Friday, April 25, 2014

Weight loss in Herbs and Foods points of view

The prevalence of extreme overweight and obesity has caused concerns of scientific community in the South East Asian population, due unhealthy diet and life style change over 2 decades of economic prosperity. Overweight and obesity have reached epidemic proportions in many Asian countries, affecting even younger age than in Western populations with economic burden in the development of  obesity-related disorders such as diabetes, hypertension, and cardiovascular diseases(1).  One of six Malaysian are either extreme overweight or obese, according to Datin Paduka Santha Kumari, chairman of the Selangor branch of the Malaysian Diabetes Association and  according to global health observatory, at least 2.8 million people die each year as a result of being overweight or obese, and an estimated 35.8 million (2.3%) of global DALYs are caused by overweight or obesity, worldwide(2).
Epidemiological studies, linking herbal medicine, foods and vitamins in preventing and treating these diseases have been inconclusive(a)
Some researchers suggested that intake of certain herbal medicine may enhance appetite suppression. According to the Georgetown University Medical Center, average daily food intake was decreased only with the herbal formulation, not the phenylpropanolamine (PPA) at the low and high doses, in comparison of the effectiveness among herbal formulation and a commonly available(3). Other researchers insisted that using herbs and supplements to induce weight loss should be taken with care, as a  considerable number of reports have been published on hepatotoxicity associated with herbal products attributed with weight-reducing properties(4)(5)(6)(7). the College of Medicine, The Ohio State University insisted that various dietary, lifestyle, and psychologic factors are involved in the etiology of Prameha, particularly in relation to disturbances in fat and carbohydrate metabolism(8), without effective management, obtaining a workable weight loss plan may be extremely difficult.
A. Weight loss in herbs points of view
1. Ephera (Ma Huang)
Ma Huang is also known as ephedra. The acrid, slightly bitter and warm herb has been used in TCM to promote urination and sweating, and rid of cold,  sooth wheezing asthma, etc. as it calms dyspnea,  asthma, cough, etc., by enhancing the functions of lung and bladder channels(9)
Ephedra sinica, the Chinese herb may be effective in induced weigh loss. According to the Dongguk University, certain chemicals found in Ephera showed an association with changes of BW and BMI through alteration of gut microbiota varied by indigenous microbiota of each subject(10). The combined study of a low-calorie diet and Ephera, in 125 otherwise healthy obese women, showed  effective in reducing BMI. RMR change was not compensated for by the herbal medicines tried. resting metabolic rate (RMR) change seemed to be affected by constitution and body composition rather than by medicine(11). The Dongeui University study of composition GGEx18( Laminaria japonica, Rheum palmatum, and Ephedra sinica) in high fat diet-induced obese mice suggested that GGEx18 improves obesity through skeletal muscle AMPK and AMPK-stimulated expression of PPARα and its target enzymes for fatty acid oxidation, through inhibited lipid accumulation, and similar activation of genes(12).
Please note that  due to its  adverse reactions of palpitations, stress, headache and insomnia and stroke, heart attacks, cardiac arrhythmias, seizures and psychotic,  the Dutch Inspectorate for Health Care and the Ministry of Health in Canada have recently requested a market recall of some ephedrine-containing herbal products in response to above adverse reactions reported in association with these products. In the Netherlands, the status of Ephedra-containing products is currently reconsidered(13).

2. Ginseng
Ginseng is a slow-growing perennial plants with fleshy roots, the genus Panax, belonging to the family Araliaceae. Depending to the climate where it grows, ginseng can be classified mainly into Panax ginseng Asian ginseng (root), Red ginseng, wild ginseng, American ginseng (root)(14).
In 10 obese middle-aged Korean women took Panax ginseng extracts for 8 wk, ginseng showed to be effective in influence on gut microbiota in promoting weigh loss but depending to the composition of gut microbiota prior to ginseng intake(15). In mice fed on a high-fat diet, ginseng saponin and ginsenosides not only exerted anti-obesity effects via the modulation of physiological lipid metabolism in vivo or intracellular signalling in cell culture systems, but also promoted anti-obesity effects, through abnormal physiology via HFD. Leptin, insulin, and adiponectin, which carry out critical functions in energy and lipid metabolism(16).

