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Biomedical subjects

G P Smith

Publications and source records attributed to G P Smith.

At least 19 recordsLinked to original sources
PubMed2006

Effects of CCK-8 on independent ingestion and central c-Fos-like immunoreactivity in rats on postnatal days 10 and 11.

Controls of the independent ingestion of food in the preweanling rat emerge in the second postnatal week. We investigated the effects of CCK-8 (0, 1, 5, or 10 microg/kg IP) on intake and c-Fos-like immunoreactive (CFLI) cells in hindbrain and forebrain on postnatal days 10 and 11. Five micrograms per kilogram decreased intake and increased the number of CFLI cells in four subnuclei of the nucleus tractus solitarius (NTS), in arcuate nucleus (ARC), and in central nucleus of the amygdala (CeA). Ten micrograms per kilogram decreased intake and increased CFLI in three NTS subnuclei as much as 5 microg/kg did, but was more potent than 5 microg/kg in the medial NTS subnucleus. Ten micrograms per kilogram increased CFLI in paraventricular (PVN) and supraoptic (SON) nuclei, but 5 microg/kg did not. Thus, reduction of intake by CCK-8 on days 10 and 11 is associated with increased hindbrain and forebrain CFLI.

Animals↗
PubMed2006

Orosensory stimulation is sufficient and postingestive negative feedback is not necessary for neuropeptide Y to increase sucrose intake.

Although central administration of neuropeptide Y (NPY) has a potent orexic effect, it is not clear how NPY changes the potency of peripheral feedbacks from the gut to prolong eating and increase meal size. It has been suggested that NPY increases the stimulating effect of orosensory sweet stimuli or that it decreases the inhibitory effect of postingestive stimuli. To clarify this issue, we compared the orexic effect of NPY (2 microg) injected into the third ventricle of the brain on the volume and microstructure of intake of 0.8M sucrose during sham feeding (SF) and real feeding (RF) in male Sprague Dawley rats. The rationale for this comparison is that orosensory stimulation occurs in SF and RF, but postingestive negative feedback is present only in RF. NPY increased the volume ingested and the rate and number of clusters of licking significantly more in SF than in RF. This demonstrates that orosensory sucrose stimulation is sufficient and postingestive negative feedback is not necessary for the orexic effect of NPY under these experimental conditions.

Analysis of Variance↗
PubMed2006

Intake, sweetness and liking during modified sham feeding of sucrose solutions.

Although sweet solids and liquids are palatable to humans and ingested frequently when readily available, the quantitative relationship between sweet taste and intake has not been reported in humans. To investigate the quantitative relationship between sweet taste and intake directly, we adapted the modified sham feeding technique, previously used in humans for the study of the orosensory control of autonomic, neuroendocrine, and metabolic mechanisms, to measure the intake of solutions both unsweetened and sweetened with four concentrations of sucrose. By limiting the sucrose stimuli to the mouth, the modified sham feeding technique measures the orosensory stimulation of intake by sucrose in the absence of inhibitory postingestive stimulation. Nine healthy women were randomly presented with two series of five solutions of cherry Kool Aid unsweetened or sweetened with one of four concentrations of sucrose (2.5%, 5%, 10%, or 20%) in a closed opaque container fitted with a straw. They were instructed to sip as much as they wanted of the liquid during 2-min trials and to spit the fluid out into another opaque container. At the end of each trial, they used Visual Analogue Scales to rate the perceived intensities of sweetness and liking of the liquid that they had just sipped and spit. Intake, liking and perceived sweetness were significantly affected by sucrose concentration (p values</=0.038). Intake at 20% was not significantly larger than 10% or 5%. The effects of sucrose were presumably due to orosensory stimulation in the absence of postingestive stimulation because the amount of liquid spit out did not differ significantly from the amount sipped.

Adult↗
PubMed2005

Independent ingestion and microstructure of feeding patterns in infant rats lacking CCK-1 receptors.

