Showing papers in "Transactions of the Association of American Physicians in 1977"

Use of propranolol in the treatment of idiopathic orthostatic hypotension.

Abstract: Five patients with idiopathic orthostatic hypotension who had physiologic and biochemical evidence of severe autonomic dysfunction were included in the study. They all exhibited markedly reduced plasma catecholamines and plasma renin activity in both recumbent and upright positions and had marked hypersensitivity to the pressor effects of infused norepinephrine. Treatment with propanolol administered intravenously (1-5 mg) produced increases in supine and upright blood pressure in 4 of the 5 individuals with rises ranging from 11/6 to 22/11 mmHg. Chronic oral administration of propranolol (40-160 mg/day) also elevated the blood pressures of these individuals with increases in the order of 20-35/15-25 mmg being observed. In 1 patient, marked hypertension was induced by propranolol and the drug had to be withdrawn. It otherwise was well tolerated and no important side effects were observed. Treatment has been continued in 3 individuals for 6-13 months with persistence of the pressor effect, although there appears to have been some decrease in the degree of response with time. Hemodynamic measurements in 1 of the patients demonstrated an increase in total peripheral resistance and essentially no change in cardiac output following propranolol therapy. The studies suggest that propranolol is a useful drug in selected patients with severe idiopathic orthostatic hypotension.

The hypereosinophilic syndrome: dramatic response to therapeutic intervention.

Abstract: The Hypereosinophilic Syndrome (HES) is a disease of unknown etiology and pathogenesis characterized by blood and bone marrow eosinophilia associated with infiltration of eosinophils into tissues and multi-system organ dysfunction. Patients with HES historically have very significant morbidity and a high mortality of 77% at 3 years. This study is a prospective (9 years) and retrospective (24 years) analysis of the therapy and prognosis of 26 patients with HES. Five patients (19%) showed no evidence of progressive organ system dysfunction and were given no therapy; all have done well. Sixteen patients with progressive organ dysfunction were treated with corticosteroids; 6 of the 16 (38%) had a good response and required no further therapy. Six of 8 patients who were corticosteroid unresponsive and had serious prognostic signs had excellent responses to hydroxyurea therapy, while 2 patients showed partial responses. Employing the above regimen, we have demonstrated that our 26 patients (including 12 with poor prognostic indicators) have a marked increase in survival (3 year mortality 4%) when compared with the historical control.

A system of cancer-related urinary glycoproteins: biochemical properties and clinical applications.

Abstract: UNLABELLED Gel-filtration and immunodiffusion reveal most patients with disseminated cancer excrete 100 to 1000 mg/day of urine proteins, mol wt 10,000-60,000, which are distinct from known plasma proteins and cancer-related antigens. By gel-filtration and ion-exchange chromatography, 5 novel urinary glycoproteins have been isolated which are responsible for about 1/2 the mass of the "low molecular weight proteinuria" of patients with advanced cancer: BJC1 and BJC2 (patient B.J., chronic myelocytic leukemia); JBB5 (J.B., metastatic pancreatic carcinoma); EDC1 (E.D., acute myelocytic leukemia); HNC1beta (H.N., acute monocytic leukemia). Mol wts respectively are 29,000, 22,000, 55,000, 27,000 and 33,000, and carbohydrate contents respectively 61%, 23%, 23%, 27% and 40%. Attention to date has focussed on EDC1 and HNC1beta, because their urinary excretion directly reflects the course of the neoplastic disease. EDC1 and HNC1beta possess the same protein but different carbohydrate moieties. They are antigenically related to inter-alpha trypsin inhibitor, mol wt 160,000, which is one of the 6 antiproteolytic proteins in normal human plasma. EDC1 and HNC1beta both possess antitryptic activity. Specific radioimmunoassays (RIA) to these 2 glycoproteins were developed. Normal individuals (n = 210) excreted 0.3 +/- .02 (ave. +/- SE) mg EDC1 per g creatinine. In 18 non-neoplastic diseases (n = 75), urinary EDC1 was .5 +/- .06 mg/g creatinine. In disseminated cancer of 7 types (n = 81) (breast, ovary, colon, squamous of head-neck and lung; melanoma; acute myelocytic leukemia), ave. EDC1 excretion ranged from 10 to 190 mg/g creatinine. A significant increase (P less than .05) was found in the localized stage of squamous cancer of head-neck-lung, but only after regional or distant spread in the other types. Similar results were found with HNC1beta, urinary excretion of which averaged 1/10 that of EDC1. Effective chemotherapy in 5 patients with leukemia or solid tumors caused prompt disappearance of urinary EDC1; the glyco-protein reappeared in the urine several weeks before clinical relapse. CONCLUSIONS (i) EDC1- and HNC1beta-proteinuria is a useful indicator of some types of localized and most types of disseminated cancer; (ii) the degree of this proteinuria reflects the effectiveness of chemotherapy; (iii) the antiproteolytic property of EDC1 and HNC1beta suggests a relation between proteolysis and tumorigenesis.

Carrier-mediated taurine uptake in the fetal mouse heart.

Abstract: Myocardial taurine concentrations have been found to be elevated in hypertension and congestive heart failure states in animals and humans. The mechanism(s) by which myocardial taurine levels increase isn't known. Biosynthesis of taurine by the heart has not been established as a significant process. The fetal mouse heart in culture was used to characterize a taurine uptake system. The uptake of taurine was found to be saturable, temperature and sodium dependent and inhibited by close structural analogs. Taurine uptake was energy dependent and accumulated taurine against a concentration gradient indicating that taurine transport is an active process. Failure of alpha-alanine, alpha-aminoisobutyric acid, glycine, leucine or threonine to decrease taurine uptake establishes that the taurine uptake system is separate and distinct from other neutral alpha-amino acid transport systems in the heart.

