Reflections on "A Cluster Analysis of institutionalized mentally retarded individuals".
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Activities of Daily Living↗
Biomedical subjects
J F White
Publications and source records attributed to J F White.
Inhibition of Na,K-ATPase and sodium pump by anticancer ether lipids and protein kinase C inhibitors ET-18-OCH3 and BM 41.440.
The anticancer ether lipid analogs ET-18-OCH3 and BM 41.440 inhibited Na, K-ATPase in the purified rat brain membrane fragments, with a potency comparable to that of their inhibition of protein kinase C. They also inhibited Na,K-ATPase in the crude membrane fraction of HL60 cells. Kinetic analysis indicated that the lipids had a mode of action different from that of ouabain, a classic inhibitor of the ATPase. The lipids also blocked 22Na uptake in the inside-out membrane vesicles of human erythrocytes. It is suggested that Na,K-ATPase might represent an additional site with which certain protein kinase C inhibitors can interact to alter cellular activities.
Animals↗
Synthesis and structure-activity relationships of 2-sulfonamido-1,3,4,6,7,11b alpha-hexahydro-2H-benzo[a]quinolizines as alpha 2-adrenoceptor antagonists.
A series of 2-sulfonamido-1,3,4,6,7,11b alpha-hexahydro-2H-benzo[a]quinolizines were synthesized and examined for alpha 2- and alpha 1-adrenoceptor antagonist activity on the rat vas deferens and anococcygeus muscle, respectively. A number of compounds in this series were shown to be potent and selective alpha 2-adrenoceptor antagonists. Studies on the resolved enantiomers of compounds 6, 10, and 16 showed that alpha 2-adrenoceptor antagonist activity resided primarily in the 2R,11bS isomers, related to the absolute configuration of the alpha 2-antagonist yohimbine, such that the benzene ring and sulfonamide groups in this series were superimposable on the pyrrole and ester groups of yohimbine.
Animals↗
Prediction of mortality in community and institutional settings.
This study attempted to re-evaluate predictors of mortality based on a large sample of mentally retarded individuals. Additionally, mortality rates were compared among several types of placements including institutions after controlling for the most salient predictors of death. The findings indicated that non-mobility and the need for medical support add to the risk of an early death for these children, and are significant indicators of mortality, regardless of level of retardation and placement.
Activities of Daily Living↗
Norepinephrine induces Na+-H+ and Cl -HCO3 exchange in Amphiuma intestine: locus and response to amiloride.
Catecholamines stimulate Na+-dependent acid secretion by Amphiuma small intestine. Studies were undertaken to localize the response within the mucosa and characterize the effect on Na+ and Cl- transport. Stripped segments of jejunum were mounted in tissue chambers that permitted isolation of villus or intervillus epithelium. In Cl-free medium, norepinephrine (NE) stimulated the transepithelial voltage (Vms) in both villus and intervillus epithelium, whereas galactose and valine elevated Vms predominately in the villus. Paired segments of whole mucosa were maintained under short circuit while the rate of acid secretion (JH) was measured by titration of the unbuffered serosal medium and unidirectional fluxes of Na+ were measured by 22Na. NE significantly stimulated net Na+ absorption (JNanet), short circuit current (Isc), and JH. Amiloride reduced JH and Isc in NE-stimulated tissues and blocked the stimulation of JNanet by NE. The NE-induced current was nearly completely and reversibly inhibited by replacement of luminal medium HCO3- or CO2. NE significantly stimulated net Cl- absorption without changing Isc or JH. It is concluded that cells throughout the mucosa respond to catecholamines with enhanced Na+ and Cl- absorption, possibly through induction or stimulation of Na+-H+ and Cl- -HCO3- exchange.
Acetazolamide↗
Alpha 2-receptors mediate catecholamine-stimulated acid secretion in Amphiuma jejunum.