Otsuka Long-Evans Tokushima fatty (OLETF) rats are a strain of Long-Evans Tokushima Otsuka (LETO) rats that do not express CCK-1 receptors, developing in adulthood, hyperphagia, obesity, and non-insulin-dependent diabetes mellitus (NIDDM). We examined weight gain and meal patterns during a 30-min independent ingestion test on postnatal days 2-4 and again on days 9-11 in OLETF and LETO rat pups. OLETF pups were significantly heavier compared with their LETO controls at both ages, and they consumed significantly more of the sweet milk diet. The difference in intake can be attributed to a significant increase in meal size and duration. Number of clusters and bursts of licking within a meal were greater in OLETF rat pups, with no difference between strains in burst and cluster size. Interlick interval (ILI) was not significantly different between OLETF and LETO pups. This measure decreased on days 9-11 compared with days 2-4 in both strains. Latency to start feeding was significantly shorter on days 2-4 in OLETF vs. LETO pups, but this difference disappeared at the second test at the older age. Two- to four-day-old OLETF pups consumed a larger volume of milk during the first minute of feeding, and their initial lick rate and decay of lick rate were significantly larger compared with their LETO controls. Lack of CCK-1 receptors, or other OLETF-related abnormalities, therefore, resulted in a satiation deficit, leading to increased meal size, hyperphagia, and increased weight gain as early as 2-4 postnatal days.

Aging↗
PubMed2005

Inhibitory effects on intake of cholecystokinin-8 and cholecystokinin-33 in rats with hepatic proper or common hepatic branch vagal innervation.

The relative potencies of cholecystokinin (CCK)-8 and CCK-33 for decreasing meal size depend on the route of administration. Inhibitory potencies are equal after intraperitoneal administration, but CCK-33 is significantly more potent after intraportal administration. This suggests that CCK-33 is a more effective stimulant of hepatic afferent vagal nerves than is CCK-8. To investigate this possibility, we administered both peptides intraperitoneally in rats with abdominal vagotomies that spared only the hepatic proper vagal nerves (H) and in rats with abdominal vagotomies that spared the common hepatic branch that contains the fibers of the hepatic proper and gastroduodenal nerves (HGD). The vagal afferent innervation in H and HGD rats was verified with a wheat germ agglutinin-horseradish tracer strategy. Intraperitoneal administration of CCK-33 decreased 30-min intake of 10% sucrose in H rats as much as in sham rats, but CCK-8 decreased intake significantly less in H rats than in sham rats. The larger inhibitory effect of CCK-33 than of CCK-8 in H rats is consistent with the hypothesis that CCK-33 is a more effective stimulant of the hepatic proper vagal afferent nerves than CCK-8. In contrast to the results in H rats, the inhibitory potencies of both peptides were significantly and equivalently reduced in HGD rats compared with sham rats. This suggests that there is an inhibitory interaction between the stimulation of the gastroduodenal and hepatic proper afferent fibers by CCK-33.

Afferent Pathways↗
PubMed2004

Complement regulation at the molecular level: the structure of decay-accelerating factor.

The human complement regulator CD55 is a key molecule protecting self-cells from complement-mediated lysis. X-ray diffraction and analytical ultracentrifugation data reveal a rod-like arrangement of four short consensus repeat (SCR) domains in both the crystal and solution. The stalk linking the four SCR domains to the glycosylphosphatidylinositol anchor is extended by the addition of 11 highly charged O-glycans and positions the domains an estimated 177 A above the membrane. Mutation mapping and hydrophobic potential analysis suggest that the interaction with the convertase, and thus complement regulation, depends on the burial of a hydrophobic patch centered on the linker between SCR domains 2 and 3.

CD55 Antigens↗
PubMed2002

Alpha-helically constrained phage display library.

The library described here is a collection of phages with six degenerate codons in gene VIII, specifying amino acids 12, 13, 15-17 and 19 of the major coat protein. The randomized positions are surface exposed in the wild-type protein and thus might be expected to tolerate a great diversity of side chains without compromising phage viability. In agreement with this supposition, the new library showed great diversity of amino acids at the randomized positions and diversity did not diminish noticeably during repeated subculture. Despite their diversity, however, the randomized positions should be strongly constrained conformationally because they lie in an extended alpha-helical portion of the protein, stabilized by numerous inter- and intra-subunit contacts--a presupposition corroborated by circular dichroism spectroscopy of many library members. To reflect this conformational homogeneity and the fact that random amino acids subtend a major fraction of the surface 'landscape' of the particle, we call the new construct an alpha landscape library. It can be used as a source of alpha-helical ligands and substitute antibodies.

Capsid Proteins↗
PubMed2001

A complex pattern of mantle flow in the Lau backarc.

