Showing papers by "Vanderbilt University published in 1989"

A Probabilistic Choice Model for Market Segmentation and Elasticity Structure

Abstract: Marketing scholars commonly characterize market structure by studying the patterns of substitution implied by brand switching. Though the approach is useful, it typically ignores the destabilizing ...

A membrane form of guanylate cyclase is an atrial natriuretic peptide receptor.

Abstract: ATRIAL natriuretic peptide (ANP) is a polypeptide hormone whose effects include the induction of diuresis, natriuresis and vasorelaxation1. One of the earliest events following binding of ANP to receptors on target cells is an increase in cyclic GMP concentration, indicating that this nucleotide might act as a mediator of the physiological effects of the hormone2,3. Guanylate cyclase exists in at least two different molecular forms: a soluble haem-containing enzyme consisting of two summits4,5 and a non-haem-containing transmembrane protein having a single subunit6. It is the membrane form of guanylate cyclase that is activated following binding of ANP to target cells3,7,8. We report here the isolation, sequence and expression of a complementary DNA clone encoding the membrane form of guanylate cyclase from rat brain. Transfec-tion of this cDNA into cultured mammalian cells results in expression of guanylate cyclase activity and ANP-binding activity. The ANP receptor/guanylate cyclase represents a new class of mammalian cell-surface receptors which contain an extracellular ligand-binding domain and an intracellular guanylate cyclase catalytic domain.

Genetic imprinting suggested by maternal heterodisomy in non-deletion Prader-Willi syndrome

Abstract: Prader-Willi syndrome (PWS) is the most common form of dysmorphic genetic obesity associated with mental retardation. About 60% of cases have a cytological deletion of chromosome 15q11q13 (refs 2, 3). These deletions occur de novo exclusively on the paternal chromosome. By contrast, Angelman syndrome (AS) is a very different clinical disorder and is also associated with deletions of region 15q11q13 (refs 6-8), indistinguishable from those in PWS except that they occur de novo on the maternal chromosome. The parental origin of the affected chromosomes 15 in these disorders could, therefore, be a contributory factor in determining their clinical phenotypes. We have now used cloned DNA markers specific for the 15q11q13 subregion to determine the parental origin of chromosome 15 in PWS individuals not having cytogenetic deletions; these individuals account for almost all of the remaining 40% of PWS cases. Probands in two families displayed maternal uniparental disomy for chromosome 15q11q13. This is the first demonstration that maternal heterodisomy--the presence of two different chromosome 15s derived from the mother--can be associated with a human genetic disease. The absence of a paternal contribution of genes in region 15q11q13, as found in PWS deletion cases, rather than a mutation in a specific gene(s) in this region may result in expression of the clinical phenotype. Thus, we conclude that a gene or genes in region 15q11q13 must be inherited from each parent for normal human development.

Coping with rheumatoid arthritis pain: catastrophizing as a maladaptive strategy

Abstract: The present study examined catastrophizing in rheumatoid arthritis (RA) patients. Subjects were 223 RA patients who were participants in a longitudinal study. Each patient completed the Catastrophizing scale of the Coping Strategies Questionnaire (CSQ) on 2 occasions separated by 6 months (time 1, time 2). The Catastrophizing scale is designed to measure negative self-statements, castastrophizing thoughts and ideation (sample items = 'I worry all the time about whether it will end,' 'It is awful and I feel that it overwhelms me'). Data analysis revealed that the Catastrophizing scale was internally reliable (alpha = 0.91) and had high test-retest reliability (r = 0.81) over a 6 month period. Correlational analyses revealed that catastrophizing recorded at time 1 was related to pain intensity ratings, functional impairment on the Arthritis Impact Measurement scale (AIMS), and depression at time 2. Predictive findings regarding catastrophizing while modest were obtained after controlling for initial scores on the dependent variables, demographic variables (age, sex, socioeconomic status), duration of pain, and disability support status. Taken together, these findings suggest that catastrophizing is a maladaptive coping strategy in RA patients. Further research is needed to determine whether cognitive-behavioral interventions designed to decrease catastrophizing can reduce pain and improve the physical and psychological functioning of RA patients.

