Showing papers by "Yale University published in 1979"

Glucose clamp technique: a method for quantifying insulin secretion and resistance.

Abstract: Methods for the quantification of beta-cell sensitivity to glucose (hyperglycemic clamp technique) and of tissue sensitivity to insulin (euglycemic insulin clamp technique) are described. Hyperglycemic clamp technique. The plasma glucose concentration is acutely raised to 125 mg/dl above basal levels by a priming infusion of glucose. The desired hyperglycemic plateau is subsequently maintained by adjustment of a variable glucose infusion, based on the negative feedback principle. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of glucose metabolism. Under these conditions of constant hyperglycemia, the plasma insulin response is biphasic with an early burst of insulin release during the first 6 min followed by a gradually progressive increase in plasma insulin concentration. Euglycemic insulin clamp technique. The plasma insulin concentration is acutely raised and maintained at approximately 100 muU/ml by a prime-continuous infusion of insulin. The plasma glucose concentration is held constant at basal levels by a variable glucose infusion using the negative feedback principle. Under these steady-state conditions of euglycemia, the glucose infusion rate equals glucose uptake by all the tissues in the body and is therefore a measure of tissue sensitivity to exogenous insulin.

Social networks, host resistance, and mortality: a nine-year follow-up study of Alameda County residents

Abstract: The relationship between social and community ties and mortality was assessed using the 1965 Human Population Laboratory survey of a random sample of 6928 adults in Alameda County, California and a subsequent nine-year mortality follow-up. The findings show that people who lacked social and community ties were more likely to die in the follow-up period than those with more extensive contacts. The age-adjusted relative risks for those most isolated when compared to those with the most social contacts were 2.3 for men and 2.8 for women. The association between social ties and mortality was found to be independent of self-reported physical health status at the time of the 1965 survey, year of death, socioeconomic status, and health practices such as smoking, alcoholic beverage consumption, obesity, physical activity, and utilization of preventive health services as well as a cumulative index of health practices.

The Influence of Mountains on the Atmosphere

Abstract: Publisher Summary The chapter reviews the meteorological phenomena that are associated with topography. The study of airflow past mountains is complicated by the wide range of scales that must be considered. The ratios of the mountain width to each of the natural length scales are important in determining the physical regime of the flow. This idea is emphasized in the chapter by treating the effects of boundary layers and buoyancy. The theory of two-dimensional mountain waves with the help of its governing equations is presented and the observations of mountain waves are presented. The chapter also examines the influence of the boundary layer on mountain flows and slope winds and mountain and valley winds. It considers the perturbation to the wind flow caused by a mountain of intermediate scale where the rotation of the Earth cannot be neglected. For this the flow near mesoscale and synoptic-scale mountains, quasi-geostrophic flow over a mountain, the effect of inertia on the flow over mesoscale mountains, and theories of lee cyclogenesis are discussed. Finally the chapter describes planetary-scale mountain waves; a vertically integrated model of topographically forced planetary waves; the vertical structure of planetary waves; models of stationary planetary waves allowing meridional propagation and lateral; and variation in the background wind.

Simple method for identification of plasmid-coded proteins.

Abstract: Proteins encoded by plasmid DNA are specifically labeled in UV-irradiated cells of Escherichia coli carrying recA and uvrA mutations because extensive degradation of the chromosome DNA occurs concurrently with amplification of plasmid DNA.

A Golgi study of radial glial cells in developing monkey telencephalon: morphogenesis and transformation into astrocytes.

