Emphasizng the interplay between methodology and ethical and legal issues, this important work takes as its subject one of medicine's most pressing arenas of ethical debate. Each chapter addresses ...relevant issues and emphasizes particular ethical principles.
Pulsar wind nebulae are formed when outflows of relativistic electrons and positrons hit the surrounding supernova remnant or interstellar medium at a shock front. The Vela pulsar wind nebula is ...powered by a young pulsar (B0833-45, age 11 kyr) and located inside an extended structure called Vela X, itself inside the supernova remnant. Previous X-ray observations revealed two prominent arcs, bisected by a jet and counter jet. Radio maps have shown high linear polarization of 60 per cent in the outer regions of the nebula. Here we report X-ray observation of the inner part of the nebula, where polarization can exceed 60 per cent at the leading edge, which approaches the theoretical limit of what can be produced by synchrotron emission. We infer that, in contrast with the case of the supernova remnant, the electrons in the pulsar wind nebula are accelerated with little or no turbulence in a highly uniform magnetic field.
Abstract LBA-3
Mutations in the transcription factor genes, RUNX1 and CEBPA, can lead to an autosomal dominant familial predisposition to MDS/AML. Using a candidate gene approach, we have detected ...domain specific heterozygous mutations in the GATA2 gene in 4 MDS/AML families which predispose to MDS/AML. The same novel heterozygous T354M missense mutation was observed in 3 families and a 355delT mutation in 1 family, all with multigenerational transmission of MDS and/or MDS/AML. Importantly, these genetic variants segregate with all affected members in each of the families. The 2 mutated threonine residues are in 5 consecutive highly conserved threonine residues at the DNA-binding, protein-protein interacting second zinc finger (ZF2) of GATA2. Neither these mutations, nor any other variants in the GATA2 coding sequence, were seen in a population screen of 695 normal individuals. Haplotype analysis suggests that the T354M mutation has multiple ancestral origins. While mutations in RUNX1 and CEBPA, can also lead to familial predisposition to MDS/AML, these patients with GATA2 mutations are unique in that there is no obvious pre-MDS or pre-leukaemic phenotype such as thrombocytopenia (RUNX1) and eosinophilia (CEBPA) in predisposed carriers. Most patients in these families have had a rapid disease course “appearing out of the blue” leading to death, with a variety of ages of onset from teenagers to early 40s. Yet remarkably, there are still asymptomatic carriers in their 60s. One of these carriers, and his 2 children, has had bone marrow prophylactically stored over 15 years ago in case of disease onset. No pathogenic GATA2 coding sequence changes were found in 268 sporadic MDS/AML patient samples. Additionally, GATA2 mutations were not found in germline samples from 35 other families predisposed to AML and various other hematological malignancies. Both the T354M and 355delT mutants appear to localize appropriately to the nucleus and maintain at least some DNA binding in electrophoretic mobility shift assays. We used the known murine Gata3 ZF2 structure bound to DNA to model the effects of the observed mutations and demonstrated that the T354 residue does not contact DNA but makes polar contact with the adjacent threonines, and via its amino group, with C349 which coordinates the zinc atom. Replacement of the T354 side-chain with the bulky methionine moiety may affect the zinc contacts and is predicted to alter the overall structure of this ZF2. In contrast, 355delT will shorten the conserved threonine string which is predicted to impact on the orientation and position of L359 which directly contacts DNA. Thus, 355delT is likely to have an effect on DNA binding. Luciferase reporter assays indicate that T354M and 355delT greatly reduce the transactivation ability of GATA2 on multiple response elements, impacting on downstream target genes such as RUNX1 and CD34. Of note, T354M shows a markedly lesser synergistic effect than wildtype (WT) GATA2 with PU.1 on the CSF1R promoter. Competition assays show that these mutations may be acting in a dominant negative fashion in some biological contexts. In stable promyelocytic HL-60 cell lines expressing regulatable GATA2 (WT or T354M), T354M allows proliferation to proceed even under stimulus to differentiate with all-trans retinoic acid. Microarray studies indicated that the down regulation of proapoptotic BCL-xS by T354M, but not WT, may be responsible for this phenotype. GATA2 is considered to be a hematopoietic “stemness” gene, highly expressed in haematopoietic stem cells and is required for megakaryocyte and mast cell production. GATA2 is down regulated during myeloid differentiation and forced overexpression prevents such differentiation. Discovery of GATA2 mutants in MDS/AML predisposed families provides new tools for probing the mechanism of GATA2 induced leukemogenesis, and possibly also for clarifying its role in maintenance of stemness. Our findings highlight the power of investigating familial predispositions to cancer identifying specific mutations with unique biological effects. They have immediate implications for diagnostic genetic testing, and longer term therapeutic implications through identification of drugable biological pathways such as apoptosis. The poor outcome associated with these mutations may suggest that an aggressive strategy is appropriate in the treatment of affected individuals in families found to be carrying GATA2 mutations.