Phylogenetic meaning of the kingdom concept: an unusual ribosomal RNA from Giardia lamblia

Abstract: An analysis of the small subunit ribosomal RNA (16S-like rRNA) from the protozoan Giardia lamblia provided a new perspective on the evolution of nucleated cells. Evolutionary distances estimated from sequence comparisons between the 16S-like rRNAs of Giardia lamblia and other eukaryotes exceed similar estimates of evolutionary diversity between archaebacteria and eubacteria and challenge the phylogenetic significance of multiple eukaryotic kingdoms. The Giardia lamblia 16S-like rRNA has retained many of the features that may have been present in the common ancestor of eukaryotes and prokaryotes.

A Neural Theory of Binocular Rivalry

Abstract: When the two eyes view discrepant monocular stimuli, stable single vision gives way to alternating periods of monocular dominance; this is the well-known but little understood phenomenon of binocular rivalry. This article develops a neural theory of binocular rivalry that treats the phenomenon as the default outcome when binocular correspondence cannot be established. The theory posits the existence of monocular and binocular neurons arrayed within a functional processing module, with monocular neurons playing a crucial role in signaling the stimulus conditions instigating rivalry and generating inhibitory signals to implement suppression. Suppression is conceived as a local process happening in parallel over the entire cortical representation of the binocular visual field. The strength of inhibition causing suppression is related to the size of the pool of monocular neurons innervated by the suppressed eye, and the duration of a suppression phase is attributed to the strength of excitation generated by the suppressed stimulus. The theory is compared with three other contemporary theories of binocular rivalry. The article closes with a discussion of some of the unresolved problems related to the theory.

Stages of change in psychotherapy: A follow-up report.

Abstract: The stages of change have already been well established with nonclinical populations. The present study was designed to cross–validate the Stages of Change Scales using a new clinical sample (N = 327). The principal component, internal consistency, and cluster profile analyses demonstrated a replica

The P450 Superfamily: Updated Listing of All Genes and Recommended Nomenclature for the Chromosomal Loci

Abstract: In this update we provide a list of the 71 P450 genes and the four P450 pseudogenes that have been characterized as of September 30, 1988. The chromosomal locations of many of these genes are also summarized. A modest revision of the initially proposed nomenclature of the P450 superfamily (Nebert et al., DNA 6, 1–11, 1987) is described specifically for the human and mouse chromosomal loci. The motivation for this revision is to conform to the rules of nomenclature for human and mouse genes. Recommendations for the naming of chromosomal loci include the root symbol "CYP" for human ("Cyp" for mouse), denoting "cytochrome P450." We recommend that this root also be used for other organisms. For a chromosomal locus, the root symbol is followed by an Arabic numeral designating the P450 family, a letter indicating the sub-family, and an Arabic numeral representing the individual gene within the family or subfamily. Numbers of the individual genes usually will be assigned in the order the genes are ident...

Benzodiazepines of long and short elimination half-life and the risk of hip fracture.

Abstract: To determine if the risk of hip fracture differed between persons receiving benzodiazepines with long (≥24 hours) or short ( (JAMA. 1989;262:3303-3307)

Overexpression of transforming growth factor α in psoriatic epidermis

Abstract: Transforming growth factor alpha (TGF-alpha) is produced by and required for the growth of epithelial cells and is angiogenic in vivo. Since epidermal hyperplasia and angiogenesis are hallmarks of psoriasis, TGF-alpha gene expression was analyzed in epidermal biopsies of normal and psoriatic skin. TGF-alpha messenger RNA and protein are much more abundant in lesional psoriatic epidermis than in normal-appearing skin of psoriatic patients or in normal epidermis. In contrast, messenger RNA levels of transforming growth factor beta 1 (TGF-beta 1), which inhibits epithelial cell growth, are not significantly different in normal, uninvolved, and lesional psoriatic epidermis. Thus, psoriatic epidermal hyperplasia may involve increased expression of a keratinocyte mitogen (TGF-alpha) rather than deficient expression of a growth inhibitor (TGF-beta 1).

Calcium/calmodulin-dependent protein kinase II.