3. Zingiber Officinale(Ginger
Ginger (Zingiber officinale) or ginger root is the genus Zingiber, belonging to the family Zingiberaceae, native to Tamil. It has been used in traditional and Chinese medicine to treat dyspepsia, gastroparesis, constipation, edema, difficult urination, colic, etc.(17).
According to the Tehran University of Medical Sciences, Slimax (extract of several plants including Zingiber officinale and Bofutsushosan) showed a significant decrease in body weight or inhibition of weight gain(18). The composition of multi-ingredient supplement containing primarily raspberry ketone, caffeine, capsaicin, garlic, ginger and Citrus aurantium, also found the improvements in body composition, waist and hip girth, in an eight-week diet and exercise weight loss program(19). In a comparison of the weight loss effect of Orlistat, a pharmacological agent promoting weight loss and ginger (Zingiber officinale Roscoe, Zingiberacae) in male albino rats, researchers at the Ain Shams University Cairo, found that ginger has a great ability to reduce body weight without inhibiting pancreatic lipase level, or affecting bilirubin concentration, with positive effect on increasing peroxisomal catalase level and HDL-cholesterol(20).

4. Cissus quadrangularis (CQ)
Cissus quadrangularis is an ancient herb used to treat a variety of indications, belonging to the grape family, probably native to India or Sri Lanka. A randomized, double-blind, placebo-controlled design involving 123 overweight and obese persons (47.2% male; 52.8% female; ages 19-50). conducted by University of Yaoundé I, the herb showed a statistically significant net reductions in weight and central obesity, as well as causes of metabolic syndrome(21). In comparison of the effectiveness of Cissus quadrangularis-only and a Cissus quadrangularis/Irvingia gabonensis combination, on weight loss in overweight and obese human subjects, Cissus quadrangularis-only group showed significant reductions on all variables compared to the placebo group, the Cissus quadrangularis/Irvingia gabonensis combination resulted in even larger reductions(22). CQR-300, a proprietary extract of Cissus quadrangularis, also showed a significant reductions in weight and blood glucose levels, while decreasing serum lipids thus improving cardiovascular risk factors, according to the University of Yaoundé I,(23).

5. Sambucus nigra
Elder also known as Common Elder, is a shrub or small tree of the genus Sambucus of 30 specie, belonging to the family Adoxaceae, native to the temperate-to-subtropical regions of both the Northern Hemisphere and the Southern Hemisphere.The herb has been used in traditional and herbal medicine to treat constipation, colic, diarrhea, colds, flu, bronchial and upper-respiratory, irritation of the skin, rheumatism, etc.
In a composition of supplement with Sambucus nigra and Asparagus officinalis study, showed an effectiveness in reduced weight, blood pressure, enhanced physical and emotional well-being and the quality of life had significantly improved (ITT analysis)(24). In Tehran University of Medical Sciences, Sambucus nigra, showed a significant decrease in body weight in numbers of animal studies(25).

6. Asparagus officinalis
Asparagus is a flowering plant belong to species the genus Asparagus, native to the western coasts of northern Spain, north to Ireland, Great Britain, and northwest Germany, northern Africa and western Asia. Asparagus has been used from early times as a vegetable and medicine, because of its delicate flavour and diuretic properties(26). Asparagus officinalis L. powder tablets provided 19 mg saponins per day study showed an effectiveness of the tablets in reduced mean weight, blood pressure, and ebhanced physical and emotional well-being and the quality of life with the rate of very good or good by most of the completers(27). In 12 weeks supplementation of a botanical extract-based weight loss formula, including Asparagus, researchers at the Poznan University of Medical Science, indicated a significantly change of the Body Composition Improvement Index (BCI), induce greater weight loss than placebo, probably through a concurrently performed exercise program--a recommended strategy for life style modification(28).

7. Slimax
Slimax (extract of several plants including Zingiber officinale and Bofutsushosan), in the reviews of the data base of studies published, showed a significant decrease in body weight. In 41 animal studies, the formaula was found to be effective in significant induced weight loss or inhibited of weight gain(29).

