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L J Kelly

Publications and source records attributed to L J Kelly.

At least 19 recordsLinked to original sources
PubMed1998

A selective human beta3 adrenergic receptor agonist increases metabolic rate in rhesus monkeys.

Activation of beta3 adrenergic receptors on the surface of adipocytes leads to increases in intracellular cAMP and stimulation of lipolysis. In brown adipose tissue, this serves to up-regulate and activate the mitochondrial uncoupling protein 1, which mediates a proton conductance pathway that uncouples oxidative phosphorylation, leading to a net increase in energy expenditure. While chronic treatment with beta3 agonists in nonprimate species leads to uncoupling protein 1 up-regulation and weight loss, the relevance of this mechanism to energy metabolism in primates, which have much lower levels of brown adipose tissue, has been questioned. With the discovery of L-755,507, a potent and selective partial agonist for both human and rhesus beta3 receptors, we now demonstrate that acute exposure of rhesus monkeys to a beta3 agonist elicits lipolysis and metabolic rate elevation, and that chronic exposure increases uncoupling protein 1 expression in rhesus brown adipose tissue. These data suggest a role for beta3 agonists in the treatment of human obesity.

Adipose Tissue, Brown↗
PubMed1998

Peroxisome proliferator-activated receptors gamma and alpha mediate in vivo regulation of uncoupling protein (UCP-1, UCP-2, UCP-3) gene expression.

A role for peroxisome proliferator-activated receptors, PPAR gamma and PPAR alpha, as regulators of energy homeostasis and lipid metabolism, has been suggested. Recently, three distinct uncoupling protein isoforms, UCP-1, UCP-2, and UCP-3, have also been identified and implicated as mediators of thermogenesis. Here, we examined whether in vivo PPAR gamma or PPAR alpha activation regulates the expression of all three UCP isoforms. Rats or lean and db/db mice were treated with PPAR gamma [thiazolidinedione (TZD)] or PPAR alpha (WY-14643) agonists, followed by measurement of messenger RNAs (mRNAs) for UCP-1, UCP-2, and UCP-3 in selected tissues where they are expressed. TZD treatment (AD 5075 at 5 mg/kg x day) of rats (14 days) increased brown adipose tissue (BAT) depot size and induced the expression of each UCP mRNA (3x control levels for UCP-1 and UCP-2, 2.5x control for UCP-3). In contrast, UCP-2 and UCP-3 mRNA levels were not affected in white adipose tissue or skeletal muscle. Chronic (30 days) low-dose (0.3 mg/kg x day) TZD treatment induced UCP-1 mRNA and protein in BAT (2.5x control). In contrast, chronic TZD treatment (30 mg/kg x day) suppressed UCP-1 mRNA (>80%) and protein (50%) expression in BAT. This was associated with further induction of UCP-2 expression (>10-fold) and an increase in the size of lipid vacuoles, a decrease in the number of lipid vacuoles in each adipocyte, and an increase in the size of the adipocytes. TZD treatment of db/db mice (BRL 49653 at 10 mg/kg x day for 10 days) also induced UCP-1 and UCP-3 (but not UCP-2) expression in BAT. PPAR alpha is present in BAT, as well as liver. Treatment of rats or db/db mice with WY-14643 did not affect expression of UCP-1, -2, or -3 in BAT. Hepatic UCP-2 mRNA was increased (4x control level) in db/db and lean mice, although this effect was not observed in rats. Thus, in vivo PPAR gamma activation can induce expression of UCP-1, -2, and -3 in BAT; whereas chronic-intense PPAR gamma activation may cause BAT to assume white adipose tissue-like phenotype with increased UCP-2 levels. PPAR alpha activation in mice is sufficient to induce liver UCP-2 expression.

Adipose Tissue, Brown↗
PubMed1996

Pharmacological characterization of a recently described human beta 3-adrenergic receptor mutant.

