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Biomedical subjects

W Patsch

Publications and source records attributed to W Patsch.

At least 37 records · Page 2Linked to original sources
PubMed1999

The relationship between lipids/lipoproteins and atherosclerosis in African Americans and whites: the Atherosclerosis Risk in Communities Study.

PURPOSE: The relationships between lipids/lipoproteins and atherosclerosis were determined in African Americans and whites to assess the consistency of the relationship between these two groups. Differences could suggest varying biological, environmental, or life-style cofactors influencing development of atherosclerosis. METHODS: In the Atherosclerosis Risk in Communities Study, 2966 African Americans and 9399 whites had determinations of LDL, HDL, HDL2, and HDL3 cholesterol, triglycerides, apolipoprotein A1 and B, and lipoprotein (a). Carotid intimal-medial thickening (IMT) was measured using B-mode ultrasound imaging. RESULTS: The associations, using linear regression, between carotid IMT and LDL cholesterol, HDL cholesterol, and other lipid measurements were significantly weaker in African Americans than whites. Averaging men and women, a 1.034 mmol/L (40 mg/dl) difference in LDL cholesterol was associated with a 0.028 mm IMT difference in whites but a 0.019 difference in African Americans. Similarly, for HDL cholesterol, a 0.44 mmol/L (17 mg/dl) difference is associated wth 0.026 mm difference in carotid IMT in whites and 0.011 mm difference in African Americans. The associations are much weaker in African Americans than whites at the bifurcation and internal carotid, the carotid sites most prone to atherosclerosis. Analysis was done stratifying for risk factors that differ between African Americans and whites, but within most, the relationships remained substantially weaker in African Americans. CONCLUSIONS: We have observed a statistically significant difference in the association between many lipids/lipoproteins and carotid IMT between African Americans and whites. Analysis of many potential cofactors have not provided an explanation for the weaker association. Although possible differences in prior levels of these lipids may provide one explanation for the finding, these results need confirmation in other studies.

Arteriosclerosis↗
PubMed1999

Relation of plasma leptin to lipoproteins in overweight children undergoing weight reduction.

BACKGROUND: In obese children, plasma leptin is elevated and correlates with the body mass index (BMI). In obese adults, plasma leptin decreases during weight reduction. Since the leptin system changes dynamically in puberty, we asked whether weight reduction in obese adolescents has similar consequences for plasma leptin as in overweight adults. In plasma, a portion of leptin is bound to several as yet uncharacterised proteins. We therefore studied the possible association of leptin with plasma lipoproteins. SUBJECTS AND METHODS: We measured plasma leptin, lipoprotein cholesterol and apolipoproteins (apo) A-I and B in 34 obese children (age 12.5+/-1.9 y, relative BMI 165.0+/-28.1%) before and after three weeks of weight reduction in a dietary camp. Lipoprotein binding of endogenous and exogenously radiolabelled leptin was studied by preparative ultracentrifugation. RESULTS: Plasma leptin was higher in obese children than in normal weight controls and fell from 16.5+/-9.8 ng/ml to 10.0+/-8.6 ng/ml after weight reduction (P < 0.001). In multivariate regression, relative BMI and apoA-I were significant predictors of baseline leptin and accounted for 38% (P = 0.003) and 15% (P = 0.006) of the variance of baseline leptin concentrations in obese children. Only the difference in plasma high-density lipoprotein (HDL)-cholesterol independently predicted the change of plasma leptin that was associated with weight reduction, explaining 29% of the variance of leptin changes (P = 0.0032). A substantial portion of both endogenous and exogenously labelled leptin was recovered with HDL isolated by ultracentrifugation. CONCLUSIONS: We conclude that plasma leptin decreases in overweight children undergoing short term weight reduction. In obese children, plasma apoA-I and HDL-cholesterol are independent predictors of leptin concentrations during weight loss, respectively. In addition, HDLs transport a variable portion of leptin in the circulation.

Adult↗
PubMed1999

Allele-specific differences in apolipoprotein C-III mRNA expression in human liver.

