Showing papers by "Vanderbilt University published in 1986"

Fairness as a Constraint on Profit Seeking: Entitlements in the Market

Abstract: Community standards of fairness for the setting of prices and wages were elicited by telephone surveys. In customer or labor markets it isacceptable for a firm to raise prices (or cut wages) when profits arethreatened, and to maintain prices when costs diminish. It is unfair toexploit shifts in demand by raising prices or cutting wages. Several market anomalies are explained by assuming that these standards of fairness influence the behavior of firms. Copyright 1986 by American Economic Association.

Optimization of Control Parameters for Genetic Algorithms

Abstract: The task of optimizing a complex system presents at least two levels of problems for the system designer. First, a class of optimization algorithms must be chosen that is suitable for application to the system. Second, various parameters of the optimization algorithm need to be tuned for efficiency. A class of adaptive search procedures called genetic algorithms (GA) has been used to optimize a wide variety of complex systems. GA's are applied to the second level task of identifying efficient GA's for a set of numerical optimization problems. The results are validated on an image registration problem. GA's are shown to be effective for both levels of the systems optimization problem.

Epidermal growth factor

Abstract: During the course of purifying nerve growth factor from the submaxillary gland of the mouse, Cohen (1960) and Levi-Montalcini and Cohen (1960) noticed that daily injections of certain gland extract fractions into newborn mice produced developmental changes that could not be ascribed to nerve growth factor. These changes included precocious opening of the eyelids (7 days compared to the usual 14 days) and a similar early eruption of the incisors. Using these gross anatomical changes as an assay, Cohen (1962) proceeded to isolate the active factor — a polypeptide which he termed epidermal growth factor (EGF).

Growth Factors and Cancer

Abstract: Growth factors, defined as polypeptides that stimulate cell proliferation, are major growth-regulatory molecules for cells in culture and probably also for cells in vivo. Nontransformed cells show an absolute requirement for growth factors for proliferation in culture and generally more than one growth factor is required. Under usual culture conditions, growth factors are more rapidly depleted than other media components and thus become rate limiting for proliferation. The loss of or decreased requirement for specific growth factors is a common occurrence in neoplastically transformed cells and may lead to a growth advantage, a cardinal feature of cancer cells. Recent work with transforming growth factors, the platelet-derived growth factor, and oncogenes has produced some insight into the mechanisms through which alterations in growth factor-receptor-response pathways could lead to a growth advantage. Evidence has been derived for autocrine secretion in which the cell produces its own growth factor. Many transformed mesenchymal cells produce PDGF (the product of the c-sis proto-oncogene) and certain transformed cells both produce and respond in a growth-stimulatory manner to TGF beta. With TGF beta, which is a growth inhibitor for certain epithelial and other cell types, the loss of the normal inhibitory response in transformed cells could have the same result as the activation of a growth-stimulatory response. Two proto-oncogenes, erbB and fms, encode growth factor receptors. In the erbB case, the viral erbB aberrant receptor produced is truncated and appears to be constitutively activated without the need for a growth factor. Recent studies suggest that the p21 product of the ras oncogene may be an obligatory intermediate in transducing the growth factor signal. Activation of ras may, therefore, activate the growth factor pathway without the need for either a growth factor or its receptor. The transcription of myc and fos is induced by growth factor stimulation of quiescent cells. The protein products of both are nuclear associated and conceivably could be involved in regulating other genes important in the control of cell proliferation. Activation or inappropriate expression of either myc or fos could produce the same end result as stimulation of a growth factor pathway leading to a growth advantage. Study of the molecular mechanism(s) of growth factor action has just begun. The excitement and attention focused on cellular oncogenes in recent years is now turning toward growth factors, not only as they concern the control of normal cell growth but also the involvement of growth factor-initiated pathways in the etiology of cancer.(ABSTRACT TRUNCATED AT 400 WORDS)

Frontal eye field as defined by intracortical microstimulation in squirrel monkeys, owl monkeys, and macaque monkeys. II. Cortical connections.

