tests were done to analyze the robustness of retrieved emissions, revealing some dependence on the applied a priori emission inventories and OH fields Furthermore, we performed a detailed validation of simulated CH_4 mixing ratios using NOAA ship and aircraft profile samples, as well as stratospheric balloon samples, showing overall good agreement We use the new SCIAMACHY retrievals for a regional analysis of CH_4 emissions from South America, Africa, and Asia, exploiting the zooming capability of the TM5 model This allows a more detailed analysis of spatial emission patterns and better comparison with aircraft profiles and independent regional emission estimates available for South America Large CH_4 emissions are attributed to various wetland regions in tropical South America and Africa, seasonally varying and opposite in phase with CH_4 emissions from biomass burning India, China and South East Asia are characterized by pronounced emissions from rice paddies peaking in the third quarter of the year, in addition to further anthropogenic emissions throughout the year
TL;DR: The bulk of evidence demonstrates that AF in patients hospitalized for AMI has serious adverse prognostic implications regarding in-hospital, but also long-term mortality, and the need for prospective studies evaluating optimal therapeutic approaches for patients with AMI complicated by AF is emphasized.
Abstract: Atrial fibrillation (AF), the most commonly encountered clinical arrhythmia, often complicates acute myocardial infarction (AMI) with an incidence between 6 and 21%. Predictors of the arrhythmia in the setting of AMI include advanced age, heart failure symptoms, and depressed left ventricular function. The bulk of evidence demonstrates that AF in patients hospitalized for AMI has serious adverse prognostic implications regarding in-hospital, but also long-term mortality. This seems to apply for all patient populations studied without significant differences related to the treatment of AMI (i.e. no reperfusion therapy vs. thrombolysis vs. percutaneous coronary intervention). Mortality is particularly high in patients who have congestive heart failure and/or a reduced left ventricular ejection fraction. Finally, there are persuasive data indicating that AF complicating AMI not only increases the risk for ischaemic stroke during hospitalization but also during follow-up. This seems to apply also for transient AF which has reversed back to sinus rhythm at the time of discharge. These observations emphasize the need for prospective studies evaluating optimal therapeutic approaches for patients with AMI complicated by AF.
01 Jan 2009
TL;DR: TNFAIP3 (A20), a key regulator of NF-κB activity, is identified as a novel tumor suppressor gene in cHL and PMBL and the significantly higher frequency of TNFAIP 3 mutations in EBV− than EBV+ cHL suggests complementing functions of TN FAIP3 inactivation and EBV infection in c HL pathogenesis.
Abstract: Proliferation and survival of Hodgkin and Reed/Sternberg (HRS) cells, the malignant cells of classical Hodgkin lymphoma (cHL), are dependent on constitutive activation of nuclear factor kappaB (NF-kappaB). NF-kappaB activation through various stimuli is negatively regulated by the zinc finger protein A20. To determine whether A20 contributes to the pathogenesis of cHL, we sequenced TNFAIP3, encoding A20, in HL cell lines and laser-microdissected HRS cells from cHL biopsies. We detected somatic mutations in 16 out of 36 cHLs (44%), including missense mutations in 2 out of 16 Epstein-Barr virus-positive (EBV(+)) cHLs and a missense mutation, nonsense mutations, and frameshift-causing insertions or deletions in 14 out of 20 EBV(-) cHLs. In most mutated cases, both TNFAIP3 alleles were inactivated, including frequent chromosomal deletions of TNFAIP3. Reconstitution of wild-type TNFAIP3 in A20-deficient cHL cell lines revealed a significant decrease in transcripts of selected NF-kappaB target genes and caused cytotoxicity. Extending the mutation analysis to primary mediastinal B cell lymphoma (PMBL), another lymphoma with constitutive NF-kappaB activity, revealed destructive mutations in 5 out of 14 PMBLs (36%). This report identifies TNFAIP3 (A20), a key regulator of NF-kappaB activity, as a novel tumor suppressor gene in cHL and PMBL. The significantly higher frequency of TNFAIP3 mutations in EBV(-) than EBV(+) cHL suggests complementing functions of TNFAIP3 inactivation and EBV infection in cHL pathogenesis.
