TREATMENT OF LEUKEMIA AND RELATED DISORDERS WITH 6-MERCAPTOPURINE

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74802/1/j.1749-6632.1954.tb40034.x.pd

The relative frequency of the several types of chronic leukemia and their management

One thousand one hundred and seventy-nine cases of leukemia in persons over the age of 13 years seen at the Simpson Memorial Institute of the University of Michigan, from 1927 through 1956, have been reviewed.Seven hundred and thirty-four cases were classified as chronic and 455 as acute.The ratio of acute to chronic cases has shown a steady rise during the period studied so that the incidence of acute leukemia seems to be definitely increasing.The incidence of all forms of chronic leukemia is probably increasing but the nature of the case selection in the present study precludes proof of this thesis.There is no evidence afforded by this series of cases that the relative frequency of chronic granulocytic leukemia and chronic lymphocytic leukemia is changing, or that there has been any change in sex distribution or age incidence in the chronic leukemias.Ionizing radiation continues to be the standard of reference when new forms of treatment for chronic leukemia are proposed, and it has not been conclusively demonstrated that survival times are increased or even equaled by the use of drugs in comparison with x-radiation or radioactive phosphorus. Nevertheless, chemotherapy has largely supplanted radiation in the treatment of chronic granulocytic and lymphocytic leukemias in this institution in recent years. With the passage of time and the enlargement of experience, the use of these therapeutic modalities has received increasing justification.The alkylating agents, Myleran, TEM, and chlorambucil, are the preferred forms of drug therapy for chronic leukemias.There is no evidence of a qualitative difference in biologic actions of these compounds, but there are quantitative variations which affect dosages, absorption rates, duration of effects, and likelihood of severe myeloid depression.At the present time, because of advantages of administration, dosage control, and relative safety, Myleran is generally preferred in chronic granulocytic leukemia and chlorambucil in chronic lymphocytic leukemia.Continuous drug administration on individually determined maintenance dosage has proved superior to intermittent courses of therapy in controlling activity of the leukemic process.Colcemide may be useful in some cases of advanced proliferative granulocytic leukemia and the antimetabolite, 6-mercaptopurine (Purinethol) may be employed in these situations.The adrenal cortical steroids are mainly of value in controlling secondary hemolysis and thrombocytopenia which occur in some patients with chronic lymphocytic leukemia and malignant reticuloendotheliosis. When satisfactory control of these manifestations cannot be established or maintained by hormonal therapy, splenectomy may be effective.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32499/1/0000586.pd

SOME OBSERVATIONS ON THE STIMULATION OF ERYTHROPOIESIS BY HUMORAL FACTORS

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71621/1/j.1749-6632.1959.tb36931.x.pd

Systems biology applications to study mechanisms of human immunodeficiency virus latency and reactivation

Eradication of human immunodeficiency virus (HIV) in infected individuals is currently not possible because of the presence of the persistent cellular reservoir of latent infection. The identification of HIV latency biomarkers and a better understanding of the molecular mechanisms contributing to regulation of HIV expression might provide essential tools to eliminate these latently infected cells. This review aims at summarizing gene expression profiling and systems biology applications to studies of HIV latency and eradication. Studies comparing gene expression in latently infected and uninfected cells identify candidate latency biomarkers and novel mechanisms of latency control. Studies that profiled gene expression changes induced by existing latency reversing agents (LRAs) highlight uniting themes driving HIV reactivation and novel mechanisms that contribute to regulation of HIV expression by different LRAs. Among the reviewed gene expression studies, the common approaches included identification of differentially expressed genes and gene functional category assessment. Integration of transcriptomic data with other biological data types is presently scarce, and the field would benefit from increased adoption of these methods in future studies. In addition, designing prospective studies that use the same methods of data acquisition and statistical analyses will facilitate a more reliable identification of latency biomarkers using different model systems and the comparison of the effects of different LRAs on host factors with a role in HIV reactivation. The results from such studies would have the potential to significantly impact the process by which candidate drugs are selected and combined for future evaluations and advancement to clinical trials

Panel Discussion On The Clinical Management Of Blood Dyscrasias In The Older Age Group†

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111245/1/jgs00338.pd

Dust heating by the interstellar radiation field in models of turbulent molecular clouds

We have calculated the radiation field, dust grain temperatures, and far infrared emissivity of numerical models of turbulent molecular clouds. When compared to a uniform cloud of the same mean optical depth, most of the volume inside the turbulent cloud is brighter, but most of the mass is darker. There is little mean attenuation from center to edge, and clumping causes the radiation field to be somewhat bluer. There is also a large dispersion, typically by a few orders of magnitude, of all quantities relative to their means. However, despite the scatter, the 850 micron emission maps are well correlated with surface density. The fraction of mass as a function of intensity can be reproduced by a simple hierarchical model of density structure.Comment: 32 pages, 14 figures, submitted to Ap

Long non-coding RNAs and latent HIV : a search for novel targets for latency reversal

