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

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

Genome-wide association study of borderline personality disorder reveals genetic overlap with the bipolar disorder, schizophrenia and major depression

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of Bipolar Disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was: (i) to detect genes and gene-sets involved in BOR; and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, Major Depression (MDD) and Schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests,and gene-set-analyses were performed in 998 BOR patients and 1,545 controls. LD score regression was used to detect genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Genebased analysis yielded two significant genes: DPYD (p=4.42x10-7) and PKP4 (p=8.67x10-7); and gene-set-analysis yielded a significant finding for exocytosis (GO:0006887, pFDR=0.019). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [p=2.99x10-3]), SCZ (rg=0.34 [p=4.37x10-5]), and MDD (rg=0.57 [p=1.04x10-3]). Our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies

Genome-wide Association Study of Borderline Personality Disorder Reveals Genetic Overlap with Bipolar Disorder, Major Depression and Schizophrenia

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case–control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10−7) and PKP4 (P=8.67 × 10−7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10−3]), SCZ (rg=0.34 [P=4.37 × 10−5]) and MDD (rg=0.57 [P=1.04 × 10−3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies

Haematological consequences of acute uncomplicated falciparum malaria: a WorldWide Antimalarial Resistance Network pooled analysis of individual patient data

Background: Plasmodium falciparum malaria is associated with anaemia-related morbidity, attributable to host, parasite and drug factors. We quantified the haematological response following treatment of uncomplicated P. falciparum malaria to identify the factors associated with malarial anaemia. Methods: Individual patient data from eligible antimalarial efficacy studies of uncomplicated P. falciparum malaria, available through the WorldWide Antimalarial Resistance Network data repository prior to August 2015, were pooled using standardised methodology. The haematological response over time was quantified using a multivariable linear mixed effects model with nonlinear terms for time, and the model was then used to estimate the mean haemoglobin at day of nadir and day 7. Multivariable logistic regression quantified risk factors for moderately severe anaemia (haemoglobin < 7 g/dL) at day 0, day 3 and day 7 as well as a fractional fall ≥ 25% at day 3 and day 7. Results: A total of 70,226 patients, recruited into 200 studies between 1991 and 2013, were included in the analysis: 50,859 (72.4%) enrolled in Africa, 18,451 (26.3%) in Asia and 916 (1.3%) in South America. The median haemoglobin concentration at presentation was 9.9 g/dL (range 5.0–19.7 g/dL) in Africa, 11.6 g/dL (range 5.0–20.0 g/dL) in Asia and 12.3 g/dL (range 6.9–17.9 g/dL) in South America. Moderately severe anaemia (Hb < 7g/dl) was present in 8.4% (4284/50,859) of patients from Africa, 3.3% (606/18,451) from Asia and 0.1% (1/916) from South America. The nadir haemoglobin occurred on day 2 post treatment with a mean fall from baseline of 0.57 g/dL in Africa and 1.13 g/dL in Asia. Independent risk factors for moderately severe anaemia on day 7, in both Africa and Asia, included moderately severe anaemia at baseline (adjusted odds ratio (AOR) = 16.10 and AOR = 23.00, respectively), young age (age < 1 compared to ≥ 12 years AOR = 12.81 and AOR = 6.79, respectively), high parasitaemia (AOR = 1.78 and AOR = 1.58, respectively) and delayed parasite clearance (AOR = 2.44 and AOR = 2.59, respectively). In Asia, patients treated with an artemisinin-based regimen were at significantly greater risk of moderately severe anaemia on day 7 compared to those treated with a non-artemisinin-based regimen (AOR = 2.06 [95%CI 1.39–3.05], p < 0.001). Conclusions: In patients with uncomplicated P. falciparum malaria, the nadir haemoglobin occurs 2 days after starting treatment. Although artemisinin-based treatments increase the rate of parasite clearance, in Asia they are associated with a greater risk of anaemia during recovery

Atomic Energy Commission Report AECU-3152

Progress report includes reports on (1) The isolation of pyrimidine deoxynucleotides from the acid-soluble fraction of thymus; (2) Non-specific protective effect of small lead shields against the lethal effects of whole body irradiation in the rat; (3) Strain differences in response to whole body irradiation and shielding procedures in the rat; (4) Renal clearance procedures in an evaluation of the effects of X-irradiation on renal function in a rat. A preliminary report; (5) The plasma erythropoietic stimulating factor. Observations on circulation erythrocytes and bone marrow of rats receiving protein-free extracts of rabbit plasma; (6)Additional observations on the plasma erythropoietic stimulating factor; (7) Studies on Trichinella Spiralia, VI-IX. (8) Effect of gamma radiation on infectivity of ascaris eggs. (9) Preliminary report of studies on taeniasis. (10) Studies on the role of labile humoral factors in irradiation injury. (11) Services of the Radiation Physics Unit. (12) Biological and physical effects of low energy monochromatic X-rays