No relevant conflicts of interest to declare.
HYPOTHESIS The number of nodal basins draining a primary cutaneous melanoma is not an independent predictor of outcome. DESIGN Post hoc analysis of patients entered into a randomized, prospective ...study. SETTING Multi-institutional academic and community medical centers. PATIENTS Patients aged 18 to 70 years with melanoma 1.0 mm or greater Breslow thickness. INTERVENTIONS Wide local excision and sentinel lymph node biopsy were performed on all patients; patients with sentinel lymph node metastases underwent completion lymphadenectomy. Patients with multiple–nodal basin drainage were compared with those with single–nodal basin drainage. MAIN OUTCOME MEASURES Sentinel lymph node status, locoregional recurrence-free survival, disease-free survival, and overall survival. RESULTS A total of 2060 patients with single–nodal basin drainage (n = 1709 83% of cohort) were included in the analysis, with a median follow-up of 50 months. On univariate analysis, the group with multiple–nodal basin drainage (n = 351) was associated with female sex and primary tumor regression (P < .001). In addition, multiple–nodal basin drainage was associated with truncal primary tumor location (73.2%), while single–nodal basin drainage was more common for extremity tumors (50.9%; P < .001). On multivariate analysis, there were no differences in the rate of sentinel lymph node metastasis, disease-free survival, or overall survival between the groups. Interestingly, locoregional recurrence was significantly worse in the single–nodal basin drainage group (P = .003). CONCLUSIONS Multiple–nodal basin drainage does not confer a worse prognosis for patients with cutaneous melanoma. In fact, single–nodal basin drainage appears to be associated with a greater risk of locoregional recurrence.Arch Surg. 2008;143(7):632-638-->
We present measurements of the polarization of X-rays in the 2-8 keV band from the pulsar in the ultracompact low mass X-ray binary 4U1626-67 using data from the Imaging X-ray Polarimetry Explorer ...(IXPE). The 7.66 s pulsations were clearly detected throughout the IXPE observations as well as in the NICER soft X-ray observations, which we use as the basis for our timing analysis and to constrain the spectral shape over 0.4-10 keV energy band. Chandra HETGS high-resolution X-ray spectra were also obtained near the times of the IXPE observations for firm spectral modeling. We find an upper limit on the pulse-averaged linear polarization of <4% (at 95% confidence). Similarly, there was no significant detection of polarized flux in pulse phase intervals when subdividing the bandpass by energy. However, spectropolarimetric modeling over the full bandpass in pulse phase intervals provide a marginal detection of polarization of the power-law spectral component at the 4.8 +/- 2.3% level (90% confidence). We discuss the implications concerning the accretion geometry onto the pulsar, favoring two-component models of the pulsed emission.
Purpose: This study aims to describe the spectrum of clinical thrombotic events and to compare the methods of laboratory evaluation for the newly described prothrombotic factor V Leiden mutation.
...Methods: Specimens from 1376 patients with thrombotic events or their relatives were tested for the factor V Leiden mutation by polymerase chain reaction plus restriction digest from Jan. 1, 1995, to Mar. 31, 1996. Activated protein C (APC) resistance test data was available for 554 of these patients. Clinical information was available for 166 patients with the mutation.
Results: Of 1376 patients tested for factor V Leiden mutation, 270 (19.6%) were positive, with 12 homozygotes and 258 heterozygotes. Of 554 patients for whom APC resistance data was available, 221 (39.9%) had low APC resistance ratios (≤2.4); of these only 97 (43.9%) were factor V Leiden–positive. Among 333 samples with normal or elevated APC resistance ratios, 19 (5.7%) were later identified with the factor V Leiden mutation, despite the normal screening test. One hundred fourteen of 166 patients (68.7%) with the mutation had at least one thrombotic event, most commonly deep venous thrombosis and pulmonary embolus. Arterial cerebrovascular thrombotic events occurred in 11 patients (10%), and myocardial infarctions in eight (7%). The mean age of all patients with arterial thrombotic events was 45.4 years.
