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Objectives: The current recommended treatment for patients with recurrent episodes of schizophrenia and related conditions is antipsychotic medication. However, many antipsychotic users remain functionally impaired and experience serious physical and mental side effects. This study aims to assess the cost-effectiveness of a gradual antipsychotic reduction and discontinuation strategy compared with maintenance treatment over 24 months from mental health services, health and social care, and societal perspectives., Methods: Nineteen mental health trusts recruited patients to the Research into Antipsychotic Discontinuation and Reduction (RADAR) randomized controlled trial. Quality-adjusted life-years were calculated from patient-reported EQ-5D-5L, with years of full capability calculated from the patient-reported ICECAP-A. Mental health services use and medication was collected from medical records. Other resource use and productivity loss was collected using self-completed questionnaires. Costs were calculated from published sources., Results: A total of 253 participants were randomized: 126 assigned to antipsychotic dose reduction and 127 to maintenance. There were no significant differences between arms in total costs for any perspectives. There were no significant difference in quality-adjusted life-years (-0.035; 95% CI: -0.123 to 0.052), whereas years of full capability were significantly lower in the reduction arm compared with the maintenance arm (baseline-adjusted difference: -0.103; 95% CI: -0.192 to -0.014). The reduction strategy was dominated by maintenance for all analyses and was not likely to be cost-effective., Conclusions: It is unlikely that gradual antipsychotic reduction and discontinuation strategy is cost-effective compared with maintenance over 2-years for patients with schizophrenia and other recurrent psychotic disorders who are on long-term antipsychotics., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Background: Immune checkpoint inhibitors (ICI) have revolutionised treating advanced cancers. ICI are administered intravenously every 2-6 weeks for up to 2 years, until cancer progression/unacceptable toxicity. Physiological efficacy is observed at lower doses than those used as standard of care (SOC). Pharmacodynamic studies indicate sustained target occupancy, despite a pharmacological half-life of 2-3 weeks. Reducing frequency of administration may be possible without compromising outcomes. The REFINE trial aims to limit individual patient exposure to ICI whilst maintaining efficacy, with potential benefits in quality of life and reduced drug treatment/attendance costs., Methods/design: REFINE is a randomised phase II, multi-arm, multi-stage (MAMS) adaptive basket trial investigating extended interval administration of ICIs. Eligible patients are those responding to conventionally dosed ICI at 12 weeks. In stage I, patients (n = 160 per tumour-specific cohort) will be randomly allocated (1:1) to receive maintenance ICI at SOC vs extended dose interval. REFINE is currently recruiting UK patients with locally advanced or metastatic renal cell carcinoma (RCC) who have tolerated and responded to initial nivolumab/ipilimumab, randomised to receive maintenance nivolumab SOC (480 mg 4 weekly) vs extended interval (480 mg 8 weekly). Additional tumour cohorts are planned. Subject to satisfactory outcomes (progression-free survival) stage II will investigate up to 5 different treatment intervals. Secondary outcome measures include overall survival, quality-of-life, treatment-related toxicity, mean incremental pathway costs and quality-adjusted life-years per patient. REFINE is funded by the Jon Moulton Charity Trust and Medical Research Council, sponsored by University College London (UCL), and coordinated by the MRC CTU at UCL. Trial Registration ISRCTN79455488. NCT04913025 EUDRACT #: 2021-002060-47. CTA 31330/0008/001-0001; MREC approval: 21/LO/0593. REFINE Protocol version 4.0., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Human subjects consuming fish oil showed a significant suppression of cyclooxygenase-2 (COX-2) expression in blood monocytes when stimulated in vitro with lipopolysaccharide (LPS), an agonist for Toll-like receptor 4 (TLR4). Results with a murine monocytic cell line (RAW 264.7) stably transfected with COX-2 promoter reporter gene also demonstrated that LPS-induced COX-2 expression was preferentially inhibited by docosahexaenoic acid (DHA, C22:6n-3) and eicosapentaenoic acid (EPA, C20:5n-3), the major n-3 polyunsaturated fatty acids (PUFAs) present in fish oil. Additionally, DHA and EPA significantly suppressed COX-2 expression induced by a synthetic lipopeptide, a TLR2 agonist. These results correlated with the preferential suppression of LPS- or lipopeptide-induced NF kappa B activation by DHA and EPA. The target of inhibition by DHA is TLR itself or its associated molecules, but not downstream signaling components. In contrast, COX-2 expression by TLR2 or TRL4 agonist was potentiated by lauric acid, a saturated fatty acid. These results demonstrate that inhibition of COX-2 expression by n-3 PUFAs is mediated through the modulation of TLR-mediated signaling pathways. Thus, the beneficial or detrimental effects of different types of dietary fatty acids on the risk of the development of many chronic inflammatory diseases may be in part mediated through the modulation of TLRs.

Background: Effects of diet on blood lipids are best known in white men, and effects of type of carbohydrate on triacylglycerol concentrations are not well defined., Objective: Our goal was to determine the effects of diet on plasma lipids, focusing on subgroups by sex, race, and baseline lipid concentrations., Design: This was a randomized controlled outpatient feeding trial conducted in 4 field centers. The subjects were 436 participants of the Dietary Approaches to Stop Hypertension (DASH) Trial [mean age: 44.6 y; 60% African American; baseline total cholesterol: < or = 6.7 mmol/L (< or = 260 mg/dL)]. The intervention consisted of 8 wk of a control diet, a diet increased in fruit and vegetables, or a diet increased in fruit, vegetables, and low-fat dairy products and reduced in saturated fat, total fat, and cholesterol (DASH diet), during which time subjects remained weight stable. The main outcome measures were fasting total cholesterol, LDL cholesterol, HDL cholesterol, and triacylglycerol., Results: Relative to the control diet, the DASH diet resulted in lower total (-0.35 mmol/L, or -13.7 mg/dL), LDL- (-0.28 mmol/L, or -10.7 mg/dL), and HDL- (-0.09 mmol/L, or -3.7 mg/dL) cholesterol concentrations (all P < 0.0001), without significant effects on triacylglycerol. The net reductions in total and LDL cholesterol in men were greater than those in women by 0.27 mmol/L, or 10.3 mg/dL (P = 0.052), and by 0.29 mmol/L, or 11.2 mg/dL (P < 0.02), respectively. Changes in lipids did not differ significantly by race or baseline lipid concentrations, except for HDL, which decreased more in participants with higher baseline HDL-cholesterol concentrations than in those with lower baseline HDL-cholesterol concentrations. The fruit and vegetable diet produced few significant lipid changes., Conclusions: The DASH diet is likely to reduce coronary heart disease risk. The possible opposing effect on coronary heart disease risk of HDL reduction needs further study.

