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Biomedical subjects

L Shulman

Publications and source records attributed to L Shulman.

17 recordsLinked to original sources

Effect of low-calorie diets on the sympathetic nervous system, body weight, and plasma insulin in overweight hypertension.

When weight reduction was found to decrease blood pressure in the overweight hypertensive patient, it was hailed as the causative factor. A growing number of recent studies indicate that this association may be secondary to a correlation between diet-associated metabolic change and the sympathetic nervous system. A select group such as overweight hypertensive patients may have a genetic predisposition for such a correlation. In overweight hypertensive patients, low-calorie diet and especially very-low-calorie diet, correlate with improved glucose metabolism, a decrease in plasma insulin concentration, and altered norepinephrine concentrations and thus sympathetic nervous system activity. Several of these studies also show a lack of effect of salt intake on blood pressure. Thus, it seems that metabolic changes caused by the decrease in caloric intake are responsible for the decrease in blood pressure. These must be investigated to understand the effect of the different diets on blood pressure. Very low-calorie diets were found very useful in breaking the vicious circle of severe nonresponsive hypertension to medication.

Blood Pressure

Combination of etanidazole with cyclophosphamide and platinum complexes.

In an effort to improve the therapeutic efficacy and selectivity of cyclophosphamide (CTX), cis-diamminedichloroplatinum(II) (CDDP), and carboplatin (Carbo), these antitumor alkylating agents were combined with the 2-nitroimidazole drug etanidazole (ETA). As revealed by tumor-cell survival assay in the FSaIIC murine fibrosarcoma, the addition of ETA (1 g/kg, i.p.) just prior to the i.p. injection of various doses of the alkylating agents resulted in increases in the tumor-cell kill produced by each drug (CTX, 10-fold; CDDP, 20-fold; and Carbo, 5- to 15-fold), whereas toxicity to bone marrow granulocyte-macrophage colony-forming units (CFU-GM) increased only about 0- to 3-fold. When CTX was combined with either CDDP or Carbo, striking increases in tumor-cell killing were observed (20- to 100-fold across the CDDP dose range and 5- to 20-fold across the dose range of Carbo), which were supra-additive for CDDP and additive for Carbo as revealed by isobologram analysis. The addition of ETA to these alkylating-agent combinations produced a further approx. 20-fold increase in tumor-cell kill for both CTX/CDDP and CTX/Carbo. This effect was greatest at the lowest dose of the platinum drug tested and was supra-additive in the case of CDDP and additive for Carbo. Following treatment with ETA/CTX/CDDP, bone marrow CFU-GM toxicity increased only about 5-fold over that of CTX/CDDP alone, but the injection of ETA/CTX/Carbo resulted in a 10- to 20-fold increase in bone marrow toxicity as compared with that obtained using CTX/Carbo alone. Tumor growth-delay studies revealed significant increases in the antitumor effect of the alkylating agents when these were given in combination with ETA. Both the ETA/CTX/CDDP and the ETA/CTX/Carbo combinations produced tumor growth delays of 23 days, which represented approx. 1.6-fold increases over those obtained using the alkylating-agent combinations alone. These results suggest that ETA could significantly improve the therapeutic efficacy of these alkylating agents, whether they are given individually or in combination.

Animals

Fetal cells in the maternal circulation: isolation by multiparameter flow cytometry and confirmation by polymerase chain reaction.

During pregnancy, nucleated fetal erythrocytes enter the maternal circulation and can be isolated efficiently from the maternal cells by multiparameter flow cytometry. Male DNA, implying presence of a male fetus, can be identified in flow-sorted maternal blood by polymerase chain reaction with oligonucleotide primers flanking single-copy Y-specific DNA sequences. Among flow-sorted samples, we correctly identified fetal sex in 17/18 (94%) pregnancies of 10-21 weeks gestation. Maternal blood thus provides a potential opportunity for prenatal diagnosis that could preclude the need for invasive procedures in current use.

Base Sequence

Growth hormone therapy.