Abstract: Physiological (intracortical microstimulation) and anatomical (transport of horseradish peroxidase conjugated to wheat germ agglutinin as shown by tetramethyl benzidine) approaches were combined in the same animals to reveal the locations, extents, and cortical connections of the frontal eye fields (FEF) in squirrel, owl, and macaque monkeys. In some of the same owl and macaque monkeys, intracortical microstimulation was also used to evoke eye movements from dorsomedial frontal cortex (the supplementary motor area). In addition, in all of the owl and squirrel monkeys, intracortical microstimulation was also used to evoke body movements from the premotor and motor cortex situated between the central dimple and the FEF. These microstimulation data were directly compared to the distribution of anterogradely and retrogradely transported label resulting from injections of tracer into the FEF in each monkey. Since the injection sites were limited to the physiologically defined FEF, the demonstrated connections were solely those of the FEF. To aid in the interpretation of areal patterns of connections, the relatively smooth cortex of owl and squirrel monkeys was unfolded, flattened, and cut parallel to the flattened surface. Cortex of macaque monkeys, which has numerous deep sulci, was cut coronally. Reciprocal connections with the ipsilateral frontal lobe were similar in all three species: dorsomedial cortex (supplementary motor area), cortex just rostral (periprincipal prefrontal cortex) to the FEF, and cortex just caudal (premotor cortex) to the FEF. In squirrel and owl monkeys, extensive reciprocal connections were made with cortex throughout the caudal half of the lateral fissure and, to a much lesser extent, cortex around the superior temporal sulcus. In macaque monkeys, only sparse connections were present with cortex of the lateral fissure, but extensive and dense connections were made with cortex throughout the caudal one-third to one-half of the superior temporal sulcus. In addition, very dense reciprocal connections were made with the cortex of the lateral, or inferior, bank of the intraparietal sulcus. Contralateral reciprocal connections in all three species were virtually limited to regions that correspond in location to the FEF and the supplementary motor area. The results of this study reveal connections between the physiologically defined frontal eye field and cortical regions known to participate in higher order visual processing, short-term memory, multimodal, visuomotor, and skeletomotor functions. Some of the demonstrated pathways may contribute to functional interactions between oculomotor and skeletomotor systems, perhaps facilitating the planning and coordination of related eye, head, and hand movements.

A protein induced during nerve growth (GAP-43) is a major component of growth-cone membranes.

Abstract: Growth cones are specialized structures that form the distal tips of growing axons. During both normal development of the nervous system and regeneration of injured nerves, growth cones are essential for elongation and guidance of growing axons. Developmental and regenerative axon growth is frequently accompanied by elevated synthesis of a protein designated GAP-43. GAP-43 has now been found to be a major component of growth-cone membranes in developing rat brains. Relative to total protein, GAP-43 is approximately 12 times as abundant in growth-cone membranes as in synaptic membranes from adult brains. Immunohistochemical localization of GAP-43 in frozen sections of developing brain indicates that the protein is specifically associated with neuropil areas containing growth cones and immature synaptic terminals. The results support the proposal that GAP-43 plays a role in axon growth.

Enhanced production and extracellular deposition of the endothelial-type plasminogen activator inhibitor in cultured human lung fibroblasts by transforming growth factor-beta.

Abstract: Cultured human embryonic lung fibroblasts were used as a model to study the effects of transforming growth factor-beta (TGF beta) on the plasminogen activator (PA) activity released by nontumorigenic cells into the culture medium. The cells were exposed to TGF beta under serum-free conditions, and the changes in PA activity and protein metabolism were analyzed by caseinolysis-in-agar assays, zymography, and polypeptide analysis. Treatment of the cells with TGF beta caused a significant decrease in the PA activity of the culture medium as analyzed by the caseinolysis-in-agar assays. The quantitatively most prominent effect of TGF beta on confluent cultures of cells was the induction of an Mr 47,000 protein, as detected by metabolic labeling. The Mr 47,000 protein was a PA inhibitor as judged by reverse zymography. It was antigenically related to a PA inhibitor secreted by HT-1080 tumor cells as demonstrated with monoclonal antibodies. The induced Mr 47,000 inhibitor was deposited into the growth substratum of the cells, as detected by metabolic labeling, immunoblotting analysis, and reverse zymography assays of extracellular matrix preparations. TGF beta also decreased the amounts of urokinase-type and tissue-type PAs accumulated in the conditioned medium, as detected by zymography. Epidermal growth factor antagonized the inhibitory effects of TGF beta by enhancing the amounts of the PAs. These results indicate that growth factors modulate the proteolytic balance of cultured cells by altering the amounts of PAs and their inhibitors.

