| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Can cholesterol lowering treatment have unwanted effects? Karpe, F., J. Regnstrom, et al. (1991), Lakartidningen 88(18): 1670-1. |
| Can dietary factors explain differences in serum cholesterol profiles among different ethnic groups (Chinese, Malays and Indians) in Singapore? Deurenberg-Yap, M., T. Li, et al. (2001), Asia Pac J Clin Nutr 10(1): 39-45. Abstract: In Singapore. there exists differences in risk factors for coronary heart disease among the three main ethnic groups: Chinese, Malays and Indians. This study aimed to investigate if differences in dietary intakes of fat, types of fat, cholesterol, fruits, vegetables and grain foods could explain the differences in serum cholesterol levels between the ethnic groups. A total of 2408 adult subjects (61.0% Chinese, 21.4% Malays and 17.6% Indians) were selected systematically from the subjects who took part in the National Health Survey in 1998. The design of the study was based on a cross-sectional study. A food frequency questionnaire was used to assess intakes of energy, total fat, saturated fat, polyunsaturated fat, monounsaturated fat, cholesterol, fruits, vegetables and cereal-based foods. The Hegsted score was calculated. Serum total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol were analysed and the ratio of total cholesterol to high density lipoprotein cholesterol was computed. The results showed that on a group level (six sex-ethnic groups), Hegsted score, dietary intakes of fat, satutrated fat, cholesterol, vegetables and grain foods were found to be correlated to serum cholesterol levels. However, selected dietary factors did not explain the differences in serum cholesterol levels between ethnic groups when multivariate regression analysis was performed, with adjustment for age, body mass index, waist-hip ratio, cigarette smoking, occupation, education level and physical activity level. This cross-sectional study shows that while selected dietary factors are correlated to serum cholesterol at a group level, they do not explain the differences in serum cholesterol levels between ethnic groups independently of age, obesity, occupation, educational level and other lifestyle risk factors. |
| Can eating baked beans lower plasma cholesterol? Cobiac, L., R. McArthur, et al. (1990), Eur J Clin Nutr 44(11): 819-22. Abstract: The plasma cholesterol lowering potential of canned baked beans was examined in a cross-over comparison with canned spaghetti. The difference in total dietary non-starch polysaccharide (NSP) of 12 g daily (6.6 g difference in soluble NSP), was insufficient to alter the plasma cholesterol, HDL cholesterol, triglyceride and glucose concentrations in 20 mildly hyper-cholesterolaemic men. Thus, eating an average of six 440 g cans of this source of baked beans per week, large servings, does not lower the plasma cholesterol when dietary fat is not displaced. |
| Can insulin promote atherogenesis by altering cellular cholesterol metabolism? Oram, J. F. (1995), J Lab Clin Med 126(3): 229-30. |
| Can low-fat/cholesterol nutrition counseling improve food intake habits and hyperlipidemia of renal transplant patients? Hines, L. (2000), J Ren Nutr 10(1): 30-5. Abstract: OBJECTIVE: To assess the impact of low-fat/cholesterol nutrition counseling on food intake habits and blood lipid levels of renal transplant patients. DESIGN: Prospective practice-based outcome study. SETTING: Acute care hospital post-renal transplant outpatient clinic. PATIENTS: Forty-three renal transplant patients not on lipid-lowering medications referred to the renal dietitian for low-fat/cholesterol nutrition counseling between September 1994 and September 1997. INTERVENTION: Individual assessment and counseling using the Healthy Heart Nutrition Guidelines Step 1 diet (<30% of total calories from fat, <300 mg cholesterol, and <10% of total calories from saturated fatty acids). MAIN OUTCOME MEASURES: Three-day food records precounseling and 3-day food records (n = 13) or descriptive intake changes (n = 30) postcounseling (time interval: 2 to 8 months). Fasting/random serum total cholesterol, high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C), as available. RESULTS: Total cholesterol (n = 43) and LDL-C (n = 22) decreased significantly (0. 54 mmol/L P <.000 and 0.53 mmol/L P <.000, respectively). There were no significant changes in HDL-C and triglycerides. Twenty percent of patients (n = 43) reached target levels of total cholesterol <5.2 mmol/L, and 35% of patients (n = 22) reached target levels of LDL-C <3.4 mmol/L. Percentage of total calories from fat decreased significantly (7.58% P <.03). Descriptive intake changes of lower fat choices were reported in the no post-food records group. CONCLUSION: Patients can make changes in food intake habits after nutrition counseling. Serum lipid levels can improve after nutrition counseling, but many patients may still require lipid lowering medications to reach target levels. Nutrition counseling should be considered for the initial treatment of hyperlipidemia in renal transplant patients. |
