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M J Lee

Publications and source records attributed to M J Lee.

At least 37 records · Page 2Linked to original sources
PubMed2001

Lysophospholipids--receptor revelations.

Upon cell activation, membrane phospholipids are metabolized into potent lysophospholipid (LP) mediators, such as sphingosine 1-phosphate and lysophosphatidic acid. LPs fulfill signaling roles in organisms as diverse as yeast and humans. The recent discovery of G protein-coupled receptors for LPs in higher eukaryotes, and their involvement in regulating diverse processes such as angiogenesis, cardiac development, neuronal survival, and immunity, has stimulated growing interest in these lipid mediators. LP receptor biology has generated insights into fundamental cellular mechanisms and may provide therapeutic targets for drug development.

Animals↗
PubMed2001

Inhibition of ALDH3A1-catalyzed oxidation by chlorpropamide analogues.

In our efforts to identify agents that would specifically inhibit ALDH3A1, we had previously studied extensively the effect of an N(1)-alkyl, an N(1)-methoxy, and several N(1)-hydroxy-substituted ester derivatives of chlorpropamide on the catalytic activities of ALDH3A1s derived from human normal stomach mucosa (nALDH3A1) and human tumor cells (tALDH3A1), and of two recombinant aldehyde dehydrogenases, viz. human rALDH1A1 and rALDH2. The N(1)-methoxy analogue of chlorpropamide, viz. 4-chloro-N-methoxy-N-[(propylamino)carbonyl]benzenesulfonamide (API-2), was found to be a relatively selective and potent inhibitor of tALDH3A1-catalyzed oxidation as compared to its ability to inhibit nALDH3A-catalyzed oxidation, but even more potently inhibited ALDH2-catalyzed oxidation, whereas an ester analogue, viz. (acetyloxy)[(4-chlorophenyl)sulfonyl]carbamic acid 1,1-dimethylethyl ester (NPI-2), selectively inhibited tALDH3A1-catalyzed oxidation as compared to its ability to inhibit nALDH3A1-, ALDH1A1- and ALDH2-catalyzed oxidations, and this inhibition was apparently irreversible. Three additional chlorpropamide analogues, viz. 4-chloro-N,O-bis(ethoxycarbonyl)-N-hydroxybenzenesulfonamide (NPI-4), N,O-bis(carbomethoxy)methanesulfohydroxamic acid (NPI-5), and 2-[(ethoxycarbonyl)oxy]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (NPI-6), were evaluated in the present investigation. Quantified were NAD-linked oxidation of benzaldehyde catalyzed by nALDH3A1 and tALDH3A1, and NAD-linked oxidation of acetaldehyde catalyzed by rALDH1A1 and rALDH2, all at 37 degrees C and pH 8.1, and in the presence and absence of inhibitor. NPI-4, NPI-5 and NPI-6 were not substrates for the oxidative reactions catalyzed by any of the ALDHs studied. Oxidative reactions catalyzed by the ALDH3A1s, rALDH1A1 and rALDH2 were each inhibited by NPI-4 and NPI-5. NPI-6 was a poor inhibitor of nALDH3A1- and tALDH3A1-catalyzed oxidations, but was a relatively potent inhibitor of rALDH1A1- and rALDH2-catalyzed oxidations. In all cases, inhibition of ALDH-catalyzed oxidation was directly related to the product of inhibitor concentration and preincubation (enzyme+inhibitor) time. As judged by the product values (microM x min) required to effect 50% inhibition (IC(50)): (1) nALDH3A1 and tALDH3A1 were essentially equisensitive to inhibition by NPI-4 and NPI-5, and both enzymes were poorly inhibited by NPI-6; (2) rALDH1A1 was, relative to the ALDH3A1s, slightly more sensitive to inhibition by NPI-4 and NPI-5, and far more sensitive to inhibition by NPI-6; and (3) rALDH1A1 was, relative to rALDH2, essentially equisensitive to inhibition by NPI-5, whereas, it was slightly more sensitive to inhibition by NPI-4 and NPI-6.

Aldehyde Dehydrogenase↗
PubMed2001

Enhancement of phospholipase D activity by overexpression of amyloid precursor protein in P19 mouse embryonic carcinoma cells.

