Nutrition Updates


Wildman RP, Muntner P, Reynolds K, McGinn AP, Rajpathak S, Wylie-Rosett J, and Sowers MR. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999–2004). Arch Intern Med. 2008;168:1617–1624.

Obesity is commonly described as a risk factor for cardiovascular and metabolic abnormalities. However, many individuals who are overweight or obese do not display cardiovascular or metabolic impairments leading to the proposal of a “fat and fit” phenotype, also described as “uncomplicated obesity”. While overweight and obesity is highly prevalent in the US population, relative proportions of obese and metabolically healthy individuals versus unhealthy obese individuals have not been characterized. Likewise, distributions of normal-weight and metabolically unhealthy versus normal-weight and healthy individuals have not been described. In the present epidemiological analysis, Wildman et al. report on the prevalence of cardiometabolically abnormal normal-weight individuals and cardiometabolically healthy obese individuals in the United States.

Physiological measures for 5440 participants aged 20 years and older (45% male) were obtained from the National Health and Nutrition Examination Survey (NHANES) 1999–2004 dataset and were extrapolated to be representative of the US population. Normal weight was defined as a BMI of <25.0, overweight was defined as a BMI between 25.0 and 29.9, and obese was defined as a BMI over 30.0. A scale for metabolic health was determined from elevated blood pressure, elevated triglycerides, elevated fasting blood glucose, insulin resistance, and high-sensitivity C-reactive protein levels (systemic inflammation levels). The presence of less than two cardiometabolic abnormalities was defined as “metabolically healthy” and two or more cardiometabolic abnormalities was defined as “metabolically abnormal”. Thus, the present categorizations allowed for six phenotypes to be described, ranging from normal-weight and metabolically healthy to obese and metabolically unhealthy. According to the present analysis, ∼29% of obese men and ∼35% of obese women are metabolically normal – reflected as approximately 19.5 million adults over the age of 20 years. Prevalence of metabolically abnormal individuals was estimated to be ∼30% in normal-weight men and ∼21% in normal-weight women. In normal-weight people, higher waist circumference, greater age, and smoking were associated with metabolic abnormalities, whereas in obese people, younger age, race/ethnicity, and physical activity were associated with fewer cardiometabolic abnormalities. The present analysis shows a large prevalence of both normal-weight metabolically abnormal individuals and overweight/obese metabolically normal individuals in the US population.

Comment: Dr. Landsberg comments that the findings reported in the Wildman et al. study focus on risk factors rather than endpoints. This study, and another in the same issue of the archives, further emphasizes the importance of visceral adiposity in the assessment of cardiovascular and metabolic risk factors in individuals at all weight ranges.

Comment: Landsberg L. Body fat distribution and cardiovascular risk: a tale of 2 sites. Arch Intern Med. 2008; 168:1607–1608.


Winkels RM, Brouwer IA, Clarke R, Katan MB, and Verhoef P. Bread cofortified with folic acid and vitamin B-12 improves the folate and vitamin B-12 status of healthy older people: a randomized controlled trial. Am J Clin Nutr. 2008;88:348–355.

Mandatory folic acid fortification of flour was initiated in the United States in the late 1990s to reduce the risk of neural tube defects. However, fortification has come under scrutiny due to the possibility that high levels of folic acid intake reverse pernicious anemia associated with vitamin B12 deficiency but can also delay diagnosis of B12 deficiency. Long-term B12 deficiency is linked with neuropathy, and B12 deficiency is a special problem in the elderly, who may have reduced capacity to absorb the vitamin. Partially as a result of this possibility of harm, other areas of the world, including parts of Europe, have yet to implement folic acid fortification. The present study by Winkels et al. examines the efficacy of bread fortified with both folic acid and vitamin B12 for improving serum levels of these vitamins in healthy older individuals dwelling in a region of no fortification (the Netherlands).