Background: Only a few published studies in children used several methods to compare body fat in large groups of fatter and leaner multiethnic children. We hypothesized that the preferred methods of determining body fat may differ in children with larger compared with smaller amounts of body fat, in boys compared with girls, and in African Americans compared with whites., Objective: Our objective was to evaluate several methods of predicting body fat in 10-12-y-old white and African American boys and girls., Design: The body fat of 129 African American and white boys and girls aged 10-12 y, distributed equally by sex and race, was measured with use of dual-energy X-ray absorptiometry (DXA), underwater weighing (densitometry), isotope dilution (H(2)18O), bioelectrical impedance, skinfold thicknesses, corporal diameters, and circumferences., Results: With use of DXA as the criterion variable, body fat was bimodally distributed in the boys and skewed to higher values in the girls. Biceps skinfold thickness had the highest predictive value of any single skinfold thickness compared with DXA fat. All formulas for estimating body fat from skinfold thicknesses, body density, or impedance performed better in the children in the upper one-half of the fat distribution (the fatter children) than in those in the lower one-half (the leaner children). Body mass index was highly correlated with body fat (R2 = 0.77); there was a good correlation for the fatter children (R2 = 0.66) and no correlation for the leaner children (R2 = 0.09). The hydration of the fat-free mass was significantly higher in the fatter children than in the leaner ones (79.2% compared with 76.7%)., Conclusions: These data are consistent with the hypothesis that all methods of estimating body fat work better in children with larger amounts of body fat. The best formulas use skinfold thicknesses, bioelectrical impedance, and a 4-compartment model.

Background: Dietary fatty acids that are more prone to oxidation than to storage may be less likely to lead to obesity., Objective: The aim of this study was to determine the effect of chain length, degree of unsaturation, and stereoisomeric effects of unsaturation on the oxidation of individual fatty acids in normal-weight men., Design: Fatty acid oxidation was examined in men consuming a weight-maintenance diet containing 40% of energy as fat. After consuming the diet for 1 wk, subjects were fed fatty acids labeled with (13)C in the methyl or carboxyl position (10 mg/kg body wt). The fatty acids fed in random order were laurate, palmitate, stearate, oleate, elaidate (the trans isomer of oleate), linoleate, and linolenate blended in a hot liquid meal. Breath samples were collected for the next 9 h and the oxidation of each fatty acid was assessed by examining liberated (13)CO(2) in breath., Results: Cumulative oxidation over the 9-h test ranged from a high of 41% of the dose for laurate to a low of 13% of the dose for stearate. Of the 18-carbon fatty acids, linolenate was the most highly oxidized and linoleate appeared to be somewhat conserved. (13)C recovery in breath from the methyl-labeled fatty acids was approximately 30% less than that from the carboxyl-labeled fatty acids., Conclusions: In summary, lauric acid is highly oxidized, whereas the polyunsaturated and monounsaturated fatty acids are fairly well oxidized. Oxidation of the long-chain, saturated fatty acids decreases with increasing carbon number.

Background: It takes several days to adapt to a high-fat diet. In an earlier study, we observed a large degree of interindividual variation in the capacity to adapt to a high-fat diet. We hypothesized that concurrent physical activity would accelerate fat oxidation during an isoenergetic high-fat diet., Objective: The objective of this study was to determine the effect of increased physical activity on the ability of young healthy men to increase fat oxidation during the shift to a high-fat diet., Design: Six young healthy men participated in a randomized, single-blind crossover study. The volunteers consumed a diet contributing 37% of energy as fat, 14% as protein, and 49% as carbohydrate for 4 d. Energy expenditure and macronutrient balance were then measured in a respiration chamber as the energy content of the isoenergetic diet was changed to 50% fat, 14% protein, and 36% carbohydrate. Treadmill walking, as the physical activity, was used to increase total daily energy expenditure to 1.8 times the resting metabolic rate during 1 of 2 stays in the metabolic chamber. Total daily energy expenditure was maintained at 1.4 times the resting metabolic rate for the other stay., Results: Energy balance was not significantly different between the 2 conditions. The 24-h respiratory quotient decreased more rapidly and to a greater extent under conditions of increased energy expenditure. Further, there was a decrease in the interindividual variability in the response of the respiratory quotient to a high-fat diet with increased energy expenditure (physical activity). Cumulative carbohydrate and protein balances were greater under conditions of increased physical activity. Conversely, cumulative fat balance was greater under sedentary conditions., Conclusion: Concurrent physical activity increases fat oxidation during the shift to a high-fat diet.

