Showing papers by "National Institutes of Health published in 1973"
TL;DR: Anfinsen as discussed by the authors provided a sketch of the rich history of research that provided the foundation for his work on protein folding and the Thermodynamic Hypothesis, and outlined potential avenues of current and future scientific exploration.
Abstract: Stanford Moore, William Stein, and Anfinsen were awarded the Nobel Prize in Chemistry in 1972 for \"their contribution
to the understanding of the connection between chemical structure and catalytic activity of the active center of the ribonuclease
molecule.\" In his Nobel Lecture, Anfinsen provided a sketch of the rich history of research that provided the foundation
for his work on protein folding and the \"Thermodynamic Hypothesis,\" and outlined potential avenues of current and
future scientific exploration.
6,520 citations
2,234 citations
TL;DR: Single bilayer liposomes, indistinguishable from those obtained by sonication, can be prepared by injecting an thanolic solution of phospholipid into water by injection of dilute suspension.
1,280 citations
TL;DR: A new geometry based on the primitive notions of a point and a growth is explored in this article, which leads to new properties and descriptions which are particularly suitable for many biological objects.
1,143 citations
TL;DR: The data demonstrate that efficient presentation of macrophage-associated antigen to the lymphocyte requires identity between macrophages and lymphocyte at some portion of the major histocompatibility complex.
Abstract: Antigen activation of DNA synthesis in immune thymus-derived lymphocytes of guinea pigs requires the cooperation of macrophages and lymphocytes. We have investigated the role of histocompatibility determinants in this macrophage-lymphocyte interaction using cells from inbred strain 2 and 13 guinea pigs. The data demonstrate that efficient presentation of macrophage-associated antigen to the lymphocyte requires identity between macrophage and lymphocyte at some portion of the major histocompatibility complex. The failure of allogeneic macrophages to effectively initiate immune lymphocyte proliferation was not the result of the presence of an inhibitor of blastogenesis released in mixtures of allogeneic cells, peculiarities of the antigen or lymphoid cells employed, nor differing kinetics of activation by allogeneic macrophages. In addition, data were presented that demonstrated that alloantisera inhibit lymphocyte DNA synthesis by functional interference with macrophage-lymphocyte interaction.
939 citations
TL;DR: In conclusion, bleomycin appeared to be useful in the treatment of patients with specific tumors refractory to standard treatment and/or whose bone marrow status precluded the use of conventional chemotherapy.
Abstract: Bleomycin, a new antibiotic antineoplastic agent, has undergone extensive clinical trial. Data from 1,174 patients were reviewed and summarized by cell type. The most commonly used dose schedule was 15 mg/m2 twice a week intravenously. Significant response rates were achieved in patients with squamous cell carcinoma of various anatomical sites, lymphomas, and testicular carcinoma. Most responses were of 1 to 2 months' duration. Drug toxicities included significant skin and pulmonary complications and some degree of drug-induced pyrexia and nausea with vomiting. Rare insignificant bone marrow depression was encountered. The limitations of a retrospective clinical review of this type using uncontrolled pooled data from various patient populations were discussed. In conclusion, however, bleomycin appeared to be useful in the treatment of patients with specific tumors refractory to standard treatment and/or whose bone marrow status precluded the use of conventional chemotherapy. The final role of bleomycin in cancer chemotherapy awaits the results of controlled prospective clinical trials.
775 citations
TL;DR: An investigation of the effects of reserpine, pheniprazine, α‐methyl‐para‐tyrosine, diethyldithiocarbamate and l ‐DOPA on the levels of dopamine and norepinephrine in the brains of the 18‐day gestational fetus indicated that the levelsof these neurotransmitters are under controls similar to those known to occur in the brain of the adult rat.