The latent cellular reservoir of HIV is recognized as the major barrier to cure from HIV infection. Long non-coding RNAs (lncRNAs) are more tissue and cell type-specific than protein coding genes, and may represent targets of choice for HIV latency reversal. Using two in vitro primary T-cell models, we identified lncRNAs dysregulated in latency. PVT1 and RP11-347C18.3 were up-regulated in common between the two models, and RP11-539L10.2 was down-regulated. The major component of the latent HIV reservoir, memory CD4+ T-cells, had higher expression of these lncRNAs, compared to naive T-cells. Guilt-by-association analysis demonstrated that lncRNAs dysregulated in latency were associated with several cellular pathways implicated in HIV latency establishment and maintenance: proteasome, spliceosome, p53 signaling, and mammalian target of rapamycin (MTOR). PVT1, RP11-347C18.3, and RP11-539L10.2 were down-regulated by latency reversing agents, suberoylanilide hydroxamic acid and Romidepsin, suggesting that modulation of lncRNAs is a possible secondary mechanism of action of these compounds. These results will facilitate prioritization of lncRNAs for evaluation as targets for HIV latency reversal. Importantly, our study provides insights into regulatory function of lncRNA during latent HIV infection

Statistical Assessment of Shapes and Magnetic Field Orientations in Molecular Clouds through Polarization Observations

We present a novel statistical analysis aimed at deriving the intrinsic shapes and magnetic field orientations of molecular clouds using dust emission and polarization observations by the Hertz polarimeter. Our observables are the aspect ratio of the projected plane-of-the-sky cloud image, and the angle between the mean direction of the plane-of-the-sky component of the magnetic field and the short axis of the cloud image. To overcome projection effects due to the unknown orientation of the line-of-sight, we combine observations from 24 clouds, assuming that line-of-sight orientations are random and all are equally probable. Through a weighted least-squares analysis, we find that the best-fit intrinsic cloud shape describing our sample is an oblate disk with only small degrees of triaxiality. The best-fit intrinsic magnetic field orientation is close to the direction of the shortest cloud axis, with small (~24 deg) deviations toward the long/middle cloud axes. However, due to the small number of observed clouds, the power of our analysis to reject alternative configurations is limited.Comment: 14 pages, 8 figures, accepted for publication in MNRA

A “How-To” Guide for Designing Judgment Bias Studies to Assess Captive Animal Welfare

Robust methods to assess nonhuman animal emotion are essential for ensuring good welfare in captivity. Cognitive bias measures such as the judgment bias task have recently emerged as promising tools to assess animal emotion. The simple design and objective response measures make judgment bias tasks suitable for use across species and contexts. In reviewing 64 studies published to date, it emerged that (a) judgment biases have been measured in a number of mammals and birds and an invertebrate; (b) no study has tested judgment bias in any species of fish, amphibian, or reptile; and (c) no study has yet investigated judgment bias in a zoo or aquarium. This article proposes that judgment bias measures are highly suitable for use with these understudied taxa and can provide new insight into welfare in endangered species housed in zoos and aquariums, where poor welfare impacts breeding success and, ultimately, species survival. The article includes a “how-to” guide to designing judgment bias tests with recommendations for working with currently neglected “exotics” including fishes, amphibians, and reptiles

Effect of implementing a heart failure admission care bundle on hospital readmission and mortality rates: interrupted time series study

This study aimed to evaluate the impact of developing and implementing a care bundle intervention to improve care for patients with acute heart failure admitted to a large London hospital. The intervention comprised three elements, targeted within 24 hours of admission: N-terminal pro-B-type natriuretic peptide (NT-proBNP) test, transthoracic Doppler two-dimensional echocardiography and specialist review by cardiology team. The SHIFT-Evidence approach to quality improvement was used. During implementation, July 2015–July 2017, 1169 patients received the intervention. An interrupted time series design was used to evaluate impact on patient outcomes, including 15 618 admissions for 8951 patients. Mixed-effects multiple Poisson and log-linear regression models were fitted for count and continuous outcomes, respectively. Effect sizes are slope change ratios pre-intervention and post-intervention. The intervention was associated with reductions in emergency readmissions between 7 and 90 days (0.98, 95% CI 0.97 to 1.00), although not readmissions between 0 and 7 days post-discharge. Improvements were seen in in-hospital mortality (0.96, 95% CI 0.95 to 0.98), and there was no change in trend for hospital length of stay. Care process changes were also evaluated. Compliance with NT-proBNP testing was already high in 2014/2015 (162 of 163, 99.4%) and decreased slightly, with increased numbers audited, to 2016/2017 (1082 of 1101, 98.2%). Over this period, rates of echocardiography (84.7–98.9%) and specialist input (51.6–90.4%) improved. Care quality and outcomes can be improved for patients with acute heart failure using a care bundle approach. A systematic approach to quality improvement, and robust evaluation design, can be beneficial in supporting successful improvement and learning