From Trees to the Forest: Genes to Genomics

Crick, Watson, and colleagues revealed the genetic code in 1953, and since that time, remarkable progress has been made in understanding what makes each of us who we are. Identification of single genes important in disease, and the development of a mechanistic understanding of genetic elements that regulate gene function, have cast light on the pathophysiology of many heritable and acquired disorders. In 1990, the human genome project commenced, with the goal of sequencing the entire human genome, and a “first draft” was published with astonishing speed in 2001. The first draft, although an extraordinary achievement, reported essentially an imaginary haploid mix of alleles rather than a true diploid genome. In the years since 2001, technology has further improved, and efforts have been focused on filling in the gaps in the initial genome and starting the huge task of looking at normal variation in the human genome. This work is the beginning of understanding human genetics in the context of the structure of the genome as a complete entity, and as more than simply the sum of a series of genes. We present 3 studies in this review that apply genomic approaches to leukemia and to transplantation to improve and extend therapies

Are There Magnetars in High Mass X-ray Binaries? The Case of SuperGiant Fast X-Ray Transients

In this paper we survey the theory of wind accretion in high mass X-ray binaries hosting a magnetic neutron star and a supergiant companion. We concentrate on the different types of interaction between the inflowing wind matter and the neutron star magnetosphere that are relevant when accretion of matter onto the neutron star surface is largely inhibited; these include the inhibition through the centrifugal and magnetic barriers. Expanding on earlier work, we calculate the expected luminosity for each regime and derive the conditions under which transition from one regime to another can take place. We show that very large luminosity swings (~10^4 or more on time scales as short as hours) can result from transitions across different regimes. The activity displayed by supergiant fast X-ray transients, a recently discovered class of high mass X-ray binaries in our galaxy, has often been interpreted in terms of direct accretion onto a neutron star immersed in an extremely clumpy stellar wind. We show here that the transitions across the magnetic and/or centrifugal barriers can explain the variability properties of these sources as a results of relatively modest variations in the stellar wind velocity and/or density. According to this interpretation we expect that supergiant fast X-ray transients which display very large luminosity swings and host a slowly spinning neutron star are characterized by magnetar-like fields, irrespective of whether the magnetic or the centrifugal barrier applies. Supergiant fast X-ray transients might thus provide a new opportunity to detect and study magnetars in binary systems.Comment: Accepted for publication in ApJ. 16 pages, 6 figure

Twenty Years of Unrelated Donor Bone Marrow Transplantation for Pediatric Acute Leukemia Facilitated by the National Marrow Donor Program

AbstractThe National Marrow Donor Program (NMDP) has facilitated unrelated donor hematopoietic cell transplants for more than 20 years. In this time period, there have been many changes in clinical practice, including improvements in HLA typing and supportive care, and changes in the source of stem cells. Availability of banked unrelated donor cord blood (incorporated into the NMDP registry in 2000) as a source of stem cells has become an important option for children with leukemia, offering the advantages of immediate availability for children with high-risk disease, the need for a lesser degree of HLA match, and expanding access for those with infrequent HLA haplotypes. Overall survival (OS) in children with acute leukemia transplanted with unrelated donor bone marrow (BM) is markedly better in more recent years, largely attributable to less treatment-related mortality (TRM). Within this cohort, 2-year survival was markedly better for patients with acute lymphoblastic leukemia (ALL) in first complete response (CR1) (74%) versus second complete response (CR2) (62%) or more advanced disease (33%). Similar findings are observed with patients with AML, suggesting earlier referral to bone marrow transplant (BMT) is optimal for survival. Notably, this improvement over time was not observed in unmodified peripheral blood stem cell (PBSC) recipients, suggesting unmodified PBSC may not be the optimal stem cell source for children

Transplant Outcomes for Children with Hypodiploid Acute Lymphoblastic Leukemia: The Cibmtr Experience

Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USAMed Coll Wisconsin, CIBMTR, Milwaukee, WI 53226 USAMed Coll Wisconsin, Milwaukee, WI 53226 USAInst Oncol Pediat, Sao Paulo, BrazilUniv Michigan, Ann Arbor, MI 48109 USAUniv S Florida, All Childrens Hosp, St Petersburg, FL 33701 USAWeb of Scienc

Fast Spectral Variability from Cygnus X-1

We have developed an algorithm that, starting from the observed properties of the X-ray spectrum and fast variability of an X-ray binary allows the production of synthetic data reproducing observables such as power density spectra and time lags, as well as their energy dependence. This allows to reconstruct the variability of parameters of the energy spectrum and to reduce substantially the effects of Poisson noise, allowing to study fast spectral variations. We have applied the algorithm to Rossi X-ray Timing Explorer data of the black-hole binary Cygnus X-1, fitting the energy spectrum with a simplified power law model. We recovered the distribution of the power law spectral indices on time-scales as low as 62 ms as being limited between 1.6 and 1.8. The index is positively correlated with the flux even on such time-scales.Comment: 14 pages, 19 figures, accepted by MNRA

Comparison of the Population Excess Fraction of <i>Chlamydia trachomatis</i> Infection on Pelvic Inflammatory Disease at 12-months in the Presence and Absence of Chlamydia Testing and Treatment:Systematic Review and Retrospective Cohort Analysis