Abstract: The levels of dopamine and norepinephrine were determined in the brains of fetal and newborn rats by means of a sensitive, radiometric-enzymatic assay. Catecholamines were converted to their 3-O-methylated derivatives in the presence of catechol-O-methyl transferase (EC 2.1.1.1) and [3 H-methyl]S-adenosylmethionine; and the [3H]-derivatives were isolated by selective extraction. The assay had a sensitivity for dopamine and norepinephrine of 100 picograms and was linear to at least 30 nanograms of catecholamines. Both amines were present at 15 days of gestation and increased 15-fold in content during the last week of gestation. The regional distribution of these neurotransmitters in the brain of the newborn rat correlated with the distribution of their biosynthetic enzymes. An investigation of the effects of reserpine, pheniprazine, α-methyl-para-tyrosine, diethyldithiocarbamate and l -DOPA on the levels of dopamine and norepinephrine in the brains of the 18-day gestational fetus indicated that the levels of these neurotransmitters are under controls similar to those known to occur in the brain of the adult rat.
775 citations
TL;DR: A simple method is reported to detect cooperative interactions in the binding of polypeptide hormones to their membrane receptors, and Insulin receptors on cultured lymphocytes and liver plasma membranes show negative cooperative interactions.
711 citations
TL;DR: DNA polymerase activity was detected in each of eight preparations of concentrated human hepatitis B antigen (HBAg) rich in Dane particles prepared by high-speed centrifugation of antigen-positive human plasma and in none of seven control preparations prepared in the same way from HBAg-negative plasma.
Abstract: DNA polymerase activity was detected in each of eight preparations of concentrated human hepatitis B antigen (HBAg) rich in Dane particles prepared by high-speed centrifugation of antigen-positive human plasma and in none of seven control preparations prepared in the same way from HBAg-negative plasma. The incorporation of (3)H-thymidine-methyl-5'-triphosphate into DNA was dependent on four deoxyribonucleoside triphosphates and MgCl(2). Treatment of the concentrated HBAg preparations with the nonionic detergent Nonidet P-40 (NP40) more than doubled the enzyme activity. Fractionation of the concentrated HBAg preparation in sucrose density gradients after treatment with NP40 revealed that the enzyme activity appeared within the density range of Dane core antigen but at a slightly higher density than the average for core antigen. The only particles observed by electron microscopy in this region of the gradient were typical 28-nm cores, suggesting that the DNA polymerase activity was associated with a subpopulation of cores. No DNA polymerase activity was found in purified 20-nm HBAg particles. The DNA product of the reaction remained associated with the 110S core and was not susceptible to DNase digestion when associated with the core. Inhibition of the reaction by actinomycin D and daunomycin suggested that the reaction was dependent on a DNA template associated with the core.
709 citations
TL;DR: It is concluded that antigen recognition by the T lymphocyte is a complex multicellular event involving more than simple antigen binding to a specific lymphocyte receptor.
Abstract: A number of recent studies have suggested that the main functional role of the product of the immune response (Ir) genes is in the process of antigen recognition by the T lymphocyte. The observation in the accompanying report that the interaction of macrophage-associated antigen with immune T lymphocytes requires that both cells share histocompatibility antigens raised the question as to whether the macrophage played a role in the genetic control of the immune response or even if the macrophage were the primary cell in which the product of the Ir gene is expressed. In the current study, parental macrophages were pulsed with an antigen, the response to which is controlled by an Ir gene lacking in that parent; these macrophages were then mixed with T cells derived from the (nonresponder x responder)F1 and the resultant stimulation was measured. No stimulation was seen when column-purified F1 lymph node lymphocytes were mixed with antigen-pulsed macrophages from the nonresponder parent. However, when the highly reactive peritoneal exudate lymphocyte population was used as the indicator cells, parental macrophages pulsed with an antigen whose Ir gene they lacked were capable of initiating F1 T-cell proliferation. The magnitude of stimulation was approximately 1/10 that seen when macrophages from either the responder parent or the F1 were used. In order to explain this observation, we hypothesize that antigen recognition sites on the T lymphocyte are physically related to a macrophage-binding site and both are linked to the serologically determined histocompatibility antigens. Thus, parental macrophages pulsed with an antigen, whose Ir gene they lack, activate F1 cells poorly because the recognition sites for the antigen are physically related to the macrophage-binding site of the responder parent while the main contacts between the cells are at the nonresponder binding sites. Experiments performed with alloantisera lend support to this hypothesis. Thus, when parental macrophages are pulsed with any antigen and added to F1 T cells, an alloantiserum directed against parental histocompatibility antigens reacts with both the lymphocyte and the macrophage and thereby inhibits macrophage-lymphocyte interaction and abolishes antigen-induced lymphocyte transformation. When the alloantisera are directed at determinants present solely on the T lymphocyte, they only inhibit the recognition of antigens controlled by the Ir gene linked to the histocompatibility antigen against which they are directed. We conclude from these studies that antigen recognition by the T lymphocyte is a complex multicellular event involving more than simple antigen binding to a specific lymphocyte receptor.