Abstract: Radial glial cells (epithelial cells of Ramon y Cajal) impregnated by a modified del Rio Hortega rapid Golgi method were studied in the occipital lobes of 38 rhesus monkeys from embryonic day 48 (E48) to birth which occurs at E165 and in 27 postnatal animals to day 365 (P365). Some radial glial cells are already recognized at E48 by their bipolar shape and elongated radial fiber, which terminates with characteristic endfeet on the walls of blood vessels or at the pial surface. At slightly older ages-between E60 and E70-all cells spanning the cerebral wall develop lamellate expansions along their radial fiber and their endfeet become PAS positive. After E60, some radial glia detach from the ventricular surface and their somas become displaced outwards in the cerebral wall. After this age, radial glial cells are easily distinguished from migrating neurons by their larger oval nucleus located in the ventricular or subventricular zone, radial fiber extending outwards to the pial surface where it terminates in one or more endfeet, and the delicate lamellate expansions on both radial fiber and soma. Displaced radial glial cells have more closely packed lamellate expansions and display a range of transitional shapes leading to either fibrous or protoplasmic astrocytes. Between E95 and E140, when neuron migration to the visual cortex tapers off, perikarya of displaced radial glial cells form a conspicuous band at the outer border of the subventricular zone. Numerous transitional forms are present in the cortical plate at this age. After birth, fewer radial glial fibers are present in occipital lobe and their length is difficult to determine in the convoluted lateral cerebral wall expanded up to 10–20 mm. However, at P7 and P20, many radial fibers still span the medial cerebral wall in the depth of the calcarine fissure where it remains less than 2 mm thick. Even here, no fibers spanning the cerebral wall were seen in 17 animals from P50 to P200 despite the presence of well-impregnated transitional forms situated near the lateral ventricle and myriad astrocytes dispersed throughout the hemisphere. By P365, end of the first year, the few short remaining radial fibers belong to ependymal cells or mature astrocytes while all immature transitional forms have disappeared.

Glucose Intolerance and Aging: Evidence for Tissue Insensitivity to Insulin

Abstract: The relative contributions of impaired insulin secretion and of impaired tissue sensitivity to insulin to the glucose intolerance of aging were examined in 84 healthy volunteers, ranging in age from 21 to 84 yr, employing the hyperglycemie and euglycemic insulin clamp techniques, respectively. HYPERGLYCEMIC CLAMP. The blood glucose concentration was acutely raised and was maintained at 125 mg/dl above basal levels for 2 h. Since the glucose concentration was held constant, the glucose infusion rate was an index of glucose metabolism (M). In young subjects, M averaged 9.48 ± 0.40 mg/kg · min compared with 6.48 ± 0.28 in old subjects ( P < 0.001). When all subjects were considered together, a progressive age-related decline in M was observed ( r = –0.665, P < 0.001). The plasma insulin response (I) was biphasic, with an early burst within the first 6 min, followed by a phase of gradually increasing insulin concentration. No difference in either the early or late phases of insulin secretion was observed between young and old subjects. Consequently, the M/l (×100) ratio, an index of tissue sensitivity to endogenous insulin, decreased from 14.90 ± 1.01 to 10.98 ± 0.81 mg/kg min per μU/ml ( P < 0.005). EUGLYCEMIC INSULIN CLAMP. The plasma insulin concentration was acutely raised and was maintained at about 100 μU/ml above basal levels by a primed continuous infusion of insulin. The blood glucose concentration was held constant at the basal level by a variable glucose infusion. M/I (×100), again, was a measure of tissue sensitivity to insulin (exogenous) and was decreased in old (4.95 ± 0.31 mg/kg · min per μU/ml) versus young (6.95 ± 0.45) subjects ( P < 0.001). Hepatic glucose production was measured with tritiated glucose during the euglycemic clamp study; it declined similarly in young (to 0.13 ± 0.05 mg/kg · min) and old (to 0.09 ± 0.03 mg · min) subjects. In conclusion, under the present experimental conditions, employing intravenous glucose and/or insulin, impaired tissue sensitivity to insulin is the primary factor responsible for the decrease in glucose tolerance observed with advancing age. Since hepatic glucose production is normally suppressed by insulin in old subjects, the site of insulin resistance must reside in peripheral tissues. Beta cell response to glucose, as determined by the hyperglycemie clamp technique, cannot account for the age-related decline in M.