Abstract: Publisher Summary This chapter discusses the presently known calcium (Ca 2+ )/calmodulin (CaM)-dependent protein kinases and some of their properties. To date, CaM kinase II is the only Ca 2+ )/CaM-dependent protein kinase known to phosphorylate a wide range of proteins and for this reason, it is sometimes referred to as the CaM-dependent multifunctional protein kinase or CaM-dependent multiprotein kinase. These properties, mainly established in vitro , together with the wide distribution of the kinase, suggest that CaM kinase II may be involved in the regulation of numerous physiological functions. The chapter summarizes the present knowledge of CaM kinase II with the particular emphasis on the molecular mechanisms involved in the regulation of kinase activity. It also reviews the literature concerning the putative physiological functions of the kinase. There is a great deal known about the in vitro properties of calmodulin (CaM) kinase II, both in terms of its substrate specificity and its regulation by CaM and autophosphorylation. Much of this characterization is based on the experiments performed with rat brain isozyme of CaM kinase II, although in the aspects examined to date isozymes of the kinase from other tissues appear to behave in a broadly similar manner in vitro . However, relatively little is known about the functions of the kinase in vivo . Investigation of the physiological role of the kinase in brain and other tissues will be a particularly exciting area for future work. The current knowledge of the in vitro properties and the availability of complimentary DNA (cDNA) clones will hopefully expedite this research.

Role of inhibition in the specification of orientation selectivity of cells in the cat striate cortex.

Abstract: Mechanisms supporting orientation selectivity of cat striate cortical cells were studied by stimulation with two superimposed sine-wave gratings of different orientations. One grating (base) generated a discharge of known amplitude which could be modified by the second grating (mask). Masks presented at nonoptimal orientations usually reduced the base-generated response, but the degree of reduction varied widely between cells. Cells with narrow orientation tuning tended to be more susceptible to mask presence than broadly tuned cells; similarly, simple cells generally showed more response reduction than did complex cells. The base and mask stimuli were drifted at different temporal frequencies which, in simple cells, permitted the identification of individual response components from each stimulus. This revealed that the reduction of the base response by the mask usually did not vary regularly with mask orientation, although response facilitation from the mask was orientation selective. In some sharply tuned simple cells, response reduction had clear local maxima near the limits of the cell's orientation-tuning function. Response reduction resulted from a nearly pure rightward shift of the response versus log contrast function. The lowest mask contrast yielding reduction was within 0.1-0.3 log unit of the lowest contrast effective for excitation. The temporal-frequency bandpass of the response-reduction mechanism resembled that of most cortical cells. The spatial-frequency bandpass was much broader than is typical for single cortical cells, spanning essentially the entire visual range of the cat. These findings are compatible with a model in which weak intrinsic orientation-selective excitation is enhanced in two stages: (1) control of threshold by nonorientation-selective inhibition that is continuously dependent on stimulus contrast; and (2) in the more narrowly tuned cells, orientation-selective inhibition that has local maxima serving to increase the slope of the orientation-tuning function.

Patterns of expression of murine Vgr-1 and BMP-2a RNA suggest that transforming growth factor-beta-like genes coordinately regulate aspects of embryonic development.

Abstract: The murine Vgr-1 (Vg-related) and BMP-2a (bone morphogenetic protein 2a) genes are members of the decapentaplegic subgroup of the transforming growth factor-beta (TGF beta) superfamily. Although genetic and biochemical studies suggest that the members of this subgroup play important roles in development, little is known about their function in mammals. Therefore, we investigated the expression of Vgr-1 and BMP-2a RNAs in embryonic, newborn, and adult tissues by in situ hybridization. Vgr-1 RNA is maternally encoded in ovarian oocytes but declines in fertilized eggs and is undectable by the two- to four-cell stage. Only low levels of transcripts are seen in blastocysts and early postimplantation stages. From mid-gestation on, Vgr-1 RNA is expressed at high levels in developing skin, especially in the suprabasal cells of the proliferating epidermis but not in the dermis or hair follicles, both of which contain TGF beta 1 and/or TGF beta 2 RNAs. In contrast, BMP-2a transcripts are seen only in the hair follicles in the cells of the hair bulb cortex. Temporally and spatially distinct patterns of BMP-2a, Vgr-1, TGF beta 1, and TGF beta 2 expression are also seen in different populations of mesenchymal cells in the developing skeletal system (cartilage and bone). Our results suggest that the coordinated expression of several members of the TGF beta superfamily is required to control the progression of specific cell types through their differentiation pathways.

