Cerebral Ketones Detected by 3T MR Spectroscopy in Patients with High-Grade Glioma on an Atkins-Based Diet.

BACKGROUND AND PURPOSE: Ketogenic diets are being explored as a possible treatment for several neurological diseases, but the physiologic impact on the brain is unknown. The objective of this study was to evaluate the feasibility of 3T MR spectroscopy to monitor brain ketone levels in patients with high-grade gliomas who were on a ketogenic diet (a modified Atkins diet) for 8 weeks. MATERIALS AND METHODS: Paired pre- and post-ketogenic diet MR spectroscopy data from both the lesion and contralateral hemisphere were analyzed using LCModel software in 10 patients. RESULTS: At baseline, the ketone bodies acetone and ß-hydroxybutyrate were nearly undetectable, but by week 8, they increased in the lesion for both acetone (0.06 ± 0.03 ≥ 0.27 ± 0.06 IU, P = .005) and ß-hydroxybutyrate (0.07 ± 0.07 ≥ 0.79 ± 0.32 IU, P = .046). In the contralateral brain, acetone was also significantly increased (0.041 ± 0.01 ≥ 0.16 ± 0.04 IU, P = .004), but not ß-hydroxybutyrate. Acetone was detected in 9/10 patients at week 8, and ß-hydroxybutyrate, in 5/10. Acetone concentrations in the contralateral brain correlated strongly with higher urine ketones (r = 0.87, P = .001) and lower fasting glucose (r = -0.67, P = .03). Acetoacetate was largely undetectable. Small-but-statistically significant decreases in NAA were also observed in the contralateral hemisphere at 8 weeks. CONCLUSIONS: This study suggests that 3T MR spectroscopy is feasible for detecting small cerebral metabolic changes associated with a ketogenic diet, provided that appropriate methodology is used.

Effect of protein source during weight loss on body composition, cardiometabolic risk and physical performance in abdominally obese, older adults: a pilot feeding study.

OBJECTIVES: The purpose of this pilot study was to begin to examine the effect of dietary protein source (soy protein versus non-soy protein) during weight loss on body composition, and cardiometabolic and functional decline risk factors in older, abdominally obese adults. DESIGN: Two-arm, single-blind, randomized, controlled trial. SETTING: Wake Forest School of Medicine, Winston-Salem NC 27157, USA. PARTICIPANTS: 25 older (68.4±5.5 years, 88% female), abdominally obese (BMI: 35.1±4.3 kg/m2; WC: 101.4±13.1 cm) men and women were randomized to participate in the study. INTERVENTION: A 12-week weight loss intervention, with participants randomized to consume soy protein-based meal replacements (S; n=12) or non-soy protein-based meal replacements (NS; n=12), in addition to prepared meals, and all participants targeted to receive an individualized caloric deficit of 500 kcal/day. MEASUREMENTS: Body weight and composition (assessed via DXA and CT), conventional biomarkers of cardiometabolic risk, and physical performance measures were assessed pre- and post-intervention. Additional endpoints of feasibility (accrual, participation, retention, compliance, and safety) are reported. RESULTS: A total of 24 participants (87% female) completed the study (96% retention) and lost an average of 7.8±3.0 kg over the 12-week period, with no difference seen between groups (p=0.83). Although nearly all measures of global and regional body composition were significantly reduced following the 12-week intervention, differences were not observed between groups. Among cardiometabolic risk factors and physical performance measures, only diastolic blood pressure was significantly lower in the NS group compared to the S group (66.7±2.7 mmHg vs 73.5±2.7 mmHg, respectively; p=0.04). Interestingly, in groups combined, despite significant reductions in body weight and lean mass, no significant changes in 400-meter walk time (+5.3±43.4 s), short physical performance battery score (+0.1±1.0), grip strength (-0.3±3.2 kg), or relative knee extensor strength (-0.0±0.0 N/m/cm3 thigh muscle volume) were observed. CONCLUSIONS: Data presented here suggest that a 12-week weight loss intervention, which incorporates S and NS meal replacement products, is associated with clinically significant weight loss and improvements in several parameters of cardiometabolic risk and unchanged physical function and strength. RESULTS do not differ by protein source and suggest that soy protein is at least as good as other protein sources for weight loss during low-calorie dietary interventions in older adults.

