Cybermedlife - Therapeutic Actions Dietary Modification - Low Calorie Diet

Nigella sativa oil with a calorie-restricted diet can improve biomarkers of systemic inflammation in obese women: A randomized double-blind, placebo-controlled clinical trial.

Abstract Title: Nigella sativa oil with a calorie-restricted diet can improve biomarkers of systemic inflammation in obese women: A randomized double-blind, placebo-controlled clinical trial. Abstract Source: J Clin Lipidol. 2016 Sep-Oct;10(5):1203-11. Epub 2015 Dec 7. PMID: 27678438 Abstract Author(s): Reza Mahdavi, Nazli Namazi, Mohammad Alizadeh, Safar Farajnia Article Affiliation: Reza Mahdavi Abstract: BACKGROUND: Inflammation is one of the primary mechanisms in the development of metabolic complications. Although anti-inflammatory characteristics of Nigella sativa (NS) have been indicated in animal models, clinical trials related to the effects of NS on inflammatory parameters are relatively scarce. OBJECTIVE: The aim of the present study was to determine the effects of NS oil combined with a calorie-restricted diet on systemic inflammatory biomarkers in obese women. METHODS: In this double-blind placebo-controlled randomized clinical trial, 90 volunteer obese (body mass index = 30-34.9 kg/m(2)) women aged 25-50 years were recruited. Participants were randomly divided into two groups, an intervention group (n = 45) and a placebo group (n = 45). Each group received either: (1) a low-calorie diet with 3 g/day of NS oil or (2) a low-calorie diet with 3 g/day placebo for 8 weeks. RESULTS: A total of 84 females (intervention group = 43; placebo group = 41) completed the trial. Subjects in the intervention group did not report any side effects with the NS oil supplementation. NS oil decreased serum levels of tumor necrosis factor-alpha (-40.8% vs -16.1%, P = .04) and high-sensitivity C-reactive protein (-54.5% vs -21.4%, P = .01) compared to the placebo group. However, there were no significant changes in interleukin-6 levels (-8.6 vs -2.4%, P = .6) in the NS group compared to the placebo group. CONCLUSIONS: NS oil supplementation combined with a calorie-restricted diet may modulate systemic inflammatory biomarkers in obese women. However, more studies are needed to clarify the efficacy of NS oil as an adjunct therapy to improve inflammatory parameters in obese subjects. Article Published Date : Aug 31, 2016

Obese Patients with Type 2 Diabetes on Conventional Versus Intensive Insulin Therapy: Efficacy of Low-Calorie Dietary Intervention.

Abstract Title: Obese Patients with Type 2 Diabetes on Conventional Versus Intensive Insulin Therapy: Efficacy of Low-Calorie Dietary Intervention. Abstract Source: Adv Ther. 2016 Feb 17. Epub 2016 Feb 17. PMID: 26886777 Abstract Author(s): Dimitrios Baltzis, Maria G Grammatikopoulou, Nikolaos Papanas, Christina-Maria Trakatelli, Evangelia Kintiraki, Maria N Hassapidou, Christos Manes Article Affiliation: Dimitrios Baltzis Abstract: INTRODUCTION: The aim of this prospective study was to assess the results of a standard low-calorie dietary intervention (7.5 MJ/day) on body weight (BW) and the metabolic profile of obese patients with type 2 diabetes mellitus (T2DM) on intensive insulin therapy (IIT: 4 insulin injections/day) versus conventional insulin therapy (CIT: 2/3 insulin injections/day). METHODS: A total of 60 patients (n = 60, 23 males and 37 postmenopausal females) were recruited and categorized into two groups according to the scheme of insulin treatment. Thirty were on IIT (13 males and 17 females) and an equal number on CIT (10 males and 20 females). BW, body mass index (BMI), HbA1c, and metabolic parameters were compared at 6 and 12 months after baseline. RESULTS: Significant reductions were observed in the BW, BMI, HbA1c (p ≤ 0.001 for all) and cholesterol (p ≤ 0.05) at 6 months post-intervention. At 1 year, median BW reduction was 4.5 kg (3.3, 5.8) for patients on IIT and 4.8 kg (3.6, 7.0) for those on CIT. The 12-month dietary intervention increased prevalence of normoglycemia in the IIT group and reduced the prevalence of obesity prevalence among the CIT participants (all p < 0.001). CIT patients with BW reduction ≥5.0% demonstrated 11-fold greater chances of being normoglycemic (odds ratio 11.3, 95% CI 1.1-110.5). BW reduction ≥7.0% was associated with CIT, being overweight, and having normal HDLc, LDLc, and cholesterol levels. A reduction in BW between 5.0% and 6.9% was associated with IIT, normoglycemia, and obesity. CONCLUSION: A 12-month 1800-kcal dietary intervention achieved significant BW and HbA1c reductions irrespectively of insulin regimen. CIT was associated with BW reduction greater than 8.0%, whereas IIT was associated with higher rates of normoglycemia. Article Published Date : Feb 16, 2016