It has been shown that phospholipase D (PLD) activity is stimulated by the beta-amyloid protein in neuronal cells. The aim of this study was to determine whether overexpression of the amyloid precursor protein (APP) affects the activity and the level of PLD expression in P19 embryonic carcinoma cells. We observed that the unstimulated basal PLD activity was higher in wild-type APP(695)-transfected cells than in non-transfected control cells. The protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA), has been shown to activate PLD. PMA-stimulated PLD activity was 3-fold higher in the APP overexpressing cells than in the control cells. P19 cells express two distinct PLD isozymes, PLD1 and PLD2. The level of PLD2 expression was increased by APP overexpression. Although the PKC inhibitor, GF109203X, inhibited PMA-stimulated PLD activity, it did not affect the high basal PLD activity induced by APP overexpression. Neuronal differentiation of the P19 cells by retinoic acid did not affect the basal or PMA stimulated-PLD activity. Interestingly, APP overexpression in the differentiated P19 cells also led to an increase in PLD activity. The PLD activity of the P19 cells is apparently regulated by amyloid protein through both PKC-dependent and -independent mechanisms.

Amyloid beta-Protein Precursor↗
PubMed2001

Determination of 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP) and its metabolite 2-hydroxyamino-PhIP by liquid chromatography/electrospray ionization-ion trap mass spectrometry.

2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic aromatic amine found in cooked meat. It is metabolically activated by the human cytochrome P450 enzymes to form the carcinogenic metabolite N2-OH-PhIP. PhIP has been found to induce tumors in rats and is a suspected human carcinogen. In the present work, we have developed and validated a liquid chromatography-electrospray ionization/ion trap mass spectrometry (LC-ESI/ITMS) method for the determination of PhIP and N2-OH-PhIP. PhIP was incubated with microsomes prepared from the human liver; the PhIP and N2-OH-PhIP formed were isolated from the biomatrices by solid-phase extraction using C18 cartridges, with recoveries greater than 86%. Subsequently, the products were separated on a microbore reversed-phase C18 liquid chromatograph coupled to an ESI-ITMS. The ESI interface and the ITMS were tuned for various parameters, and data acquisition was performed in selective ion monitoring mode. The detection limit of PhIP and N2-OH-PhIP was 1 and 10 pg, respectively. The method is highly sensitive and selective, has simple sample preparation protocols, and should be applicable to the study of the metabolic activation of PhIP in various human tissues.

Chromatography, Liquid↗
PubMed2001

Molecular identification of IgE-dependent histamine-releasing factor as a B cell growth factor.

The culture supernatants of LK1 cells, murine erythroleukemia cells, showed B cell-stimulating activity. Purification and NH(2)-terminal sequence analysis revealed that one of the candidates was murine IgE-dependent histamine-releasing factor (IgE-HRF), which is known to induce histamine from basophils. Recombinant IgE-HRF (rHRF) obtained from Escherichia coli- or 293-transformed embryonal kidney cells was tested for B cell-stimulating activity. Both rHRFs stimulated B cell proliferation in a dose-dependent manner. However, boiling or anti-HRF Ab abolished the B cell stimulatory effects of rHRF. Recombinant HRF showed strong synergistic effects with IL-2, IL-4, and IL-5 for B cell activation, with maximal activity in the presence of anti-CD40 AB: Recombinant HRF increased MHC class II expression of B cells. It also increased Ig production from B cells. Treatment with polymyxin B, a neutralizing peptide antibiotic of LPS, did not reduce the activity of rHRF. In addition, FACS analysis using PE-conjugated rHRF showed that HRF bound to B cells. Recombinant HRF up-regulated the expression of IL-1 and IL-6 in B cells. In vivo administration of rHRF or the cDNA for rHRF increased total and Ag-specific Ig synthesis. Taken together, these results indicate that HRF stimulates B cell activation and function.

Animals↗
PubMed2001

Intracardiac echocardiographic guidance and monitoring during percutaneous endomyocardial gene injection in porcine heart.

