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BACKGROUND: Low folate status and elevated plasma homocysteine are associated with increased risk of neural tube defects and cardiovascular disease. Homocysteine responses to folate may be influenced by genetic variants in folate metabolism. OBJECTIVE: We determined the effect of folate-enhancing dietary interventions on plasma folate and plasma total homocysteine (tHcy) with respect to the methylenetetrahydrofolate reductase 677C-->T genotype. DESIGN: A total of 126 healthy subjects (42 TT, 42 CT, and 42 CC genotypes) completed 3 dietary interventions (4 mo each) in random order: 1) exclusion diet (avoidance of folic acid-fortified foods and ingestion of a placebo daily), 2) folate-rich diet (increased intake of fortified and naturally folate-rich foods to achieve 400 microg folate/d), and 3) supplement (exclusion diet plus a folate supplement of 400 microg/d). RESULTS: Plasma folate was higher (P < or = 0.001) and plasma tHcy lower (P < or = 0.001) after the folate-rich and supplement interventions than after the exclusion diet. Plasma folate was significantly greater after supplementation than after the folate-rich diet, but there was no significant difference in tHcy concentration (P = 0.72). TT homozygotes had higher plasma tHcy (14.5 compared with 8.9 micromol/L, P < or = 0.001) and lower plasma folate (14.8 compared with 19.0 nmol/L, P < or = 0.01) than did subjects with the CC genotype after the exclusion diet. CT heterozygotes had intermediate concentrations. The trend toward higher tHcy in TT homozygotes persisted throughout the study but was less marked with increasing folate intake (TT compared with CC after supplementation, P = 0.097). CONCLUSIONS: A folate-rich diet including folic acid-fortified foods or low-dose supplements effectively increases folate status. TT homozygotes require higher folate intakes than do individuals with the CT or CC genotype to achieve similar tHcy concentrations but are responsive to folate intervention. Copyright © 2002 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

INTRODUCTION: The long-term effects on diet of dietary advice to eat fruit and vegetables or fatty fish are not well described. MATERIALS AND METHODS: From 1990 to 1996 3114 men aged 37-70 with treated angina were recruited from general practices in South Wales. A dietitian randomly allocated the eligible men to receive advice to eat more fruit and vegetables, or advice to eat more fatty fish, or both these types of advice or neither. In 2000, a brief self-completion questionnaire was sent to a sample of 1191 of the men known to be alive at the end of March 1999. RESULTS: The questionnaire was returned by 944 of the 1036 men alive at the time the questionnaire was sent. Those given fish advice were consuming more fatty fish but the difference was modest 21.9 g day(-1) vs. 14.0 g day(-1) (P < 0.01). The differences in fruit and vegetables intake between those given fruit advice and those not given fruit advice were small 373.2 g day(-1) vs. 351.7 g day(-1) (P = 0.05). DISCUSSION: Men of this age group may be particularly resistant to fruit and vegetables advice; population-based interventions or interventions targeted at women might be more effective. [ABSTRACT FROM AUTHOR]

Advanced nuclear reactor designs and advanced fuel types offer safety features that may reduce environmental consequences in an accident scenario when compared to conventional reactors and fuels. One advanced reactor fuel is tri-structural isotropic (TRISO) fuel particles which are approximately 0.9 mm in diameter. TRISO particle mobility, assuming the particle is unruptured and the encapsulated radionuclides are contained, was explored by a theoretical examination of transport through atmosphere, soil and groundwater, surface water, and non-human biota pathways. TRISO particles are too large and dense to travel in the atmosphere except under extreme conditions. TRISO particles are also too large to penetrate most soil profiles and so cannot be transported to or by groundwater. TRISO particles will settle out of the water column in surface waters and thus the transport will depend on the energy of the water body (e.g., waves or floods). TRISO particles could be transported by non-human biota. The size of TRISO particles could allow them to be intentionally ingested by non-human biota as a gastrolith or mimic something typical in an organism's diet. Generally, TRISO particles will have reduced environmental mobility compared to releases of radionuclides in the event of a conventional nuclear reactor accident. The extent of transport has implications in emergency planning zone designations and other considerations for licensing and deploying TRISO-fueled reactors. Further research and experimental work exploring TRISO particle mobility is required to understand the full environmental mobility of TRISO particles in the environment., (Copyright © 2021. Published by Elsevier Ltd.)