The beta 3-adrenergic receptor is the predominant subtype of beta-adrenergic receptor expressed in adipose tissue. Recently, a naturally occurring mutation in the human beta 3-receptor gene has been described which results in substitution of the tryptophan residue at position 64 in the first intracellular loop with an arginine residue. The polymorphism, which is prevalent in the human population, has been associated with increases in some parameters of obesity and Type II diabetes. In order to characterize the pharmacological effects of this amino acid substitution, the W64R mutation was made in the human beta 3 receptor gene and the resulting mutant receptor expressed in CHO cells. Activation by various agonists showed no significant differences (t-test, P > 0.05) between the wild type and mutant receptors. These studies show that, when expressed in a heterologous system, the W64R mutant receptor is pharmacologically and functionally indistinguishable from the wild type beta 3-adrenergic receptor.

Adrenergic alpha-Agonists↗
PubMed1996

Minimum prostate-specific antigen (PSA) level diagnostic of prostate cancer.

The PSA levels in benign prostatic hyperplasia (BPH) and prostate adenocarcinoma (PA) overlap, both below and above 4 to 10 ng/mL. There is no known PSA level diagnostic of PA. In this study, data were obtained in 160 consecutive men aged 58 to 87. Prebiopsy PSA levels (PSA-1) were obtained prior to "sextant" gun biopsies in 97 cases diagnosed as noncarcinoma, and in 56 cases diagnosed as PA. Multiple hematoxylin and eosin sections were made of each biopsy, and Gleason scores given the PAs. Cases were followed up to 30 months with repeated PSA levels and additional biopsies. The highest PSA level in NPA in this series was 54.6 ng/mL.

Adenocarcinoma↗
PubMed1995

Changing attitudes about the employability of the deaf and hard of hearing.

Hearing students viewed a videotape featuring positive deaf and hard of hearing role models in a variety of employment settings. Attitudes about the employability of these individuals were measured in a pretest posttest control group design. Attitudes after viewing the role model videotape were significantly more positive than those reported prior to viewing the videotape. Respondents were able to generalize their positive attitudes beyond the limited number of occupations featured in the tape to other occupations. Further, the attitude change was of an enduring nature, with posttest two results indicating no significant attitude change from posttest one attitudes. The findings of the present study indicate that video-tape can be an effective means of introducing positive deaf and hard of hearing role models in both educational and employment settings.

Adult↗
PubMed1994

Endogenous vasodilators modulate pulmonary vascular anaphylaxis.

We examined the role of endothelium-derived nitric oxide during antigen-induced contraction in pulmonary arteries isolated from actively sensitized guinea pigs. Ovalbumin (10(-2) mg/ml)-induced contraction was not sustained, and tension returned to baseline within 15 min. Pretreatment with methylene blue (10(-5) M) increased both the amplitude and the duration of the contractile response in these tissues. At 15 min, tension remained elevated and was > 70% of the peak amplitude. Removal of the endothelium with saponin (200 micrograms/ml) increased the magnitude of the contraction by > 125%; however, the duration of the response was unaffected. After pretreatment with saponin, methylene blue no longer increased the amplitude of antigen-induced contraction but its effect on the duration was unchanged. Pretreatment with nitro-L-arginine methyl ester significantly increased the magnitude of the contraction in each of the tissues. These results suggest that the response of guinea pig pulmonary arteries to antigen is modulated by two types of endogenous vasodilators, endothelium-derived nitric oxide that inhibits the initial phase of the response and an endothelium-independent relaxing factor that is guanosine 3',5'-cyclic monophosphate dependent and attenuates the duration of anaphylactic contraction.

Anaphylaxis↗
PubMed1994

Genetic polymorphism of apolipoprotein A-IV in the chimpanzee: common deletion of a conserved 12-nucleotide tandem repeat.