Shear-wave splitting analysis of local events recorded on land and on the ocean floor in the Tonga arc and Lau backarc indicate a complex pattern of azimuthal anisotropy that cannot be explained by mantle flow coupled to the downgoing plate. These observations suggest that the direction of mantle flow rotates from convergence-parallel in the Fiji plateau to north-south beneath the Lau basin and arc-parallel beneath the Tonga arc. These results correlate with helium isotopes that map mantle flow of the Samoan plume into the Lau basin through an opening tear in the Pacific plate.

Journal Article↗
PubMed2001

John Davis and the meanings of licking.

This paper reviews the contribution of John Davis to understanding how meal size is organized and controlled in the rat. By measuring the rate and pattern of licking of various liquid diets during sham feeding and real feeding, Davis demonstrated that meal size is the result of the central integration of positive feedback from orosensory stimulation and negative feedback from postingestive stimulation of the stomach and small intestine. The potency of these feedbacks is modulated by a variety of factors including experience and deprivation. At the microstructural level, orosensory stimulation increases burst size or cluster size, while postingestive negative feedback decreases the number of bursts or clusters. His results remind us that behavior is the basic science of ingestion, important in itself, and essential for the investigation of the neural mechanisms that organize it.

Animals↗
PubMed2001

Release of endogenous cholecystokinin in response to gastric preloads in rats on postnatal days 9--12.

Release of endogenous cholecystokinin (CCK) from the small intestine by gastric loads was investigated in rats on postnatal days 9--12 (P9--P12). After 5--6 h of deprivation, pups received 5% b.wt. loads of water, 0.9% NaCl, 20% glucose, 20% maltose, 200 mg soybean trypsin inhibitor (SBTI) in 0.9% saline or sham load. Plasma was collected 15 min after the loads, and the concentration of bioactive CCK was measured by a specific and sensitive bioassay. Loads of SBTI and water significantly increased plasma CCK compared to sham loads, but loads of saline, glucose, and maltose did not. The efficacy of the water load was not demonstrated in adult rats. The results suggest that the previously reported reduction of intake during independent ingestion by hypertonic preloads of glucose and maltose was not mediated by the release of CCK sufficient to be detected in the plasma under these conditions.

Animals↗
PubMed2001

Hypertonic glucose preloads act preabsorptively to decrease intake in rats on postnatal day 18.

To determine if preloads of glucose act preabsorptively or postabsorptively to inhibit intake, 18-day-old rat pups were deprived for 24 h and then provided with sweet milk during a 30-min independent ingestion test. Five minutes before the test, gastric preloads (5% body weight, BW) or intraperitoneal injections (4 ml/kg BW) of isotonic, hypotonic, and hypertonic solutions of glucose or 2-deoxy-D-glucose (2-DG) were administered. There were two major results: First, preloads of 20% glucose decreased intake much more than intraperitoneal injections of 20% glucose. Second, a preload of 20% 2-DG, which decreases, rather than increases glucose utilization, was as effective as a preload of 20% glucose in decreasing intake. These results are consistent with a preabsorptive osmotic mechanism, but not with a postabsorptive metabolic mechanism, for mediating most, if not all, of the inhibition of intake 5 min after preloads of 20% glucose in rats on postnatal day 18 (P18).

Animals↗
PubMed2001

The impact of sucrose-derived unconditioned and conditioned negative feedback on the microstructure of ingestive behavior.

We describe at the microstructural level the impact of unconditioned and conditioned negative feedback on the licking behavior of the rat. Seven groups of rats were trained to ingest one of seven different concentrations of sucrose (0.025, 0.05, 0.1, 0.2, 0.4, 0.6, and 0.8 M sucrose) under real-feeding conditions until intake was stable. They were then given three sham-feeding tests with the same solution. We compared the size of the clusters (SC) and number of clusters (NC) during the 17-min period when intake rate was declining in the real-feeding test with SC and NC during the corresponding 17-min period in the following sham-feeding test. Intake increased significantly over the three sham-feeding tests with the three highest concentrations, indicating the extinction of conditioned negative feedback. With these three solutions, we compared the microstructure of licking behavior in the first with that in the third sham-feeding test to determine if conditioned negative feedback affected SC or NC or both. The effect of both unconditioned and conditioned negative feedback on licking behavior was to decrease the NC without significantly affecting their size. We conclude that negative feedback derived from the accumulation of sucrose in the gastrointestinal tract decreases the probability of initiating a bout of licking during a pause. It has no effect on the ability to continue a bout of licking once it has begun.

