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D Nelson

Publications and source records attributed to D Nelson.

At least 19 recordsLinked to original sources
PubMed1992

Analogs of Ac-CCK-7 incorporating dipeptide mimics in place of Met28-Gly29.

A series of analogs of Ac-CCK-7 [Ac-Tyr(SO3H)-Met28-Gly29-Trp-Met-Asp- Phe-NH2, (1)] were prepared in which the Met28-Gly29 dipeptide was replaced by omega-aminoalkanoic acids. Compounds were assessed in binding assays using homogenated rat pancreatic membranes and bovine striatum as the source of CCK-A and CCK-B receptors, respectively, and for anorectic activity after intraperitoneal administration to rats. The analog incorporating 4-aminobutanoic acid (5) was only 8 times less potent than 1 in the pancreatic binding assay, was more potent in the striatal binding assay, and was more potent than 1 in reducing food intake in rats. Using a bioactive cyclic analog of Ac-CCK-7 as a template, several rigid spacers were designed and tested as substitutes for the Met28-Gly29 dipeptide. The analogs incorporating 3-aminobenzoic acid (20) and (1S)-trans-2-aminocyclopentanecarboxylic acid (26) proved highly effective in the binding assays and as anorectic agents. We hypothesize that for stimulation of CCK-A receptors, the main function of the N-terminal tripeptide of Ac-CCK-7 is to orient the tyrosine sulfate with respect to Trp30 and that the bioactive arrangement of these elements lies among those which are readily available to both 20 and 26. NOESY and distance-constrained molecular dynamics experiments carried out on 20 and 26 identified conformations in which the relative orientation of the tyrosine hydroxide and the alpha-carbon atom of tryptophan were similar, providing the basis for further drug design efforts.

Amino Acid Sequence↗
PubMed1992

Relationships between energy level and insulin secretion in isolated rat islets of Langerhans. Manipulation of [ATP]/[ADP][Pi] by 2-deoxy-D-glucose.

Perifusion of islets with nominally phosphate-free buffer containing increasing concentrations of 2-deoxy-D-glucose (2.5 to 10 mM) produced increments in high alpha-ketoisocaproic acid-induced secretion of insulin beyond those observed in the absence of the sugar analogue. 3-O-methyl-D-glucose, a poorly metabolized sugar, was without effect. Insulin release evoked by 40 mM KCl was not altered by 2-deoxyglucose. The concentration of intracellular inorganic phosphate was lower in islets perifused with 2-deoxyglucose and declined to a lower level after addition of 20 mM alpha-ketoisocaproic acid. The enhancement of alpha-ketoisocaproic acid-induced hormone secretion by 2-deoxyglucose was not seen in islets perifused with medium containing 1.5 mM phosphate; instead a small inhibition was observed. It is postulated that conditions which lower intracellular [Pi] facilitate, either directly or indirectly, hormone release although the mechanism of this effect remains to be elucidated.

Adenine Nucleotides↗
PubMed1992

Glutamine catabolism by heart muscle. Properties of phosphate-activated glutaminase.

1. Rat heart homogenates catabolized glutamine in the presence of rotenone, an inhibitor of the respiratory chain. 2. The reaction was markedly stimulated by phosphate and inhibited by glutamate, but not greatly affected by ammonia. 3. Glutamine breakdown was enhanced by lactate, malate, citrate and ATP, and almost completely blocked by 1 mM-N-ethylmaleimide. 4. The Km for glutamine measured in homogenates supplemented with either 50 mM- or 100 mM-phosphate and at pH 7.3 or 8.0 was about 4 mM, whereas the Vmax was larger at higher anion concentrations and at the more alkaline pH. 5. Activity of glutaminase was 3-fold greater in isolated mitochondria than in muscle homogenates. Distribution of the activity was the same as that of a mitochondrial marker, cytochrome c oxidase. 6. Properties of glutaminase with respect to its dependence on the concentrations of phosphate, glutamine and H+ were the same in intact and broken mitochondria and very similar to those in homogenates. However, the specific activity of the enzyme was considerably smaller in frozen-thawed than in intact organelles. 7. It is concluded that heart mitochondria possess a kidney-type phosphate-activated glutaminase that can serve as a source of myocardial glutamate.

Animals↗
PubMed1992

Sumatriptan and 5-benzyloxytryptamine: contractility of two 5-HT1D receptor ligands in canine saphenous veins.