In an effort to develop a guiding and monitoring tool for transmyocardial gene transfer, we have evaluated the feasibility of intracardiac echocardiography (ICE) to guide percutaneous endomyocardial gene transfer (PEGT), and monitor complications, in a pig model. ICE (5.5-10 MHz), complemented by fluoroscopy, was utilized to guide a needle injection into the heart in 19 normal pigs. Using this system, we injected Evans blue dye into eight pigs (group I), a mixture of pCK-CAT plasmid and India ink into seven pigs (group II), and pCK-LacZ plasmid into four pigs (group III). In all pigs, ICE contributed to the injection procedure by guiding the catheter to anatomically distinct sites, and by assisting stabilization of the catheter-endocardial contact. ICE predicted the injection sites correctly in 56 of 64 sites (87.5%) in group I, and in 42 of 42 sites (100%) in group II. Leakage of injectate into the left ventricular cavity could be detected by the microbubbles generated. The sites of injections appeared as foci of bright myocardial echodensity, which persisted until the end of the procedure. The procedures were not associated with significant morbidity or mortality. The expression of the chloramphenicol acetyltransferase (CAT) gene was identified in 40 sites from 42 injections (95.2%) in group II. In group III, histology showed positive beta-galactosidase staining of myocytes limited around the needle track with low transfection efficiency (<1%). These results suggest that real-time ICE monitoring proves safe and useful during PEGT for guiding needle injection, monitoring leakage, ensuring delivery of injectate into the myocardium, and instantly diagnosing cardiac complications, resulting in successful gene transfer.

Animals↗
PubMed2001

Preconditioning with fetal cord blood facilitates engraftment of primary childhood T-cell acute lymphoblastic leukemia in immunodeficient mice.

Childhood T-cell acute lymphoblastic leukemia (T-ALL) is one of the most common childhood cancers. It is reported that preconditioning sublethally irradiated immunodeficient NOD/SCID (nonobese diabetic/X-linked severe combined immunodeficient) mice with human cord blood mononuclear cells facilitates the engraftment, expansion, and dissemination in these mice of primary T-ALL cells obtained from patients at the time of diagnosis. Cells recovered from mouse bone marrow or spleen resembled the original leukemia cells from patients with respect to surface lineage markers and T-cell receptor Vbeta gene rearrangements. Moreover, the pattern of leukemia dissemination in mouse tissues, resulting in universally fatal leukemia, is reminiscent of the human clinical disease. In addition, the fidelity of the model to the human disease is documented with regard to the presence of morphologically identifiable human leukemia cells in mouse bone marrow and blood and the maintenance of leukemia-initiating capacity within the leukemia-engrafted mouse. Therefore, several lines of independent approaches are used to suggest that the engrafted cells are of human leukemia origin and are not derived from cord blood. The in vivo model described here should enable the study of the growth properties of primary T-ALL cells obtained from patients and should prove useful in evaluating the potential efficacy of therapeutic strategies directed toward T-ALL.

Adolescent↗
PubMed2001

Endogenous production of nitric oxide by vascular endothelial growth factor down-regulates proliferation of choriocarcinoma cells.

The trophoblast-like choriocarcinoma cell line BeWo expresses a receptor for vascular endothelial growth factor (VEGF) and proliferates in response to VEGF. Nitric oxide (NO) seems to play a key role in the VEGF-induced proliferation of endothelial cells but the NO mechanistic regulation of VEGF-stimulated trophoblast proliferation is presently unclear. We assessed the effect of exogenous VEGF on BeWo cell proliferation by [3H]thymidine incorporation. The VEGF-induced proliferation of BeWo cells was significantly increased by the NO synthase (NOS) inhibitor, N(omega)-nitro-l-arginine methyl ester (L-NAME), but was inhibited by the NO donor, sodium nitroprusside. Treatment of the cells with 10 ng/ml of VEGF increased not only eNOS expression but also NO production. The extracellular signal-regulated kinase (Erk) of the mitogen-activated protein kinase (MAPK) family was activated by VEGF as demonstrated by the phosphorylation of Erk in Western blots. The effects of VEGF on NO production and the expression of endothelial NOS (eNOS) were attenuated by treating BeWo cells with the selective inhibitor of MAPK kinase, PD98059. VEGF-stimulated proliferation of BeWo cells was inhibited by the tyrosine kinase inhibitor genistein but increased by PD98059. Other kinase inhibitors, including LY294002 (phosphoinositide 3-kinase inhibitor) and SB203580 (P38 MAPK inhibitor), had no effect on the proliferation of the cells and NO production. These results indicate that endogenous NO production down-regulates the VEGF-stimulated proliferation of BeWo cells and that the activation of Erk plays an important role in this mechanism.