B. Weight loss in foods points of view
Epidemiological studies, linking certain foods in reduced weight loss for obese individual have produced certain positive results, but researchers emphasized that weight loss can not be in the expenses of intake of nutrients(30a).
1. Oats
Oat is a species of cereal grain grown for its seed and was first cultivated in Europe but is now grown all over the world, especially in Scotland and England. It is one of good crop to plant in the poor soil after crops are harvested in the Fall(30).
Oat, rich in beta-glucan, may hold a magic power in regulation of  metabolism and liver-protecting effect. According to Chung-Shan Medical University, consumption of oat reduced obesity, abdominal fat, and improved lipid profiles and liver functions with no adverse effects(31). Whole-grain ready-to-eat oat cereal, in a randomized study of 144 Free-living, overweight and obese adults (N=204, body mass index 25 to 45) with baseline LDL cholesterol levels 130 to 200 mg/dL, had favorable effects on fasting lipid levels and waist circumference(32). Other study suggested that at-derived beta-glucan, combined with moderate exercise also improved lipid profile and caused a decrease in weight(33).

2. Salmon
Salmon is the common name for Salmonidae. They are anadromous, born in fresh water, migrate to the ocean, then travel thousands of miles in the deep sea cold water throughout their life cycle and within to five years returning to the exacted location where they were born to reproduce and die(34).
Dietary salmon oil, in rat study showed to reduced weight loss of CXB-E and -H tested mice, but induced with weight gain in recombinant inbred strains. This findings may suggested that body weight response to salmon oil feeding is controlled by multiple genes(35). A novel oral form of salmon calcitonin (sCT), according to the study at 1Nordic Bioscience, also showed to improve fasting and postprandial glycemic control and insulin sensitivity and may be considered as a promising agent for the treatment of obesity-related insulin resistance and type 2 diabetes patients(36)(37).

3. Brown rice
Brown rice or unpolished rice is a kind of whole, natural grain with very brown color of which only the outermost layer of the rice kernel are removed, thus preventing the lost of nutrients(38).
The study of the weigh effect of brown rice on metabolic parameters in type 2 diabetes, showed a positive effect of consumption of the brown rice (LB)  in association with a decreased waist circumference in type 2 diabetic patients(39). Other randomized study of forty women between 20 and 35 years of age in the comparison of white rice and mixed rice of weight control, including brown rice, indicated that meal replacement with mixed rice was superior to replacement with white rice in weight control, improving antioxidant enzyme activity(40).

4. Chicken
Chicken are domesticated fowl belonging to the subspecies of Gallus domesticus and is raised all over the world for its delicious meats and eggs. It can be roasted, broiled, grilled or poached into a very delicious, tasteful and nutritious meal(41).
In the comparison of weight loss and total lipid profile changes in overweight women consuming beef or chicken, researchers at 1Rippe Lifestyle Institute, Shrewsbury showed a interest result of weight loss and improved lipid profile can be accomplished through diet and exercise, regardless to dietary protein source including lean beef or chicken(42). But the study at University of Navarra, showed a opposite result in the study of frequent consumption of selenium-enriched chicken meat(43), it may be the result of the presence of antioxidant selenium in the meat.

5. Water
According to Virginia Tech, consuming 500 ml water prior to each main meal may lead to greater weight loss than a hypocaloric diet alone in middle-aged and older adults, because of it acutely reduces meal energy intake(EI)(44) but not younger subjects(45). The Choose Healthy Options Consciously Everyday (CHOICE) randomized clinical trial, suggested that replacing caloric beverages with water or diet beverages induced 2% to 2.5% weight loss(46).

6. Nuts
Dietary consumption of nuts with  rich sources of multiple nutrients is associated with health benefits and weight loss,epidemiologically.  but in well-controlled nut-feeding trials, no changes in body weight were observed(47). Pistachio nuts, a member of the cashew family, can be consumed as a portion-controlled snack for individuals restricting calories to lose weight without concern that pistachios will cause weight gain(48).


7. Green tea
Green tea contains more amount of antioxidants than any drinks or food with the same volume, and is the leaves of Camellia sinensis, undergone minimal oxidation during processing, originated from China. Green tea has been a precious drink in traditional Chinese culture and used exceptional in socialization for more than 4000 thousand years. Because of their health benefits, they have been cultivated for commercial purposes all over the world.
According to Maastricht University, caffeine intake and green tea supplementation are associated to improved weight maintenance, partly through thermogenesis and fat oxidation, in a randomized placebo-controlled double blind parallel trial in 76 overweight and moderately obese subjects(49). Catechins the antioxiands found abundantly in green tea, significantly decreased body weight and significantly maintained body weight after a period of weight loss, depending to the moderators of habitual caffeine intake and ethnicity(50). In a high-protein diet, green tea-caffeine mixture, failed to exert the same effect on body weight maintenance(51).