New approaches to instruction: because wisdom can't be told

Abstract: The subtitle of this chapter is borrowed from an article published in 1940 by Charles L. Cragg. He begins with the following quotation from Balzac: So he had grown rich at last, and thought to transmit to his only son all the cut-and-dried experience which he himself had purchased at the price of his lost illusions; a noble last illusion of age. Except for the part about growing rich, we find that Balzac's ideas fit our experiences quite well. In our roles as parents, friends, supervisors, and professional educators we frequently attempt to prepare people for the future by imparting the wisdom gleaned from our own experiences. Sometimes our efforts are rewarded, but we are often less successful than we would like to be and we need to understand why. Our goal in this chapter is to examine the task of preparing people for the future by exploring the notion that wisdom can't be told. Our arguments are divided into four parts. First, we consider in more detail the notion that wisdom cannot be told. The argument is not that people are unable to learn from being shown or told. Clearly, we can remind people of important sets of information and tell them new information, and they can often tell it back to us. However, this provides no guarantee that people will develop the kinds of sensitivities necessary to use relevant information in new situations.

Mesangial cell, glomerular and renal vascular responses to endothelin in the rat kidney. Elucidation of signal transduction pathways.

Abstract: We investigated the actions of endothelin in anesthetized rats and cultured mesangial cells. Intravenous infusion of endothelin (10 pmol/min) decreased renal blood flow by 44% at 20 min without changing arterial pressure, which subsequently rose significantly from 124 +/- 3 to 133 +/- 4 mmHg over 60 min. Micropuncture during the nonhypertensive period revealed increases in afferent (65%) and efferent (82%) arteriolar resistances, thereby reducing nephron plasma flow rate. The glomerular ultrafiltration coefficient (Kf) fell from 0.097 +/- 0.035 to 0.031 +/- 0.011 nl/(s.mmHg) as did single nephron filtration rate (41 +/- 3 to 19 +/- 3 nl/min). Addition of 5 nM endothelin to mesangial cells plated on a silicone rubber substrate increased the intensity and number of tension-generated wrinkles, and caused their reappearance in forskolin prerelaxed cells. 20-30 s following exposure of fura-2 loaded mesangial cells to 10 nM endothelin, single cell intracellular calcium concentration ([Ca]i) increased from a mean baseline value of 66 +/- 11 (SE) to a peak of 684 +/- 250 nM (P less than 0.05) followed by a sustained elevation at 145 +/- 42 nM. Anion exchange HPLC revealed rapid (15 s) and dose-dependent stimulation of inositol 1,4,5-trisphosphate (IP3) generation following exposure of [3H]myoinositol preloaded mesangial cells to 10-100 nM endothelin. Endothelin also led to intracellular alkalinization of 2'7'-bis(2-carboxy-ethyl)-5(and-6)carboxyfluorescein (BCECF)-loaded mesangial cells and its addition was associated with dramatic augmentation of mitogenic activity. Thus, endothelin exerts potent constrictor effects on renal arterioles which precede its systemic hypertensive action. It lowers Kf and contracts mesangial cells, likely through stimulation of IP3 generation and elevation of [Ca]i. It is a potent mesangial cell mitogen. These studies define functional responses and signal transduction pathways for endothelin in the rat kidney and propose a potential role for this peptide in the control of mesangial cell function, glomerular filtration rate, and renal vascular tone.

The antihypertensive effects of fish oil. A controlled study of polyunsaturated fatty acid supplements in essential hypertension.