Sumatriptan and 5-benzyloxytryptamine are ligands with high affinity for 5-HT1D receptors in the caudate nucleus. Both compounds contracted canine saphenous veins, in vitro. Benzyloxytryptamine was less potent as a contractile agonist than sumatriptan which was less potent than serotonin. In high concentrations (greater than 10(-5) M) serotonin-induced contraction resulted, in part, from activation of alpha-adrenoceptors as determined by blockade of contraction with prazosin (10(-6) M) and idazoxan (10(-6) M). Likewise, benzyloxytryptamine but not sumatriptan also activated contractile alpha-receptors in the canine saphenous vein. Furthermore, benzyloxytryptamine antagonized contraction to sumatriptan in an apparently non-competitive fashion. Thus, benzyloxytryptamine, although possessing some alpha-receptor agonist activity, like sumatriptan, can interact with serotonin receptors in canine saphenous veins. Although effects of sumatriptan and benzyloxytryptamine quantitatively differed in canine saphenous veins, both agents showed similar affinity and agonist efficacy at 5-HT1D receptors in brain. These studies may reflect potential differences between the 5-HT1D receptor in brain and the 5-HT1-like receptor in canine saphenous veins.

Animals↗
PubMed1992

Vertebral deformity in men.

Vertebral fracture is the most prevalent manifestation of osteoporosis in women, but there is very little information concerning vertebral fracture in men. These studies begin to determine the prevalence, radiographic character, and relationship to bone mineral density of vertebral deformity in men. A group of 144 white men aged 34-94 years (83% between 50 and 80 years) were studied. Thoracic and lumbar spine radiographs were obtained using standardized techniques, and morphometric measures of vertebrae (T6-L5) were obtained using a computerized digitization pad. Vertebral deformities (wedge, midbody, and crush) were identified using several criteria. In addition, a skeletal radiologist independently identified vertebral deformities, as well as vertebrae affected by epiphysitis (Scheuermann's disease), using classic radiographic criteria. Bone mineral density was measured at lumbar spine and proximal femoral sites using dual-photon absorptiometry. The prevalence of vertebral deformity was related to the criteria used for their identification. Utilizing vertebral-specific criteria (anterior/posterior or midbody/posterior vertebral height more than 3 SD below vertebral specific mean), 10% of subjects had vertebral deformity. Wedge deformity occurred primarily in thoracic vertebrae and were more common than midbody deformity, which occurred more commonly in lumbar vertebrae. Crush deformities were not observed. Evidence of vertebral epiphysitis was present in 9% of subjects but was not responsible for vertebral deformity sufficient to be falsely identified using the more than -3 SD criterion. Bone mineral density in subjects with vertebral deformity was clearly reduced at both vertebral (p = 0.003) and proximal femoral (p = 0.002) measurements sites. The number of vertebral deformities was negatively correlated with vertebral bone mineral density.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Comparison of single-photon and dual-energy x-ray absorptiometry of the radius.

We compared dual-energy x-ray absorptiometry (DXA) for measurement of the radius with the conventional single-photon absorptiometry (SPA) method. To evaluate reproducibility, 34 healthy male and female subjects were measured twice each by both methods. While the instruments measured bone mineral content (BMC) similarly, projected area was consistently lower by SPA and therefore bone mineral density (BMD) was higher by an average of 10%. We report similar coefficients of variation for the two methods, which are 0.8% (SPA) and 0.7% (DXA) for BMC (P = 0.71) and 0.8% (SPA) and 1.4% (DXA) for BMD (P = 0.02). We also evaluated the relationship between the methods with data from 196 clinic patients who were measured once each on both instruments. The BMD measurements from the two instruments were highly correlated (r = 0.97) in these patients, which permits the conversion of databases from SPA to DXA-equivalents. We conclude that DXA can replace SPA for radial bone densitometry.

Absorptiometry, Photon↗
PubMed1992

A dynamic dual isotope radionuclear method of quantifying penile blood flow.

A new radionuclear method of quantifying arterial and venous blood flow of the penis is described. The technique is based on the simultaneous recording of the change in blood volume and venous outflow in the flaccid and erect states, which is produced pharmacologically. The change in penile blood volume is determined by measuring the change in the technetium-labeled red blood cell activity with time. Venous outflow is recorded with a xenon washout technique. The isotope data are used to compute arterial and venous flows with a complex computerized mathematical formula. Three basic blood flow patterns have been noted that distinguish normal patients from those with arterial insufficiency and venous leakage. The study is relatively easy and noninvasive to perform, and it appears to quantify penile blood flow accurately.

Adult↗
PubMed1992

Motorcycle fatalities in New Mexico: the association of helmet nonuse with alcohol intoxication.