Metabolism of fructose to oxalate and glycolate.

Much attention has been recently directed at fructose consumption because of its association with obesity and subsequent development of chronic diseases. It was recently reported that an increased fructose intake increases the risk of forming kidney stones. It was postulated that fructose consumption may increase urinary oxalate, a risk factor for calcium oxalate kidney stone disease. However, conflicting results have been obtained in human studies examining the relationship between fructose metabolism and oxalate synthesis. To test whether fructose intake influences urinary excretions impacting kidney stone risk, healthy subjects consumed diets controlled in their contents of fructose, oxalate, calcium, and other nutrients. Subjects consumed diets containing 4, 13, and 21% of calories as fructose in a randomized order. No changes in the excretions of oxalate, calcium, and uric acid were observed. In vitro investigations with cultured liver cells incubated with (13)C-labeled sugars indicated that neither fructose nor glucose was converted to oxalate by these cells. Fructose metabolism accounted for 12.4 ± 1.6% of the glycolate detected in the culture medium and glucose 6.4 ± 0.9%. Our results suggest that mechanisms for stone risk associated with fructose intake may lie in factors other than those affecting the major stone risk parameters in urine.

Monitoring heart function in larval Drosophila melanogaster for physiological studies.

We present various methods to record cardiac function in the larval Drosophila. The approaches allow heart rate to be measured in unrestrained and restrained whole larvae. For direct control of the environment around the heart another approach utilizes the dissected larvae and removal of the internal organs in order to bathe the heart in desired compounds. The exposed heart also allows membrane potentials to be monitored which can give insight of the ionic currents generated by the myocytes and for electrical conduction along the heart tube. These approaches have various advantages and disadvantages for future experiments that are discussed. The larval heart preparation provides an additional model besides the Drosophila skeletal NMJ to investigate the role of intracellular calcium regulation on cellular function. Learning more about the underlying ionic currents that shape the action potentials in myocytes in various species, one can hope to get a handle on the known ionic dysfunctions associated to specific genes responsible for various diseases in mammals.

Effects of dietary protein on the composition of weight loss in post-menopausal women.

OBJECTIVES: To determine whether a hypocaloric diet higher in protein can prevent the loss of lean mass that is commonly associated with weight loss. DESIGN: An intervention study comparing a hypocaloric diet moderately high in protein to one lower in protein. SETTING: Study measurements were taken at the Wake Forest University General Clinical Research Center (GCRC) and Geriatric Research Center (GRC). PARTICIPANTS: Twenty-four post-menopausal, obese women (mean age = 58 +/- 6.6 yrs; mean BMI = 33.0 +/- 3.6 kg/m2). INTERVENTION: Two 20-week hypocaloric diets (both reduced by 2800 kcal/wk) were compared: one maintaining dietary protein intake at 30% of total energy intake (1.2-1.5 g/kg/d; HI PROT), and the other maintaining dietary protein intake at 15% of total energy (0.5-0.7 g/kg/d; LO PROT). The GCRC metabolic kitchen provided lunch and dinner meals which the women picked up 3 days per week and ate outside of the clinic. MEASUREMENTS: Body composition, including total body mass, total lean mass, total fat mass, and appendicular lean mass, assessed by dual energy x-ray absorptiometry, was measured before and after the diet interventions. RESULTS: The HI PROT group lost 8.4 +/- 4.5 kg and the LO PROT group lost 11.4 +/- 3.8 kg of body weight (p = 0.11). The mean percentage of total mass lost as lean mass was 17.3% +/- 27.8% and 37.5% +/- 14.6%, respectively (p = 0.03). CONCLUSION: Maintaining adequate protein intake may reduce lean mass losses associated with voluntary weight loss in older women.