Background: Dietary fat contents are highly variable. Failure to compensate for the positive fat balance that occurs during the shift to a high-fat, low-carbohydrate diet by increasing energy expenditure or by decreasing food intake may result in the gain of fat mass., Objective: The objective of this study was to investigate the time course of fat oxidation during adaptation to an isoenergetic high-fat, low-carbohydrate diet., Design: After a 5-d control diet, dietary fat was increased from 37% of energy to 50% of energy for 4 d in 6 healthy, young lean men. Respiratory quotient and substrate macronutrient oxidation and balance were measured in a respiratory chamber. Fasting concentrations of insulin, glucose, and triacylglycerol; maximal oxygen consumption (f1.gif" BORDER="0">O(2)max) during treadmill exercise; and free-living energy expenditure were determined. Body fat was measured by dual-energy X-ray absorptiometry and visceral adipose tissue by computerized tomography., Results: Compared with the baseline diet, the high-fat, low-carbohydrate diet resulted in positive fat and protein balances and a negative carbohydrate balance. Insulin concentration and the postabsorptive respiratory quotient were positively correlated with the fat balance during the high-fat, low-carbohydrate diet, whereas f1.gif" BORDER="0">O(2)max during treadmill exercise was negatively related to fat balance. With use of stepwise regression, f1.gif" BORDER="0">O(2)max was the best predictor of fat balance. There was a negative correlation between fat balance and carbohydrate balance (r(2) = 0.88)., Conclusion: Both baseline insulin concentration and f1.gif" BORDER="0">O(2)max during treadmill exercise predict fat balance during the shift to a high-fat diet under isoenergetic conditions.

The increased risk of morbidity and mortality from obesity, central body fat, and weight gain, and the beneficial effects of weight reduction argue that the cost associated with obesity could be beneficially affected by prevention of weight gain or induction of weight loss. Genetic, metabolic, and demographic predictors of weight gain have been identified that allow selection of high-risk individuals. Among the metabolic predictors are a low metabolic rate, insulin sensitivity, and a high respiratory quotient. Demographic predictors include current smokers, certain dieting behaviors, lower socio-economic class, a low level of education, use of contraceptives, status post-partum, and rapid weight gain in childhood. Several studies suggest that weight gain can be prevented. Targets for such strategies might be high-risk families, current smokers, those who are planning to stop smoking, and those with a low metabolic rate. For those who fail primary prevention, treatment may be appropriate. The greater the degree of excess weight, the greater the risk and the more appropriate treatment becomes to reduce body weight.

Epidemiologic studies across societies have shown consistent differences in blood pressure that appear to be related to diet. Vegetarian diets are consistently associated with reduced blood pressure in observational and interventional studies, but clinical trials of individual nutrient supplements have had an inconsistent pattern of results. Dietary Approaches to Stop Hypertension (DASH) was a multicenter, randomized feeding study, designed to compare the impact on blood pressure of 3 dietary patterns. DASH was designed as a test of eating patterns rather than of individual nutrients in an effort to identify practical, palatable dietary approaches that might have a meaningful impact on reducing morbidity and mortality related to blood pressure in the general population. The objectives of this article are to present the scientific rationale for this trial, review the methods used, and discuss important design considerations and implications.

The DASH Diet, Sodium Intake and Blood Pressure Trial (DASH-Sodium) is a multicenter, randomized trial comparing the effects of 3 levels of sodium intake and 2 dietary patterns on blood pressure among adults with higher than optimal blood pressure or with stage 1 hypertension (120-159/80-95 mm Hg). The 2 dietary patterns are a control diet typical of what many Americans eat, and the DASH diet, which, by comparison, emphasizes fruits, vegetables, and low-fat dairy foods, includes whole grains, poultry, fish, and nuts, and is reduced in fats, red meat, sweets, and sugar-containing beverages. The 3 sodium levels are defined as higher (typical of current US consumption), intermediate (reflecting the upper limit of current US recommendations), and lower (reflecting potentially optimal levels). Participants are randomly assigned to 1 of the 2 dietary patterns using a parallel group design and are fed each of the 3 sodium levels using a randomized crossover design. The study provides participants with all of their food during a 2-week run-in feeding period and three 30-day intervention feeding periods. Participants attend the clinic for 1 meal per day, 5 days per week, and take home food for other meals. Weight is monitored and individual energy intake adjusted to maintain baseline weight. The primary outcome is systolic blood pressure measured at the end of each intervention feeding period. Systolic blood pressure is compared across the 3 sodium levels within each diet and across the 2 diets within each sodium level. If effects previously observed in clinical trials are additive, sodium reduction and the DASH diet together may lower blood pressure to an extent not as yet demonstrated for nonpharmacologic treatment. The DASH-Sodium results will have important implications for the prevention and treatment of high blood pressure.

There is a difference of opinion about whether the percentage of dietary fat plays an important role in the rising prevalence of overweight and in its treatment once it has developed. We believe that ample research from animal and clinical studies, from controlled trials, and from epidemiologic and ecologic analyses provides strong evidence that dietary fat plays a role in the development and treatment of obesity. A reduction in fat intake reduces the gap between total energy intake and total energy expenditure and thus is an effective strategy for reducing the present epidemic of obesity worldwide. A review of the results from 28 clinical trials that studied the effects of a reduction in the amount of energy from fat in the diet showed that a reduction of 10% in the proportion of energy from fat was associated with a reduction in weight of 16 g/d. We thus conclude that dietary fat plays a role in the development of obesity. To reduce the prevalence of obesity, there must be an increase in energy expenditure, a reduction in total energy intake, or both. This goal can be facilitated by reducing the amount of fat in the diet.

Osborne-Mendel (OM) and S5B/Pl rats differ in their sensitivity to develop obesity when fed a high fat (HF) diet; OM rats become obese, whereas S5B/Pl rats remain thin. We have investigated the possibilities that either an impaired leptin response or resistance to leptin action underlies the sensitivity to this form of obesity in OM rats. In Experiment 1, OM and S5B/Pl rats fed a nonpurified diet were killed at d 0 or were fed either a HF (56% fat energy) or a low fat (LF, 10% fat energy) diet for 2 or 7 d. The HF diet increased serum leptin significantly by d 2 to levels that were similar in both rat strains. At 7 d, leptin levels were lower than at d 2 but remained higher than levels in the d 0 control groups. The leptin mRNA:18S RNA ratio in epididymal adipose tissue increased to higher levels in HF-fed OM rats than in S5B/Pl rats fed that diet. However, although the LF diet had no effect in S5B/Pl rats, it increased leptin mRNA levels in epididymal adipose tissue of OM rats compared with the controls fed the nonpurified diet. In Experiment 2, OM and S5B/Pl rats were fed HF or LF diets for 5 wk. At that time, their feeding response to a range of leptin doses (0, 1, 5 or 10 microgram) given intracerebroventricularly was tested after overnight food deprivation. There was a similar dose-dependent reduction in energy intake in response to leptin in both OM and S5B/Pl rats. These responses were independent of the diet. The data suggest that the susceptibility of OM rats to HF diet-induced obesity is not related to either a loss of central sensitivity to leptin or a failure to enhance leptin production acutely, although the failure to maintain chronically increased levels of serum leptin could contribute to the obesity.