| Can the clinical efficacy of the HMG CoA reductase inhibitors be explained solely by their effects on LDL-cholesterol? Gaw, A. (1996), Atherosclerosis 125(2): 267-9. |
| Can we apply the National Cholesterol Education Program Adult Treatment Panel definition of the metabolic syndrome to Asians? Tan, C. E., S. Ma, et al. (2004), Diabetes Care 27(5): 1182-6. Abstract: OBJECTIVE: Limited information is available about the metabolic syndrome in Asians. Furthermore, the definition of central obesity using waist circumference may not be appropriate for Asians. The objectives of this study were to determine the optimal waist circumference for diagnosing central obesity in Asians and to estimate the prevalence of the metabolic syndrome in an Asian population. RESEARCH DESIGN AND METHODS: We used data from the 1998 Singapore National Health Survey, a cross-sectional survey involving 4,723 men and women of Chinese, Malay, and Asian-Indian ethnicity aged 18-69 years. Receiver operating characteristic analysis suggested that waist circumference >80 cm in women and >90 cm in men was a more appropriate definition of central obesity in this population. The prevalence of the metabolic syndrome was then determined using the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria with and without the modified waist circumference criteria. RESULTS: In Asians, decreasing waist circumference increased the crude prevalence of the metabolic syndrome from 12.2 to 17.9%. Using the modified Asian criteria, the prevalence of the metabolic syndrome increased from 2.9% in those aged 18-30 years to 31.0% in those aged 60-69 years. It was more common in men (prevalence 20.9% in men versus 15.5% in women; P < 0.001) and Asian Indians (prevalence 28.8% in Asian-Indians, 24.2% in Malays, and 14.8% in Chinese; P < 0.001). CONCLUSIONS: NCEP ATP III criteria, applied to an Asian population, will underestimate the population at risk. With a lower waist circumference cutoff, the prevalence of the metabolic syndrome is comparable to that in Western populations. Ethnic differences are likely to exist between populations across Asia. |
| Cancer and low levels of plasma cholesterol: the relevance of cholesterol precursors and products to incidence of cancer Larking, P. W. (1999), Prev Med 29(5): 383-90. Abstract: BACKGROUND: It is proposed that the mechanism responsible for the low plasma cholesterol-cancer associations reported in the literature is related to blood and tissue levels of cholesterol precursors and products, reflecting rates of cholesterol synthesis rather than the plasma cholesterol level itself. METHODS: Data have been collated from Japanese and Northern European studies on plasma levels of a cholesterol precursor, lathosterol, and one product, cholestanol, each a marker of cholesterol metabolism. Situations in which the rate of cholesterol synthesis is altered have also been examined for their relationship to cancer incidence. RESULTS: The data though minimal suggest that lathosterol and cholestanol may be higher in the blood of the Japanese compared with the Northern Europeans, despite lower plasma cholesterol levels in the Japanese. In accord with the hypothesis the Japanese have a low incidence of many cancers. Cholesterol synthesis is lowered when dietary cholesterol and fat intake are increased and incidence of cancer is increased in these states. Conversely cholesterol synthesis is raised in vegetarianism, the Mediterranean diet, pregnancy, and lactation, and incidence of some cancers is lowered. CONCLUSIONS: At least some of the variation in cancer incidence with plasma cholesterol levels and also with dietary saturated fat and cholesterol, as well as vegetarianism, the Mediterranean diet, pregnancy, and lactation, can be accounted for by their effects on the rate of cholesterol synthesis and the level of cholesterol precursors and/or products so generated. |