Advanced age, but not anergy, is associated with altered serum polyunsaturated fatty acid levels.

Unknown factors present in the serum of older adults impair lymphocyte function and may be responsible for anergy (absence of delayed-type hypersensitivity (DTH)) present in many older adults. Polyunsaturated fatty acids (PUFAs) and their metabolites are immunomodulatory and may play a role in clinical conditions of advanced age, including immune dysfunction. We hypothesized that PUFAs could be the factor(s) present in serum that contribute to impaired immune responses in older adults. Prior studies of serum PUFAs in older adults neither adequately control dietary PUFA intake, nor investigated the relationship of PUFAs and DTH responses. We determined serum PUFA concentrations in young adults with normal immune responses, and older adults with impaired (anergic elderly) or normal immunity (nonanergic elderly) before and after administering a standardized diet. After controlling for dietary intake, advancing age was associated with markedly higher serum concentrations of arachidonic acid (AA), dihomo-gamma-linoleic acid (DGLA), and eicosapentaenoic acid (EPA) and a lower AA:EPA ratio. Other serum PUFAs and the AA:DGLA ratio were unaffected by age. However, there was no difference between older adults with or without anergy. These data suggest advanced age is associated with marked alterations of serum PUFAs that are only apparent after strictly controlling dietary intake. However, there was no association of serum PUFA concentrations with DTH status among older adults.

Statistical issues in analyzing 24-hour dietary recall and 24-hour urine collection data for sodium and potassium intakes.

Dietary recalls and urine assays provide different metrics for assessing sodium and potassium intakes. Means, variances, and correlations of data obtained from these two modes of measurement differ. Pooling of these data is not straightforward, and results from studies employing the different modes may not be comparable. To explore differences between these metrics, the authors used data from the Trial of Nonpharmacologic Intervention in the Elderly (TONE), which included repeated standardized 24-hour dietary recalls and 24-hour urine collections administered over 3 years of follow-up, to estimate sodium and potassium intakes. The authors examined data from 341 control participants assigned to usual care that were collected between August 1992 and December 1995. Dietary recalls yielded estimates of sodium intake that averaged 22% less than those from urine assays and estimates of potassium intake that averaged 16% greater than those from urine assays. Sodium intake estimates were less repeatable (r = 0.22 for diet; r = 0.30 for urine) than potassium intake estimates (r = 0.49 for diet; r = 0.50 for urine), making relations with outcomes more difficult to characterize. Overall, the performance of the two measurement modes was fairly similar across demographic subgroups. Errors in separate estimations of long term sodium and potassium intakes using short term data were strongly correlated, more strongly than the underlying long term intakes of these electrolytes. Because of the correlated measurement error, estimated regression coefficients for linear models including both electrolytes as predictors may be confounded such that the separate relations between these nutrients and outcomes such as blood pressure cannot be reliably estimated by common analytical strategies.

Effects of reduced sodium intake on hypertension control in older individuals: results from the Trial of Nonpharmacologic Interventions in the Elderly (TONE).