STUDY OBJECTIVE: To determine the relationship among helmet use, alcohol use, and ethnicity in people killed on motorcycles. DESIGN: Retrospective review of all motorcycle fatalities in New Mexico from 1984 through 1988. SETTING: Office of the Medical Investigator, State of New Mexico. TYPE OF PARTICIPANTS: All decedents of motorcycle crashes in New Mexico from 1984 through 1988. INTERVENTIONS: Review of all autopsies, medical investigator reports, traffic fatality reports, and toxicological studies on fatally injured motorcyclists. RESULTS: Nine of the helmeted drivers (18%) were legally intoxicated compared with 67 of the nonhelmeted drivers (51%) (chi 2 = 15.7, P less than .0001); 42 of the white nonHispanic decedents (37%), ten of Hispanic decedents (12%), and none of the Native-American decedents were wearing helmets. The head and neck region was the most severely injured body region in 42 of the nonhelmeted cases (84%) and in eight of the helmeted cases (50%) (Fisher's exact test, P less than .02). CONCLUSION: There is an association between nonuse of helmets and alcohol intoxication in fatally injured motorcyclists in New Mexico. Strategies for preventing motorcycle fatalities should address alcohol abuse and ethnicity in conjunction with helmet use.

Abbreviated Injury Scale↗
PubMed1992

Computed tomography-guided fixation of unstable posterior pelvic ring disruptions.

Open reduction and internal fixation (ORIF), the current treatment of choice of posterior pelvic ring disruptions with instability, has significant disadvantages. These include relatively "blind" placement of the fixation screws, infection, exsanguinating hemorrhage, and high wound complication rates. We feel fluoroscopy does not offer significant clarity in defining the posterior structure. Advantages of computed tomography (CT)-guided sacral fixation are direct visualization of the course of the screws and absence of significant wound complications. This technique provides superior visualization of the nerve roots and sacral canal compared to fluoroscopic methods. Thirteen patients (10 unilateral and 3 bilateral) with unstable but reducible sacral fractures or sacroiliac joint (SIJ) disruptions underwent CT-guided posterior pelvic ring fixation using a cannulated screw system. Skeletal traction was required intraoperatively in one case by a traction-counteraction pulley system in the CT scanner. All other reductions were performed by preoperative skeletal traction or manually by the surgeons after anesthesia in the scanner or after push-pull films demonstrated instability. The guide pin, using depth and angulation measurements derived from the scout CT scans, was positioned across the fracture or SIJ. Following CT confirmation of the position of the pin, the screw tract was drilled and the cannulated screw was placed into position. Radiographic and clinical follow-up observation (7-24 months) showed healing with no significant complications in all 13 patients. Computed tomography-guided sacral fixation is a safe alternative to ORIF in selected patients with reducible unstable pelvic fractures.

Adolescent↗
PubMed1992

Structure activity studies of tryptophan30 modified analogs of Ac-CCK-7.

Cholecystokinin represents a family of gut hormones which among other activities, have been proposed to participate in satiety signaling. Ac-CCK-7[Ac-Tyr(SO3H)-Met-Gly-Trp30-Met-Asp-Phe-NH2 (2)] possesses the full spectrum of activity and potency of the intact hormone; thus analogs of 2 may be useful as anorectic agents. A series of derivatives has been prepared in which the tryptophan indole moiety of 2 has been modified. The new compounds were assayed in CCK binding assays using homogenated rat pancreatic membranes and bovine striatum as a source of CCK-A and CCK-B receptors respectively and in vivo in rats for anorectic activity. Although previous studies have concluded that the indole ring of Trp30 is a critical pharmacophore for the interaction of CCK with both its A and B type receptors, we find 2-Nal30-Ac-CCK-7 (20) to be nearly equipotent to 2 in both CCK binding and as an anorectic agent sensitive to blockade by the Merck CCK-A receptor antagonist MK-329. The extreme structural sensitivity of this anorectic activity is illustrated by the 1-naphthylalanine30 (19) and (benzo[b]thien-2-yl)alanine30 (21) analogs which are 30 and 100 times less potent than 2 respectively. Other mono- and bicyclic Trp30 replacements, including substituted phenylalanines, 3-quinolinylalanine, and 2-(5,6,7,8-tetrahydro)naphthylalanine, gave inactive compounds.

Amino Acid Sequence↗
PubMed1992

Synthesis and properties of polymerized, diaspirin cross-linked hemoglobins.