626 citations
TL;DR: It is argued that the relationships between occupational conditions and psychological functioning result from a continuing interplay between job and man, in which the effects of job on man are far from trivial.
Abstract: The central issue of this paper is whether men's adult occupational experiences affect or only reflect their psychological functioning. Our analysis isolates a small set of occupational conditions, twelve in all, which defines the structural imperatives of the job. These occupational conditions are found to be substantially related to men's psychological functioning, off as well as on the job. We argue that the relationships between occupational conditions and psychological functioning result from a continuing interplay between job and man, in which the effects of job on man are far from trivial. This argument is borne out by an assessment of the reciprocal effects of the substantive complexity of the work (a critically important occupational condition, for which we have the requisite longitudinal data) and several facets of psychological functioning. Substantive complexity has a decidedly greater impact on psychological functioning than the reverse.
TL;DR: The findings indicate that the detection of ASH identifies the pathognomonic anatomic abnormality in IHSS and includes a wider spectrum of patients (i.e. those without obstruction as well as clinically normal family members of patients with IhSS), and suggests that a more appropriate term for this disease entity is asymmetric septal hypertrophy or ASH.
Abstract: Idiopathic hypertrophic subaortic stenosis (IHSS) is characterized by subaortic obstruction to left ventricular (LV) outflow. However, the obstruction is variable and many patients have no resting gradient and no clinical evidence of IHSS. Although a characteristic systolic movement of the anterior mitral valve leaflet can be demonstrated echocardiographically in many patients with IHSS, this may be absent in patients without obstruction under baseline conditions. Several necropsy studies of patients with IHSS have demonstrated that the ventricular septum characteristically is asymmetrically hypertrophied in relation to the posterior left ventricular wall. Since echocardiography can measure the thickness of the ventricular septum and the posterior LV free wall during life, we have evaluated the sensitivity and specificity of asymmetric septal hypertrophy (ASH) in diagnosing IHSS. The ventricular septum and posterior LV free wall were measured in 15 patients with IHSS documented by catheterization, 11 pati...
TL;DR: The overall recommendation at present is that patients with prostatic cancer should not be treated until their symptoms require relief, and at that time it is recommended starting treatment with 1.0 mg DES daily.
Abstract: The results of these clinical trials over the past 12 years have revealed an unsuspected toxicity of DES used in treating patients with cancer of the prostate when given in a dose of 5.0 mg daily. The first VA study did not show that orchiectomy was superior to estrogen in treating cancer of the prostate or that the combination orchiectomy plus estrogen had much to offer beyond the benefits of estrogen alone when indicated. The preponderance of evidence from the second study shows that 1.0 mg of DES appears to be about as effective as the 5.0 mg dose in treating cancer of the prostate but does not carry the excess hazard of cardiovascular deaths. Our overall recommendation at present is that patients with prostatic cancer should not be treated until their symptoms require relief, and at that time we recommend starting treatment with 1.0 mg DES daily. These recommendations may change as we continue to analyze our data.
TL;DR: Among 6297 individuals reported to a kidney-transplant registry, the risk of developing lymphoma was about 35 times higher than normal and was derived almost entirely from a risk of reticulum-cell sarcoma, which was 350 times greater than expected.
TL;DR: An ATPase that accounts for about 0.3% of the total cell protein has been isolated in 90% purity from Acanthamoeba castellanii and shows some activity toward nucleoside triphosphates other than ATP but does not hydrolyze ADP or AMP.
TL;DR: Computer simulations show that the persistence of the biennial pattern of measles outbreaks implies that the vaccine is not being used uniformly throughout the population, for populations in which most members are vaccinated.