8. Coffee
Coffee made from the roasted seeds of the genus Coffee, belonging to the family Rubiaceae native to southern Arabia. Coffee may consist certain substances.
In a randomized, double-blind, placebo-controlled, linear dose, crossover study, green coffee extract, consistent with human and animal studies and a meta-analysis may be an effective nutraceutical in reducing weight in preobese adults(52). Mannooligosaccharides (MOS), extracted from coffee, exhibited a potential functional use for weight management and improvement in adipose tissue distribution, but varying in gender(53)
Unfortunately, green coffee extract (GCE), according to University of Exeter, in reviews of the effect against weight loss of existed data, showed a significant poor methodological quality and suggested that more rigorous trials are needed to assess the usefulness of GCE as a weight loss tool(54). Other study, reported a case of Brazil Potent Slimming Coffee and possibly also other weight-loss products may be contaminated with sibutramine and as a result cause severe adverse reactions after stabbing herself in the stomach with a knife(55).

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References
(1) Rising Burden of Obesity in Asia by Ambady Ramachandran and Chamukuttan Snehalatha(Journey of Obesity)
(2) Obesity - Situation and trends(WHO)
(3) Influence of a combination of herbs on appetite suppression and weight loss in rats by Talpur NA1, Echard BW, Manohar V, Preuss HG.(PubMed)
(4) [Hepatotoxicity induced by herbs and medicines used to induce weight loss].[Article in Spanish]by Herrera S1, Bruguera M.(PubMed)
(5) A case report of adult lead toxicity following use of Ayurvedic herbal medication by Breeher L1, Gerr F, Fuortes L.(PubMed)
(6) [Chronic lead intoxication associated with Ayurvedic medication].[Article in Dutch] by Kanen BL1, Perenboom RM.(PubMed)
(7) Potential toxicity of caffeine when used as a dietary supplement for weight loss by Pendleton M1, Brown S, Thomas C, Odle B.(PubMed)
(8) Multinutrient supplement containing ephedra and caffeine causes weight loss and improves metabolic risk factors in obese women: a randomized controlled trial by Hackman RM1, Havel PJ, Schwartz HJ, Rutledge JC, Watnik MR, Noceti EM, Stohs SJ, Stern JS, Keen CL.(PubMed)
(9) Ma Huang(Popular Chinese herbs)
(10) Prameha in Ayurveda: correlation with obesity, metabolic syndrome, and diabetes mellitus. Part 2--management of Prameha by Sharma H1, Chandola HM.(PubMed)
(11) Effect of herbal Ephedra sinica and Evodia rutaecarpa on body composition and resting metabolic rate: a randomized, double-blind clinical trial in Korean premenopausal women by Kim HJ1, Park JM, Kim JA, Ko BP(PubMed)
(12) The herbal composition GGEx18 from Laminaria japonica, Rheum palmatum, and Ephedra sinica reduces obesity via skeletal muscle AMPK and PPARα by Shin SS1, Park D, Lee HY, Hong Y, Choi J, Oh J, Lee H, Lee HR, Kim MR, Shen ZB, Cui HH, Yoon M.(PubMed)
(13) [Ephedrine and ephedra in weight loss products and other preparations].[Article in Dutch] by van der Hooft CS1, Stricker BH.(PubMed)
(14) Ginseng, Asian (Panax ginseng) and Ginseng, North America(Popular Chinese Herbs)
(15) Influence of Panax ginseng on obesity and gut microbiota in obese middle-aged Korean women by Song MY1, Kim BS2, Kim H(PubMed)
(16) Lipid metabolic effect of Korean red ginseng extract in mice fed on a high-fat diet by Song YB1, An YR, Kim SJ, Park HW, Jung JW, Kyung JS, Hwang SY, Kim YS.(PubMed)
(17) Popular #Herbs - #Ginger (Zingiber officinale)(Popular Chinese herbs)
(18) A systematic review of the efficacy and safety of herbal medicines used in the treatment of obesity by Hasani-Ranjbar S1, Nayebi N, Larijani B, Abdollahi M.(PubMed)