We investigated the effect of chronic dexfenfluramine (DFEN) treatment on macronutrient selection in a three-choice diet paradigm using Sprague-Dawley rats. Baseline macronutrient intakes were measured for several days before the initiation of treatment. In Experiment 1, daily intraperitoneal injections of DFEN (1.5 mg/kg) or saline were administered 60 min before dark onset for 12 consecutive days and 24 h macronutrient intakes were measured. DFEN significantly reduced absolute fat intake (kcal) by 30% and relative fat intake (% of total energy) by 14% in animals that received dexfenfluramine treatment compared to controls over the 12-day period. Absolute carbohydrate intake was increased 24% compared to controls, but this difference was not significant. These changes in food intake resulted in a 10% lower total energy intake. Upon discontinuation of the drug, fat intake of the DFEN-treated rats rebounded to control levels within 24 h. In Experiment 2, rats were assigned to carbohydrate- or fat-preferring groups based on the ratio of their average daily carbohydrate to fat intake (kcal). All animals then received DFEN. During DFEN treatment, fat-preferring rats reduced their daily fat intake from 62 to 53% of total energy. The low baseline fat intake of carbohydrate-preferring rats was reduced even further by DFEN (from 24 to 15% of total energy). These corresponding effects of DFEN on macronutrient selection in both fat- and carbohydrate-preferring rats indicate that chronic DFEN treatment selectively suppressed fat intake independent of the preferred macronutrient diet.

Objective: To compare reported energy intake with energy expenditure using doubly labeled water (DLW). Additionally, we compared reported nutrient intakes of our subject population with national survey population data from the third National Health and Nutrition Examination Survey (NHANES III)., Design: This was a cross-sectional study of children, balanced by race and gender, primarily characterized by 4 body types: lean, obese, centrally fat, or peripherally fat., Subjects/setting: Children (n=118; mean age=10 years) kept 8-day food records, with nutritionists recording weekday school lunch intakes. These subjects, assisted by their parents, recorded all breakfasts, dinners, snacks, and weekend lunches., Statistical Analyses Performed: Data were analyzed using least squares analysis of variance with the general linear models procedure. Tukey's test was used for multiple comparisons of predicted treatment means., Results: Mean daily energy intake was underreported by 17% to 33% of energy expenditure. The tendency to underreport increased with age. Underreporting occurred in all groups and subgroups studied. Reported mean intakes of vitamin A, vitamin E, vitamin B-6, calcium, zinc, and copper were less than 70% of the Recommended Dietary Allowance (RDA) for African-American girls, whereas African-American boys reported similarly low intakes of copper. On average, white girls reported intakes less than 70% of the RDA for zinc and copper, whereas white boys reported low intakes of copper (60% of the RDA). Reported intakes in general were somewhat lower than those reported in NHANES III., Applications/conclusions: Dietetics professionals may modify the nutritional advice they give to patients/subjects based on food intake records and other data. For children, particularly, it is imperative that ethnic and gender differences be taken into consideration and that all foods eaten be accounted for as much as possible.

Changes in substrate oxidation with isoenergetic high-carbohydrate (HC) and high-fat (HF) diets in male nonathletic subjects, aerobically trained athletes, and weight-trained athletes were examined in a crossover study. A whole-room respiration chamber was used to measure 24-h energy expenditure (EE) and substrate oxidation with control, HC, or HF diets for 7 d. The nonathletic group had higher 24-h EE (P < 0.05), exercise EE (P < 0.03), and resting metabolic rate (P < 0.04) than did the aerobically trained athletes when these measurements were corrected for lean body mass. Fat oxidation was significantly correlated with lean body mass and diet. However, athletic status had no effect on substrate oxidation. Carbohydrate oxidation across groups increased acutely by 23% after 24 h of the HC diet (P < 0.0001). Carbohydrate balance increased significantly over time with the HC diet (P < 0.002) and decreased acutely after return to the control diet (P < 0.0001). With the HF diet, carbohydrate balance increased and was significantly different from balance with the control diet by day 7 (P < 0.03). Fat balance decreased significantly with both the HF (P < 0.04) and HC (P = 0.0075) diets by day 7. Carbohydrate oxidation correlated with carbohydrate intake with both the control (r = 0.61, P < 0.01) and HC diets (r = 0.59, P < 0.02), but not the HF diet. Fat oxidation was not correlated with fat intake. In conclusion, substrate oxidation in a respiration chamber is significantly affected by diet, but not by prior athletic training.

The Differential Display technique has been used to identify differences in mRNA expression in adipose tissue after the introduction of a high fat diet to two strains of rat (OM and S5B/PI) that differ in their susceptibility to develop obesity on this diet. The insulin receptor tyrosine kinase inhibitor protein (fetuin) was shown to be differentially expressed in OM but not S5B/PI rats. This circulating protein may play a role in the development of peripheral insulin resistance associated with high fat diets.