Animals↗
PubMed2001

Membrane-targeted complement inhibitors.

Undesirable complement activation contributes to the pathology of many human diseases by damaging tissue and promoting inflammation. Because complement-mediated damage is caused by the deposition of complement components on the cell surface, several strategies have been devised to target complement regulator proteins to cell membranes. These strategies have resulted in engineered proteins that have improved potency in vitro and enhanced therapeutic benefit in animal models of disease. One membrane-targeted complement inhibitor has now entered clinical development and this class of second-generation agents may provide effective therapies for the treatment of a variety of disease states.

CD59 Antigens↗
PubMed2001

Identifying diagnostic peptides for lyme disease through epitope discovery.

Serum antibodies from patients with Lyme disease (LD) were used to affinity select peptide epitopes from 12 large random peptide libraries in phage display format. The selected peptides were surveyed for reactivity with a panel of positive sera (from LD patients) and negative sera (from subjects without LD), thus identifying 17 peptides with a diagnostically useful binding pattern: reactivity with at least three positive sera and no reactivity with any of the negative sera. The peptides define eight sequence motifs, none of which can be matched convincingly with segments of proteins from Borrelia burgdorferi, the LD pathogen; evidently, then, they are "mimotopes," mimicking natural pathogen epitopes without matching contiguous amino acids of pathogen proteins. Peptides like these could be the basis of a new diagnostic enzyme-linked immunosorbent assay for LD, with sufficient specificity and sensitivity to replace expensive immunoblotting tests that are currently required for definitive serological diagnosis. Moreover, the method used to discover these peptides did not require any knowledge of the pathogen and involved generic procedures that are applicable to almost any infectious disease, including emerging diseases for which no pathogen has yet been identified.

Amino Acid Sequence↗
PubMed2001

Gastric negative feedback produced by volume and nutrient during a meal in rats.

To investigate the gastric negative-feedback control of eating during a meal, we implanted male rats with pyloric cuffs and gastric catheters and gave them access to sweet milk for 30 min after overnight deprivation. Ingested milk and infused milk or saline were confined to the stomach because the pyloric cuffs were closed in all tests. Rats received five consecutive tests with no gastric infusion or with infusions of 3, 6, or 12 ml of milk or saline during the first 6 min of the test meal. Only 12-ml infusions decreased intake significantly compared with no infusion. Because 12 ml of saline inhibited intake as much as 12 ml of milk, the decreased intake was due to volume or rate of infusion, not nutrient. Although infusions of 3 and 6 ml of milk did not decrease intake, they decreased the number of licks after the infusions significantly more than equal volumes of saline. Thus a large volume or rapid rate of gastric infusion decreases intake, and some other aspect of small milk infusions decreases the rate of licking.

Animals↗
PubMed2000

The controls of eating: a shift from nutritional homeostasis to behavioral neuroscience.

The experimental analysis of the controls of eating has undergone a paradigmatic shift in the past decade. Instead of seeing meals as a problem of how intake serves metabolism and nutritional homeostasis, meals are now seen as a problem in behavioral neuroscience. The major developments underlying this significant change are behavioral, neurological, and theoretical. Behavioral analysis has shown that a central pattern generator in the caudal brainstem organizes eating movements and that the size of a liquid meal is determined by the number and size of clusters of licking. Neurologic analysis has shown that eating is under orosensory positive-feedback control and postingestive, preabsorptive, negative-feedback control. These feedback controls are activated by food ingested during a meal. The sensory information of the feedbacks is carried by afferent fibers that project to the caudal brainstem. The new theory is based on the fact that the feedback controls are stimulated by food acting directly on mucosal receptors along the gastrointestinal tract, from the mouth to the end of the small intestine. Thus, they are referred to as direct controls, and the caudal brainstem is sufficient for organizing their action. All other controls, such as metabolic, rhythmic, and ecologic, that do not contact the mucosal receptors are indirect controls. Indirect controls act by modulating the potency of the central effects of the direct controls, and they require the forebrain and its reciprocal connections with the caudal brainstem for their control of eating and meal size.

Animals↗