The receptors mediating adrenergic stimulation of acid secretion by Amphiuma jejunum were characterized in this study using alpha- and beta-adrenergic agonists and antagonists. Isolated segments of jejunum were mounted in Ussing chambers and bathed in Cl- -free (SO4(2-] medium. Shortcircuit current (Isc) and acid secretion (JH) were recorded, the latter by measuring the rate of alkalinization of the serosal medium. The beta-adrenergic receptor antagonist, propranolol (10(-4) M), had no effect on the Isc and JH stimulated by norepinephrine (NE). The alpha 2-adrenergic agonists, clonidine and UK-14,304, mimicked the effect of NE, with effective concentrations providing 50% maximal delta Isc of 2.0 X 10(-7) and 9.0 X 10(-8) M, respectively. NE added subsequently produced no greater stimulation. In contrast, the alpha 1-adrenergic agonists, phenylephrine and methoxamine, produced little stimulation of JH and Isc; NE added subsequently stimulated the Isc. The alpha 1-adrenergic antagonist prazosin had no effect on the NE-induced Isc or JH, whereas the alpha 2-adrenergic antagonist yohimbine inhibited the NE-stimulated Isc with a half-maximal effective concentration of 3.5 X 10(-7) M. Yohimbine (10(-4) M) reduced the NE-stimulated Isc by 88%, whereas the spontaneous Isc was reduced by only 12%. These results demonstrate that alpha 2-adrenergic receptors on the basolateral membrane of Amphiuma enterocytes mediate NE-enhanced, but not spontaneous, intestinal acid secretion.
Animals↗
Is there a Cl- pump?
Three universally accepted mechanisms of Cl- transport across plasma membranes exist and they are 1) anion-coupled antiport, 2) cation-coupled symport, and 3) coupling to primary active ion transport through electrical and/or chemical processes. No unequivocal direct evidence has been provided for primary active Cl- transport (Cl- pump) despite numerous reports of cellular Cl- -stimulated adenosinetriphosphatase (ATPases) and of Cl- transport that cannot be accounted for by the three well-documented Cl- transport processes. It has been demonstrated that Cl- -stimulated ATPase activity is localized to both mitochondrial and microsomal aspects of the cellular apparatus. However, one group ascribes microsomal localization of Cl- -stimulated ATPase activity to mitochondrial contamination of that membrane fraction. Therefore, no Cl- pump could ever exist naturally in any plasma membrane. The other group simply states that there is plasma membrane localization of Cl- -stimulated ATPase activity that could function as a Cl- pump. Both arguments are logically advanced and their conclusions are consistent with their respective premises. Resolution to the question Is there a Cl- pump? rests with each reader's critique and objective evaluation.
Acetabularia↗
Post-embedding methods for immunolocalization of elastin and related components in tissues.
Elastic tissue is composed of amorphous-appearing elastin and 12-nm diameter microfibrils, one component of which has recently been isolated and characterized as the 31 KD microfibril-associated glycoprotein MAGP. Monospecific antibodies to each of these components have been developed in this laboratory. The parameters that determine optimal localization of colloidal gold probes for post-embedding immunolabeling of elastic tissue components have been systematically studied in a variety of normal and developing tissues in mammals and birds. Protein A-gold probes stabilized with dextran have been shown to provide complexes that remain stable after more than 2 years. Conditions have been defined that permit precise localization within the extracellular matrix of antibodies to MAGP and to elastin, singly and together. Best results were obtained with acrylic resins (Lowicryl K4M or LR White). Fixation in glutaraldehyde or other aldehydic fixatives, with or without osmium, did not affect the immunostaining of elastic tissue with affinity-purified antibodies to tropoelastin, or to anti-[alpha-elastin] or anti-[alkali-insoluble elastin]. Immunostaining with the anti-MAGP antibody was less robust and was possible in tissues which had been fixed only lightly before embedding in Lowicryl K4M or LR White. This staining was enhanced by metaperiodate oxidation of the sections as well as by reduction of the tissues with sodium borohydride en bloc, followed by hyaluronidase digestion of the sections. The effects on immunostaining of a range of enzyme digestions have also been examined. Conditions have thus been defined that make possible detailed study of the relationship between elastic tissue, elastin-associated microfibrils, and other microfibrillar structures in normal and abnormal tissues during development and aging.