We investigated the effect of a combined carbohydrate and energy deficit in the regulation of food intake during 1 d. Seven lean, male subjects were studied in a crossover design. After 7 d of consuming a baseline diet (40% of energy as fat, 45% as carbohydrate, and 15% as protein), subjects were deprived of carbohydrate for 24 h; baseline amounts of fat and protein were consumed but only one-third of the baseline amount of carbohydrate. On the following outcome day, subjects were free to select ad libitum from a selection of either high-carbohydrate or low-carbohydrate food. On the baseline diet subjects consumed on average 10.9 +/- 1.7 MJ/d (carbohydrate: 305 +/- 49 g/d; fat: 116 +/- 18 g/d) and there was no difference in baseline intake between the two phases of the crossover study. During the deficit day, intake was reduced to 7.7 +/- 1.2 MJ/d [carbohydrate: 110 +/- 25 g/d (66% reduction); fat: 116 +/- 18 g/d]. On the outcome day, energy intake from high-carbohydrate foods was on average 10.5 MJ/d (carbohydrate: 430 +/- 112 g/d; fat: 48 +/- 20 g/d) compared with 16.6 MJ/d from high-fat foods (carbohydrate: 312 +/- 84 g/d; fat: 258 +/- 78 g/d). We conclude that the restoration of an energy deficit is not the main factor determining acute food intake. Rather, the data support the hypothesis that, under the conditions of our experiment, the intake of carbohydrate required to maintain carbohydrate balance was a more important factor in the regulation of acute food intake than was the restoration of energy deficit is not.

Contradictory reports on the protective effect of fish consumption on cardiovascular disease (CVD) risk could be due to variations in the intake of n-3 and n-6 polyunsaturated fatty acids (PUFAs). Metabolic competition between n-3 and n-6 PUFAs suggests that n-6 PUFAs in vegetable oils could attenuate the efficacy of n-3 PUFAs in fish oil to favorably alter endpoints relevant to CVD risk. We determined the effects of varying dietary amounts of fish oil on lipid and thrombotic endpoints relevant to risk factors for CVD and whether these effects were attenuated by vegetable oils. Two randomized, double-blind, placebo-controlled, parallel studies were conducted in human subjects fed varying amounts of n-3 and n-6 PUFAs; n-3 PUFA intake was varied by using fish or placebo oil capsules, and n-6 PUFA intake was modified by incorporating varying amounts of safflower oil into the diet. Endpoints included changes in membrane fatty acid composition, blood lipids, and thrombotic profile. The results indicated that absolute amounts of fish oil, and not the relative amounts of fish and vegetable oil (ratios of n-3 to n-6 PUFAs), determined the magnitude of the reduction of arachidonic acid and increase in eicosapentaenoic acid in phospholipids of plasma and platelets. The suppression of plasma triacylglycerols by fish oil was not affected by varying amounts of dietary n-6 PUFAs. Fibrinogen concentrations decreased with 15 g but not with 9 g fish oil/d fed at the same ratio of n-3 to n-6 PUFAs. The efficacy of fish oil in favorably modifying certain risk factors for CVD was not attenuated by vegetable oil.

Approximately 25% of hemophilia A patients infused with factor VIII (fVIII) mount an immune response, which leads to its inactivation. Anti-fVIII autoantibodies are also seen rarely in individuals with normal fVIII. We have previously demonstrated that some anti-A2 and anti-C2 domain antibodies are fVIII inhibitors and that many patients have additional inhibitors with a fVIII light chain (LCh) epitope outside C2. Because the contribution of the different antibodies to the plasma inhibitor titer had been examined in a limited number of patients (14), we report in this study a more extensive analysis of 55 plasmas. The dominant inhibitors in 62% (13 of 21) of autoantibody plasmas were directed only against C2 or A2, but not both, whereas this pattern was found in only 15% (5 of 34) of hemophilic plasmas. In addition, anti-A2 inhibitors were present in 71% (24 of 34) of hemophilic plasmas, but only 33% (7 of 21) of autoantibody plasmas. These results demonstrated that the inhibitor response in hemophiliacs was more complex and the epitope specificity was somewhat different. A comparison of hemophiliacs treated only with plasma fVIII or recombinant fVIII showed no significant differences in the complexity of the inhibitor response, as > or = 2 different inhibitor antibodies were present in 78% (18 of 23) of the former and 82% (9 of 11) of the latter. In contrast, the major inhibitors in 35% (8 of 23) of hemophiliacs treated with plasma fVIII were directed against C2 and another LCh epitope within residues 1649-2137, but not A2, while none (0 of 11) treated with recombinant fVIII had this pattern.

Progress in understanding the genetics of obesity has moved rapidly in the past few years. The genes for all of the single gene defects that produce obesity in experimental animals have now been cloned. The new insights from these models are one spur for the examination of possible links to human obesity. In thinking about the biology of obesity produced by single gene defects, it must be kept in mind that adrenalectomy can prevent the phenotypic expression in all of the single gene models of obesity. Thus, nongenetic components can play a major role in regulating even single gene models of obesity. Transgenic mice have also expanded our understanding of obesity. Transgenic models that both increase and decrease body fat have been published. Of particular interest from the perspective of the physiological control of obesity is the destruction of the uncoupling protein in brown adipose tissue, which is followed by hyperphagia and obesity, suggesting that the sympathetic nervous system is involved in both modulation of food intake and energy storage. Gene mapping using quantitative trait loci and studies of candidate genes have been applied to experimental models of animals with differing susceptibilities to dietary fat and have been applied to the human genome in more detail.

Several health hazards and social disabilities are associated with obesity. Increased mortality is associated with increased body weight. A high rate of mortality results from heart disease, diabetes mellitus, gallbladder disease, high blood pressure, and cancer. Physiologic cardiovascular changes occur, leading to left ventricular hypertrophy and lipid abnormalities. Hypertension, stroke, and venous stasis are increased. Pulmonary abnormalities include obstructive sleep apnea, which can be associated with secondary polycythemia and right ventricular hypertrophy. Gallstones, gallbladder disease, and accumulation of fat on the liver are significantly increased. Gout and reproductive abnormalities in women are common. Osteoarthritis of the knees and spine occur, although osteoporosis is rare. Risk for endometrial and breast cancer is increased, particularly in the presence of increased central fat. Changes in the skin include stretch marks, acanthosis negricans, hirsutism, intertrigo, and multiple papillomas. Impaired psychosocial function is manifested as social isolation, loss of job mobility, increased employee absenteeism, and economic and social discrimination.