Abstract: Both n–3 and n–6 polyunsaturated fats have been suggested to lower blood pressure, an effect ascribed to altered biosynthesis of eicosanoids. To test these hypotheses, we studied blood pressure and eicosanoid production during supplementation of dietary fat for four weeks in 32 men with mild essential hypertension. Supplementation was preceded and followed by four-week run-in and recovery periods. Groups of eight subjects received either 10 ml or 50 ml of fish oil (3 or 15 g of n–3 fatty acids) daily, 50 ml of safflower oil (39 g of n–6 fatty acids), or 50 ml of a mixture of oils that approximated the types of fat present in the American diet. The biosynthesis of eicosanoids was assessed by the measurement of urinary metabolites. Blood pressure decreased in the men who received the high dose of fish oil (systolic pressure by a mean of 6.5 mm Hg [P<0.03] and diastolic pressure by 4.4 mm Hg [P<0.015]), but not in the other groups. Although the formation of vasodilatory prostacyclins (prostaglandins...

Access to Knowledge of Spatial Structure at Novel Points of Observation

Abstract: Adults were asked to judge the self-to-object directions in a room from novel points of observation that differed from their actual point at times only by a rotation and at other times only by a translation. The results show for the rotation trials that the errors and latencies when a novel point was imagined were worse than the baseline responses from their actual points of observation, and the latencies varied as a function of the magnitude of the to-be-imagined rotation. For the translation trials, on the other hand, the errors and latencies when a novel point was imagined were comparable to the baseline responses from their actual point and did not vary significantly across the different imagined station points. The evidence indicates that subjects know the objectto-object relations directly, without going through the origin of a coordinate system. In addition, similarities in processing during imagination on the one hand, and perception and action on the other are discussed. The spatial structure of a place consists of the distances and directions relating its objects, features, and events. Observers often produce spatially coordinated action while on the move and plan actions before reaching the station points from which they intend to launch them. This is the case when one plans a route before embarking on a trip. And it is implied whenever one launches an act while on the move, because the motor plan to control the act must be set before the launching point is reached. Because of this, observers need access to knowledge of the spatial structure of places from novel station points. The present experiments are about observers' abilities to imagine the spatial structure available at novel points of observation and about some of the conditions that facilitate access to such knowledge. In each experiment observers stood at one point of observation and viewed the locations of target objects scattered around them in a room. Then they were asked to close their eyes, imagine they occupied a novel point of observation, and aim a pointer at the targets relative to the novel point.

Evidence of significant radiographic damage in rheumatoid arthritis within the first 2 years of disease.

Abstract: Quantitative radiographic scores for joint space narrowing erosion, and malalignment in the hands and wrists of 200 patients with rheumatoid arthritis (RA) were significantly correlated with duration of disease. Nonetheless, most of the 42 patients who reported disease for less than 2 years had evidence of radiographic damage, including 35 with joint space narrowing, 28 with erosions but only one with malalignment. Significant radiographic damage in the absence of malalignment may be seen in many patients within the first 2 years after presentation of RA.

Epidermal growth factor stimulates tyrosine phosphorylation of phospholipase C-II independently of receptor internalization and extracellular calcium

Abstract: Epidermal growth factor (EGF) rapidly stimulates the formation of inositol 1,4,5-trisphosphate in a variety of cell types. Previously we have found that in intact cells stimulation of phospholipase C (PLC) activity by EGF is correlated with the retention of increased amounts of PLC activity by a phosphotyrosine immunoaffinity matrix, suggesting that the EGF-receptor tyrosine kinase phosphorylates PLC. We now define parameters of the mechanism by which EGF addition to A-431 cells stimulates phosphotyrosine immunoisolation of PLC activity and demonstrate that EGF addition to A-431 cells increases tyrosine phosphorylation of PLC. EGF rapidly and reversibly stimulated the anti-phosphotyrosine recovery of increased PLC activity when cells were treated with growth factor at 3 degrees C, indicating that receptor internalization is not required and that the phosphorylation event occurs prior to formation of inositol 1,4,5-trisphosphate. Also, the EGF stimulation of anti-phosphotyrosine recovery of PLC activity occurred in the absence of extracellular Ca2+. Stimulation of PLC activity in intact cells by other agonists, such as bradykinin or ATP, did not result in increased anti-phosphotyrosine recovery of PLC activity, suggesting two separate mechanisms exist in A-431 cells for hormone-stimulated formation of inositol phosphates. Finally, using monoclonal antibodies that specifically recognize three distinct PLC isozymes, we show that an approximately 145-kDa PLC isozyme (PLC-II) is present in A-431 cells and that EGF treatment of A-431 cells stimulates phosphorylation of PLC-II on both tyrosine and serine residues.