Apolipoprotein A-IV (apoA-IV protein; APOA4 gene) is structurally polymorphic in various mammalian species, including human, baboon, dog, horse, and mouse. To analyze the extent of genetic variation in the chimpanzee APOA4 gene, we screened 115 common chimpanzees (Pan troglodytes) (86 unrelated wild captured parents and 29 captive-born offspring) using isoelectric focusing followed by immunoblotting for protein polymorphism and using polymerase chain reaction (PCR) assay for DNA polymorphism. At the protein level the unrelated sample of chimpanzees is highly variable, having four alleles, APOA4*1, APOA4*2, APOA4*3, and APOA4*4, with frequencies of 0.192, 0.430, 0.331, and 0.047, respectively. The chimpanzee APOA4 locus, with four common alleles and a gene diversity of 67%, is more variable than previously reported variations in baboons (five alleles with 52% gene diversity) and humans (two alleles with 15% gene diversity). PCR amplification of chimpanzee DNAs, using a pair of human oligonucleotide primers covering a region of 300 nucleotides in the third exon, revealed a common 12-nucleotide deletion (allele frequency = 0.192) that correlates exactly with the APOA4*1 allele detected by isoelectric focusing and immunoblotting. DNA sequencing of the 300-nucleotide PCR amplified product revealed the deletion of 12 nucleotides near the carboxyl terminal region of the mature apoA-IV protein. This in-frame deletion, which codes for and eliminates four amino acids [glutamic acid (GAG), glutamine (CAG), glutamine (CAG), and glutamine (CAG)], occurs in a region that is evolutionarily conserved among rats, mice, chimpanzees, and humans. The partial DNA sequencing of the 3' end of the chimpanzee APOA4 gene revealed 99% identity with the human APOA4 gene.

Alleles↗
PubMed1993

Antigen-induced contraction of guinea pig isolated pulmonary arteries and lung parenchyma.

We characterized the kinetics of and determined the mediators involved in antigen-induced contraction of pulmonary arteries (PA) and lung parenchyma isolated from actively sensitized guinea pigs. Ovalbumin (10(-2) mg/ml) induced contractions of PA rings, which reached maximum amplitude by 2 min and decayed to 50% of maximum by 4-6 min. Pyrilamine (10(-6) M) delayed the onset of contraction and decreased the peak of the response by > 50%. Metiamide (10(-4) M) partially reversed this effect. The addition of indomethacin (10(-6) M) to the combination of pyrilamine and metiamide had no significant effect. The further addition of the leukotriene (LT) D4/LTE4 receptor antagonist SKF 104353 (10(-5) M) reduced the contraction by > 80%. The maximum amplitude of antigen-induced contraction of parenchymal strips was reached by 15 min and was sustained for > 60 min. In these tissues, SKF 104353 inhibited the contraction by approximately 35%, but the histamine receptor antagonists and indomethacin had no significant effect. These results suggest that both histamine and sulfidopeptide LTs mediate antigen-induced contraction of PA, whereas sulfidopeptide LTs, but not histamine, are involved in the parenchymal response.

Animals↗
PubMed1993

Is this problem urgent? Attitudes in a community hospital emergency room.

As health care resources become increasingly scarce, some suggest that emergency rooms are misused or overused. This study examined whether patients believe their problems are urgent, whether health care providers agree, and what factors influence these decisions. In many cases, using less expensive alternative care is appropriate. Widespread education to change patients' attitudes about the urgency of their medical concerns could reduce inappropriate hospital visits.

Adolescent↗
PubMed1992

Apolipoprotein H (beta-2-glycoprotein I) polymorphism in Asians.

Apolipoprotein H (APOH) (beta-2-glycoprotein I) polymorphism has been studied in 1159 Asians. The sample included 872 Chinese, 179 Asiatic Indians (Dravidian), 91 Filipinos, and 17 Malays. APOH polymorphism was determined by isoelectric focusing of sera in thin-layer polyacrylamide gels containing 3 M urea followed by immunoblotting. The frequencies of the three alleles--APOH*1, APOH*2, and APOH*3--were found to be 0.031, 0.900, and 0.069 in the Chinese; 0.061, 0.866, and 0.073 in the Dravidian Indians; 0.055, 0.923, and 0.022 in the Filipinos; and 0.088, 0.882, and 0.029 in the Malays. The phenotypic distribution was at Hardy-Weinberg equilibrium in all the populations.