Underwater weighing has been the gold standard for the measurement of body composition in humans; however, the two formulas widely used, the Siri and Bronze, were developed using young adult white males. The development of newer techniques in the past 20 years has greatly expanded the accuracy and ease of measuring body composition. These methods have improved the ability to model relationships between body compartments. This article reviews the compartmental models and then critiques the methods available to measure body composition.

In July 1990, the Recombinate Study Group initiated a prospective, open-labeled investigation of recombinant factor VIII (r-FVIII) to assess its safety and efficacy and to characterize the natural history of inhibitor development in previously untreated patients (PUPs) with hemophilia A. All study subjects have severe FVIII deficiency (baseline FVIII level < or = 2% of normal) and no history of blood product exposure before study entry. Following the first r-FVIII infusion, plasma was screened for inhibitors once every 3 months, and plasma recovery of r-FVIII at 30 minutes and 24 hours postinfusion was assayed at least once every 6 months. As of May 1993, 73 of 79 patients originally enrolled in the trial continue to participate. The median number of r-FVIII exposure-days for the 71 subjects who have received at least one r-FVIII infusion is 11. A total of 1,785 infusions have been administered to treat 810 bleeding events. Ninety-two percent of bleeding events responded as anticipated to one or two infusions. Two, nonrecurring, acute adverse reactions occurred coincident with r-FVIII infusion, one of which was unrelated and the other, possibly related to the infusion. Seventeen (23.9%) subjects have developed inhibitors: five with peak titers more than 10 Bethesda units (BU) and 12 with peak titers < or = 10 BU (range, 0.5 to 10). Survival analysis showed that the probability of remaining inhibitor-free in this group of patients with severe hemophilia A is 88.4% after 8, 73.6% after 10, and 61.6% after 25 r-FVIII exposure-days. Inhibitors disappeared in five (29.4%) subjects on retesting 2 to 16 months after the last positive inhibitor assay. r-FVIII is safe and effective in the treatment of hemophilia A-related bleeding. To date, the inhibitor risk associated with its use is comparable to that in patients treated with plasma-derived concentrates. The majority of inhibitors identified are low in titer and do not preclude continued on-demand therapy with r-FVIII.

Objective: To compare two training techniques for validity and reliability of dietary instruments and the measurement of total energy expenditure (TEE) to determine whether technique could influence the accuracy of food portion estimates., Design: Adult women were randomized into a control group and an experimental group for comparison of training technique., Setting: University and research center., Subjects: Five hundred women were screened using the Three-Factor Eating Questionnaire to identify restrained eaters or disinhibitors. Other criteria for selection included good health; absence of thyroid, respiratory, or other diseases; normal menstrual cycles; between the ages of 18 and 50 years. Forty-nine were recruited, with an attrition rate of 10% for a total sample of 44 subjects., Intervention: The control group (n = 26) was trained with food models and the experimental group (n = 18) was trained with a combination of food models and life-sized food photographs. All subjects completed two 24-hour recalls and 14 consecutive days of food records. TEE was measured by the doubly-labeled water method., Main Outcome Measures: Training would improve the accuracy of food portion estimates., Statistical Analyses Performed: Analysis of variance, the paired t test, Pearson's correlation coefficient, and Wilcoxon's ranking test., Results: The mean reported intake between instruments was found to be reliable; however, the comparison with TEE was underreported by 21.4% and was thus nonvalid. Training technique made no difference in validity or reliability. Both training techniques improved the accuracy of food portion estimates; however, improvement was enhanced with food photographs., Applications/conclusion: The findings indicate that training can improve food portion estimates, and dietary instruments may provide reliable but nonvalid results.

In early hepatic fibrosis, increased amounts of type III collagen are deposited. Persistently high serum concentrations of aminoterminal type III procollagen propeptide (PIIIP) correlate with the activity of the fibrogenic process. Another index for the detection of fibrosis, the PGA index, combines the prothrombin time, gamma-glutamyl transpeptidase activity, and serum apolipoprotein A1 concentration (the latter falls with progressive fibrosis). We compared PIIIP measurements and PGA index in patients with various histological forms of alcoholic liver disease (104), primary biliary cirrhosis (38), and chronic B virus hepatitis (27), and in healthy age-matched controls (30). The ability of each test to identify correctly patients with fibrosis or cirrhosis was assessed with receiver operating curves. The PGA index was much higher in all groups of patients with alcoholic liver disease than in controls (p < 0.0001). PIIIP concentrations were also substantially higher than in controls (p < 0.05 for fatty liver, p < 0.0001 for all other groups), especially in the group with alcoholic hepatitis and cirrhosis. For the detection of cirrhosis the PGA was 91% sensitive and 81% specific and the PIIIP concentration was 94% sensitive and 81% specific. The two tests combined had 85% sensitivity, but 93% specificity. Among patients with primary biliary cirrhosis, both PGA index and PIIIP concentration correlated well with the severity of the disease, determined by the Mayo score (r = 0.72 and 0.66 respectively). The combined tests were 96% sensitive for the detection of fibrosis. All patients with chronic B virus hepatitis had raised PGA and PIIIP values in comparison with controls (p < 0.0001) but there were no differences between subgroups. Substantially raised PIIIP concentrations thus identify the subgroup of alcoholic patients with both hepatitis and cirrhosis. The combination of PGA index and PIIIP concentration may be useful for targeting treatment with antifibrotic drugs and to reduce the need for liver biopsy.