Background: The podocyte cell is believed to play an important role in idiopathic nephrotic syndrome (INS) of childhood. In adults with cellular and collapsing focal segmental glomerulosclerosis (FSGS), the expression of cell-cycle regulatory proteins such as p27, p57, and cyclin D is decreased and expression of cyclin A, Ki-67, and p21 is observed in podocyte cells suggestive of a dysregulated podocyte phenotype. We investigated for alterations in the expression of cyclin kinase inhibitors, p27, p57, p21, and cyclins D and A in the podocyte cell of children with INS., Methods: Forty-two kidney biopsies were investigated; 14 with minimal-change disease (MCD), seven with diffuse mesangial hypercellularity (DMH), 12 with FSGS, four with Alport syndrome (AS), and five normal biopsies. The sections were examined by immunohistochemistry using dual staining method. Podocyte cells were first identified by Wilm's tumor-1 staining after which expressions of cell-cycle regulatory proteins were analyzed. A quantitative analysis was performed for the proportion of podocyte cells that expressed each cell cycle regulatory protein., Results: On light microscopy, all podocyte cells expressed p27, while p57 and p21 expression was seen in a portion of podocyte cells in normal kidney biopsies. Cyclin D was expressed in a small percent of podocyte cells though the expression was more marked in mesangial and endothelial cells. Cyclin A expression was not seen in normal biopsies. The mean expression of p27 decreased significantly in order from normal (100%), MCD (45.9%), DMH (22.4%), and FSGS (16.7%), and the difference between MCD and FSGS was significant. p21 was significantly and equally reduced in MCD (2.3%), DMH (0%), and FSGS (0.7%) compared to normal (66.6%). There was no significant difference in expression of p57, cyclin D and cyclin A in the podocyte cells between normal and children with INS. Children with AS showed a significant decrease in p27 and p21 expression, while the expression of p57, cyclin D and cyclin A were unchanged from normal, thus demonstrating a pattern similar to INS., Conclusion: The podocyte cell in children with INS down-regulates expression of cyclin kinase inhibitors such as p21 and p27, but not p57, but does not up-regulate cyclin D and cyclin A that are needed to overcome the G1/S transition and move the cell forward in the cell cycle process. Thus, the podocyte cell remains trapped in the G1 arrest phase. In children with INS or AS, the dysregulated podocyte phenotype is different than the one described in adults with cellular or collapsing FSGS.

Background: Various mechanisms have been proposed to explain the association between plasma total homocysteine (tHcy) and risk of cardiovascular disease, including oxidative activity of homocysteine., Objective: To explore the putative role of reactive oxygen species in the association between plasma tHcy and risk of cardiovascular disease in healthy individuals., Design: A double-blind, placebo-controlled crossover intervention to increase folate intake through diet (increased consumption of folate-rich foods) and supplement (400 micro g folic acid) was carried out in 126 healthy men and women. Measurements were made of antioxidant activity in red blood cells and plasma, and products of oxidant damage in plasma., Results: Diet and supplement-based interventions led to an increase in measures of folate status and a reduction in plasma tHcy. This was not associated with any significant change in measures of antioxidant activity (plasma and red blood cell glutathione peroxidase activity and red blood cell superoxide dismutase activity) or oxidant damage (plasma malondialdehyde), although an improvement in plasma total antioxidant capacity just failed to reach significance., Conclusions: In healthy individuals lowering plasma tHcy does not have any functional implications regarding oxidative damage.