The immediate pressor response to saralasin: a measure of the degree of angiotensin II vascular receptor vacancy.

Abstract: (1) An immediate pressor response so saralasin, 10 microgram/kg/min, occurred in 52 of 57 (91%) hypertensive patients. (2) We propose that the amplitude of the immediate pressor response functions as an in vivo measure of the number of initially vacan angiotensin II vascular receptors. (3) The immediate pressor response to saralasin forecasts the subsequent sustained response, both of which are related to the renin-sodium profile. (4) The dual blood pressure responses to saralasin, immediate and sustained, make this drug useful for the pharmacological identification of high, normal, and low renin hypertensive patients as they are presently classified. (5) The ability of saralasin to elevate the BP immediately in most hypertensive patients shows the need for caution in its use. It is a safe drug from this standpoint if very small infusions (0.01-0.10 microgram/kg/min) are first tried in hypertensive patients whose PRA is unknown.

Treatment of breast cancer with antiestrogen: approach to medical hypophysectomy?

Abstract: Tamoxifen (ICI 46474), an antiestrogen, was given to 89 selected patients with stage IV breast cancer at a dose of 20 mg orally every 12 hours Forty-seven percent of the patients had objective tumor regression averaging 11+ months with 25 of 42 women still in remission In the first 39 patients where the minimum follow-up period is 16 months the average duration of remission is more than 15 months with 8 of 19 patients still in remission These results are approaching those of surgical hypophysectomy, where, in our experience the average remission lasts about 18 months Thus, Tamoxifen is a highly effective antitumor agent and is probably the initial treatment of choice for women with hormone responsive breast cancer Antiestrogen induced objective remissions in 5 of 19 patients who had previously responded to surgical hypophysectomy, and 5 additional patients showed no progression of disease lasting 15+ months Estradiol and estrone were detectable in the serum of these patients whereas, prolactin and growth hormone were not detectable Thus, antiestrogen can induce remissions in some patients in the absence of the pituitary gland, and this constitutes additional palliation and provides evidence that estrogens can directly stimulate tumor growth Four of 7 patients who obtained remissions from Tamoxifen obtained further improvement from hypophysectomy, and 1 of 8 patients who failed to benefit from antiestrogen improved after hypophysectomy These results suggest that prolactin and growth hormone may also play a role in stimulating tumor growth in some patients

Nucleotide sequence of a human gene coding for a polypeptide hormone

Abstract: In summary, a general approach is presented to purify and sequence DNA fragments of a specific gene starting with a heterogeneous mixture of mRNAs. The methodology has been applied to the determination of the DNA sequence of a portion of the gene for human chorionic somatomammotropin. Most of the possible translation codons of the genetic code were found to be used. Some selectivity in the codon choices was found, and this may be important for RNA or gene regulation or structure. The stop codon UAG was found and a second stop codon in the same reading frame was found nine bases farther down. Finally, a "palindrome" sequence was detected in the 3' noncoding region.

The parasinusoidal location of megakaryocytes in marrow: a determinant of platelet release and a physiologic version of vascular invasion and metastasis.

Abstract: Our observations confirm the supposition of others that megakaryocytes in marrow are not randomly positioned. They reside in proximity to vascular sinuses. Platelet release occurs, at least in part, through penetration of the endothelial cell of the vascular sinus wall by megakaryocyte cytoplasmic processes. Platelets are released into the marrow sinus as packets of demarcating megakaryocyte cytoplasm that presumably undergo further maturation into single platelets in the circulation. The initial probing into the abluminal surface of endothelial cells by megakaryocyte cytoplasm is similar to the penetration of tumor cells in experimental models into the luminal surface of endothelial cells. Platelet release and circulation may be a physiologic version of vascular invasion and metastasis. Further studies of this process may provide important insights into cell-cell interactions.

Immunoglobulin production by human-mouse somatic cell hybrids.

Abstract: Studies on immunoglobulin production in human-mouse somatic cell hybrids suggest: 1. The structural genes for heavy chain immunoglobulins are carried on chromsome 6, probably on the short arm or the proximal half of the long arm of the chromosome. 2. The structural gene for kappa light chain immunoglobulin may be carried on chromsome 11. 3. The occurrence of immunoglobulin molecules on the cell surface requires the presence of chromosome 2.

The George M. Kober lecture: a genetical view of modern medicine.

Abstract: A genetic approach to medicine provides a powerful concept for understanding of the etiology of many diseases. Significant investigative and therapeutic advances have already been made in the chromosomal and Mendelian diseases using genetic concepts which initially were discovered completely unrelated to medicine. The combination of unfettered basic biomedical research together with family and population studies is likely to bring new insights to understanding, prevention and treatment of the yet poorly understood multifactorial diseases which represent the greatest public health problems in the Western world. Identification of specific genes involved in susceptibility and resistance to these diseases and their interaction with various environmental factors will allow a more rational preventive medicine in the future.

Structure of human hemoglobin messenger RNA and its relation to hemoglobinopathies.

Abstract: 1. One-fifth to 1/4 of globin mRNA is untranslated sequence other than polyadenylic acid. 2. The untranslated sequences of mRNA vary markedly in their sequence and in their length. 3. Globin mRNAs demonstrate a marked bias in codon selection. 4. Viral mRNA shows a quite different pattern of codon selection; therefore, the selection of codons is not uniform for all mRNAs functioning in animal cells. 5. Elongated hemoglobin chains can be accounted for by frame-shift mutations, or point mutations within the normal termination codon. The additional amino acids are then coded for by sequences that are normally untranslated. 6. Certain hemoglobin deletion mutants occur at sites where there are partially reiterated sequences within the heomoglobin messenger RNA.