Glomerular actions of endothelin in vivo.

Abstract: In Munich-Wistar rats, a micropipette was inserted into a first-order branch of the left main renal artery and continuously infused with human/porcine endothelin (0.4 ng/min). Micropuncture measurements revealed substantial differences within the cortical microcirculation of the same left kidney: SNGFR was some 35% lower in glomeruli exposed to endothelin compared with non-endothelin-perfused glomeruli (P less than 0.005). Similarly, glomerular plasma flow rate was some 38% lower in the endothelin-exposed glomeruli (P less than 0.001). The hypoperfusion and hypofiltration in the endothelin-exposed glomeruli reflected an increase in resistances in the afferent and efferent arterioles. There was no difference in the value of the glomerular capillary ultrafiltration coefficient between the two populations of glomeruli. We also studied kidneys that underwent 25 min of renal artery clamping 48 h before study. Antiendothelin antibody infused into one of the branches of the main renal artery ameliorated the vasoconstriction characteristic of postischemic nephrons: within the cortical microcirculation, the SNGFR in glomeruli exposed to antiendothelin antibody was 27.0 +/- 3.1 nl/min as compared with 17.4 +/- 1.7 measured in glomeruli not perfused with the antibody (P less than 0.001). Similarly, glomerular plasma flow rate was higher in the glomeruli exposed to antiendothelin antibody (128.7 +/- 14.4 nl/min vs. 66.6 +/- 5.6, P less than 0.005). Resistances in both the afferent and efferent arterioles were substantially lower in the antibody-exposed glomeruli. It is, therefore, suggested that endothelin, presumably released from damaged endothelium, may play an important intermediary role in the hypoperfusion and hypofiltration observed in postischemic kidneys.

Regulation of intestinal epithelial cell growth by transforming growth factor type beta

Abstract: A nontransformed rat jejunal crypt cell line (IEC-6) expresses transforming growth factor type beta 1 (TGF-beta 1) mRNA, secretes latent 125I-labeled TGF-beta 1 competing activity into culture medium, and binds 125I-labeled TGF-beta 1 to specific, high-affinity (Kd = 3.7 pM) cell surface receptors. IEC-6 cell growth is markedly inhibited by TGF-beta 1 and TGF-beta 2 with half-maximal inhibition occurring between 0.1 and 1.0 ng of TGF-beta 1 per ml. TGF-beta 1-mediated growth inhibition is not associated with the appearance of biochemical markers of enterocyte differentiation such as alkaline phosphatase expression and sucrase activity. TGF-beta 1 (10 ng/ml) increases steady-state levels of its own mRNA expression within 8 hr of treatment of rapidly growing IEC-6 cells. In freshly isolated rat jejunal enterocytes that are sequentially eluted from the crypt villus axis, TGF-beta 1 mRNA expression is most abundant in terminally differentiated villus tip cells and least abundant in the less differentiated, mitotically active crypt cells. We conclude that TGF-beta 1 is an autoregulated growth inhibitor in IEC-6 cells that potentially functions in an autocrine manner. In the rat jejunal epithelium, TGF-beta 1 expression is most prominently localized to the villus tip--i.e., the region of the crypt villus unit that is characterized by the terminally differentiated phenotype. These data suggest that TGF-beta 1 may function in coordination of the rapid cell turnover typical for the intestinal epithelium.

Subjective hierarchies in spatial memory.