Conclusions: The factor V mutation is a common cause of venous thromboses but may also be associated with the early presentation of arterial thrombotic events. The APC resistance test is a sensitive screening assay but has limitations of its specificity in clinical practice. (J Vasc Surg 1997;25:271-6.)
We report on a \(\sim 5\sigma\) detection of polarized 3-6 keV X-ray emission from the supernova remnant Cassiopeia A with the Imaging X-ray Polarimetry Explorer (IXPE). The overall polarization ...degree of \(1.8 \pm 0.3\)% is detected by summing over a large region, assuming circular symmetry for the polarization vectors. The measurements imply an average polarization degree for the synchrotron component of \(\sim 2.5\)%, and close to 5% for the X-ray synchrotron-domimated forward-shock region. These numbers are based on an assessment of the thermal and non-thermal radiation contributions, for which we used a detailed spatial-spectral model based on Chandra X-ray data. A pixel-by-pixel search for polarization provides a few tentative detections from discrete regions at the \(\sim 3\sigma\) confidence level. Given the number of pixels, the significance is {insufficient} to claim a detection for individual pixels, but implies considerable turbulence on scales smaller than the angular resolution. Cas A's X-ray continuum emission is dominated by synchrotron radiation from regions within \(\lesssim 10^{17}\) cm of the forward- and reverse shocks. We find that i) the measured polarization angle corresponds to a radially-oriented magnetic field, similar to what has been inferred from radio observations; ii) the X-ray polarization degree is lower than in the radio band (\(\sim 5\)%). Since shock compression should impose a tangential magnetic field structure, the IXPE results imply that magnetic-fields are reoriented within \(\sim 10^{17}\)cm of the shock. If the magnetic-field alignment is due to locally enhanced acceleration near quasi-parallel shocks, the preferred X-ray polarization angle suggests a size of \(3\times 10^{16}\) cm for cells with radial magnetic fields.
Scheduled to launch in late 2021, the Imaging X-ray Polarimetry Explorer (IXPE) is a NASA Small Explorer Mission in collaboration with the Italian Space Agency (ASI). The mission will open a new ...window of investigation - imaging X-ray polarimetry. The observatory features 3 identical telescopes each consisting of a mirror module assembly with a polarization-sensitive imaging X-ray detector at the focus. A coilable boom, deployed on orbit, provides the necessary 4-m focal length. The observatory utilizes a 3-axis-stabilized spacecraft which provides services such as power, attitude determination and control, commanding, and telemetry to the ground. During its 2-year baseline mission, IXPE will conduct precise polarimetry for samples of multiple categories of X-ray sources, with follow-on observations of selected targets.
Objective
To evaluate quality of life (QOL) in adults with juvenile idiopathic arthritis (JIA), using validated measures of functional disability and generic health status, and to quantify their ...educational attainment and employment status.
Methods
The adult rheumatology departmental database was used to identify patients. Functional disability and generic health status/QOL were assessed by the Health Assessment Questionnaire (HAQ) and the Short Form 36‐item health profile (SF‐36), respectively. Educational achievement and employment status were assessed by questionnaire.
Results
Complete data were available for 82 of the 101 patients identified. The median age of patients was 30 years, and the median disease duration was 21 years. No deaths were recorded. All subtypes of JIA were represented. Thirty‐nine percent of patients had active disease (based on the physician global assessment scale score). The median HAQ score was 1.125 (range 0–3). SF‐36 scores for bodily pain, general health, physical functioning, vitality, emotion, and social isolation were significantly worse in patients compared with controls, and this trend increased with increasing age of the patients and disease duration. The SF‐36 mental summation scores of patients were low compared with those of controls, for all subtypes of JIA, and this finding was independent of the degree of functional disability (by HAQ and SF‐36 physical summation scores). The educational attainment of patients was comparable to that of local controls, but unemployment rates for patients were 3‐fold higher than those for controls.
Conclusion
This is the largest study in which the SF‐36 was used to assess generic health status and QOL in adults with JIA. Many patients had active disease in adulthood, and although the physical outcome of adults with JIA is relatively good, a profound effect on generic health status and QOL was demonstrated for all types of JIA. Furthermore, despite excellent educational attainment, there was a high rate of unemployment among patients.
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