Magnetars and pulsars: a missing link

There is growing evidence that soft gamma-ray repeaters (SGRs) and anomalous X-ray pulsars (AXPs) are isolated neutron stars with superstrong magnetic fields, i.e., magnetars, marking them a distinguished species from the conventional species of spindown-powered isolated neutron stars, i.e., radio pulsars. The current arguments in favor of the magnetar interpretation of SGR/AXP phenomenology will be outlined, and the two energy sources in magnetars, i.e. a magnetic dissipation energy and a spindown energy, will be reviewed. I will then discuss a missing link between magnetars and pulsars, i.e., lack of the observational evidence of the spindown-powered behaviors in known magnetars. Some recent theoretical efforts in studying such behaviors will be reviewed along with some predictions testable in the near future.Comment: Invited talk at the Sixth Pacific Rim Conference on Stellar Astrophysics, a tribute to Helmut A. Abt, July 11-17, 2002, Xi'an. To appear in the proceedings (eds. K. S. Cheng, K. C. Leung & T. P. Li

Traditional Roles in a Non‐Traditional Setting: Genetic Counseling in Precision Oncology

Next generation sequencing technology is increasingly utilized in oncology with the goal of targeting therapeutics to improve response and reduce side effects. Interpretation of tumor mutations requires sequencing of paired germline DNA, raising questions about incidental germline findings. We describe our experiences as part of a research team implementing a protocol for whole genome sequencing (WGS) of tumors and paired germline DNA known as the Michigan Oncology Sequencing project (MI‐ONCOSEQ) that includes options for receiving incidental germline findings. Genetic counselors (GCs) discuss options for return of results with patients during the informed consent process and document family histories. GCs also review germline findings and actively participate in the multi‐disciplinary Precision Medicine Tumor Board (PMTB), providing clinical context for interpretation of germline results and making recommendations about disclosure of germline findings. GCs have encountered ethical and counseling challenges with participants, described here. Although GCs have not been traditionally involved in molecular testing of tumors, our experiences with MI‐ONCOSEQ demonstrate that GCs have important applicable skills to contribute to multi‐disciplinary care teams implementing precision oncology. Broader use of WGS in oncology treatment decision making and American College of Medical Genetics and Genomics (ACMG) recommendations for active interrogation of germline tissue in tumor‐normal dyads suggests that GCs will have future opportunities in this area outside of research settings.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147078/1/jgc40655.pd

Inhibition of plasmin-mediated TAFI activation may affect development but not progression of abdominal aortic aneurysms

Objective: Thrombin-activatable fibrinolysis inhibitor (TAFI) reduces the breakdown of fibrin clots through its action as an indirect inhibitor of plasmin. Studies in TAFI-deficient mice have implicated a potential role for TAFI in Abdominal Aortic Aneurysm (AAA) disease. The role of TAFI inhibition on AAA formation in adult ApoE-/- mice is unknown. The aim of this paper was to investigate the effects of TAFI inhibition on AAA development and progression. Methods: Using the Angiotensin II model of AAA, male ApoE-/- mice were infused with Angiotensin II 750ng/kg/min with or without a monoclonal antibody inhibitor of plasmin-mediated activation of TAFI, MA-TCK26D6, or a competitive small molecule inhibitor of TAFI, UK-396082. Results: Inhibition of TAFI in the Angiotensin II model resulted in a decrease in the mortality associated with AAA rupture (from 40.0% to 16.6% with MA-TCK26D6 (log-rank Mantel Cox test p = 0.16), and 8.3% with UK-396082 (log-rank Mantel Cox test p = 0.05)). Inhibition of plasmin-mediated TAFI activation reduced the incidence of AAA from 52.4% to 30.0%. However, late treatment with MA-TCK26D6 once AAA were already established had no effect on the progression of AAA in this model. Conclusions: The formation of intra-mural thrombus is responsible for the dissection and early rupture in the angiotensin II model of AAA, and this process can be prevented through inhibition of TAFI. Late treatment with a TAFI inhibitor does not prevent AAA progression. These data may indicate a role for inhibition of plasmin-mediated TAFI activation in the early stages of AAA development, but not in its progression

Differences in genotype and virulence among four multidrug-resistant <i>Streptococcus pneumoniae</i> isolates belonging to the PMEN1 clone

