Michael P. Hurley

Differential regulation of myeloid leukemias by the bone marrow microenvironment

Like their normal hematopoietic stem cell counterparts, leukemia stem cells (LSCs) in chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) are presumed to reside in specific niches in the bone marrow microenvironment (BMM) and may be the cause of relapse following chemotherapy. Targeting the niche is a new strategy to eliminate persistent and drug-resistant LSCs. CD44 (refs. 3,4) and interleukin-6 (ref. 5) have been implicated previously in the LSC niche. Transforming growth factor-β1 (TGF-β1) is released during bone remodeling and plays a part in maintenance of CML LSCs, but a role for TGF-β1 from the BMM has not been defined. Here, we show that alteration of the BMM by osteoblastic cell–specific activation of the parathyroid hormone (PTH) receptor attenuates BCR-ABL1 oncogene–induced CML-like myeloproliferative neoplasia (MPN) but enhances MLL-AF9 oncogene–induced AML in mouse transplantation models, possibly through opposing effects of increased TGF-β1 on the respective LSCs. PTH treatment caused a 15-fold decrease in LSCs in wild-type mice with CML-like MPN and reduced engraftment of immune-deficient mice with primary human CML cells. These results demonstrate that LSC niches in CML and AML are distinct and suggest that modulation of the BMM by PTH may be a feasible strategy to reduce LSCs, a prerequisite for the cure of CML.

Array Analysis of Viral Gene Transcription during Lytic Infection of Cells in Tissue Culture with Varicella-Zoster Virus

ABSTRACT Varicella-zoster virus (VZV), a neurotropic alphaherpesvirus, causes childhood chickenpox (varicella), becomes latent in dorsal root and autonomic ganglia, and reactivates decades later to cause shingles (zoster) and other neurologic complications. Although the sequence and configuration of VZV DNA have been determined, relatively little is known about viral gene expression in productively infected cells. This is in part because VZV is highly cell associated, and sufficient titers of cell-free virus for use in synchronizing infection do not develop. PCR-based transcriptional arrays were constructed to simultaneously determine the relative abundance of the ≈70 predicted VZV open reading frames (ORFs). Fragments (250 to 600 bp) from the 5′ and 3′ end of each ORF were PCR amplified and inserted into plasmid vectors. The virus DNA inserts were amplified, quantitated, and spotted onto nylon membranes. Probing the arrays with radiolabeled cDNA synthesized from VZV-infected cells revealed an increase in the magnitude of the expressed VZV genes from days 1 to 3 after low-multiplicity virus infection but little change in their relative abundance. The most abundant VZV transcripts mapped to ORFs 9/9A, 64, 33/33A, and 49, of which only ORF 9 corresponded to a previously identified structural gene. Array analysis also mapped transcripts to three large intergenic regions previously thought to be transcriptionally silent, results subsequently confirmed by Northern blot and reverse transcription-PCR analysis. Array analysis provides a formidable tool to analyze transcription of an important ubiquitous human pathogen.

Cost-effectiveness of preoperative imaging for appendicitis after indeterminate ultrasonography in the second or third trimester of pregnancy.

OBJECTIVE: To assess the cost-effectiveness of diagnostic laparoscopy, computed tomography (CT), and magnetic resonance imaging (MRI) after indeterminate ultrasonography in pregnant women with suspected appendicitis. METHODS: A decision-analytic model was developed to simulate appendicitis during pregnancy taking into consideration the health outcomes for both the pregnant women and developing fetuses. Strategies included diagnostic laparoscopy, CT, and MRI. Outcomes included positive appendectomy, negative appendectomy, maternal perioperative complications, preterm delivery, fetal loss, childhood cancer, lifetime costs, discounted life expectancy, and incremental cost-effectiveness ratios. RESULTS: Magnetic resonance imaging is the most cost-effective strategy, costing

Altitude and the risk of cardiovascular events in incident US dialysis patients

6,767 per quality-adjusted life-year gained relative to CT, well below the generally accepted

Comorbidities and kidney transplant evaluation in the elderly.

50,000 per quality-adjusted life-year threshold. In a setting where MRI is unavailable, CT is cost-effective even when considering the increased risk of radiation-associated childhood cancer (

The impact of carperitide usage on the cost of hospitalization and outcome in patients with acute heart failure: High value care vs. low value care campaign in Japan

560 per quality-adjusted life-year gained relative to diagnostic laparoscopy). Unless the negative appendectomy rate is less than 1%, imaging of any type is more cost-effective than proceeding directly to diagnostic laparoscopy. CONCLUSIONS: Depending on imaging costs and resource availability, both CT and MRI are potentially cost-effective. The risk of radiation-associated childhood cancer from CT has little effect on population-level outcomes or cost-effectiveness but is a concern for individual patients. For pregnant women with suspected appendicitis, an extremely high level of clinical diagnostic certainty must be reached before proceeding to operation without preoperative imaging.