One hundred and forty-three participants (39% male) between the ages of 50 and 75 years were randomly assigned to receive either fortified bread (folic acid: 33 µg/slice; vitamin B12: 2 µg/slice; n = 72) or placebo bread (unfortified; n = 70). Participants were instructed to consume at least three slices of the bread per day for 12 weeks, with the goal of increasing intake of folic acid by 100 µg/d and B12 by 6 µg/d. Blood samples were collected at baseline and after 12 weeks of bread consumption. The placebo and fortified bread groups did not differ with respect to bread intake, with each consuming around 4.5 slices of bread per day. Intake of the fortified bread was associated with a mean daily additional intake of ∼136 µg folic acid and ∼9.6 µg vitamin B12. Daily consumption of the fortified bread was associated with increased serum folate concentrations and vitamin B12 concentrations relative to the beginning of the study and relative to the placebo condition. Additionally, the proportion of participants who were marginally B12 deficient was decreased from 8% to 0%. The authors indicate that cofortification with folic acid and vitamin B12 will improve vitamin status in older individuals, and would be of particular benefit for those with B12 insufficiency.

Comment: Drs. Refsum and Smith in an accompanying editorial pose many of the common questions and concerns with population-wide fortification with nutrients. While fortification with folic acid was, at the outset, widely anticipated to reduce neural tube defects and to produce benefits with respect to cardiovascular disease, there is a possibility that such fortification may also lead to harm in high doses. Low B12 status in the presence of high folate status is linked with memory impairment and anemia. Other evidence shows that a balance between vitamin B12 given in combination with folic acid may be beneficial in improving cognition and in the prevention of breast cancer. However, even in light of such observations, the burden is upon governing bodies to ensure that the safety and efficacy of B12 fortification has been thoroughly investigated prior to any steps being taken toward wide-scale fortification.

Comment: Refsum H and Smith AD. Are we ready for mandatory fortification with vitamin B-12? Am J Clin Nutr. 2008;88:253–254.


Widenhorn-Müller K, Hille K, Klenk J, and Weiland U. Influence of having breakfast on cognitive performance and mood in 13- to 20-year-old high school students: results of a crossover trial. Pediatrics. 2008;122:279–284.

Intake of breakfast is widely presumed to benefit cognitive performance in young people. The effects of breakfast may be related to elevations in blood glucose levels, which have been suppressed after an overnight fast. Many studies have shown that breakfast improves cognition relative to a no-breakfast condition. Moreover, breakfasts that provide a more sustained release of blood glucose (low glycemic index) tend to have a more profound benefit on cognitive performance relative to high-glycemic breakfasts. Widenhorn-Müller et al. recruited 104 (54 male) boarding school students between the ages of 13 and 20 years. Participants were randomized into two conditions (breakfast first session; breakfast second session) and were tested twice according to a crossover design – once after having eaten breakfast and once after having no breakfast. Breakfasts consisted of 60 g whole-wheat bread, 20 g butter, 20 g sweetened nougat spread, and 30 g of jam. All breakfasts were consumed between 07:30 and 08:00, and cognitive testing ran from 08:15 to 10:15. Cognitive assessments included measures for sustained attention, learning and memory, and mood.

Breakfast intake resulted in greater self-reported alertness for all participants. Males showed better visuospatial memory performance relative to no breakfast and also reported more positive feelings after breakfast. Females did not show similar improvements following the meal. This study captures a relatively large population for this type of meal research, and the use of a repeated measures design reduces variability in cognitive data. While the finding that breakfast improved some measures of mood and cognition relative to no breakfast is not new, the present study adds novel information regarding breakfast and mental performance between males and females.


Sekikawa A, Curb JD, Ueshima H, El-Saed A, Kadowaki T, Abbott RD, Evans RW, Rodriguez BL, Okamura T, Sutton-Tyrrell K, Nakamura Y, Masaki K, Edmundowicz D, Kashiwagi A, Willcox BJ, Takamiya T, Mitsunami K, Seto TB, Murata K, White RL, Kuller LH; ERA JUMP (Electron-Beam Tomography, Risk Factor Assessment Among Japanese and U.S. Men in the Post-World War II Birth Cohort) Study Group. Marine-derived n-3 fatty acids and atherosclerosis in Japanese, Japanese-American, and white men: a cross-sectional study. J Am Coll Cardiol. 2008;52:417–424.