Objective: To assess and compare the effects of natural folate (100 micro g) with those of folic acid from fortified sources (100 micro g/day) on plasma folate and homocysteine., Design: Randomized controlled trial (parallel groups)., Setting: Men and women living in South Wales, UK., Subjects: A total of 135 healthy individuals recruited from the local workforce and blood donor sessions. All subjects possessed the 'wild-type' CC genotype for C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR)., Interventions: Subjects underwent one of the following dietary interventions for 4 months: (1) fortified diet-usual diet plus 100 microg/day folic acid from fortified foods; (2) natural folate diet-usual diet plus 100 microg/day folate from natural sources; (3) control-usual diet., Results: The fortified group increased reported intake of folic acid from fortified foods compared to other groups (P<0.001) achieving an extra 98 microg/day (95% CI 88-108). The natural folate group increased reported intake of natural source folates compared with the other two groups (P<0.001), but achieved a mean increase of only 50 microg/day (95% CI 34-66). Plasma folate increased (P<0.01) by a similar amount in both intervention groups compared to controls (fortified group 2.97, 95% CI 0.8-5.1; natural group 2.76, 95% CI 0.6-4.9. Plasma homocysteine, vitamins B(6) and B(12) were not significantly changed., Conclusions: Subjects achieved increases in folate intake using fortified foods more easily than by folate-rich foods, however both sources increased plasma folate by a similar amount. These levels of intake were insufficient to reduce homocysteine concentrations in MTHFR CC homozygotes, but may be more effective in other genotypes.

Cardiovascular disease has a multifactorial aetiology that is influenced by both genetic and environmental factors. Endothelial dysfunction is a key event in the pathogenesis of vascular disease that occurs before structural vascular changes or clinical symptoms are evident. Conventional risk factors, for example hypertension and diabetes mellitus, are associated with endothelial dysfunction, but the influence of other putative risk factors is not clear. The methylenetetrahydrofolate reductase (MTHFR) C677T genotype, a common polymorphism that induces hyperhomocysteinaemia, has been proposed as being a genetic risk factor for cardiovascular disease. A total of 126 healthy adults recruited by MTHFR C677T genotype (42 of each genotype, i.e. CC, CT and TT) underwent assessment of endothelial function. Brachial artery endothelium-dependent flow-mediated dilatation (FMD) was measured using high-resolution ultrasonic vessel "wall-tracking". Using multiple regression analysis, MTHFR genotype and 21 other subject and subject-lifestyle variables were investigated as potential predictors of endothelial function. FMD was influenced positively by frequency of aerobic exercise and by hormone replacement therapy, and negatively by increases in systolic blood pressure. MTHFR C677T genotype and the associated variation in plasma homocysteine levels did not influence FMD. Additionally, other factors, including plasma cholesterol and self-supplementation with either antioxidant vitamins or cod liver oil, showed no significant relationship with FMD, although these findings are compromised by the narrow range studied for cholesterol and the small number of subjects taking supplements. These observations have implications for risk factor management in the primary prevention of cardiovascular disease in healthy individuals.

Galloway-Mowat syndrome is an autosomal recessive disorder characterized by early onset nephrotic syndrome and central nervous system anomalies. Mutations in podocyte proteins, such as nephrin, alpha-actinin 4, and podocin, are associated with proteinuria and nephrotic syndrome. The genetic defect in Galloway-Mowat syndrome is as yet unknown. We postulated that in Galloway-Mowat syndrome the mutation would be in a protein that is expressed both in podocytes and neurons, such as synaptopodin, GLEPP1, or nephrin. We therefore analyzed kidney tissue from normal children (n=3), children with congenital nephrotic syndrome of the Finnish type (CNF, n=3), minimal change disease (MCD, n=3), focal segmental glomerulosclerosis (FSGS, n=3), and Galloway-Mowat syndrome (n=4) by immunohistochemistry for expression of synaptopodin, GLEPP1, intracellular domain of nephrin (nephrin-I), and extracellular domain of nephrin (nephrin-E). Synaptopodin, GLEPP1, and nephrin were strongly expressed in normal kidney tissue. Nephrin was absent, and synaptopodin and GLEPP1 expression were decreased in CNF. The expression of all three proteins was reduced in MCD and FSGS; the decrease in expression being more marked in FSGS. Synaptopodin, GLEPP1, and nephrin expression was present, although reduced in Galloway-Mowat syndrome. We conclude that the reduced expression of synaptopodin, GLEPP1, and nephrin in Galloway- Mowat syndrome is a secondary phenomenon related to the proteinuria, and hence synaptopodin, GLEPP1, and nephrin are probably not the proteins mutated in Galloway-Mowat syndrome.