Oxidative Stress Responses to Nigella sativa Oil Concurrent with a Low-Calorie Diet in Obese Women: A Randomized, Double-Blind Controlled Clinical Trial.

Abstract Title: Oxidative Stress Responses to Nigella sativa Oil Concurrent with a Low-Calorie Diet in Obese Women: A Randomized, Double-Blind Controlled Clinical Trial. Abstract Source: Phytother Res. 2015 Jul 14. Epub 2015 Jul 14. PMID: 26179113 Abstract Author(s): Nazli Namazi, Reza Mahdavi, Mohammad Alizadeh, Safar Farajnia Article Affiliation: Nazli Namazi Abstract: The aim of the present study was to determine the effects of Nigella sativa (NS) oil concurrent with a low-calorie diet on lipid peroxidation and oxidative status in obese women. In this double-blind placebo-controlled randomized clinical trial, 50 volunteer obese (body mass index = 30-35 kg/m(2) ) women aged 25-50 years old were recruited. Participants were randomly divided into intervention (n = 25) and placebo (n = 25) groups. They received a low-calorie diet with 3 g/day NS oil or low-calorie diet with 3 g/day placebo for 8 weeks. Forty-nine women (intervention group = 25; placebo group = 24) completed the trial. NS oil concurrent with a low-calorie diet decreased weight in the NS group compared to the placebo group (-4.80 ± 1.50 vs. -1.40 ± 1.90 kg; p < 0.01). Comparison of red blood cell superoxidase dismutase (SOD) indicated significant changes in the NS group compared to the placebo group at the end of the study (88.98 ± 87.46 vs. -3.30 ± 109.80 U/gHb; p < 0.01). But no significant changes in lipid peroxidation, glutathione peroxidase, and total antioxidant capacity concentrations were observed. NS oil concurrent with a low-calorie diet decreased weight and increased SOD levels in obese women. However, more studies are suggested to confirm the positive effects of NS in obesity and its complications. Copyright © 2015 John Wiley&Sons, Ltd. Article Published Date : Jul 13, 2015

Lifestyle intervention with weight reduction: first-line treatment in mild obstructive sleep apnea.

Abstract Title: Lifestyle intervention with weight reduction: first-line treatment in mild obstructive sleep apnea. Abstract Source: Am J Respir Crit Care Med. 2009 Feb 15;179(4):320-7. Epub 2008 Nov 14. PMID: 19011153 Abstract Author(s): Henri P I Tuomilehto, Juha M Seppä, Markku M Partinen, Markku Peltonen, Helena Gylling, Jaakko O I Tuomilehto, Esko J Vanninen, Jouko Kokkarinen, Johanna K Sahlman, Tarja Martikainen, Erkki J O Soini, Jukka Randell, Hannu Tukiainen, Matti Uusitupa, Abstract: RATIONALE: Obesity is the most important risk factor for obstructive sleep apnea (OSA). However, although included in clinical guidelines, no randomized controlled studies have been performed on the effects of weight reduction on mild OSA. OBJECTIVES: The aim of this prospective, randomized controlled parallel-group 1-year follow-up study was to determine whether a very low calorie diet (VLCD) with supervised lifestyle counseling could be an effective treatment for adults with mild OSA. METHODS: Seventy-two consecutive overweight patients (body mass index, 28-40) with mild OSA were recruited. The intervention group (n = 35) completed the VLCD program with supervised lifestyle modification, and the control group (n = 37) received routine lifestyle counseling. The apnea-hypopnea index (AHI) was the main objectively measured outcome variable. Change in symptoms and the 15D-Quality of Life tool were used as subjective measurements. MEASUREMENTS AND MAIN RESULTS: The lifestyle intervention was found to effectively reduce body weight (-10.7 +/- 6.5 kg; body mass index, -3.5 +/- 2.1 [mean +/- SD]). There was a statistically significant difference in the mean change in AHI between the study groups (P = 0.017). The adjusted odds ratio for having mild OSA was markedly lowered (odds ratio, 0.24 [95% confidence interval, 0.08-0.72]; P = 0.011) in the intervention group. All common symptoms related to OSA, and some features of 15D-Quality of Life improved after the lifestyle intervention. Changes in AHI were strongly associated with changes in weight and waist circumference. CONCLUSIONS: VLCD combined with active lifestyle counseling resulting in marked weight reduction is a feasible and effective treatment for the majority of patients with mild OSA, and the achieved beneficial outcomes are maintained at 1-year follow-up. Article Published Date : Feb 15, 2009