BACKGROUND: Sequence variations at the apolipoprotein (apo)C-III gene locus have been associated with increased plasma triglycerides. In particular, the S2 allele of an SstI polymorphism in the 3' untranslated region has been associated with hypertriglyceridemia in many populations. The aim of this study was to determine whether the variant S2 allele is related to increased mRNA expression in vivo. METHODS: We measured allele-specific apoC-III expression in liver biopsies of five obese subjects, using restriction isotyping and a primer extension method, both based on the SstI polymorphism. RESULTS: The expression of mRNA by the S1 and S2 alleles was similar in two patients, whereas the mRNA encoded by the S2 allele was 14%, 26%, and 29% more abundant than the wild-type mRNA in the remaining three patients. Because other polymorphisms at the apoC-III gene locus have been implicated in the S2-associated hypertriglyceridemia, we determined apoC-III haplotypes comprising promoter polymorphisms at -935, -641, -630, -625, -482, -455, as well as the SstI sites and a BbvI site, both located in the 3' untranslated region. None of these polymorphisms nor any haplotype exhibited a perfect association with allele-specific expression, but variation at the T-482C site correlated in four of five subjects with the relative allele abundance. CONCLUSION: These data provide preliminary evidence for allele-specific differences in apoC-III mRNA expression in vivo and suggest that such differences may contribute to associations of apoC-III gene polymorphisms with hypertriglyceridemia.

3' Untranslated Regions↗
PubMed1999

Transcriptional elongation of the rat apolipoprotein A-I gene: identification and mapping of two arrest sites and their signals.

Previous studies have shown that the elongation phase of apoA-I gene transcription is regulated and contributes to hormone-induced changes in the expression of this gene in rat liver. We have now identified, by in vitro transcription studies with HeLa nuclear extracts, two transcriptional arrest sites within exon 3 and intron 3, respectively. Two truncated transcripts of 510 and approximately 1100 nucleotides in length, termed attenuator 1 RNA and attenuator 2 RNA, respectively, were observed when a rat apoA-I genomic fragment extending from -309 to +1842 relative to the transcription start site was transcribed in vitro in the presence of KCl or Sarkosyl. The attenuation events were promoter-independent as transcription of the apoA-I gene driven by the cytomegalovirus promoter resulted in transcriptional arrest at both sites. Transcription studies using deletion constructs as templates identified nucleotides +976 to +1158 as a region that contained the signal for transcriptional arrest at attenuator site 2. Computational analysis predicted a stem;-loop structure in the nascent RNA immediately upstream of the arrest site. Deletion of attenuator 2 signal or deletion of sequences +147 to +216 located far upstream of the actual elongation block site 1 abrogated arrest at site 1. Thus, complex long-range interactions may be involved in the transcriptional arrest at site 1. These elongation blocks identified in vitro are consistent with earlier in vivo data based on nuclear run-on assays and represent, to our knowledge, the first example describing transcriptional attenuation as a mechanism controlling the expression of a member of the apolipoprotein gene family.

Animals↗
PubMed1998

African American-white differences in lipids, lipoproteins, and apolipoproteins, by educational attainment, among middle-aged adults: the Atherosclerosis Risk in Communities Study.

Measures of socioeconomic status have been shown to be related positively to levels of high density lipoprotein (HDL) cholesterol in white men and women and negatively in African American men. However, there is little information regarding the association between educational attainment and HDL fractions or apolipoproteins. The authors examined these associations in 9,407 white and 2,664 African American men and women aged 45-64 years who participated in the Atherosclerosis Risk in Communities Study baseline survey, and they found racial differences. A positive association for HDL cholesterol, its fractions HDL2 and HDL3 cholesterol, and its associated apolipoprotein A-I was found in white men and white women, but a negative association was found in African American men, and there was no association in African American women. In whites, there was also an inverse association of low density lipoprotein (LDL) cholesterol and apolipoprotein B with educational attainment. With the exception of African American men, advanced education was associated with a more favorable cardiovascular lipid profile, which was strongest in white women. Racial differences in total cholesterol (women only), plasma triglycerides, LDL cholesterol, apolipoprotein B (women only), HDL cholesterol, HDL2 and HDL3 cholesterol, and apolipoprotein A-I were reduced at higher levels of educational attainment. Apart from triglycerides in men and HDL3 cholesterol in women, these African American-white lipid differences associated with educational attainment remained statistically significant after multivariable adjustment for lifestyle factors. Lipoprotein(a) showed no association with educational attainment. These findings confirm African American-white differences in lipids, lipoproteins, and apolipoproteins across levels of educational attainment that were not explained by conventional nondietary lifestyle variables. Understanding these differences associated with educational attainment will assist in identifying measures aimed at prevention of cardiovascular disease.