| Cancer incidence in the National Health and Nutrition Survey I. Follow-up data: diabetes, cholesterol, pulse and physical activity Steenland, K., S. Nowlin, et al. (1995), Cancer Epidemiol Biomarkers Prev 4(8): 807-11. Abstract: We examined cancer incidence among 14,407 men and women who were enrolled in the National Health and Nutrition Survey I in the early 1970s and then followed through 1987. We studied 657 male and 593 female cancer cases, using Cox regression. Analyses were conducted for all cancers, lung, colorectal, breast, and prostate cancer. Analyses focused on diabetes, cholesterol, pulse, and physical activity, four risk factors with limited or inconsistent prior evidence. All four risk factors were modestly associated with all cancers for men but not for women. For diabetic men, the rate ratio for all cancers was 1.38 95% confidence interval (CI) = 1.00-1.91; the elevated risk was particularly evident for colorectal and prostate cancer. Slight inverse trends of cancer risk with cholesterol were apparent for men but not for women and were diminished compared to prior analyses of these data with less follow-up. Males with the lowest quartile of cholesterol versus the highest had a rate ratio of 1.21 (CI = 0.98-1.51) for all cancers. A modest positive trend between pulse and all cancers was seen for males rate ratio of 1.27 (CI = 1.04-1.57) for the highest versus the lowest quartile). The rate ratio for men with the least amount of nonrecreational physical activity was 1.29 (CI = 0.99-1.69). There is some evidence in these data that findings for cholesterol and nonrecreational physical activity could be artifacts of the early effects of disease because they diminished when cases were restricted to those with longer follow-up. |
| Candidate reference methods for determining target values for cholesterol, creatinine, uric acid, and glucose in external quality assessment and internal accuracy control. I. Method setup Stockl, D. and H. Reinauer (1993), Clin Chem 39(6): 993-1000. Abstract: In Germany, the target values for External Quality Assessment (EQA) and internal accuracy control are determined by Reference Methods for several analytes, including cholesterol, creatinine, uric acid, and glucose. We present candidate Reference Methods for these compounds, based on isotope dilution-gas chromatography--mass spectrometry methods that have been developed at INSTAND, one of the two official Germany EQA reference institutions. Each Reference Method target value is calculated from six independent measurements performed on three different days. The mean method CVs ranged from 0.66% for glucose to 0.96% for creatinine. The inaccuracy (bias) of the methods is < 0.7%, as compared with the Standard Reference Material 909 of the National Institute of Standards and Technology. The maximum total error of a Reference Method value, including the 95% confidence interval and systematic errors, is < 2.3%. The presented candidate Reference Methods have been successfully used to set target values in the German EQA scheme and the internal accuracy control of routine laboratories. |
| Candidate reference methods for determining target values for cholesterol, creatinine, uric acid, and glucose in external quality assessment and internal accuracy control. II. Method transfer Thienpont, L. M., A. P. Leenheer, et al. (1993), Clin Chem 39(6): 1001-6. Abstract: We describe the testing of transferability of candidate Reference Methods developed by INSTAND for cholesterol, creatinine, uric acid, and glucose. The methods are based on isotope dilution-gas chromatography--mass spectrometry. The study consisted of two parts: setup of the methods and self-evaluation for readiness in the collaborating laboratory, followed by independent measurements in parallel with INSTAND. Criteria used for judging the transferability and general reliability of the candidate Reference Methods were: the accuracy and precision of the collaborating laboratory and the agreement between the two laboratories. The accuracy was judged from the results on the Standard Reference Material 909 from the National Institute of Standards and Technology. For all analytes except glucose the bias from the certified value was < 0.7%. The mean intralaboratory imprecision ranged from 0.66% to 1.24%. The agreement between the results was tested by an advanced linear-regression analysis and Student's t-test. In general, the results demonstrate that the candidate Reference Methods developed by INSTAND can be successfully transferred without loss of their inherent precision and accuracy. |