Abnormal hypothalamic-pituitary-adrenal function in anorexia nervosa. Pathophysiologic mechanisms in underweight and weight-corrected patients.

Abstract: To study the pathophysiology of hypercortisolism in patients with anorexia nervosa, we examined plasma ACTH and cortisol responses to ovine corticotropin-releasing hormone before and after correction of weight loss. We also studied patients with bulimia whose weight was normal, since this disorder has been suspected to be a variant of anorexia nervosa. Before their weight loss was corrected, the anorexic patients had marked hypercortisolism but normal basal plasma ACTH. The hypercortisolism was associated with a marked reduction in the plasma ACTH response to corticotropin-releasing hormone. When these patients were studied three to four weeks after their body weight had been restored to normal, the hypercortisolism had resolved but the abnormal response to corticotropin-releasing hormone remained unchanged. On the other hand, at least six months after correction of weight loss their responses were normal. The bulimic patients whose weight was normal also had a normal response to corticotropin-releasing hormone. We conclude that in underweight anorexics, the pituitary responds appropriately to corticotropin-releasing hormone, being restrained in its response by the elevated levels of cortisol. This suggests that hypercortisolism in anorexics reflects a defect at or above the hypothalamus. The return to eucortisolism soon after correction of the weight loss indicates resolution of this central defect despite persistence of abnormalities in adrenal function.

The relationship of corpus callosum connections to electrical stimulation maps of motor, supplementary motor, and the frontal eye fields in owl monkeys

Abstract: Microstimulation and anatomical techniques were combined to reveal the organization and interhemispheric connections of motor cortex in owl monkeys. Movements of body parts were elicited with low levels of electrical stimulation delivered with microelectrodes over a large region of precentral cortex. Movements were produced from three physiologically defined cortical regions. The largest region, the primary motor field, M-I, occupied a 4-6mm strip of cortex immediately rostral to area 3a. M-I represented body movements from tail to mouth in a grossly somatotopic mediolateral cortical sequence. Specific movements were usually represented at more than one location, and often at as many as six or seven separate locations within M-I. Although movements related to adjoining joints typically were elicited from adjacent cortical sites, movements of nonadjacent joints also were produced by stimulation of adjacent sites. Thus, both sites producing wrist movements and sites producing shoulder movements were found next to sites producing digit movements. Movements of digits of the forepaw were evoked at several locations including a location rostral to or within cortex representing the face. Overall, the somatotopic organization did not completely correspond to previous concepts of M-I in that it was neither a single topographic representation, nor two serial or mirror symmetric representations, nor a “nesting about joints” representation. Instead, M-I is more adequately described as a mosaic of regions, each representing movements of a restricted part of the body, with multiple representations of movements that tend to be somatotopically related. A second pattern of representation of body movements, the supplementary motor area (SMA), adjoined the rostromedial border of M-I. SMA represented the body from tail to face in a caudorostral cortical sequence, with the most rostral portion related to eye movements. Movements elicited by near-threshold levels of current were often restricted to a single muscle or joint, as in M-I, and the same movement was sometimes multiply represented. Typically, more intense stimulating currents were required for evoking movements in SMA than in M-I. A third motor region, the frontal eye field (FEF), bordered the representation of eyelids and face in M-I. Eye movements elicited from this cortex consisted of rapid horizontal and downward deviation of gaze into the contralateral visual hemifield.

Tears of the anterior cruciate ligament in adolescents.

Abstract: Tears of the anterior cruciate ligament in adolescents are rare. From 1977 to 1983 we did a surgical reconstruction of that ligament, using the semitendinosus and gracilis tendons, in twenty-four athletes who were twelve to fifteen years old. We routinely supplemented that procedure with the Ellison or Losee extra-articular reconstruction. The length of follow-up averaged thirty-five months. There were sixteen excellent, seven good, and one fair-plus result. Only one patient showed a significant growth abnormality. Use of the semitendinosus and gracilis tendons did not significantly decrease the strength of flexion or internal rotation as measured by the Cybex-II dynamometer.