Black or African American↗
PubMed1998

Uncoupling protein-2 gene: reduced mRNA expression in intraperitoneal adipose tissue of obese humans.

The mitochondrial uncoupling protein-2 (UCP-2) is a recently discovered homologue of the brown adipose tissue-specific uncoupling protein and could be involved in the regulation of energy balance. Since obesity is associated with disturbed energy homeostasis, we tested the hypothesis that UCP-2 gene expression is deficient in this disorder. We determined, by a competitive reverse transcription-polymerase chain reaction assay, UCP-2 mRNA expression in intra- and extraperitoneal adipose tissues of 107 morbidly obese subjects and 31 lean control subjects. In both obese and non-obese subjects, UCP-2 mRNA abundance was higher in the intraperitoneal than in the extraperitoneal tissue (p < 0.05), but no association was observed between intra- and extraperitoneal expression in either group. Compared with lean control subjects, both male and female obese subjects displayed significantly lower average UCP-2 mRNA expression in the intraperitoneal adipose tissue (p < 0.006), while UCP-2 mRNA abundance in extraperitoneal adipose tissue was not different between obese and non-obese men and women. Intraperitoneal UCP-2 mRNA remained low in nine obese subjects who lost 23 +/- 12 kg of weight over a period of 10 +/- 5 months subsequent to weight reducing surgery. These data support the concept that impaired adipose tissue expression of UCP2 may play a role in the pathophysiology of obesity.

Adipose Tissue↗
PubMed1998

Plasma leptin levels: interaction of obesity with a common variant of insulin receptor substrate-1.

Obesity is associated with insulin resistance and other major cardiovascular risk factors. A common amino acid polymorphism at codon 972 of the insulin receptor substrate-1 (IRS-1) has been shown to interact with obesity in the expression of insulin resistance. The plasma concentration of the adipocyte-specific hormone leptin is increased in obesity and is correlated with adipose tissue mass. Because in vitro studies demonstrated inhibitory effects of leptin on insulin signaling, leptin may be involved in obesity-associated insulin resistance. To gain insight into the relationship between insulin and leptin in obesity, we studied plasma leptin levels and several cardiovascular risk factors, as well as their modification by the IRS-1 codon 972 genotype, in 156 obese individuals and 131 lean control subjects. In both groups, 10% of the subjects were heterozygous for the IRS-1 codon 972 variant. Obese individuals harboring the IRS-1 variant displayed significantly lower plasma concentrations of leptin than obese subjects without the polymorphism (means, 26.7 versus 37.8 ng/mL, P<0.0293). In a subgroup of obese patients, leptin mRNA abundance was measured in the adipose tissue and was significantly lower in carriers of the IRS-1 variant than in subjects with the wild-type variant (P<0.0291). Our data suggest that insulin signaling influences plasma leptin concentrations at the mRNA expression level and argue against leptin as a major causative factor of insulin resistance.

Adult↗
PubMed1998

Uncoupling protein-1 mRNA expression in obese human subjects: the role of sequence variations at the uncoupling protein-1 gene locus.

Uncoupling protein-1 (UCP-1) activity in brown adipose tissue increases thermogenesis, contributes to facultative energy expenditure in humans, and has been implicated in the pathogenesis of rodent obesity. To determine genetic factors controlling UCP-1 expression in humans, we measured intra- and extraperitoneal UCP-1 mRNA abundance levels by a competitive RT-PCR method and compared expression levels with common sequence variations in the beta3-adrenergic receptor gene and the distal UCP-1 gene promoter in obese human subjects. While median and average UCP-1 mRNA levels in both the intra- and extraperitoneal tissue were lower in subjects heterozygous for the Trp64Arg mutation in the beta3-adrenergic receptor gene, this difference was not statistically significant. However, a strong association of intraperitoneal UCP-1 mRNA abundance with the UCP-1 gene polymorphism at -3826 relative to the transcription start site was observed that explained 19.3% of the interindividual variability. The minor allele imparted a dose-dependent reduction on UCP gene expression. The importance of sequence variations at the UCP-1 gene locus as a common source of UCP-1 mRNA abundance variability was supported by allele-specific expression studies utilizing a newly identified polymorphism in exon 2 of the UCP-1 gene that predicts a substitution of alanine by threonine. In four subjects heterozygous for the -3826 polymorphism, the mRNA species transcribed from the wild-type allele accounted for 63+/-6% percent of total intraperitoneal mRNA abundance. In one subject homozygous for the minor promoter allele, wild-type mRNA was also more abundant than variant mRNA. Thus, the UCP-1 polymorphism at -3826 is probably only a marker for a frequent mutation causing reduced mRNA expression.