| Capacitance and resistance of the bilayer lipid membrane formed of phosphatidylcholine and cholesterol Naumowicz, M., A. D. Petelska, et al. (2003), Cell Mol Biol Lett 8(1): 5-18. Abstract: Capacity and electric resistance of lipid membranes composed of lecithin and cholesterol were determined. The components were chosen for the study because they were present in biological membranes. Capacitance of the lecithin and cholesterol membranes amounts to 0.38 and 0.61 microF/cm(2), and resistance to 1.44(10(4)and 2.12(10(6)Omega cm(2), respectively. A 1:1 complex appears as a result of lecithin-cholesterol membrane formation. Parameters of the membrane formed of the lecithin-cholesterol complex were determined: surface concentration (Gamma(3)), capacitance (C(3)), and conductance (R;(3)(-1), as well as the stability constant (K) of the complex. The mean values of those magnitudes are as follows: 4.265(10(-6)mol/m(2), 0.54 microF/cm(2), 1.381(10(-6)Omega(-1)cm(-2)and 3.748(10(7), respectively. |
| Capillary electrochromatography of cholesterol and its ester derivatives Thiam, S., S. A. Shamsi, et al. (2000), Anal Chem 72(11): 2541-6. Abstract: Separation of cholesterol and its ester derivatives using micellar electrokinetic chromatography is a challenge due to the extreme hydrophobicity of these compounds. In this work, an isocratic capillary electrochromatography (CEC) method has been developed to separate a complex mixture of cholesterol and its 12-ester derivatives. The proportions of mobile phase (tetrahydrofuran, acetonitrile, water), as well as the effects of acid modifiers, buffer concentrations, voltage, and temperature on the separation of cholesterol derivatives were investigated. Addition of a polymeric surfactant, poly(sodium N-undecanoyl-L-glycinate), to the mobile phase reduced migration time and improved resolution of the analytes. The CEC method developed allows baseline separation of a complex mixture of cholesterol and 12 ester derivatives in less than 40 min. Finally, the method is applied to the characterization of cholesterol, cholesterol linoleate, and cholesterol oleate extracted from atherosclerotic plaque deposits in the arterial walls of a human aorta. |
| Capillary gas chromatography for the assessment of cholesterol oxides in the heart Gangopadhyay, H., G. A. Cordis, et al. (1991), J Pharm Biomed Anal 9(10-12): 1003-8. Abstract: Recent studies indicated the presence of cholesterol oxides in biological tissues such as heart under pathophysiological conditions. Currently, no suitable method is available to separate and quantitate these oxides in biological tissues. This study was undertaken to develop a method suitable for the quantification of cholesterol oxides in heart. Since under normal conditions cholesterol oxidation does not occur, we exposed isolated perfused rat heart to oxygen-derived free radicals, which are known to oxidize cholesterol in heart. Free radical treated hearts were homogenized and lipids extracted by conventional techniques. The extracted lipids were saponified, and non-saponified portions were extracted with ether. Silyl derivatives of the extracted products were subjected to capillary gas chromatography. One microlitre of the sample was injected onto an SE 54 Supelco capillary column and run by stepwise temperature programming from 230 to 260 degrees C at a rate of 20 degrees C min-1, and then from 260 to 290 degrees C at 6 degrees C min-1. 5-Androsten-3 beta-ol-17-one was used as internal standard. The separated cholesterol oxides were identified by comparing with authentic standards. This method was suitable to separate 7 alpha-hydroxycholesterol, dihydroxycholesterol, 7 beta-hydroxycholesterol, 20 alpha-hydroxycholesterol, cholesterol-5 alpha,6 alpha-epoxide, and 5-cholestene in heart. Since some of these oxides are cytotoxic to the heart, identification of these oxides should be important to understand the pathophysiology of myocardial disease and for the successful therapy to prevent them. |