Objectives: We sought to study the effect of low-dose folic acid supplementation or optimization of dietary folate intake on plasma homocysteine and endothelial function in healthy adults., Background: Elevated homocysteine is associated with cardiovascular disease, but it is not known whether this relationship is causal. Individuals homozygous (TT) for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene ( approximately 12% of the population) have increased homocysteine levels, particularly in association with suboptimal folate intake., Methods: Healthy subjects (n = 126; 42 of each MTHFR genotype) were included in this cross-over study of three interventions of four months each: 1) placebo plus natural diet; 2) daily 400-microg folic acid supplement plus natural diet; and 3) increased dietary folate intake to 400 microg/day., Results: At baseline, homocysteine was inversely related to plasma folate and was higher in TT homozygotes. For the whole group, plasma folate increased by 46% after dietary folate and by 79% after supplementation, with reductions of homocysteine of 14% and 16%, respectively. Within the genotype, TT homozygotes exhibited the most marked changes in these variables. Brachial artery endothelial function, as determined by a change in end-diastolic diameter in response to increased flow, was not changed by increased folate intake (98 +/- 73 microm at baseline, 110 +/- 69 microm after a high-folate diet, 114 +/- 59 microm after supplementation and 118 +/- 68 microm after placebo). Plasma von Willebrand factor antigen was unaltered., Conclusions: Optimization of dietary folate or low-dose folic acid supplementation reduces plasma homocysteine but does not enhance endothelial function, irrespective of the MTHFR (C667T) genotype.

Background: Patients with non-insulin-dependent diabetes mellitus (NIDDM) exhibit poor clinical outcomes from myocardial ischemia. This may reflect an impairment in their cardiac insulin-response system., Methods and Results: We used AV balance and intracoronary infusion techniques to compare the intrinsic cardiac responsiveness to insulin in 26 coronary disease patients with (n=13) and without (n=13) NIDDM. During fasting, NIDDM hearts demonstrated lower fractional extraction of glucose from arterial plasma than controls (1.0+/-0.5% versus 2.1+/-0.5%, P<0.05) despite higher circulating insulin levels (26+/-5 versus 13+/-4 microU. mL, P<0.05). This was compensated for by higher circulating glucose levels, so that net cardiac glucose uptake in the 2 groups was equivalent (5.2+/-1.1 versus 5.3+/-1.1 micromol. min). Intracoronary insulin infusion produced an approximately 3-fold increase in fractional extraction and net uptake of glucose across the heart in both groups (to 3.7+/-0.4% and 18.3+/-3.5 micromol. min in NIDDM and to 5.4+/-0.7% and 17.7+/-4.3 micromol. min in controls) accompanied by an approximately 30% increase in net lactate uptake, suggesting preserved insulin action on both glucose uptake and glucose oxidation in the NIDDM heart. In nondiabetics, insulin consistently increased coronary blood flow, but this effect was absent in NIDDM., Conclusions: In contrast to their peripheral tissues and coronary vasculature, the myocardium of patients with NIDDM expresses a competent insulin-response system with respect to glucose metabolism. This suggests that insulin resistance is mediated at the level of individual organs and that different mechanisms are involved in muscle and vascular tissue.