Structure of Tobacco Mosaic Virus at 3.6 Å Resolution: Implications for Assembly

Abstract: X-ray fiber diffraction analysis of tobacco mosaic virus (TMV) has led to the building of a molecular model of the intact virus, based on a map at 3.6 A resolution derived from five separated Bessel orders. This has been made possible by advances in the solution of the fiber diffraction phase problem. It is now possible to understand much of the chemical basis of TMV assembly, particularly in terms of intersubunit electrostatic interactions and RNA binding. Consideration of the molecular structure in conjunction with physical chemical studies by several groups of investigators suggests that the nucleating aggregate for initiation of TMV assembly is a short (about two turns) helix of protein subunits, probably inhibited from further polymerization in the absence of RNA by the disordering of peptide loop near the inner surface of the virus.

Structural analysis of social behavior: application to a study of interpersonal process in differential psychotherapeutic outcome.

Abstract: Research strategies employing Structural Analysis of Social Behavior (SASB) were demonstrated in a study comparing 4 therapists, each of whom saw a good and a poor outcome case (N = 8), on interpersonal process variables in the third session. SASB represents complex interactive processes in a manner that is both theoretically cogent and empirically sound. Good versus poor therapeutic outcome was differentiated on the basis of the following interpersonal process variables: greater levels of "helping and protecting" and "affirming and understanding*' and significantly lower levels of "blaming and belittling" were associated with high-change cases. Patient behaviors of "disclosing and expressing" were significantly more frequent in high-change cases, whereas "walling off and avoiding" and "trusting and relying" were significantly more frequent in low-change cases. Additionally, negative complementarity was greater in poor outcome cases. Implications for research methodology and interpersonal theory are discussed.

Calmodulin binding domains: characterization of a phosphorylation and calmodulin binding site from myosin light chain kinase.

Abstract: A protein kinase phosphorylation site in chicken gizzard myosin light chain kinase (MLCK) has been identified, and a synthetic peptide analogue of this site has been shown to be a high-affinity calmodulin binding peptide as well as a substrate for cyclic AMP dependent protein kinase. Phosphorylation of the site in MLCK is diminished when reactions are done in the presence of calmodulin. A fragment of MLCK containing the phosphorylation site was shown to have the amino acid sequence Ala-Arg-Arg-Lys-Trp-Gln-Lys-Thr-Gly-His-Ala-Val-Arg-Ala-Ile-Gly-Arg-Leu- Ser-Ser. The interaction of calmodulin with a synthetic peptide based on this sequence was characterized by using circular dichroism and fluorescence spectroscopies and inhibition of calmodulin activation of MLCK. The peptide-calmodulin complex had an estimated dissociation constant in the range of 1 nM, underwent spectroscopic changes in the presence of calmodulin consistent with the induction of an alpha-helical structure, and interacted with calmodulin with an apparent 1:1 stoichiometry. Studies with other synthetic peptide analogues indicated that the phosphorylation of the serine residues diminished the ability of the peptide to interact with calmodulin even though the serines are not required for calmodulin binding. On the basis of the primary and secondary structural characteristics of these peptide analogues, a potential calmodulin binding region in another calmodulin binding protein, the gamma subunit of rabbit skeletal muscle phosphorylase kinase, was identified.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical and cytogenetic survey of 39 individuals with Prader-Labhart-Willi syndrome

Abstract: In a clinical and cytogenetic survey of 39 individuals with Prader-Labhart-Willi syndrome (PLWS) (23 males and 16 females ranging in age from 2 weeks to 39 years), an interstitial deletion of chromosome 15 (breakpoints q11 and q13) was identified in 21 cases and apparently normal chromosomes in the remainder. Studies of parental chromosome 15 variants showed that the del[15q] was paternal in origin, although chromosomes of both parents were normal. All chromosome deletions were de novo events. Possible causes for the chromosome deletion and the role of chromosome rearrangements in individuals with PLWS are discussed. Clinical characteristics of the deletion and nondeletion groups were recorded and compared with 124 individuals reported in the literature. Individuals with the chromosome deletion were found to have lighter hair, eye, and skin color, greater sun sensitivity, and higher intelligence scores than individuals with normal chromosomes. Correlation studies of metacarpophalangeal pattern profile variables and dermatoglyphic findings indicate apparent homogeneity of the deletion group and heterogeneity of individuals with PLWS and normal chromosomes.