| Capillary gas chromatography quantification of cholesterol in copper-oxidized low-density lipoprotein Tanaka, M. and S. Kanamaru (1993), Biol Pharm Bull 16(6): 538-43. Abstract: A simple analytical method, using capillary gas chromatography-mass spectrometry (GC-MS) was used to investigate the oxidative modification of cholesterol in copper-oxidized low-density lipoprotein (oxidized LDL). The incubation of LDL and 5 microM CuSO4 in 0.15 M NaCl/0.02 M Tris-HCl buffer at pH 7.4 led to the peroxidation of LDL as shown by the detection of a thiobarbituric acid-reactive substance (TBA-RS). Oxidized LDL was shown to cause a significant fall in the unesterified and esterified cholesterol content, while oxysterols such as 7-hydroxycholesterol (7-OH) and 7-ketocholesterol (7-Keto) were formed from cholesterol, these conversions occurred in a dose- and time-dependent manner. Both oxysterols were identified by GC-MS on a fused-silica capillary column. In addition, copper-oxidized high-density lipoprotein (oxidized HDL) also resulted in the generation of TBA-RS and oxysterols. In addition, changes in the composition and amount of oxysterols during the incubation of macrophages with oxidized LDL were investigated. The incubation of macrophages with oxidized LDL resulted in the accumulation of cholesterol, 7-OH and 7-Keto derivatives in macrophages and this accumulation also occurred in a dose-dependent manner. These results suggest that the measurement of oxysterols may afford an additional index of oxidized LDL, and that foam cell formation and early atherosclerotic lesions may be responsible for the accumulation of oxysterols in macrophages. In addition, this study shows that HDL is also modified when submitted to an oxidative process. |
| Carbamazepine-induced increases in total serum cholesterol: clinical and theoretical implications Brown, D. W., T. A. Ketter, et al. (1992), J Clin Psychopharmacol 12(6): 431-7. Abstract: To assess the effect of carbamazepine (CBZ) upon total serum cholesterol, we examined 38 inpatients with affective illness and one with multiple personality disorder who received a course of CBZ monotherapy. CBZ therapy yielded significant increases in total serum cholesterol that became evident during the second week of therapy, persisted throughout therapy, and reversed in the first few weeks after discontinuation of therapy. CBZ-induced increases in total cholesterol appeared independent of initial mood state, diagnostic subtype, baseline cholesterol or thyroid indices; CBZ levels, doses, and level-to-dose ratios; and the degree of change in mood and thyroid indices. CBZ induction of enzymes mediating cholesterol synthesis is a possible mechanism of the increase in total cholesterol observed with CBZ therapy. Although preclinical studies suggest possible influence of cholesterol on neurotransmitter regulation and behavior, clinical studies have yielded conflicting data. There are insufficient data to support a role for cholesterol in the anticonvulsant and psychotropic mechanisms of CBZ. The increase in total serum cholesterol seen with CBZ therapy is likely due to an increase in the high density lipoprotein fraction and is thus not likely to be clinically problematic in relationship to atherosclerosis. |
| Carbohydrate-deficient transferrin (CDT) and HDL cholesterol (HDL) are highly correlated in male alcohol dependent patients Szegedi, A., M. J. Muller, et al. (2000), Alcohol Clin Exp Res 24(4): 497-500. Abstract: BACKGROUND: Serum levels of total HDL cholesterol (HDL) are reportedly influenced by recent alcohol intake. We examined the correlation between HDL cholesterol and widely used markers of excessive alcohol intake, such as carbohydrate-deficient transferrin (CDT), gamma-glutamyl-transferase (GGT), or mean corpuscular volume of erythrocytes (MCV), of which CDT is thought to be the most specific. METHODS: Several serological markers i.e., CDT, GGT, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), MCV, and HDL were determined in 100 actively drinking male patients with alcohol dependence (DSM-IV) and in 27 non-alcohol-dependent controls, according to routine procedures. Spearman's rank correlation coefficients were calculated. RESULTS: We found a highly significant positive correlation between HDL and CDT (r(s) = 0.55; p < 0.0005) in patients, but not in controls (r(s) = 0.13;p = 0.51). HDL was also positively correlated with GGT, ALAT, ASAT, and MCV only in patients. CONCLUSIONS: HDL cholesterol, as a widely determined parameter, may represent a useful routine marker for recent excessive alcohol intake. High HDL cholesterol levels should alert clinicians to investigate a patient's recent pattern of alcohol consumption. |