Abstract: Two experiments investigated the structure of spatial memories. Subjects learned locations of objects in spatial layouts (Experiment 1) or locations of object names on maps (Experiment 2). Physical and perceptual boundaries were absent in these spatial arrays. Subjects then participated in three tasks: item recognition, in which the variable of interest was spatial priming; free and cued recall; and Euclidean distance estimation. Ordered-tree analysis of individual subjects' recall protocols produced hierarchical trees consistent with regularities in output order. Spatial priming and distance estimations depended on whether pairs of objects appeared in the same subtree or in different subtrees. These findings indicate that spatial memories have a hierarchical component, even when physical and perceptual boundaries are nonexistent. Priming also increased with depth of clustering in ordered trees. This result supports spreading-activation theories of retrieval but provides evidence against several "non-spreading-activation" theories. Language: en

The Protein Kinase Domain of the ANP Receptor Is Required for Signaling

Abstract: A plasma membrane form of guanylate cyclase is a cell surface receptor for atrial natriuretic peptide (ANP). In response to ANP binding, the receptor-enzyme produces increased amounts of the second messenger, guanosine 3',5'-monophosphate. Maximal activation of the cyclase requires the presence of adenosine 5'-triphosphate (ATP) or nonhydrolyzable ATP analogs. The intracellular region of the receptor contains at least two domains with homology to other proteins, one possessing sequence similarity to protein kinase catalytic domains, the other to regions of unknown function in a cytoplasmic form of guanylate cyclase and in adenylate cyclase. It is now shown that the protein kinase-like domain functions as a regulatory element and that the second domain possesses catalytic activity. When the kinase-like domain was removed by deletion mutagenesis, the resulting ANP receptor retained guanylate cyclase activity, but this activity was independent of ANP and its stimulation by ATP was markedly reduced. A model for signal transduction is suggested in which binding of ANP to the extracellular domain of its receptor initiates a conformational change in the protein kinase-like domain, resulting in derepression of guanylate cyclase activity.

Evidence for cytochrome P-450NF, the nifedipine oxidase, being the principal enzyme involved in the bioactivation of aflatoxins in human liver.

Abstract: In vitro studies with human liver indicate that the major catalyst involved in the bioactivation of the hepato-carcinogen aflatoxin B1 (AFB1) to its genotoxic 2,3-epoxide derivative is cytochrome P-450NF (P-450NF), a previously characterized protein that also catalyzes the oxidation of nifedipine and other dihydropyridines, quinidine, macrolide antibiotics, various steroids, and other compounds Evidence was obtained using activation of AFB1 as monitored by umuC gene expression response in Salmonella typhimurium TA1535/pSK1002 and enzyme reconstitution, immunochemical inhibition, correlation of response with levels of P-450NF and nifedipine oxidase activity in different liver samples, stimulation of activity by 7,8-benzoflavone, and inhibition of activity by troleandomycin Similar results were obtained when levels of 2,3-dihydro-2-(N7-guanyl)-3-hydroxyaflatoxin B1 formed in DNA were measured P-450NF or a closely related protein also appears to be the major catalyst involved in the activation of aflatoxin G1 and sterigmatocystin, the latter compound being more genotoxic than AFB1 in these systems Several drugs and conditions are known to influence the levels and activity of P-450NF in human liver, and the activity of the enzyme can be estimated by noninvasive assays These findings provide a test system for the hypothesis that a specific human disease state (liver cancer) is linked to the level of oxidative metabolism in populations in which aflatoxin ingestion is high

Children with Recurrent Abdominal Pain and Their Parents: More Somatic Complaints, Anxiety, and Depression than Other Patient Families?

Abstract: Patients presenting with abdominal pain were classified into two groups: the recurrent abdominal pain (RAP) group (n = 41), consisting of patients without identifiable organic etiology for abdominal pain, and the organic group (n = 28), consisting of patients with organic findings (primarily ulcer-related conditions) A control group of well patients (n = 41) also participated RAP and organic patients had higher anxiety, depression, and somatic complaints than well patients, but did not differ from each other Anxiety, depression, and somatization were greater in RAP mothers than well mothers Father symptomatology did not differ for the groups Results suggest that psychological distress does not discriminate between patients with and without identifiable organic etiology for abdominal pain The high levels of anxiety and depression in RAP and organic patients suggest that they should be targeted in efforts to address "the new hidden morbidity" in pediatrics