Adult↗
PubMed1991

Genetic studies of human apolipoproteins. XIX. Apolipoproteins E and A-IV phenotyping from whole blood and blood stains.

Apolipoproteins E and A-IV reveal common, genetically determined, structural polymorphisms, which can be detected in serum or plasma, using isoelectric focusing and immunoblotting techniques. In the present study, we have investigated the possibility of detecting the gene products of these two polymorphic loci in whole blood and blood stains. A total of 68 plasma samples and their corresponding whole blood samples were screened. Phenotypic patterns obtained in whole blood were identical to those obtained in plasma for both the APO E and APO A-IV polymorphisms. The signal-to-noise ratio in the APO E patterns was higher in whole blood than in fresh plasma. The gene products of both the APO E and APO A-IV were found to be very stable in several months old blood stains. The detection of apolipoprotein polymorphisms in whole blood and blood stains signifies their potential applications, on a wider scale, to several areas including forensic serology, paternity testing, clinical and population genetic studies.

Apolipoproteins A↗
PubMed1990

Genetic studies of human apolipoproteins: XIV. A simple agarose isoelectric focusing gel method for apolipoprotein E phenotyping.

A new and simplified procedure is described for apolipoprotein E (APO E) phenotyping from native plasma or serum samples. Diluted or dialyzed samples are separated on agarose isoelectric focusing gels followed by protein blotting on nitrocellulose membranes. APO E banding patterns are localized immunologically using polyclonal goat anti-APO E antiserum as the primary antibody and rabbit anti-goat IgG conjugated with alkaline phosphatase as the secondary antibody. The method was used in parallel with our previously described polyacrylamide gel system to screen 110 unrelated and healthy US whites. Both gel systems gave identical APO E phenotypes, and allele frequencies were comparable with reported US white values. This simplified method can be used on a large number of population and clinical samples with minimum cost and effort.

Apolipoproteins E↗
PubMed1990

Disulfide bonds are neither required, present, nor compatible with full activity of human recombinant acidic fibroblast growth factor.

Human acidic fibroblast growth factor (aFGF) is a potent broad-spectrum mitogen that contains three Cys residues within its monomeric structure. We have found that site-directed mutants in which any one of these Cys residues is converted to serine remain highly active, although variably dependent on heparin, so none of the three possible intramolecular disulfide bonds that can be formed are required for mitogenic activity. Furthermore, a dispensable disulfide bond that might stabilize the active conformation is not present since all three Cys residues are accessible to chemical modification in recombinant as well as brain-derived aFGFs. Finally, formation of a disulfide bond between the two Cys residues conserved among all seven known members of the FGF family results in a virtually inactive product that can subsequently be reactivated by reduction. Thus, despite the extracellular function of aFGF, its Cys residues do not form intramolecular disulfide bonds in the active conformation.

Animals↗
PubMed1989

Repeated antigen challenge induces airway hyperresponsiveness with tissue eosinophilia in guinea pigs.

To test the hypothesis that the development of airway hyperresponsiveness (AHR) lasting greater than or equal to 3 days after the last antigenic exposure required repeated mediator release, we compared dose-response changes in lung resistance (RL) to acetylcholine (ACh) in animals sensitized with 1% ovalbumin (OA), 4% Bordatella pertussis aerosol and subsequently challenged with 0.5% OA aerosol twice weekly for 4-6 wk vs. animals receiving saline aerosol instead of OA. Despite antihistamine pretreatment, each OA challenge produced cyanosis and inspiratory indrawing. Blood gas analysis in six guinea pigs revealed an immediate fall in arterial PO2 (PaO2) from 104.3 +/- 4.9 to 35.4 +/- 2.2 Torr after a 1-min exposure to aerosolized OA. ACh dose-response measurements of RL 3 days after the last OA challenge demonstrated a leftward shift and an increased magnitude of response. These differences were less marked at 7 days, and by 14 days after the last OA challenge, ACh dose-response curves were not different from those of control guinea pigs. Sensitization without repeated antigen challenge did not cause hyperresponsiveness. Morphometric analysis showed significantly increased numbers of eosinophils in the epithelium of airways in hyperresponsive guinea pigs, without neutrophil infiltration or alterations in epithelium and airway wall areas. We conclude that repeated antigenic challenge, but not sensitization alone, causes prolonged AHR in guinea pigs, which is associated with tissue eosinophilia.