(19) Eight weeks of supplementation with a multi-ingredient weight loss product enhances body composition, reduces hip and waist girth, and increases energy levels in overweight men and women by Lopez HL1, Ziegenfuss TN, Hofheins JE, Habowski SM, Arent SM, Weir JP, Ferrando AA.(PubMed)
(20) Comparative evaluation of the efficacy of ginger and orlistat on obesity management, pancreatic lipase and liver peroxisomal catalase enzyme in male albino rats by Mahmoud RH1, Elnour WA.(PubMed)
(21) The use of a Cissus quadrangularis formulation in the management of weight loss and metabolic syndrome by Oben J1, Kuate D, Agbor G, Momo C, Talla X.(PubMed)
(22) The use of a Cissus quadrangularis/Irvingia gabonensis combination in the management of weight loss: a double-blind placebo-controlled study. by Oben JE1, Ngondi JL, Momo CN, Agbor GA, Sobgui CS.(PubMed)
(23) The effect of Cissus quadrangularis (CQR-300) and a Cissus formulation (CORE) on obesity and obesity-induced oxidative stress by Oben JE1, Enyegue DM, Fomekong GI, Soukontoua YB, Agbor GA.(PubMed)
(24) An observational study and quantification of the actives in a supplement with Sambucus nigra and Asparagus officinalis used for weight reduction by Chrubasik C1, Maier T, Dawid C, Torda T, Schieber A, Hofmann T, Chrubasik S.(PubMed)
(25) A systematic review of the efficacy and safety of herbal medicines used in the treatment of obesity by Hasani-Ranjbar S1, Nayebi N, Larijani B, Abdollahi M(PubMed)
(26) #Healthy #Foods - Vegetables - Asparagus (Asparagus officinalis)(health tips for better living and living health)
(27) An observational study and quantification of the actives in a supplement with Sambucus nigra and Asparagus officinalis used for weight reduction by Chrubasik C1, Maier T, Dawid C, Torda T, Schieber A, Hofmann T, Chrubasik S.(PubMed)
(28) Efficacy of 12 weeks supplementation of a botanical extract-based weight loss formula on body weight, body composition and blood chemistry in healthy, overweight subjects--a randomised double-blind placebo-controlled clinical trial by Opala T1, Rzymski P, Pischel I, Wilczak M, Wozniak J.(PubMed)
(29) A systematic review of the efficacy and safety of herbal medicines used in the treatment of obesity by Hasani-Ranjbar S1, Nayebi N, Larijani B, Abdollahi M.(PubMed)
(30) #Healthy #Foods - Oats ((Avena sativa) (Health tips for better living and living health)
(31a) Association between mood and diet quality in subjects with metabolic syndrome participating in a behavioural weight-loss programme: A cross-sectional assessment by Perez-Cornago A, Zulet MA, Martinez JA.(PubMed)
(31b) Dietary quality-adherence to the dietary guidelines in Tehranian adolescents: Tehran Lipid and Glucose Study by Mirmiran P1, Azadbakht L, Azizi F.(PubMed)
(31) Oat prevents obesity and abdominal fat distribution, and improves liver function in humans by Chang HC1, Huang CN, Yeh DM, Wang SJ, Peng CH, Wang CJ.(PubMed)
(32) Whole-grain ready-to-eat oat cereal, as part of a dietary program for weight loss, reduces low-density lipoprotein cholesterol in adults with overweight and obesity more than a dietary program including low-fiber control foods by Maki KC1, Beiseigel JM, Jonnalagadda SS, Gugger CK, Reeves MS, Farmer MV, Kaden VN, Rains TM.(PubMed)
(33) Oat-derived beta-glucan significantly improves HDLC and diminishes LDLC and non-HDL cholesterol in overweight individuals with mild hypercholesterolemia, Reyna-Villasmil N1, Bermúdez-Pirela V, Mengual-Moreno E, Arias N, Cano-Ponce C, Leal-Gonzalez E, Souki A, Inglett GE, Israili ZH, Hernández-Hernández R, Valasco M, Arraiz N.(PubMed)
(34) #Healthy #Foods - Seafoods - Salmon (Healthy tips for better living and living health)
(35) Genetically determined body weight loss in mice fed diets containing salmon oil by LeBoeuf RC1, Veldee MS.(PubMed)