Animals↗
PubMed2001

Sphingosine 1-phosphate activates Akt, nitric oxide production, and chemotaxis through a Gi protein/phosphoinositide 3-kinase pathway in endothelial cells.

Sphingosine 1-phosphate (SPP) binds to members of the endothelial differentiation gene family (EDG) of receptors and leads to diverse signaling events including cell survival, growth, migration and differentiation. However, the mechanisms of how SPP activates these proangiogenic pathways are poorly understood. Here we show that SPP signals through the EDG-1 receptor to the heterotrimeric G protein G(i), leading to activation of the serine/threonine kinase Akt and phosphorylation of the Akt substrate, endothelial nitric-oxide synthase (eNOS). Inhibition of G(i) signaling, and phosphoinositide 3-kinase (PI 3-kinase) activity resulted in a decrease in SPP-induced endothelial cell chemotaxis. SPP also stimulates eNOS phosphorylation and NO release and these effects are also attenuated by inhibition of G(i) signaling, PI 3-kinase, and Akt. However, inhibition of NO production did not influence SPP-induced chemotaxis but effectively blocked the chemotactic actions of vascular endothelial growth factor. Thus, SPP signals through G(i) and PI 3-kinase leading to Akt activation and eNOS phosphorylation.

Animals↗
PubMed2001

The effect of nicotine and haloperidol co-treatment on nicotinic receptor levels in the rat brain.

Genetic and biological data have suggested a role for the neuronal nicotinic acetylcholine receptors in the neuropathophysiology of schizophrenia. Studies in human postmortem brain demonstrate dose-dependent increases in nicotinic receptor binding in normal smokers. We found this upregulation to be reduced in schizophrenic smokers, many of whom had taken typical neuroleptics during their lifetime. The present study examined the hypothesis that typical antipsychotic drug treatment might modulate nicotinic receptor upregulation in a rat model. Nicotine, administered alone or in combination with haloperidol, increased both high and low affinity neuronal nicotinic receptors in a region specific manner. Haloperidol had no generalized effect on basal levels of nicotinic receptor binding or nicotine induced upregulation of nicotinic receptors. However, haloperidol attenuated high affinity nicotinic receptor upregulation in thalamus and low affinity receptor upregulation in hippocampus. These results suggest that haloperidol is not likely to affect nicotinic receptor regulation by smoking in most brain regions.

Aconitine↗
PubMed2001

Inhibition of ALDH3A1-catalyzed oxidation by chlorpropamide analogues.