Bacterial endotoxins and host immune responses

Abstract: Publisher Summary This chapter discusses the nature of endotoxins and their interactions with cells of the immune system. The direct interaction of endotoxin with B lymphocytes leading to the formation of antibodies to endotoxin as well as a spectrum of other immunoglobulin molecules is discussed. In addition, the interactions of endotoxins with T cells and macrophages and the associated immunoregulatory effects are discussed. The central role of the lipid A portion of the endotoxin molecule in cellular activation and the molecular events occurring at the cell surface in the course of stimulation are presented. The potential of endotoxins as therapeutic manipulators of the immune response in man is also evaluated. Major direct interactions of endotoxins with B lymphocytes have been documented, leading to synthesis and secretion of antibody directed not only against antigenic determinants on the endotoxin molecules themselves, but also with specificities characteristic of the complete repertoire of variable region gene products. Knowledge of the immunobiology of endotoxins has prompted investigations in their therapeutic uses in man as both antigenically distinct and cross-reactive immunogens in protection against gram-negative infections.

Presence of heparan sulfate in the glomerular basement membrane.

Abstract: The glomerular basement membrane was subjected to digestion with specific enzymes to determine the chemical nature (sialoglycoproteins, collagenous peptides, or glycosaminoglycans) of the anionic sites previously demonstrated in the laminae rarae. Enzyme digestion was carried out both in situ and in vitro. Kidneys were perfused in situ with enzyme solutions followed by perfusion with fixative containing the cationic dye, ruthenium red, to detect the anionic sites. Glomerular basement membranes were isolated by detergent treatment of glomeruli and incubated with enzyme solutions, followed by incubation with cationized ferritin (pI 7.3-7.5) to label the anionic sites. Only highly purified enzymes free of proteolytic activity were used. The findings were the same both in situ and in vitro. The anionic sites were unaffected by treatment with neuraminidase, chondroitinase ABC, and testicular or leech hyaluronidase. However, they could no longer be demonstrated after digestion with crude heparinase, purified heparitinase, or Pronase or after nitrous acid oxidation. The results demonstrate that the sites contain heparan sulfate since they are removed by treatment with heparitinase and by nitrous acid oxidation—procedures specific for heparan sulfate; and that sialoglycoproteins or other glycosaminoglycans do not represent major components of these sites since the latter are not affected by digestion with neuraminidase and other glycosaminoglycan-specific enzymes. Identical findings were obtained on basement membranes in other locations (Bowman's capsule, tubule epithelium, and endothelium of peritubular capillaries). The presence of heparan sulfate in the glomerular basement membrane is discussed in relation to the charge-selective properties of the glomerular filter and in relation to its potential involvement in various types of glomerular injury.

Anionic sites in the glomerular basement membrane. In vivo and in vitro localization to the laminae rarae by cationic probes.

Abstract: Cationized ferritin (CF) of narrow pI range (7.3-7.5) and the basic dye ruthenium red (RR) have been used as cationic probes to partially characterize anionic sites previously demonstrated in the glomerular basement membrane (GBM). When CF was given i.v. to normal rats and the left kidney was fixed by perfusion 15 min thereafter, clusters of CF molecules were found throughout the lamina rara interna (LRI), lamina rara externa (LRE), and mesangial matrix distributed at regular (approximately 60 nm) intervals. When kidneys were perfused with aldehyde fixative containing RR, small (20 nm) RR-stained particles were seen in the same locations distributed with the same 60 nm repeating pattern, forming a quasiregular, lattice-like arrangement. Fine (approximately 3 nm) filaments connected the sites and extended between them and the membranes of adjoining endothelial and epithelial cells. When CF was given i.v. followed by perfusion with RR in situ, both probes localized to the same sites. CF remained firmly bound after prolonged perfusion with 0.1-0.2 M KCl or NaCl. It was displaced by perfusion with buffers of high ionic strength (0.4-0.5 M KCl) or pH (less than 3.0 or greater than 10.0). CF also bound (clustered at approximately 60 nm intervals) to isolated GBM's, and binding was lost when such isolated GBM's were treated with buffers of high ionic strength or pH. These experiments demonstrate the existence of a quasi-regular, lattice-like network of anionic sites in the LRI and LRE and the mesangial matrix. The sites are demonstrable in vivo (by CF binding), in fixed kidneys (by RR staining), and in isolated GBM's (by CF binding). The results obtained with CF show that the binding of CF (and probably also RR) to the laminae rarae is electrostatic in nature since it is displaced by treatment with buffers of high ionic strength or pH. With RR the sites resemble in morphology and staining properties the proteoglycan particles found in connective tissue matrices and in association with basement membranes in several other locations.