Almonds vs complex carbohydrates in a weight reduction program.

Abstract Title: Almonds vs complex carbohydrates in a weight reduction program. Abstract Source: Int J Obes Relat Metab Disord. 2003 Nov;27(11):1365-72. PMID: 14574348 Abstract Author(s): M A Wien, J M Sabaté, D N Iklé, S E Cole, F R Kandeel Abstract: OBJECTIVE: To evaluate the effect of an almond-enriched (high monounsaturated fat, MUFA) or complex carbohydrate-enriched (high carbohydrate) formula-based low-calorie diet (LCD) on anthropometric, body composition and metabolic parameters in a weight reduction program. DESIGN: A randomized, prospective 24-week trial in a free-living population evaluating two distinct macronutrient interventions on obesity and metabolic syndrome-related parameters during weight reduction. SUBJECTS: In total, 65 overweight and obese adults (age: 27-79 y, body mass index (BMI): 27-55 kg/m(2)). INTERVENTION: A formula-based LCD enriched with 84 g/day of almonds (almond-LCD; 39% total fat, 25% MUFA and 32% carbohydrate as percent of dietary energy) or self-selected complex carbohydrates (CHO-LCD; 18% total fat, 5% MUFA and 53% carbohydrate as percent of dietary energy) featuring equivalent calories and protein. MAIN OUTCOME MEASUREMENTS: Various anthropometric, body composition and metabolic parameters at baseline, during and after 24 weeks of dietary intervention. RESULTS: LCD supplementation with almonds, in contrast to complex carbohydrates, was associated with greater reductions in weight/BMI (-18 vs -11%), waist circumference (WC) (-14 vs -9%), fat mass (FM) (-30 vs -20%), total body water (-8 vs -1%) and systolic blood pressure (-11 vs 0%), P=0.0001-0.05. A 62% greater reduction in weight/BMI, 50% greater reduction in WC and 56% greater reduction in FM were observed in the almond-LCD as compared to the CHO-LCD intervention. Ketone levels increased only in the almond-LCD group (+260 vs 0%, P<0.02). High-density lipoprotein cholesterol (HDL-C) increased in the CHO-LCD group and decreased in the almond-LCD group (+15 vs -6%, P=0.05). Glucose, insulin, diastolic blood pressure, total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C) and LDL-C to HDL-C ratio decreased significantly to a similar extent in both dietary interventions. Homeostasis model analysis of insulin resistance (HOMA-IR) decreased in both study groups over time (almond-LCD: -66% and CHO-LCD: -35%, P<0.0001). Among subjects with type 2 diabetes, diabetes medication reductions were sustained or further reduced in a greater proportion of almond-LCD as compared to CHO-LCD subjects (96 vs 50%, respectively) [correction].  CONCLUSION: Our findings suggest that an almond-enriched LCD improves a preponderance of the abnormalities associated with the metabolic syndrome. Both dietary interventions were effective in decreasing body weight beyond the weight loss observed during long-term pharmacological interventions; however, the almond-LCD group experienced a sustained and greater weight reduction for the duration of the 24-week intervention. Almond supplementation of a formula-based LCD is a novel alternative to self-selected complex carbohydrates and has a potential role in reducing the public health implications of obesity. Article Published Date : Nov 01, 2003
Prev12Next
Therapeutic Actions DIETARY MODIFICATION Low Calorie Diet

NCBI pubmed

Lipid-Lowering Therapy With Ezetimibe Decreases Spontaneous Atherothrombotic Occlusions in a Rabbit Model of Plaque Erosion: A Role of Serum Oxysterols.