In our efforts to identify agents that would specifically inhibit ALDH3A1, we had previously studied extensively the effect of an N(1)-alkyl, an N(1)-methoxy, and several N(1)-hydroxy-substituted ester derivatives of chlorpropamide on the catalytic activities of ALDH3A1s derived from human normal stomach mucosa (nALDH3A1) and human tumor cells (tALDH3A1), and of two recombinant aldehyde dehydrogenases, viz. human rALDH1A1 and rALDH2. The N(1)-methoxy analogue of chlorpropamide, viz. 4-chloro-N-methoxy-N-[(propylamino)carbonyl]benzenesulfonamide (API-2), was found to be a relatively selective and potent inhibitor of tALDH3A1-catalyzed oxidation as compared to its ability to inhibit nALDH3A-catalyzed oxidation, but even more potently inhibited ALDH2-catalyzed oxidation, whereas an ester analogue, viz. (acetyloxy)[(4-chlorophenyl)sulfonyl]carbamic acid 1,1-dimethylethyl ester (NPI-2), selectively inhibited tALDH3A1-catalyzed oxidation as compared to its ability to inhibit nALDH3A1-, ALDH1A1- and ALDH2-catalyzed oxidations, and this inhibition was apparently irreversible. Three additional chlorpropamide analogues, viz. 4-chloro-N,O-bis(ethoxycarbonyl)-N-hydroxybenzenesulfonamide (NPI-4), N,O-bis(carbomethoxy)methanesulfohydroxamic acid (NPI-5), and 2-[(ethoxycarbonyl)oxy]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (NPI-6), were evaluated in the present investigation. Quantified were NAD-linked oxidation of benzaldehyde catalyzed by nALDH3A1 and tALDH3A1, and NAD-linked oxidation of acetaldehyde catalyzed by rALDH1A1 and rALDH2, all at 37 degrees C and pH 8.1, and in the presence and absence of inhibitor. NPI-4, NPI-5 and NPI-6 were not substrates for the oxidative reactions catalyzed by any of the ALDHs studied. Oxidative reactions catalyzed by the ALDH3A1s, rALDH1A1 and rALDH2 were each inhibited by NPI-4 and NPI-5. NPI-6 was a poor inhibitor of nALDH3A1- and tALDH3A1-catalyzed oxidations, but was a relatively potent inhibitor of rALDH1A1- and rALDH2-catalyzed oxidations. In all cases, inhibition of ALDH-catalyzed oxidation was directly related to the product of inhibitor concentration and preincubation (enzyme+inhibitor) time. As judged by the product values (microMxmin) required to effect 50% inhibition (IC(50)): (1) nALDH3A1 and tALDH3A1 were essentially equisensitive to inhibition by NPI-4 and NPI-5, and both enzymes were poorly inhibited by NPI-6; (2) rALDH1A1 was, relative to the ALDH3A1s, slightly more sensitive to inhibition by NPI-4 and NPI-5, and far more sensitive to inhibition by NPI-6; and (3) rALDH1A1 was, relative to rALDH2, essentially equisensitive to inhibition by NPI-5, whereas, it was slightly more sensitive to inhibition by NPI-4 and NPI-6.

Aldehyde Dehydrogenase↗
PubMed2001

Glutathione S-transferase mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1.

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that can activate the c-Jun N-terminal kinase and the p38 signaling pathways. It plays a critical role in cytokine- and stress-induced apoptosis. To further characterize the mechanism of the regulation of the ASK1 signal, we searched for ASK1-interacting proteins employing the yeast two-hybrid method. The yeast two-hybrid assay indicated that mouse glutathione S-transferase Mu 1-1 (mGSTM1-1), an enzyme involved in the metabolism of drugs and xenobiotics, interacted with ASK1. We subsequently confirmed that mGSTM1-1 physically associated with ASK1 both in vivo and in vitro. The in vitro binding assay indicated that the C-terminal portion of mGSTM1-1 and the N-terminal region of ASK1 were crucial for binding one another. Furthermore, mGSTM1-1 suppressed stress-stimulated ASK1 activity in cultured cells. mGSTM1-1 also blocked ASK1 oligomerization. The ASK1 inhibition by mGSTM1-1 occurred independently of the glutathione-conjugating activity of mGSTM1-1. Moreover, mGSTM1-1 repressed ASK1-dependent apoptotic cell death. Taken together, our findings suggest that mGSTM1-1 functions as an endogenous inhibitor of ASK1. This highlights a novel function for mGSTM1-1 insofar as mGSTM1-1 may modulate stress-mediated signals by repressing ASK1, and this activity occurs independently of its well-known catalytic activity in intracellular glutathione metabolism.

Animals↗
PubMed2001

Sphingosine 1-phosphate-induced endothelial cell migration requires the expression of EDG-1 and EDG-3 receptors and Rho-dependent activation of alpha vbeta3- and beta1-containing integrins.