Adipose Tissue↗
PubMed1998

Heterozygosity for the C282Y mutation in the hemochromatosis gene is associated with increased serum iron, transferrin saturation, and hemoglobin in young women: a protective role against iron deficiency?

Genetic hemochromatosis (GH) is the most common autosomal-recessive disorder (1 in 300 in populations of Celtic origin). Homozygosity for a C282Y mutation in the hemochromatosis (HFE) gene is the underlying defect in approximately 80% of patients with GH, and 3. 2-13% of Caucasians are heterozygous for this gene alteration. Because the high frequency of this mutation may result from a selection advantage, the hypothesis was tested that the C282Y mutation confers protection against iron deficiency in young women. To address this question the genotype of codon 282 was determined in a cohort of 468 unrelated female healthcare workers, ages 18-40 years. In all study participants, a complete blood count was obtained, and erythrocyte distribution width, serum iron, transferrin, transferrin saturation, and ferritin were measured. Two individuals were homozygous for the C282Y mutation, 44 were heterozygous, and 416 were homozygous for the wild-type allele. Heterozygous women had significantly higher values for hemoglobin (P = 0.006), serum iron (P = 0.013), and transferrin saturation (P = 0. 006) than women homozygous for the wild-type allele. Our data provide evidence for a protective role of the C282Y mutation in the HFE gene against iron deficiency in young women and suggest that a more efficient utilization of nutritional iron may have contributed to the high prevalence of the mutation in Caucasian populations.

Adolescent↗
PubMed1997

Human obese gene expression: alternative splicing of mRNA and relation to adipose tissue localization.

BACKGROUND: The adipocyte-specific protein leptin signals the size of the adipose tissue mass to hypothalamic regions, thereby influencing food intake and energy metabolism. Human obesity is often associated with high leptin levels implying leptin resistance or defective leptin function. Two leptin mRNA species differing only by the presence or absence of a CAG codon encoding glutamine at position 49 of the mature protein arise from alternative splicing owing to two splice acceptor sites immediately following each other at the intron 2 - exon 3 junction. Since glutamine 49 is part of a highly conserved region, we studied possible functional implications of alternative splicing for human obesity. METHODS: We determined, in lean and obese individuals, the relative abundance of both mRNA species in intra- and extraperitoneal adipose tissue in relation to ob gene transcript abundance and plasma leptin levels. RESULTS: Leptin mRNA levels in adipose tissue and concentrations of leptin in plasma were significantly higher in obese subjects than in controls. In both obese and control subjects, leptin mRNA levels were higher in extraperitoneal than in intraperitoneal adipose tissue. Furthermore, leptin mRNA abundance correlated with average fat cell size. In all tissue samples, the predominant ob gene transcript contained the codon for glutamine 49 and the molar ratio of the two leptin mRNA species was similar in patients and controls. No correlation was observed between splice site usage and leptin mRNA abundance or leptin concentration in plasma in our study group. CONCLUSIONS: Differences in the primary structure of leptin due to the presence or absence of glutamine 49 are unlikely to contribute to the apparent 'leptin resistance' commonly observed in obese individuals.

Adipocytes↗
PubMed1997

Uncoupling protein gene: quantification of expression levels in adipose tissues of obese and non-obese humans.