Background: The impact of Chlamydia trachomatis (chlamydia) control on the incidence of pelvic inflammatory disease (PID) is theoretically limited by the proportion of PID caused by chlamydia. We estimate the population excess fraction (PEF) of treated chlamydia infection on PID at 12-months in settings with widespread chlamydia control (testing and treatment) and compare this to the estimated PEF of untreated chlamydia. Methods: We used two large retrospective population-based cohorts of women of reproductive age from settings with widespread chlamydia control to calculate the PEF of treated chlamydia on PID at 12-months. We undertook a systematic review to identify further studies that reported the risk of PID in women who were tested for chlamydia (infected and uninfected). We used the same method to calculate the PEF in eligible studies then compared all estimates of PEF. Results: The systematic review identified a single study, a randomised control led trial of chlamydia screening (POPI-RCT). In the presence of testing and treatment <10% of PID at 12-months was attributable to treated (baseline) chlamydia infections (Manitoba: 8.86%(95%CI 7.15-10.75); Denmark: 3.84%(3.26-4.45); screened-arm POPI-RCT: 0.99%(0.00-29.06)). In the absence of active chlamydia treatment 26.44% (11.57-46.32) of PID at 12-months was attributable to untreated (baseline) chlamydia infections (deferred-arm POPI-RCT). The PEFs suggest that eradicating baseline chlamydia infections could prevent 484 cases of PID at 12-months per 100,000 women in the untreated setting and 13- 184 cases of PID per 100,000 tested women in the presence of testing and treatment. Conclusion: Testing and treating chlamydia reduced the PEF of chlamydia on PID by 65% compared to the untreated setting. But in the presence of testing and treatment over 90% of PID could not be attributed to a baseline chlamydia infection. More information is needed about the aetiology of PID to develop effective strategies for improving the reproductive health of women

On the bolometric quiescent luminosity and luminosity swing of black hole candidate and neutron star low mass X-ray transients

Low mass X-ray transients (LMXRTs) hosting black hole candidates (BHCs) display on average a factor of ~100 larger swing in the minimum (quiescent) to maximum (outburst) X-ray luminosity than neutron stars (NSs), despite the fact that the swing in the mass inflow rate is likely in the same range. Advection dominated accretion flows (ADAFs) were proposed to interpret such a difference. The residual optical/UV emission of quiescent LMXRTs, after subtraction of the companion star spectrum, is produced by synchrotron radiation in the (latest version) of ADAF and therefore is part of the ADAF's luminosity budget. We demonstrate that, once the residual optical/UV emission is taken into account, the bolometric luminosity swing of BHCs is consistent with that of NSs. We explore here an alternative scenario to ADAFs in which very little mass accretion onto the collapsed star takes place in the quiescence intervals. The residual optical/UV emission of BHCs are expected to derive from the energy released by the matter transferred from the companion star at radii comparable to the circularisation radius. The quiescent X-ray luminosity originates either from accretion onto the BH at very low rates and/or from coronal activity in the companion star or in the outer disk. For comparably small mass inflow rates, the NSs in these systems are likely in the radio pulsar regime. In the interaction of the radio pulsar relativistic wind with matter transferred from the companion star, a shock forms, the power law-like emission of which powers both the harder X-ray emission and most of the residual optical/UV. The soft, thermal-like X-ray component may arise from the cooling of the NS surface. This scenario matches well both the X-ray and bolometric luminosity swing of LMXRTs. (ABRIDGED).Comment: 13 pages (including 2 postscript figures - use emulateapj macro). Accepted for publication in Ap

Alternate-Day Micafungin Antifungal Prophylaxis in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation: A Pharmacokinetic Study

Disseminated fungal infection is a major cause of morbidity and mortality in children undergoing hematopoietic stem cell transplantation (HSCT). Prophylaxis with amphotericin B can be limited by renal toxicity. Oral triazoles can be limited by poor absorption, large interindividual pharmacokinetic (PK) variability, and hepatic toxicity, leading to interruptions in therapy and breakthrough infections. Intravenous (i.v.) micafungin has potential advantages, because of its better safety profile, specifically in terms of hepatic and renal toxicity, and lack of drug-drug interactions with common medications used in the HSCT setting. We hypothesized that higher dose micafungin (3 mg/kg) every other day will provide drug exposure similar to standard dosing (1 mg/kg) given daily, and improve patient compliance in very young children in whom oral medications can be challenging, at reduced administration costs. Both animal and adult patient data support the use of this approach. Fifteen children (M/F = 11/4, aged ≤10 years; mean: 3.9 years, range: 0.6-10 years) with various hematologic, metabolic, and immune deficiency disorders undergoing HSCT received a single dose of micafungin (3 mg/kg) i.v. over 1 hour. Dose selection was based on published PK data in pediatric patients, and exploration of different dosing regimens using Monte Carlo PK/PD simulation. Blood samples were drawn around this dose and PK analysis was conducted using standard noncompartmental methods. Micafungin at 3 mg/kg dose was well tolerated in all patients. Measurable plasma concentrations were present in all cases at 48 hours. Half-life and clearance observed were comparable to previous pediatric PK data, with clearance being higher than adults as expected. Volume of distribution was higher in our patients compared to published pediatric data, likely because of a larger proportion of very young children in our study cohort. After correction for protein binding, concentrations at the end of the dosing interval during maintenance treatment remain above the minimum inhibitory concentration (MIC) of highly susceptible fungal pathogens. These data suggest that alternate day micafungin dosing, as described here, may provide an attractive alternative for antifungal prophylaxis in HSCT patients and merits further evaluation

The Noninvasive Urinary Polyomavirus Haufen Test Predicts BK Virus Nephropathy in Children After Hematopoietic Cell Transplantation: A Pilot Study

After hematopoietic cell transplantation (HCT), polyoma-BK virus is associated with hemorrhagic cystitis and also with polyomavirus nephropathy (PVN). However, the true burden of post-HCT PVN is unknown because kidney biopsies are avoided due to their bleeding risk. The novel, non-invasive urinary PV-Haufen test detects PVN in kidney transplant recipients with >95% positive/negative predictive values. We hypothesized that the detection of PV-Haufen in voided urine samples–a positive PV-Haufen test–was also clinically significant after HCT