The inspiratory workload of patient-initiated mechanical ventilation

Abstract: We quantified inspiratory effort during patient-triggered ventilator cycles in 20 critically ill patients receiving assisted mechanical ventilation (AMV). An index of the patient's work per liter of ventilation (WP) was defined as the difference in the mechanical work done by the ventilator during controlled and assisted breathing cycles at similar settings of tidal volume and flow. WP was estimated graphically from plots of airway pressure against inflation volume for peak flow settings of 60 L/min and 100 L/min. During patient-initiated cycles, effort did not cease with the onset of gas delivery. Values for WP varied widely but at both flow settings frequently equalled or exceeded the total workload expected for a spontaneously breathing normal subject. Furthermore, the patient's component of the mechanical workload during AMV was often a large percentage of the work performed during spontaneous breathing 30 s after discontinuing ventilator support (at 60 L/min: mean 62.6%; range 30.3 to 116.3%). The addition of deadspace to the external circuit increased VE and WP significantly. Both the maximally negative pressure generated against an occluded airway and the deflection of esophageal pressure in the first 100 ms after the onset of inspiratory effort were highly correlated with WP, suggesting the importance of strength and ventilatory drive as determinants of patient effort. WP correlated poorly with measures of chest mechanics, and there was no separation of WP values for the two flow rates we studied, perhaps because both settings exceeded the patient's spontaneous demand for airflow (FD).(ABSTRACT TRUNCATED AT 250 WORDS)

Sensitivity to perspective structure while walking without vision.

Abstract: Experiments are reported of the nonvisual sensitivity of observers to their paths of locomotion and to the resulting changes in the structure of their perspectives, ie changes in the network of directions and distances spatially relating them to objects fixed in the surrounding environment. In the first experiment it was found that adults can keep up to date on the changing structure of their perspectives even in the absence of sights and sounds that specify changes in self-to-object relations. They do this rapidly, accurately, and, according to the subjects' reports, automatically, as if perceiving the new perspective structures. The second experiment was designed to investigate the role of visual experience in the development of sensitivity to occluded changes in perspective structure by comparing the judgments of sighted adults with those of late-blinded adults (who had extensive life histories of vision) and those of early-blinded adults (who had little or no history of vision). The three groups perfo...

Functional reorganization in somatosensory cortical areas 3b and 1 of adult monkeys after median nerve repair: possible relationships to sensory recovery in humans

Abstract: Previous studies have shown that the primary somatosensory cortex of adult mammals undergoes somatotopic reorganization in response to peripheral nerve transection. The present study assesses how cortical organization is affected when a transected nerve subsequently regenerates. The median nerve to one hand of adult owl monkeys was transected and repaired. Following nerve regeneration, the representations of the hand in cortical areas 3b and 1 were studied with neurophysiological mapping methods. The major results were as follows: Peripherally, median nerve transection, repair, and regeneration resulted in reinnervation of the median nerve skin territory. Centrally, both the initial loss and subsequent regeneration of median nerve inputs caused reorganizational changes in cortex. Reorganizational changes were specifically restricted to regions of the hand cortex where inputs from the median nerve were normally represented. The functional features of cortical regions that recovered tactile responsiveness from reinnervated skin regions were abnormal in several respects. Most notably, these regions contained recording sites with abnormally located or multiple cutaneous receptive fields, and contained major topographical changes, such as reestablishment of palmar pad or digit representations in small, discontinuous patches of cortex. Normal organizational features were reestablished to a more limited extent. These features included recovery of delimited, discrete receptive fields and reestablishment of topographic representations for localized skin areas. Different transformations in topographical organization were seen in areas 3b and 1 of the same monkey. These results suggest that nerve regeneration reestablishes the cortical capacity to process tactile information from reinnervated skin via a prolonged reorganizational process that appears dependent on peripheral and central factors. Cortical recovery mechanisms clearly appear to have limitations, since preinjury patterns of cortical organization are not widely recovered even almost 1 year after repair. We suggest possible relationships between cortical reorganizational changes in these primates, and postrepair sensory changes in humans.