Sphingosine 1-phosphate (SPP), a platelet-derived bioactive lysophospholipid, is a regulator of angiogenesis. However, molecular mechanisms involved in SPP-induced angiogenic responses are not fully defined. Here we report the molecular mechanisms involved in SPP-induced human umbilical vein endothelial cell (HUVEC) adhesion and migration. SPP-induced HUVEC migration is potently inhibited by antisense phosphothioate oligonucleotides against EDG-1 as well as EDG-3 receptors. In addition, C3 exotoxin blocked SPP-induced cell attachment, spreading and migration on fibronectin-, vitronectin- and Matrigel-coated surfaces, suggesting that endothelial differentiation gene receptor signaling via the Rho pathway is critical for SPP-induced cell migration. Indeed, SPP induced Rho activation in an adherence-independent manner, whereas Rac activation was dispensible for cell attachment and focal contact formation. Interestingly, both EDG-1 and -3 receptors were required for Rho activation. Since integrins are critical for cell adhesion, migration, and angiogenesis, we examined the effects of blocking antibodies against alpha(v)beta(3), beta(1), or beta(3) integrins. SPP induced Rho-dependent integrin clustering into focal contact sites, which was essential for cell adhesion, spreading and migration. Blockage of alpha(v)beta(3)- or beta(1)-containing integrins inhibited SPP-induced HUVEC migration. Together our results suggest that endothelial differentiation gene receptor-mediated Rho signaling is required for the activation of integrin alpha(v)beta(3) as well as beta(1)-containing integrins, leading to the formation of initial focal contacts and endothelial cell migration.

Base Sequence↗
PubMed2001

Synthesis and muscarinic activity of 1,2,3,4-tetrahydropyrimidine derivatives.

3-Methyl-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde O-substituted oximes 4 and 1-(3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl)ethanone O-substituted oximes 9 have been prepared as bioisosteric congeners of arecoline which is a muscarinic agonist for treatment of Alzheimer's disease. Starting from pyrimidine-5-carbaldehyde 1, formation of the 3-methylpyrimidinium salt and subsequent reduction afforded 1,2,3,4-tetrahydropyrimidine derivatives which were converted into oxalate salts in the interest of purity and stability. Binding affinities of prepared compounds for the cloned human muscarinic M1 receptor (h-M1) were determined by radioligand binding assay using [3H]-N-methylscopolamine (NMS).

Animals↗
PubMed2001

In early development of the rat mRNA for the major myelin protein P(0) is expressed in nonsensory areas of the embryonic inner ear, notochord, enteric nervous system, and olfactory ensheathing cells.

The myelin protein P(0) has a major structural role in Schwann cell myelin, and the expression of P(0) protein and mRNA in the Schwann cell lineage has been extensively documented. We show here, using in situ hybridization, that the P(0) gene is also activated in a number of other tissues during embryonic development. P(0) mRNA is first detectable in 10-day-old embryos (E10) and is at this time seen only in cells in the cephalic neural crest and in the otic placode/pit. P(0) expression continues in the otic vesicle and at E12 P(0) expression in this structure largely overlaps with expression of another myelin gene, proteolipid protein. In the developing ear at E14, P(0) expression is complementary to expression of serrate and c-ret mRNAs, which later are expressed in sensory areas of the inner ear, while expression of bone morphogenetic protein (BMP)-4 and P(0), though largely complementary, shows small areas of overlap. P(0) mRNA and protein are detectable in the notochord from E10 to at least E13. In addition to P(0) expression in a subpopulation of trunk crest cells at E11/E12 and in Schwann cell precursors thereafter, P(0) mRNA is also present transiently in a subpopulation of cells migrating in the enteric neural crest pathway, but is down-regulated in these cells at E14 and thereafter. P(0) is also detected in the placode-derived olfactory ensheathing cells from E13 and is maintained in the adult. No signal is seen in cells in the melanocyte migration pathway or in TUJ1 positive neuronal cells in tissue sections. The activation of the P(0) gene in specific tissues outside the nervous system was unexpected. It remains to be determined whether this is functionally significant, or whether it is an evolutionary relic, perhaps reflecting ancestral use of P(0) as an adhesion molecule.

Animals↗
PubMed2001

Proportional treatment effects for count response panel data: effects of binary exercise on health care demand.

We define conditional and marginal treatment effects appropriate for count data, and then conduct an empirical analysis for the effects of exercise on health care demand using panel data from the Health Retirement Study. The response variables are office visits to doctors and hospitalization days, and the treatments of interest are light and vigorous exercises. We found that short-run light exercise increases health care demand by 3-5%, whereas long-run light exercise decreases it by 3-6%. We also found that short-run vigorous exercise decreases health care demand by 1-2%, whereas long-run vigorous exercise decreases it by 1-3%. However, many of these numbers are not statistically significantly different from zero. These findings suggest that it will be difficult to reduce health care cost much by encouraging people to do more exercise--at least in the short-run.

Adult↗