Background: Synaptopodin is a proline-rich protein intimately associated with actin microfilaments present in the podocytes' foot processes. We investigated for synaptopodin expression in children with idiopathic nephrotic syndrome (INS), including minimal change disease (MCD), diffuse mesangial hypercellularity (DMH), and focal segmental glomerulosclerosis (FSGS); in children with congenital nephrotic syndrome of the Finnish type (CNF); and in normal kidney tissue. In particular, we examined whether an association exists between synaptopodin expression in podocyte cells and the response to steroids in INS, and whether synaptopodin expression can predict FSGS upon the initial kidney biopsy in children who progress from MCD or DMH to FSGS., Methods: Immunohistochemistry was performed for synaptopodin expression on renal tissues from MCD (N = 18), DMH (N = 7), FSGS (N = 13), CNF (N = 9), and normal children (N = 7). Synaptopodin expression in nonsclerosed glomeruli was quantitated by computerized image analysis on the Optimastrade mark software for both luminance (L) and percentage of glomerular area (A)., Results: Synaptopodin expression was absent in areas of sclerosis. In nonsclerosed glomeruli, synaptopodin was significantly less expressed in all groups of INS and in CNF compared with normal (P < 0.0001 for both L and A, in each MCD, DMH, FSGS, and CNF). In INS, synaptopodin expression decreased in order from MCD to DMH to FSGS, reaching statistical significance between MCD and FSGS (P = 0.001 for L and P = 0.05 for A). Greater synaptopodin expression in podocytes was associated with a significantly better response to steroid therapy (P < 0.05 for both L and A). On the other hand, the expression of synaptopodin did not predict progression of MCD or DMH to FSGS., Conclusion: We conclude that measurement of synaptopodin has the potential to be used as a marker to study the alteration in podocyte cell and response to therapy in INS.

Administration of supplemental glucose and/or insulin is postulated to improve the outcome from myocardial ischemia by increasing the heart's relative utilization of glucose as an energy substrate. To examine the degree to which circulating glucose and insulin levels actually influence myocardial substrate preference in vivo, we infused conscious, chronically catheterized rats with D-[1-(13)C]glucose and compared steady-state (13)C enrichment of plasma glucose with that of myocardial glycolytic ([3-(13)C]alanine) and oxidative ([4-(13)C]glutamate) intermediary metabolites. In fasting rats, [3-(13)C]alanine-to-[1-(13)C]glucose and [4-(13)C]glutamate-to-[3-(13)C]alanine ratios averaged 0.16 +/- 0.12 and 0.14 +/- 0.03, respectively, indicating that circulating glucose contributed 32% of myocardial glycolytic flux, whereas subsequent flux through pyruvate dehydrogenase contributed 14% of total tricarboxylic acid (TCA) cycle activity. Raising plasma glucose to 11 mmol/l, or insulin to 500 pmol/l, increased these contributions equivalently. At supraphysiological (>6,500 pmol/l) insulin levels, the plasma glucose contribution to glycolysis increased further, and addition of hyperglycemia made it the sole glycolytic substrate, yet [4-(13)C]glutamate-to-[3-(13)C]alanine ratios remained /=40% of myocardial TCA cycle flux.

Menopausal status is a risk factor for coronary artery disease death, but the mechanism underlying this association is uncertain. To test whether estrogen ameliorates the effects of acute myocardial ischemia in ways likely to translate into a mortality difference, we compared the response to brief (6-min) and prolonged (45-min) coronary occlusion in vivo in five groups (each n = 16) of rats: ovariectomized females; ovariectomized females after 6 wk 17beta-estradiol replacement; male rats supplemented with estradiol for 6 wk; normal males; and normal females. Coronary occlusion produced a uniform ischemic risk area averaging 53 +/- 3% of left ventricular volume. After a brief occlusion, reperfusion ventricular tachycardia/fibrillation occurred with >85% frequency in all groups. During a prolonged occlusion, ischemic ventricular tachycardia occurred in 100% and sustained tachycardia requiring cardioversion in >75% of rats in all groups. Myocardial infarct size averaged 52 +/- 4% of the ischemic risk area and was similarly unaffected by gender or estrogen status. We conclude that neither short-term estrogen withdrawal, replacement, nor supplementation significantly affects the potentially lethal outcomes from acute coronary occlusion in this species.