The mitochondrial uncoupling protein (UCP), which is exclusively expressed in brown adipose tissue, regulates energy expenditure in rodents but its importance in the energy homeostasis of adult humans is uncertain. To study associations of UCP gene expression with human obesity, we determined, by a competitive reverse transcription-polymerase chain reaction assay, UCP mRNA expression levels in intra- and extraperitoneal adipose tissues of 79 obese subjects and 17 lean controls. UCP mRNA and internal standard RNA were reverse transcribed and coamplified in one reaction in which the same primers were used. The signal intensities of UCP mRNA products were compared with the signal intensities of standard RNA products to quantify UCP mRNA abundance. UCP mRNA was detected in all intra- and extraperitoneal adipose tissues studied. In both obese and non-obese subjects, UCP mRNA abundance was higher in the intraperitoneal than in the extraperitoneal tissue (P < 0.001). Compared to lean controls, morbidly obese subjects showed a significantly lower age- and gender-adjusted UCP mRNA expression level in the intraperitoneal adipose tissue (3.467 +/- 2.483 vs. 6.917 +/- 4.292 amol/fmol beta-actin mRNA; mean +/- SD, P < 0.002), while UCP mRNA abundance in extraperitoneal adipose tissue did not differ between obese and nonobese subjects. These data are consistent with reduced energy expenditure in obesity, but it remains to be determined whether the association of decreased intraperitoneal UCP mRNA expression with obesity status reflects a causal contribution of brown adipose tissue function to the pathogenesis of obesity.

Adipose Tissue, Brown↗
PubMed1996

HindIII DNA polymorphism in the lipoprotein lipase gene and plasma lipid phenotypes and carotid artery atherosclerosis.

Lipoprotein lipase (LPL) is the rate limiting enzyme in the hydrolysis of core triglyceride in chylomicron and very low density lipoprotein (VLDL) thus affecting a broad spectrum of plasma lipid levels. In this paper, we investigated the association of a HindIII polymorphism in the LPL gene with plasma lipid levels and carotid artery wall thickness measured by B-mode ultrasonography. A total of 238 Caucasian subjects were selected from the Atherosclerosis Risk In Community (ARIC) study (male = 1.31, female = 107) based on their fasting triglyceride and LDL-cholesterol levels: normolipidemic (n = 48), hypertriglyceridemic (n = 44), hypercholesterolemic (n = 36), and hypertriglyceridemic-hypercholesterolemic (n = 110) groups. We observed a marginally significant association between lipid phenotypes and HindIII genotypes (P = 0.04) in males, with the hypertriglyceridemic and hypercholesterolemic groups having a higher frequency (0.65) of the H+H+ genotype than the other two groups (pooled: 0.55). In males, there was also a significant association between HindIII genotypes and carotid artery wall thickness after considering the effects of age, body mass index, cigarette smoking, lipid phenotype and diabetes status (P = 0.013), with the H+H+ genotype having a higher average value of carotid artery wall thickness (0.84 +/- 0.15 mm) than the other two genotype groups (0.76 +/- 0.14 mm in H+H(+)-genotype class, 0.75 +/- 0.13 mm in H-H- genotype class). In females, no significant associations among LPL HindIII genotype, lipid phenotype and carotid artery wall thickness were observed. These results suggest that the LPL HindIII polymorphism influences LPL-catalyzed, triglyceride-rich lipoprotein metabolism and carotid artery atherosclerosis in a gender-specific manner.

Adult↗
PubMed1996

Apolipoprotein A-II influences the substrate properties of human HDL2 and HDL3 for hepatic lipase.

Hepatic lipase has a demonstrated dual role in plasma lipid transport in that it participates in the removal of remnants of triglyceride-rich lipoproteins from the circulation and in the metabolism of plasma HDL. The study presented here investigated the substrate properties for hepatic lipase of HDL differing in density and apolipoprotein (apo) composition. Rates of fatty acid liberation were twofold higher in HDL2 compared with the respective HDL3 subspecies. Within each density class, enzyme-catalyzed fatty acid release was nearly twofold higher from HDL containing apoA-II compared with HDL devoid of apoA-II. When native HDL3 devoid of apoA-II was reconstituted with dimeric apoA-II in vitro, rates of fatty acid liberation in reconstituted particles were similar to those in native HDL3 containing apoA-II. HDL containing apoA-II competed more effectively with small VLDL for binding of hepatic lipase than HDL devoid of apoA-II. HDL3, particularly apoA-II-containing HDL3, reduced lipolysis of triglyceride and total fatty acid liberation in small VLDL. We conclude that the substrate properties of HDLs for hepatic lipase are influenced by both their size and apoA-II content. Moreover, size as well as apoA-II content may indirectly affect remnant clearance.

Apolipoprotein A-II↗
PubMed1996

Polymorphic markers in apolipoprotein C-III gene flanking regions and hypertriglyceridemia.