Abstract: London, W. P. (Mathematical Research Branch, National Institute of Arthritis, Metabolism, and Digestive Diseases, Bethesda, Md. 20014) and J. A. Yorke. Recurrent outbreaks of measles, chickenpox and mumps. I. Seasonal variation in contact rates. Am J Epidemiol 98:453-468, 1973. —Recurrent outbreaks of measles, chickenpox and mumps in cities are studied with a mathematical model of ordinary differential delay equations. For each calendar month a mean contact rate (fraction of susceptibles contacted per day by an infective) is estimated from the monthly reported cases over a 30to 35-year period. For each disease the mean monthly contact rate is 1.7 to 2 times higher in the winter months than in the summer months; the seasonal variation is attributed primarily to the gathering of children in school. Computer simulations that use the seasonally varying contact rates reproduce the observed pattern of undamped recurrent outbreaks: annual outbreaks of chickenpox and mumps and biennial outbreaks of measles. The two-year period of measles outbreaks is the signature of an endemic infectious disease that would exhaust itself and become nonendemic if there were a minor increase in infectivity or a decrease in the length of the incubation period. For populations in which most members are vaccinated, simulations show that the persistence of the biennial pattern of measles outbreaks implies that the vaccine is not being used uniformly throughout the population.
TL;DR: The decrease in insulin receptors in the ob/ob mouse correlates well with the insulin resistance which they exhibit and Scatchard analysis suggests that this decrease in binding is due to a decrease in the number of receptor sites in the membrane of the obese mouse, especially those of higher affinity.
TL;DR: It was found that interactions between amino acids of opposite charge and between large hydrophobic amino acids in the overlapping region between two chains are maximal when the chains are staggered by 0D, 1D, 2D, 3D and 4D, where D = 234 ± 1 residues.
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TL;DR: Animal scale-up is discussed as a formal approach to drug distribution in the body which permits consideration of scale through the individual processes that occur, some of which are physical, such as blood flows, tissue binding, and kidney clearances.
Abstract: The title of this paper is freely adapted from a problem common to the art and science of chemical engineering: “plant scale-up” or “process scale-up.” A chemical reaction or a set of chemical reactions is discovered which leads to a potentially useful product. The basic chemistry is worked out, often in considerable detail, at the bench in glassware. It is necessary to design a plant which will make the product economically and consistent with other constraints imposed by society.
TL;DR: The observations indicate that the presence of the porphyrin ring covalently bonded with cysteines 14 and 17 is essential for cytochrome c to exist in the stable native conformation.
TL;DR: Clinical and necropsy findings are described in 10 patients with quadricuspid semilunar valves, and previous reports of 197 cases are reviewed, finding the valve was functionally abnormal in 5 of 11 cases studied.
Abstract: Clinical and necropsy findings are described in 10 patients with quadricuspid semilunar valves, and previous reports of 197 cases are reviewed. Quadricuspid semilunar valves occur infrequently, and usually the pulmonic valve is affected. The quadricuspid pulmonic valve typically functions normally. The quadricuspid aortic valve was functionally abnormal in 5 of 11 cases studied.
TL;DR: Unrecognized myocardial infarction appears to be as prevalent in the 1970's as it was in the 1950's, and the reasons for this prevalence and possible solutions to the problem are discussed.
Abstract: The occurrence, prognosis and characteristics of persons with nonfatal unrecognized myocardial infarction were studied prospectively in a population of 5,127 men and women followed up biennially for 18 years. Of 259 electrocardiographically documented myocardial infarctions, 60 (23 percent) were discovered only by routine electrocardiogram at the time of biennial examination. Of these unrecognized infarctions, 32 (53 percent) were actually silent. In the other 47 percent of cases, the patients gave a history of interim symptoms judged to be compatible with acute infarction. In addition, of the 32 patients judged to have a silent infarction, 22 reported interim illnesses that could have been compatible with myocardial infarction. Only 10 of the 60 patients (17 percent) reported no interim illnesses or symptoms. Of the 28 patients with symptomatic infarction, 6 (21 percent) did not visit their physician despite severe symptoms; 20 gave a history of interim chest pain, 1 a history of epigastric pain and 7 a history of severe dyspnea. Patients who subsequently had unrecognized myocardial infarction typically visited physicians infrequently. Unrecognized myocardial infarction was distinctly rare in patients with prior angina pectoris. Patients with prior diabetes or high blood pressure appeared more likely to have unrecognized infarction. Unrecognized myocardial infarction appears to be as prevalent in the 1970's as it was in the 1950's. The reasons for this prevalence and possible solutions to the problem are discussed.