Adding Insult to Injury: Discontinuous Insurance Following Spine Trauma

BACKGROUND Altitude is associated with all-cause mortality in US dialysis patients, but its association with cardiovascular outcomes has not been assessed. We hypothesized that higher altitude would be associated with lower rates of cardiovascular events due to an altered physiological response of dialysis patients to altitude induced hypoxia. METHODS We studied 984,265 patients who initiated dialysis from 1995 to 2006. Patients were stratified by the mean elevation of their residential zip codes and were followed from the start of dialysis to the occurrence of several validated cardiovascular endpoints: myocardial infarction, stroke, cardiovascular death and a composite of these end points. Incidence rate ratios across altitude strata were estimated using proportional hazards regression. RESULTS All outcomes occurred less frequently among patients living at higher altitude compared with patients living at or near sea level, and the association appeared monotonic for all outcomes except for stroke, which was most incident in the 250-1999 ft group. Compared with otherwise similar patients residing at or near sea level, patients living at ≥ 6000 ft had 31% [95% confidence interval (CI): 21-41%] lower rates of myocardial infarction, 27% (95% CI: 15-37%) lower rates of stroke and 19% (95% CI: 14-24%) lower rates of cardiovascular death. Additional adjustment for biometric information did not materially change these findings. Effect modification between race and altitude was only consistently significant for Native Americans. Altitude did not significantly alter the rates of non-cardiovascular death. CONCLUSION We conclude that dialysis patients at higher altitude experience lower rates of cardiovascular events compared to otherwise similar patients at lower altitude.

Characterizing the Relationship Between Free Drug Samples and Prescription Patterns for Acne Vulgaris and Rosacea

Background/Aims: The elderly are the fastest growing subpopulation with end-stage renal disease. The goal of our study was to define characteristics of elderly patients who were considered ineligible for transplantation compared to those who were listed. Methods: 984 patients were referred for evaluation during a 2-year period. Records of patients ≥65 years of age (n = 123) were reviewed. Patients who were listed versus not listed were characterized. Factors associated with waitlisting were determined using standard statistical tools. Results: Half of elderly transplant candidates were accepted for listing compared to 75.4% of those aged <65 years. In multivariable logistic regression, older age (OR 1.29 per year ≥65, 95% CI 1.14-1.45), coronary artery disease (OR 8.57, 95% CI 2.41-30.53), and poor mobility (OR 13.97, 95% CI 4.76-41.00) were independently associated with denial of listing. The receiver operating characteristic curve showed good discrimination for denial of listing (area under the receiver operating characteristic curve of 0.88). Conclusion: Elderly candidates carry a heavy burden of comorbidities and over half of those evaluated are deemed unsuitable for waitlisting. Better delineation of characteristics associated with suitability for transplant candidacy in the elderly is warranted to facilitate appropriate referrals by physicians and management of expectations in potential candidates.

Supine Exercise Echocardiographic Measures of Systolic and Diastolic Function in Children

BACKGROUND The usefulness of carperitide in patients with acute heart failure (AHF) has not been confirmed; carperitide is expensive, and thus, its routine use has not been shown to add much value in clinical settings. We analyzed the impact of carperitide usage on the outcome and cost of hospitalization in AHF patients. METHODS Data obtained from the Diagnosis Procedure Combination (DPC) database from July 2014 until June 2015 from 371 hospitals were analyzed. Emergent patients with acute heart failure (ICD code I50* and DPC code 050130) who did not undergo any surgical procedures were enrolled. We compared the outcomes and cost between the carperitide group and non-carperitide group using propensity score matched analysis. RESULTS In 37,891 heart failure patients (52.2% male; 79.2±11.9years), 13,421 pairs were selected according to the propensity score matching. In-hospital death occurred more frequently in the carperitide group (n=997; 7.4%) than in the non-carperitide group (n=844; 6.3%; p<0.01). Carperitide use was also related with higher costs of hospitalizations, and total dose of carperitide administered during hospitalization decreased with the increasing case volume (p<0.01). On the other hand, carperitide usage was frequently recognized in hospitals with larger annual case volumes (32.1%, Q1; 37.3%, Q2; 40.7%, Q3, p-value<0.01). CONCLUSIONS Carperitide usage negatively affected patient outcomes and cost of hospitalization. In hospitals with lower annual case volume, clinicians should pay attention to the total dose and duration of carperitide. On the other hand, in hospitals with larger annual case volumes, clinicians should pay attention to the thresholds/indications to prescribe carperitide in AHF patients.

Parathyroid Hormone-Induced Modulation of the Bone Marrow Microenvironment Reduces Leukemic Stem Cells in Murine Chronic Myelogenous-Leukemia-Like Disease Via a TGFbeta-Dependent Pathway

BACKGROUND Spine trauma patients may represent a group for whom insurance fails to provide protection from catastrophic medical expenses, resulting in the transfer of financial burden onto individual families and public payers. This study compares the rate of insurance discontinuation for patients who underwent surgery for traumatic spine injury with and without spinal cord injury with the rate for matched control subjects. METHODS We used the MarketScan database to perform a retrospective cohort study of privately insured spine trauma patients who underwent surgery from 2006 to 2010. Kaplan-Meier survival analysis was used to assess the time to insurance discontinuation. Cox proportional-hazards regression was used to determine hazard ratios for insurance discontinuation among spine trauma patients compared with the matched control population. RESULTS The median duration of existing insurance coverage was 20.2 months for those with traumatic spinal cord injury, 25.6 months for those with traumatic spine injury without spinal cord injury, and 48.0 months for the matched control cohort (log-rank p < 0.0001). After controlling for multiple covariates, the hazard ratios for discontinuation of insurance were 2.02 (95% CI [confidence interval], 1.83 to 2.23) and 2.78 (95% CI, 2.31 to 3.35) for the trauma patients without and with spinal cord injury, respectively, compared with matched controls. CONCLUSIONS Rates of insurance discontinuation are significantly higher for trauma patients with severe spine injury compared with the uninjured population, indicating that patients with disabling injuries are at increased risk for loss of insurance coverage.