Background: Rapid reperfusion of an occluded coronary artery salvages regional mechanical function, but this benefit may not be realized for hours or days because of postischemic stunning. Recovery from stunning is incompletely understood but may involve adaptive changes in heart glucose metabolism., Methods and Results: To examine whether reversible coronary occlusion produces sustained changes in regional glucose metabolism in vivo, we performed a 20-minute left coronary artery occlusion followed by 24 hours of open-artery reperfusion in intact rats. Coronary occlusion produced stunning of the anterolateral left ventricle that resolved over 24 hours. When examined at 24 hours, reperfused regions were fully contractile and viable by vital staining and microscopy but demonstrated 25% reduction in blood flow and 50% increased uptake of circulating glucose, as estimated by in vivo [(13)N]NH(3) and [(18)F]fluorodeoxyglucose (FDG) tracer uptake. Reperfused regions had largely inactive glycogen synthase, low rates of glycogen synthesis, and persistent 50% glycogen depletion but increased flux of plasma [1-(13)C]glucose into myocardial [3-(13)C]alanine, indicating preferential shunting of imported glucose away from storage and into glycolysis., Conclusions: Sustained increases in regional glycolytic consumption of circulating glucose occur during reperfusion of a limited-duration coronary occlusion. This suggests a role for glycolytic ATP in the recovery from postischemic stunning in vivo. Furthermore, [(13)N]NH(3) /FDG regional mismatch may constitute a clinically accessible late metabolic signature of regional myocardial ischemia.

Ischemic preconditioning depletes the myocardium of glycogen, thus blunting lactic acidosis during subsequent episodes of ischemia. Preconditioning also protects against reperfusion arrhythmias and infarction. To test whether glycogen depletion is necessary for this ischemic tolerance, we preconditioned two groups of intact rats with a series of 3-min coronary artery occlusions. In one group, preconditioning lowered the glycogen concentration of the ischemic region by approximately 50% (24.9 +/- 2.5 to 12.5 +/- 1.8 mumol/g; P < 0.01). In the other, the heart was first loaded with glycogen via glucose-insulin infusion so that preconditioning merely reduced its glycogen concentration back to normal physiological levels. Compared with nonpreconditioned control rats, preconditioned rats with both normal and subnormal glycogen concentrations were protected from reperfusion arrhythmias after a 6-min coronary occlusion (incidence: control rats, 100%; normal glycogen rats, 11%; reduced glycogen rats, 11%). In contrast, only rats with subnormal glycogen concentration after preconditioning exhibited reduced lactate formation and infarct size after a 45-min coronary occlusion [infarct size (percentage of risk area): control rats, 53 +/- 10%; normal glycogen rats, 50 +/- 16%, P = not significant; subnormal glycogen rats, 18 +/- 10%, P < 0.01]. Thus, in the intact rat, myocardial glycogen depletion appears to be necessary for the infarct-limiting, but not for the antiarrhythmic, effects of ischemic preconditioning.

The effects of the antidepressant drugs desipramine, fluoxetine and tranylcypromine and the non-antidepressant control cocaine on angiotensin II function were determined in vivo by use of angiotensin-induced drinking in rats and in vitro using contractile responses of the rat uterus. The results of the drinking studies showed that the three antidepressants, but not cocaine, reduced the dipsogenic effects of angiotensin II. In vitro, all of the drugs reduced the effects of not only angiotensin but also acetylcholine and oxytocin on the uterus. The inhibition appeared to be non-competitive in all cases. These results indicate that the antidepressant drugs reduced the activity of angiotensin II, albeit non-selectively, and suggest that the previously reported effects of antidepressants on isoprenaline-induced drinking in rats reflect an action on angiotensin activity rather than a reduction of beta-adrenoceptor activity as previously suggested.

The glomeruli of kidneys subjected to reduced perfusion pressure were examined morphometrically. The left renal artery was narrowed for 30 min in anesthetized dogs with (n = 6) or without (n = 7) converting-enzyme inhibition (captopril). The kidneys were then rapidly fixed by glutaraldehyde perfusion at high flow rate. In a comparison of glomeruli of kidneys subjected to pressure reduction in captopril-treated and untreated dogs, there was significantly greater mesangial contraction in the latter, but morphometric analysis revealed no significant differences in the glomerular surface area available for filtration as evidenced by glomerular capillary volume fractions, surface areas of the filtering basement membrane between epithelial and endothelial cells, or the length densities of the glomerular epithelial slits. In a comparison of the left (pressure reduction) and right (no pressure reduction) kidneys in the captopril-treated dogs, there was no significant effect of reduction of renal perfusion pressure per se on mesangial contraction or glomerular filtration surface area when angiotensin (ANG) II formation was blocked. Thus ANG II caused mesangial cell contraction after renal artery stenosis, but this did not significantly change glomerular ultrafiltration surface area.