Growth hormone from human pituitary glands has been available for 30 years. Because of the scarce supply and the danger of transmitting Creutzfeldt-Jakob disease, use of the hormone was discontinued in 1984. Fortunately, synthetic growth hormone produced with recombinant DNA technology became available in 1985 and eliminated the risk of Creutzfeldt-Jakob disease. Growth hormone is approved for use in the treatment of pituitary deficiency syndromes and, when properly administered at an early stage, is capable of inducing normal skeletal and muscular development. It also has been successfully used to augment growth in patients with Turner's syndrome or constitutional growth delay not associated with obvious growth hormone defects. Side effects are generally not serious, but antibodies to growth hormone develop in about 30 percent of patients.

Growth Disorders

The interferon-induced protein kinase PK-i from mouse L cells.

Interferon-treated L cells are characterized by an increased protein kinase activity that can selectively phosphorylate the small subunit of eukaryotic initiation factor 2. This protein kinase, PK-i, has been extensively purified and shown to be a potent inhibitor of mRNA translation. The purified PK-i contains the endogenously phosphorylated 67,000 Mr protein characteristic of interferon-treated cell extracts. PK-i can also phosphorylate arginine-rich histones. Purified PK-i can be activated by preincubation with ATP (but not adenylyl imidodiphosphate) and low concentrations of double-stranded RNA. The activation results in an increase in the first rate of eIF-2 phosphorylation. Activated PK-i becomes resistant to high concentrations of double-stranded RNA and more thermostable. A stimulator of PK-i activity, factor A, was isolated, as well as a specific phosphoprotein phosphatase that dephosphorylates the 67,000 Mr protein and eIF-2. These two factors, which are present in untreated L cells, may regulate the translation inhibitory activity of the interferon-induced and double-stranded RNA-activated protein kinase PK-i.

Animals

An interferon-induced phosphodiesterase degrading (2'-5') oligoisoadenylate and the C-C-A terminus of tRNA.

A phosphodiesterase characterized by a generally higher activity on 2'-5' than on 3'-5' phosphodiester bonds was isolated from mouse L cells treated with interferon. A similar enzyme was purified from mouse reticulocytes. The phosphodiesterase 2'-PDi splits the 2'-phosphate bond of pppA2'p5'A2'p5'A, the oligonucleotide activator of ribonuclease F. The level of phosphodiesterase 2'-PDi is increased by interferon treatment of L cells. The phosphodiesterase was also shown to degrade the C-C-A terminus of tRNA and to reduce the amino acid acceptance of tRNA in cell-free extracts, thereby causing a tRNA-reversible inhibition of mRNA translation.

Amino Acyl-tRNA Synthetases

Kinetics of the induction of three translation-regulatory enzymes by interferon.

Three enzymes that cause inhibition of mRNA translation, eukaryotic initiation factor 2 protein kinase PK-i, oligoisoadenylate synthetase E, and phosphodiesterase 2'-PDi, have been recently isolated from interferon-treated cells. We show that the rise in these three enzyme activities may be used to study the response of uninfected cells to interferon. For each enzyme, a specific microassay that can be carried out on extracts from 2-5 x 10(4) monolayer cells from mouse, monkey, or man was developed. With these assays, the kinetics of induction of the three enzymes in mouse L cells are compared. The dose dependence for protein kinase PK-i induction is shown to be similar to that for the development of the antiviral state. Actinomycin D and anti-interferon serum block enzyme induction if added to the cells early after interferon treatment. The quantitative measurements of the intracellular level of these enzymes provide a new and convenient model to study the cell's response to interferon.

Adenine Nucleotides

Drug abuse--a major public health hazard.

An attempt is made to reveal the escalation of drug abuse in our community as a public health hazard, to initiate the concept of a team approach as the only way to provide early effective treatment, and also to develop preventive measures as the necessary alternative to ostracism and punishment.

Ethanol

Presence of human chromosome 21 alone is sufficient for hybrid cell sensitivity to human interferon.

Human/mouse somatic cell hybrids with chromosome 21 as the only detectable human genetic material were sensitive to both human leukocyte and fibroblast interferons. The presence of additional human chromosomes decreased the amount of interferon needed to attain a given level of virus resistance. Decreased cytopathic effects, decreased virus yields, and the appearance of a specific phosphorylated protein associated with interferon treatment were all observed in hybrids maintaining only human chromosome 21. The phosphorylated protein found in extracts of these human interferon-treated hybrid cells was of mouse origin.

Animals

Discharge planning.

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Adaptation, Psychological