Related Articles Lipid-Lowering Therapy With Ezetimibe Decreases Spontaneous Atherothrombotic Occlusions in a Rabbit Model of Plaque Erosion: A Role of Serum Oxysterols. Arterioscler Thromb Vasc Biol. 2018 Feb 15;: Authors: Honda K, Matoba T, Antoku Y, Koga JI, Ichi I, Nakano K, Tsutsui H, Egashira K Abstract OBJECTIVE: Plaque erosion is increasing its importance as one of the mechanisms of acute coronary syndromes in this statin era. However, the clinical efficacy of currently used lipid-lowering agents in the prevention of thrombotic complications associated with plaque erosion has not been clarified. Therefore, we examined the therapeutic effects of ezetimibe or rosuvastatin monotherapy on spontaneous atherothrombotic occlusion. APPROACH AND RESULTS: Femoral arteries of Japanese white rabbits, fed a high-cholesterol diet, were injured by balloon catheter, and then angiotensin II was continuously administrated. In 94% of these arteries, spontaneous thrombotic occlusions were observed after 5 weeks (median) of balloon injury. Histochemical analyses indicated that the injured arteries had similar pathological features to human plaque erosions; (1) spontaneous thrombotic occlusion, (2) lack of endothelial cells, and (3) tissue factor expression in vascular smooth muscle cells. Ezetimibe (1.0 mg/kg per day), but not rosuvastatin (0.6 mg/kg per day), significantly decreased thrombotic occlusion of arteries accompanied with accelerated re-endothelialization and the decreases of serum oxysterols despite the comparable on-treatment serum cholesterol levels. The 7-ketocholesterol inhibited the migration of human umbilical vein endothelial cells. Both 7-ketocholesterol and 27-hydroxycholesterol increased tissue factor expression in cultured rat vascular smooth muscle cells. Tissue factor expression was also induced by serum from vehicle- or rosuvastatin-treated rabbits, but the induction was attenuated with serum from ezetimibe-treated rabbits. CONCLUSIONS: We have established a novel rabbit model of spontaneous atherothromobotic occlusion without plaque rupture that is feasible to test the therapeutic effects of various pharmacotherapies. Ezetimibe may decrease atherothrombotic complications after superficial plaque erosion by reducing serum oxysterols. PMID: 29449331 [PubMed - as supplied by publisher]

Halofuginone dually regulates autophagic flux through nutrient-sensing pathways in colorectal cancer.

Related Articles Halofuginone dually regulates autophagic flux through nutrient-sensing pathways in colorectal cancer. Cell Death Dis. 2017 May 11;8(5):e2789 Authors: Chen GQ, Gong RH, Yang DJ, Zhang G, Lu AP, Yan SC, Lin SH, Bian ZX Abstract Autophagy has a key role in metabolism and impacts on tumorigenesis. Our previous study found that halofuginone (HF) exerts anticancer activity in colorectal cancer (CRC) by downregulating Akt/mTORC1 (mechanistic target of rapamycin complex 1) signaling pathway. But whether and how HF regulates autophagy and metabolism to inhibit cancer growth remains an open question. Here, we unveil that HF activates ULK1 by downregulation of its phosphorylation site at Ser757 through Akt/mTORC1 signaling pathway, resulting in induction of autophagic flux under nutrient-rich condition. On the other hand, HF inactivates ULK1 by downregulation of its phosphorylation sites at Ser317 and Ser777 through LKB1/AMPK signaling pathway, resulting in autophagic inhibition under nutrient-poor condition. Furthermore, Atg7-dependent autophagosome formation is also induced under nutrient-rich condition or blocked in nutrient-poor environment, respectively, upon HF treatment. More interestingly, we also found that HF inhibits glycolysis under nutrient-rich condition, whereas inhibits gluconeogenesis under nutrient-poor condition in an Atg7-dependent manner, suggesting that autophagy has a pivotal role of glucose metabolism upon HF treatment. Subsequent studies showed that HF treatment retarded tumor growth in xenograft mice fed with either standard chow diet or caloric restriction through dual regulation of autophagy in vivo. Together, HF has a dual role in autophagic modulation depending on nutritional conditions for anti-CRC. PMID: 28492544 [PubMed - indexed for MEDLINE]

Effect of phentermine on weight reduction in a pediatric weight management clinic.