We report a mother and son who were found to have macrothrombocytopenia, prolonged bleeding time, and abnormal platelet responses to thrombin. Transmission electron microscopy performed on the son's platelets demonstrated an unusual arrangement of membrane complexes formed by association of the open canalicular and dense tubular systems. Number and appearance of platelet alpha-granules, dense bodies, and mitochondria were normal. These platelets demonstrated normal agonist-induced Ca2+ flux in response to collagen and supranormal responses to arachidonic acid but displayed no increase in intracellular free Ca2+ in response to thrombin. Platelet surface glycoproteins IIb-IIIa, Ib, and granular membrane protein-140 measured by fluorescence-activated flow cytometry, along with platelet content of von Willebrand factor and fibrinogen, were normal. The von Willebrand factor binding function of GP-Ib on these platelets was also normal. We believe that this family demonstrates a unique macrothrombocytopenia syndrome characterized by deficient Ca2+ mobilization in response to thrombin that is not related to a defect in GP-Ib.

The availability of monoclonal-antibody-purified factor VIII (FVIII) concentrates allows us to test the hypothesis, based on in vitro observations, that their use in HIV seropositive haemophiliacs would result in a difference in the rate of deterioration of immune function. We designed a multicentre, prospective, randomised, controlled study of symptom-free HIV-infected patients with haemophilia A who were assigned to receive either an intermediate-purity or monoclonal-antibody-purified product. All had CD4 lymphocyte counts of 100-600/microL, were negative for hepatitis B surface antigen, had not received any antiretroviral or immunomodulating drugs before study entry, and had previously received replacement therapy with intermediate purity FVIII concentrates. Use of antiretroviral therapy was permitted. 60 patients were recruited and 30 were assigned to each group. 35 completed the 3 year study, 20 in the monoclonal arm and 15 in the intermediate-purity arm. Among those completing the study, there were no differences between the two groups in the occurrence of AIDS-defining diagnoses (1 in each group). There were, however, striking and significant differences in terms of changes in absolute CD4 counts. The group receiving monoclonal-antibody-purified concentrates had essentially stable counts while a significant drop was observed in the group receiving intermediate-purity FVIII. These differences were independent of the use of antiretroviral therapy. These observations support the use of high-purity concentrates in the treatment of symptom-free HIV-positive patients with haemophilia A, and they should be taken into account along with cost, by doctors making therapeutic decisions.

d-Fenfluramine is an appetite suppressant drug that acts by releasing serotonin from axon terminals and inhibiting its reuptake. S 5B/P1 rats, which are resistant to dietary-fat induced obesity, and Osborne-Mendel rats, which are sensitive, were adapted to ad lib feeding of either a low- or high-fat diet. d-Fenfluramine (10 mg/kg, IP) was injected daily for 12 days. Other than a slightly greater suppression of food intake in Osborne-Mendel rats, there was little difference in response to d-fenfluramine between S 5B/P1 and Osborne-Mendel rats eating the low-fat diet. However, in Osborne-Mendel rats d-fenfluramine completely abolished the excess food intake and weight gain associated with the high-fat diet. Purine nucleotide (GDP) binding on day 13 was higher in S 5B/P1 rats than in Osborne-Mendel rats and was increased by d-fenfluramine in animals of both strains eating the low-fat diet. The high-fat diet increased GDP binding only in S 5B/P1 rats and blocked the fenfluramine-induced increase in GDP binding in both strains. We speculate that d-fenfluramine blocks a feeding reward system stimulated by the high-fat diet.

Individuals weighing greater than 100 kg represent a small fraction of the population and yet pose a major health risk to themselves. It is proposed that individuals be classified according to their body mass index (BMI). Class 0 individuals have a BMI of 20-25 kg/m2 and are not obese; Class I individuals have a BMI of 25-30 kg/m2 and are at low risk from their obesity; Class II individuals have a BMI of 30-35 kg/m2 and have moderate risk; Class III individuals have a BMI of 35-40 kg/m2 and have high risk associated with their obesity; Class IV individuals have a BMI of greater than 40 kg/m2 and are at very high risk for illness. Class IV is the primary group for surgical consideration. The pathophysiologic consequences of excess weight result in large part from increased food intake and/or decreased physical activity. Individuals in Class IV have additional problems related to their weight, including cardiomyopathy, Pickwickian/sleep apnea syndrome, pituitary/gonadal dysfunction, acanthosis nigricans, and significant osteoarthritis.

The currently available drugs for treatment of obesity act on two pharmacologic systems in the central nervous system: the noradrenergic system and the serotonergic system. There are clear and convincing clinical data that these drugs are effective and safe. However, several types of barriers exist to their proper and effective use, including public perceptions that obesity is a disease resulting from lack of willpower, professional expectations that anorexiant drugs should cure obesity, hindrance by state licensing agencies, regulatory rigidity, limited research funding, and legislative inaction. In spite of these limitations, several new and potentially valuable drugs are under development, and given an appropriate clinical and therapeutic environment, the future is bright for treatment of obesity.

Food intake can be increased or decreased after either central or peripheral administration of peptides. Galanin, neuropeptide Y, opioid peptides, growth-hormone-releasing hormone, and desacetyl-melanocyte stimulating hormone increase food intake whereas insulin, glucagon, cholecystokinin, anorectin, corticotropin-releasing hormone, neurotensin, bombesin, cyclo-his-pro, and thyrotropin-releasing hormone reduce food intake. Many of these peptides have reciprocal effects on food intake and sympathetic activity with those peptides that stimulate food intake reducing sympathetic activity and vice versa. In addition, neuropeptide Y specifically increases carbohydrate intake. Galanin and opioid peptides on the other hand increase fat intake whereas enterostatin reduces fat intake. Glucagon decreases protein intake. The effect of peptides on specific nutrients suggests that peptides may work in part by modulating basic feeding mechanisms to lead to the selection of specific nutrients from the diet. This hypothesis might be called a nutrient-specific model of peptide-induced food intake.