We report on the comparative genomics and characterization of the virulence phenotypes of four &lt;i&gt;S. pneumoniae&lt;/i&gt; strains that belong to the multidrug resistant clone PMEN1 (Spain&lt;sup&gt;23F&lt;/sup&gt; ST81). Strains SV35-T23 and SV36-T3 were recovered in 1996 from the nasopharynx of patients at an AIDS hospice in New York. Strain SV36-T3 expressed capsule type 3 which is unusual for this clone and represents the product of an in vivo capsular switch event. A third PMEN1 isolate - PN4595-T23 - was recovered in 1996 from the nasopharynx of a child attending day care in Portugal, and a fourth strain - ATCC700669 - was originally isolated from a patient with pneumococcal disease in Spain in 1984. We compared the genomes among four PMEN1 strains and 47 previously sequenced pneumococcal isolates for gene possession differences and allelic variations within core genes. In contrast to the 47 strains - representing a variety of clonal types - the four PMEN1 strains grouped closely together, demonstrating high genomic conservation within this lineage relative to the rest of the species. In the four PMEN1 strains allelic and gene possession differences were clustered into 18 genomic regions including the capsule, the blp bacteriocins, erythromycin resistance, the MM1-2008 prophage and multiple cell wall anchored proteins. In spite of their genomic similarity, the high resolution chinchilla model was able to detect variations in virulence properties of the PMEN1 strains highlighting how small genic or allelic variation can lead to significant changes in pathogenicity and making this set of strains ideal for the identification of novel virulence determinant

The effect of post-discharge educational intervention on patients in achieving objectives in modifiable risk factors six months after discharge following an episode of acute coronary syndrome, (CAM-2 Project): a randomized controlled trial

<p>Abstract</p> <p>Objectives</p> <p>We investigated whether an intervention mainly consisting of a signed agreement between patient and physician on the objectives to be reached, improves reaching these secondary prevention objectives in modifiable cardiovascular risk factors six-months after discharge following an acute coronary syndrome.</p> <p>Background</p> <p>There is room to improve mid-term adherence to clinical guidelines' recommendations in coronary heart disease secondary prevention, specially non-pharmacological ones, often neglected.</p> <p>Methods</p> <p>In CAM-2, patients discharged after an acute coronary syndrome were randomly assigned to the intervention or the usual care group. The primary outcome was reaching therapeutic objectives in various secondary prevention variables: smoking, obesity, blood lipids, blood pressure control, exercise and taking of medication.</p> <p>Results</p> <p>1757 patients were recruited in 64 hospitals and 1510 (762 in the intervention and 748 in the control group) attended the six-months follow-up visit. After adjustment for potentially important variables, there were, between the intervention and control group, differences in the mean reduction of body mass index (0.5 vs. 0.2; p < 0.001) and waist circumference (1.6 cm vs. 0.6 cm; p = 0.05), proportion of patients who exercise regularly and those with total cholesterol below 175 mg/dl (64.7% vs. 56.5%; p = 0.001). The reported intake of medications was high in both groups for all the drugs considered with no differences except for statins (98.1% vs. 95.9%; p = 0.029).</p> <p>Conclusions</p> <p>At least in the short term, lifestyle changes among coronary heart disease patients are achievable by intensifying the responsibility of the patient himself by means of a simple and feasible intervention.</p

Frequent Long-Range Epigenetic Silencing of Protocadherin Gene Clusters on Chromosome 5q31 in Wilms' Tumor

Wilms' tumour (WT) is a pediatric tumor of the kidney that arises via failure of the fetal developmental program. The absence of identifiable mutations in the majority of WTs suggests the frequent involvement of epigenetic aberrations in WT. We therefore conducted a genome-wide analysis of promoter hypermethylation in WTs and identified hypermethylation at chromosome 5q31 spanning 800 kilobases (kb) and more than 50 genes. The methylated genes all belong to α-, β-, and γ-protocadherin (PCDH) gene clusters (Human Genome Organization nomenclature PCDHA@, PCDHB@, and PCDHG@, respectively). This demonstrates that long-range epigenetic silencing (LRES) occurs in developmental tumors as well as in adult tumors. Bisulfite polymerase chain reaction analysis showed that PCDH hypermethylation is a frequent event found in all Wilms' tumor subtypes. Hypermethylation is concordant with reduced PCDH expression in tumors. WT precursor lesions showed no PCDH hypermethylation, suggesting that de novo PCDH hypermethylation occurs during malignant progression. Discrete boundaries of the PCDH domain are delimited by abrupt changes in histone modifications; unmethylated genes flanking the LRES are associated with permissive marks which are absent from methylated genes within the domain. Silenced genes are marked with non-permissive histone 3 lysine 9 dimethylation. Expression analysis of embryonic murine kidney and differentiating rat metanephric mesenchymal cells demonstrates that Pcdh expression is developmentally regulated and that Pcdhg@ genes are expressed in blastemal cells. Importantly, we show that PCDHs negatively regulate canonical Wnt signalling, as short-interfering RNA–induced reduction of PCDHG@ encoded proteins leads to elevated β-catenin protein, increased β-catenin/T-cell factor (TCF) reporter activity, and induction of Wnt target genes. Conversely, over-expression of PCDHs suppresses β-catenin/TCF-reporter activity and also inhibits colony formation and growth of cancer cells in soft agar. Thus PCDHs are candidate tumor suppressors that modulate regulatory pathways critical in development and disease, such as canonical Wnt signaling