Related Articles Effect of phentermine on weight reduction in a pediatric weight management clinic. Int J Obes (Lond). 2017 Jan;41(1):90-93 Authors: Ryder JR, Kaizer A, Rudser KD, Gross A, Kelly AS, Fox CK Abstract Phentermine is the most widely prescribed obesity medication in adults, yet studies of its use in the pediatric population are limited. We conducted a retrospective chart review of adolescents with obesity treated in a pediatric weight management clinic to examine the weight loss effectiveness of phentermine added to standard of care (SOC) lifestyle modification therapy versus SOC alone. All patients receiving phentermine plus SOC (n=25) were matched with a comparison group receiving only SOC (n=274). Differences at 1, 3 and 6 months were evaluated using generalized estimated equations adjusting for age, sex and baseline body mass index (BMI) and robust variance standard error estimates for confidence intervals and P-values. Phentermine use was associated with a greater percent change in BMI at 1 month (-1.6%; 95% confidence interval (CI): -2.6, -0.6%; P=0.001), 3 months (-2.9%; 95% CI: -4.5, -1.4%; P<0.001) and 6 months (-4.1%; 95% CI: -7.1, -1.0%; P=0.009) compared with SOC alone, with no differences in systolic or diastolic blood pressure between groups. Heart rate was higher at all time-points in the phentermine plus SOC compared with SOC-only group. These data suggest that short-term use of phentermine added to SOC may enhance weight loss in adolescents with obesity in the clinical setting. PMID: 27773937 [PubMed - indexed for MEDLINE]

Weight losses with low-energy formula diets in obese patients with and without type 2 diabetes: systematic review and meta-analysis.

Related Articles Weight losses with low-energy formula diets in obese patients with and without type 2 diabetes: systematic review and meta-analysis. Int J Obes (Lond). 2017 Jan;41(1):96-101 Authors: Leslie WS, Taylor R, Harris L, Lean ME Abstract AIM: To provide a systematic review, of published data, to compare weight losses following very low calorie (<800 kcal per day VLCD) or low-energy liquid-formula (>800 kcal per day LELD) diets, in people with and without type 2 diabetes mellitus (T2DM). METHODS: Systematic electronic searches of Medline (1946-2015) and Embase (1947-2015) to identify published studies using formula total diet replacement diets (VLCD/LELD). Random effects meta-analysis using weighted mean difference (WMD) in body weight between groups (with and without diabetes) as the summary estimate. RESULTS: Final weight loss, in the five included studies, weighted for study sizes, (n=569, mean BMI=35.5-42.6 kg/m2), was not significantly different between participants with and without T2DM: -1.2 kg; 95% CI: -4.1 to 1.6 kg). Rates of weight loss were also similar in the two groups -0.6 kg per week (T2DM) and 0.5 kg per week (no diabetes), and for VLCD (<800 kcal per day) and LELD (>800 kcal per day). CONCLUSIONS: Weight losses with liquid-formula diets are very similar for VLCD and LELD and for obese subjects with or without T2DM. They can potentially achieve new weight loss/ maintenance targets of >15-20% for people with severe and medically complicated obesity. PMID: 27698345 [PubMed - indexed for MEDLINE]

Heat-killed and live Lactobacillus reuteri GMNL-263 exhibit similar effects on improving metabolic functions in high-fat diet-induced obese rats.