Animals↗
Effects of age on the adaptive behavior of institutionalized and noninstitutionalized individuals with Down syndrome.
The effects of age on the adaptive behavior of individuals with Down syndrome and matched individuals in other diagnostic categories were compared in three studies. The only study that provided evidence of a decline in competence among older individuals with Down syndrome was the one study in which the oldest age category was 60 years and over. In that study, a significant Age X Diagnosis interaction was found for the Motor Development factor of the Client Development Evaluation Report, reflecting a sharp drop in the scores of some of the oldest subjects with Down syndrome. These results resemble those of other recent research in two respects: the age at which the decline in competence occurred and the nature of that decline.
Activities of Daily Living↗
Experimental drug-induced immune thrombocytopenia in monkeys.
In these studies we report the induction, by 7,8-dimethoxy-1H-3-benzaepin-2-amine HCl, of immune thrombocytopenia in monkeys and its characterization by flow cytometry. Three of eight monkeys developed thrombocytopenia following administration of high doses (35 mg/kg) of the drug. The characteristics of the thrombocytopenia, including rapid induction on rechallenge with the drug, met the criteria indicative of drug-induced immune thrombocytopenia. Platelet surface-associated immunoglobulin could be detected by flow cytometry as early as 21 days before the onset of thrombocytopenia. A critical concentration of antibody on the platelet surface appeared to be necessary for elimination of the platelets from the blood. Evidence from experiments using the serum from an affected monkey suggested that drug interaction with the platelet surface produced a site for antibody binding, possibly a neoantigen, which required the continued presence of the drug.
Animals↗
Interactions of adrenaline and magnesium on the cardiovascular system of the baboon.
Cardiovascular variables were measured in baboons before and during an adrenaline infusion at 1 microgram/kg/min, and following two bolus injections of either MgSO4 60 mg/kg or saline. Arterial blood pressure (ABP), systemic vascular resistance (SVR), central venous pressure (CVP), pulmonary arterial pressure and pulmonary capillary wedge pressure were all elevated by the adrenaline infusion. Cardiac output (CO), stroke volume (SV) and heart rate were unchanged but multifocal arrhythmias occurred. Mg infusion abolished arrhythmias and markedly increased CO and SV. SVR was reduced below baseline values by Mg, and ABP and CVP returned toward baseline. Saline did not alter adrenaline-induced changes in any way. It is concluded that Mg has powerful antiarrhythmic effects in the presence of catecholamines and, in addition, may have useful alpha-adrenergic antagonist effects.
Animals↗
Na microelectrode study of pathways of Na entry into Amphiuma intestinal absorptive cells.
To define the pathways of Na+ entry into intestinal villus cells, intracellular Na+ activity (aiNa) was measured in Amphiuma duodenum using conventional and Na-sensitive microelectrodes. Replacement of Na+ in the luminal medium reduced aiNa rapidly; replacement of Na+ in the serosal medium caused a slow decline of aiNa. Hence, mucosal and serosal membranes are both permeable to Na+. Ouabain addition to the serosal medium caused aiNa to increase over 4 h. When Na+ was present only in the mucosal medium and Na+ transport was inhibited with ouabain, aiNa increased over 4 h. With galactose or valine (20 mM) in the mucosal medium aiNa was greater at 2 h relative to paired control tissues. The gain in aiNa was unaffected by replacement of luminal medium Cl- with gluconate or exposure to 1 mM furosemide or amiloride. Amiloride, at 1 mM, was detected by the Na-sensitive neutral carrier. Over a wide range of Na+ concentrations in the luminal medium the rate of Na+ entry across the mucosal membrane correlated strongly (r = 0.95) with the electrochemical gradient for Na+ across the luminal membrane. It is concluded that aiNa of urodele intestinal cells is maintained at a low level by the operation of a Na+-K+ pump. Na+ entry across the luminal membrane occurs by diffusion and by the cotransport with sugars and amino acids. Luminal NaCl cotransport and Na+-H+ exchange do not appear to contribute to Na entry to a measurable extent but it is possible that these transport processes operate at a slow rate, but were inhibited secondary to inhibition of the Na-K pump.