Swallowing and speech production in Parkinson's disease

Abstract: Videofluoroscopy was used to examine movement patterns during swallowing and speech production in 6 parkinsonian subjects and 6 age-matched controls. Motility patterns for liquid and semisolid swallows were documented. We performed temporospatial analyses of oropharyngeal structures, particularly the velum, which is prominently involved in both motor speech production and swallowing. Differences were found between groups and conditions. All of the parkinsonian subjects exhibited abnormal oropharyngeal movement patterns and timing during the volitional oral as well as the pharyngeal stage of swallowing; only 50% of these subjects admitted to any swallowing difficulty upon questioning. Two of the subjects with Parkinson's disease aspirated liquids. Duration of velar movement during speech production significantly differentiated the groups (p less than 0.01), reflecting reduced range of velar motion. Our findings suggest that rigidity and bradykinesia underlie the volitional speech abnormality as well as the disordered oral and pharyngeal stages of swallowing. Findings indicate that parkinsonian patients may be "silent aspirators" with decreased cough reflexes and lack of awareness of aspiration. The clinical value of videofluoroscopic monitoring of swallowing is that aspiration may be detected and managed early.

Corticocortical connections of area 2 of somatosensory cortex in macaque monkeys: a correlative anatomical and electrophysiological study.

Abstract: The cortical connections of electrophysiologically identified locations in the body representations in somatosensory cortex of macaque monkeys were investigated after injections of horseradish peroxidase, wheat germ agglutinin (WGA) conjugated with horseradish peroxidase, tritiated WGA, or tritiated proline. After extensive microelectrode mapping of portions of the body representations in areas 3b, 1, 2, and 5 and careful determinations of electrophysiological borders between areas, restricted injections of tracers were placed, usually into the representation of the hand in area 2. Other injections were placed in the foot representation in area 2 or in area 1, in the wrist representation in area 1, and in the forearm and wrist representation in area 5. Connection patterns were related to the physiological mapping results and to cortical cytoarchitecture. Injections confined to a lateral portion of area 2 representing the glabrous digits of the hand revealed reciprocal connections with the digit representations in areas 1 and 3b. Projections to area 2 were largely from layer III neurons in both of these fields, and return projections terminated largely in supragranular layers. Other inputs were from layer III cells in one or more separate locations in area 5 and in one or more closely spaced foci in the expected location of S-II in the lateral sulcus. These connections were also reciprocal with terminations apparent in layers IV and III. A few neurons in area 4 were labeled in some of these cases. Results were similar after an injection in the foot representation in area 2 with the differences that infragranular neurons, in addition to supragranular neurons, formed a substantial part of the projection to area 2, terminations as well as projections were noted from area 4, interconnections were found more rostrally in area 6, and a dense focus of label was apparent in the dorsal bank of cingulate sulcus in the apparent location of the supplementary motor area. Injections in the foot representation in area 1 revealed dense layer IV terminations in the foot representation in area 2, as well as connections with area 3b, the S-H region, and areas 5 and 7. The injection in the wrist representation in area 1 resulted in dense terminations in the portion of area 5 responsive to the distal forearm and hand, sparser connections with a lateral location in part of area 2 related to the hand, and interconnections with 3b and S-11. Finally, an injection in the forearm representation of a part of area 5 that is highly responsive to cutaneous stimuli revealed connections with area 1, area 7, and S-II. The results suggest that (1) somatotopically matched locations in area 3b and 1 provide much of the cutaneous receptor information for processing in area 2, (2) the highly cutaneous zone of area 5 receives cutaneous receptor information directly from area 1, (3) area 2 relays to area 5, and (4) major outputs of areas 1, 2, and at least a specialized cutaneous portion of area 5 are to the S-II region.