Obesity occurs in both clinical and animal forms in a variety of specific models which allow study of its underlining endocrine and mechanistic features. Among the neuroendocrine varieties of obesity, polycystic ovaries are probably the most common. The importance of the gonadal feedback system for regulation of food intake and obesity is indicated by the effects of castration in experimental animals which is a widely used mechanism for producing experimental obesity. Cushing syndrome and hypothalamic obesity are rare clinical syndromes. The current evidence suggests that there are two types of hypothalamic obesity from a mechanistic point of view--one associated with hyperphagia as a necessary and sufficient cause and a disturbance of the autonomic nervous system without hyperphagia as a second mechanism. Although genetic factors underlie most types of human obesity, there are several dymorphic forms of obesity including the Prader-Willy syndrome, Cohen's syndrome, Carpenter's syndrome, Ahlstrom's syndrome and the Bardet-Biedel syndrome. The Prader-Willi syndrome is characterized by obesity hypotonia hypogonadism and mental retardation. In animals, a dominant form of inheritance of obesity is seen in the yellow mouse. Current evidence suggests that this syndrome can be explained by reduced acetylation of MSH in the pituitary and/or hypothalamus. Several recessively inherited forms of obesity exist including the obese mouse, the diabetes mouse, fatty rat, the fat mouse, tubby mouse and the corpulent rat. In addition, there are a number of polygenic types of experimental obesity. The final mechanistic classification of obesity are those due to dietary manipulation. For both human beings and animals, a highly fat diet appears to be particularly problematic for the development of obesity.(ABSTRACT TRUNCATED AT 250 WORDS)

A survey of opinions on the causes and effectiveness of treatment of obesity was carried out on 50 physicians and scientists involved in obesity research. Responses were grouped by region (Europe, North America, and United Kingdom), sex, age (30-50 and greater than 50 y) and degree (MD or PhD). Genetic factors were considered the most important causes of obesity overall. Females viewed lack of physical activity, carbohydrate craving, and weight cycling as significantly more important causes than did their male colleagues and viewed exercise as a more effective treatment. There were regional variations in the assessment of the importance of metabolic defects and weight cycling as causes of obesity and in the usefulness of diet in the treatment of obesity. The older group of respondents rated low-fat diet more highly as a treatment than did their younger colleagues. All groups viewed serotonergic and thermogenic drugs as effective treatments whose usefulness would increase during the next 10 years.

The mechanisms underlying different types of obesity have been gradually clarified. Animal models with hypothalamic, genetic or dietary obesity have been examined with a feedback model. Four common final pathways are involved in this model. One of these final common pathways is the sympathetic nervous system. Most Obesities kNown Are Low In Sympathetic Activity states the MONA LISA Hypothesis. A second common pathway is the endocrine system involving adrenal glucocorticosteroids. The third common pathway is hyperphagia. Although not essential for most obesities, hyperphagia may be essential in animals with injury to the hypothalamic paraventricular nucleus. The final pathway is reduced physical activity. The tonic activity of these systems and their response to changes in the diet affect nutrient partitioning between fat and protein. This framework has been used to review genetic obesity, hypothalamic obesity and dietary obesity.

The influence of acetylcysteine, administered at presentation to hospital, on the subsequent clinical course of 100 patients who developed paracetamol-induced fulminant hepatic failure was analysed retrospectively. Mortality was 37% in patients who received acetylcysteine 10-36 h after the overdose, compared with 58% in patients not given the antidote. In patients given acetylcysteine, progression to grade III/IV coma was significantly less common than in those who did not receive the antidote (51% vs 75%), although the median peak prothrombin time was similar for both groups. Whether the beneficial effect is related to replenishment of glutathione stores or a consequence of another hepatic protective mechanism of acetylcysteine requires further study.

To determine the accuracy of skinfold thickness measurements in body composition assessment, skinfold thicknesses, bioelectrical impedance, body density by underwater weighing, and total body water by deuterium dilution were determined in 105 healthy adults who varied widely in body fatness. Body fat ranged from 2.9% to 61.2% of body weight and a substantial number of obese subjects was included. The correlation between body fat calculated from skinfold equations and body fat measured by underwater weighing was in the same range as that between body fat estimated from impedance and underwater weighing. However, body fat calculated both from skinfold equations and bioelectrical impedance tended to be underestimated compared with body fat calculated from underwater weighing and total body water in the most obese subjects. In obese subjects it was not possible to measure significant numbers of skinfold thicknesses because of the inadequate size of the calipers.

An enzyme immunoassay (Ortho-HCV ELISA) for antibodies against the hepatitis C virus (HCV) was used to test 143 serum samples from 53 patients with autoimmune chronic active hepatitis (AI-CAH). Optical density (OD) values in the assay correlated closely with serum globulin (r = 0.8846, p much less than 0.0005) and IgG (r = 0.6281, p less than 0.0005) concentrations but not with immunosuppressant therapy. OD values were positive in 20 (65%) of 31 with active disease and in only 1 (5%) of 22 in remission (p less than 0.0005). The association between positive results and active disease and high serum globulin levels was confirmed by serial studies in 6 of the patients. In contrast, none of 31 patients with primary biliary cirrhosis and only 2 of 24 with non-hepatic disorders associated with high IgG concentrations were positive, and these controls showed no correlation between OD values and serum globulins or IgG. The findings suggest that serum from AI-CAH patients may contain a component that gives false-positive results in the assay.

Adult female rats were ovariectomized (OVX) or sham-operated and 4-5 weeks later OVX groups were treated with estradiol benzoate (EB), progesterone, both hormones, or the oil vehicle. All rats were sacrificed on the 4th day of hormone treatment following an overnight fast and a terminal meal. Interscapular brown adipose tissue (BAT) pads of EB-treated groups were heavier and contained more lipid than those of the other OVX groups. Lipid content of adipose tissue differed according to site (BAT less than inguinal less than parametrial = retroperitoneal), but only BAT exhibited differential responsiveness to hormonal treatments. There was also a trend for increased oxygen consumption by BAT from EB-treated rats. It is concluded that BAT may be involved in the process of increased energy expenditure by estrogen-treated rats.