Epidemiological evidence shows that Japanese men have lower levels of atherosclerosis relative to Caucasian men, despite having higher rates of smoking and similar rates of type 2 diabetes. Japanese men who have moved to the United States have shown increases in coronary heart disease, but rates in Japanese-American men remain lower than for Caucasian men. Recent research indicates that a high intake of marine-derived omega-3 fatty acids may have antiatherogenic effects. As the Japanese are high consumers of fatty fish, Sekikawa et al. propose that high serum levels of marine-derived fatty acids would be associated with lower levels of atherosclerosis in Japanese men relative to Caucasian men residing in the United States. Moreover, they propose that Japanese-American men would have lower rates of atherosclerosis relative to US-dwelling Caucasian men but higher rates than Japanese men.

Nine hundred and twenty-six men aged 40–49 years were recruited from three separate locations. Japanese men (n = 313) were recruited from Kusatsu, Japan, Caucasian men (n = 310) were recruited from Allegheny County, Pennsylvania, and Japanese-American men (n = 303) were recruited from offspring of participants in the Honolulu Heart Program (third- or fourth-generation American; Honolulu, Hawaii). Primary outcome measures included serum fatty acid concentrations, intima-media thickness of the carotid artery, and coronary artery calcification. In the present study, Japanese-born Japanese men had higher or similar levels of cardiovascular risk factors in comparison with those in the other groups, but they had the lowest rates of atherosclerosis and had higher serum levels of marine-derived omega-3 fatty acids relative to Japanese-Americans or Caucasian men. Third- and fourth- generation Japanese-American men had similar rates of atherosclerosis as Caucasian men. Japanese men also had lower rates of obesity than Japanese-American men and Caucasian men. Japanese-American men showed similar rates of obesity as Caucasian men, but they had higher rates of hypertension and diabetes and higher levels of blood glucose and triglycerides than Caucasian men. The authors propose that very high levels of marine-derived omega-3 fatty acids may be protective against atherosclerosis independent of other cardiovascular risk factors in Japanese men, and this may be independent of genetic factors.

Comment: Dr. Harris highlights other populations with high fatty fish intake, including the Inuit and Norwegian people. The Inuit, in particular, are a classic example of the cardioprotective effects of very high omega-3 intake. However, in the Inuit, rates of cardiovascular disease are on the increase, perhaps due, in part, to the introduction of foods high in saturated and trans-fats into the traditional diet. While high levels of omega-3 dietary intake may indeed provide some protection against the development of atherosclerosis, intake of other types of fat, such as saturated fats, may offset these protective effects.

Comment: Harris W. Omega-3 fatty acids: the “Japanese” factor? J Am Coll Cardiol. 2008;52:425–427.


Osika W and Montgomery SM. Physical control and coordination in childhood and adult obesity: longitudinal birth cohort study. BMJ. 2008;33:a699.

Obesity is associated with diabetes, vascular disease, cognitive impairment, and neurological dysfunction in adults. However, some propose that pre-existing poor neurological function may lead to obesity. For example, obese individuals or those with type 2 diabetes showing cognitive impairment may have suffered childhood disruptions in neurological development leading to their adult body mass status. Osika and Montgomery explored the possibility that impaired physical control in childhood might be reflective of later development of obesity using data from the National Child Development Study in Great Britain. The cohort includes everyone born between March 3 and March 8, 1959, with data sampling occurring throughout childhood and into adulthood.

Of participants for whom BMI data was available at age 33, 7990 individuals had data from age 7 relating to teacher reports of physical coordination, and 6875 individuals had data from doctor assessments at age 11. Physical coordination was described in terms of poor hand control, poor coordination, and clumsiness (teacher report) or copying scores, making squares, and picking up matches (doctor assessment). Obesity was defined as an adult BMI of ≥30. All three measures of poor coordination at age 7 were significantly associated with later development of obesity, independent of body mass status at age 7. Worse performance on the copying designs, picking up matches, and making squares tests at age 11 was associated with obesity and independent of body mass status at age 11. The present data suggest a link between childhood neurological function and adult body mass index, with individuals who show poorer performance having greater risk for the development of obesity. The authors acknowledge limitations relating to the analysis, including diet and exercise, socioeconomic factors, and individual differences. One possible factor might suggest that individuals who are less physically coordinated may engage less often in exercise and thus be at risk for overweight. The measures of physical coordination in the present study are only a small indicator of psychomotor function and neurological development; thus, more rigorous measurement of long-term neurological function in relationship to body weight status is needed.