Social processes and proofs of theorems and programs

Abstract: It is argued that formal verifications of programs, no matter how obtained, will not play the same key role in the development of computer science and software engineering as proofs do in mathematics. Furthermore the absence of continuity, the inevitability of change, and the complexity of specification of significantly many real programs make the formal verification process difficult to justify and manage. It is felt that ease of formal verification should not dominate program language design.

Dopamine auto- and postsynaptic receptors: electrophysiological evidence for differential sensitivity to dopamine agonists.

Abstract: The responses of dopamine cells in the substantia nigra to iontophoretically administered dopamine and intravenous apomorphine were compared to the responses of spontaneously active neurons in the caudate nucleus. Dopaminergic cells were six to ten times more sensitive to dopamine and intravenous apomorphine than 86 percent of the caudate cells tested. This differential sensitivity of dopamine auto- and postsynaptic receptors may explain the apparently paradoxical behavioral effects induced by small compared to large doses of some dopamine agonists and may provide a means of developing new types of drugs to antagonize dopaminergic influence in the central nervous system.

Global stability of parameter-adaptive control systems

Abstract: This paper examines two relatively uncomplicated algorithms for adaptively controlling a single-input, single-output process admitting a continuous-time linear model wlth unknown parameters. It is shown that each algorithm is capable of causing a closed-loop process output to approach and track a suitably defined reference signal while at the same time providing global system stability.

A review of the epidemiology of human breast cancer

Abstract: A comprehensive review of what was known of the epidemiology of breast cancer as of the early 1970s was published by MacMahon et al. in 1973. This review covers the major aspects of the epidemiology of breast cancer included in the 1973 review and additionally emphasizes recently reported work. Attention is directed to the following: magnitude of the problem in the U.S.; demographic characteristics of breast cancer cases; international variation; laterality of breast cancer; reproductive variables; benign breast diseases; multiple primary cancers involving the breast and other sites; familial aggregation and genetics; endogenous hormones (estrogens progesterone prolactin androgens and thyroid); exogenous estrogens; diet; body build; radiation; exposure to radiation in screening for breast cancer; mammographic parenchymal patterns; viruses; other exposures of current interest (reserpine hair dyes); and breast cancer in males. The high incidence and mortality rates and the detrimental impact on the quality of life of those affected indicate that breast cancer in the U.S. continues to be a serious problem for women. An annual age-adjusted incidence rate of 84.9/100000 women was reported for the 1973-1976 years; the annual age-adjusted mortality rate among women in the U.S. was 27.7/100000 over this same time period. From these figures it may be estimated that each year in the U.S. almost 100000 cases of breast cancer are diagnosed and over 30000 deaths occur. Age specific incidence rates increase rapidly with age until about 45-50 years of age after which they continue to increase but at a slower rate. In addition to age a few other risk factors including a history of bilateral premenopausal breast cancer in a 1st degree relative a history of breast cancer in the contralateral breast and residence from an early age in North America compared to Asia are associated with large relative risks. Other risk factors including whether or not an oophorectomy has been performed age at 1st birth a history of fibrocystic disease previous exposure to high levels of radiation in the chest socioeconomic status obesity and a previous cancer in the ovary or endometrium are associated with relative risks of at least 2 but less than 4-fold. Finally age at menarche age at menopause marital status place of residence and the white compared to the black race are associated with small but real differentials in risk.