(36) Oral salmon calcitonin improves fasting and postprandial glycemic control in lean healthy rats by Feigh M1, Nielsen RH, Hansen C, Henriksen K, Christiansen C, Karsdal MA.(PubMed)
(37) A novel oral form of salmon calcitonin improves glucose homeostasis and reduces body weight in diet-induced obese rats by Feigh M1, Henriksen K, Andreassen KV, Hansen C, Henriksen JE, Beck-Nielsen H, Christiansen C, Karsdal MA.(PubMed)
(38) #Healthy #Foods - Whole Grain - Brown rice or Hulled rice's(Health tips for beter living and living health)
(39) Intake of brown rice lees reduces waist circumference and improves metabolic parameters in type 2 diabetes by Kim TH1, Kim EK, Lee MS, Lee HK, Hwang WS, Choe SJ, Kim TY, Han SJ, Kim HJ, Kim DJ, Lee KW.(PubMed)
(40) Meal replacement with mixed rice is more effective than white rice in weight control, while improving antioxidant enzyme activity in obese women by Kim JY1, Kim JH, Lee da H, Kim SH, Lee SS.(PubMed)
(41) #Healthy #Foods - Chicken (Gallus gallus domesticus)(Health tips for btter living and living health)
(42) Weight loss and total lipid profile changes in overweight women consuming beef or chicken as the primary protein source by Melanson K1, Gootman J, Myrdal A, Kline G, Rippe JM.(PubMed)
(43) Frequent consumption of selenium-enriched chicken meat by adults causes weight loss and maintains their antioxidant status by Navas-Carretero S1, Cuervo M, Abete I, Zulet MA, Martínez JA.(PubMed)
(44) Water consumption increases weight loss during a hypocaloric diet intervention in middle-aged and older adults by Dennis EA1, Dengo AL, Comber DL, Flack KD, Savla J, Davy KP, Davy BM(PubMed)
(45) Pre-meal water consumption reduces meal energy intake in older but not younger subjects by
Van Walleghen EL1, Orr JS, Gentile CL, Davy BM.(PubMed)
(46) Replacing caloric beverages with water or diet beverages for weight loss in adults: main results of the Choose Healthy Options Consciously Everyday (CHOICE) randomized clinical trial by  Tate DF1, Turner-McGrievy G, Lyons E, Stevens J, Erickson K, Polzien K, Diamond M, Wang X, Popkin B.(PubMed)
(47) Nut consumption and body weight by Sabaté J.(PubMed)
(48) Pistachio nuts reduce triglycerides and body weight by comparison to refined carbohydrate snack in obese subjects on a 12-week weight loss program by Li Z1, Song R, Nguyen C, Zerlin A, Karp H, Naowamondhol K, Thames G, Gao K, Li L, Tseng CH, Henning SM, Heber(PubMed)
(48) Impact of peanuts and tree nuts on body weight and healthy weight loss in adults by Mattes RD1, Kris-Etherton PM, Foster GD.(PubMed)
(49) Body weight loss and weight maintenance in relation to habitual caffeine intake and green tea supplementation by Westerterp-Plantenga MS1, Lejeune MP, Kovacs EM.(PubMed)
(50) The effects of green tea on weight loss and weight maintenance: a meta-analysis by Hursel R1, Viechtbauer W, Westerterp-Plantenga MS.(PubMed)
(51) Green tea catechin plus caffeine supplementation to a high-protein diet has no additional effect on body weight maintenance after weight loss by Hursel R1, Westerterp-Plantenga MS.(PubMed)
(52) Randomized, double-blind, placebo-controlled, linear dose, crossover study to evaluate the efficacy and safety of a green coffee bean extract in overweight subjects by Vinson JA1, Burnham BR, Nagendran MV.(PubMed)
(53) A weight-loss diet including coffee-derived mannooligosaccharides enhances adipose tissue loss in overweight men but not women, by St-Onge MP1, Salinardi T, Herron-Rubin K, Black RM.(PubMed)
(54) The use of green coffee extract as a weight loss supplement: a systematic review and meta-analysis of randomised clinical trials by Onakpoya I1, Terry R, Ernst E.(PubMed)
(55) [Life-threatening psychosis caused by using sibutramine-contaminated weight-loss coffee].
[Article in Dutch] by Bertholee D1, ter Horst PG, Wieringa A, Smit JP.(PubMed)

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