During the course of our studies it became clear that there were therapeutic applications for which a polymeric hemoglobin having an extended half-life in circulation would be appropriate. Therefore, a process for the glutaraldehyde-polymerization of diaspirin cross-linked hemoglobin (DCLHb) was developed and used to prepare glutaraldehyde-polymerized DCLHb (GP-DCLHb) in lactated Ringer's solution in sufficient quantities for biological testing. Both isovolemic exchange-transfusion and "top-load" studies (rats; primates and swine, respectively) were completed in which a broad spectrum of physiologic, histopathologic and analytical parameters were monitored and assessed. In general, GP-DCLHb in lactated Ringer's solution was well-tolerated physiologically. When compared to DCLHb, GP-DCLHb offers the advantages of reduced renal clearance of hemoglobin and an extended half-life in circulation. GP-DCLHb has the disadvantages that (1) glutaraldehyde is an ineffective virucidal agent under the conditions of the polymerization reaction and a separate virus inactivation step is required; (2) low-endotoxin (LAL-negative) GP-DCLHb solutions are pyrogenic (rabbits); and (3) unusual deposition of hemoglobin-containing material in the small arterioles of the liver and kidney (rats) was sometimes seen even after a period of time (2 weeks) during which treatment-related organ pathologies are usually resolved, a finding peculiar to GP-DCLHb among the various hemoglobin derivatives we have tested.

Animals↗
PubMed1992

Preparation and characterization of diaspirin cross-linked hemoglobin solutions for preclinical studies.

During 1990 and 1991 the capability for repetitive, consecutive production of DCLHb solution to meet a rigorous and complete set of product criteria was demonstrated. In addition, through periodic monitoring of product stored under controlled conditions, the stability of all lots of DCLHb solution during frozen storage was demonstrated for more than a year. In this way, assurance was provided that the DCLHb solution used in preclinical testing met all product criteria throughout the biological testing period.

Aspirin↗
PubMed1991

Depolarization-induced changes in cellular energy production.

Addition of high concentrations of KC1 to preparations of rat brain synaptosomes incubated with either glucose or pyruvate caused a transient stimulation of oxygen uptake. This increased respiration was insensitive to 1 mM ouabain and 10 microM ruthenium red but was dependent upon the presence of calcium. With 40 mM KCl in the incubation medium, the levels of high-energy phosphate compounds in the synaptosomes were unaltered, whereas pyridine nucleotides underwent a rapid, albeit small and temporary, oxidation. It is postulated that there is a calcium-dependent mechanism in synaptosomes through which the function of the mitochondrial respiratory chain or of oxidative phosphorylation is stimulated directly without the involvement of either adenine nucleotides or mitochondrial dehydrogenases.

Adenosine Triphosphate↗
PubMed1991

Relationships between energy level and insulin secretion in isolated rat islets of Langerhans. A study at various pH values.

To define better the role of [ATP]/[ADP] in insulin release from pancreatic islets, changes in the adenine nucleotide ratios elicited by alterations in external pH were correlated with the secretion profiles produced by administration of two metabolic secretagogues, 16 mM glucose and 10 mM alpha-ketoisocaproic acid. Experiments were carried out in buffers with and without bicarbonate, in the pH range 6.5-7.7. Insulin release was dependent on pHe irrespective of the secretagogue used. Secretion profiles for alpha-ketoisocaproic acid were the same both with and without bicarbonate; the release was decreased below pH 7.1 but maintained at 7.4-7.7. The same pattern was seen with glucose in media buffered with Hepes. With bicarbonate present, secretion caused by high glucose showed a bell-shaped dependence on [H+], with reductions at the acid and alkaline sides of pH 7.1-7.4. [ATP] and [ADP] were higher when Hepes was the buffer, at all pH values studied. The [ATP]/[ADP] declined with increasing pH under both basal and stimulated conditions; the values were always larger after stimulation although at pH 7.7 with bicarbonate present and glucose as the stimulant the difference was very small. It is concluded that: (i) the [ATP]/[ADP] in pancreatic islets is markedly dependent on pHe; (ii) there is no straight-forward correlation between either [ATP] or the absolute value for [ATP]/[ADP] and insulin secretion; and (iii) a rise in [ATP]/[ADP] is necessary for glucose-stimulated insulin release although it is not always the rate-determining event.

Adenosine Diphosphate↗
PubMed1991

(-)threo-chlorocitric acid decreases sham feeding of sucrose in rats.