Related Articles Heat-killed and live Lactobacillus reuteri GMNL-263 exhibit similar effects on improving metabolic functions in high-fat diet-induced obese rats. Food Funct. 2016 May 18;7(5):2374-88 Authors: Hsieh FC, Lan CC, Huang TY, Chen KW, Chai CY, Chen WT, Fang AH, Chen YH, Wu CS Abstract Our objective was to investigate and compare the effects of heat-killed (HK) and live Lactobacillus reuteri GMNL-263 (Lr263) on insulin resistance and its related complications in high-fat diet (HFD)-induced rats. Male Sprague-Dawley rats were fed with a HFD with either HK or live Lr263 for 12 weeks. The increases in the weight gain, serum glucose, insulin, and lipid profiles in the serum and liver observed in the HFD group were significantly reduced after HK or live Lr263 administration. Feeding HK or live Lr263 reversed the decreased number of probiotic bacteria and increased the number of pathogenic bacteria induced by high-fat treatment. The decreased intestinal barrier in the HFD group was markedly reversed by HK or live Lr263 treatments. The elevations of pro-inflammatory associated gene expressions in both adipose and hepatic tissues by high-fat administration were markedly decreased by HK or live Lr263 treatments. The increased macrophage infiltration noticed in adipose tissue after high-fat treatment was effectively suppressed by HK or live Lr263 consumption. The insulin resistance associated gene expressions in both adipose and hepatic tissues, which were downregulated in the HFD group, were markedly enhanced after HK or live Lr263 administration. HK or live Lr263 consumption significantly decreased hepatic lipogenic gene expressions stimulated by high-fat treatment. Administration of HK or live Lr263 significantly reduced hepatic oil red O staining and ameliorated the hepatic steatosis observed in high-fat treated rats. Our data suggested that similar to live Lr263, HK Lr263 exerted significant effects on attenuating obesity-induced metabolic abnormalities by reducing insulin resistance and hepatic steatosis formation. PMID: 27163114 [PubMed - indexed for MEDLINE]

Black tea polyphenols and polysaccharides improve body composition, increase fecal fatty acid, and regulate fat metabolism in high-fat diet-induced obese rats.

Related Articles Black tea polyphenols and polysaccharides improve body composition, increase fecal fatty acid, and regulate fat metabolism in high-fat diet-induced obese rats. Food Funct. 2016 May 18;7(5):2469-78 Authors: Wu T, Guo Y, Liu R, Wang K, Zhang M Abstract With the current changes in diet and living habits, obesity has become a global health problem. Thus, the weight-reducing function of tea has attracted considerable attention. This study investigated the anti-obesity effect and the mechanism of black tea (BT) polyphenols and polysaccharides in male Sprague-Dawley rats. The BT polyphenols and polysaccharides reduced the body weight, Lee's index, visceral fat weight, and fat cell size but improved the biochemical profile and increased the fecal fatty acid content, thereby preventing high-fat diet-induced obesity. A gene expression profile array was used to screen eight upregulated and five downregulated differentially expressed genes that affect fat metabolic pathways, such as glycerolipid and glycerophospholipid metabolism, fatty acid degradation, glycolysis and gluconeogenesis, bile and pancreatic secretion, the insulin signaling pathway, and steroid hormone secretion. The BT polyphenols and polysaccharides suppressed the formation and accumulation of fat and promoted its decomposition to prevent obesity. PMID: 27161951 [PubMed - indexed for MEDLINE]

Anthocyanins in obesity-associated thrombogenesis: a review of the potential mechanism of action.

Related Articles Anthocyanins in obesity-associated thrombogenesis: a review of the potential mechanism of action. Food Funct. 2016 May 18;7(5):2169-78 Authors: Thompson K, Pederick W, Santhakumar AB Abstract Platelet dysfunction, oxidative stress and dyslipidemia are important contributors to pro-thrombotic progression particularly in obese and hyper-cholesterolemic populations. Becoming an increasingly widespread endemic, obesity causes a dysfunction in the metabolic system by initiating endothelial dysfunction; increasing free radical production; lipid peroxidation; platelet hyperactivity and aggregation; thereby accelerating thrombogenesis. In the event of increased free radical generation under pro-thrombotic conditions, antioxidants act as scavengers in reducing physiological oxidative stress; free radical-mediated thrombosis and hemostatic function. Anthocyanin, a subclass of the polyphenol family flavonoids has been shown to exhibit anti-dyslipidemic and anti-thrombotic properties by virtue of its antioxidant activity. Current anti-platelet/coagulant therapeutics target specific receptor pathways to relieve the extent of dysfunction and plaque acceleration in pro-thrombotic individuals. Though effective, they have been associated with high bleeding risk and increased response variability. The following review focuses on the potential role of natural dietary anthocyanins in targeting simultaneous mechanistic pathways in alleviating platelet activation, dyslipidemia, and oxidative stress-associated thrombus acceleration in obese pro-thrombotic populations. PMID: 27043127 [PubMed - indexed for MEDLINE]