Time functions in numerical relativity: Marginally bound dust collapse

Abstract: We explore the problem of the existence of global maximal ($K=0$) and constant-mean-curvature ($K={K}_{0}$) time functions in general relativity. We attempt a rigorous definition of numerical relativity so as to bridge the gap between the field and mathematical relativity. We point out that numerical relativity can in principle construct any globally hyperbolic solution to Einstein's equations. This involves the construction of Cauchy time functions. Therefore we review what is known about the existence and uniqueness of such functions when their mean curvature is specified to be a constant on each time slice. We note that in strong-field solutions which contain singularities the question of existence is intimately connected to the nature of the singularity. Defining the class of "crushing singularities" we prove new theorems showing that $K=0$ or $K={K}_{0}$ time functions uniformly avoid such singularities (which include both Cauchy horizons and some curvature singularities). We then study the inhomogeneous generalizations of the Oppenheimer-Snyder spherical-dust-collapse spacetimes. These Tolman-Bondi solutions are classified as to their causal structure and found to contain naked singularities of a new type if the collapse is sufficiently inhomogeneous. We calculate the $K=0$ and $K={K}_{0}$ time slices for a variety of these spacetimes. We find that since some extreme dust collapses lead to noncrushing singularities, maximal time slicing can hit the singularity before covering the domain of outer communications of the resulting black hole. Furthermore, the use of $K={K}_{0}$ slices in the presence of a naked singularity is discussed.

Functional organization of rat olfactory bulb analysed by the 2-deoxyglucose method.

Abstract: The spatial patterns of activity elicited in the rat olfactory bulb under different odor conditions have been analysed using the 2-deoxyglucose (2DG) technique. Rats were injected with 14C-2DG, exposed to controlled environments of amyl acetate, camphor, cage air, dimethyl disulfide, and pure air and autoradiographs prepared by the method of Sokoloff. Amyl acetate was associated with regions of glomerular layer densities in the anterolateral and mid- to posteromedial parts of the bulbar circumference, as previously reported. The extents of the densities increased with increasing concentration. Camphor odor was associated with regions of increased density in the anterodorsal and mid- to posteromedial parts of the bulb. Exposure to cage air produced scattered densities in the posteromedial and posterolateral bulb. Exposure to dimethyl disulfide gave variable results. Pure air was associated with a minimal number of small dense foci. The results with amyl acetate, camphor and cage air suggest that patterns for different odors are distinguishably different but overlapping. The regions of activity are greatest in extent and density with the highest odor concentrations. These define the regions within which more restricted and isolated foci appear at lower concentrations. The results thus provide evidence for the specific role of spatial factors in the neural processing of odor quality and odor concentration.

To know with the nose: keys to odor identification

Abstract: Successful odor identification depends on (i) commonly encountered substances, (ii) a long-standing connection between an odor and its name, and (iii) aid in recalling the name. The absence of any one ingredient impairs performance dramatically, but the presence of all three permits ready identification of scores of substances, with performance seemingly limited only by the inherent confusability of the stimuli.

Risks of General Anesthesia and Elective Operation in the Hypertensive Patient

Abstract: To determine the risks of general anesthesia and elective surgical procedures in patients who have histories of hypertension, the authors prospectively studied 676 consecutive operations in a series of patients more than 40 years old. All patients were examined preoperatively, monitored intraoperati

Issues in the Creation of Organizations: Initiation, Innovation, and Institutionalization

Abstract: Kimberly presents a case study of the birth and early development of an innovative medical school. When the school opened in 1971, the existing 86 medical schools all offered similar programs: two years of basic science training in lecture halls and laboratories, followed by two years of direct contact with patients in clinical settings. In the new school, students were taught didactically only during the first year. During the second year, each student was assigned to a community physician who acted as an advisor and who discussed with students those patients afflicted with the diseases the student was currently studying. Available evidence indicated that the school's innovative curriculum was favorably received by the students and that they performed as well as their peers on standardized year-end exams. The author found the case of this medical school to be of particular interest from an organizational viewpoint in that: (1) the early development of the school was shaped by the first dean's entrepreneurial activity, ambitions, visions, strengths, and weaknesses; (2) the uncertainty resulting from the school's novelty forced individuals to assume new roles and face unclear performance criteria; and (3) the transition of an innovative school to an institutionalized one was problematic because it modified the decision-making process. The author suggests that those things which lead to an organization's success during its early years are not the same as those that lead to longer-run success. He says that a new organization creates new norms, values, and procedures whereas the elements of an existing organization interact within an established culture. He concludes that organizational birth is a phenomenon about which relatively little is known, but which may be an important constraint on later development. A comparative analysis of the birth, life, and death of organization is advocated.