The contribution of changes in rate of gastric emptying to the anorectic effect of (-)-threo-chlorocitric acid (chlorocitrate) was assessed by examining the effect of this drug in sham feeding rats, a preparation where gastric distention does not occur. Gavage administration of chlorocitrate (100-400 mg.kg-1) decreased sham and real feeding of 20% sucrose in a dose-related manner. In sham-feeding rats, the minimal effective dose was 200 mg.kg-1. The anorectic effect was evident at 60 min after 200 mg.kg-1 and 30 min after 400 mg.kg-1. In real-feeding rats, the minimal effective dose was 100 mg.kg-1 and for all doses tested the effect was apparent at the 15-min time point. In a second experiment, the effect of chlorocitrate (100-400 mg.kg-1) on gastric emptying of 20% sucrose was examined. Chlorocitrate (200 and 400 mg.kg-1) had a modest but significant inhibitory effect on gastric emptying; however, the effect was not dose-related. Inasmuch as chlorocitrate decreased sham feeding, its anorectic effect cannot be solely attributed to inhibition of gastric emptying. However, because chlorocitrate was more potent in the real-feeding condition relative to sham feeding, and the time course of the response in the two feeding conditions was different, part of chlorocitrate's anorectic effect may depend on postingestive cues such as gastric distention.

Animals↗
PubMed1991

Evolution and distribution of (GT)n repetitive sequences in mammalian genomes.

The dinucleotide repetitive sequence, (GT)n, is highly interspersed in eukaryotic genomes and may have functional roles in genetic recombination or the modulation of transcriptional activity. We have examined the distribution and conservation of position of GT repetitive sequences in several mammalian genomes. The distribution of GT repetitive sequences in the human genome was determined by the analysis of over 3700 cosmid clones containing human insert DNA. On average, a GT repetitive sequence occurs every 30 kb in DNA from euchromatic regions. GT repetitive sequences are significantly underrepresented in centric heterochromatin. The density of GT repetitive sequences in the human genome could also be estimated by analyzing GenBank genomic sequences that include introns and flanking sequences. The frequency of GT repetitive sequences found in GenBank human DNA sequences was in close agreement with that obtained by experimental methods. GenBank genomic sequences also revealed that (GT)n repetitive sequences (n greater than 6) occur every 18 and 21 kb, on average, in mouse and rat genomes. Comparative analysis of 31 homologous sequences containing (GT)n repetitive sequences from several mammals representing four orders revealed that the positions of these repeats have been conserved between closely related species, such as humans and other primates. To a lesser extent, positions of GT repetitive sequences have been conserved between species in distantly related groups such as primates and rodents. The distribution and conservation of GT repetitive sequences is discussed with respect to possible functional roles of the repetitive sequence.

Animals↗
PubMed1991

Carboxylic acids and tetrazoles as isosteric replacements for sulfate in cholecystokinin analogues.

A series of analogues of the satiety-inducing peptide cholecystokinin (CCK-8) was prepared in which the sulfated tyrosine required for activation of peripheral receptors was replaced with a carboxy(alkyl)- or tetrazolyl(alkyl)-phenylalanine to investigate whether an organic acid could serve the role of the sulfate group at the receptor. The necessary intermediates were prepared by previously reported procedures or by alkylation of carboxy(alkyl)- or tetrazolyl(alkyl)phenylmethyl bromides with a glycine-derived anion followed by protecting-group manipulations, and these were incorporated into derivatives of acetyl-CCK-7 using solid-phase synthesis. Peptide analogues were evaluated in a CCK-binding assay for affinity for either peripheral (CCK-A) receptors using homogenated rat pancreatic membranes as the receptor source or for central (CCK-B) receptors using bovine striatum as the receptor source. They were further evaluated for effects on food intake in rats after intraperitoneal (ip) injection. A number of the compounds reported are active in the CCK-A receptor binding assay although less potent than acetyl-CCK-7 and decrease food intake with comparable potency to acetyl-CCK-7. In a meal feeding model designed to assess appetite suppressant activity, acetyl-CCK-7 has an ED50 of 7 nmol/kg ip, while the ED50s of Ac-Phe(4-CH2CO2H)-Met-Gly-Trp-Met-Asp-Phe-NH2 (28) and Ac-Phe[4-(tetrazol-5-yl)]-Met-Gly-Trp-Met-Asp-Phe-NH2 (34) were 9 and 11 nmol/kg ip, respectively. An analogue of 28 lacking the N-terminal acetamido group, 3-[4-(carboxymethyl)-phenyl]propanoyl-Met-Gly-Trp-Met-Asp-Phe-NH2 (50), was also active in the meal feeding assay with an ED50 of 3 nmol/kg ip. Its anorexic effect was blocked by simultaneous administration of the CCK-A receptor antagonist MK 329, indicating that the observed anorexic activity is mediated by CCK-A receptors. We conclude from this work that the requirement for a negative charge at the CCK-A receptor provided in the natural substrate by a sulfate group can be satisfied by organic acids.

Animals↗