Acetylcholine↗
PubMed1987

Airflow-induced bronchospasm. Imbalance between airway cooling and airway drying?

We used an animal model of airflow-induced bronchospasm (AIB) to examine the role of airway cooling in responses to dry air challenge. A bronchoscope was wedged in situ into perfused lower lobes of anesthetized dogs. Through the bronchoscope, dry air was delivered, resistance to collateral flow (Rcs) was measured, and airway wall temperature (Taw) was monitored. A dry-air challenge through the bronchoscope produced a fall in Taw and a rise in Rcs, presumably related to evaporative heat loss (EHL) and/or an increase in osmolarity. By changing the temperature of blood perfusing the lobe it was possible to lower Taw without affecting either EHL or osmolarity. Four series of experiments were performed. In the first series, Taw was lowered in 2 ways: by increasing dry air flow and by cooling the pulmonary perfusate. After a 2-min challenge with dry air, Rcs rose. After lowering Taw with cooled blood for 2 min, Rcs did not rise. In the second series of studies, Taw was lowered for 15-min periods by reducing the temperature of blood. Neither cooling per se nor rewarming after the 15 min of cooling initiated increases in lung tone. In the third series of experiments, a 2-min dry air challenge was performed while the lobe was perfused with cool blood. Despite greater reductions in Taw during the dry-air challenge, responses after the challenge were virtually abolished. In a final series of experiments in which pulmonary perfusion was stopped during challenge, airway cooling was enhanced, and responses were again significantly attenuated. Thus, cooling actually depressed increases in Rcs produced by dry-air challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Endometrial tissue in peritoneal fluid.

Peritoneal fluid (PF) was studied for the presence of endometrial tissue in a consecutive series of 67 women (with documented tubal patency) undergoing diagnostic laparoscopy, tubal lavage, and hysteroscopy. PF was completely aspirated from the cul-de-sac both before and after uterine irrigation. The PF was then analyzed for the presence of endometrial tissue. In native PF no significant difference in the incidence of endometrial tissue between patients with (19%) and without (11%) endometriosis (P = 0.6) was observed. Refluxed PF, obtained after uterine irrigation, showed a significantly higher incidence of endometrial tissue in women with endometriosis (76%) as compared to controls (42%) (P = 0.03). We propose two models to explain the development of endometriosis. These are not mutually exclusive, may be independent of each other, and may represent two distinct pathophysiologic disease processes.

Adolescent↗
PubMed1986

Pulmonary blood flow affects recovery from constriction in dog lung periphery.

The influence of blood flow through the pulmonary circulation on the time course of recovery of the lung periphery from challenge with three bronchoconstrictive agents was studied in dogs. The rate of perfusion of the left lower lobe was varied between 0 and 300 ml/min. A fiber-optic bronchoscope (OD = 5.5 mm) was wedged in a small airway in the same lobe, and resistance to airflow through the collateral system was continuously monitored. The lung was challenged with histamine aerosol for 1 min, or with intravenous boluses of histamine, acetylcholine, or methacholine. The time constant (tau) of recovery from each of the challenges was measured under the various pulmonary blood flow conditions. The mean tau of the recoveries from histamine was inversely related to the rate of blood flow. However, pulmonary blood flow had no effect on recovery from challenge with acetylcholine or methacholine, two agents metabolized by cholinesterase in lung tissue. From this study we conclude that recovery of the lung periphery from histamine is perfusion dependent, whereas recovery from acetylcholine or methacholine is perfusion independent. This suggests that the rate of blood flow through the pulmonary circulation could play an important role in recovery of the peripheral airways from certain mediators of bronchoconstriction.

Acetylcholine↗