Hypertriglyceridemia and hyperlipidemia are common disorders associated with coronary artery disease and premature death. The proteins encoded by the apolipoprotein (apo) A-I/C-III/A-IV gene cluster are involved in the metabolism of both triglycerides and cholesterol. In a large sample of individuals from the ARIC study, six polymorphic markers were typed and plasma lipid values were measured to determine whether the well-established association between the Sst I S2 allele in the 3'-untranslated region of the apo C-III gene and hypertriglyceridemia was due to disequilibrium with variation in the 5' regulatory region of the apo C-III gene. The Sst I polymorphism was significantly associated with hypertriglyceridemia (P = .006) but not with carotid artery wall thickness, plasma apo C-III levels, or elevated cholesterol. The frequency of the S2 allele was 0.14 in those with high triglyceride levels and 0.05 in those with low triglyceride levels. None of the 5' flanking polymorphisms were significantly associated with any of the plasma lipids studied. There was substantial linkage disequilibrium between the Sst I polymorphism and each of the 5' apo C-III polymorphisms; however, the significant association between the apo C-III haplotypes and hypertriglyceridemia (odds ratio, 4.0; P < .0001) was solely attributable to the effects of the Sst I polymorphism (odds ratio, 3.96). As a part of these analyses, we also defined a unique haplotype that is inversely associated with the occurrence of hypertriglyceridemia, suggesting further molecular analyses of this important gene region.

Adult↗
PubMed1996

Treatment of prostate cancer with gonadotropin-releasing hormone analogue: effect on lipoprotein[a].

Because of its association with cardiovascular disease, lipoprotein[a] (Lp[a]) has attracted the interest of the medical community. Even though serum concentrations of Lp[a] are mainly controlled by the apolipoprotein[a] gene locus, hormonal and metabolic factors, including manipulations of sex hormone levels, have been associated with changes in Lp[a] levels. We report here that the GnRH analog buserelin reduced concentrations of Lp[a] by 48% in elderly males suffering from cancer of the prostate. In contrast, apolipoprotein B levels increased during treatment, whereas other lipid factors, including serum cholesterol, triglyceride, high and low density lipoprotein cholesterol, and apolipoprotein A-I, were not affected. Although the study does not exclude a specific Lp(a)-lowering effect of buserelin, our results suggest that GnRH analogs may reduce Lp[a] levels in the circulation.

Aged↗
PubMed1996

Effect of gemfibrozil on levels of lipoprotein[a] in type II hyperlipoproteinemic subjects.

Plasma lipoprotein[a] (Lp[a]) levels are highly correlated with angiographically demonstrable coronary heart disease, and elevated Lp[a] is an independent risk factor for atherosclerosis. Previous studies have provided evidence that the levels of Lp[a] and triglyceride are related, suggesting that Lp[a] might be altered by gemfibrozil, a drug well known for its efficacy in reducing plasma triglycerides. Accordingly, 18 type IIa and 16 type IIb hyperlipoproteinemic males aged 35-58 were treated for 3 months with 600 mg of gemfibrozil twice daily. The efficacy of the drug in altering lipid and lipoprotein levels was different in the two type groups. In type IIa and IIb subjects the respective changes in median levels were: total cholesterol, -7.5 and -8.5% triglycerides, -35.6 and -54.4%; HDL-cholesterol, +9.0 and +11.0%; and Lp[a], -17.2 and +6.1%. Before and after gemfibrozil treatment, 7 type IIa and 10 type IIB subjects were given a 100 g/2 m2 oral-fat load; triglycerides and Lp[a] were measured post-prandially at 0, 2, 4, 6, 8, and 10 h. The differences between before- and after-gemfibrozil post-prandial curve integrated areas (PPCIA) were compared for triglycerides and Lp[a]. The changes in median PPCIA for triglycerides in types IIa and IIB were -54% and -53%, and for Lp[a] were -8% and +8%, respectively. These results indicate i) that the levels of Lp[a] are about 2 times higher in type IIa than IIb subjects, and ii) that although gemfibrozil elicits a rather uniform decrease in fasting and post-prandial triglyceride levels in type IIa and IIb patients, the drug causes heterogeneous changes in Lp[a], suggesting that different metabolic mechanisms may be dominant in subjects showing opposing effects.

Adult↗