Taddio A, Shah V, Hancock R, Smith RW, Stephens D, Atenafu E, Beyene J, Koren G, Stevens B, and Katz J. Effectiveness of sucrose analgesia in newborns undergoing painful medical procedures. CMAJ 2008;179:37–43.

Sucrose intake can have analgesic properties in infants and adults, and these effects are thought to be mediated by the endogenous opioid system. Single oral loads of sucrose reduce pain in newborns undergoing medical procedures such as heel-lancing and venipuncture, but sucrose's efficacy has not been determined in all procedures to which a neonate is exposed nor have the effects of sucrose in the offspring of diabetic mothers been assessed. Taddio et al. measured the ability of oral loads of sucrose to offset pain from intramuscular injections of vitamin K, venipuncture, and heel lancing in neonates from diabetic and non-diabetic mothers.

Two hundred and forty infants (120 from diabetic mothers) were randomly assigned to receive either sucrose (2 ml of 25% sucrose; n = 120) or placebo (2 ml sterile water; n = 120). Sucrose was given 2 minutes prior to painful procedures performed within 2 days of birth. Liquids were given orally via syringe over the anterior surface of the tongue. Procedures were videotaped and affective measures of pain were scored according to the Premature Infant Pain Profile. Pain measures included stereotypical facial expressions and changes in heart rate and oxygen saturation. Exposure to oral sucrose modestly reduced pain scores in infants born to diabetic and non-diabetic mothers. When each procedure was examined individually, the only procedure to be associated with reduced pain scores in the presence of sucrose was venipuncture. Administration of sucrose was not effective as an analgesic for heel lance or vitamin K injections, and was not effective when administered close to the time of birth. Finally, sucrose did not significantly alter heel-lance blood-glucose readings relative to placebo in offspring of diabetic mothers. In the present study, sucrose was given in the absence of other medications or pacifiers, both of which can enhance sucrose's effectiveness as an analgesic in acute procedures.

Comment: Management of acute pain in neonates continues to be of clinical significance. Dr. Anand touches upon concerns relating to the experience of acute pain in very young children and downstream effects of pain in pain processing and stress responses. In addition to the Taddio study described above, a second paper in the same issue of CMAJ investigated the use of a topical coolant spray to reduce pain in intravenous cannulation. Such measures, using different modalities, indicate there is no “one-size-fits-all” tool for every painful procedure.

Comment: Anand KJS. Analgesia for skin breaking procedures in newborns and children: What works best? CMAJ 2008;179:11–12.


Melamed ML, Michos ED, Post W, and Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med. 2008;168:1629–1637.

Knowledge of the role of vitamin D in health is expanding, with vitamin D levels relating to cardiovascular and bone health as well as cognitive functioning. Supplementation with vitamin D (calcitriol or paricalcitol) is associated with reduced mortality in renal disease, and lower all-cause mortality in older individuals. The present study by Melamed et al. examined the relationship between all-cause mortality and serum 25-hydroxyvitamin D levels in the general population. NHANES III data and linked mortality files for 13,331 adults over the age of 20 years were analyzed.

Participants' vitamin D levels were ascertained from 1988 through 1994, and mortality was followed up until 2000. Mortality was categorized into all-cause, cancer, and cardiovascular disease. The lowest quartile of 25-hydroxyvitamin D (<17.8 ng/mL) was associated with increased risk for all-cause mortality. Lower levels of vitamin D were similarly, but non-significantly, associated with increased risk for death from cancer and cardiovascular disease. Higher risk for vitamin D deficiency was seen with older age, being female, current smoking, and non-white ethnicity. Higher physical activity, use of vitamin D supplements, and measurement during a non-winter season were inversely associated with vitamin D deficiency. The association between low levels of serum 25-hydroxyvitamin D and mortality was strongest for individuals without existing cardiovascular disease, hypertension, or diabetes, suggesting that risk seen with vitamin D deficiency is not related to poor health in general.