Absorption↗
Client characteristics and residential placement patterns.
Recent emphases on deinstitutionalization and community placement have been accompanied by the development of a range of residential placement alternatives and by shifts in the control of placement decisions. In this study we examined the patterns of placement into these alternatives for 66,367 clients receiving services for mentally retarded persons from the state of California and evaluated the ability of client characteristics to discriminate among clients in four residential placement types. Results of the discriminant analyses suggest that client characteristics, including maladaptive behavior, age, ethnicity, medical problems, ambulation, toileting, and speech, are important factors in the consideration of residential placement for mentally retarded people.
Activities of Daily Living↗
The accessory nerve nucleus in the baboon.
In the savanna baboon, Papio cynocephalus, the accessory nerve nucleus was identified by using a mixture of 20% free horseradish peroxidase (HRP) and 2.5% HRP conjugated to wheat germ agglutinin (WGA) in a 5% aqueous detergent solution (Nonidet P-40). Following surgical exposure of the appropriate nerve branch to the sternocleidomastoid or trapezius muscle, the nerve was transected, placed in an Argyle tubing collar, and bathed in 5-10 microliter of the tracer. After a 48-hour survival time and vascular perfusion-fixation, 40-micron sections of the lower medulla oblongata and the cervical spinal cord were treated according to the tetramethyl benzidine (TMB)-HRP method of Mesulam (J. Histochem. Cytochem. 26: 106-117, 1978). The accessory nucleus extends as a distinct column of neurons from lower medullary levels into the rostral part of C5. One to ten labeled cells were present in each section, and all labeled neurons were located on the side of the bathed nerve. The rostral portion of the accessory nucleus occupies a central position, its intermediate portion occupies a lateral position, and its caudal portion occupies a central position within the ventral horn. All labeled neurons were confined to Rexed's lamina IX, ranged from 15 to 75 micron in diameter, and were either distinctly round (oval) or stellate in shape. Neurons within the baboon accessory nucleus supplying the sternocleidomastoid muscle were located from lower medullary to upper C2 spinal cord levels, while those supplying the trapezius muscle extended from C2 to C5.
Accessory Nerve↗
Modes of Cl- transport across the mucosal and serosal membranes of urodele intestinal cells.
The characteristics of Cl- movement across luminal and basolateral membranes of Amphiuma intestinal absorptive cells were studied using Cl(-)-sensitive microelectrodes and tracer 36Cl techniques. Intracellular Cl- activity (aiCl) was unchanged when serosal Cl- was replaced; when luminal Cl- was replaced cell Cl- was rapidly lost. Accordingly, the steady state aiCl could be varied by changing the luminal [Cl]. As luminal [Cl] was raised from 1 to 86 mM, aiCl rose in a linear manner, the mucosal membrane hyperpolarized, and the transepithelial voltage became serosa negative. In contrast, the rate of Cl- transport from the cell into the serosal medium, measured as the SITS-inhibitable portion of the Cl- absorptive flux, attained a maximum when aiCl reached an apparent value of 17 mM, indicating the presence of a saturable, serosal transport step. The stilbene-insensitive absorptive flux was linear with luminal [Cl], suggestive of a paracellular route of movement. Intracellular aCl was near electrochemical equilibrium at all but the lowest values of luminal [Cl] after interference produced by other anions was taken into account. aiCl was unaffected by Na replacement, removal of medium K, or elevation of medium HCO-3. Mucosae labeled with 36Cl lost isotope into both luminal and serosal media at the same rate and from compartments of equal capacity. Lowering luminal [Cl] or addition of theophylline enhanced luminal Cl- efflux. It is concluded that a conductive Cl leak pathway is present in the luminal membrane. Serosal transfer is by a saturable, stilbene-inhibitable pathway. Luminal Cl- entry appears to be passive, but an electrogenic uptake cannot be discounted.