TL;DR: Protein interactions of the synaptic adhesion molecule neuroligin 2 that drive postsynaptic differentiation at inhibitory synapses are identified and deleted in mice perturbs GABAergic and glycinergic synaptic transmission and leads to a loss of post Synaptic specializations specifically at perisomatic inhibitorysynaptic synapses.
TL;DR: In this article, the authors presented the first global assessment of the anthropogenic alteration of river flow regimes, in particular of flow variability, by water withdrawals and dams/reservoirs.
Abstract: . Global-scale information on natural river flows and anthropogenic river flow alterations is required to identify areas where aqueous ecosystems are expected to be strongly degraded. Such information can support the identification of environmental flow guidelines and a sustainable water management that balances the water demands of humans and ecosystems. This study presents the first global assessment of the anthropogenic alteration of river flow regimes, in particular of flow variability, by water withdrawals and dams/reservoirs. Six ecologically relevant flow indicators were quantified using an improved version of the global water model WaterGAP. WaterGAP simulated, with a spatial resolution of 0.5 degree, river discharge as affected by human water withdrawals and dams around the year 2000, as well as naturalized discharge without this type of human interference. Compared to naturalized conditions, long-term average global discharge into oceans and internal sinks has decreased by 2.7% due to water withdrawals, and by 0.8% due to dams. Mainly due to irrigation, long-term average river discharge and statistical low flow Q90 (monthly river discharge that is exceeded in 9 out of 10 months) have decreased by more than 10% on one sixth and one quarter of the global land area (excluding Antarctica and Greenland), respectively. Q90 has increased significantly on only 5% of the land area, downstream of reservoirs. Due to both water withdrawals and reservoirs, seasonal flow amplitude has decreased significantly on one sixth of the land area, while interannual variability has increased on one quarter of the land area mainly due to irrigation. It has decreased on only 8% of the land area, in areas downstream of reservoirs where consumptive water use is low. The impact of reservoirs is likely underestimated by our study as small reservoirs are not taken into account. Areas most affected by anthropogenic river flow alterations are the Western and Central USA, Mexico, the western coast of South America, the Mediterranean rim, Southern Africa, the semi-arid and arid countries of the Near East and Western Asia, Pakistan and India, Northern China and the Australian Murray-Darling Basin, as well as some Arctic rivers. Due to a large number of uncertainties related e.g. to the estimation of water use and reservoir operation rules, the analysis is expected to provide only first estimates of river flow alterations that should be refined in the future.
TL;DR: In this article, Li et al. developed an approach to find ground state solutions, i.e., nontrivial solutions with least possible energy, based on a direct reduction of the indefinite variational problem to a definite one.
TL;DR: In this paper, the impact of climate change on groundwater recharge and the number of affected people was computed for four climate scenarios by two climate models using the global water resources and use model WaterGAP.
Abstract: Climate change will lead to significant changes of groundwater recharge and thus renewable groundwater resources. Using the global water resources and use model WaterGAP, the impact of climate change on groundwater recharge and the number of affected people was computed for four climate scenarios by two climate models. Vulnerability of humans to decreased groundwater resources depends on both the degree of decrease and the sensitivity of the human system to the decrease. For each grid cell, a sensitivity index composed of a water scarcity indicator, an indicator for dependence of water supply on groundwater and the Human Development Index was quantified. Combining per cent groundwater recharge decrease with the sensitivity index, global maps of vulnerability to the impact of decreased groundwater recharge in the 2050s were derived. In the A2 (B2) emissions scenario, 18.4–19.3% (16.1–18.1%) of the global population of 10.7 (9.1) billion would be affected by groundwater recharge decreases of at least 10%, and 4.8–5.7% (3.8–3.8%) of the global population would be in the two highest vulnerability classes. The highest vulnerabilities are found at the North African rim of the Mediterranean Sea, in southwestern Africa, in northeastern Brazil and in the central Andes, which are areas of moderate to high sensitivity. For most of the areas with high population density and high sensitivity, model results indicate that groundwater recharge is unlikely to decrease by more than 10% until the 2050s. However, a fifth to a third of the population may be affected by a groundwater recharge increase of more than 10%, with negative impacts in the case of shallow water tables. The spatial distribution of vulnerability, even at the continental scale, differs more strongly between the two climate models than between the two emissions scenarios.