BACKGROUND: Few trials have evaluated the effects of reduced sodium intake in older individuals, and no trial has examined the effects in relevant subgroups such as African Americans. PATIENTS AND METHODS: The effects of sodium reduction on blood pressure (BP) and hypertension control were evaluated in 681 patients with hypertension, aged 60 to 80 years, randomly assigned to a reduced sodium intervention or control group. Participants (47% women, 23% African Americans) had systolic BP less than 145 mm Hg and diastolic BP less than 85 mm Hg while taking 1 antihypertensive medication. Three months after the start of intervention, medication was withdrawn. The primary end point was occurrence of an average systolic BP of 150 mm Hg or more, an average diastolic BP of 90 mm Hg or more, the resumption of medication, or a cardiovascular event during follow-up (mean, 27.8 months). RESULTS: Compared with control, mean urinary sodium excretion was 40 mmol/d less in the reduced sodium intervention group (P<.001); significant reductions in sodium excretion occurred in subgroups defined by sex, race, age, and obesity. Prior to medication withdrawal, mean reductions in systolic and diastolic BPs from the reduced sodium intervention, net of control, were 4.3 mm Hg (P<.001) and 2.0 mm Hg (P =.001). During follow-up, an end point occurred in 59% of reduced sodium and 73% of control group participants (relative hazard ratio = 0.68, P<.001). In African Americans, the corresponding relative hazard ratio was 0.56 (P =.005); results were similar in other subgroups. In dose-response analyses, end points were progressively less frequent with greater sodium reduction (P for trend =.002). CONCLUSION: A reduced sodium intake is a broadly effective, nonpharmacologic therapy that can lower BP and control hypertension in older individuals.

Lifestyle interventions influence relative errors in self-reported diet intake of sodium and potassium.

PURPOSE: To characterize the distribution of errors in self-reported sodium and potassium dietary intakes relative to more objective urine measures among participants receiving lifestyle interventions. METHODS: We analyzed longitudinal data from 900 individuals with hypertension who had been enrolled in a randomized controlled clinical trial to establish whether usual care or three lifestyle interventions (weight loss, sodium reduction, and combined weight loss and sodium reduction) could effectively substitute for phamacotherapy. Repeated standardized 24-hour diet recalls and 24-hour urine collections were collected over up to three years of follow-up to estimate sodium and potassium intakes. By contrasting self-reported and urine-based sodium and potassium data collected before and during interventions, we examined the relative impact of intervention assignment on estimated intakes, repeatability, and multivariate measurement error. RESULTS: Relative to urine-based measures, mean self-reported sodium intakes were biased about 10% lower among participants assigned to combined weight loss and sodium reduction, but were unaffected by the other interventions. The repeatability of self-report measures increased slightly with time, particularly among participants assigned to sodium interventions. Errors in self-reported sodium and potassium intakes were correlated before the start of the intervention, but became uncorrelated among individuals assigned to sodium restriction interventions. CONCLUSIONS: Lifestyle interventions may influence not only diet intake, but also the measurement of diet intake.

Effect of apolipoprotein A-IV genotype and dietary fat on cholesterol absorption in humans.

We investigated the effect of the A-IV-2 allele, which encodes a Q360H substitution in apolipoprotein (apo) A-IV, and dietary fat on cholesterol absorption in humans. In three separate studies we compared fractional intestinal cholesterol absorption between groups of subjects heterozygous for the A-IV-2 allele (1/2) and homozygous for the common allele (1/1) receiving high cholesterol ( approximately 800 mg/day) diets with different fatty acid compositions. All subjects had the apoE 3/3 genotype. There was no difference in cholesterol absorption between the two genotype groups receiving a high saturated fat diet (33% of total energy as fat; 18% saturated, 3% polyunsaturated, 12% monounsaturated) or a low fat diet (22% of total energy as fat; 7% saturated, 7% polyunsaturated, 8% monounsaturated) diet. However, on a high polyunsaturated fat diet (32% of total energy as fat; 7% saturated, 13% polyunsaturated, 12% monounsaturated) mean fractional cholesterol absorption was 56. 7% +/- 1.9 in 1/1 subjects versus 47.5% +/- 2.1 in 1/2 subjects (P = 0.004). A post hoc analysis of the effect of the apoA-IV T347S polymorphism across all diets revealed a Q360H x T347S interaction on cholesterol absorption, and suggested that the A-IV-2 allele lowers cholesterol only in subjects with the 347 T/T genotype. We conclude that a complex interaction between apoA-IV genotype and dietary fatty acid composition modulates fractional intestinal cholesterol absorption in humans.

Addition of eicosapentaenoic acid to gamma-linolenic acid-supplemented diets prevents serum arachidonic acid accumulation in humans.