| Carbohydrate-fat exchange and regulation of hepatic cholesterol and plasma lipoprotein metabolism in the guinea pig Fernandez, M. L., D. M. Sun, et al. (1995), Metabolism 44(7): 855-64. Abstract: Adult female guinea pigs were fed semipurified diets containing increasing concentrations of saturated fat (2.5%, 7.5%, 15%, and 25% wt/wt) to determine effects of exchanging fat-carbohydrate calories on lipoprotein metabolism. Plasma very-low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) did not vary but plasma low-density lipoprotein (LDL) concentrations increased with increasing fat calories. LDL cholesterol values were 42 +/- 25, 61 +/- 17, 92 +/- 25, and 98 +/- 21 mg/dL (mean +/- SD, n = 5), respectively. The relative proportion of cholesteryl ester increased and triacylglycerol (TAG) decreased for VLDL, LDL, and HDL as dietary fat increased. Plasma lecithin cholesterol acyltransferase (LCAT) activity was positively correlated with HDL cholesteryl ester content. Hepatic cholesterol and TAG concentrations were highest in animals fed 25% fat (P <.01). Hepatic apolipoprotein (apo) B/E receptor maximal binding capacity (Bmax) was 30% higher in animals fed 2.5% and 7.5% fat as compared with those fed 15% and 25% fat (P <.01) and inversely correlated with plasma LDL (r = -.85, P <.01). In contrast, HDL binding to guinea pig hepatic membranes exhibited a significant positive correlation with dietary fat quantity (r =.98, P <.001), consistent with a dose-response with increasing fat calories. The activity of hepatic 3-hydroxy-3-methyl glutaryl coenzyme A (HMG CoA) reductase was not affected by the amount of dietary fat, whereas the activity of acyl CoA:cholesterol acyltransferase (ACAT) was significantly increased in animals fed 25% fat (P <.05). Hepatic free-cholesterol and ACAT activity exhibited a positive correlation for all dietary groups (r =.75, P <.001). These results demonstrate that exchange of saturated dietary fat for carbohydrate calories results in significant modifications in the regulation of metabolic pathways that determine plasma LDL concentrations and hepatic cholesterol homeostasis. |
| Carbon tetrachloride-induced hepatotoxicity enhances the development of pulmonary foam cells in rats fed a cholesterol-cholic acid diet Shibuya, K., M. Tajima, et al. (1997), Toxicol Pathol 25(5): 487-94. Abstract: The effect of CCl4-hepatotoxicity on the development of pulmonary foam cells (PFCs) was studied using 4 groups of rats. Rats in the control group were fed a standard diet; rats in the second group were fed a hyper beta-lipoproteinemic (HB) diet consisting of the standard diet, 4% cholesterol, and 1% cholic acid; rats in the third group were fed the standard diet and administered with CCl4 (1.0 ml/kg, i.p., fortnightly) (CT); and rats in the fourth group were fed the HB diet and administered with CCl4 (HT). At feeding week 10, rats in the HB and HT groups developed hyper beta-lipoproteinemia. The ratios of foamy, lipid-ingested monocytes (FMs) to blood monocytes (BMs) and the histologic scores of PFC development were significantly greater in the HB and HT groups than in the control and CT groups, respectively. The ratio of PFCs to alveolar macrophages from bronchopulmonary lavage fluid was significantly higher in the HT group than in the CT group. At feeding week 20, rats in the CT and HT groups suffered hepatic injury and hypo beta-lipoproteinemia. Despite hypo beta-lipoproteinemia, the FM and PFC development, the ratio of BMs in differential leukocyte counts, and latex-phagocytotic activity of BMs were enhanced in the HT group. Furthermore, markedly enlarged FMs, described here as giant-FMs, that contained numerous lipid droplets in their abundant cytoplasm appeared in the peripheral blood from rats in the HT group. Histologically, embolism caused by giant-FMs in the pulmonary blood vessels and intraalveolar accumulation of PFCs were detected with a high incidence in the HT group. The present study suggests that CCl4-hepatotoxicity may affect lipoprotein synthesis in the liver of hyper beta-lipoproteinemic rats and defective or modified lipoproteins can be phagocytosed actively by BMs, and then BMs transform into FMs or giant-FMs, resulting in the PFC development and pulmonary embolism by giant-FMs. |
| Carboxy-substituted 2-azetidinones as cholesterol absorption inhibitors Vaccaro, W. D., R. Sher, et al. (1998), Bioorg Med Chem Lett 8(3): 319-22. Abstract: Metabolism initiated SAR studies led to the discovery of a new class of potent 2-azetidinone cholesterol absorption inhibitors. These studies found that a heteroatom at the para position of the C-4 phenyl ring is not a requirement for cholesterol absorption inhibition as was suggested by earlier findings. Substitution of Ph-linker-COOR for PhOMe at the C-4 position enhanced cholesterol absorption inhibition. |