Animals↗
Effect of sugars and amino acids on amphibian intestinal Cl- transport and intracellular Na+, K+, and Cl- activity.
The effect of glucose, galactose, and valine on intestinal Cl- transport and intracellular Cl-, Na+, and K+ activity was investigated in isolated segments of Amphiuma small intestine. By use of double-barreled Cl- -specific microelectrodes, it was observed that galactose and valine reduced the luminal membrane potential (psi m) and eliminated the difference between the Cl- equilibrium potential (ECl) and psi m, i.e., the Cl- accumulation potential (ECl-psi m) approached zero. Simultaneously, Cl- absorption (JnetCl) was reduced in short-circuited tissues and Na+ absorption was enhanced. In contrast, after exposure to glucose, psi m and ECl-psi m declined only transiently and JnetCl was unaltered. In tissues pretreated with galactose to reduce Cl- transport, addition of glucose to the serosal medium restored Cl- accumulation across the luminal membrane and the Cl- absorptive current. Glucose, galactose, and valine each reduced intracellular K+ activity significantly. Galactose and valine each increased [corrected] intracellular Na activity (aiNa) markedly, whereas glucose increased aiNa only slightly. In conclusion, intestinal ion transport can be limited by the availability of metabolic substrate. The nonmetabolized solutes galactose and valine inhibited Cl- uptake and net Cl- absorption while stimulating net Na absorption, as though net Na+ absorption has priority over Cl- transport at the cellular level. Cl- transport is reduced at both mucosal and serosal membranes. At the luminal membrane electrogenic Cl- uptake is slowed or a backleak of Cl- is enhanced; at the serosal membrane Cl- exchange with Na+ (and HCO3-) driven by the Na+ gradient is reduced. The availability of metabolizable glucose to the cell prevents the reduction in net Cl- absorption.
Amino Acids↗
Evidence against luminal one-for-one Cl(-)-HCO-3 exchange in urodele small intestine.
The ratio of Cl- absorbed to HCO3- secreted by the in vitro small intestine of Amphiuma was measured using 36Cl and titration. The aim was to estimate the stoichiometry and thereby elucidate the underlying transport mechanisms. For every mole of HCO3- secreted 1.8 mol of Cl- underwent net absorption. Indirect measures of net Cl- absorption and HCO3- secretion were validated. Several known and putative Cl- transport inhibitors were examined for their ability to inhibit the anion transport events. Disulfonic stilbenes [4-acetamido-4'-isothiocyanostilbene-2',2'-disulfonic acid and 4,4'-diisothiocyano-2,2'-disulfonate stilbene (DIDS)] and the diuretics piretanide and furosemide inhibited the Cl- absorptive flux (JClm----s) and simultaneously the HCO3- secretory flux (JHCO3-). The diuretics acetazolamide and bumetanide also reduced JHCO3- and JClm----s, although the latter effect was not statistically significant. The ratio of inhibition, delta JClm----s/delta JHCO3-, varied from 1.2 to 1.8 for the different inhibitors. The presence of Cl(-)-HCO3- exchange at the serosal membrane was deduced from the reduction of JClm----s and JHCO3- by serosally added stilbenes, the reduction of Cl- absorption when serosal Cl- was replaced (reduced Cl(-)-Cl- exchange), inhibition of the secretory-to-mucosal Cl- flux by serosal stilbenes, and enhancement of JHCO3- when serosal medium HCO3- was elevated. Addition of DIDS to the mucosal medium did not alter the secretory flux. The observations are not consistent with one-for-one exchange of Cl- for HCO3- at the mucosal membrane. Other possible mechanisms including rheogenic Cl- uptake in parallel with electrodiffusional efflux of HCO3- are discussed. The observed coupling ratio is compatible with a one-for-one exchange of Cl- for HCO3- at the serosal membrane.
Animals↗
Effects of theophylline and cAMP on Amphiuma small intestine.
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Animals↗