Previous studies reveal that supplementation of human diets with gamma-linolenic acid (GLA) reduces the generation of lipid mediators of inflammation and attenuates clinical symptoms of chronic inflammatory disorders such as rheumatoid arthritis. However, we have shown that supplementation with this same fatty acid also causes a marked increase in serum arachidonate (AA) levels, a potentially harmful side effect. The objective of this study was to design a supplementation strategy that maintained the capacity of GLA to reduce lipid mediators without causing elevations in serum AA levels. Initial in vitro studies utilizing HEP-G2 liver cells revealed that addition of eicosapentaenoic acid (EPA) blocked Delta-5-desaturase activity, the terminal enzymatic step in AA synthesis. To test the in vivo effects of a GLA and EPA combination in humans, adult volunteers consuming controlled diets supplemented these diets with 3.0 g/d of GLA and EPA. This supplementation strategy significantly increased serum levels of EPA, but did not increase AA levels. EPA and the elongation product of GLA, dihomo-gamma-linolenic acid (DGLA) levels in neutrophil glycerolipids increased significantly during the 3-wk supplementation period. Neutrophils isolated from volunteers fed diets supplemented with GLA and EPA released similar quantities of AA, but synthesized significantly lower quantities of leukotrienes compared with their neutrophils before supplementation. This study revealed that a GLA and EPA supplement combination may be utilized to reduce the synthesis of proinflammatory AA metabolites, and importantly, not induce potentially harmful increases in serum AA levels.

Solution structure of a synthetic peptide corresponding to a receptor binding region of FSH (hFSH-beta 33-53).

The receptor binding surface of human follicle-stimulating hormone (hFSH) is mimicked by synthetic peptides corresponding to the hFSH-beta chain amino acid sequences 33-53 [Santa-Coloma, T. A., Dattatreyamurty, D., and Reichert, L. E., Jr. (1990), Biochemistry 29, 1194-1200], 81-95 [Santa-Coloma, T. A., Reichert, L. E., Jr. (1990), J. Biol. Chem. 265, 5037-5042], and the combined sequence (33-53)-(81-95) [Santa-Coloma, T. A., Crabb, J. W., and Reichert, L. E., Jr. (1991), Mol. Cell. Endocrinol. 78, 197-204]. These peptides have been shown to inhibit binding of hFSH to its receptor. Circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy were used to determine the structure of the first peptide in this series, the 21 amino acid peptide hFSH-beta-(33-53), H2N-YTRDLVYKDPARPKIQKTCTF-COOH. Analysis of CD data indicated the presence of approximately equal amounts of antiparallel beta-pleated sheet, turns including a beta-turn, "other" structures, and a small amount of alpha-helix. The major characteristics of the structure were found to be relatively stable at acidic pH and the predominant effect of increased solvent polarity was a small increase in alpha-helical content. One- and two-dimensional NMR techniques were used to obtain full proton and carbon signal assignments in aqueous solution at pH 3.1. Analysis of NMR results confirmed the presence of the structural features revealed by CD analysis and provided a detailed picture of the secondary structural elements and global folding pattern in hFSH-beta-(33-53). These features included an antiparallel beta-sheet (residues 38-51 and 46-48), turns within residues 41-46, and 50-52 (a beta-turn) and a small N-terminal helical region comprised of amino acids 34-36. One of the turns is facilitated by prolines 42 and 45. Proline-45 was constrained to the trans conformation, whereas proline-42 favored the trans conformer (approximately 70%) over the cis (approximately 30%). Two resonances were observed for the single alanine residue (A-43) sequentially proximal to P-42, but the rest of the structure was minimally affected by the isomerization at proline-42. The major population of molecules, containing trans-42 and trans-45 prolines, presented 120 NOEs. Distance geometry calculations with 140 distance constraints and energy minimization refinements were used to derive a moderately well-defined model of the peptide's structure.(ABSTRACT TRUNCATED AT 400 WORDS)