TL;DR: Mathematical solutions and numerical illustrations are presented for the steady-state distribution of membrane potential in an extensively branched neuron model, when steady electric current is injected into only one dendritic branch, and simple proportionality with input resistance does not hold.
TL;DR: This finding supports the proposal that neurons of primate motor cortex may function in a transcortical servo-loop.
Abstract: In primates, sensory input can generate reflex motor cortex output in association with learned movement when the sensory input has a strong and direct connection to the motor cortex-for example, when a stimulus calling for repositioning of the hand consists of a perturbation of hand position. This finding supports the proposal that neurons of primate motor cortex may function in a transcortical servo-loop.
TL;DR: The full data concerning the history of attenuated poliovirus strains developed by one of us for vaccine production are brought together in the report below to be both helpful and informative to those involved in the production and control of poliov virus vaccine (oral) prepared from these strains.
TL;DR: Observations suggest that concomitant with continuous triglyceride hydrolysis, apoLP-glu and apo LP-ala leave the very low density lipoprotein density range resulting in molecules relatively poor in triglyceride and relatively rich in apoLDL.
TL;DR: It is concluded that the levels of metabolites measured in brain obtained with the freeze‐blowing technique more closely resemble those which occur in vivo.
Abstract: — A new apparatus is described which removes and freezes brains of conscious rats more rapidly than was heretofore possible. The apparatus consists of two probes which are driven simultaneously into the cranial vault of the rat immobilized in a specially constructed restraining cage. When in position, air under pressure enters through one probe and blows the supratentorial portion of the brain tissue (situated between the olfactory bulbs and the superior colliculi) out the other probe and into a thin chamber previously cooled in liquid N2. This method stops brain tissue metabolism more rapidly than the previously-described methods of microwave irradiation, decapitation into liquid N2, or whole-animal immersion into liquid N2, as evidenced by the measurement of labile metabolites and redox states. Thus, samples of freeze-blown brain had higher levels of a-oxoglutarate, creatine phosphate, pyruvate, glucose and glucose-6-phosphate and lower levels of lactate, malate and AMP than brain tissue obtained by the other methods. The free cytoplasmic [NAD+]/[NADH2], [NADP+]/[NADPH2] and [ATP]/[ADP] [HPO42-] ratios were higher in freeze-blown samples. These data indicate that more extensive anoxic metabolism occurred when methods other than freeze-blowing were used. We conclude that the levels of metabolites measured in brain obtained with the freeze-blowing technique more closely resemble those which occur in vivo.
TL;DR: It is concluded that increasing HR within a physiologic range by diminishing vagal tone during myocardial ischemia decreases electrical stability of the ventricle by increasing ischemIA consequent to the rate-induced increase in myocardian oxygen requirements, and a direct electrophysiologic action of the vagus on the ventricular myocardium.
Abstract: Previous investigations have shown that a slower heart rate (HR) and myocardial ischemia independently diminish the electrical stability of the heart. It therefore was suggested that increasing heart rate during myocardial infarction might diminish the incidence of serious ventricular arrhythmias. However, since increased HR during experimental acute myocardial ischemia augments the degree of ischemia, an evaluation of the presumed "protective" effects of increased HR on the electrical stability of acutely ischemic myocardium was undertaken. The differences in refractory periods (RP) of eight contiguous areas of the left ventricle were determined as a function of HR. In nonischemic myocardium, the disparity of RP was less at an HR of 180 than 60. However, in ischemic myocardium the disparity increased in three of six animals as the HR was increased from 60 to 90, in seven of 10 animals as HR was increased from 60 to 120, and in all animals when the HR was increased from 60 to 180. The increased disparity ...