How to screen for non-adherence to antihypertensive therapy

The quality of assessment of non-adherence to treatment in hypertensive is poor. Within this review, we discuss the different methods used to assess adherence to blood-pressure-lowering medications in hypertension patients. Subjective reports such as physicians’ perceptions are inaccurate, and questionnaires completed by patients tend to overreport adherence and show a low diagnostic specificity. Indirect objective methods such as pharmacy database records can be useful, but they are limited by the robustness of the recorded data. Electronic medication monitoring devices are accurate but usually track adherence to only a single medication and can be expensive. Overall, the fundamental issue with indirect objective measures is that they do not fully confirm ingestion of antihypertensive medications. Detection of antihypertensive medications in body fluids using liquid chromatography–tandem mass spectrometry is currently, in our view, the most robust and clinically useful method to assess non-adherence to blood-pressure-lowering treatment. It is particularly helpful in patients presenting with resistant, refractory or uncontrolled hypertension despite the optimal therapy. We recommend using this diagnostic strategy to detect non-adherence alongside a no-blame approach tailoring support to address the perceptions (e.g. beliefs about the illness and treatment) and practicalities (e.g. capability and resources) influencing motivation and ability to adhere

Whole genome sequencing to investigate the emergence of clonal complex 23 Neisseria meningitidis serogroup Y disease in the United States

In the United States, serogroup Y, ST-23 clonal complex Neisseria meningitidis was responsible for an increase in meningococcal disease incidence during the 1990s. This increase was accompanied by antigenic shift of three outer membrane proteins, with a decrease in the population that predominated in the early 1990s as a different population emerged later in that decade. To understand factors that may have been responsible for the emergence of serogroup Y disease, we used whole genome pyrosequencing to investigate genetic differences between isolates from early and late N. meningitidis populations, obtained from meningococcal disease cases in Maryland in the 1990s. The genomes of isolates from the early and late populations were highly similar, with 1231 of 1776 shared genes exhibiting 100% amino acid identity and an average πN = 0.0033 and average πS = 0.0216. However, differences were found in predicted proteins that affect pilin structure and antigen profile and in predicted proteins involved in iron acquisition and uptake. The observed changes are consistent with acquisition of new alleles through horizontal gene transfer. Changes in antigen profile due to the genetic differences found in this study likely allowed the late population to emerge due to escape from population immunity. These findings may predict which antigenic factors are important in the cyclic epidemiology of meningococcal disease

Anti-inflammatory agents and monoHER protect against DOX-induced cardiotoxicity and accumulation of CML in mice

Cardiac damage is the major limiting factor for the clinical use of doxorubicin (DOX). Preclinical studies indicate that inflammatory effects may be involved in DOX-induced cardiotoxicity. Nɛ-(carboxymethyl) lysine (CML) is suggested to be generated subsequent to oxidative stress, including inflammation. Therefore, the aim of this study was to investigate whether CML increased in the heart after DOX and whether anti-inflammatory agents reduced this effect in addition to their possible protection on DOX-induced cardiotoxicity. These effects were compared with those of the potential cardioprotector 7-monohydroxyethylrutoside (monoHER)

Human Apolipoprotein A-I-Derived Amyloid: Its Association with Atherosclerosis

Amyloidoses constitute a group of diseases in which soluble proteins aggregate and deposit extracellularly in tissues. Nonhereditary apolipoprotein A-I (apoA-I) amyloid is characterized by deposits of nonvariant protein in atherosclerotic arteries. Despite being common, little is known about the pathogenesis and significance of apoA-I deposition. In this work we investigated by fluorescence and biochemical approaches the impact of a cellular microenvironment associated with chronic inflammation on the folding and pro-amyloidogenic processing of apoA-I. Results showed that mildly acidic pH promotes misfolding, aggregation, and increased binding of apoA-I to extracellular matrix elements, thus favoring protein deposition as amyloid like-complexes. In addition, activated neutrophils and oxidative/proteolytic cleavage of the protein give rise to pro amyloidogenic products. We conclude that, even though apoA-I is not inherently amyloidogenic, it may produce non hereditary amyloidosis as a consequence of the pro-inflammatory microenvironment associated to atherogenesis